Cushings Disease
Conditions
Keywords
pituitary tumors, pasireotide, cabergoline, combination treatment, UFC, hormone disorder, cortisol, adrenocorticotropic hormone, Cushing Disease
Brief summary
The main purpose of this prospective, multicenter, open-label phase II study, was to evaluate the efficacy and safety of pasireotide alone or in combination with cabergoline in patients with Cushing's disease.
Detailed description
This was an open-label, multi-center, international, non-comparative study with adult patients with confirmed diagnosis of Cushing's disease. Given the fact that CD patients may need a multimodality treatment approach, the trial design aimed to mimic CD treatment by using a medical stepwise approach. Therefore, the whole patient population started treatment with Pasireotide and only in patients within this population who did not achieve biochemical control, cabergoline was added. The whole patient population had never received pasireotide or had received it in the past (reasons of discontinuation not related to safety). Core Phase * Pasireotide naïve patients started pasireotide monotherapy at the dose of 0.6 mg s.c. bid. If at the end of the 8 week treatment period, the biochemical control was not achieved and the 0.6mg bid dose was well tolerated, the pasireotide dose was increased to 0.9mg bid. If the 0.9mg bid dose of pasireotide did not lead to biochemical control, cabergoline was added with a starting dose of 0.5mg qd. If the combination dose of 0.9mg bid of pasireotide plus 0.5mg qd cabergolinedid not achieve biochemical control, the cabergoline dose will be increased to 1.0mg qd. * Patients who were currently being treated with maximal tolerated doses of pasireotide monotherapy for at least 8 weeks at screening without achieving normal mUFC, entered the study with a combination therapy starting with cabergoline 0.5mg qd. Extension Phase • After 35 weeks of treatment in core phase, patients had the option to continue study treatment if pasireotide was not yet approved for commercial use and/or reimbursed - if country reimbursement was applicable - in each respective country, or until 31st December 2017, or once an applicable roll over protocol became available, or whichever occurred first. Novartis had a local transition plan in order to ensure that all trial patients had access to the study medication without any delay in their treatment
Interventions
DRUGPasireotide with or without cabergoline
The trial consisted of Pasireotide-untreated patients who started pasireotide 0.6mg twice a day for 8 weeks. If biochemical control was not achieved by the end of the 8 weeks, and the 0.6mg dose is well-tolerated, the dose was increased to 0.9mg twice a day for another 8 weeks. If biochemical control is not achieved, cabergoline was added and patients began combination treatment with cabergoline at the starting dose of 0.5mg once a day for 8 weeks. If biochemical control is still not achieved at the end of the third 8 week period, the dose of cabergoline was increased to 1.0mg once a day. Patients could also immediately start the combination treatment by adding cabergoline 0.5mg once a day at study entry to their current maximal tolerated dose of pasireotide. Patients continued with the combination treatment for 8 weeks. If biochemical control was not not achieved by the end of the 8 week period, the dose of cabergoline was increased to 1mg once a day.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent obtained prior to screening procedures 2. Adult patients with confirmed diagnosis of ACTH-dependent Cushing's disease as evidenced by all of the following: 1. The mean of three 24-hour urine samples collected within 2 weeks \> 1xULN with 2 out of 3 samples \>ULN 2. Morning plasma ACTH within the normal or above normal range 3. Either MRI confirmation of pituitary adenoma \> 6 mm, or inferior petrosal sinus gradient \>3 after CRH stimulation for those patients with a tumor less than or equal to 6 mm\*. For patients who have had prior pituitary surgery, histopathology confirming an ACTH staining adenoma \*If IPSS had previously been performed without CRH (e.g. with DDAVP), then a central to peripheral pre-stimulation gradient \> 2 was required. If IPSS had not previously been performed, IPSS with CRH stimulation was required. 3. Patients with de novo Cushing's disease could only be included only if they were not considered candidates for pituitary surgery (e.g. poor surgical candidates, surgically unapproachable tumors, patients who refused to have surgical treatment) 4. Male or female patients aged 18 years or greater 5. Karnofsky performance status ≥ 60 (i.e. required occasional assistance, but was able to care for most of their personal needs) 6. Patients on medical treatment for Cushing's disease the following washout periods must have been completed before screening assessments were performed * Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week * Pituitary directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARγ agonists (rosiglitazone or pioglitazone): 4 weeks * Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks * Octreotide (immediate release formulation): 1 week * Progesterone receptor antagonist (mifepristone): 4 weeks 7. Patients could have been considered to enter the trial if they met any one of the following criteria: 1) They were naive to pasireotide 2) They had received pasireotide in the past and have been discontinued because of lack of efficacy (2 weeks for washout prior to screening for patients treated with pasireotide subcutaneously and 12 weeks of washout prior to screening for patients treated with pasireotide LAR) 3) Patients who were on maximal tolerated dose but had not achieved biochemical control 8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, if they were using highly effective methods of contraception during dosing and for 30 days after stopping study medication. 9. Male participants in the trial must have agreed to use a condom during intercourse, and not to father a child during the study and for the period of 30 days following stopping of the study treatment.
