Safety and Efficacy of Different Dose Levels of Pasireotide in Patients With de Novo, Persistent or Recurrent Cushing's Disease

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of two different doses of Pasireotide in patients with de novo or recurrent/persistent Cushing's Disease.

Official Title
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A Randomized, Double-blind Study to Assess the Safety and Efficacy of Different Dose Levels of Pasireotide (SOM230) Subcutaneous (sc) Over a 6 Month Treatment Period in Patients With de Novo, Persistent or Recurrent Cushing's Disease

Conditions
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Cushing's Disease

Intervention / Treatment
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* Drug: Pasireotide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria 18 years or greater Confirmed diagnosis of ACTH-dependent Cushing's disease Not considered candidate for pituitary surgery Exclusion criteria History of pituitary irradiation in the last 10 years Cushing's syndrome not caused by pituitary tumor Patients with active malignant disease (cancer) in the last 5 years Women who are pregnant or lactating Other protocol-defined inclusion/exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pasireotide 600 ug<br>At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country. | Drug: Pasireotide<br> <br> |
| Experimental: Pasireotide 900 ug<br>At randomization, participants received 900 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country. | Drug: Pasireotide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of mUFC (Urinary Free Cortisol) Responders by Randomized Dose Group | A responder in the primary efficacy analysis was a patient with a mUFC≤ULN at Month 6 and whose dose was not increased prior to Month 6. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in mUFC | Twenty four hour urine samples were collected to obtain mUFC measurements. A negative change from baseline indicates improvement. | baseline, 3 months, 12 months | 
| Time to First UFC Response | Time to first UFC response is defined as the number of months from baseline to first attainment of UFC response. | 12 months | 
| Percent Change From Baseline in Serum Cortisol | Blood samlpes were drawn to obtain serum cortisol levels. A negative change from baseline indicates improvement. | baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78 months | 
| Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) | Blood samples were drawn to obtain ACTH levels. A negative change from baseline indicates improvement. | baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78 months | 
| Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) | Sitting blood pressure assessments were performed at every study visit. A negative change from baseline indicates improvement. | baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 | 
| Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI) | BMI was determined by using height and weight measurements. A negative change from baseline indicates improvement. | baseline, month 3, month 6, month 12, month 24, month 36, month 48 and month 60 | 
| Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference | Waist circumference was measured with a measuring tape correctly positioned. A negative change from baseline indicates improvement. | baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 | 
| Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides | Blood samples were drawn to obtain total cholesterol and triglycerides' levels. A negative change from baseline indicates improvement. | baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 | 
| Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Beck Depression Inventory (BDI-II) Score | The BDI-II is a 21 item self-report rating inventory measuring characteristic attitudes and symptoms of depression. The BDI-II contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The scores range as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; and 29-63: severe depression. A negative change from baseline indicates imrpovement. | baseline, month 3, month 6, month 12, month 18, month 24 | 
| Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score | The Ferriman Gallwey scoring system is used to score the degree of excess male pattern body hair. The scorecard of every body location under survey begins from 0 (no excessive terminal hair growth) to 4 (extensive terminal hair growth) and the numbers are added up to a maximum count of 36. A score >= 6 indicates the hirsutism. A negative change from baseline indicates imrpovement. | baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 | 
| Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) | BMD was measured using Lunar or Hologic dual-energy X-ray absorptiometry (DXA) Instruments. Measurements were done in the lumbar vertebrae (L1-L4), proximal femur (total hip) and proximal femur (femur neck). A negative change from baseline indicates imrpovement. | baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 | 
| Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition | Body composition as in percentage of body fat by region was assessed by total body scan. A negative change from baseline indicates improvement. | baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 | 
| Change From Baseline in Tumor Volume | Pituitary magnetic resonance imaging (MRI) was performed to determine tumor volume. A negative change from baseline indicates imrpovement. | baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78 months | 
| Percentage Change From Baseline in Health Related Quality of Life (HRQL) Score | A Cushing's syndrome health related quality of life (HRQL) questionnaire was completed. The Cushing's Syndrome HRQL questionnaire contains 12 sentences with 5 possible answers each. The answers are based on Likert scales, with 5 response categories: Always, Often, Sometimes, Rarely and Never; or Very much, Quite a bit, Somewhat, Very little, and Not at all. The answers to each of the items are rated on a scale of 1 to 5. 1 corresponds to the response category Always or Very much and 5 corresponds to the category Never or Not at all. The score is the sum of all item responses and can range from 12 to 60 points. The lower the score, the greater the Cushing's Syndrome impacts on HRQoL. A positive change from baseline indicates improvement. | baseline, 3 months, 6 months, 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cushing's Disease, pasireotide, SOM230