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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Recordati AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

13 Jun 2024 → ongoing

Decision date (initial)

2024-05-13

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2023-505316-37-00

ClinicalTrials.gov

NCT05928390

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy of pasireotide s.c. on blood glucose concentration during an MMTT in patients with PBH after 12 weeks of treatment.

Secondary objectives 27

1. Secondary - For the Core phase Key secondary objective: 1. To evaluate the efficacy of pasireotide s.c. on the rate of composite (and individual components) level 2 hypoglycaemic events (by SMBG) OR the frequency of level 3 hypoglycaemic events at 12 weeks of treatment
2. Secondary objectives 1. To evaluate the change of blood glucose nadir and peak during a mixed meal tolerance test (MMTT) at baseline and the MMTT after 12 weeks of treatment with pasireotide s.c. in patients with PBH
3. 2. To evaluate the efficacy of pasireotide s.c. on the change from baseline of level 2 hypoglycaemic events during a MMTT in patients with PBH after 12 weeks of treatment
4. 3. To assess the effect of pasireotide s.c. on HRQoL (SF-36, Dumping Score Questionnaire, Hypoglycaemia Fear Survey-II and Patient Global Assessment) at week 12 of treatment
5. 4. To evaluate the safety profile of pasireotide s.c. during the whole 12-week treatment period
6. Exploratory objectives for the Core Phase 1. To evaluate the efficacy of pasireotide s.c. on the rate of composite (and individual components) level 2 hypoglycaemic events (by SMBG) OR the frequency of level 3 hypoglycaemic events at 4 and 8 weeks of treatment
7. 2. To evaluate the efficacy of pasireotide s.c. on the rate of level 2 hypoglycaemic events (overall, diurnal and nocturnal) at 4, 8 and 12 weeks of treatment (by CGM)
8. 3. To evaluate the effect of pasireotide s.c. on the duration of all level 2 hypoglycaemic events by CGM (overall, diurnal and nocturnal)
9. 4. To evaluate the effect of pasireotide s.c. on the percent time (total hours of CGM readings below 54 mg/dL divided by total CGM wear time) with all Level 2 hypoglycaemia events (overall, diurnal and nocturnal)
10. 5. To assess the effect of pasireotide s.c. on the changes of insulin, glucagon and GLP-1 secretion during the MMTT at 12 weeks of treatment
11. 6. To evaluate the use of rescue therapy and/or rescue carbohydrates required for the treatment of level 2 and level 3 hypoglycaemic events
12. 7. To evaluate the efficacy of pasireotide s.c. on the pulse rate during the MMTT at 12 weeks of treatment
13. 8. To evaluate the efficacy of pasireotide s.c. on haematocrit during the MMTT at 12 weeks of treatment
14. Secondary - For the Extension phase 1. To evaluate the safety profile of pasireotide s.c. during the whole extension period
15. Exploratory objectives - For the Extension phase 1. To evaluate the efficacy of pasireotide s.c. on blood glucose concentration during an MMTT in patients with PBH after 24 weeks of treatment.
16. 2. To evaluate the efficacy of pasireotide s.c. on the rate of composite (and individual components) level 2 hypoglycaemic events (by SMBG) OR the frequency of level 3 hypoglycaemic events at 16, 20, 24, 32, 40 and 48 weeks of treatment
17. 3. To evaluate the change of blood glucose nadir and peak during a MMTT at baseline and the MMTT after 24 weeks of treatment with pasireotide s.c. in patients with PBH
18. 4. To evaluate the efficacy of pasireotide s.c. on the change from baseline on level 2 hypoglycaemic events during a MMTT in patients with PBH after 24 weeks of treatment
19. 5. To assess the effect of pasireotide s.c. on HRQoL (SF-36, Dumping Score Questionnaire, Hypoglycaemia Fear Survey-II and Patient Global Assessment) at Weeks 24 and 48 of treatment
20. 6. To evaluate the efficacy of pasireotide s.c. on rate of level 2 hypoglycaemic events (overall, nocturnal and diurnal) at weeks 16, 20, 24, 32, 40 and 48 of treatment (by CGM)
21. 7. To evaluate the effect of pasireotide s.c. on the duration of level 2 hypoglycaemic events (overall, diurnal and nocturnal) at Weeks 16, 20, 24, 32, 40 and 48 of treatment (by CGM)
22. 8. To evaluate the effect of pasireotide s.c. on the percent time (total hours of CGM readings below 54 mg/dL divided by total CGM wear time) with Level 2 hypoglycaemia (overall, diurnal and nocturnal) at Weeks 16, 20, 24, 32, 40 and 48 of treatment
23. 9. To assess the effect of pasireotide s.c. on the changes of insulin, glucagon and GLP-1 secretion during the MMTT at 24 weeks of treatment
24. 10. To evaluate the use of rescue therapy and/or rescue carbohydrates required for the treatment of level 2 hypoglycaemic events or level 3 hypoglycaemic events
25. 11. To evaluate the efficacy of pasireotide s.c. on the pulse rate during the MMTT at 24 weeks of treatment
26. 12. To evaluate the efficacy of pasireotide s.c. on haematocrit during the MMTT at 24 weeks of treatment
27. PHARMACOKINETIC OBJECTIVE: To investigate the pharmacokinetic profile of pasireotide in PBH patients. Plasma concentrations of pasireotide over time (t-10 min – t180 min) on treatment period week 12 and week 24 will be determined. Primary Pharmacokinetic parameters (Cmax, tmax, AUC0-t) will be determined by Non-Compartmental Analysis (NCA).

