Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing's Disease

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind, multicenter, phase III study to evaluate the safety and efficacy of 2 dosing regiments of Pasireotide long acting release (LAR) in patients with Cushing's disease.

Official Title
-----------------
A Randomized, Double-blind, Multicenter, Phase III Study to Evaluate the Efficacy and Safety of Pasireotide LAR in Patients With Cushing's Disease

Conditions
-----------------
Cushing's Disease

Intervention / Treatment
-----------------
* Drug: pasireotide LAR
* Drug: SOM230 LAR 30 mg
* Drug: SOM230 LAR 10 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is able to care for most of their personal needs) For patients on medical treatment for Cushing's disease the following washout periods must be completed before screening assessments are 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 Exclusion Criteria: Patients who are considered candidates for surgical treatment at the time of study entry Patients who have received pituitary irradiation within the last ten years prior to visit 1 Patients who have had any previous pasireotide treatment Patients who have been treated with mitotane during the last 6 months prior to Visit 1 Diabetic patients on antihyperglycemic medications with poor glycemic control as evidenced by HbA1c >8% Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF >470 ms, hypokalemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval Female patients who are pregnant or lactating, or are of childbearing potential (defined as all women physiologically capable of becoming pregnant) and not practicing an effective method of contraception/birth control. Sexually active males must use a condom during intercourse while taking the drug and for 2 months after the last dose of study drug and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 mg LAR dose<br>Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. | Drug: pasireotide LAR<br>* Pasireotide long-acting was administered as an intra-muscular depot intragluteal injection once every 28 days (±2 days). Patients were administered pasireotide long-acting 10 mg or 30 mg for four months, followed by either continuation of the starting dose, or dose up-titration (if mUFC was still >1.5xULN unless titration was precluded by safety reasons).<br>* Other names: SOM230;Drug: SOM230 LAR 10 mg<br>* starting does of SOM230 LAR 10 mg i.m. administered once every 28 days for 4 months, followed by dose up-titration or continuation of the starting dose.<br>|
| Experimental: 30 mg LAR dose<br>Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. | Drug: pasireotide LAR<br>* Pasireotide long-acting was administered as an intra-muscular depot intragluteal injection once every 28 days (±2 days). Patients were administered pasireotide long-acting 10 mg or 30 mg for four months, followed by either continuation of the starting dose, or dose up-titration (if mUFC was still >1.5xULN unless titration was precluded by safety reasons).<br>* Other names: SOM230;Drug: SOM230 LAR 30 mg<br>* starting dose of 30 mg i.m. administered once every 28 days for 4 months, followed by dose up-titration or continuation of starting dose.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 Regardless of Dose Titration | Percentage of participants that attained a mean urinary free cortisol (mUFC) <= 1.0 x upper limit of normal (ULN) at Month 7 regardless of dose up-titration at Month 4. Patients who discontinued before month 4 evaluations classed as non-responders. For patients missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value. | Month 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants That Attained a mUFC ≤ 1.0 x ULN at Month 7 and Had Not Had a Dose Increase at Month 4 | Percentage of participants that attain a mUFC ≤ 1.0×ULN at Month 7 and had not had a dose increase at Month 4. Patients who had a dose increase prior to Month 7 were counted as non-responders in this analysis. Patients who discontinued before month 4 evaluations classed as non-responders. For patients missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value. A responder was defined as a patient who attains mUFC ≤1.0 X ULN and had not had a dose increase at Month 4. | Month 7 | 
| Actual Change in Mean Urinary Free Cortisol (mUFC) From Baseline | Actual change in mUFC (nmol/24h) from baseline by randomized groups. | baseline, Month 7 (M7), Month 12 (M12), Month 24 (M24) , Month 36 (M36) | 