Exclusion criteria
1. Patients with compression of the optic chiasm that caused any visual field defect that required surgical intervention 2. Diabetic patients with poor glycemic control as evidenced by HbA1c \>8% 3. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF \>450 ms in males, and \> 460 ms in females. hypokalemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval. 4. Patients with clinically significant valvular disease. 5. Patients with Cushing's syndrome due to ectopic ACTH secretion 6. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia 7. Patients who had congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, history of acute MI less than one year prior to study entry or clinically significant impairment in cardiovascular function 8. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with ALT/AST \> 2 X ULN, serum bilirubin \>2.0 X ULN 9. Patients with serum creatinine \>2.0 X ULN 10. Patients with WBC \<3 X 10e9/L; Hb 90% \< LLN; PLT \<100 X 10e9/L 11. Patients with presence of Hepatitis B surface antigen (HbsAg) 12. Patients with presence of Hepatitis C antibody test (anti-HCV) 13. Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to pasireotide or cabergoline 14. Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynauds syndrome. 15. Pregnant or nursing (lactating) women where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\> 5 mIU/ml) 16. Patients with end-stage renal failure and/or hemodialysis 17. Patients with presence of active or suspected acute or chronic uncontrolled infection 18. Patients with a history of non-complance to medical regimens or who were considered potentially unreliable or were unable to complete the entire study 19. Patients with presence of Hepatitis B surface antigen (HbsAg) 20. Patients with presence of Hepatitis C antibody test (anti-HCV) 21. Patients with severe hepatic impairment (Child Pugh C) and hpersensitivity to pasireotide or cabergoline 22. Patients with lung, pericardial, and retroperitoneal fibrosis; gastroduodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynaud's syndrome 23. Pregnant or nursing (lactating) women where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\> 5mIU/mL) 24. Patients with end-stage renal failure and/or hemodialysis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35 | Baseline up to week 35 | Participants who attained mUFC ≤ 1.0 x ULN (upper limit of normal) with pasireotide alone or in combination with cabergoline. The 24h-UFC concentration results from three samples, collected during the screening period, were averaged to obtain the Baseline urinary free cortisol level. mean 24h-UFC was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit. Imputation: subjects who completed the end of treatment visit at Week 35, but had missing evaluation of mean urinary free cortisol (mUFC). The last available mUFC assessment at or after previous visit (week) before last week was carried forward as the last week mUFC assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension | Mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured. |
| Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Baseline up to week 235 | Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured. |
| Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Baseline up to week 235 | Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured. |
| Duration (Weeks) of Controlled or Partially Controlled Response | from the date patient's first normalization (mUFC ≤ 1.0xULN) or at least 50% reduction from baseline up to the date when the patient's mUFC > 1.0 x ULN | Duration of controlled or partially controlled response is defined as the period starting from the date of patient's first normalization (mUFC ≤ 1.0 x ULN) or at least 50% reduction from baseline up to the date when the patient's mUFC \> 1.0 x ULN and the reduction from baseline falls to less than 50% from the first time |
| Plasma Adrenocorticotropic Hormone (ACTH) | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension | A pre-dose blood draw for plasma ACTH sampling was taken at visits. Samples were analyzed by a central laboratory. |
| Serum Cortisol Levels | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension | A pre-dose blood draw for an 8 am fasting serum cortisol measurement were taken at visits. Samples were analyzed by a central laboratory. |
| Sitting Systolic Blood Pressure at Week 35 | Baseline and week 35 | The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures |
| Sitting Diastolic Blood Pressure at Week 35 | Baseline and week 35 | The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures |
| Body Weight at Week 35 | Baseline and week 35 | Weight was was one of the measures of clinical symptoms of CD |
| Body Mass Index at Week 35 | Baseline and week 35 | Body mass index was one of the measurements of clinical symptoms of CD. Body mass index=weight in kg divided by the square of the body height (in meters) |
| Waist Circumference at Week 35 | Baseline and week 35 | Waist circumference was one of the measurements of clinical signs of CD |
| LDL, HDL and Total Cholesterol at Week 35 | Baseline and week 35 | LDL=Low density lipoprotein, HDL=high density llipoprotein and total protein were analyzed by a central laboratory |
| Mean Scores of Cushing QoL Standardized Score at Week 17 and 35 | Baseline and week 17 and 35 | Patients who completed nine or more items for the 12-item Cushing's syndrome QoL questionaire were considered evaluable for that assessment. Raw scores were obtained for the 12 items using the following scoring: 1) always or very much, 2) often or quite a bit, 3) sometimes or somewhat, 4) rarely or very little, 5) never or not at all. Then the standardized score, Y, was calculated for each patient as follows: Y = 100\* (X - n) / n\*5 - n\*1) = 100 \* (X - n) / 4\*n where X denoted the raw score and n the number of questions answered by the patient. The higher the score, the better the QoL. The best possible standardized score was 100 and the worst possible standardized score was 0 |
| Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline, week 17 and 35 | SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults. These are the scores on the original scale which have not been transformed in any way. The possible range of scores is 0 to 100, with higher scores representing better outcomes. |
| Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline |
| Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline |
| Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline |
| Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline |
| Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension | Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline |
| Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Baseline, weeks 1, 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension | Facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad were assessed. Two photographs, one frontal and one lateral from the shoulders up will be taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position will be taken to assess striae, and hirsutism. The photographs must be assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline |
| Number of Patients With Shift From Standing Easily to Not Being Able to Stand | Baseline up to week 267 | To test proximal muscle strength patients should be placed in a low seated position (for instance on an examination room stool). They should be asked to extend the arms in front of them. From this seated position patients will be asked to stand up. Patients will be evaluated using the following scale: 3. - completely unable to stand 2. - able to stand only by using arms as assistance 1\. - able to stand after several efforts without using arms as assistance 0. - able to stand easily with arms extended |
Countries
Argentina, Belgium, Brazil, Colombia, France, Germany, Greece, Hungary, India, Italy, Malaysia, Mexico, Netherlands, Spain, Turkey (Türkiye), United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Patients Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension | 68 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Core Phase | Abnormal lab value | 1 |
| Core Phase | Adverse Event | 7 |
| Core Phase | Death | 2 |
| Core Phase | Protocol Violation | 2 |
| Core Phase | Unsatisfactory therapeutic effect | 3 |
| Core Phase | Withdrawal by Subject | 1 |
| Extension Phase | Adverse Event | 3 |
| Extension Phase | Death | 1 |
| Extension Phase | Protocol Violation | 1 |
| Extension Phase | Unsatisfactory therapeutic effect | 8 |
| Extension Phase | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Customized < 65 years | 64 participants |
| Age, Customized ≥ 65 years | 4 participants |
| Clinical symptoms of dorsal fat pad Mild | 19 Participants |
| Clinical symptoms of dorsal fat pad Moderate | 14 Participants |
| Clinical symptoms of dorsal fat pad None | 3 Participants |
| Clinical symptoms of dorsal fat pad Not done | 26 Participants |
| Clinical symptoms of dorsal fat pad Severe | 6 Participants |
| Clinical symptoms of facial rubor Mild | 17 Participants |
| Clinical symptoms of facial rubor Moderate | 11 Participants |
| Clinical symptoms of facial rubor None | 10 Participants |
| Clinical symptoms of facial rubor Not done | 26 Participants |
| Clinical symptoms of facial rubor Severe | 4 Participants |
| Clinical symptoms of hirsutism Mild | 12 Participants |
| Clinical symptoms of hirsutism Moderate | 7 Participants |
| Clinical symptoms of hirsutism None | 13 Participants |
| Clinical symptoms of hirsutism Not done | 33 Participants |
| Clinical symptoms of hirsutism Severe | 3 Participants |
| Clinical symptoms of striae Mild | 10 Participants |
| Clinical symptoms of striae Moderate | 4 Participants |
| Clinical symptoms of striae None | 20 Participants |
| Clinical symptoms of striae Not done | 26 Participants |
| Clinical symptoms of striae Severe | 8 Participants |
| Clinical symptoms of supraclavicular fat pad Mild | 17 Participants |
| Clinical symptoms of supraclavicular fat pad Moderate | 13 Participants |
| Clinical symptoms of supraclavicular fat pad None | 8 Participants |
| Clinical symptoms of supraclavicular fat pad Not done | 26 Participants |
| Clinical symptoms of supraclavicular fat pad Severe | 4 Participants |
| Cushing's disease status De novo | 10 Participants |
| Cushing's disease status Persistent/recurrent | 58 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants |
| Race/Ethnicity, Customized Black | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 44 Participants |
| Race/Ethnicity, Customized Native American | 5 Participants |
| Race/Ethnicity, Customized Other | 8 Participants |
| Sex: Female, Male Female | 60 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 68 |
| other Total, other adverse events | 67 / 68 |
| serious Total, serious adverse events | 15 / 68 |
Outcome results
Primary
Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35
Participants who attained mUFC ≤ 1.0 x ULN (upper limit of normal) with pasireotide alone or in combination with cabergoline. The 24h-UFC concentration results from three samples, collected during the screening period, were averaged to obtain the Baseline urinary free cortisol level. mean 24h-UFC was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit. Imputation: subjects who completed the end of treatment visit at Week 35, but had missing evaluation of mean urinary free cortisol (mUFC). The last available mUFC assessment at or after previous visit (week) before last week was carried forward as the last week mUFC assessment.
