Efficacy and Safety of Pasireotide Diaspartate in Post-Bariatric Hypoglycaemia: A Double-Blind, Randomized, Placebo-Controlled Phase II Study

Trial ID: 2023-505316-37-00
Protocol: SOM230-RECAG-CL-0576
Sponsor: Recordati AG

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Diseases & Conditions

Hyperinsulinaemic hypoglycaemia Postprandial hypoglycaemia

Objectives

The primary objective of this study is to evaluate the **efficacy** of pasireotide subcutaneous (s.c.) administration on blood glucose concentration during a mixed meal tolerance test (MMTT) in patients with Post-Bariatric Hypoglycaemia (PBH) after 12 weeks of treatment. This is clinically relevant as it aims to address the management of hypoglycaemic episodes in PBH, a condition that can significantly impact patient quality of life and metabolic stability.

Secondary objectives include:

Evaluating the efficacy of pasireotide s.c. on the rate and duration of level 2 and level 3 hypoglycaemic events at various time points, using both self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM).
Assessing the effect of pasireotide s.c. on the percent time with level 2 hypoglycaemia, the use of rescue therapy, and the requirement for rescue carbohydrates.
Investigating the impact of pasireotide s.c. on physiological parameters such as pulse rate, haematocrit, and the secretion of insulin, glucagon, and GLP-1 during the MMTT.
Evaluating the effect on health-related quality of life (HRQoL) using various questionnaires and surveys.
Assessing the safety profile of pasireotide s.c. throughout the treatment period.
For the extension phase, similar evaluations will be conducted at extended time points to further assess the long-term efficacy and safety of pasireotide s.c.
Investigating the pharmacokinetic profile of pasireotide in PBH patients, including plasma concentrations and primary pharmacokinetic parameters.

Participants

The clinical trial involves a total of **42 participants** diagnosed with **Post-Bariatric Hypoglycaemia** (PBH). The study population includes both male and female subjects who are 18 years of age or older. Participants are required to have undergone bariatric surgery more than six months prior to screening and must have a medically documented diagnosis of PBH, with specific glucose measurement criteria and symptoms. The trial excludes vulnerable populations and focuses on individuals who can self-inject subcutaneously, with training provided. Participants must have experienced at least four post-prandial hypoglycaemic events during a 28-day run-in period and have a Karnofsky Performance Status of 60 or higher, indicating they require occasional assistance but can manage most personal needs. Lifestyle considerations include the requirement that dietary control alone has not sufficiently managed PBH symptoms. Prior treatments for PBH, such as GLP-1 antagonists, GLP-1 agonists, and somatostatin receptor analogues, must be discontinued for specified periods before the screening period. The selection process ensures that participants have provided informed consent and are capable of adhering to the study protocol.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **pasireotide diaspartate** administered subcutaneously in patients with **Post-Bariatric Hypoglycaemia** (PBH). The trial is structured into a core phase lasting 12 weeks, followed by an extension phase extending up to 48 weeks. Participants will be randomly assigned to receive either pasireotide at varying doses (50 µg, 100 µg, or 200 µg) or a placebo, administered three times daily. The primary objective is to assess changes in blood glucose levels during a mixed-meal tolerance test (MMTT) from baseline to 12 weeks of treatment.

The study will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, previous treatments, and the ability to self-inject. Participants must have a documented diagnosis of PBH and meet glucose measurement criteria. Following the screening, eligible participants will enter a 28-day run-in period to establish baseline hypoglycaemic events. The core phase includes study visits at weeks 4, 8, and 12 to monitor changes in hypoglycaemic events, glucose levels, and other health parameters. The extension phase will include additional visits at weeks 16, 20, 24, 32, 40, and 48 to further evaluate long-term effects and safety.

The expected duration of participant involvement is up to 48 weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study procedures. The study aims to provide comprehensive data on the efficacy of pasireotide in managing PBH, with secondary endpoints focusing on the frequency and severity of hypoglycaemic events, quality of life assessments, and safety evaluations through laboratory tests and ECG findings. The trial is anticipated to conclude by February 2026, with recruitment starting in April 2024.