| Percentage Change in Mean Urinary Free Cortisol (mUFC) From Baseline | Percentage change in mUFC (nmol/24h) from baseline by randomized groups. | M7, M12, M24, M36 | 
| Percentage of Patients Who Attain mUFC ≤ 1.0 x ULN | Controlled responder: mUFC ≤ 1.0×ULN by randomized groups. | M7, M12, M24, M36 | 
| Percentage of Patients Who Attain mUFC ≤1.0 x ULN or Have at Least 50 % Reduction From Baseline in mUFC | Controlled responder: mUFC ≤ 1.0×ULN. Partially controlled responder: at least 50% reduction in mUFC from Baseline, and mUFC >1.0×ULN. | M7, M12, M24, M36 | 
| Percentage of Patients Who Are Controlled Responders (mUFC ≤ 1.0 xULN) on at Least 4 of the 7 mUFC Assessments by Month 7 & on at Least 7 of the 12 mUFC Assessments by Month 12. | Percentage of patients with mUFC ≤ 1.0 x ULN at a minimum of 4 months up to and including Month 7, and at a minimum of 7 months up to and including Month 12 by randomized groups. | Month 7, Month 12 | 
| Percentage of Patients With Uncontrolled Response at Month 7 & Month 12 Within the Subset of Patients Who Had Uncontrolled Response at a) Months 1 and 2; b) Months 1, 2, and 3 | Percentage of patients with mUFC > 1.0 xULN at Month 7 and Month 12 within the subset of patients who were uncontrolled at a) Months 1 & 2, b) Months 1, 2, & 3 by randomized groups. | Month 7, Month12 | 
| Percent of Participants Attaining a mUFC ≤ 1.0 x ULN or at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points | Time to first achievement of attaining a mUFC ≤ 1.0 x ULN or at least a 50% reduction in mUFC from baseline by randomized groups. | Momth 7, Month 12 | 
| Percent of Participants Attaining a Duration of Controlled or Partially Controlled Response at Indicated Time Points | 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% for the first time. | Month 6, 12, 18 | 
| Percentage Change From Baseline on Plasma Adrenocorticotropic Hormone (ACTH) Over Time | Percentage change in ACTH (pmol/L) from Baseline by randomized groups. | Months 7, 12, 24 & 36 | 
| Percentage Change From Baseline on Serum Cortisol Over Time | Percentage change in serum cortisol (nmol/L) from Baseline by randomized groups. | Months 7, 12, 24 & 36 | 
| Actual Change From Baseline in Clinical Signs Over Time: Blood Pressure | Change in blood pressure measurements from Baseline | Month 7 | 
| Actual Change From Baseline in Clinical Signs Over Time: Body Mass Index (BMI) | Change in BMI measurements from Baseline | Month 7 | 
| Actual Change From Baseline in Clinical Signs Over Time: Weight | Change in weight measurements from Baseline | Month 7 | 
| Actual Change From Baseline in Clinical Signs Over Time: Body Composition: Region | Change in body composition: region measurements from Baseline | Month 7 | 
| Actual Change From Baseline in Clinical Signs Over Time: Waist Circumference | Change in waist circumference measurements from Baseline | Month 7 | 
| Actual Change From Baseline in Clinical Signs Over Time: Cholesterol & Triglycerides | Change in parameter measurements: cholesterol & triglycerides from Baseline | Month 7 | 
| Percentage Change From Baseline in Clinical Signs Over Time | Percentage change in parameter measurements: blood pressure, body mass index, waist circumference, fasting serum lipid profile, weight, bone density and body composition (examined by DXA scan) from Baseline | Month 7 | 
| Percentage of Participants Having a Favorable Shift From Baseline in Clinical Signs | This includes patients with improvements in symptoms from baseline. Clinical signs over time include: facial rubor, fat pads, hirsutism, striae, (via photographs by a second local physician who was blinded to the treatment dose and time point of the photograph) and muscle strength. | Month 7 | 
| Percentage of Participants That Attained a Mean Urinary Free Cortisol (mUFC) <= 1.0 x Upper Limit of Normal (ULN) at Month 7 Regardless of Dose Up-titration at Month 4. | All of the participants who discontinued prior to month 4 evaluations were classed as non-responders. For participants missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value. Analysis split by screening strata of mUFC Stratum 1: mUFC 1.5x to < 2.0 x ULN Stratum 2: mUFC 2.0x to <= 5.0 x ULN | Month 7 | 
