Cushing's Disease
Conditions
Keywords
Cushing's disease, LCI699, osilodrostat, Pituitary Gland, Adrenocorticotropic, Hormone, ACTH, UFC
Brief summary
The purpose of this study was to confirm efficacy and safety of osilodrostat for the treatment of patients with Cushing's disease who are candidates for medical therapy.
Detailed description
The study LCI699C2302 (LINC-4) is a multi-center, randomized, double-blind study to evaluate the safety and efficacy of osilodrostat in patients with Cushing's disease. Enrolled patients were initially randomized to either osilodrostat or placebo, in a 2:1 ratio, for a 12-week double-blind period (Period 1). Randomization was stratified by history of pituitary radiation. After Week 12, all patients received open-label osilodrostat until the end of the Core phase at Week 48 (Period 2). After Week 48, patients could join an optional 48 week extension period.
Interventions
DRUGosilodrostat
In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg.
DRUGosilodrostat Placebo
Matching Placebo in the form of filmcoated tablets for oral administration
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: * Confirmed Cushing's Disease (CD) that is persistent or recurrent as evidenced by all of the following criteria being met (i.e., a, b and c): 1. mUFC \> 1.3 x ULN (Mean of three 24-hour urine samples collected preferably on 3 consecutive days, during screening after washout of prior medical therapy for CD (if applicable), confirmed by the central laboratory and available before Day 1), with ≥2 of the individual UFC values being \> 1.3 x ULN. 2. Morning plasma Adrenocorticotropic hormone (ACTH) above Lower Limit of Normal 3. Confirmation (based on medical history) of pituitary source of excess ACTH as defined by any one or more of the following three criteria: i. Histopathologic confirmation of an ACTH-staining adenoma in patients who have had prior pituitary surgery. OR ii. Magnetic resonance imaging (MRI) confirmation of pituitary adenoma \> 6 mm OR iii. Bilateral inferior petrosal sinus sampling (BIPSS) with either corticotropic-releasing hormone (CRH) or desmopressin (DDAVP) stimulation for patients with a tumor ≤ 6mm. The criteria for a confirmatory BIPSS test are any of the following: Pre-dose central to peripheral ACTH gradient \> 2; Post-dose central to peripheral ACTH gradient \> 3 after either CRH or DDAVP stimulation * Patients that received glucocorticoid replacement therapy must have discontinued such therapy for at least seven days or 5 half-lives prior to screening, whichever is longer. * Patients with de novo CD can be included only if they are not considered candidates for surgery (e.g., poor surgical candidates due to co-morbidities, inoperable tumors, patients who refuse to have surgical treatment, or surgical treatment is not available). Key
Exclusion criteria
* Patients with pseudo-Cushing's syndrome. This may be diagnosed by a normal late night salivary cortisol value collected during the screening period and after washout of prior CD medication. * Patients with risk factors for QT corrected (QTc) prolongation or Torsade de Pointes, including: patients with a baseline QT corrected (Fridericia QT formula) (QTcF) \> 450 ms for males and QTcF \> 460 ms for females; personal or family history of long QT syndrome; concomitant medications known to prolong the QT interval; patients with hypokalemia, hypocalcaemia, or hypomagnesaemia, if not corrected before pre-dose Day 1. * Patients likely to require adrenalectomy, pituitary surgery, or radiation therapy during the placebo-controlled period (Weeks 1-12) for the treatment of severe hypercortisolism or pituitary tumor growth causing compression of the optic chiasm. * Patients with compression of the optic chiasm due to a macroadenoma or patients at high risk of compression of the optic chiasm (tumor within 2 mm of optic chiasm). * Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1, AIP). * Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH independent (adrenal) Cushing's syndrome. Pregnant or nursing (lactating) women. 8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after completion of dosing. Highly effective contraception methods include: A. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. B. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study drug. In case of bilateral oophorectomy, documentation is required (e.g. operative report, pelvic ultrasound or other reliable imaging method). C. Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject. D. Combination of any two of the following (a+b or a+c, or b+c): 1. Use of oral\*, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception 2. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. \*In the case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study drug. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Randomized Participants With a Complete Response | at Week 12 | A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12. Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in mUFC | Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96 | To assess the change in mean urinary free cortisol (mUFC) from baseline by treatment arm. |
| Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN | up to 12 weeks | To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier. |
| Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response | up to 12 weeks | To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier. The median time-to-first control and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982). |
| Time-to-first Control of mUFC - % Event Probability Estimates | up to 12 weeks | To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier. % Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point. % Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for Confidence Interval (CI) of Kaplan-Meier (KM) estimates. |
| Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants | up to 48 weeks | To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC \> 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks. |
| Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC | from week 26 to week 48 | To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC \> 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks. The median time-to-escape and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982). |
| Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates | week 26 and week 36 | Escape is defined as the first loss of control of urinary free cortisol (UFC) that meets all of the following criteria: 1. prior normalization of UFC has occurred (median urinary free cortisol (mUFC)≤ upper limit of normal (ULN)); 2. patient reached the highest tolerated dose of osilodrostat; 3. 2 consecutive mUFC (collected at scheduled visits) were above 1.3x ULN; 4. the loss of control of UFC is not related to a dose interruption or dose reduction due to safety reasons; 5. happened beyond Week 26 when the patients have a chance to be treated with doses as high as 30 mg bid. * Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point. * Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for CI of KM estimates. |
| Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | Baseline, week 48 | The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement. |
| Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | Baseline, week 48 | The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement. T-score is the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and ethnicity as the patient. The WHO criteria are: Normal is a T-score of -1.0 or higher |
| Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | baseline, week 12, 36 and 48 | Overall response rate defined as percentage of complete responders (mUFC ≤ ULN) plus partial responders (≥ 50% reduction in mUFC from baseline and \>ULN) at week 12, 36, 48 by treatment arms for all patients. |
| Change in Fasting Plasma Glucose | Baseline, weeks 12, 36, and 48 | Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm |
| Change in Hemoglobin A1C | Baseline, weeks 12, 36, and 48 | Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm |
| Change in Cholesterol | Baseline, weeks 12, 36, and 48 | Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm |
| Change in LDL Cholesterol | Baseline, weeks 12, 36, and 48 | Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm |
| Change in HDL Cholesterol | Baseline, weeks 12, 36, and 48 | Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm |
| Change in Triglyceride | Baseline, weeks 12, 36, and 48 | Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm |
| Change in Standing Systolic Blood Pressure | Baseline, weeks 12, 36, and 48 | Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm |
| Percentage of Participants With mUFC ≤ ULN at Week 36 | At Week 36 | The complete response rate in both arms combined at Week 36. A complete responder at Week 36 is defined as a participant who had mean urine free cortisol \<= upper limit of normal (mUFC \<= ULN) at Week 36. Participants with missing mUFC at Week 36 were counted as non-responders. |
| Change in Standing Diastolic Blood Pressure | Baseline, weeks 12, 36, and 48 | Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm |
| Change in Supine Diastolic Blood Pressure | Baseline, weeks 12, 36, and 48 | Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm |
| Change in Weight | Baseline, weeks 12, 36, and 48 | Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm |
| Change in Waist Circumference | Baseline, weeks 12, 36, and 48 | Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm |
| Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | baseline, Week 12, Week 36 and Week 48 | Change from baseline to Week 12, Week 36, and Week 48 in each of the following clinical signs of Cushing's disease, captured by: a semi-quantitative Likert scale for facial rubor, striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses (bruises) by randomized treatment arm. The number/proportion of participants with an improvement or no change compared to baseline are reported |
| Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. | The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness'). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement. |
| Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. | The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness'). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement. |
| Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. | The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness'). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement. |
| Change From Baseline in EQ-5D-5L Utility Index | Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. | EQ-5D-5L Utility Index: The EQ-5D-5L questionnaire is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L measures 5 items on mobility, self-care, usual activities, pain/discomfort, anxiety/depression, measured on 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. A utility index can be computed from the EQ 5D-5L descriptive system with utility scores ranging from -0.281 (worst imaginable health state) to 1 (best imaginable health state), with -0.281 representing an unconscious health state. A single index value is analyzed for the EQ-5D-5L score. An increase from baseline in the EQ-ED-5L utility index is indicative of an improvement. |
| Change From Baseline in EQ-5D VAS | Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. | The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with a scale of 0-100, with endpoints labeled 100='the best health you can imagine' and 0='the worst health you can imagine'. A single index value is analyzed for the EQ-5D-5L VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement. |
| Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. | The Beck Depression Inventory II (BDI-II) is a patient reported instrument that consists of 21 items designed to assess the intensity of depression in clinical and normal patients in the preceding two weeks. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. A global score ranges from 0 to 63 and is calculated with a higher score representing a greater level of depression. The following scoring guidelines for interpretation of BDI-II have been suggested (Smarr, 2011): Minimal range =0-13, Mild depression =14-19, Moderate depression =20-28 and Severe depression = 29-63. A reduction from baseline in BDI-II is indicative of an improvement. |
| Change From Baseline in Serum Cortisol | Baseline, Week 12, Week 36, Week 48 | Change from baseline in serum cortisol |
| Change From Baseline in Late Night Saliva Cortisol | Baseline, Week 12, Week 36, Week 48 | Change from baseline in late night saliva cortisol (nmol/L) |
| Change From Baseline in Morning Saliva Cortisol | Baseline, Week 12, Week 36, Week 48 | Change from baseline in morning saliva cortisol (nmol/L) |
| Change From Baseline in Hair Cortisol Levels | Baseline, Week 26, Week 48 | Change from baseline in hair cortisol levels |
| Plasma Osilodrostat Concentrations (ng/mL) | pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26 | Plasma osilodrostat concentrations (ng/mL) |
| Change in Supine Systolic Blood Pressure | Baseline, weeks 12, 36, and 48 | Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm |
Countries
Belgium, Brazil, Canada, China, Costa Rica, Greece, Poland, Portugal, Russia, Spain, Switzerland, Thailand, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). There are 73 participants in the FAS who were randomized and received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Osilodrostat Group Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration). | 48 |
| Osilodrostat Placebo Group Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration). | 25 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Phase - up to Week 48 | Adverse Event | 1 | 2 |
| Core Phase - up to Week 48 | Physician Decision | 1 | 0 |
| Core Phase - up to Week 48 | Withdrawal by Subject | 4 | 0 |
| Optional Extension Phase | Adverse Event | 5 | 1 |
| Optional Extension Phase | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Osilodrostat Group | Osilodrostat Placebo Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 46 Participants | 25 Participants | 71 Participants |
| Age, Continuous | 42.3 Years STANDARD_DEVIATION 13.82 | 38.9 Years STANDARD_DEVIATION 12.33 | 41.2 Years STANDARD_DEVIATION 13.35 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 8 Participants | 17 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 34 Participants | 15 Participants | 49 Participants |
| Sex: Female, Male Female | 43 Participants | 18 Participants | 61 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 25 | 0 / 48 | 0 / 25 | 0 / 73 |
| other Total, other adverse events | 45 / 48 | 21 / 25 | 47 / 48 | 24 / 25 | 71 / 73 |
| serious Total, serious adverse events | 2 / 48 | 1 / 25 | 10 / 48 | 0 / 25 | 10 / 73 |
Outcome results
Primary
Percentage of Randomized Participants With a Complete Response
A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12. Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint.
