Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease
- Conditions
- Cushings Disease
- Interventions
- Registration Number
- NCT01915303
- Lead Sponsor
- Novartis Pharmaceuticals
- 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
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 68
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description pasireotide +/- cabergoline Pasireotide with or without cabergoline pasireotide alone or with cabergoline
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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 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)
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.
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.
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
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
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.
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
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
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.
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 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 - 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 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 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
Trial Locations
- Locations (3)
Oregon Health and Science University SOM230B2411
🇺🇸Portland, Oregon, United States
Novartis Investigative Site
🇹🇷Pendik / Istanbul, Turkey
University of Alabama at Birmingham The Kirklin Clinic
🇺🇸Birmingham, Alabama, United States