| Percentage of Patients That Attain a Reduction of at Least 50% in mUFC From Baseline | All of the participants who discontinued prior to month 4 evaluations were classed as non-responders. For participants missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value. Analysis split by screening strata of mUFC Stratum 1: | Months 7, 12, 24 & 36 | 
| Percent of Participants Attaining a Time to First Achievement of at Least a 50% Reduction in mUFC From Baseline at Indicated Time Points | Time to first achievement of a 5by randomized groups.0% reduction in mUFC from baseline | every month in the core phase and every 3 months in the extension phase) up to and including the cut-off date for the Month 12 CSR (10-Nov-2015) | 
| Percent of Participants With a Duration of at Least 50% Reduction in mUFC From Baseline at Indicated Time Points | Duration of 50% reduction from baseline is defined as the period starting from the date of patient's first 50% reduction from baseline | Months 6, 12 & 18 | 
| Pharmacokinetic (PK) Parameter: Ctrough | Pasireotide trough levels (Ctrough) was 1 of the parameters used for PK assessments. Ctrough is the pre-dose PK concentration with an elapsed time from previous injection of 28+/-2 days. All patients randomized to the study had at least 1 PK observation & were therefore included in the pharmacokinetic analysis set. PK observations with missing concentrations, missing dose, missing elapsed time or an elapsed time from previous injection outside of 28 ±2 days window were excluded. Given that SOM230 LAR was administered once a month, Ctrough was collected every 28 days and thus this provides a summary of Ctrough values provided by incident dose (last dose administered prior to PK sample collection), not by randomized dose, hence each column is equivalent to an incident dose & not an arm/group. Patients randomized to either 10mg or 30mg could be titrated down to 5mg due to safety, or titrated up to 40mg, hence the 4 incident doses/columns that were allowed per protocol during this study. | Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337 | 
| Pharmacokinetic (PK) Parameter: Cmax | Pasireotide peak levels (Cmax) was one of the parameters used for PK assessments. Cmax is the post-dose PK concentration with an elapsed time from the previous injection of 21+/-2 days. All patients randomized to the study had at least one PK observation and were therefore included in the pharmacokinetic analysis set (PAS). Cmax PK observations (Day 20 and Day 104) with an elapsed time from the previous injection outside of 21+/-2 days window were excluded. Given that SOM230 LAR was administered once a month, the Cmax were collected every 28 days in this study, thus this provides a summary of Cmax values provided by incident dose (last dose administered prior to PK sample collection), not by randomized dose, hence each column is equivalent to an incident dose and not an arm/group. Patients randomized to either the 10mg or 30mg could be titrated down to 5mg due to safety, or titrated up to 40mg, hence the 4 incident doses/columns that were allowed per protocol during this study. | Days 22, 106, 190 | 
| Actual Change in Standardized Score of Cushing's Disease HRQoL (CushingQOL) Score From Baseline | CushingQol is a disease-specific patient-reported outcome instrument. It is a single-domain 12 item Cushing's disease quality of life instrument. The Cushing's syndrome quality of life (CushingQoL) questionnaire is a single domain questionnaire which includes 12 self-report items scored using a five point Likert scale anchored at (1=always/very much and 5=never/not at all). The patient is asked to report what they think or feel about their Cushing's syndrome and how much the illness has interfered in usual activities over the past 4 weeks. The total score is standardized on a 0-100 scale with lower scores indicating a greater impact on quality of life. | Months 7, 12, 24 & 36 | 
| Actual Change in SF-12v2 Score From Baseline - Mental Component Summary | 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. | Months 7, 12 & 24 | 
| Actual Change in SF-12v2 Score From Baseline - Physical Component Summary | 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. | Months 7, 12 & 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SOM230, Cushing's Disease, Mean Urinary Free Cortisol, Pasireotide, Pasireotide LAR, Pasireotide long-acting release, secondary hypercortisolism, secondary hypercorticism, Itsenko-Cushing disease, increased secretion of adrenocorticotropic hormone (ACTH), hyperpituitarism