Time frame: at Week 12
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osilodrostat Group | Percentage of Randomized Participants With a Complete Response | 37 Participants |
| Osilodrostat Placebo Group | Percentage of Randomized Participants With a Complete Response | 2 Participants |
p-value: <0.000195% CI: [7.06, 343.19]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Beck Depression Inventory-II - Total Score Derived
The Beck Depression Inventory II (BDI-II) is a patient reported instrument that consists of 21 items designed to assess the intensity of depression in clinical and normal patients in the preceding two weeks. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. A global score ranges from 0 to 63 and is calculated with a higher score representing a greater level of depression. The following scoring guidelines for interpretation of BDI-II have been suggested (Smarr, 2011): Minimal range =0-13, Mild depression =14-19, Moderate depression =20-28 and Severe depression = 29-63. A reduction from baseline in BDI-II is indicative of an improvement.
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Actual Change from Baseline at Week 12 (n=46,24) | -1.4 Scores on a scale | Standard Deviation 7.99 |
| Osilodrostat Group | Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Actual Change from Week 12 at Week 36 (n=44,23) | -2.0 Scores on a scale | Standard Deviation 4.7 |
| Osilodrostat Group | Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Actual Change from Baseline at Week 48 (n=42,22) | -4.3 Scores on a scale | Standard Deviation 7.52 |
| Osilodrostat Group | Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Actual Change from Week 36 at Week 48 (n=42,22) | -1.1 Scores on a scale | Standard Deviation 4.83 |
| Osilodrostat Group | Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Actual - baseline (n=48,25) | 12.2 Scores on a scale | Standard Deviation 10.22 |
| Osilodrostat Placebo Group | Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Actual Change from Week 36 at Week 48 (n=42,22) | -0.4 Scores on a scale | Standard Deviation 3.39 |
| Osilodrostat Placebo Group | Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Actual - baseline (n=48,25) | 8.4 Scores on a scale | Standard Deviation 7.82 |
| Osilodrostat Placebo Group | Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Actual Change from Baseline at Week 12 (n=46,24) | -3.9 Scores on a scale | Standard Deviation 5.42 |
| Osilodrostat Placebo Group | Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Actual Change from Baseline at Week 48 (n=42,22) | -4.0 Scores on a scale | Standard Deviation 7.7 |
| Osilodrostat Placebo Group | Change From Baseline in Beck Depression Inventory-II - Total Score Derived | Actual Change from Week 12 at Week 36 (n=44,23) | 0.6 Scores on a scale | Standard Deviation 6.29 |
Secondary
Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected
The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement.
Time frame: Baseline, week 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | FEMORAL NECK QC CORRECTED - baseline - Actual (n=43,24) | 0.8 g/cm2 | Standard Deviation 0.16 |
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | FEMORAL NECK QC CORRECTED - week 48 - Actual change from baseline (n=28,19) | 0.0 g/cm2 | Standard Deviation 0.04 |
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | HIP QC CORRECTED - baseline - Actual (n=43,24) | 0.9 g/cm2 | Standard Deviation 0.14 |
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | HIP QC CORRECTED - week 48 - Actual change from baseline (n=28,19) | 0.0 g/cm2 | Standard Deviation 0.03 |
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | SPINAL CORD QC CORRECTED - baseline - Actual (n=42,23) | 1.0 g/cm2 | Standard Deviation 0.15 |
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | SPINAL CORD QC CORRECTED - week 48 - Actual change from baseline (n=28,18) | 0.0 g/cm2 | Standard Deviation 0.04 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | SPINAL CORD QC CORRECTED - baseline - Actual (n=42,23) | 1.0 g/cm2 | Standard Deviation 0.18 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | FEMORAL NECK QC CORRECTED - baseline - Actual (n=43,24) | 0.8 g/cm2 | Standard Deviation 0.14 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | HIP QC CORRECTED - week 48 - Actual change from baseline (n=28,19) | 0.0 g/cm2 | Standard Deviation 0.02 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | FEMORAL NECK QC CORRECTED - week 48 - Actual change from baseline (n=28,19) | 0.0 g/cm2 | Standard Deviation 0.03 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | SPINAL CORD QC CORRECTED - week 48 - Actual change from baseline (n=28,18) | 0.0 g/cm2 | Standard Deviation 0.04 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | HIP QC CORRECTED - baseline - Actual (n=43,24) | 0.9 g/cm2 | Standard Deviation 0.11 |
Secondary
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected
The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement. T-score is the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and ethnicity as the patient. The WHO criteria are: Normal is a T-score of -1.0 or higher
Time frame: Baseline, week 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | FEMORAL NECK QC CORRECTED - baseline - Actual (n=43,24) | -1.2 scores on a scale | Standard Deviation 1.06 |
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | FEMORAL NECK QC CORRECTED - Actual change from baseline at week 48 (n=28,19) | 0.1 scores on a scale | Standard Deviation 0.3 |
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | HIP QC CORRECTED - baseline - Actual (n=43,24) | -0.7 scores on a scale | Standard Deviation 1.08 |
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | HIP QC CORRECTED - Actual change from baseline at week 48 (n=28,19) | 0.0 scores on a scale | Standard Deviation 0.27 |
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | SPINAL CORD QC CORRECTED - baseline - Actual (n=42,23) | -1.2 scores on a scale | Standard Deviation 1.1 |
| Osilodrostat Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | SPINAL CORD QC CORRECTED - Actual change from baseline at week 48 (n=28,18) | 0.1 scores on a scale | Standard Deviation 0.32 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | SPINAL CORD QC CORRECTED - baseline - Actual (n=42,23) | -1.1 scores on a scale | Standard Deviation 1.4 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | FEMORAL NECK QC CORRECTED - baseline - Actual (n=43,24) | -1.3 scores on a scale | Standard Deviation 0.89 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | HIP QC CORRECTED - Actual change from baseline at week 48 (n=28,19) | 0.0 scores on a scale | Standard Deviation 0.16 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | FEMORAL NECK QC CORRECTED - Actual change from baseline at week 48 (n=28,19) | 0.1 scores on a scale | Standard Deviation 0.21 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | SPINAL CORD QC CORRECTED - Actual change from baseline at week 48 (n=28,18) | 0.1 scores on a scale | Standard Deviation 0.33 |
| Osilodrostat Placebo Group | Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected | HIP QC CORRECTED - baseline - Actual (n=43,24) | -0.8 scores on a scale | Standard Deviation 0.84 |
Secondary
Change From Baseline in EQ-5D-5L Utility Index
EQ-5D-5L Utility Index: The EQ-5D-5L questionnaire is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L measures 5 items on mobility, self-care, usual activities, pain/discomfort, anxiety/depression, measured on 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. A utility index can be computed from the EQ 5D-5L descriptive system with utility scores ranging from -0.281 (worst imaginable health state) to 1 (best imaginable health state), with -0.281 representing an unconscious health state. A single index value is analyzed for the EQ-5D-5L score. An increase from baseline in the EQ-ED-5L utility index is indicative of an improvement.
