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

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

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.

Study Overview

• Status: Completed
• Conditions: Cushing's Disease
• Intervention / Treatment: Drug: Pasireotide

• Study Type: Interventional
• Enrollment (Actual): 162
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1405BCH
    • Novartis Investigative Site
  • Buenos Aires, Argentina, C1232AAC
    • Novartis Investigative Site
  • Buenos Aires
    • Capital Federal, Buenos Aires, Argentina, 1425EKP
      • Novartis Investigative Site
• Belgium
  • Edegem, Belgium, 2650
    • Novartis Investigative Site
  • Gent, Belgium, 9000
    • Novartis Investigative Site
• Brazil
  • PR
    • Curitiba, PR, Brazil, 80060-900
      • Novartis Investigative Site
  • RJ
    • Rio de Janeiro, RJ, Brazil, 21941-913
      • Novartis Investigative Site
  • RS
    • Porto Alegre, RS, Brazil, 90560-030
      • Novartis Investigative Site
  • SP
    • Ribeirao Preto, SP, Brazil, 14048-900
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 05403-000
      • Novartis Investigative Site
    • São Paulo, SP, Brazil, 01401-901
      • Novartis Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2S2
      • Novartis Investigative Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H2W 1T8
      • Novartis Investigative Site
• China
  • Beijing, China, 100028
    • Novartis Investigative Site
  • Shanghai, China, 200025
    • Novartis Investigative Site
  • Beijing
    • Beijing, Beijing, China, 100730
      • Novartis Investigative Site
• Denmark
  • Arhus, Denmark, 8000
    • Novartis Investigative Site
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
  • Herlev, Denmark, DK-2730
    • Novartis Investigative Site
• Finland
  • Helsinki, Finland, FIN-00290
    • Novartis Investigative Site
• France
  • Angers, France, 49033
    • Novartis Investigative Site
  • Grenoble Cédex 9, France, 38043
    • Novartis Investigative Site
  • LILLE Cedex, France, 59037
    • Novartis Investigative Site
  • Limoges cedex, France, 87042
    • Novartis Investigative Site
  • Marseille cedex 05, France, 13385
    • Novartis Investigative Site
  • Paris, France, 75014
    • Novartis Investigative Site
  • Pessac Cedex, France, 33604
    • Novartis Investigative Site
  • St Priest en Jarez Cedex, France, 42277
    • Novartis Investigative Site
  • Toulouse Cedex 9, France, 31000
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 10098
    • Novartis Investigative Site
  • Essen, Germany, 45122
    • Novartis Investigative Site
  • Muenchen, Germany, 80336
    • Novartis Investigative Site
  • Würzburg, Germany, 97080
    • Novartis Investigative Site
• Greece
  • GR
    • Athens, GR, Greece, 115 27
      • Novartis Investigative Site
    • Athens, GR, Greece, 105 52
      • Novartis Investigative Site
• Israel
  • Haifa, Israel, 3339419
    • Novartis Investigative Site
  • Heifa, Israel, 35152
    • Novartis Investigative Site
  • Jerusalem, Israel, 9112001
    • Novartis Investigative Site
  • Petach Tikva, Israel, 49100
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • AN
    • Ancona, AN, Italy, 60126
      • Novartis Investigative Site
  • FE
    • Cona, FE, Italy, 44100
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
    • Milano, MI, Italy, 20149
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
  • PI
    • Pisa, PI, Italy, 56124
      • Novartis Investigative Site
  • TO
    • Orbassano, TO, Italy, 10043
      • Novartis Investigative Site
    • Torino, TO, Italy, 10126
      • Novartis Investigative Site
• Mexico
  • Distrito Federal
    • México, Distrito Federal, Mexico, 14269
      • Novartis Investigative Site
    • México, Distrito Federal, Mexico, 06720
      • Novartis Investigative Site
• Poland
  • Warszawa, Poland, 01 809
    • Novartis Investigative Site
• Portugal
  • Porto, Portugal, 4200-319
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08041
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Balcova / Izmir, Turkey, 35340
    • Novartis Investigative Site
  • Fatih / Istanbul, Turkey, 34098
    • Novartis Investigative Site
• United States
  • California
    • Stanford, California, United States, 94304
      • Stanford University Medical Center Stanford Cancer Center (3)
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University Chicago Hospital Dept. of Univ of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute The Melanoma Program
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center- New York Presbyterian Columbia University DeptofMed
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation Dept. of Cleveland Clinic (6)
