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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Cushing's Disease, Acromegaly

Intervention / Treatment
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* Drug: Pasireotide s.c.
* Drug: Sitagliptin
* Drug: Liraglutide
* Drug: Insulin
* Drug: Pasireotide LAR
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Incretin based therapy (randomized group)<br>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.<br>* Administered to Cushing's disease participants.<br>* Other names: SOM230;Drug: Sitagliptin<br>* Taken for approximately 16 weeks during the core study phase or until the drug was found not to be effective<br>Drug: Liraglutide<br>* Participant switched to liraglutide if sitagliptin was found not to be effective.<br>Drug: Insulin<br>* 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.<br>Drug: Pasireotide LAR<br>* Administered to Acromegaly participants.<br>* Other names: SOM230;Drug: Metformin<br>* 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.<br>|
| Experimental: Insulin (randomized group)<br>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.<br>* Administered to Cushing's disease participants.<br>* Other names: SOM230;Drug: Insulin<br>* 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.<br>Drug: Pasireotide LAR<br>* Administered to Acromegaly participants.<br>* Other names: SOM230;Drug: Metformin<br>* 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.<br>|
| Other: Non-Randomized Arm<br>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.<br>* Administered to Cushing's disease participants.<br>* Other names: SOM230;Drug: Insulin<br>* 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.<br>Drug: Pasireotide LAR<br>* Administered to Acromegaly participants.<br>* Other names: SOM230;Drug: Metformin<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cushing's disease, acromegaly, pasireotide, hyperglycemia