Cushing Disease
Conditions
Keywords
Cushing's disease, ACTH, Cortisol, ACTH dependent Cushing's disease
Brief summary
Cushing's disease is a rare serious condition that is caused by an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. This study assessed the long-term safety and efficacy of pasireotide in participants with Cushing's disease.
Interventions
DRUGPasireotide
Pasireotide 600 μg or 900 μg was administered as an SC injection.
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
* Participants who have completed the 15 days of Pasireotide treatment in the CSOM230B2208 study and have achieved normalization of 24-hour urinary free cortisol. Participants who did not achieve normalization of 24 -hour urinary free cortisol may be enrolled if in the opinion of the investigator the participant is getting significant clinical benefits from treatment with Pasireotide . * The participant did not experience any unacceptable adverse events of tolerability issues during the original 15 day treatment. * Female participants of childbearing potential who have not undergone clinically documented total hysterectomy and/or ovariectomy or tubal ligation must agree to use barrier contraception throughout the course of the extension study, and for one month after the study has ended.
Exclusion criteria
* Participant who have developed poorly controlled diabetes mellitus as indicated by ketoacidosis or hemoglobin (Hgb) A1C (HgbA1C) \> 10 since starting \[study CSOM230B2208\]. * Participant with persistent alanine aminotransferase (ALT)/ aspartate transaminase (AST) or alkaline phosphatase levels more than 2.5X upper limit of normal (ULN), serum creatinine \> 2.0 X ULN, serum bilirubin \> 2 X ULN. * Participant with abnormal coagulation (Prothrombin time (PT) and partial thromboplastin time (PTT) elevated by 30% above normal limits), white blood cells (WBC) \<3.0x1'000'000'000/L; Hgb \<12.0g/dL for females, Hgb \<13.0g/dL for males; PLT \<100x1'000'000'000/L. Other protocol-defined inclusion /
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders With Mean Urinary Free Cortisol (UFC) Within Normal Limits | Month 6 | A participant was considered a responder if the mean UFC from the two 24-hour urine samples collected at Month 6 was within normal limits. The normal range for UFC is 55 to 276 nmol/day. |
| Change From Baseline in Mean Urinary Free Cortisol (UFC) | Core Baseline, Days 14/15 (Core study), Months 6, 12, 24 and 102 | 24-hour urine samples were collected to obtain mean UFC measurements. A negative mean change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Trough Concentrations (Ctrough) of Pasireotide in UFC Responders | Day 15 (Core study) and Month 6 | Participants with Cushing's disease were considered responders if mean UFC levels from the 24-hour urine collections at Day 15 (Core study) and at extension Month 6, were within normal limits. Ctrough levels of pasireotide were measured at Day 15 of Core study and Month 6. |
| Number of Participants Who Had At Least One Adverse Event (AE) | Up to approximately 106 months | An AE was any undesirable sign, symptom or medical condition occurring after starting study drug even if the event is not considered to be related to study drug. AEs were assessed according to incident dose group: Pasireotide 1200 μg sc total daily dose (TDD), Pasireotide 1800 μg SC TDD and Pasireotide SC Any Dose. The incident dose for an AE was the last total daily dose administered on or prior to the AE onset date. |
| Change From Baseline in Gene-expression and Protein in Blood and Urine for Biomarker Development | Baseline to end of the study | — |
| Change From Baseline in Plasma Adrenocorticotropic Hormone (ACTH) Levels | Core Baseline, Day 15 (Core study), Months 6, 12, 24 and Month 105 (end of the study) | Blood samples were withdrawn to obtain the ACTH levels. A negative change from baseline indicates improvement. |
| Change From Baseline in Serum Cortisol Levels | Core Baseline, Day 15 (Core study), Months 6, 12, 24, and Month 105 (end of the study) | Blood samples were withdrawn to obtain the serum cortisol levels. A negative change from baseline indicates improvement. |
Countries
France, Germany, Italy, United Kingdom, United States
Participant flow
Pre-assignment details
The study included participants with Cushing's disease who received 15 days of pasireotide treatment in the Core Study CSOM230B2208 (NCT00088608). This study was an extension study of the Core Study.