Treatment

The clinical trial involves the administration of **pasireotide diaspartate**, a **cyclohexapeptide somatostatin analogue**, as the experimental medication. This compound is provided in the form of a **solution for injection** and is administered via **subcutaneous injection**. The dosage is set at a maximum of 600 micrograms per day, with the total dose not exceeding 600 micrograms over the course of the treatment. The treatment period is capped at 48 weeks. The medication is manufactured by Recordati Rare Diseases SARL and is identified by the sponsor product code SOM230. The primary objective of the trial is to evaluate the efficacy of pasireotide in managing blood glucose levels in patients with Post-Bariatric Hypoglycaemia (PBH) after 12 weeks of treatment.

The study also includes a **placebo** as a non-experimental treatment to serve as a comparator. The placebo is similarly provided as a **solution for injection** and is administered through **subcutaneous injection**. The placebo is designed to match the experimental treatment in terms of administration route and dosage, with a maximum daily dose of 600 micrograms and a total dose limit of 600 micrograms over the 48-week treatment period. The placebo is also produced by Recordati Rare Diseases SARL and is identified by the sponsor product code PLACEBO. The use of a placebo allows for a double-blind, randomized, placebo-controlled study design, which is essential for assessing the true efficacy and safety of the experimental treatment.

Efficacy

The efficacy of pasireotide subcutaneous (s.c.) in patients with **Post-Bariatric Hypoglycaemia** (PBH) will be assessed through a double-blind, randomized, placebo-controlled, dose-finding phase II study. The primary endpoint for evaluating efficacy is the change in blood glucose levels, specifically measured by the peak to nadir glucose area under the curve (AUC) during a mixed-meal tolerance test (MMTT) from baseline to 12 weeks of treatment. Patients will receive pasireotide s.c. at doses of 50 µg, 100 µg, or 200 µg three times daily (tid) compared to placebo tid.

Secondary endpoints include several measures:

Change from baseline in the rate of level 2 hypoglycaemic events (glucose level <54 mg/dL or 3.0 mmol/L) measured by self-monitoring of blood glucose (SMBG) at weeks 4, 8, and 12.
Response rate defined as the proportion of patients with no level 2 hypoglycaemic events during a 3-hour MMTT after 12 weeks of treatment.
Change from baseline in the rate of level 3 hypoglycaemic events (requiring external assistance) at weeks 4, 8, and 12.
Change from baseline in the duration and percent time of level 2 hypoglycaemic events measured by continuous glucose monitoring (CGM) at weeks 4, 8, and 12.
Change from baseline in the frequency of use of rescue therapy and/or rescue carbohydrates at home to manage level 2 and level 3 hypoglycaemic events at weeks 4, 8, and 12.
Proportion of participants with changes in pulse rate and haematocrit during the MMTT after 12 weeks of treatment.
Absolute and percent changes in insulin, glucagon, and GLP-1 secretion from baseline during the MMTT after 12 weeks of treatment.
Changes in health-related quality of life (HRQoL) scores from baseline to week 12.
Incidence of adverse events (AEs), laboratory, and ECG findings throughout the treatment period.

These efficacy parameters will be measured and collected at specified timepoints using validated scales and laboratory tests, ensuring a comprehensive assessment of the treatment's impact on PBH.

Inclusion and Exclusion 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.
Patients with a medically documented diagnosis of PBH and documented glucose measurement (<70 mg/dl or 3.9 mmol/L) with symptoms of hypoglycaemia, and resolution following administration of rescue carbohydrates.
Patients must have ≥ 4 post-prandial hypoglycaemia during the 28-day run-in period (in average ≥1 event over a 7-day week) defined as: • Blood glucose <54 mg/dL (3.0 mmol/L) as measured by SMBG (level 2) or • Level 3 hypoglycaemic event
(The previous inclusion criterion number 7 has been deleted).
Patients in whom dietary control has not sufficiently controlled symptoms of 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 such treatments are prohibited for a period of at least 2 weeks or 5 half-life times prior to entering the screening period.
GLP-1 antagonists and GLP-1 agonists for patients who have been treated with in the past for the indication of PBH, are prohibited for a period of at least 4 weeks before the start of the screening period.
SGLT2 inhibitors (glifozins) for patients who have been treated with in the past for the indication of PBH, are prohibited for a period of at least 4 weeks before the start of the screening 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 screening period as follows: • Octreotide s.c. for ≥ 72 hours (3 days) • Octreotide LAR for ≥ 56 days (8 weeks) • Lanreotide Autogel for ≥ 98 days (14 weeks) • Lanreotide SR ≥ 28 days (4 weeks) • Pasireotide s.c. for ≥ 72 hours (3 days) • Pasireotide LAR for ≥ 84 days (12 weeks)

