Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease (MACS2125)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01915303
First received: June 10, 2013
Last updated: June 2, 2014
Last verified: June 2014
  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
Drug: Cabergoline
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
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:
  • mUFC [ 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 in Group 1

  • mUFC [ Time Frame: at week 17 ] [ Designated as safety issue: No ]
    Proportion of patients who attain a mUFC ≤ 1.0 x ULN at week 17 with pasireotide with combination of cabergoline in Group 2


Secondary Outcome Measures:
  • Percentage change in mUFC from baseline to study end at each scheduled visit when UFC is measured [ Time Frame: at weeks 0, 4, 8, 13, 17, 22, 26, 31, 35 for group 1 ] [ Designated as safety issue: No ]
    Percentage change in mUFC from baseline to study end at each scheduled visit when UFC is measured for Group 1 patients

  • Proportion of patients attain mUFC ≤ 1.0 x ULN as assessed at each scheduled visit when UFC is measured [ Time Frame: at weeks 0, 4, 8, 13, 17, 22, 26, 31, 35 for group 1 ] [ 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 for Group 1 patients

  • 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 0, 4, 8, 13, 17, 22, 26, 31, 35 for group 1 ] [ 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 for Group 1 patients

  • 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 for Group 1 and Group 2 patients, separately

  • Change from baseline in plasma ACTH and serum cortisol over time [ Time Frame: at baseline visit and weeks 0, 4, 8, 13, 17, 22, 26, 31 and 35 for group 1 ] [ Designated as safety issue: No ]
    Change from baseline in plasma ACTH and serum cortisol over time for Group 1 patients

  • Ctrough at baseline [ Time Frame: at baseline ] [ Designated as safety issue: Yes ]
    Ctrough at baseline for Group 2 patients only

  • Ctrough at week 8 [ Time Frame: at week 8 ] [ Designated as safety issue: Yes ]
    Ctrough at week 8 for Group 2 patients only

  • Ctrough [ Time Frame: at week 17 ] [ Designated as safety issue: Yes ]
    Ctrough at week 17 for Group 2 patients only

  • Cmax at baseline [ Time Frame: at baseline ] [ Designated as safety issue: Yes ]
    Cmax at baseline for Group 2 patients only

  • Cmax at week 8 [ Time Frame: at week 8 ] [ Designated as safety issue: Yes ]
    Cmax at week 8 for Group 2 patients only

  • Cmax [ Time Frame: at week 17 ] [ Designated as safety issue: Yes ]
    Cmax at week 17 for Group 2 patients only

  • Toxicity will be assessed using NCI-CTCAE v.4 and for laboratory assessments [ Time Frame: at screening, baseline visits, and at weeks 4, 8, 13, 17, 22, 26, 31, 35 and study completion visit ] [ Designated as safety issue: Yes ]
    Toxicity will be assessed using NCI-CTCAE v.4 and for laboratory assessments that include biochemistry, hematology, urinalysis; special safety assessments that include the regular monitoring and recording of blood glucose insulin, HbA1c, GH and IGF-1, thyroid and liver function tests, gallbladder examinations and ECGs. Concomitant medications/significant non-drug therapies will be assessed too for group 1 patients

  • Percentage change in mUFC from baseline to study end at each scheduled visit when UFC is measured [ Time Frame: at weeks 0, 4, 8, 13, 17 for group 2 ] [ Designated as safety issue: No ]
    Percentage change in mUFC from baseline to study end at each scheduled visit when UFC is measured for Group 1 patients

  • Proportion of patients attain mUFC ≤ 1.0 x ULN as assessed at each scheduled visit when UFC is measured [ Time Frame: at weeks 0, 4, 8, 13, 17 for group 2 ] [ Designated as safety issue: No ]
    Proportion of patients attain mUFC ≤ 1.0 x ULN as assessed at each scheduled visit when UFC is measured for group 2 patients

