Cushings DiseasePhase 2NCT01915303
Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease
A Phase 2 study testing Pasireotide with or without cabergoline in people with Cushings Disease, run by Novartis Pharmaceuticals at 29 sites in 16 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cushings Disease
- What is being tested?
- Pasireotide with or without cabergoline
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 68 participants
- Where
- 29 sitesin 16 countries
- Study dates
- 6 Mar 2014to 4 Sep 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Show all 17Show fewer
- 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.
Who cannot join
- 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
Show all 24Show fewer
- 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
Trial locations and contacts
29 sites in 16 countries.
29 sites in 16 countries
Brazil4 sites
Novartis Investigative Site
Curitiba, Paraná, 80030-110
Novartis Investigative Site
Porto Alegre, Rio Grande do Sul, 90560-030
Novartis Investigative Site
Rio de Janeiro, Rio de Janeiro, 21941-913
Novartis Investigative Site
São Paulo, São Paulo, 05403 000
India3 sites
Novartis Investigative Site
Chandigarh, 160 012
Novartis Investigative Site
New Delhi, 110029
Novartis Investigative Site
Vellore, Tamil Nadu, 632004
Turkey (Türkiye)3 sites
Novartis Investigative Site
Istanbul, TUR, 34098
Novartis Investigative Site
Izmir, 35340
Novartis Investigative Site
Pendik / Istanbul, Turkey, 34899
United States2 sites
University of Alabama at Birmingham The Kirklin Clinic
Birmingham, Alabama, 35294
Oregon Health and Science University SOM230B2411
Portland, Oregon, 97239
Belgium2 sites
Novartis Investigative Site
Ghent, 9000
Novartis Investigative Site
Leuven, 3000
Greece2 sites
Novartis Investigative Site
Athens, 106 76
Novartis Investigative Site
Thessaloniki, GR 54636
Hungary2 sites
Novartis Investigative Site
Budapest, 1062
Novartis Investigative Site
Budapest, 1085
Mexico2 sites
Novartis Investigative Site
Durango, 34270
Novartis Investigative Site
Mexico City, Mexico City, 14269
Spain2 sites
Novartis Investigative Site
Alzira, Valencia, 46600
Novartis Investigative Site
Málaga, Andalusia, 29010
About this study
Official title: 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
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.
Read the 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
- Conditions
- Cushings Disease
- Being tested
- Pasireotide with or without cabergoline
- Keywords
- pituitary tumors, pasireotide, cabergoline, combination treatment, UFC, hormone disorder, cortisol, adrenocorticotropic hormone, Cushing Disease
- Medical subject headings
- Adrenocortical Hyperfunction, Pituitary Neoplasms, Pituitary ACTH Hypersecretion
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Pasireotide with or without cabergolineDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| pasireotide +/- cabergoline | Experimental | pasireotide alone or with cabergoline Receives: Drug: Pasireotide with or without cabergoline |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline up to week 35
Secondary outcomes (21)
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.
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.
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.
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
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: Baseline and week 35
Body Weight at Week 35
Weight was was one of the measures of clinical symptoms of CD
Measured: 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)
Measured: Baseline and week 35
Waist Circumference at Week 35
Waist circumference was one of the measurements of clinical signs of CD
Measured: 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
Measured: 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
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
- - able to stand after several efforts without using arms as assistance 0. - able to stand easily with arms extended
Measured: Baseline up to week 267
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Aug 2013 (estimated)
- Study start6 Mar 2014
- Primary completion5 Sep 2016
- Study completion4 Sep 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cushings DiseaseStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 68 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01915303
- Sponsor's protocol ID
- CSOM230B2411
- Status last verified
- Aug 2020
- First submitted
- 10 Jun 2013
- Last updated
- 18 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Publications
Feelders RA, Fleseriu M, Kadioglu P, Bex M, Gonzalez-Devia D, Boguszewski CL, Yavuz DG, Patino H, Pedroncelli AM, Maamari R, Chattopadhyay A, Biller BMK, Pivonello R. Long-term efficacy and safety of subcutaneous pasireotide alone or in combination with cabergoline in Cushing's disease. Front Endocrinol (Lausanne). 2023 Oct 9;14:1165681. doi: 10.3389/fendo.2023.1165681. eCollection 2023.
PubMed 37876540
Study at a glance
From the registry record, last updated by the sponsor on 18 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT01915303
- Acronym / sponsor ID
- CSOM230B2411
- Conditions
- Cushings Disease
- Keywords
- pituitary tumors, pasireotide, cabergoline, combination treatment, UFC, hormone disorder, cortisol, adrenocorticotropic hormone
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Terminated
- Enrolment
- 68 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 6 Mar 2014 (actual)
- Primary completion
- 5 Sep 2016 (actual)
- Study completion
- 4 Sep 2019 (actual)
- First posted
- 2 Aug 2013 (estimated)
- Results
- Posted 18 Sep 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| pasireotide +/- cabergoline | Experimental | Drug: Pasireotide with or without cabergolinepasireotide alone or with cabergoline |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- 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:
- 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)
Key exclusion criteria (24 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pasireotide with or without cabergolineThe 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. | Drug | pasireotide +/- cabergoline |
Primary outcome
Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35
Time frame: 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.
21 secondary outcomes
Mean Urinary Free Cortisol (mUFC) at Scheduled Visits
Time frame: 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
Time frame: 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
Time frame: Baseline up to week 235
Duration (Weeks) of Controlled or Partially Controlled Response
Time frame: 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)
Time frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Serum Cortisol Levels
Time frame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
Sitting Systolic Blood Pressure at Week 35
Time frame: Baseline and week 35
Sitting Diastolic Blood Pressure at Week 35
Time frame: Baseline and week 35
Body Weight at Week 35
Time frame: Baseline and week 35
Body Mass Index at Week 35
Time frame: Baseline and week 35
Waist Circumference at Week 35
Time frame: Baseline and week 35
LDL, HDL and Total Cholesterol at Week 35
Time frame: Baseline and week 35
Mean Scores of Cushing QoL Standardized Score at Week 17 and 35
Time frame: Baseline and week 17 and 35
Mean Scores of SF-12v2 Domain Scores at Week 17 and 35
Time frame: Baseline, week 17 and 35
Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline up to week 267
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37876540Feelders RA, Fleseriu M, Kadioglu P, Bex M, Gonzalez-Devia D, Boguszewski CL, Yavuz DG, Patino H, Pedroncelli AM, Maamari R, Chattopadhyay A, Biller BMK, Pivonello R. Long-term efficacy and safety of subcutaneous pasireotide alone or in combination with cabergoline in Cushing's disease. Front Endocrinol (Lausanne). 2023 Oct 9;14:1165681. doi: 10.3389/fendo.2023.1165681. eCollection 2023.
- Individual participant dataSharing planned: Yes. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
29 sites in 16 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pasireotide with or without cabergoline in people with Cushings Disease, run by Novartis Pharmaceuticals at 29 sites in 16 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 18 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 29 sites in Brazil, India, Turkey (Türkiye), United States, Belgium and 11 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35 (time frame: Baseline up to week 35). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01915303, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Sep 2020.