Conditions and MedDRA coding

Post-Bariatric Hypoglycaemia

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Male or non-pregnant female patients ≥ 18 years of age.
2. 2. Patients able to provide and have provided signed written informed consent prior to study participation.
3. 3. Patients capable of self-injecting subcutaneously. Specific training to self-inject the study drug will be provided.
4. 4. Post-bariatric surgery more than 6 months prior to screening.
5. 5. 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.
6. 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 <54 mg/dL (3.0 mmol/L) as measured by SMBG (level 2) or • Level 3 hypoglycaemic event
7. 7. (The previous inclusion criterion number 7 has been deleted).
8. 8. Patients in whom dietary control has not sufficiently controlled symptoms of PBH.
9. 9. Karnofsky Performance Status ≥ 60 (i.e., requires occasional assistance, but is able to care for most of their personal needs).
10. 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. 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. 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. 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 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)

Exclusion criteria 27

1. 1. Bariatric patients who have lap band.
2. 10. History of liver disease, such as cirrhosis or chronic active hepatitis B and C.
3. 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.
4. 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.
5. 13. Patients with symptomatic cholelithiasis and/ or acute or chronic pancreatitis.
6. 14. Patients with abnormal coagulation (PT and PTT elevated by 30% above normal limits).
7. 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).
8. 16. Patients who are hypothyroid and not on adequate replacement therapy.
9. 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.
10. 18. Patients requiring gastrostomy tube feedings.
11. 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.
12. 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 <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).
13. 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
14. 21. 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).
15. 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).
16. 23. Significant acute illness within the two weeks prior to dosing.
17. 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.
18. 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.
19. 3. Patients with hypocortisolism, as defined by serum cortisol levels
20. 4. (The previous exclusion criterion number 4 has been deleted).
21. 5. (The previous exclusion criterion number 5 has been deleted).
22. 6. Patients who have a known hypersensitivity to somatostatin receptor analogues.
23. 7. Patients currently using medications that may interfere with glucose metabolism within 5 half-lives of drug.
24. 8. Patients with history of or current insulinoma.
25. 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 < 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
26. 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. 27. Potentially unreliable or vulnerable patients (e.g., person kept in detention) and those judged by the Investigator to be unsuitable for the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in the blood glucose levels, as measured by the peak to nadir glucose AUC, during the MMTT at baseline to the MMTT at 12 weeks of treatment with pasireotide s.c. 50 µg, or 100 µg or 200 µg tid vs placebo tid.