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Sciences University Dept.ofOregonHealth&SciencesU.
  • Texas
    • Dallas, Texas, United States, 75390-8527
      • University of Texas Southwestern Medical Center Clinical-TranslationalRes.Ctr.
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(8)
  • Washington
    • Seattle, Washington, United States
      • Swedish Medical Center Dept.ofSeattle Neuroscience(2)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of mUFC (Urinary Free Cortisol) Responders by Randomized Dose Group	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.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in mUFC	Twenty four hour urine samples were collected to obtain mUFC measurements. A negative change from baseline indicates improvement.	baseline, 3 months, 12 months
Time to First UFC Response	Time to first UFC response is defined as the number of months from baseline to first attainment of UFC response.	12 months
Percent Change From Baseline in Serum Cortisol	Blood samlpes were drawn to obtain serum cortisol levels. A negative change from baseline indicates improvement.	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
Percent Change From Baseline in Mean Adrenocorticotropic Hormone (ACTH)	Blood samples were drawn to obtain ACTH levels. A negative change from baseline indicates improvement.	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
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Sitting Sytolic Blood Pressure (SBP) and Sitting Diastolic Blood Pressure (DBP)	Sitting blood pressure assessments were performed at every study visit. A negative change from baseline indicates improvement.	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Mass Index (BMI)	BMI was determined by using height and weight measurements. A negative change from baseline indicates improvement.	baseline, month 3, month 6, month 12, month 24, month 36, month 48 and month 60
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Waist Circumference	Waist circumference was measured with a measuring tape correctly positioned. A negative change from baseline indicates improvement.	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Total Cholesterol and Triglycerides	Blood samples were drawn to obtain total cholesterol and triglycerides' levels. A negative change from baseline indicates improvement.	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Beck Depression Inventory (BDI-II) Score	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.	baseline, month 3, month 6, month 12, month 18, month 24
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Ferriman-Galway Hirsutism Score	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.	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Bone Mineral Density (BMD)	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.	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
Mean Change From Baseline in Clinical Signs and Symptoms of Cushing's Disease: Body Composition	Body composition as in percentage of body fat by region was assessed by total body scan. A negative change from baseline indicates improvement.	baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
Change From Baseline in Tumor Volume	Pituitary magnetic resonance imaging (MRI) was performed to determine tumor volume. A negative change from baseline indicates imrpovement.	baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78 months
Percentage Change From Baseline in Health Related Quality of Life (HRQL) Score	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.	baseline, 3 months, 6 months, 12 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Lacroix A, Gu F, Schopohl J, Kandra A, Pedroncelli AM, Jin L, Pivonello R. Pasireotide treatment significantly reduces tumor volume in patients with Cushing's disease: results from a Phase 3 study. Pituitary. 2020 Jun;23(3):203-211. doi: 10.1007/s11102-019-01021-2.
• 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.

Helpful Links

• Visit NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.
• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: February 9, 2007
• First Submitted That Met QC Criteria: February 9, 2007
• First Posted (Estimate): February 12, 2007

Study Record Updates

• Last Update Posted (Estimate): March 8, 2016
• Last Update Submitted That Met QC Criteria: February 5, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: SOM230; Cushing's Disease; pasireotide
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Hypothalamic Diseases; Hyperpituitarism; Pituitary Diseases; Adenoma; Pituitary Neoplasms; ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pasireotide
• Other Study ID Numbers: CSOM230B2305; 2006-004111-22 (EudraCT Number)