  • 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 0, 4, 8, 13, 17 for group 2 ] [ 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 for group 2 patients

  • Change from baseline in plasma ACTH and serum cortisol over time [ Time Frame: at baseline visit and weeks 0, 4, 8, 13, 17 ] [ Designated as safety issue: No ]
    Change from baseline in plasma ACTH and serum cortisol over time for group 2 patients

  • Toxicity will be assessed using NCI-CTCAE v.4 and for laboratory assessments [ Time Frame: at screening, baseline visits, and at weeks 4, 8, 13, 17 and study completion visit ] [ Designated as safety issue: Yes ]
    Toxicity will be assessed using NCI-CTCAE v.4 and for laboratory assessments that include biochemistry, hematology, urinalysis; special safety assessments that include the regular monitoring and recording of blood glucose insulin, HbA1c, GH and IGF-1, thyroid and liver function tests, gallbladder examinations and ECGs. Concomitant medications/significant non-drug therapies will be assessed too for group 2 patients


Estimated Enrollment: 128
Study Start Date: March 2014
Estimated Study Completion Date: November 2016
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1
Group 1 consists of patients who are not treated with pasireotide at screening.
Drug: Pasireotide
Group 1 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.
Drug: Cabergoline
Group 2 patients will immediately start the combination treatment by adding cabergoline 0.5mg once a day at study entry to their current 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.
Experimental: Group 2
Group 2 consists of patients who are currently treated with maximal tolerated doses of pasireotide monotherapy at 0.3mg, 0.6mg or 0.9mg twice a day for at least 8 weeks, but still with elevated UFC.
Drug: Pasireotide
Group 1 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.
Drug: Cabergoline
Group 2 patients will immediately start the combination treatment by adding cabergoline 0.5mg once a day at study entry to their current 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 will enroll two groups of patients. Pasireotide naive patients at the time of screening (Group 1), and patients receiving maximal tolerated dose of pasireotide at the time of screening (Group 2). Group 1 patients will begin study treatment of pasireotide at 0.6mg twice a day for 8 weeks. After 8 weeks, if cortisol level is not controlled and the dose is tolerated well, pasireotide will be increased to 0.9mg for another 8 weeks. If during or at the end of the 8 week period, cortisol level is still not controlled cabergoline will be added at 0.5mg once a day. Cabergoline can be increased up to 1.0mg once a day in combination with pasireotide. Group 2 patients will immediately begin combination treatment by adding cabergoline at 0.5mg once a day to the current pasireotide treatment. Cabergoline dose can be increased up to 1.0mg once a day if cortisol is not controlled at a lower dose.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria for Group 1:

  1. 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.
  2. 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)
  3. Male or female patients aged 18 years or greater
  4. Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is able to care for most of their personal needs)
  5. 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
  6. Patients have been on pasireotide in the past but discontinued because of lack of efficacy are also allowed to enter Group 1. Patients treated with pasireotide subcutaneously must have been discontinued from the treatment for at least 4 weeks before screening. Patients treated with pasireotide LAR must have been discontinued from the treatment for at least 12 weeks before screening.
  7. 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.

Inclusion criteria for Group 2:

  1. 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.
  2. 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)
  3. Patients currently treated with maximal tolerated doses of pasireotide for at least 8 weeks at the time of screening but have not achieved biochemical control. These patients will enter the study starting combination therapy.
  4. 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.

Exclusion criteria for Group 1 and Group 2:

  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
  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

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

  Show 64 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01915303     History of Changes
Other Study ID Numbers: CSOM230B2411
Study First Received: June 10, 2013
Last Updated: June 2, 2014
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:
Adrenal Gland Diseases
Cushing Syndrome
Pituitary ACTH Hypersecretion
Adrenocortical Hyperfunction
Endocrine System Diseases
Hyperpituitarism
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Adrenocorticotropic Hormone
Cabergoline
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Dopamine Agonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 24, 2014