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in EQ-5D-5L Utility Index | Actual Change from Baseline at Week 12 (n=46,24) | -0.000 Scores on a scale | Standard Deviation 0.1402 |
| Osilodrostat Group | Change From Baseline in EQ-5D-5L Utility Index | Actual Change from Week 12 at Week 36 (n=44,23) | 0.025 Scores on a scale | Standard Deviation 0.1283 |
| Osilodrostat Group | Change From Baseline in EQ-5D-5L Utility Index | Actual Change from Baseline at Week 48 (n=42,22) | 0.044 Scores on a scale | Standard Deviation 0.1393 |
| Osilodrostat Group | Change From Baseline in EQ-5D-5L Utility Index | Actual Change from Week 36 at Week 48 (n=42,22) | 0.023 Scores on a scale | Standard Deviation 0.0762 |
| Osilodrostat Group | Change From Baseline in EQ-5D-5L Utility Index | Actual - baseline (n=48,24) | 0.825 Scores on a scale | Standard Deviation 0.1486 |
| Osilodrostat Placebo Group | Change From Baseline in EQ-5D-5L Utility Index | Actual Change from Week 36 at Week 48 (n=42,22) | -0.008 Scores on a scale | Standard Deviation 0.0367 |
| Osilodrostat Placebo Group | Change From Baseline in EQ-5D-5L Utility Index | Actual - baseline (n=48,24) | 0.903 Scores on a scale | Standard Deviation 0.1125 |
| Osilodrostat Placebo Group | Change From Baseline in EQ-5D-5L Utility Index | Actual Change from Baseline at Week 12 (n=46,24) | 0.021 Scores on a scale | Standard Deviation 0.0771 |
| Osilodrostat Placebo Group | Change From Baseline in EQ-5D-5L Utility Index | Actual Change from Baseline at Week 48 (n=42,22) | 0.033 Scores on a scale | Standard Deviation 0.0826 |
| Osilodrostat Placebo Group | Change From Baseline in EQ-5D-5L Utility Index | Actual Change from Week 12 at Week 36 (n=44,23) | 0.010 Scores on a scale | Standard Deviation 0.0487 |
Secondary
Change From Baseline in EQ-5D VAS
The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with a scale of 0-100, with endpoints labeled 100='the best health you can imagine' and 0='the worst health you can imagine'. A single index value is analyzed for the EQ-5D-5L VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement.
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in EQ-5D VAS | Actual Change from Baseline at week 12 (n=46,24) | 0.5 Scores on a scale | Standard Deviation 13.57 |
| Osilodrostat Group | Change From Baseline in EQ-5D VAS | Actual Change from Week 12 at Week 36 (n=44,23) | 6.0 Scores on a scale | Standard Deviation 11.08 |
| Osilodrostat Group | Change From Baseline in EQ-5D VAS | Actual Change from Baseline at week 48 (n=42,22) | 9.4 Scores on a scale | Standard Deviation 13.13 |
| Osilodrostat Group | Change From Baseline in EQ-5D VAS | Actual Change from Week 36 at Week 48 (n=42,22) | 3.2 Scores on a scale | Standard Deviation 8.4 |
| Osilodrostat Group | Change From Baseline in EQ-5D VAS | Actual - baseline (n=48,23) | 70.3 Scores on a scale | Standard Deviation 17.26 |
| Osilodrostat Placebo Group | Change From Baseline in EQ-5D VAS | Actual Change from Week 36 at Week 48 (n=42,22) | -0.8 Scores on a scale | Standard Deviation 4.44 |
| Osilodrostat Placebo Group | Change From Baseline in EQ-5D VAS | Actual - baseline (n=48,23) | 76.7 Scores on a scale | Standard Deviation 17.88 |
| Osilodrostat Placebo Group | Change From Baseline in EQ-5D VAS | Actual Change from Baseline at week 12 (n=46,24) | -0.3 Scores on a scale | Standard Deviation 10.52 |
| Osilodrostat Placebo Group | Change From Baseline in EQ-5D VAS | Actual Change from Baseline at week 48 (n=42,22) | 5.8 Scores on a scale | Standard Deviation 9.45 |
| Osilodrostat Placebo Group | Change From Baseline in EQ-5D VAS | Actual Change from Week 12 at Week 36 (n=44,23) | 3.7 Scores on a scale | Standard Deviation 9.29 |
Secondary
Change From Baseline in Hair Cortisol Levels
Change from baseline in hair cortisol levels
Time frame: Baseline, Week 26, Week 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in Hair Cortisol Levels | Baseline - actual (n=19,9) | 38.9 pg/mg | Standard Deviation 37.48 |
| Osilodrostat Group | Change From Baseline in Hair Cortisol Levels | Actual Change from Baseline at Week 26 (n=16,7) | -15.8 pg/mg | Standard Deviation 32.83 |
| Osilodrostat Group | Change From Baseline in Hair Cortisol Levels | Actual Change from Baseline at Week 48 (n=14,6) | -17.8 pg/mg | Standard Deviation 26.66 |
| Osilodrostat Placebo Group | Change From Baseline in Hair Cortisol Levels | Baseline - actual (n=19,9) | 10.5 pg/mg | Standard Deviation 10.47 |
| Osilodrostat Placebo Group | Change From Baseline in Hair Cortisol Levels | Actual Change from Baseline at Week 26 (n=16,7) | -1.1 pg/mg | Standard Deviation 12.72 |
| Osilodrostat Placebo Group | Change From Baseline in Hair Cortisol Levels | Actual Change from Baseline at Week 48 (n=14,6) | -9.7 pg/mg | Standard Deviation 8.9 |
Secondary
Change From Baseline in Late Night Saliva Cortisol
Change from baseline in late night saliva cortisol (nmol/L)
Time frame: Baseline, Week 12, Week 36, Week 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in Late Night Saliva Cortisol | Baseline - actual (n=48,25) | 11.7 nmol/L | Standard Deviation 28.68 |
| Osilodrostat Group | Change From Baseline in Late Night Saliva Cortisol | Actual Change from Baseline at Week 12 (n=46,24) | -8.5 nmol/L | Standard Deviation 29.6 |
| Osilodrostat Group | Change From Baseline in Late Night Saliva Cortisol | Actual Change from Baseline at Week 36 (n=42,25) | -9.6 nmol/L | Standard Deviation 30.82 |
| Osilodrostat Group | Change From Baseline in Late Night Saliva Cortisol | Actual Change from Baseline at Week 48 (n=41,22) | -9.3 nmol/L | Standard Deviation 29.05 |
| Osilodrostat Placebo Group | Change From Baseline in Late Night Saliva Cortisol | Actual Change from Baseline at Week 48 (n=41,22) | -5.0 nmol/L | Standard Deviation 5.75 |
| Osilodrostat Placebo Group | Change From Baseline in Late Night Saliva Cortisol | Baseline - actual (n=48,25) | 9.0 nmol/L | Standard Deviation 6.74 |
| Osilodrostat Placebo Group | Change From Baseline in Late Night Saliva Cortisol | Actual Change from Baseline at Week 36 (n=42,25) | -5.8 nmol/L | Standard Deviation 6.84 |
| Osilodrostat Placebo Group | Change From Baseline in Late Night Saliva Cortisol | Actual Change from Baseline at Week 12 (n=46,24) | 1.3 nmol/L | Standard Deviation 8.87 |
Secondary
Change From Baseline in Morning Saliva Cortisol
Change from baseline in morning saliva cortisol (nmol/L)
Time frame: Baseline, Week 12, Week 36, Week 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in Morning Saliva Cortisol | Baseline - actual (n=48,25) | 17.2 nmol/L | Standard Deviation 30 |
| Osilodrostat Group | Change From Baseline in Morning Saliva Cortisol | Actual Change from Baseline at Week 12 (n=46,24) | -11.6 nmol/L | Standard Deviation 30.05 |
| Osilodrostat Group | Change From Baseline in Morning Saliva Cortisol | Actual Change from Baseline at Week 36 (n=40,25) | -11.8 nmol/L | Standard Deviation 30.74 |
| Osilodrostat Group | Change From Baseline in Morning Saliva Cortisol | Actual Change from Baseline at Week 48 (n=41,22) | -11.8 nmol/L | Standard Deviation 31.74 |
| Osilodrostat Placebo Group | Change From Baseline in Morning Saliva Cortisol | Actual Change from Baseline at Week 48 (n=41,22) | -6.0 nmol/L | Standard Deviation 10.97 |
| Osilodrostat Placebo Group | Change From Baseline in Morning Saliva Cortisol | Baseline - actual (n=48,25) | 14.1 nmol/L | Standard Deviation 12.29 |
| Osilodrostat Placebo Group | Change From Baseline in Morning Saliva Cortisol | Actual Change from Baseline at Week 36 (n=40,25) | -9.3 nmol/L | Standard Deviation 11.82 |
| Osilodrostat Placebo Group | Change From Baseline in Morning Saliva Cortisol | Actual Change from Baseline at Week 12 (n=46,24) | -0.3 nmol/L | Standard Deviation 11.21 |
Secondary
Change From Baseline in mUFC
To assess the change in mean urinary free cortisol (mUFC) from baseline by treatment arm.