Time frame: Baseline up to week 35
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35 | 50.0 percentage of responders |
Secondary
Body Mass Index at Week 35
Body mass index was one of the measurements of clinical symptoms of CD. Body mass index=weight in kg divided by the square of the body height (in meters)
Time frame: Baseline and week 35
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Body Mass Index at Week 35 | Baseline | 31.3 kg/m2 | Standard Deviation 6.6 |
| All Patients | Body Mass Index at Week 35 | Week 35 n=41 | 28.4 kg/m2 | Standard Deviation 6.8 |
Secondary
Body Weight at Week 35
Weight was was one of the measures of clinical symptoms of CD
Time frame: Baseline and week 35
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Body Weight at Week 35 | Baseline | 82.2 kg | Standard Deviation 19.1 |
| All Patients | Body Weight at Week 35 | Week 35 n=41 | 75.6 kg | Standard Deviation 20.4 |
Secondary
Duration (Weeks) of Controlled or Partially Controlled Response
Duration of controlled or partially controlled response is defined as the period starting from the date of patient's first normalization (mUFC ≤ 1.0 x ULN) or at least 50% reduction from baseline up to the date when the patient's mUFC \> 1.0 x ULN and the reduction from baseline falls to less than 50% from the first time
Time frame: from the date patient's first normalization (mUFC ≤ 1.0xULN) or at least 50% reduction from baseline up to the date when the patient's mUFC > 1.0 x ULN
Population: Core and extension full analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Patients | Duration (Weeks) of Controlled or Partially Controlled Response | Core n=36 | 13.1 weeks |
| All Patients | Duration (Weeks) of Controlled or Partially Controlled Response | Extension n=20 | 22.0 weeks |
Secondary
LDL, HDL and Total Cholesterol at Week 35
LDL=Low density lipoprotein, HDL=high density llipoprotein and total protein were analyzed by a central laboratory
Time frame: Baseline and week 35
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | LDL, HDL and Total Cholesterol at Week 35 | Total Baseline | 69.4 mmol/L | Standard Deviation 3.7 |
| All Patients | LDL, HDL and Total Cholesterol at Week 35 | HDL Baseline | 1.5 mmol/L | Standard Deviation 0.3 |
| All Patients | LDL, HDL and Total Cholesterol at Week 35 | HDL Week 35 n=41 | 1.5 mmol/L | Standard Deviation 0.4 |
| All Patients | LDL, HDL and Total Cholesterol at Week 35 | LDL Baseline | 3.2 mmol/L | Standard Deviation 1 |
| All Patients | LDL, HDL and Total Cholesterol at Week 35 | LDL Week 35 n=41 | 2.8 mmol/L | Standard Deviation 1 |
| All Patients | LDL, HDL and Total Cholesterol at Week 35 | Total Week 35 n=41 | 68.6 mmol/L | Standard Deviation 4.8 |
Secondary
Mean Scores of Cushing QoL Standardized Score at Week 17 and 35
Patients who completed nine or more items for the 12-item Cushing's syndrome QoL questionaire were considered evaluable for that assessment. Raw scores were obtained for the 12 items using the following scoring: 1) always or very much, 2) often or quite a bit, 3) sometimes or somewhat, 4) rarely or very little, 5) never or not at all. Then the standardized score, Y, was calculated for each patient as follows: Y = 100\* (X - n) / n\*5 - n\*1) = 100 \* (X - n) / 4\*n where X denoted the raw score and n the number of questions answered by the patient. The higher the score, the better the QoL. The best possible standardized score was 100 and the worst possible standardized score was 0
Time frame: Baseline and week 17 and 35
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Mean Scores of Cushing QoL Standardized Score at Week 17 and 35 | Baseline Mean | 41.6 scores on a scale | Standard Deviation 20.2 |
| All Patients | Mean Scores of Cushing QoL Standardized Score at Week 17 and 35 | Week 17 n=54 | 46.3 scores on a scale | Standard Deviation 19.7 |
| All Patients | Mean Scores of Cushing QoL Standardized Score at Week 17 and 35 | Week 35 n=40 | 47.6 scores on a scale | Standard Deviation 20.8 |
Secondary
Mean Scores of SF-12v2 Domain Scores at Week 17 and 35
SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults. These are the scores on the original scale which have not been transformed in any way. The possible range of scores is 0 to 100, with higher scores representing better outcomes.
Time frame: Baseline, week 17 and 35
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline Bodily pain scale | 42.9 scores on a scale | Standard Deviation 11.93 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 17 n=52 Bodily pain scale | 45.1 scores on a scale | Standard Deviation 10.75 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 35 n=40 Bodily pain scale | 44.9 scores on a scale | Standard Deviation 10.79 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline n=67 General health scale: | 38.9 scores on a scale | Standard Deviation 9.23 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 17 n=52 General health scale: | 40.9 scores on a scale | Standard Deviation 8.52 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 35 n=40 General health scale: | 40.7 scores on a scale | Standard Deviation 8.94 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline n=67 Mental component | 42.4 scores on a scale | Standard Deviation 10.17 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 17 n=52 Mental component | 41.9 scores on a scale | Standard Deviation 9.68 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 35 n=40 Mental component | 42.1 scores on a scale | Standard Deviation 8.32 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline n=67 Mental health | 41.9 scores on a scale | Standard Deviation 10.48 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 17 n=52 Mental health | 43.0 scores on a scale | Standard Deviation 9.54 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 35 n=40 Mental health | 42.4 scores on a scale | Standard Deviation 8.44 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline n=67 Physical component summary | 42.7 scores on a scale | Standard Deviation 9.03 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 17 n=52 Physical component summary | 44.0 scores on a scale | Standard Deviation 8.52 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 35 n=40 Physical component summary | 43.4 scores on a scale | Standard Deviation 9.59 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline n=67 Physical functioning | 42.1 scores on a scale | Standard Deviation 10.17 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 17 n=52 Physical functioning | 41.9 scores on a scale | Standard Deviation 8.93 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 35 n=40 Physical functioning | 42.1 scores on a scale | Standard Deviation 11.1 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline n=67 Role emotional | 39.7 scores on a scale | Standard Deviation 11.67 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 17 n=52 Role emotional | 38.0 scores on a scale | Standard Deviation 9.95 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 35 n=40 Role emotional | 38.7 scores on a scale | Standard Deviation 10.7 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline n=67 Role physical scale: | 42.3 scores on a scale | Standard Deviation 10.45 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 17 n=52 Role physical scale: | 42.8 scores on a scale | Standard Deviation 8.73 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 35 n=40 Role physical scale: | 41.3 scores on a scale | Standard Deviation 9.63 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline n=67 Social functioning | 42.2 scores on a scale | Standard Deviation 11.22 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 17 n=52 Social functioning | 43.0 scores on a scale | Standard Deviation 8.7 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 35 n=40 Social functioning | 43.3 scores on a scale | Standard Deviation 9.66 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Baseline n=67 Vitality scale: | 47.2 scores on a scale | Standard Deviation 10.02 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 17 n=52 Vitality scale: | 45.7 scores on a scale | Standard Deviation 10.29 |
| All Patients | Mean Scores of SF-12v2 Domain Scores at Week 17 and 35 | Week 35 n=40 Vitality scale: | 45.6 scores on a scale | Standard Deviation 8.78 |
Secondary
Mean Urinary Free Cortisol (mUFC) at Scheduled Visits
Mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.
