Pasireotide s.c. in Patients With Post-Bariatric Hypoglycaemia

Study Overview
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Brief Summary
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The Total duration of trial participation for each participant with post-bariatric hypoglycemia will be a maximum of 59 weeks, with the following duration of trial periods 19 weeks for the Core Phase. It is composed of: a Screening period: a maximum of 3 weeks a Run-in period (no treatment): 4 weeks a Blinded Treatment Phase: 12 weeks 36 weeks Extension Phase = an open-label Treatment period 4 weeks for the safety follow-up period (without any treatment).

Detailed Description
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Subjects with post-bariatric hypoglycemia will be screened for participation in this trial. Eligible patients will complete the rest of the Core phase by entering a run-in period of 4 weeks without any treatment. At the end of the run-in period, participants will be randomized to receive in a blinded manner either pasireotide 50 µg or pasireotide 100 µg or pasireotide 200 µg or Placebo subcutaneously three times a day (prior to each meal). Participants will blindly self-administer their treatment for a total of 12 weeks when the primary endpoint will be assessed. All participants completing the core phase will be offered to enter the extension phase. Participants will openly self-administer pasireotide 50 µg or pasireotide 100 µg or pasireotide 200 µg subcutaneously three times a day for a total of 36 weeks of treatment. There will be no more placebo during this extension phase of treatment. Dose changes/adjustments will be possible only during the extension phase and the decision to change the dose of pasireotide will be left to the investigator's judgment. All participants will come for a safety visit after discontinuation or completion of treatment.

Official Title
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A Double-blind Randomized Placebo-controlled Dose-finding Phase II Study to Assess the Efficacy and Safety of Pasireotide s.c. in Patients With Post-Bariatric Hypoglycaemia

Conditions
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Post-Bariatric Hypoglycemia

Intervention / Treatment
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* Drug: Pasireotide Diaspartate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or- non-pregnant female patients ≥ 18 years of age Patients able to provide and have provided signed written informed consent prior to study participation. Patients capable of self-injecting subcutaneously. Specific training to self-inject the study drug will be provided. Post-bariatric surgery more than 6 months prior to screening Patient with a documented diagnosis of PBH defined as having: postprandial neuroglycopenia occurring >1 hour after meals no hypoglycaemia in fasting conditions documented history of Whipple's triad documented history of hypoglycaemia based on glucose value <50mg/dL or 2.8 mmol/L on a sporadic or scheduled blood analysis - OR - glucose value <60 mg/dL or 3.3 mmol/L at 90, 120, 150 or 180 min during an OGTT (oral glucose tolerance test) - OR- glucose value <54 mg/dL at 60, 90, 120 or 180 min during a 3-hour MMTT (mixed meal tolerance test) Patients must have at least one glucose level < 54 mg/dL at 30, 90, 120, 150 or 180 min during the 3-hour MMTT at screening Historical evidence of previous level 3 hypoglycaemia events at any time Patients who have failed diet recommended by the treating physician for the PBH Karnofsky Performance Status ≥ 60 (i.e., requires occasional assistance, but is able to care for most of their personal needs) Patients who received other therapies for PBH (such as acarbose, gama guar, pectin, diazoxide) must have stopped all treatments and allow a wash out period of at least 2 weeks prior to entering the run-in period. Patients who have been treated with GLP-1 antagonists in the past must have a wash-out period of at least 4 weeks before the start of the run-in period Patients who have been treated with SGLT2 inhibitors (glifozins) in the past must have a wash-out period of at least 4 weeks before the start of the run-in period Patients who have been treated with somatostatin receptor analogues in the past, must have an appropriate interval between the last administration of somatostatin receptor analogues treatment and the start of the run-in period as follows: Octreotide s.c. for ≥ 72 hours Octreotide LAR for ≥ 56 days (8 weeks) Lanreotide Autogel for ≥ 98 days (14 weeks) Lanreotide SR ≥ 28 days (4 weeks) Exclusion Criteria (main ones): Bariatric patients who have lap band. Patients with a current diagnosis of uncontrolled Diabetes Mellitus. However, diabetic patients in remission, as defined below, are eligible: With an HbA1c at screening <6.5% Not taking any medications for hyperglycaemia for at least 3 months prior to screening. Their qualifying Level 3 hypoglycaemia events (see above) must have occurred at least 1 month after the discontinuation of the glucose lowering agent(s). Patients previously treated with pasireotide at any time Patients who have a known hypersensitivity to somatostatin receptor analogues. Patients currently using medications that may interfere with glucose metabolism within 5 half-lives of drug. Patients with history of or current insulinoma Patients who have any severe and/or uncontrolled medical condition or other conditions that could affect their participation in the study (defined in the core text of the protocol) Patients with symptomatic cholelithiasis and/ or acute or chronic pancreatitis. Patients with abnormal coagulation (PT and PTT elevated by 30% above normal limits). Patients on continuous anticoagulation therapy. Patients who were on anticoagulant therapy must complete a washout period of at least 10 days and have confirmed normal coagulation parameters before study inclusion (patients receiving aspirin once a day are allowed to be enrolled). Patients who are hypothyroid and not on adequate replacement therapy. Patients who have undergone major surgery/surgical therapy for any cause within 1 month. Patients should have recovered from the surgery and be in good clinical condition before entering the study. Bradycardia and QT-related exclusion criteria (in the core text of the protocol) Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation. (Use of an investigational drug within 1 month prior to dosing). Significant acute illness within the two weeks prior to dosing/randomization. Female patients who are pregnant, intending to become pregnant or breastfeed during the study or lactating, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. Women of childbearing potential (WOCBP) who are unwilling of using highly effective contraception methods (definition in core protocol) Potentially unreliable or vulnerable patients (e.g., person kept in detention) and those judged by the investigator to be unsuitable for the study.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pasireotide s.c. 50 mcg<br>Pasireotide 50 mcg s.c. tid | Drug: Pasireotide Diaspartate<br>* Injectable ampoules<br>* Other names: Pasireotide;|
| Experimental: Pasireotide 100 mcg<br>Pasireotide 100 mcg s.c. tid | Drug: Pasireotide Diaspartate<br>* Injectable ampoules<br>* Other names: Pasireotide;|
| Experimental: Pasireotide 200 mcg<br>Pasireotide 200 mcg s.c. tid | Drug: Pasireotide Diaspartate<br>* Injectable ampoules<br>* Other names: Pasireotide;|
| Placebo Comparator: Placebo<br>Placebo s.c. tid | Drug: Pasireotide Diaspartate<br>* Injectable ampoules<br>* Other names: Pasireotide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level 2 hypoglycaemic events (plasma glucose <54 mg/dL) during a 3-hour MMTT (mixed meal tolerance test) | The response rate defined as the proportion of patients with no level 2 hypoglycaemic events (plasma glucose <54 mg/dL) at 90, 120, 150 and 180 min during a 3-hour MMTT after 12 weeks of treatment with pasireotide s.c. 50 µg, or 100 µg or 200 µg tid vs placebo tid respectively | 12 weeks |