Time frame: Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 5 (n=46,25) | -252.8 nmol/24hr | Standard Deviation 338.48 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 29 (n=43,25) | -331.4 nmol/24hr | Standard Deviation 299.63 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 14 (n=45,25) | -191.7 nmol/24hr | Standard Deviation 446.77 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 32 (n=44,25) | -341.3 nmol/24hr | Standard Deviation 298.96 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 2 (n=47,24) | -139.3 nmol/24hr | Standard Deviation 404.45 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 36 (n=43,25) | -349.6 nmol/24hr | Standard Deviation 310.46 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 17 (n=45,25) | -238.8 nmol/24hr | Standard Deviation 362.46 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 40 (n=43,23) | -333.4 nmol/24hr | Standard Deviation 307.63 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 8 (n=44,25) | -330.2 nmol/24hr | Standard Deviation 303.35 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 48 (n=42,22) | -325.1 nmol/24hr | Standard Deviation 314.3 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 20 (n=44,24) | -294.5 nmol/24hr | Standard Deviation 316.65 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 60 (n=33,19) | -364.4 nmol/24hr | Standard Deviation 339.57 |
| Osilodrostat Group | Change From Baseline in mUFC | actual - baseline | 421.4 nmol/24hr | Standard Deviation 291.25 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 72 (n=31,17) | -381.2 nmol/24hr | Standard Deviation 338.68 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 12 (n=44,24) | -332.7 nmol/24hr | Standard Deviation 315.5 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 84 (n=23,17) | -398.6 nmol/24hr | Standard Deviation 377.81 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 26 (n=43,25) | -345.2 nmol/24hr | Standard Deviation 306.35 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 96 (n=6,7) | -414.5 nmol/24hr | Standard Deviation 347.83 |
| Osilodrostat Group | Change From Baseline in mUFC | change from baseline at week 23 (n=44,25) | -314.1 nmol/24hr | Standard Deviation 307.6 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 96 (n=6,7) | -616.4 nmol/24hr | Standard Deviation 881.92 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | actual - baseline | 451.5 nmol/24hr | Standard Deviation 535.09 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 2 (n=47,24) | 164.9 nmol/24hr | Standard Deviation 543.82 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 5 (n=46,25) | -37.3 nmol/24hr | Standard Deviation 280.84 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 8 (n=44,25) | -35.0 nmol/24hr | Standard Deviation 325.3 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 12 (n=44,24) | -49.1 nmol/24hr | Standard Deviation 332.29 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 14 (n=45,25) | -209.5 nmol/24hr | Standard Deviation 407.62 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 17 (n=45,25) | -284.5 nmol/24hr | Standard Deviation 557.47 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 20 (n=44,24) | -355.1 nmol/24hr | Standard Deviation 538.96 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 23 (n=44,25) | -387.8 nmol/24hr | Standard Deviation 466.15 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 26 (n=43,25) | -365.4 nmol/24hr | Standard Deviation 458.28 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 29 (n=43,25) | -391.4 nmol/24hr | Standard Deviation 534.57 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 32 (n=44,25) | -298.0 nmol/24hr | Standard Deviation 655.52 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 36 (n=43,25) | -372.9 nmol/24hr | Standard Deviation 519.17 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 40 (n=43,23) | -364.7 nmol/24hr | Standard Deviation 542.28 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 48 (n=42,22) | -367.5 nmol/24hr | Standard Deviation 554.16 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 60 (n=33,19) | -335.2 nmol/24hr | Standard Deviation 571.06 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 72 (n=31,17) | -372.4 nmol/24hr | Standard Deviation 624.69 |
| Osilodrostat Placebo Group | Change From Baseline in mUFC | change from baseline at week 84 (n=23,17) | -196.0 nmol/24hr | Standard Deviation 916.83 |
Secondary
Change From Baseline in Serum Cortisol
Change from baseline in serum cortisol
Time frame: Baseline, Week 12, Week 36, Week 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in Serum Cortisol | Baseline - actual (n=47,25) | 565.8 nmol/L | Standard Deviation 169.01 |
| Osilodrostat Group | Change From Baseline in Serum Cortisol | Actual Change from Baseline at Week 12 (n=44,24) | -276.0 nmol/L | Standard Deviation 178.43 |
| Osilodrostat Group | Change From Baseline in Serum Cortisol | Actual Change from Baseline at Week 36 (n=42,25) | -267.0 nmol/L | Standard Deviation 174.18 |
| Osilodrostat Group | Change From Baseline in Serum Cortisol | Actual Change from Baseline at Week 48 (n=41,22) | -210.7 nmol/L | Standard Deviation 161.07 |
| Osilodrostat Placebo Group | Change From Baseline in Serum Cortisol | Actual Change from Baseline at Week 48 (n=41,22) | -131.0 nmol/L | Standard Deviation 236.88 |
| Osilodrostat Placebo Group | Change From Baseline in Serum Cortisol | Baseline - actual (n=47,25) | 486.1 nmol/L | Standard Deviation 198.12 |
| Osilodrostat Placebo Group | Change From Baseline in Serum Cortisol | Actual Change from Baseline at Week 36 (n=42,25) | -157.8 nmol/L | Standard Deviation 225.56 |
| Osilodrostat Placebo Group | Change From Baseline in Serum Cortisol | Actual Change from Baseline at Week 12 (n=44,24) | 73.0 nmol/L | Standard Deviation 185.29 |
Secondary
Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness'). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 12 (n=46,24) | 6.2 Scores on a scale | Standard Deviation 14.85 |
| Osilodrostat Group | Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 12 at Week 36 (n=44,23) | 4.7 Scores on a scale | Standard Deviation 9.01 |
| Osilodrostat Group | Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 48 (n=42,22) | 11.7 Scores on a scale | Standard Deviation 16.3 |
| Osilodrostat Group | Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 36 at Week 48 (n=42,22) | 0.1 Scores on a scale | Standard Deviation 8.43 |
| Osilodrostat Group | Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual - Baseline (n=48,25) | 49.1 Scores on a scale | Standard Deviation 19.6 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 36 at Week 48 (n=42,22) | 2.5 Scores on a scale | Standard Deviation 7.52 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual - Baseline (n=48,25) | 56.9 Scores on a scale | Standard Deviation 18.99 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 12 (n=46,24) | 8.6 Scores on a scale | Standard Deviation 12.06 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 48 (n=42,22) | 12.8 Scores on a scale | Standard Deviation 14.24 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 12 at Week 36 (n=44,23) | -0.5 Scores on a scale | Standard Deviation 9.99 |
Secondary
Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness'). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 12 (n=46,24) | 6.3 Scores on a scale | Standard Deviation 13.29 |
| Osilodrostat Group | Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 12 at Week 36 (n=44,23) | 6.6 Scores on a scale | Standard Deviation 12.4 |
| Osilodrostat Group | Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 48 (n=42,22) | 13.3 Scores on a scale | Standard Deviation 19.83 |
| Osilodrostat Group | Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 36 at Week 48 (n=42,22) | 23.59 Scores on a scale | Standard Deviation 11.27 |
| Osilodrostat Group | Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual - baseline (n=48,25) | 46.9 Scores on a scale | Standard Deviation 22.32 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 36 at Week 48 (n=42,22) | 2.7 Scores on a scale | Standard Deviation 12.17 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual - baseline (n=48,25) | 57.7 Scores on a scale | Standard Deviation 21.91 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 12 (n=46,24) | 5.6 Scores on a scale | Standard Deviation 13.38 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 48 (n=42,22) | 12.1 Scores on a scale | Standard Deviation 15.59 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 12 at Week 36 (n=44,23) | 2.2 Scores on a scale | Standard Deviation 12.11 |
Secondary
Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness'). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 12 (n=46,24) | 6.1 Scores on a scale | Standard Deviation 17.21 |
