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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01915303
First received: June 10, 2013
Last updated: July 25, 2016
Last verified: July 2016
  Purpose
This study is to assess whether pasireotide alone and combined with cabergoline will give reliefs on patients with recurrent, persistent and newly diagnosed Cushing's disease. The study will also assess study drug safety, the changes in Quality of Life and on clinical signs and symptoms of Cushing's disease.

Condition Intervention Phase
Cushing's Disease
Drug: Pasireotide with or without cabergoline
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Proportion of patients who attain mUFC ≤1.0 ULN at week 35 with pasireotide alone or in combination with cabergoline [ Time Frame: at week 35 ] [ Designated as safety issue: No ]
    Proportion of patients who attain mUFC ≤ 1.0 x ULN at week 35 with pasireotide alone or in combination with cabergoline


Secondary Outcome Measures:
  • Percentage change in mUFC from baseline to study end at each scheduled visit when UFC is measured [ Time Frame: at weeks 4, 8, 13, 17, 22, 26, 31, 35 ] [ Designated as safety issue: No ]
    Percentage change in mUFC from baseline to study end at each scheduled visit when UFC is measured

  • Proportion of patients attain mUFC ≤ 1.0 x ULN as assessed at each scheduled visit when UFC is measured [ Time Frame: at weeks 4, 8, 13, 17, 22, 26, 31 ] [ Designated as safety issue: No ]
    Proportion of patients that attain mUFC ≤ 1.0 x ULN as assessed at each scheduled visit when UFC is measured

  • Proportion of patients who attain mUFC ≤ 1.0 x ULN or have at least 50% reduction from baseline in mUFC as assessed at each scheduled visit when UFC is measured [ Time Frame: at weeks 4, 8, 13, 17, 22, 26, 31, 35 ] [ Designated as safety issue: No ]
    Proportion of patients who attain mUFC ≤ 1.0 x ULN or have at least 50% reduction from baseline in mUFC as assessed at each scheduled visit when UFC is measured

  • Duration 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 ] [ Designated as safety issue: No ]
    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

  • Change from baseline in plasma ACTH and serum cortisol over time [ Time Frame: at 4, 8, 13, 17, 22, 26, 31 and 35 ] [ Designated as safety issue: No ]
    Change from baseline in plasma ACTH and serum cortisol over time

  • Toxicity will be assessed using NCI-CTCAE v.4 and for laboratory assessments [ Time Frame: at baseline visits, and at weeks 4, 8, 13, 17, 22, 26, 31, 35 and study completion visit ] [ Designated as safety issue: Yes ]
    Shift tables using CTC grades to compare baseline to the worst post-baseline value


Enrollment: 69
Study Start Date: March 2014
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: pasireotide +/- cabergoline
pasireotide alone or with cabergoline
Drug: Pasireotide with or without cabergoline
The trial consists of Pasireotide-untreated patients will start pasireotide 0.6mg twice a day for 8 weeks. If biochemical control is not achieved by the end of the 8 weeks, and the 0.6mg dose is well-tolerated, the dose will be increased to 0.9mg twice a day for another 8 weeks. If biochemical control is not achieved, cabergoline will be added and patients will begin 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 wlil be increased to 1.0mg once a day. Patients can 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 will continue with the combination treatment for 8 weeks. If biochemical control is not achieved by the end of the 8 week period, the dose of cabergoline will be increased to 1mg once a day.

Detailed Description:
This study is to assess whether pasireotide alone and combined with cabergoline will give reliefs on patients with recurrent, persistent and newly diagnosed Cushing's disease. The study will also assess study drug safety, the changes in Quality of Life and on clinical signs and symptoms of Cushing's disease. The study consists pasireotide-untreated patients at screening and patients currently treated with maximal tolerated doses of pasireotide. Core phase will consist of pasireotide-untreated patients at screening - this includes patients who have never received pasireotide or patients who have received pasireotide sometime in the past but it was not discontinued because of safety. These patients will start pasireotide at 0.6mg twice a day for 8 weeks. Should biochemical control not be achieved the dose will be increased to 0.9mg twice a day. If biochemical control is still not achieved, cabergoline at increasing dose will be added. Patients currently treated with maximal tolerated doses of pasireotide monotherapy for at least 8 weeks at 0.3mg twice a day, 0.6mg twice a day or 0.9mg twice a day, but still did not achieve biochemical control will add cabergoline at increasing dose. After 35 weeks of treatment at core phase, patients will have the option to continue study treatment in extension phase if pasireotide is not yet approved for commercial use and/or reimbursed - if country reimbursement is applicable.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. Written informed consent obtaine prior to screening procedures
  2. Adult patients with confirmed diagnosis of ACTH-dependent Cushing's disease as evidenced by all of the following:

