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

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

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).

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.

Inclusion Criteria:

1. Male or- non-pregnant female patients ≥ 18 years of age

2. Patients able to provide and have provided signed written informed consent prior to study participation.

3. Patients capable of self-injecting subcutaneously. Specific training to self-inject the study drug will be provided.

4. Post-bariatric surgery more than 6 months prior to screening

5. Patients with a medically documented diagnosis of PBH and documented glucose measurement (less than 70 mg/dl or 3.9 mmol/L) with symptoms of hypoglycaemia, and resolution following administration of rescue carbohydrates

6. 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 less than 54 mg/dL (3.0 mmol/L) as measured by SMBG (level 2) or
   • Level 3 hypoglycaemic event

7. (The previous inclusion criterion number 7 has been deleted).

8. Patients in whom dietary control has not sufficiently controlled symptoms of PBH.

9. Karnofsky Performance Status ≥ 60 (i.e., requires occasional assistance, but is able to care for most of their personal needs)

10. 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.

11. 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.

12. 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.

13. 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)
    • Pasireotide s.c. for ≥ 72 hours (3 days)
    • Pasireotide LAR for ≥ 84 days (12 weeks)

Exclusion Criteria :

1. Bariatric patients who have lap band.

2. Patients with a current diagnosis of uncontrolled Diabetes Mellitus. However, diabetic patients in remission, as defined below, are eligible:

   • With an HbA1c at screening less than 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).

3. Patients with hypocortisolism, as defined by serum cortisol levels minor of LLN with presence of clinical signs and symptoms of adrenal insufficiency (e.g., weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia, or hypoglycaemia) as judged by the Investigators

4. (The previous exclusion criterion number 4 has been deleted).

5. (The previous exclusion criterion number 5 has been deleted).

6. Patients who have a known hypersensitivity to somatostatin receptor analogues.

7. Patients currently using medications that may interfere with glucose metabolism within 5 half-lives of drug.

8. Patients with history of or current insulinoma.

9. 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 less than 3.0 x 109/L
   • Absolute Neutrophil Count (ANC) less than 1.5 x 109/L
   • Platelets less than100 x 109/L
   • Hgb less than 11 g/dL
   • INR ≥ 1.5
   • eGFR less than 30 mL/min/1.73m2
   • Alkaline phosphatase more than 2.5 x ULN
   • Serum total bilirubin more than1.5 x ULN
   • ALT and AST more than 1.5 x ULN

10. History of liver disease, such as cirrhosis or chronic active hepatitis B andC

11. 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.

12. 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.

13. Patients with symptomatic cholelithiasis and/ or acute or chronic pancreatitis.

14. Patients with abnormal coagulation (PT and PTT elevated by 30% above normal limits).

15. 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).

16. Patients who are hypothyroid and not on adequate replacement therapy.

17. 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.

18. Patients requiring gastrostomy tube feedings.

19. 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.

20. 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.

21. Bradycardia and QT-related exclusion criteria:

    • Patients with long QT syndrome or QTcF more than 450 ms for male and QTcF more than 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 less than50 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 less than or = 3.5 mEq/L).
    • Hypomagnesemia (Magnesium less than 0.7 mmol/L).

22. 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).

23. Significant acute illness within the two weeks prior to dosing.

24. 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.

25. 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.

26. 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.

27. Potentially unreliable or vulnerable patients (e.g., person kept in detention) and those judged by the Investigator to be unsuitable for the study.