Time frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Population: Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Baseline | 501.6 nmol/24h | Standard Deviation 488.66 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Core Week 2 n-8 | 217.0 nmol/24h | Standard Deviation 100.69 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Core Week 4 n=59 | 242.1 nmol/24h | Standard Deviation 203.47 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Core Week 8 n=58 | 230.0 nmol/24h | Standard Deviation 195.21 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Core Week 13 n=51 | 231.0 nmol/24h | Standard Deviation 240.98 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Core Week 17 n=57 | 310.3 nmol/24h | Standard Deviation 429.64 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Core Week 22 n=50 | 214.0 nmol/24h | Standard Deviation 202.8 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Core Week 26 n=54 | 211.6 nmol/24h | Standard Deviation 173.58 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Core Week 31 n=46 | 154.3 nmol/24h | Standard Deviation 104.16 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Core Week 35 n=45 | 184.8 nmol/24h | Standard Deviation 140.13 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 43 n=22 | 136.1 nmol/24h | Standard Deviation 91.13 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 51 n=20 | 156.8 nmol/24h | Standard Deviation 108.91 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 59 n=24 | 157.7 nmol/24h | Standard Deviation 111.63 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 67 n=17 | 213.8 nmol/24h | Standard Deviation 194.99 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 75 n=18 | 157.6 nmol/24h | Standard Deviation 166.28 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 83 n=20 | 157.9 nmol/24h | Standard Deviation 134.98 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 91 n=18 | 180.0 nmol/24h | Standard Deviation 302.36 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 99 n=13 | 222.5 nmol/24h | Standard Deviation 375.67 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 107 n=12 | 118.5 nmol/24h | Standard Deviation 122.01 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 115 n=13 | 126.0 nmol/24h | Standard Deviation 80.09 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 123 n=13 | 147.5 nmol/24h | Standard Deviation 157.77 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 131 n=11 | 76.4 nmol/24h | Standard Deviation 49.92 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 139 n=9 | 92.9 nmol/24h | Standard Deviation 73.18 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 147 n=9 | 90.1 nmol/24h | Standard Deviation 55.31 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 155 n=4 | 76.3 nmol/24h | Standard Deviation 39.05 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 163 n=6 | 141.1 nmol/24h | Standard Deviation 142.42 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 171 n=6 | 89.5 nmol/24h | Standard Deviation 61.87 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 179 n=4 | 61.3 nmol/24h | Standard Deviation 43.06 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 187 n=4 | 89.9 nmol/24h | Standard Deviation 52.44 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 195 n=3 | 46.1 nmol/24h | Standard Deviation 40.21 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 203 n=4 | 194.0 nmol/24h | Standard Deviation 259.15 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 211 n=3 | 107.3 nmol/24h | Standard Deviation 37.68 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 219 n=2 | 70.6 nmol/24h | Standard Deviation 46.74 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 227 n=2 | 47.1 nmol/24h | Standard Deviation 7.99 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 235 n=3 | 62.0 nmol/24h | Standard Deviation 23.83 |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 243 n=1 | 117.7 nmol/24h | — |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 251 n=1 | 202.9 nmol/24h | — |
| All Patients | Mean Urinary Free Cortisol (mUFC) at Scheduled Visits | Ext Week 267 n=1 | 249.0 nmol/24h | — |
Secondary
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad
Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
Population: Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Core Week 1 n=40 | 6 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Core Week 2 n-37 | 4 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Core Week 4 n=37 | 5 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Core Week 8 n=37 | 5 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Core Week 13 n=32 | 4 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Core Week 17 n=32 | 8 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Core Week 22 n=28 | 8 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Core Week 26 n=31 | 12 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Core Week 31 n=32 | 13 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Core Week 35 n=26 | 9 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 43 n=11 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 59 n=10 | 4 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 75 n=12 | 5 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 91 n=10 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 107 n=9 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 123 n=10 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 139 n=7 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 155 n=4 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 171 n=3 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 187 n=3 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 203 n=4 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 219 n=2 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 235 n=3 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 251 n=1 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad | Ext Week 267 n=1 | 0 participants |
Secondary
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor
Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
Population: Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Core Week 1 n=40 | 5 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Core Week 2 n=37 | 8 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Core Week 4 n=38 | 8 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Core Week 8 n=37 | 12 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Core Week 13 n=32 | 11 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Core Week 17 n=32 | 11 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Core Week 22 n=28 | 10 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Core Week 26 n=31 | 14 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Core Week 31 n=32 | 15 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Core Week 35 n=26 | 13 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 43 n=11 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 59 n=11 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 75 n=12 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 91 n=10 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 107 n=9 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 123 n=10 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 139 n=7 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 155 n=4 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 171 n=3 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 187 n=3 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 203 n=4 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 219 n=2 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 235 n=3 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 251 n=1 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor | Ext Week 267 n=1 | 0 participants |
Secondary
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism
Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