| Osilodrostat Group | Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 12 at Week 36 (n=44,23) | 4.1 Scores on a scale | Standard Deviation 9.94 |
| Osilodrostat Group | Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 48 (n=42,22) | 11.1 Scores on a scale | Standard Deviation 17.84 |
| Osilodrostat Group | Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 36 at Week 48 (n=42,22) | 0.1 Scores on a scale | Standard Deviation 9.6 |
| Osilodrostat Group | Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual - baseline (n=48,25) | 49.9 Scores on a scale | Standard Deviation 20.34 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 36 at Week 48 (n=42,22) | 2.4 Scores on a scale | Standard Deviation 8.96 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual - baseline (n=48,25) | 56.7 Scores on a scale | Standard Deviation 21.11 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 12 (n=46,24) | 9.6 Scores on a scale | Standard Deviation 13.61 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Baseline at Week 48 (n=42,22) | 13.0 Scores on a scale | Standard Deviation 16.3 |
| Osilodrostat Placebo Group | Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment | Actual Change from Week 12 at Week 36 (n=44,23) | -1.3 Scores on a scale | Standard Deviation 12.36 |
Secondary
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease
Change from baseline to Week 12, Week 36, and Week 48 in each of the following clinical signs of Cushing's disease, captured by: a semi-quantitative Likert scale for facial rubor, striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses (bruises) by randomized treatment arm. The number/proportion of participants with an improvement or no change compared to baseline are reported
Time frame: baseline, Week 12, Week 36 and Week 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase. Values for improvement or no change are reported. Hirsutism applies only to females, and thus the number analyzed is lower than for other clinical signs.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Central Obesity - week 12 (n=42,21) | 37 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Hirsutism - week 12 (n=36,16) | 34 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Striae - week 12 (n=41,20) | 38 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Supraclavicular Fat Pad - week 12 (n=42,21) | 41 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Dorsal Fat Pad - week 12 (n=41,21) | 35 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Proximal Muscle Atrophy - week 12 (n=42,21) | 38 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Facial Rubor - week 12 (n=42,20) | 36 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Ecchymoses - week 12 (n=42,20) | 39 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Facial Rubor - week 36 (n=41,23) | 39 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Hirsutism - week 36 (n=34,17) | 28 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Striae - week 36 (n=40,23) | 38 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Supraclavicular Fat Pad - week 36 (n=41,24) | 40 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Dorsal Fat Pad - week 36 (n=40,24) | 36 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Proximal Muscle Atrophy - week 36 (n=41,23) | 37 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Central Obesity - week 36 (n=41,24) | 37 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Ecchymoses - week 36 (n=41,23) | 39 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Facial Rubor - week 48 (n=39,21) | 37 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Hirsutism - week 48 (n=33,15) | 29 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Striae - week 48 (n=38,21) | 38 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Supraclavicular Fat Pad - week 48 (n=39,22) | 38 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Dorsal Fat Pad - week 48 (n=38,22) | 36 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Proximal Muscle Atrophy - week 48 (n=39,22) | 35 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Central Obesity - week 48 (n=39,22) | 35 Participants |
| Osilodrostat Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Ecchymoses - week 48 (n=39,21) | 38 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Central Obesity - week 48 (n=39,22) | 21 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Facial Rubor - week 12 (n=42,20) | 19 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Dorsal Fat Pad - week 36 (n=40,24) | 22 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Hirsutism - week 12 (n=36,16) | 15 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Striae - week 48 (n=38,21) | 21 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Striae - week 12 (n=41,20) | 19 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Proximal Muscle Atrophy - week 36 (n=41,23) | 22 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Supraclavicular Fat Pad - week 12 (n=42,21) | 19 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Proximal Muscle Atrophy - week 48 (n=39,22) | 21 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Dorsal Fat Pad - week 12 (n=41,21) | 17 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Central Obesity - week 36 (n=41,24) | 21 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Proximal Muscle Atrophy - week 12 (n=42,21) | 20 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Supraclavicular Fat Pad - week 48 (n=39,22) | 22 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Central Obesity - week 12 (n=42,21) | 21 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Ecchymoses - week 36 (n=41,23) | 22 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Ecchymoses - week 12 (n=42,20) | 19 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Ecchymoses - week 48 (n=39,21) | 20 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Facial Rubor - week 36 (n=41,23) | 22 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Facial Rubor - week 48 (n=39,21) | 21 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Hirsutism - week 36 (n=34,17) | 16 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Dorsal Fat Pad - week 48 (n=38,22) | 20 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Striae - week 36 (n=40,23) | 23 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Hirsutism - week 48 (n=33,15) | 15 Participants |
| Osilodrostat Placebo Group | Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease | Supraclavicular Fat Pad - week 36 (n=41,24) | 24 Participants |
Secondary
Change in Cholesterol
Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in Cholesterol | Cholesterol (mmol/L) - change from baseline at week 36 (n=44,25) | -1.0 mmol/L | Standard Deviation 1.28 |
| Osilodrostat Group | Change in Cholesterol | Cholesterol (mmol/L) - actual - baseline (n=45,25) | 5.7 mmol/L | Standard Deviation 1.3 |
| Osilodrostat Group | Change in Cholesterol | Cholesterol (mmol/L) - change from baseline at week 48 (n=42,22) | -0.6 mmol/L | Standard Deviation 1.36 |
| Osilodrostat Group | Change in Cholesterol | Cholesterol (mmol/L) - change from baseline at week 12 (n=44,24) | -0.8 mmol/L | Standard Deviation 0.95 |
| Osilodrostat Placebo Group | Change in Cholesterol | Cholesterol (mmol/L) - change from baseline at week 48 (n=42,22) | -0.4 mmol/L | Standard Deviation 1.18 |
| Osilodrostat Placebo Group | Change in Cholesterol | Cholesterol (mmol/L) - actual - baseline (n=45,25) | 5.3 mmol/L | Standard Deviation 1.15 |
| Osilodrostat Placebo Group | Change in Cholesterol | Cholesterol (mmol/L) - change from baseline at week 36 (n=44,25) | -0.4 mmol/L | Standard Deviation 0.89 |
| Osilodrostat Placebo Group | Change in Cholesterol | Cholesterol (mmol/L) - change from baseline at week 12 (n=44,24) | 0.0 mmol/L | Standard Deviation 0.65 |
Secondary
Change in Fasting Plasma Glucose
Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in Fasting Plasma Glucose | Fasting glucose (mg/dL) - baseline - actual (n=47,24) | 97.3 mg/dL | Standard Deviation 18.14 |
| Osilodrostat Group | Change in Fasting Plasma Glucose | Fasting glucose (mg/dL) - change from baseline at week 12 (n=44,23) | -4.3 mg/dL | Standard Deviation 14.84 |
| Osilodrostat Group | Change in Fasting Plasma Glucose | Fasting glucose (mg/dL) - change from baseline at week 36 (n=43,24) | -6.7 mg/dL | Standard Deviation 12.48 |
| Osilodrostat Group | Change in Fasting Plasma Glucose | Fasting glucose (mg/dL) - change from baseline at week 48 (n=41,21) | -5.6 mg/dL | Standard Deviation 14.13 |
| Osilodrostat Placebo Group | Change in Fasting Plasma Glucose | Fasting glucose (mg/dL) - change from baseline at week 48 (n=41,21) | 1.8 mg/dL | Standard Deviation 13.92 |
| Osilodrostat Placebo Group | Change in Fasting Plasma Glucose | Fasting glucose (mg/dL) - baseline - actual (n=47,24) | 91.4 mg/dL | Standard Deviation 15.15 |