Participants by arm
| Arm | Count |
|---|---|
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC Participants received pasireotide 600 μg BID SC to achieve or maintain UFC normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Abnormal Laboratory Values | 2 |
| Overall Study | Adverse Event | 1 |
| Overall Study | New Cancer Therapy | 5 |
| Overall Study | Participants Withdrew Consent | 3 |
| Overall Study | Reason not Specified | 2 |
| Overall Study | Unsatisfactory Therapeutic Effect | 3 |
Baseline characteristics
| Characteristic | Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC |
|---|---|
| Age, Continuous | 43.0 years STANDARD_DEVIATION 11.62 |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 8 |
| other Total, other adverse events | 19 / 19 | 8 / 8 |
| serious Total, serious adverse events | 2 / 19 | 2 / 8 |
Outcome results
Primary
Change From Baseline in Mean Urinary Free Cortisol (UFC)
24-hour urine samples were collected to obtain mean UFC measurements. A negative mean change from baseline indicates improvement.
Time frame: Core Baseline, Days 14/15 (Core study), Months 6, 12, 24 and 102
Population: Primary Efficacy Population included participants from ITT whose mean UFC at core-baseline, based on at least 2 UFC samples, was \>1.0x ULN or for whom the one and only UFC sample available at baseline was \>2.0xULN. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Mean Urinary Free Cortisol (UFC) | Core Baseline | 1219.74 nanomoles per 24 hours (nmol/24h) | Standard Deviation 752.9 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Mean Urinary Free Cortisol (UFC) | Change from Core Baseline to Day 14/Day 15 | -710.57 nanomoles per 24 hours (nmol/24h) | Standard Deviation 740.6 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Mean Urinary Free Cortisol (UFC) | Change from Core Baseline to Month 6 | -801.85 nanomoles per 24 hours (nmol/24h) | Standard Deviation 819.4 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Mean Urinary Free Cortisol (UFC) | Change from Core Baseline to Month 12 | -1202.1 nanomoles per 24 hours (nmol/24h) | Standard Deviation 1084.1 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Mean Urinary Free Cortisol (UFC) | Change from Core Baseline to Month 24 | -1241.1 nanomoles per 24 hours (nmol/24h) | Standard Deviation 925.6 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Mean Urinary Free Cortisol (UFC) | Change from Core Baseline to Month 102 | -2417.0 nanomoles per 24 hours (nmol/24h) | — |
Primary
Percentage of Responders With Mean Urinary Free Cortisol (UFC) Within Normal Limits
A participant was considered a responder if the mean UFC from the two 24-hour urine samples collected at Month 6 was within normal limits. The normal range for UFC is 55 to 276 nmol/day.
Time frame: Month 6
Population: Primary Efficacy Population included participants from ITT whose mean UFC at core-baseline, based on at least 2 UFC samples, was \>1.0x upper limit of normal (ULN) or for whom the one and only UFC sample available at baseline was \>2.0xULN.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Percentage of Responders With Mean Urinary Free Cortisol (UFC) Within Normal Limits | 22.2 percentage of responders |
Secondary
Change From Baseline in Gene-expression and Protein in Blood and Urine for Biomarker Development
Time frame: Baseline to end of the study
Population: We have exhausted all efforts to locate this data and it has since been destroyed, therefore no data is available to report for this outcome measure.
Secondary
Change From Baseline in Plasma Adrenocorticotropic Hormone (ACTH) Levels
Blood samples were withdrawn to obtain the ACTH levels. A negative change from baseline indicates improvement.
Time frame: Core Baseline, Day 15 (Core study), Months 6, 12, 24 and Month 105 (end of the study)
Population: Primary Efficacy Population included participants from ITT whose mean UFC at core-baseline, based on at least 2 UFC samples, was \>1.0x ULN or for whom the one and only UFC sample available at baseline was \>2.0xULN. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Plasma Adrenocorticotropic Hormone (ACTH) Levels | Core Baseline | 13.72 picomoles per litre (pmol/L) | Standard Deviation 11 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Plasma Adrenocorticotropic Hormone (ACTH) Levels | Change from Core Baseline to Day 15 | -1.28 picomoles per litre (pmol/L) | Standard Deviation 7.1 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Plasma Adrenocorticotropic Hormone (ACTH) Levels | Change from Core Baseline to Month 6 | -3.36 picomoles per litre (pmol/L) | Standard Deviation 9.4 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Plasma Adrenocorticotropic Hormone (ACTH) Levels | Change from Core Baseline to Month 12 | -3.60 picomoles per litre (pmol/L) | Standard Deviation 15.2 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Plasma Adrenocorticotropic Hormone (ACTH) Levels | Change from Core Baseline to Month 24 | -4.50 picomoles per litre (pmol/L) | Standard Deviation 8.3 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Plasma Adrenocorticotropic Hormone (ACTH) Levels | Change from Core Baseline to Month 105 | 0.00 picomoles per litre (pmol/L) | — |
Secondary
Change From Baseline in Serum Cortisol Levels
Blood samples were withdrawn to obtain the serum cortisol levels. A negative change from baseline indicates improvement.
Time frame: Core Baseline, Day 15 (Core study), Months 6, 12, 24, and Month 105 (end of the study)
Population: Primary Efficacy Population included participants from ITT whose mean UFC at core-baseline, based on at least 2 UFC samples, was \>1.0x ULN or for whom the one and only UFC sample available at baseline was \>2.0xULN. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Serum Cortisol Levels | Core Baseline | 723.60 nanomoles per liters (nmol/L) | Standard Deviation 221.5 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Serum Cortisol Levels | Change from Core Baseline to Day 15 | -25.96 nanomoles per liters (nmol/L) | Standard Deviation 125.1 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Serum Cortisol Levels | Change from Core Baseline to Month 6 | -150.60 nanomoles per liters (nmol/L) | Standard Deviation 308.9 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Serum Cortisol Levels | Change from Core Baseline to Month 12 | -66.06 nanomoles per liters (nmol/L) | Standard Deviation 301.9 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Serum Cortisol Levels | Change from Core Baseline to Month 24 | -227.53 nanomoles per liters (nmol/L) | Standard Deviation 283.1 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Change From Baseline in Serum Cortisol Levels | Change from Core Baseline to Month 105 | -166.00 nanomoles per liters (nmol/L) | — |
Secondary
Number of Participants Who Had At Least One Adverse Event (AE)
An AE was any undesirable sign, symptom or medical condition occurring after starting study drug even if the event is not considered to be related to study drug. AEs were assessed according to incident dose group: Pasireotide 1200 μg sc total daily dose (TDD), Pasireotide 1800 μg SC TDD and Pasireotide SC Any Dose. The incident dose for an AE was the last total daily dose administered on or prior to the AE onset date.
Time frame: Up to approximately 106 months
Population: Safety Population included participants from ITT Population. ITT Population included participants who completed 15 days of treatment in the Core study, experienced significant clinical benefit without any unacceptable AEs, and received at least 1 dose in the extension period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Number of Participants Who Had At Least One Adverse Event (AE) | 19 Participants |
| Pasireotide 900 μg BID SC | Number of Participants Who Had At Least One Adverse Event (AE) | 8 Participants |
Secondary
Plasma Trough Concentrations (Ctrough) of Pasireotide in UFC Responders
Participants with Cushing's disease were considered responders if mean UFC levels from the 24-hour urine collections at Day 15 (Core study) and at extension Month 6, were within normal limits. Ctrough levels of pasireotide were measured at Day 15 of Core study and Month 6.
Time frame: Day 15 (Core study) and Month 6
Population: Pharmacokinetic (PK) Population included participants from ITT who had at least one post dosing PK assessment up to the implementation of Amendment 2 when no further blood samples were collected for PK assessment (24 May 2007).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Plasma Trough Concentrations (Ctrough) of Pasireotide in UFC Responders | Day 15 (Core Study) | 7.0 nanograms per milliliter (ng/mL) | Standard Deviation 4.3 |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | Plasma Trough Concentrations (Ctrough) of Pasireotide in UFC Responders | Month 6 | 17.4 nanograms per milliliter (ng/mL) | Standard Deviation 11.6 |