Population: Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Core Week 1 n=35 | 5 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Core Week 2 n-33 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Core Week 4 n=32 | 4 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Core Week 8 n=32 | 4 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Core Week 13 n=27 | 4 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Core Week 17 n=28 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Core Week 22 n=25 | 5 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Core Week 26 n=27 | 8 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Core Week 31 n=28 | 9 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Core Week 35 n=23 | 7 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 43 n=10 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 59 n=9 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 75 n=10 | 3 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 91 n=9 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 107 n=8 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 123 n=9 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 139 n=7 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 155 n=4 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 171 n=4 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 187 n=3 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 203 n=4 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 219 n=2 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 235 n=3 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 251 n=1 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism | Ext Week 267 n=1 | 0 participants |
Secondary
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae
Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
Population: Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Core Week 1 n=40 | 5 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Core Week 2 n-37 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Core Week 4 n=38 | 5 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Core Week 8 n=37 | 8 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Core Week 13 n=32 | 7 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Core Week 17 n=32 | 7 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Core Week 22 n=28 | 7 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Core Week 26 n=31 | 9 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Core Week 31 n=32 | 12 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Core Week 35 n=26 | 8 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 43 n11= | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 59 n=11 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 75 n=12 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 91 n=10 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 107 n=9 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 123 n=10 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 139 n=7 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 155 n=4 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 171 n=3 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 187 n=3 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 203 n=4 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 219 n=2 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 235 n=3 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 251 n=1 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae | Ext Week 267 n=1 | 1 participants |
Secondary
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad
Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Population: Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Core Week 1 n=40 | 6 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Core Week 2 n-37 | 7 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Core Week 4 n=37 | 6 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Core Week 8 n=37 | 8 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Core Week 13 n=32 | 8 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Core Week 17 n=32 | 9 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Core Week 22 n=28 | 9 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Core Week 26 n=31 | 10 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Core Week 31 n=32 | 12 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Core Week 35 n=26 | 11 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 43 n=11 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 59 n=11 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 75 n=12 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 91 n=10 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 107 n=9 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 123 n=10 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 139 n=7 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 155 n=4 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 171 n=3 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 187 n=3 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 203 n=4 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 219 n=2 | 1 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 235 n=3 | 2 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 251 n=1 | 0 participants |
| All Patients | Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad | Ext Week 267 n=1 | 0 participants |
Secondary
Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism
Facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad were assessed. Two photographs, one frontal and one lateral from the shoulders up will be taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position will be taken to assess striae, and hirsutism. The photographs must be assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline
Time frame: Baseline, weeks 1, 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Core Week 4 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Core Week 35 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 43 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 59 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 67 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 83 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 91 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 99 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 107 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 115 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 123 Facial rubor baseline n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Core Week 1 Hirsutism baseline n=12 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Core Week 2 Hirsutism baseline n=12 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 59 Striae baseline n=10 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 99 Striae baseline n=10 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 107 Striae baseline n=10 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 115 Striae baseline n=10 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 123 Striae baseline n=10 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 99 Supraclavicular fat pad BL n=17 | 1 participants |
| All Patients | Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism | Ext Week 107 Supraclavicular fat pad BL n=17 | 1 participants |
Secondary
Number of Patients With Shift From Standing Easily to Not Being Able to Stand
To test proximal muscle strength patients should be placed in a low seated position (for instance on an examination room stool). They should be asked to extend the arms in front of them. From this seated position patients will be asked to stand up. Patients will be evaluated using the following scale: 3. - completely unable to stand 2. - able to stand only by using arms as assistance 1\. - able to stand after several efforts without using arms as assistance 0. - able to stand easily with arms extended
Time frame: Baseline up to week 267
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Number of Patients With Shift From Standing Easily to Not Being Able to Stand | Core Week 26 | 1 participants |
| All Patients | Number of Patients With Shift From Standing Easily to Not Being Able to Stand | Core Week 35 | 1 participants |
Secondary
Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC
Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.
Time frame: Baseline up to week 235
Population: Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Baseline | 4.4 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Core Week 17 n=57 | 54.4 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Core Week 35 n=45 | 68.9 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Ext Week 43 n=22 | 86.4 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Ext Week 67 n=17 | 76.5 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Ext Week 91 n=18 | 83.3 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Ext Week 115 n=13 | 92.3 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Ext Week 139 n=9 | 77.8 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Ext Week 163 n=6 | 83.3 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Ext Week 187 n=4 | 100 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Ext Week 211 n=3 | 66.7 percentage of responders |
| All Patients | Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC | Ext Week 235 n=3 | 100 percentage of responders |
Secondary
Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN
Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.
