Study of Management of Pasireotide-induced Hyperglycemia in Adult Patients With Cushing's Disease or Acromegaly

A Multi-center, Randomized, Open-label, Phase IV Study to Investigate the Management of Pasireotide-induced Hyperglycemia With Incretin Based Therapy or Insulin in Adult Patients With Cushing's Disease or Acromegaly

The study was designed to investigate the optimal management of hyperglycemia developed during pasireotide treatment in participants with Cushing's disease or Acromegaly, which was not manageable with metformin.

This was a Phase IV, multi-center, randomized, open-label study. Eligible patients started pasireotide subcutaneously (s.c.) for Cushing's disease and pasireotide LAR (long-acting release) for Acromegaly.

Participants being treated with pasireotide s.c or LAR at screening were eligible as long as they met protocol criteria during the screening period. If previously normo-glycemic participants experienced an increase in their fasting blood glucose and met the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to have elevated blood glucose above target on metformin within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks.

Participants who continued to receive clinical benefit after completing the Core Phase could enter an optional Extension Phase if pasireotide was not commercially available in their country or a local access program was not available to provide drug. Patients continued in the Extension Phase until the last participant randomized in the Core Phase completed 16 weeks of treatment post-randomization.

Study Overview

• Status: Completed
• Conditions: Acromegaly; Cushing's Disease
• Intervention / Treatment: Drug: Pasireotide s.c.; Drug: Sitagliptin; Drug: Liraglutide; Drug: Insulin; Drug: Pasireotide LAR; Drug: Metformin

• Study Type: Interventional
• Enrollment (Actual): 249
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Wilrijk, Belgium, 2610
    • Novartis Investigative Site
• Brazil
  • RJ
    • Rio de Janeiro, RJ, Brazil, 21941-590
      • Novartis Investigative Site
  • RS
    • Porto Alegre, RS, Brazil, 90560-030
      • Novartis Investigative Site
  • SC
    • Joinville, SC, Brazil, 89201260
      • Novartis Investigative Site
  • SP
    • São Paulo, SP, Brazil, 05403 000
      • Novartis Investigative Site
• China
  • Beijing
    • Beijing, Beijing, China, 100730
      • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
• Denmark
  • Aalborg, Denmark, 9000
    • Novartis Investigative Site
  • Aarhus, Denmark, DK-8000
    • Novartis Investigative Site
  • Herlev, Denmark, DK-2730
    • Novartis Investigative Site
  • Odense C, Denmark, DK-5000
    • Novartis Investigative Site
• Germany
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Freiburg, Germany, 79106
    • Novartis Investigative Site
  • Oldenburg, Germany, 26122
    • Novartis Investigative Site
• India
  • Karnataka
    • Bangalore, Karnataka, India, 560054
      • Novartis Investigative Site
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632004
      • Novartis Investigative Site
• Peru
  • Lima
    • San Isidro, Lima, Peru, 27
      • Novartis Investigative Site
• Poland
  • Warszawa, Poland, 00-909
    • Novartis Investigative Site
  • Wroclaw, Poland, 50 367
    • Novartis Investigative Site
• Russian Federation
  • Saint Petersburg, Russian Federation, 197341
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Songkla, Thailand, 90110
    • Novartis Investigative Site
• Turkey
  • Altunizade, Turkey, 34662
    • Novartis Investigative Site
  • Ankara, Turkey, 06500
    • Novartis Investigative Site
  • Antalya, Turkey, 07070
    • Novartis Investigative Site
• United States
  • California
    • Multiple Locations, California, United States
      • Diabetes and Endocrine Associates La Mesa Location
    • Torrance, California, United States, 90502
      • LA Biomedical Research at Harbor UCLA Medical Center SC - SOM230B2219
    • Ventura, California, United States, 93003
      • Coastal Metabolic Research Centre SC
  • Florida
    • Jacksonville, Florida, United States, 32223
      • East Coast Institute for Research East Coast Inst. for Res(ECIR)
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University SC - SOM230B2411
  • Montana
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Robert Wood Johnson Medical School - Rutgers SC
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center New York Presbyterian Neuroendocrine Unit
    • New York, New York, United States, 10029
      • The Mount Sinai Hospital SC
    • New York, New York, United States, 10075
      • Lenox Hill Hospital/Manhattan Eye, Ear and Throat Hospital SC
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Endocrinology Associates SC
  • Tennessee
    • Nashville, Tennessee, United States, 37212-8210
      • Vanderbilt Clinical Trials Center SOM230B2219
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine Ben Taub General Hosp.
  • Virginia
    • Chesapeake, Virginia, United States, 23321
      • Virginia Endocrinology Research SC-2
  • Washington
    • Seattle, Washington, United States, 98122-4379
      • Swedish Medical Center Dept.ofSeattle Neuroscience(2)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients greater than or equal to 18 years old
• Confirmed diagnosis of Cushing's disease or acromegaly

