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

NCT01915303 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: CSOM230B2411
• Study Type: interventional
• Target: 68
• Locations: 16 countries
• Sites: 29

Brief 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.

Conditions

Cushings Disease

Keywords

pituitary tumors; pasireotide; cabergoline; combination treatment; UFC; hormone disorder; cortisol; adrenocorticotropic hormone; Cushing Disease

Outcome Measures

Primary Outcomes (1)

• 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.

  Baseline up to week 35

Secondary Outcomes (21)

• Mean Urinary Free Cortisol (mUFC) at Scheduled Visits

  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

  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

  Baseline up to week 235

• Duration (Weeks) of Controlled or Partially Controlled Response

  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)

  Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension

Study Arms (1)

pasireotide +/- cabergoline

EXPERIMENTAL

pasireotide alone or with cabergoline

Drug: Pasireotide with or without cabergoline

Interventions

Pasireotide with or without cabergoline DRUG

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.

pasireotide +/- cabergoline

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• 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

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (29)

University of Alabama at Birmingham The Kirklin Clinic

Birmingham, Alabama, 35294, United States

Location

Oregon Health and Science University SOM230B2411

Portland, Oregon, 97239, United States

Location

Novartis Investigative Site

Caba, Buenos Aires, C1280AEB, Argentina

Location

Novartis Investigative Site

Ghent, 9000, Belgium

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Curitiba, Paraná, 80030-110, Brazil

Location

Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, 21941-913, Brazil

Location

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, 90560-030, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 05403 000, Brazil

Location

Novartis Investigative Site

Bogota, Cundinamarca, 110111, Colombia

Location

Novartis Investigative Site

Vandœuvre-lès-Nancy, 54511, France

Location

Novartis Investigative Site

Erlangen, 91054, Germany

Location

Novartis Investigative Site

Athens, 106 76, Greece

Location

Novartis Investigative Site

Thessaloniki, GR 54636, Greece

Location

Novartis Investigative Site

Budapest, 1062, Hungary

Location

Novartis Investigative Site

Budapest, 1085, Hungary

Location

Novartis Investigative Site

Vellore, Tamil Nadu, 632004, India

Location

Novartis Investigative Site

Chandigarh, 160 012, India

Location

Novartis Investigative Site

New Delhi, 110029, India

Location

Novartis Investigative Site

Napoli, 80131, Italy

Location

Novartis Investigative Site

Wilayah Persekutuan, 62502, Malaysia

Location

Novartis Investigative Site

Mexico City, Mexico City, 14269, Mexico

Location

Novartis Investigative Site

Durango, 34270, Mexico

Location

Novartis Investigative Site

Rotterdam, 3015 GD, Netherlands

Location

Novartis Investigative Site

Málaga, Andalusia, 29010, Spain

Location

Novartis Investigative Site

Alzira, Valencia, 46600, Spain

Location

Novartis Investigative Site

Pendik / Istanbul, Turkey, 34899, Turkey (Türkiye)

Location

Novartis Investigative Site

Istanbul, TUR, 34098, Turkey (Türkiye)

Location

Novartis Investigative Site

Izmir, 35340, Turkey (Türkiye)

Location

Related Publications (1)

• 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.

  PMID: 37876540 DERIVED

MeSH Terms

Conditions

Adrenocortical Hyperfunction; Pituitary Neoplasms; Pituitary ACTH Hypersecretion

Interventions

pasireotide; Cabergoline

Condition Hierarchy (Ancestors)

Adrenal Gland Diseases; Endocrine System Diseases; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Hypothalamic Neoplasms; Supratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypothalamic Diseases; Pituitary Diseases; Hyperpituitarism

Intervention Hierarchy (Ancestors)

Ergolines; Ergot Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2013
• First Posted: August 2, 2013
• Study Start: March 6, 2014
• Primary Completion: September 5, 2016
• Study Completion: September 4, 2019
• Last Updated: September 18, 2020
• Results First Posted: September 18, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will share

Locations

GR (2); MY (1); FR (1); US (2); ME (2); BE (2); NL (1); BR (4); DE (1); CO (1); HU (2); TU (3); AR (1); ES (2); IN (3); IT (1)