Safety and Efficacy of Different Dose Levels of Pasireotide in Patients With de Novo, Persistent or Recurrent Cushing's Disease

• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This study will evaluate the safety and efficacy of two different doses of Pasireotide in patients with de novo or recurrent/persistent Cushing's Disease.

Condition or disease	Intervention/treatment	Phase
Cushing's Disease	Drug: Pasireotide	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	162 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Randomized, Double-blind Study to Assess the Safety and Efficacy of Different Dose Levels of Pasireotide (SOM230) Subcutaneous (sc) Over a 6 Month Treatment Period in Patients With de Novo, Persistent or Recurrent Cushing's Disease
Study Start Date :	December 2006
Actual Primary Completion Date :	March 2010
Actual Study Completion Date :	May 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pasireotide 600 ug; At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	Drug: Pasireotide
Experimental: Pasireotide 900 ug; At randomization, participants received 900 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.	Drug: Pasireotide

Outcome Measures

Primary Outcome Measures :

1. Number of mUFC (Urinary Free Cortisol) Responders by Randomized Dose Group [ Time Frame: 6 months ]
   A responder in the primary efficacy analysis was a patient with a mUFC≤ULN at Month 6 and whose dose was not increased prior to Month 6.

Secondary Outcome Measures :

1. Change From Baseline in mUFC [ Time Frame: baseline, 3 months, 12 months ]
   Twenty four hour urine samples were collected to obtain mUFC measurements. A negative change from baseline indicates improvement.
2. Time to First UFC Response [ Time Frame: 12 months ]
   Time to first UFC response is defined as the number of months from baseline to first attainment of UFC response.
3. Percent Change From Baseline in Serum Cortisol [ Time Frame: baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78 months ]
   Blood samlpes were drawn to obtain serum cortisol levels. A negative change from baseline indicates improvement.
4. Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH) [ Time Frame: baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78 months ]
   Blood samples were drawn to obtain ACTH levels. A negative change from baseline indicates improvement.
5. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP) [ Time Frame: baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 ]
   Sitting blood pressure assessments were performed at every study visit. A negative change from baseline indicates improvement.
6. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI) [ Time Frame: baseline, month 3, month 6, month 12, month 24, month 36, month 48 and month 60 ]
   BMI was determined by using height and weight measurements. A negative change from baseline indicates improvement.
7. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference [ Time Frame: baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 ]
   Waist circumference was measured with a measuring tape correctly positioned. A negative change from baseline indicates improvement.
8. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides [ Time Frame: baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 ]
   Blood samples were drawn to obtain total cholesterol and triglycerides' levels. A negative change from baseline indicates improvement.
9. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Beck Depression Inventory (BDI-II) Score [ Time Frame: baseline, month 3, month 6, month 12, month 18, month 24 ]

   The BDI-II is a 21 item self-report rating inventory measuring characteristic attitudes and symptoms of depression. The BDI-II contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The scores range as follows:

   0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; and 29-63: severe depression. A negative change from baseline indicates imrpovement.

10. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score [ Time Frame: baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 ]
    The Ferriman Gallwey scoring system is used to score the degree of excess male pattern body hair. The scorecard of every body location under survey begins from 0 (no excessive terminal hair growth) to 4 (extensive terminal hair growth) and the numbers are added up to a maximum count of 36. A score >= 6 indicates the hirsutism. A negative change from baseline indicates imrpovement.
11. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD) [ Time Frame: baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 ]
    BMD was measured using Lunar or Hologic dual-energy X-ray absorptiometry (DXA) Instruments. Measurements were done in the lumbar vertebrae (L1-L4), proximal femur (total hip) and proximal femur (femur neck). A negative change from baseline indicates imrpovement.
12. Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition [ Time Frame: baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60 ]
    Body composition as in percentage of body fat by region was assessed by total body scan. A negative change from baseline indicates improvement.
13. Change From Baseline in Tumor Volume [ Time Frame: baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78 months ]
    Pituitary magnetic resonance imaging (MRI) was performed to determine tumor volume. A negative change from baseline indicates imrpovement.
14. Percentage Change From Baseline in Health Related Quality of Life (HRQL) Score [ Time Frame: baseline, 3 months, 6 months, 12 months ]
    A Cushing's syndrome health related quality of life (HRQL) questionnaire was completed. The Cushing's Syndrome HRQL questionnaire contains 12 sentences with 5 possible answers each. The answers are based on Likert scales, with 5 response categories: Always, Often, Sometimes, Rarely and Never; or Very much, Quite a bit, Somewhat, Very little, and Not at all. The answers to each of the items are rated on a scale of 1 to 5. "1" corresponds to the response category "Always" or "Very much" and "5" corresponds to the category "Never" or "Not at all". The score is the sum of all item responses and can range from 12 to 60 points. The lower the score, the greater the Cushing's Syndrome impacts on HRQoL. A positive change from baseline indicates improvement.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria

• 18 years or greater
• Confirmed diagnosis of ACTH-dependent Cushing's disease
• Not considered candidate for pituitary surgery

Exclusion criteria

• History of pituitary irradiation in the last 10 years
• Cushing's syndrome not caused by pituitary tumor
• Patients with active malignant disease (cancer) in the last 5 years
• Women who are pregnant or lactating

Other protocol-defined inclusion/exclusion criteria apply.

Contacts and Locations

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Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

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Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Yedinak CG, Hopkins S, Williams J, Ibrahim A, Cetas JS, Fleseriu M. Medical Therapy with Pasireotide in Recurrent Cushing's Disease: Experience of Patients Treated for At Least 1 Year at a Single Center. Front Endocrinol (Lausanne). 2017 Feb 27;8:35. doi: 10.3389/fendo.2017.00035. eCollection 2017.

Schopohl J, Gu F, Rubens R, Van Gaal L, Bertherat J, Ligueros-Saylan M, Trovato A, Hughes G, Salgado LR, Boscaro M, Pivonello R; Pasireotide B2305 Study Group. Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing's disease: results from an open-ended, open-label extension trial. Pituitary. 2015 Oct;18(5):604-12. doi: 10.1007/s11102-014-0618-1.

MacKenzie Feder J, Bourdeau I, Vallette S, Beauregard H, Ste-Marie LG, Lacroix A. Pasireotide monotherapy in Cushing's disease: a single-centre experience with 5-year extension of phase III Trial. Pituitary. 2014 Dec;17(6):519-29. doi: 10.1007/s11102-013-0539-4.

Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Sen K, Salgado LR, Colao A, Biller BM; Pasireotide B2305 Study Group. High variability in baseline urinary free cortisol values in patients with Cushing's disease. Clin Endocrinol (Oxf). 2014 Feb;80(2):261-9. doi: 10.1111/cen.12259. Epub 2013 Jul 15.

Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR, Biller BM; Pasireotide B2305 Study Group. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med. 2012 Mar 8;366(10):914-24. doi: 10.1056/NEJMoa1105743. Erratum in: N Engl J Med. 2012 Aug 23;367(8):780.

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Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT00434148 History of Changes
Other Study ID Numbers:	CSOM230B2305; 2006-004111-22 ( EudraCT Number )
First Posted:	February 12, 2007
Results First Posted:	February 6, 2013
Last Update Posted:	March 8, 2016
Last Verified:	February 2016

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Cushing's Disease; pasireotide; SOM230

Additional relevant MeSH terms:

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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; Pasireotide; Somatostatin; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs