Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease

Study Overview
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Brief Summary
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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
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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

Official Title
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A Phase II Trial to Assess the Efficacy and Safety of Pasireotide s.c. Alone or in Combination With Cabergoline in Patients With Cushing's Disease

Conditions
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Cushings Disease

Intervention / Treatment
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* Drug: Pasireotide with or without cabergoline


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Written informed consent obtained prior to screening procedures Adult patients with confirmed diagnosis of ACTH-dependent Cushing's disease as evidenced by all of the following: The mean of three 24-hour urine samples collected within 2 weeks > 1xULN with 2 out of 3 samples >ULN Morning plasma ACTH within the normal or above normal range 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. 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) Male or female patients aged 18 years or greater Karnofsky performance status ≥ 60 (i.e. required occasional assistance, but was able to care for most of their personal needs) 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 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 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. 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: Patients with compression of the optic chiasm that caused any visual field defect that required surgical intervention Diabetic patients with poor glycemic control as evidenced by HbA1c >8% 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. Patients with clinically significant valvular disease. Patients with Cushing's syndrome due to ectopic ACTH secretion Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia 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 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 Patients with serum creatinine >2.0 X ULN Patients with WBC <3 X 10e9/L; Hb 90% < LLN; PLT <100 X 10e9/L Patients with presence of Hepatitis B surface antigen (HbsAg) Patients with presence of Hepatitis C antibody test (anti-HCV) Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to pasireotide or cabergoline Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynauds syndrome. 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) Patients with end-stage renal failure and/or hemodialysis Patients with presence of active or suspected acute or chronic uncontrolled infection Patients with a history of non-complance to medical regimens or who were considered potentially unreliable or were unable to complete the entire study Patients with presence of Hepatitis B surface antigen (HbsAg) Patients with presence of Hepatitis C antibody test (anti-HCV) Patients with severe hepatic impairment (Child Pugh C) and hpersensitivity to pasireotide or cabergoline Patients with lung, pericardial, and retroperitoneal fibrosis; gastroduodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynaud's syndrome 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) Patients with end-stage renal failure and/or hemodialysis

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pasireotide +/- cabergoline<br>pasireotide alone or with cabergoline | Drug: Pasireotide with or without cabergoline<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to week 35 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension | 
| 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. | Baseline up to week 235 | 
| 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. | Baseline up to week 235 | 
| 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 | 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 | 
| Plasma Adrenocorticotropic Hormone (ACTH) | A pre-dose blood draw for plasma ACTH sampling was taken at visits. Samples were analyzed by a central laboratory. | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension | 
| 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. | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension | 
| 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 | Baseline and week 35 | 
| 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 | Baseline and week 35 | 
| Body Weight at Week 35 | Weight was was one of the measures of clinical symptoms of CD | Baseline and week 35 | 
| 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) | Baseline and week 35 | 
| Waist Circumference at Week 35 | Waist circumference was one of the measurements of clinical signs of CD | Baseline and week 35 | 
| 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 | Baseline and week 35 | 
| 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 | Baseline and week 17 and 35 | 
| 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. | Baseline, week 17 and 35 | 
| 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 | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension | 
| 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 | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension | 
| 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 | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension | 
| 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 | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension | 
| 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 | Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension | 
| 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 | Baseline, weeks 1, 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension | 
| 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 | Baseline up to week 267 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pituitary tumors, pasireotide, cabergoline, combination treatment, UFC, hormone disorder, cortisol, adrenocorticotropic hormone, Cushing Disease