Clinical trial NCT05928390: Pasireotide s.c. in Patients With Post-Bariatric Hypoglycaemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Post-Bariatric Hypoglycemia
Keywords: PBH
Post Bariatric
Lead sponsor: RECORDATI GROUP
Sponsor class: INDUSTRY
First posted: 2023-07-03
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 defined as:

   * Blood glucose less than 54 mg/dL (3.0 mmol/L) as measured by SMBG (level 2) or
   * Neuroglycopenia event 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\&#39;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.

Primary outcomes:
measure: Evaluation of the efficacy of pasireotide s.c. on blood glucose concentration during an MMTT in patients with PBH after 12 weeks of treatment.
timeFrame: 12 weeks
Secondary outcomes:
measure: Efficacy of pasireotide s.c. on the rate of level 2 hypoglycaemic event measured by SMBG
timeFrame: 4, 8 and 12 weeks
measure: Efficacy of pasireotide s.c. on level 2 hypoglycaemic events after MMTT
timeFrame: 12 weeks
measure: Efficacy of pasireotide s.c. on the rate of level 3 hypoglycaemic events
timeFrame: 4, 8 and 12 weeks
measure: Efficacy of pasireotide s.c. on the rate of level 2 hypoglycaemic events by CGM
timeFrame: 4, 8 and 12 weeks
measure: Effect of pasireotide s.c. on the duration of level 2 hypoglycaemic events by CGM
timeFrame: 4,8 and 12 weeks
measure: Effect of pasireotide s.c. on the percent time with Level 2 hypoglycaemia by CGM
timeFrame: 4,8 and 12 weeks
measure: Use of rescue therapy and/or rescue carbohydrates required for the treatment of level 2 hypoglycaemic events
timeFrame: 4, 8 and 12 weeks
measure: Use of rescue therapy and/or rescue carbohydrates required for the treatment of level 3 hypoglycaemic events
timeFrame: 4, 8 and 12 weeks
measure: Efficacy of pasireotide s.c. on the pulse rate during the MMTT
timeFrame: 12 weeks
measure: Efficacy of pasireotide s.c. on haematocrit during the MMTT
timeFrame: 12 weeks
measure: Effect of pasireotide s.c. on the changes of glucagon
timeFrame: 12 weeks
measure: Effect of pasireotide s.c. on the changes of insulin
timeFrame: 12 weeks
measure: Effect of pasireotide s.c. on the changes of GLP-1 secretion
timeFrame: 12 weeks
measure: Safety profile of pasireotide
timeFrame: 12 weeks
measure: Efficacy of pasireotide s.c. on rate of level 2 hypoglycaemic events by CGM
timeFrame: 16, 20, 24, 32, 40 and 48 weeks
measure: Efficacy of pasireotide s.c. on rate of level 2 hypoglycaemic events by SMBG
timeFrame: 16,20,24,32,40 and 48 weeks
measure: Efficacy of pasireotide s.c. on rate of level 3 hypoglycaemic events
timeFrame: 16,20,24,32,40 and 48 weeks
measure: Effect of pasireotide s.c. on the duration of level 2 hypoglycaemic events by CGM
timeFrame: 16, 20, 24, 32, 40 and 48 weeks
measure: Effect of pasireotide s.c. on the percent time with Level 2 hypoglycaemic events by CGM
timeFrame: 16, 20, 24, 32, 40 and 48 weeks
measure: Use of rescue therapy and/or rescue carbohydrates required for the treatment of level 2 hypoglycaemic events
timeFrame: 16, 20, 24, 32, 40 and 48 weeks
measure: Use of rescue therapy and/or rescue carbohydrates required for the treatment of level 3 hypoglycaemic events
timeFrame: 16, 20, 24, 32, 40 and 48 weeks
measure: Efficacy of pasireotide s.c. on the pulse rate during the MMTT
timeFrame: 24 weeks
measure: Efficacy of pasireotide s.c. on haematocrit during the MMTT
timeFrame: 24 weeks
measure: Effect of pasireotide s.c. on the changes of insulin
timeFrame: 24 weeks
measure: Effect of pasireotide s.c. on the changes of glucagon
timeFrame: 24 weeks
measure: Effect of pasireotide s.c. on the changes of GLP-1 secretion
timeFrame: 24 weeks
measure: Safety profile of pasireotide s.c.
timeFrame: 48 weeks
measure: Effect of pasireotide s.c. on HRQoL in SF-36 health survey
timeFrame: 12, 24 and 48 weeks
Other outcomes:
measure: Effect of pasireotide s.c. on HRQoL in Hypoglycaemia Fear Survey-II
timeFrame: 12, 24 and 48 weeks
measure: Effect of pasireotide s.c. on HRQoL in Dumping Score Questionnaire
timeFrame: 12, 24 and 48 weeks
measure: Effect of pasireotide s.c. on HRQoL in Patient Global Assessment
timeFrame: 12, 24 and 48 weeks
Locations:
city: Palo Alto
country: United States
facility: Stanford University School of Medicine, Endocrinology, 800 Welch Road,
state: California
city: Lawrenceville
country: United States
facility: Georgia Clinical Research, LLC, 2878 Five Forks Trickum SW, Suite 2A
state: Georgia
city: Chicago
country: United States
facility: Northwestern University - Feinberg School of Medicine - Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Metairie
country: United States
facility: NOLA Care
state: Louisiana
city: Annapolis
country: United States
facility: Velocity Clinical Research - Annapolis
state: Maryland
city: Boston
country: United States
facility: Joslin Diabetes CenterJoslin Diabetes Center, One Joslin Place
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic - Rochester, 200 First Street, SW, 55905
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center, 111 E 210th Street,
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Clinical Research Solution: Endocrine and Psychiatry Center, 9539 Huffmeister Rd,
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr,
state: Texas
city: Madison
country: United States
facility: University of Wisconsin Health W. E. Clinic END, 451 Junction Rd,
state: Wisconsin
city: Leuven,
country: Belgium
facility: Universitaire Ziekenhuizen Leuven, Department of Gastroenterology and Hepatology,Herestraat 49
city: Paris
country: France
facility: AP-HP Hopital Europeen Georges Pompidou, 20, rue Leblanc,
city: Pierre-Benite Cedex
country: France
facility: HCL Centre Hospitalier Lyon Sud
city: Toulouse
country: France
facility: Hopital Rangueil, Attachée de Recherche Clinique, Centre Investigation Clinique, CHU, Cedex 9, France
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna - Policlinico di Sant Orsola
city: Padova
country: Italy
facility: Azienda Ospedale - Università Padova, Clinica Medica 3, Via Giustiniani, 2,
city: Palermo
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli IRCCS - Universita Cattolica del Sacro Cuore, L.go Gemelli 8
city: Barcellona
country: Spain
facility: Hospital Clinic Barcelona, Lipid Clinic End, Nutr. Service Hospital Clinic, C. Villarroel, 170,
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron, Passeig Vall d´Hebron 119-129, Spain
city: Barcelona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Girona
country: Spain
facility: Hospital Universitari de Girona Dr. Josep Trueta
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos, C/ Prof Martin Lagos s/n, Spain
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Bristol
country: United Kingdom
facility: North Bristol NHS Trust
city: London,
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust, Denmark Hill, SE5 9RS
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
Study officials:
affiliation: Recordati AG
name: Arnd H MUELLER, MD
role: STUDY_DIRECTOR
References: