Post-Bariatric Hypoglycemia
Conditions
Keywords
PBH, Post Bariatric
Brief summary
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
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.
Interventions
DRUGPasireotide Diaspartate
Injectable ampoules
Sponsors
RECORDATI GROUP
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of the efficacy of pasireotide s.c. on blood glucose concentration during an MMTT in patients with PBH after 12 weeks of treatment. | at baseline and at 12 weeks | Change in the blood glucose levels, as measured by the peak to nadir glucose AUC during MMTT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| KEY SECONDARY_CORE PHASE: Evaluation the change of blood glucose nadir and peak during a mixed meal tolerance test (MMTT) at baseline | at baseline and at 12 weeks | Change from baseline in the rate of the composite (and individual components) of clinically significant hypoglycaemic events as measured as the frequency of level 2 hypoglycaemic events (glucose level \<54 mg/dL or 3.0 mmol/L) measured by SMBG OR the frequency of level 3 hypoglycaemic (requiring external assistance) events/4-weeks at 12 weeks of treatment with pasireotide vs placebo |
| CORE PHASE: Evaluation of the change of blood glucose nadir and peak during a mixed meal tolerance test (MMTT) at baseline and the MMTT | baseline and 12 weeks | Change in the nadir and peak of blood glucose levels, |
| CORE PHASE: Evaluation of the efficacy of pasireotide s.c. on the change from baseline of level 2 hypoglycaemic events during a MMTT in patients with PBH | at 12 weeks | Change from baseline in the proportion of patients with no level 2 hypoglycaemic events (plasma glucose \<54 mg/dL or 3.0 mmol/L) at 60, 90, 105, 120, 135, 150, 165 and 180 min during a 3-hour MMTT |
| CORE PHASE: Assessessment of the effect of pasireotide s.c. on HRQoL (SF-36 score) | at 12 weeks | The 36-item Short Form Health Survey (SF-36) is a patient reported outcomes measure that consists of a 36-item self-report inventory. The SF-36 is an accepted metric for benchmarking indications against normative population-based statistics. It assesses health-related limitations in eight dimensions: physical functioning (PF), role limitations due to physical functioning (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH). Two summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS), can be calculated from the eight-dimension scores (scale scores). |
| CORE PHASE: Assessessment of the effect of pasireotide s.c. on HRQoL (Dumping Score Questionnaire) | at 12 weeks | DSQ is a disease specific patient reported outcome (PRO) scale that was developed according to the FDA and EMEA guidelines. The questionnaire utilizes a 5-point Likert scale (0, none; 1, mild; 2, moderate; 3, severe; and 4, very severe) to ask a patient to evaluate the intensity of 10 early dumping symptoms (within 30 minutes (\<30 minutes) after food ingestion). In addition, the questionnaire also evaluates 5 late dumping symptoms (more than 1.5 hours (\>90 minutes) after food ingestion |
| CORE PHASE: Assessessment of the effect of pasireotide s.c. on HRQoL (Patient Global Assessment) | at 12 weeks | It will incorporate a patient global assessment question: "Considering all the way that your disease affects you, rate how you are feeling during the last 7 days compared with your situation before starting the study?" Patients Global Assessment will be measured utilizing a 7-point scale (from 1= a lot worse to 7= a lot better). |
| CORE PHASE: Assessessment of the effect of pasireotide s.c. on HRQoL (Hypoglycaemia Fear Survey-II) from baseline | at 12 weeks | The Hypoglycaemia Fear Survey (HFS) originally was developed to measure behaviours and worries related to fear of hypoglycaemia (FOH) in adults with type 1 diabetes. Both the original HFS (HFS-I) and the revised version (HFS-II) are composed of two subscales, the Behaviour (HFS-B) and Worry (HFS-W). |
| CORE PHASE: Evaluation of the safety profile of pasireotide s.c (AEs) | for 12 weeks | Incidence of AEs for pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or placebo tid. |
| EXTENSION PHASE: evaluation of the safety profile of pasireotide s.c. during the whole extension period: (AEs) | for 36 weeks | Incidence of AEs for pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or placebo tid. |
| CORE PHASE: Evaluation of the safety profile of pasireotide s.c (Labs) | for 12 weeks | Incidence of laboratory findings for pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or placebo tid. Changes from baseline in laboratory values and vital signs |
| EXTENSION PHASE: evaluation of the safety profile of pasireotide s.c. during the whole extension period: (Labs) | for 36 weeks | Incidence of laboratory findings for pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or placebo tid. Changes from baseline in laboratory values and vital signs |
| CORE PHASE: Evaluation of the safety profile of pasireotide s.c (ECG) | for 12 weeks | Incidence of ECG findings for pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or placebo tid. Changes from baseline in ECG readings, |
| EXTENSION PHASE: evaluation of the safety profile of pasireotide s.c. during the whole extension period: (ECG) | for 36 weeks | Incidence of ECG findings for pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or placebo tid. Changes from baseline in ECG readings, |
| CORE PHASE: Evaluation of the safety profile of pasireotide s.c (imaging) | for 12 weeks | Changes from baseline in gallbladder imaging |
| EXTENSION PHASE: evaluation of the safety profile of pasireotide s.c. during the whole extension period:(imaging) | for 36 weeks | Changes from baseline in gallbladder imaging |
Countries
Belgium, France, Italy, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORArnd H MUELLER, MD
Recordati AG
Outcome results
None listed