| Osilodrostat Placebo Group | Change in Fasting Plasma Glucose | Fasting glucose (mg/dL) - change from baseline at week 36 (n=43,24) | -1.1 mg/dL | Standard Deviation 12.93 |
| Osilodrostat Placebo Group | Change in Fasting Plasma Glucose | Fasting glucose (mg/dL) - change from baseline at week 12 (n=44,23) | -1.7 mg/dL | Standard Deviation 10.59 |
Secondary
Change in HDL Cholesterol
Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in HDL Cholesterol | HDL Cholesterol (mmol/L) - Actual change from baseline at week 36 (n=44,25) | -0.3 mmol/L | Standard Deviation 0.27 |
| Osilodrostat Group | Change in HDL Cholesterol | HDL Cholesterol (mmol/L) - Actual change from baseline at week 12 (n=44,24) | -0.3 mmol/L | Standard Deviation 0.29 |
| Osilodrostat Group | Change in HDL Cholesterol | HDL Cholesterol (mmol/L) - Actual - change from baseline at week 48 (n=42,22) | -0.2 mmol/L | Standard Deviation 0.27 |
| Osilodrostat Group | Change in HDL Cholesterol | HDL Cholesterol (mmol/L) - Actual - baseline (n=45,25) | 1.6 mmol/L | Standard Deviation 0.35 |
| Osilodrostat Placebo Group | Change in HDL Cholesterol | HDL Cholesterol (mmol/L) - Actual - change from baseline at week 48 (n=42,22) | -0.1 mmol/L | Standard Deviation 0.29 |
| Osilodrostat Placebo Group | Change in HDL Cholesterol | HDL Cholesterol (mmol/L) - Actual change from baseline at week 12 (n=44,24) | 0.0 mmol/L | Standard Deviation 0.28 |
| Osilodrostat Placebo Group | Change in HDL Cholesterol | HDL Cholesterol (mmol/L) - Actual change from baseline at week 36 (n=44,25) | -0.2 mmol/L | Standard Deviation 0.25 |
| Osilodrostat Placebo Group | Change in HDL Cholesterol | HDL Cholesterol (mmol/L) - Actual - baseline (n=45,25) | 1.5 mmol/L | Standard Deviation 0.38 |
Secondary
Change in Hemoglobin A1C
Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in Hemoglobin A1C | Hemoglobin A1C (%) - Actual - baseline | 6.0 percentage of Hemoglobin A1C | Standard Deviation 0.92 |
| Osilodrostat Group | Change in Hemoglobin A1C | Hemoglobin A1C (%) - Actual change from baseline at week 12 (n=46,24) | -0.2 percentage of Hemoglobin A1C | Standard Deviation 0.44 |
| Osilodrostat Group | Change in Hemoglobin A1C | Hemoglobin A1C (%) Actual change from baseline at week 36 (n=44,25) | -0.2 percentage of Hemoglobin A1C | Standard Deviation 0.54 |
| Osilodrostat Group | Change in Hemoglobin A1C | Hemoglobin A1C (%) Actual change from baseline at week 48 (n=41,21) | -0.2 percentage of Hemoglobin A1C | Standard Deviation 0.58 |
| Osilodrostat Placebo Group | Change in Hemoglobin A1C | Hemoglobin A1C (%) Actual change from baseline at week 48 (n=41,21) | 0.1 percentage of Hemoglobin A1C | Standard Deviation 0.37 |
| Osilodrostat Placebo Group | Change in Hemoglobin A1C | Hemoglobin A1C (%) - Actual - baseline | 5.7 percentage of Hemoglobin A1C | Standard Deviation 0.56 |
| Osilodrostat Placebo Group | Change in Hemoglobin A1C | Hemoglobin A1C (%) Actual change from baseline at week 36 (n=44,25) | -0.1 percentage of Hemoglobin A1C | Standard Deviation 0.46 |
| Osilodrostat Placebo Group | Change in Hemoglobin A1C | Hemoglobin A1C (%) - Actual change from baseline at week 12 (n=46,24) | 0.0 percentage of Hemoglobin A1C | Standard Deviation 0.27 |
Secondary
Change in LDL Cholesterol
Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in LDL Cholesterol | LDL Cholesterol (mmol/L) - Actual - baseline (n=45,24) | 3.4 mmol/L | Standard Deviation 1.12 |
| Osilodrostat Group | Change in LDL Cholesterol | LDL Cholesterol (mmol/L) - Actual change from baseline at week 12 (n=44,23) | -0.5 mmol/L | Standard Deviation 0.8 |
| Osilodrostat Group | Change in LDL Cholesterol | LDL Cholesterol (mmol/L) - Actual change from baseline at week 36 (n=44,24) | -0.6 mmol/L | Standard Deviation 1.08 |
| Osilodrostat Group | Change in LDL Cholesterol | LDL Cholesterol (mmol/L) - Actual change from baseline at week 48 (n=41,21) | -0.5 mmol/L | Standard Deviation 0.99 |
| Osilodrostat Placebo Group | Change in LDL Cholesterol | LDL Cholesterol (mmol/L) - Actual change from baseline at week 48 (n=41,21) | -0.2 mmol/L | Standard Deviation 0.92 |
| Osilodrostat Placebo Group | Change in LDL Cholesterol | LDL Cholesterol (mmol/L) - Actual - baseline (n=45,24) | 3.0 mmol/L | Standard Deviation 1.07 |
| Osilodrostat Placebo Group | Change in LDL Cholesterol | LDL Cholesterol (mmol/L) - Actual change from baseline at week 36 (n=44,24) | -0.2 mmol/L | Standard Deviation 0.7 |
| Osilodrostat Placebo Group | Change in LDL Cholesterol | LDL Cholesterol (mmol/L) - Actual change from baseline at week 12 (n=44,23) | 0.1 mmol/L | Standard Deviation 0.47 |
Secondary
Change in Standing Diastolic Blood Pressure
Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in Standing Diastolic Blood Pressure | Standing Diastolic Blood Pressure (mmHg) - Actual - baseline (n=46,25) | 87.2 mmHg | Standard Deviation 12.74 |
| Osilodrostat Group | Change in Standing Diastolic Blood Pressure | Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=44,24) | -4.8 mmHg | Standard Deviation 11.14 |
| Osilodrostat Group | Change in Standing Diastolic Blood Pressure | Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25) | -6.0 mmHg | Standard Deviation 12.09 |
| Osilodrostat Group | Change in Standing Diastolic Blood Pressure | Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22) | -4.4 mmHg | Standard Deviation 11.64 |
| Osilodrostat Placebo Group | Change in Standing Diastolic Blood Pressure | Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22) | -3.9 mmHg | Standard Deviation 13.36 |
| Osilodrostat Placebo Group | Change in Standing Diastolic Blood Pressure | Standing Diastolic Blood Pressure (mmHg) - Actual - baseline (n=46,25) | 88.2 mmHg | Standard Deviation 10.83 |
| Osilodrostat Placebo Group | Change in Standing Diastolic Blood Pressure | Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25) | -4.4 mmHg | Standard Deviation 13.98 |
| Osilodrostat Placebo Group | Change in Standing Diastolic Blood Pressure | Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=44,24) | -1.4 mmHg | Standard Deviation 9.84 |
Secondary
Change in Standing Systolic Blood Pressure
Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in Standing Systolic Blood Pressure | Standing Systolic Blood Pressure (mmHg) - Actual - baseline (n=46,25) | 132.4 mmHg | Standard Deviation 19.16 |
| Osilodrostat Group | Change in Standing Systolic Blood Pressure | Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=44,24) | -7.1 mmHg | Standard Deviation 18.08 |
| Osilodrostat Group | Change in Standing Systolic Blood Pressure | Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25) | -9.3 mmHg | Standard Deviation 19.09 |
| Osilodrostat Group | Change in Standing Systolic Blood Pressure | Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22) | -9.1 mmHg | Standard Deviation 19.45 |
| Osilodrostat Placebo Group | Change in Standing Systolic Blood Pressure | Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22) | -11.0 mmHg | Standard Deviation 22.3 |
| Osilodrostat Placebo Group | Change in Standing Systolic Blood Pressure | Standing Systolic Blood Pressure (mmHg) - Actual - baseline (n=46,25) | 130.0 mmHg | Standard Deviation 17.72 |
| Osilodrostat Placebo Group | Change in Standing Systolic Blood Pressure | Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25) | -7.0 mmHg | Standard Deviation 21.04 |
| Osilodrostat Placebo Group | Change in Standing Systolic Blood Pressure | Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=44,24) | -0.9 mmHg | Standard Deviation 11.77 |
Secondary
Change in Supine Diastolic Blood Pressure
Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in Supine Diastolic Blood Pressure | Supine Diastolic Blood Pressure (mmHg) - Actual - baseline (n=48,25) | 83.9 mmHg | Standard Deviation 11.71 |
| Osilodrostat Group | Change in Supine Diastolic Blood Pressure | Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=46,24) | -6.3 mmHg | Standard Deviation 11.05 |
| Osilodrostat Group | Change in Supine Diastolic Blood Pressure | Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=44,25) | -7.7 mmHg | Standard Deviation 11.92 |
| Osilodrostat Group | Change in Supine Diastolic Blood Pressure | Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22) | -5.8 mmHg | Standard Deviation 11.6 |
| Osilodrostat Placebo Group | Change in Supine Diastolic Blood Pressure | Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22) | -3.7 mmHg | Standard Deviation 10.92 |
| Osilodrostat Placebo Group | Change in Supine Diastolic Blood Pressure | Supine Diastolic Blood Pressure (mmHg) - Actual - baseline (n=48,25) | 81.4 mmHg | Standard Deviation 11.21 |
| Osilodrostat Placebo Group | Change in Supine Diastolic Blood Pressure | Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=44,25) | -3.4 mmHg | Standard Deviation 11.37 |
