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

NCT02060383 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: CSOM230B22192012-002916-16
• Study Type: interventional
• Target: 249
• Locations: 12 countries
• Sites: 43

Brief Summary

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.

Conditions

Cushing's Disease; Acromegaly

Keywords

Cushing's disease; acromegaly; pasireotide; hyperglycemia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Change in HbA1c From Randomization (R) Over Time 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

  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

  Randomization to up to 16 weeks

• Absolute Change in HbA1c From Baseline to End of Core Phase

  Baseline, up to 32 weeks (end of Core phase)

• Absolute Change in FPG From Baseline to End of Core Phase

  Baseline, Up to 32 weeks (end of Core Phase)

Study Arms (3)

Incretin based therapy (randomized group)

EXPERIMENTAL

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.; Drug: Sitagliptin; Drug: Liraglutide; Drug: Insulin; Drug: Pasireotide LAR; Drug: Metformin

Insulin (randomized group)

EXPERIMENTAL

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.; Drug: Insulin; Drug: Pasireotide LAR; Drug: Metformin

Non-Randomized Arm

OTHER

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.; Drug: Insulin; Drug: Pasireotide LAR; Drug: Metformin

Interventions

Pasireotide s.c. DRUG

Administered to Cushing's disease participants.

Also known as: SOM230

Incretin based therapy (randomized group); Insulin (randomized group); Non-Randomized Arm

Sitagliptin DRUG

Taken for approximately 16 weeks during the core study phase or until the drug was found not to be effective

Incretin based therapy (randomized group)

Liraglutide DRUG

Participant switched to liraglutide if sitagliptin was found not to be effective.

Incretin based therapy (randomized group)

Insulin DRUG

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.

Incretin based therapy (randomized group); Insulin (randomized group); Non-Randomized Arm

Pasireotide LAR DRUG

Administered to Acromegaly participants.

Also known as: SOM230

Incretin based therapy (randomized group); Insulin (randomized group); Non-Randomized Arm

Metformin DRUG

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.

Incretin based therapy (randomized group); Insulin (randomized group); Non-Randomized Arm

Eligibility Criteria

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

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (43)

Diabetes and Endocrine Associates La Mesa Location

Multiple Locations, California, United States

Location

LA Biomedical Research at Harbor UCLA Medical Center SC - SOM230B2219

Torrance, California, 90502, United States

Location

Coastal Metabolic Research Centre SC

Ventura, California, 93003, United States

Location

East Coast Institute for Research East Coast Inst. for Res(ECIR)

Jacksonville, Florida, 32223, United States

Location

Washington University SC - SOM230B2411

St Louis, Missouri, 63110, United States

Location

Great Falls Clinic

Great Falls, Montana, 59405, United States

Location

Robert Wood Johnson Medical School - Rutgers SC

New Brunswick, New Jersey, 08901, United States

Location

The Mount Sinai Hospital SC

New York, New York, 10029, United States

Location

Columbia University Medical Center New York Presbyterian Neuroendocrine Unit

New York, New York, 10032, United States

Location

Lenox Hill Hospital/Manhattan Eye, Ear and Throat Hospital SC

New York, New York, 10075, United States

Location

Allegheny Endocrinology Associates SC

Pittsburgh, Pennsylvania, 15212, United States

Location

Vanderbilt Clinical Trials Center SOM230B2219

Nashville, Tennessee, 37212-8210, United States

Location

Baylor College of Medicine Ben Taub General Hosp.

Houston, Texas, 77030, United States

Location

Virginia Endocrinology Research SC-2

Chesapeake, Virginia, 23321, United States

Location

Swedish Medical Center Dept.ofSeattle Neuroscience(2)

Seattle, Washington, 98122-4379, United States

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Wilrijk, 2610, Belgium

Location

Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, 21941-590, Brazil

Location

Novartis Investigative Site

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

Location

Novartis Investigative Site

Joinville, Santa Catarina, 89201260, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 05403 000, Brazil

Location

Novartis Investigative Site

Beijing, Beijing Municipality, 100730, China

Location

Novartis Investigative Site

Guangzhou, Guangdong, 510000, China

Location

Novartis Investigative Site

Chengdu, Sichuan, 610041, China

Location

Novartis Investigative Site

Aalborg, 9000, Denmark

Location

Novartis Investigative Site

Aarhus, DK-8000, Denmark

Location

Novartis Investigative Site

Herlev, DK-2730, Denmark

Location

Novartis Investigative Site

Odense C, DK-5000, Denmark

Location

Novartis Investigative Site

Erlangen, 91054, Germany

Location

Novartis Investigative Site

Freiburg im Breisgau, 79106, Germany

Location

Novartis Investigative Site

Oldenburg, 26122, Germany

Location

Novartis Investigative Site

Bangalore, Karnataka, 560054, India

Location

Novartis Investigative Site

Vellore, Tamil Nadu, 632004, India

Location

Novartis Investigative Site

San Isidro, Lima region, 27, Peru

Location

Novartis Investigative Site

Warsaw, 00-909, Poland

Location

Novartis Investigative Site

Wroclaw, 50 367, Poland

Location

Novartis Investigative Site

Saint Petersburg, 197341, Russia

Location

Novartis Investigative Site

Bangkok, 10400, Thailand

Location

Novartis Investigative Site

Bangkok, 10700, Thailand

Location

Novartis Investigative Site

Songkhla, 90110, Thailand

Location

Novartis Investigative Site

Altunizade, 34662, Turkey (Türkiye)

Location

Novartis Investigative Site

Ankara, 06500, Turkey (Türkiye)

Location

Novartis Investigative Site

Antalya, 07070, Turkey (Türkiye)

Location

Related Publications (2)

• 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.

  PMID: 34275099 DERIVED

• 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.

  PMID: 27405306 DERIVED

MeSH Terms

Conditions

Pituitary ACTH Hypersecretion; Acromegaly; Hyperglycemia

Interventions

pasireotide; Sitagliptin Phosphate; Liraglutide; Insulin; Metformin

Condition Hierarchy (Ancestors)

Hyperpituitarism; Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Bone Diseases, Endocrine; Bone Diseases; Musculoskeletal Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Biguanides; Guanidines; Amidines; Organic Chemicals

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 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 10, 2014
• First Posted: February 12, 2014
• Study Start: May 23, 2014
• Primary Completion: February 5, 2018
• Study Completion: March 26, 2018
• Last Updated: May 29, 2019
• Results First Posted: May 29, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will share

Locations

TH (3); PE (1); DK (4); PL (2); TU (3); US (15); CN (3); IN (2); BE (2); RU (1); BR (4); DE (3)