Exclusion Criteria:

• Patients who require surgical intervention
• Patients receiving DPP-4 inhibitors or GLP-1 receptor agonists within 4 weeks prior to study entry
• HbA1c > 10 % at screening
• Known hypersensitivity to somatostatin analogues Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Incretin based therapy (randomized group); Participants randomized to the incretin based arm started with sitagliptin once daily. If sitagliptin did not control the participant's hyperglycemia, sitagliptin was stopped and participants switched to liraglutide once daily. If despite treatment with liraglutide, hyperglycemia was not controlled then the participant was eligible for rescue therapy with addition of insulin.	Drug: Pasireotide s.c.; Administered to Cushing's disease participants.; Other Names: SOM230; Drug: Sitagliptin; Taken for approximately 16 weeks during the core study phase or until the drug was found not to be effective; Drug: Liraglutide; Participant switched to liraglutide if sitagliptin was found not to be effective.; Drug: Insulin; Participant took insulin for 16 weeks. Insulin was also administered as rescue therapy in the incretin-based therapy arm if required. Insulin was administered to the BL-insulin group at the discretion of the Principal Investigator. Note: OAD and No OAD groups within the non-randomized arm did not take Insulin.; Drug: Pasireotide LAR; Administered to Acromegaly participants.; Other Names: SOM230; Drug: Metformin; If previously normo-glycemic participants experienced increase in their fasting blood glucose and meeting the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to experience increase in their fasting blood glucose within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks. Metformin treatment was not required for the BL Insulin and OAD groups, within the non-randomized arm, but may have been prescribed at the discretion of the investigator. Note: No OAD group within the non-randomized arm did not take metformin.
Experimental: Insulin (randomized group); Participants randomized to the insulin arm started with once daily dose of basal insulin. The dose was up or down titrated at the discretion of the investigator. If blood glucose levels remained uncontrolled on basal insulin, participant switched to basal insulin plus prandial insulin.	Drug: Pasireotide s.c.; Administered to Cushing's disease participants.; Other Names: SOM230; Drug: Insulin; Participant took insulin for 16 weeks. Insulin was also administered as rescue therapy in the incretin-based therapy arm if required. Insulin was administered to the BL-insulin group at the discretion of the Principal Investigator. Note: OAD and No OAD groups within the non-randomized arm did not take Insulin.; Drug: Pasireotide LAR; Administered to Acromegaly participants.; Other Names: SOM230; Drug: Metformin; If previously normo-glycemic participants experienced increase in their fasting blood glucose and meeting the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to experience increase in their fasting blood glucose within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks. Metformin treatment was not required for the BL Insulin and OAD groups, within the non-randomized arm, but may have been prescribed at the discretion of the investigator. Note: No OAD group within the non-randomized arm did not take metformin.
Other: Non-Randomized Arm; This arm represents the non-randomized participants: Cushing's Disease (CD) or Acromegaly participants, who received pasireotide s.c. or LAR (long-acting release) respectively, but who were not randomized to the Incretin or Insulin arms. For the purpose of analysis, this non-randomized arm is further split into 3 groups: Baseline insulin group (BL insulin) includes participants who were receiving insulin at study entry; Oral antidiabetic drugs (OAD) group includes participants who developed hyperglycemia that was controlled by metformin and/or other background anti-diabetic treatment; No OAD group includes participants who did not receive any anti-diabetic medication during the core phase of the trial	Drug: Pasireotide s.c.; Administered to Cushing's disease participants.; Other Names: SOM230; Drug: Insulin; Participant took insulin for 16 weeks. Insulin was also administered as rescue therapy in the incretin-based therapy arm if required. Insulin was administered to the BL-insulin group at the discretion of the Principal Investigator. Note: OAD and No OAD groups within the non-randomized arm did not take Insulin.; Drug: Pasireotide LAR; Administered to Acromegaly participants.; Other Names: SOM230; Drug: Metformin; If previously normo-glycemic participants experienced increase in their fasting