Secondary endpoints 26

1. Secondary and exploratory – For the Core phase Key secondary endpoint: 1. 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 s.c. 50 µg, or 100 µg or 200 µg tid vs placebo tid.
2. Secondary endpoints: 1. Change in the nadir and peak of blood glucose levels, during the MMTT at baseline to the MMTT at 12 weeks of treatment with pasireotide s.c. 50 µg, or 100 µg or 200 µg tid vs placebo tid
3. 2. 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 after 12 weeks of treatment with pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or vs placebo tid respectively
4. 3. Changes in HRQoL (SF-36 score, Hypoglycaemia Fear Survey-II, Dumping Score Questionnaire and Patient Global Assessment) from baseline to week 12 of treatment with pasireotide s.c. 50, or 100 or 200 µg tid or placebo tid
5. 4. Incidence of AEs, laboratory, and ECG findings at pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or placebo tid. Changes from baseline in laboratory values, ECG readings, gallbladder imaging and in vital signs
6. Exploratory endpoints: 1. 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 4 and 8 weeks of treatment with pasireotide s.c. 50 µg, or 100 µg or 200 µg tid vs placebo tid
7. 2. Change from baseline in the rate of level 2 hypoglycaemic events (glucose level <54 mg/dL or 3.0 mmol/L for at least 15 minutes) including the overall, diurnal and nocturnal events measured by CGM at 4, 8 and 12 weeks of treatment with pasireotide s.c. 50 µg, or 100 µg or 200 µg tid vs placebo tid
8. 3. Change from baseline in duration of Level 2 hypoglycaemic events (glucose level <54 mg/dL or 3.0 mmol/L for at least 15 minutes), including the overall, diurnal and nocturnal events by CGM at 4, 8, and 12 weeks of treatment with pasireotide s.c. 50, or 100 or 200 µg tid or placebo tid
9. 4. Change from baseline in percent time with Level 2 hypoglycaemic events (glucose level <54 mg/dL or 3.0 mmol/L for at least 15 min) including the overall, diurnal and nocturnal events by CGM at 4, 8, and 12 weeks of treatment with pasireotide s.c. 50, or 100 or 200 µg tid or placebo tid
10. 5. Absolute and percent changes in insulin, glucagon and GLP-1 secretion from baseline during the MMTT after 12 weeks of treatment with pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or placebo tid
11. 6. Change from baseline in the frequency of use of rescue therapy and/or rescue carbohydrates at home to manage Level 2 or Level 3 hypoglycaemic events at 4, 8, and 12 weeks of treatment with pasireotide s.c. 50 µg, or 100 µg or 200 µg tid vs placebo tid
12. 7. Proportion of participants with change in pulse rate <10 bpm during the MMTT after 12 weeks of treatment with pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or placebo tid
13. 8. Proportion of participants with change in haematocrit <3% during the MMTT after 12 weeks of treatment with pasireotide s.c. 50 µg, or 100 µg or 200 µg tid or placebo tid
14. Secondary and Exploratory endpoints For the Extension Phase. Secondary For the Extension phase 1. Incidence of AEs, laboratory, and ECG findings with pasireotide s.c. tid. Changes from baseline in laboratory values, ECG readings, gallbladder imaging and in vital signs during the whole extension period
15. Exploratory For the Extension phase 1. Change in the blood glucose levels, as measured by the peak to nadir glucose AUC, during the MMTT at baseline to the MMTT at 24 weeks of treatment with pasireotide s.c. tid.
16. 2. Change from baseline in the rate of the composite (and individual components) of clinically significant hypoglycaemic events as measured as the frequency level 2 hypoglycaemic events (glucose level <54 mg/dL or 3.0 mmol/L) measured by SMBG or Level 3 hypoglycaemic events (requiring external assistance) at weeks 16, 20, 24, 32, 40 and 48 of treatment with pasireotide s.c. tid
17. 3. Change in the nadir and the peak of blood glucose levels, during the MMTT at baseline to the MMTT at 24 weeks of treatment with pasireotide s.c. tid
18. 4. 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 after 24 weeks of treatment with pasireotide s.c. tid
19. 5. Changes in HRQoL (SF-36 score, Dumping Score Questionnaire, Hypoglycaemia Fear Survey-II and Patient Global Assessment) from baseline with pasireotide s.c. tid at weeks 24 and 48 of treatment
20. 6. Change from baseline in the rate of level 2 hypoglycaemic events (blood glucose <54 mg/dL or 3.0 mmol/L for at least 15 minutes) including the overall, diurnal and nocturnal events by CGM with pasireotide s.c. tid at weeks 16, 20, 24, 32, 40 and 48 of treatment
21. 7. Change from baseline in duration of Level 2 hypoglycaemic events (glucose level <54 mg/dL or 3.0 mmol/L for at least 15 minutes) including the overall, diurnal and nocturnal events by CGM with pasireotide s.c. tid at weeks 16, 20, 24, 32, 40 and 48 of treatment
22. 8. Change from baseline in percent time with Level 2 hypoglycaemic events (glucose level <54 mg/dL or 3.0 mmol/L for at least 15 minutes) including the overall, diurnal and nocturnal events by CGM with pasireotide s.c. tid at weeks 16, 20, 24, 32, 40 and 48 of treatment
23. 9. Absolute and percent changes in insulin, glucagon and GLP-1 secretion from baseline during the MMTT after 24 weeks of treatment with pasireotide s.c. tid
24. 10. Change from baseline in the frequency of use of rescue therapy and/or rescue carbohydrates at home to manage Level 2 or Level 3 hypoglycaemic events during treatment with pasireotide s.c. tid at weeks 16, 20, 24, 32, 40 and 48 of treatment
25. 11. Proportion of participants with change in pulse rate <10 bpm during the MMTT at 24 weeks of treatment with pasireotide s.c. tid
26. 12. Proportion of participants with change in haematocrit <3% during the MMTT 24 weeks of treatment with pasireotide s.c. tid

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Recordati AG

Sponsor organisation

Recordati AG

Address

Uferstrasse 90

City

Basel Town

Postcode

4057

Country

Switzerland

Scientific contact point

Organisation

Recordati AG

Contact name

Arnd Mueller

Public contact point

Organisation

Recordati AG

Contact name

Clinical Trial Information Desk

Third parties 6

Locations

4 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 88 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

17 submissions — initial application plus substantial / non-substantial modifications