    1. The mean of three 24-hour urine samples collected within 2 weeks > 1xULN with 2 out of 3 samples >ULN
    2. Morning plasma ACTH within the normal or above normal range
    3. 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 is required. If IPSS had not previously been performed, IPSS with CRH stimulation is required.
  3. Patients with de novo Cushing's disease can be included only if they are not considered candidates for pituitary surgery (e.g. poor surgical candidates, surgically unapproachable tumors, patients who refuse to have surgical treatment)
  4. Male or female patients aged 18 years or greater
  5. Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is able to care for most of their personal needs)
  6. 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
    • Progesterone receptor antagonist (mifepristone): 4 weeks
  7. Patients can be considered to enter the trial if they meet any one of the following criteria: 1) They are naive to pasireotide 2) They have 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 are on maximal tolerated dose but have not achieved biochemical control
  8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, if they are using highly effective methods of contraception during dosing and for 30 days after stopping study medication.
  9. Male participants in the trial must agree 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:

  1. Patients with compression of the optic chiasm causing any visual field defect that requires surgical intervention
  2. Diabetic patients with poor glycemic control as evidenced by HbA1c >8%
  3. 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.
  4. Patients with clinically significant valvular disease.
  5. Patients with Cushing's syndrome due to ectopic ACTH secretion
  6. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia
  7. Patients who have 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
  8. 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
  9. Patients with serum creatinine >2.0 X ULN
  10. Patients with WBC <3 X 10e9/L; Hb 90% < LLN; PLT <100 X 10e9/L
  11. Patients with presence of Hepatitis B surface antigen (HbsAg)
  12. Patients with presence of Hepatitis C antibody test (anti-HCV)
  13. Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to pasireotide or cabergoline
  14. Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynauds syndrome.
  15. Pregnant or nursing (lactating) women where pregnancy is 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)
  16. Patients with end-stage renal failure and/or hemodialysis
  17. Patients with presence of active or suspected acute or chronic uncontrolled infection
  18. Patients with a history of non-complance to medical regimens or who are considered potentially unreliable or whill be unable to complete the entire study
  19. Patients with presence of Hepatitis B surface antigen (HbsAg)
  20. Patients with presence of Hepatitis C antibody test (anti-HCV)
  21. Patients with severe hepatic impairment (Child Pugh C) and hpersensitivity to pasireotide or cabergoline
  22. Patients with lung, pericardial, and retroperitoneal fibrosis; gastroduodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynaud's syndrome
  23. Pregnant or nursing (lactating) women where pregnancy is defined as the state of a female after conception and until the terminiation of gestation, confirmed by a positive hCG laboratory test (> 5mIU/mL)
  24. Patients with end-stage renal failure and/or hemodialysis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01915303

  Show 33 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01915303     History of Changes
Other Study ID Numbers: CSOM230B2411 
Study First Received: June 10, 2013
Last Updated: July 25, 2016
Health Authority: United States: Food and Drug Administration
Australia: National Health and Medical Research Council
Brazil: Ministry of Health
Colombia: National Institutes of Health
Venezuela: Ministry of Health and Social Development
India: Ministry of Health
Turkey: Ministry of Health
United States: Institutional Review Board
Bulgaria: Bulgarian Drug Agency
Belgium: Federal Agency for Medicinal Products and Health Products
Hungary: National Institute of Pharmacy
Netherlands: Dutch Healthcare Authority
Germany: Ethics Commission
Germany: Ministry of Health
Greece: Ethics Committee
Greece: Ministry of Health and Welfare
Spain: Ethics Committee
Spain: Ministry of Health
France: Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé
Italy: The Italian Medicines Agency
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica

Keywords provided by Novartis:
Cushing's disease, pituitary tumors, pasireotide, cabergoline, combination treatment, UFC, hormone disorder, cortisol, adrenocorticotropic hormone

Additional relevant MeSH terms:
Pituitary ACTH Hypersecretion
ACTH-Secreting Pituitary Adenoma
Hyperpituitarism
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Endocrine System Diseases
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Pituitary Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Cabergoline
Antineoplastic Agents
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 29, 2016