blood glucose and meeting the criteria for diabetes while on pasireotide, they started anti-diabetic treatment using metformin. If they continued to experience increase in their fasting blood glucose within the first 16 weeks, they were randomized in a 1:1 ratio to receive treatment with incretin based therapy or insulin for approximately 16 weeks. Metformin treatment was not required for the BL Insulin and OAD groups, within the non-randomized arm, but may have been prescribed at the discretion of the investigator. Note: No OAD group within the non-randomized arm did not take metformin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c From Randomization to Approximately 16 Weeks	Absolute change in HbA1c from randomization to end of core phase (16 weeks) in incretin based therapy arm and insulin arm, and mean difference of change in HbA1c between the two treatment groups based on an ANOVA model using treatment (Incretin, Insulin) and the two randomization stratification factors (Disease: Cushing's disease vs Acromegaly; Baseline glycemic status: HbA1c <7% vs HbA1c ≥ 7%) as fixed effects. For Participants who discontinued the study or required rescue treatment before the time of assessing the primary endpoint, the last HbA1c assessment collected 8 weeks (56 days) after randomization (and prior to or on the date of start of rescue treatment) was carried forward. If the participant discontinued the study or used rescue treatment within 8 weeks after randomization, it was considered missing.	Randomization, 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c From Randomization (R) Over Time Per Randomized Arm	Absolute change in HbA1c overtime from randomization (i.e. start of randomized antidiabetic treatment) to end of core phase per randomized arm	Randomization (R), Week (W) 4 post R, W 8 post R, W 16 post R, end of Core phase (up to week 16 post R)
Change in FPG (Fasting Plasma Glucose) From Randomization Until End of Core Phase	Absolute change in fasting glucose overtime from randomization (i.e. start of randomized antidiabetic treatment) to end of core phase per randomized arm	Randomization, R(randomization) Week 2, R-Week 4, R-Week 6, R-Week 8, R-Week 10, R-Week 12, R-Week 14, R-Week 16, end of Core phase
Percentage of Participants in the Incretin-based Arm Who Required Anti-diabetic Rescue Therapy With Insulin	The percentage of participants who received anti-diabetic rescue therapy in incretin based therapy is summarized.	Randomization to up to 16 weeks
Absolute Change in HbA1c From Baseline to End of Core Phase	Absolute change in HbA1c from baseline to end of core phase in the incretin based therapy arm and the insulin arm	Baseline, up to 32 weeks (end of Core phase)
Absolute Change in FPG From Baseline to End of Core Phase	Absolute change in FPG from baseline to end of core phase in the incretin based therapy arm and the insulin arm.	Baseline, Up to 32 weeks (end of Core Phase)
Percentage of Participants With ≤ 0.3% HbA1c Increase to End of Core Phase	Percentage of participants with ≤ 0.3% HbA1c increase in the incretin based therapy arm and the insulin arm.	Randomization, up to 16 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Silverstein JM. Hyperglycemia induced by pasireotide in patients with Cushing's disease or acromegaly. Pituitary. 2016 Oct;19(5):536-43. doi: 10.1007/s11102-016-0734-1.
• Samson SL, Gu F, Feldt-Rasmussen U, Zhang S, Yu Y, Witek P, Kalra P, Pedroncelli AM, Pultar P, Jabbour N, Paul M, Bolanowski M. Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study. Pituitary. 2021 Dec;24(6):887-903. doi: 10.1007/s11102-021-01161-4. Epub 2021 Jul 18.

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2014
• Primary Completion (Actual): February 5, 2018
• Study Completion (Actual): March 26, 2018

Study Registration Dates

• First Submitted: February 10, 2014
• First Submitted That Met QC Criteria: February 11, 2014
• First Posted (Estimate): February 12, 2014

Study Record Updates

• Last Update Posted (Actual): May 29, 2019
• Last Update Submitted That Met QC Criteria: May 7, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: acromegaly; hyperglycemia; Cushing's disease; pasireotide
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; 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; Musculoskeletal Diseases; Hypothalamic Diseases; Bone Diseases; Bone Diseases, Endocrine; Hyperpituitarism; Pituitary Diseases; Adenoma; Pituitary Neoplasms; Hyperglycemia; Acromegaly; ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Liraglutide; Metformin; Sitagliptin Phosphate; Somatostatin; Pasireotide
• Other Study ID Numbers: CSOM230B2219; 2012-002916-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No