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Exclusion Criteria

Bariatric patients who have lap band.
History of liver disease, such as cirrhosis or chronic active hepatitis B and C.
Presence of Hepatitis B surface antigen (HbsAg) and/ or Presence of Hepatitis C antibody test (anti-HCV). Patients with positive HCV Ab must undergo reflex HCV RNA testing, and patients with HCV RNA positivity will be excluded. Patients with positive HCV Ab and negative HCV RNA are eligible.
History of, or current alcohol and/or drug misuse/abuse within the past 12 months. A drug/alcohol test will not be required; however, previous medical history will be reviewed.
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 before screening. Patients should have recovered from the surgery and be in good clinical condition before entering the study.
Patients requiring gastrostomy tube feedings.
Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study.
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).
Clinically significant abnormal laboratory values considered by the Investigator or the medical monitor of the sponsor to be clinically significant or which could have affected the interpretation of the study results
Bradycardia and QT-related exclusion criteria: • Patients with long QT syndrome or QTcF >450 ms for male and QTcF >460 ms for female detected at screening. • Patients with uncontrolled or significant cardiac disease, including recent myocardial infarction, unstable angina, congestive heart failure, clinically significant/symptomatic heart rate < 50 bpm, or high-grade AV block, sustained ventricular tachycardia, ventricular fibrillation. • History of syncope or family history of idiopathic sudden death. • Sustained or clinically significant cardiac arrhythmias. • Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism, or cardiac failure. • Family history of long QT syndrome. • Concomitant medications known to prolong the QT interval. • Hypokalaemia (Potassium < or = 3.5 mEq/L). • Hypomagnesemia (Magnesium < 0.7 mmol/L).
Participation in any clinical investigation within 4 weeks prior to screening or longer if required by local regulation. (Use of an investigational drug within 1 month prior to screening).
Significant acute illness within the two weeks prior to dosing.
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. Highly effective contraception methods include: • Combined (estrogen and progesterone containing) (oral, intravaginal, transdermal) hormonal contraception associated with inhibition of ovulation. • Progesterone-only hormonal (oral, injectable, implantable) contraception associated with inhibition of ovulation. • Intrauterine device. • Intrauterine hormone-releasing system. • Bilateral tubal occlusion. • Sexual abstinence defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
Patients with hypocortisolism, as defined by serum cortisol levels
(The previous exclusion criterion number 4 has been deleted).
(The previous exclusion criterion number 5 has been deleted).
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 such as: • Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunodeficiency, including a positive HIV test result (ELISA and Western blot). An HIV test will not be required; however, previous medical history will be reviewed. • Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with this study treatment. • Life-threatening autoimmune and ischemic disorders. • Inadequate end organ function as defined by: • Inadequate bone marrow function: • WBC < 3.0 x 109/L • Absolute Neutrophil Count (ANC) < 1.5 x 109/L • Platelets < 100 x 109/L • Hgb < 11 g/dL • INR ≥ 1.5 • eGFR < 30 mL/min/1.73m2 • Alkaline phosphatase >2.5 x ULN • Serum total bilirubin >1.5 x ULN • ALT and AST > 1.5 x ULN
Sexually active males unwilling to use a condom during intercourse while taking the drug and for 4 weeks after pasireotide s.c. last dose. A condom is required to be used also by vasectomized men to prevent delivery of the drug via seminal fluid.
Potentially unreliable or vulnerable patients (e.g., person kept in detention) and those judged by the Investigator to be unsuitable for the study.