Time frame: Baseline up to week 235
Population: Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Baseline | 4.4 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Core Week 17 n=57 | 28.1 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Core Week 35 n=45 | 48.9 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Ext Week 43 n=22 | 63.6 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Ext Week 67 n=17 | 47.1 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Ext Week 91 n=18 | 61.1 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Ext Week 115 n=13 | 76.9 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Ext Week 139 n=9 | 77.8 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Ext Week 163 n=6 | 66.7 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Ext Week 187 n=4 | 75.0 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Ext Week 211 n=3 | 66.7 percentage of responders |
| All Patients | Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN | Ext Week 235 n=3 | 100 percentage of responders |
Secondary
Plasma Adrenocorticotropic Hormone (ACTH)
A pre-dose blood draw for plasma ACTH sampling was taken at visits. Samples were analyzed by a central laboratory.
Time frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Baseline | 16.3 pmol/L | Standard Deviation 16.3 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Core Week 2 n-62 | 12.4 pmol/L | Standard Deviation 9.91 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Core Week 4 n=63 | 14.2 pmol/L | Standard Deviation 12.5 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Core Week 8 n=61 | 13.3 pmol/L | Standard Deviation 11.9 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Core Week 13 n=53 | 11.9 pmol/L | Standard Deviation 10.98 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Core Week 17 n=58 | 12.3 pmol/L | Standard Deviation 9.03 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Core Week 22 n=49 | 13.7 pmol/L | Standard Deviation 13.82 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Core Week 26 n=55 | 12.4 pmol/L | Standard Deviation 12.09 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Core Week 31 n=49 | 12.1 pmol/L | Standard Deviation 11.02 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Core Week 35 n=40 | 11.0 pmol/L | Standard Deviation 8.71 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 43 n=23 | 11.5 pmol/L | Standard Deviation 8.12 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 51 n=21 | 10.4 pmol/L | Standard Deviation 6.8 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 59 n=23 | 10.7 pmol/L | Standard Deviation 6.89 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 67 n=22 | 11.0 pmol/L | Standard Deviation 7.23 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 75 n=22 | 9.1 pmol/L | Standard Deviation 4.16 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 83 n=19 | 9.8 pmol/L | Standard Deviation 8.2 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 91 n=19 | 10.6 pmol/L | Standard Deviation 8.34 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 99 n=16 | 11.3 pmol/L | Standard Deviation 8.5 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 107 n=13 | 9.3 pmol/L | Standard Deviation 6.61 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 115 n=15 | 9.5 pmol/L | Standard Deviation 7.22 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 123 n=14 | 10.6 pmol/L | Standard Deviation 8.24 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 131 n=12 | 8.2 pmol/L | Standard Deviation 6.01 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 139 n=10 | 10.0 pmol/L | Standard Deviation 7.01 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 147 n=9 | 10.4 pmol/L | Standard Deviation 7.02 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 155 n=9 | 10.4 pmol/L | Standard Deviation 7.02 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 163 n=5 | 10.0 pmol/L | Standard Deviation 4.85 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 171 n=5 | 7.4 pmol/L | Standard Deviation 3.36 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 179 n=5 | 7.0 pmol/L | Standard Deviation 3.32 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 187 n=5 | 8.6 pmol/L | Standard Deviation 5.32 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 195 n=4 | 9.0 pmol/L | Standard Deviation 4.76 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 203 n=4 | 8.0 pmol/L | Standard Deviation 2.94 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 211 n=3 | 11.0 pmol/L | Standard Deviation 4.58 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 219 n=2 | 6.0 pmol/L | Standard Deviation 0 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 227 n=2 | 7.0 pmol/L | Standard Deviation 1.41 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 235 n=3 | 10.3 pmol/L | Standard Deviation 3.21 |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 243 n=1 | 6.0 pmol/L | — |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 251 n=1 | 7.0 pmol/L | — |
| All Patients | Plasma Adrenocorticotropic Hormone (ACTH) | Ext Week 267 n=1 | 4.0 pmol/L | — |
Secondary
Serum Cortisol Levels
A pre-dose blood draw for an 8 am fasting serum cortisol measurement were taken at visits. Samples were analyzed by a central laboratory.