| Osilodrostat Placebo Group | Change in Supine Diastolic Blood Pressure | Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=46,24) | -0.1 mmHg | Standard Deviation 8.31 |
Secondary
Change in Supine Systolic Blood Pressure
Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in Supine Systolic Blood Pressure | Supine Systolic Blood Pressure (mmHg) - Actual - baseline (n=48,25) | 131.7 mmHg | Standard Deviation 18.33 |
| Osilodrostat Group | Change in Supine Systolic Blood Pressure | Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=46,24) | -8.0 mmHg | Standard Deviation 17.54 |
| Osilodrostat Group | Change in Supine Systolic Blood Pressure | Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25) | -9.7 mmHg | Standard Deviation 19.88 |
| Osilodrostat Group | Change in Supine Systolic Blood Pressure | Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=42,22) | -7.4 mmHg | Standard Deviation 19.38 |
| Osilodrostat Placebo Group | Change in Supine Systolic Blood Pressure | Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=42,22) | -7.5 mmHg | Standard Deviation 18.91 |
| Osilodrostat Placebo Group | Change in Supine Systolic Blood Pressure | Supine Systolic Blood Pressure (mmHg) - Actual - baseline (n=48,25) | 127.8 mmHg | Standard Deviation 18.69 |
| Osilodrostat Placebo Group | Change in Supine Systolic Blood Pressure | Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25) | -4.4 mmHg | Standard Deviation 17.43 |
| Osilodrostat Placebo Group | Change in Supine Systolic Blood Pressure | Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=46,24) | 2.3 mmHg | Standard Deviation 15.91 |
Secondary
Change in Triglyceride
Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in Triglyceride | Triglyceride (mmol/L) - Actual - baseline (n=45,25) | 1.5 mmol/L | Standard Deviation 0.79 |
| Osilodrostat Group | Change in Triglyceride | Triglyceride (mmol/L) - Actual change from baseline at week 12(n=44,24) | 0.0 mmol/L | Standard Deviation 0.53 |
| Osilodrostat Group | Change in Triglyceride | Triglyceride (mmol/L) - Actual change from baseline at week 36 (n=44,25) | -0.1 mmol/L | Standard Deviation 0.55 |
| Osilodrostat Group | Change in Triglyceride | Triglyceride (mmol/L) - Actual change from baseline at week 48 (n=42,22) | 0.1 mmol/L | Standard Deviation 0.92 |
| Osilodrostat Placebo Group | Change in Triglyceride | Triglyceride (mmol/L) - Actual change from baseline at week 48 (n=42,22) | -0.2 mmol/L | Standard Deviation 0.62 |
| Osilodrostat Placebo Group | Change in Triglyceride | Triglyceride (mmol/L) - Actual - baseline (n=45,25) | 1.7 mmol/L | Standard Deviation 0.85 |
| Osilodrostat Placebo Group | Change in Triglyceride | Triglyceride (mmol/L) - Actual change from baseline at week 36 (n=44,25) | -0.1 mmol/L | Standard Deviation 0.71 |
| Osilodrostat Placebo Group | Change in Triglyceride | Triglyceride (mmol/L) - Actual change from baseline at week 12(n=44,24) | -0.2 mmol/L | Standard Deviation 0.54 |
Secondary
Change in Waist Circumference
Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in Waist Circumference | Waist Circumference (cm)) - Actual - baseline (n=48,25) | 102.5 cm | Standard Deviation 17.01 |
| Osilodrostat Group | Change in Waist Circumference | Waist Circumference (cm) - Actual change from baseline at week 12 (n=46,24) | -1.0 cm | Standard Deviation 4.43 |
| Osilodrostat Group | Change in Waist Circumference | Waist Circumference (cm)) - Actual change from baseline at week 36 (n=44,25) | -3.9 cm | Standard Deviation 6.36 |
| Osilodrostat Group | Change in Waist Circumference | Waist Circumference (cm) - Actual change from baseline at week 48 (n=42,22) | -4.1 cm | Standard Deviation 6.1 |
| Osilodrostat Placebo Group | Change in Waist Circumference | Waist Circumference (cm) - Actual change from baseline at week 48 (n=42,22) | -5.3 cm | Standard Deviation 5.68 |
| Osilodrostat Placebo Group | Change in Waist Circumference | Waist Circumference (cm)) - Actual - baseline (n=48,25) | 103.4 cm | Standard Deviation 15.52 |
| Osilodrostat Placebo Group | Change in Waist Circumference | Waist Circumference (cm)) - Actual change from baseline at week 36 (n=44,25) | -2.1 cm | Standard Deviation 8.6 |
| Osilodrostat Placebo Group | Change in Waist Circumference | Waist Circumference (cm) - Actual change from baseline at week 12 (n=46,24) | -0.5 cm | Standard Deviation 3.35 |
Secondary
Change in Weight
Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Change in Weight | Weight (kg) - Actual - baseline (n=48,25) | 78.8 kg | Standard Deviation 17.46 |
| Osilodrostat Group | Change in Weight | Weight (kg) - Actual change from baseline at week 12(n=46,24) | -0.8 kg | Standard Deviation 3.09 |
| Osilodrostat Group | Change in Weight | Weight (kg) - Actual change from baseline at week 36 (n=44,25) | -3.0 kg | Standard Deviation 5.53 |
| Osilodrostat Group | Change in Weight | Weight (kg) - Actual change from baseline at week 48 (n=42,22) | -3.6 kg | Standard Deviation 6.53 |
| Osilodrostat Placebo Group | Change in Weight | Weight (kg) - Actual change from baseline at week 48 (n=42,22) | -5.5 kg | Standard Deviation 6.38 |
| Osilodrostat Placebo Group | Change in Weight | Weight (kg) - Actual - baseline (n=48,25) | 77.3 kg | Standard Deviation 16.9 |
| Osilodrostat Placebo Group | Change in Weight | Weight (kg) - Actual change from baseline at week 36 (n=44,25) | -4.8 kg | Standard Deviation 5.63 |
| Osilodrostat Placebo Group | Change in Weight | Weight (kg) - Actual change from baseline at week 12(n=46,24) | -0.1 kg | Standard Deviation 2.12 |
Secondary
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48
Overall response rate defined as percentage of complete responders (mUFC ≤ ULN) plus partial responders (≥ 50% reduction in mUFC from baseline and \>ULN) at week 12, 36, 48 by treatment arms for all patients.
Time frame: baseline, week 12, 36 and 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 12 Partial responders | 2 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 36 Overall responders (complete or partial responders) | 40 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 12 Non-responders | 9 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 12 Complete responders | 37 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 48 Complete responders | 34 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 36 Complete responders | 38 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 48 Partial responders | 5 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 12 Overall responders (complete or partial responders) | 39 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 48 Overall responders (complete or partial responders) | 39 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 36 Partial responders | 2 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 48 Non-responders | 9 Participants |
| Osilodrostat Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 36 Non-responders | 8 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 48 Non-responders | 6 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 12 Complete responders | 2 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 12 Partial responders | 2 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 12 Overall responders (complete or partial responders) | 4 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 12 Non-responders | 21 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 36 Complete responders | 21 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 36 Partial responders | 3 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 36 Overall responders (complete or partial responders) | 24 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 36 Non-responders | 1 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 48 Complete responders | 16 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 48 Partial responders | 3 Participants |
| Osilodrostat Placebo Group | Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 | week 48 Overall responders (complete or partial responders) | 19 Participants |
Secondary
Percentage of Participants With mUFC ≤ ULN at Week 36
The complete response rate in both arms combined at Week 36. A complete responder at Week 36 is defined as a participant who had mean urine free cortisol \<= upper limit of normal (mUFC \<= ULN) at Week 36. Participants with missing mUFC at Week 36 were counted as non-responders.
Time frame: At Week 36
Population: Full Analysis Set participants: comprises all randomized participants who received at least one dose of osilodrostat. Only a single arm is reported since the endpoint is 'To assess the complete response rate in both arms combined at Week 36 in patients receiving osilodrostat treatment.'