Time frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Serum Cortisol Levels | Baseline | 738.6 nmol/L | Standard Deviation 332.53 |
| All Patients | Serum Cortisol Levels | Core Week 2 n-62 | 626.1 nmol/L | Standard Deviation 281.57 |
| All Patients | Serum Cortisol Levels | Core Week 4 n=64 | 663.6 nmol/L | Standard Deviation 292.38 |
| All Patients | Serum Cortisol Levels | Core Week 8 n=61 | 649.0 nmol/L | Standard Deviation 297.11 |
| All Patients | Serum Cortisol Levels | Core Week 13 n=53 | 628.8 nmol/L | Standard Deviation 269.43 |
| All Patients | Serum Cortisol Levels | Core Week 17 n=58 | 683.0 nmol/L | Standard Deviation 282.28 |
| All Patients | Serum Cortisol Levels | Ext Week 91 n=19 | 501.2 nmol/L | Standard Deviation 235.89 |
| All Patients | Serum Cortisol Levels | Core Week 22 n=49 | 625.4 nmol/L | Standard Deviation 216.29 |
| All Patients | Serum Cortisol Levels | Core Week 26 n=55 | 632.7 nmol/L | Standard Deviation 278.75 |
| All Patients | Serum Cortisol Levels | Core Week 31 n=49 | 597.5 nmol/L | Standard Deviation 247.6 |
| All Patients | Serum Cortisol Levels | Core Week 35 n=40 | 538.2 nmol/L | Standard Deviation 205.4 |
| All Patients | Serum Cortisol Levels | Ext Week 43 n=23 | 525.5 nmol/L | Standard Deviation 178.63 |
| All Patients | Serum Cortisol Levels | Ext Week 51 n=21 | 512.2 nmol/L | Standard Deviation 243.59 |
| All Patients | Serum Cortisol Levels | Ext Week 59 n=21 | 547.5 nmol/L | Standard Deviation 193.67 |
| All Patients | Serum Cortisol Levels | Ext Week 67 n=22 | 495.4 nmol/L | Standard Deviation 213.03 |
| All Patients | Serum Cortisol Levels | Ext Week 75 n=21 | 458.5 nmol/L | Standard Deviation 170.88 |
| All Patients | Serum Cortisol Levels | Ext Week 83 n=19 | 419.5 nmol/L | Standard Deviation 141.26 |
| All Patients | Serum Cortisol Levels | Ext Week 99 n=16 | 470.9 nmol/L | Standard Deviation 248 |
| All Patients | Serum Cortisol Levels | Ext Week 107 n=13 | 463.4 nmol/L | Standard Deviation 189.27 |
| All Patients | Serum Cortisol Levels | Ext Week 115 n=15 | 501.7 nmol/L | Standard Deviation 212.27 |
| All Patients | Serum Cortisol Levels | Ext Week 123 n=14 | 441.6 nmol/L | Standard Deviation 150.98 |
| All Patients | Serum Cortisol Levels | Ext Week 131 n=12 | 413.8 nmol/L | Standard Deviation 325.5 |
| All Patients | Serum Cortisol Levels | Ext Week 139 n=10 | 404.0 nmol/L | Standard Deviation 90.87 |
| All Patients | Serum Cortisol Levels | Ext Week 147 n=10 | 585.4 nmol/L | Standard Deviation 216.92 |
| All Patients | Serum Cortisol Levels | Ext Week 155 n=8 | 472.5 nmol/L | Standard Deviation 122.96 |
| All Patients | Serum Cortisol Levels | Ext Week 163 n=6 | 617.0 nmol/L | Standard Deviation 212.11 |
| All Patients | Serum Cortisol Levels | Ext Week 171 n=5 | 648.6 nmol/L | Standard Deviation 243.79 |
| All Patients | Serum Cortisol Levels | Ext Week 179 n=5 | 599.0 nmol/L | Standard Deviation 388.78 |
| All Patients | Serum Cortisol Levels | Ext Week 187 n=5 | 609.8 nmol/L | Standard Deviation 292.85 |
| All Patients | Serum Cortisol Levels | Ext Week 195 n=4 | 418.8 nmol/L | Standard Deviation 138.69 |
| All Patients | Serum Cortisol Levels | Ext Week 203 n=4 | 514.0 nmol/L | Standard Deviation 212.27 |
| All Patients | Serum Cortisol Levels | Ext Week 211 n=3 | 551.3 nmol/L | Standard Deviation 339.87 |
| All Patients | Serum Cortisol Levels | Ext Week 219 n=2 | 482.0 nmol/L | Standard Deviation 25.46 |
| All Patients | Serum Cortisol Levels | Ext Week 227 n=2 | 324.5 nmol/L | Standard Deviation 177.48 |
| All Patients | Serum Cortisol Levels | Ext Week 235 n=3 | 384.7 nmol/L | Standard Deviation 165.17 |
| All Patients | Serum Cortisol Levels | Ext Week 243 n=1 | 679.0 nmol/L | — |
| All Patients | Serum Cortisol Levels | Ext Week 251 n=1 | 574.0 nmol/L | — |
| All Patients | Serum Cortisol Levels | Ext Week 267 n=1 | 638.0 nmol/L | — |
Secondary
Sitting Diastolic Blood Pressure at Week 35
The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures
Time frame: Baseline and week 35
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Sitting Diastolic Blood Pressure at Week 35 | Baseline | 81.8 mmHg | Standard Deviation 9.12 |
| All Patients | Sitting Diastolic Blood Pressure at Week 35 | Week 35 n=41 | 77.2 mmHg | Standard Deviation 12.42 |
Secondary
Sitting Systolic Blood Pressure at Week 35
The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures
Time frame: Baseline and week 35
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Sitting Systolic Blood Pressure at Week 35 | Baseline | 125.9 mmHg | Standard Deviation 14.3 |
| All Patients | Sitting Systolic Blood Pressure at Week 35 | Week 35 n=41 | 119.5 mmHg | Standard Deviation 18.6 |
Secondary
Waist Circumference at Week 35
Waist circumference was one of the measurements of clinical signs of CD
Time frame: Baseline and week 35
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Waist Circumference at Week 35 | Baseline | 104.1 cm | Standard Deviation 19.1 |
| All Patients | Waist Circumference at Week 35 | Week 35 n=41 | 99.1 cm | Standard Deviation 18.2 |