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osilodrostat Group | Percentage of Participants With mUFC ≤ ULN at Week 36 | 80.8 Percentage of participants |
Secondary
Plasma Osilodrostat Concentrations (ng/mL)
Plasma osilodrostat concentrations (ng/mL)
Time frame: pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26
Population: Pharmacokinetic Analysis Set (PAS): comprises all participants who received at least one dose of osilodrostat and have at least one evaluable pharmacokinetic concentration (post-first-dose) at any visit. The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase. Note that participants took several different doses of study medication in this dose titration study.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 1 1-2 hrs post dose (n=1,43,0) | 3.85 ng/mL | — |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 5 pre dose (n=2,18,17) | 0.576 ng/mL | Geometric Coefficient of Variation 141.9 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 5 1-2 hrs post dose (n=2,9,29) | 3.64 ng/mL | Geometric Coefficient of Variation 60.5 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 8 0 hrs pre dose (n=2,4,13) | 0.971 ng/mL | Geometric Coefficient of Variation 76.7 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 8 1-2 hrs post dose (n=3,6,14) | 3.70 ng/mL | Geometric Coefficient of Variation 47.6 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 12 0 hrs pre dose (n=2,8,11) | 1.55 ng/mL | Geometric Coefficient of Variation 3.7 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 12 1-2 hrs post dose (n=4,34,0) | 4.93 ng/mL | Geometric Coefficient of Variation 32 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 14 0 hrs pre dose (n=4,55,0) | 0.974 ng/mL | Geometric Coefficient of Variation 129.7 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 14 1-2 hrs post dose (n=6,49,6) | 3.74 ng/mL | Geometric Coefficient of Variation 161.4 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 20 0 hrs pre dose (n=10,19,15) | 1.63 ng/mL | Geometric Coefficient of Variation 71.1 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 20 1-2 hrs post dose (n=13,18,12) | 6.09 ng/mL | Geometric Coefficient of Variation 27.3 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 26 0 hrs pre dose (n=12,13,10) | 1.77 ng/mL | Geometric Coefficient of Variation 86.4 |
| Osilodrostat Group | Plasma Osilodrostat Concentrations (ng/mL) | week 26 1-2 hrs post dose (n=16,14,10) | 5.28 ng/mL | Geometric Coefficient of Variation 31.5 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 2 1-2 hrs post dose (n=0,42,0) | 9.76 ng/mL | Geometric Coefficient of Variation 53.4 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 8 1-2 hrs post dose (n=3,6,14) | 8.31 ng/mL | Geometric Coefficient of Variation 45.6 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 5 pre dose (n=2,18,17) | 2.07 ng/mL | Geometric Coefficient of Variation 82.1 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 20 1-2 hrs post dose (n=13,18,12) | 8.66 ng/mL | Geometric Coefficient of Variation 94 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 20 0 hrs pre dose (n=10,19,15) | 1.95 ng/mL | Geometric Coefficient of Variation 68.1 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 5 1-2 hrs post dose (n=2,9,29) | 11.1 ng/mL | Geometric Coefficient of Variation 31.5 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 12 1-2 hrs post dose (n=4,34,0) | 11.7 ng/mL | Geometric Coefficient of Variation 78.9 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 26 1-2 hrs post dose (n=16,14,10) | 8.04 ng/mL | Geometric Coefficient of Variation 50.7 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 8 0 hrs pre dose (n=2,4,13) | 2.64 ng/mL | Geometric Coefficient of Variation 53.7 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 14 0 hrs pre dose (n=4,55,0) | 1.96 ng/mL | Geometric Coefficient of Variation 74.9 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 26 0 hrs pre dose (n=12,13,10) | 2.12 ng/mL | Geometric Coefficient of Variation 77.8 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 14 1-2 hrs post dose (n=6,49,6) | 9.69 ng/mL | Geometric Coefficient of Variation 35.8 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 12 0 hrs pre dose (n=2,8,11) | 2.45 ng/mL | Geometric Coefficient of Variation 39.2 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 1 1-2 hrs post dose (n=1,43,0) | 7.29 ng/mL | Geometric Coefficient of Variation 101 |
| Osilodrostat Placebo Group | Plasma Osilodrostat Concentrations (ng/mL) | week 2 0 hrs pre dose (n=0,41,0) | 2.19 ng/mL | Geometric Coefficient of Variation 107.5 |
| All Participants | Plasma Osilodrostat Concentrations (ng/mL) | week 8 0 hrs pre dose (n=2,4,13) | 4.99 ng/mL | Geometric Coefficient of Variation 55.6 |
| All Participants | Plasma Osilodrostat Concentrations (ng/mL) | week 8 1-2 hrs post dose (n=3,6,14) | 23.3 ng/mL | Geometric Coefficient of Variation 68.1 |
| All Participants | Plasma Osilodrostat Concentrations (ng/mL) | week 12 0 hrs pre dose (n=2,8,11) | 5.03 ng/mL | Geometric Coefficient of Variation 74.6 |
| All Participants | Plasma Osilodrostat Concentrations (ng/mL) | week 20 1-2 hrs post dose (n=13,18,12) | 26.0 ng/mL | Geometric Coefficient of Variation 99.3 |
| All Participants | Plasma Osilodrostat Concentrations (ng/mL) | week 14 1-2 hrs post dose (n=6,49,6) | 22.6 ng/mL | Geometric Coefficient of Variation 37.8 |
| All Participants | Plasma Osilodrostat Concentrations (ng/mL) | week 26 0 hrs pre dose (n=12,13,10) | 6.89 ng/mL | Geometric Coefficient of Variation 85.1 |
| All Participants | Plasma Osilodrostat Concentrations (ng/mL) | week 5 pre dose (n=2,18,17) | 5.06 ng/mL | Geometric Coefficient of Variation 109.6 |
| All Participants | Plasma Osilodrostat Concentrations (ng/mL) | week 5 1-2 hrs post dose (n=2,9,29) | 25.8 ng/mL | Geometric Coefficient of Variation 84.4 |
| All Participants | Plasma Osilodrostat Concentrations (ng/mL) | week 20 0 hrs pre dose (n=10,19,15) | 6.21 ng/mL | Geometric Coefficient of Variation 74.3 |
| All Participants | Plasma Osilodrostat Concentrations (ng/mL) | week 26 1-2 hrs post dose (n=16,14,10) | 33.1 ng/mL | Geometric Coefficient of Variation 31.4 |
Secondary
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates
Escape is defined as the first loss of control of urinary free cortisol (UFC) that meets all of the following criteria: 1. prior normalization of UFC has occurred (median urinary free cortisol (mUFC)≤ upper limit of normal (ULN)); 2. patient reached the highest tolerated dose of osilodrostat; 3. 2 consecutive mUFC (collected at scheduled visits) were above 1.3x ULN; 4. the loss of control of UFC is not related to a dose interruption or dose reduction due to safety reasons; 5. happened beyond Week 26 when the patients have a chance to be treated with doses as high as 30 mg bid. * Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point. * Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for CI of KM estimates.
Time frame: week 26 and week 36
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Osilodrostat Group | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates | % Event probability estimates (95% CI) at 26 Weeks | 0 Percent (event probability estimates) |
| Osilodrostat Group | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates | % Event probability estimates (95% CI) at 36 Weeks | 0 Percent (event probability estimates) |
| Osilodrostat Placebo Group | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates | % Event probability estimates (95% CI) at 26 Weeks | 21.3 Percent (event probability estimates) |
| Osilodrostat Placebo Group | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates | % Event probability estimates (95% CI) at 36 Weeks | NA Percent (event probability estimates) |
| All Participants | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates | % Event probability estimates (95% CI) at 26 Weeks | 15.6 Percent (event probability estimates) |
| All Participants | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates | % Event probability estimates (95% CI) at 36 Weeks | 15.6 Percent (event probability estimates) |
Secondary
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC
To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC \> 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks. The median time-to-escape and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).
Time frame: from week 26 to week 48
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osilodrostat Group | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC | NA days |
| Osilodrostat Placebo Group | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC | NA days |
| All Participants | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC | NA days |
Secondary
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants
To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC \> 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks.
Time frame: up to 48 weeks
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osilodrostat Group | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants | 0 Participants |
| Osilodrostat Placebo Group | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants | 2 Participants |
| All Participants | Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants | 2 Participants |
Secondary
Time-to-first Control of mUFC - % Event Probability Estimates
To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier. % Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point. % Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for Confidence Interval (CI) of Kaplan-Meier (KM) estimates.
Time frame: up to 12 weeks
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Osilodrostat Group | Time-to-first Control of mUFC - % Event Probability Estimates | 2 Weeks | 25.0 Percent (event probability estimates) |
| Osilodrostat Group | Time-to-first Control of mUFC - % Event Probability Estimates | 5 Weeks | 60.4 Percent (event probability estimates) |
| Osilodrostat Group | Time-to-first Control of mUFC - % Event Probability Estimates | 8 Weeks | 79.4 Percent (event probability estimates) |
| Osilodrostat Group | Time-to-first Control of mUFC - % Event Probability Estimates | 12 Weeks | NA Percent (event probability estimates) |
| Osilodrostat Placebo Group | Time-to-first Control of mUFC - % Event Probability Estimates | 12 Weeks | 28.0 Percent (event probability estimates) |
| Osilodrostat Placebo Group | Time-to-first Control of mUFC - % Event Probability Estimates | 2 Weeks | 16.0 Percent (event probability estimates) |
| Osilodrostat Placebo Group | Time-to-first Control of mUFC - % Event Probability Estimates | 8 Weeks | 28.0 Percent (event probability estimates) |
| Osilodrostat Placebo Group | Time-to-first Control of mUFC - % Event Probability Estimates | 5 Weeks | 20.0 Percent (event probability estimates) |
Secondary
Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response
To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier. The median time-to-first control and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).
Time frame: up to 12 weeks
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Osilodrostat Group | Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response | 35 Days |
| Osilodrostat Placebo Group | Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response | NA Days |
Secondary
Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN
To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.
Time frame: up to 12 weeks
Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Osilodrostat Group | Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN | 45 Participants |
| Osilodrostat Placebo Group | Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN | 8 Participants |