A Study to Investigate the Efficacy and Safety of Apraglutide Compared With Placebo in Adult Participants With Short Bowel Syndrome Associated With Intestinal Failure (SBS-IF)

Официальное название

A Parallel-group Treatment, Phase 3, Double-blind, Randomized, 2-arm Study to Investigate the Efficacy and Safety of Apraglutide Compared With Placebo in Adult Participants With Short Bowel Syndrome Associated With Intestinal Failure (SBS-IF)

Обзор

This Phase 3 placebo-controlled study is planned to further investigate the efficacy, safety, and tolerability of apraglutide in the overall SBS-IF (short bowel syndrome associated with intestinal failure) population during 24 weeks of study treatment. It is expected that approximately 124 participants will be randomized worldwide to either apraglutide or placebo in a 1:1 ratio in this trial.

Подробное описание

This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group, Phase 3 study to investigate the efficacy, safety, and tolerability of apraglutide compared with placebo in adults with SBS-IF. The study population will be representative of the SBS-IF general population and will include adult participants (≥18 years of age) who are dependent on, and who are receiving, PS at least 3 days per week. Eligible participants will be randomized 1:1 to receive SC apraglutide or placebo once weekly for 24 weeks stratified by anatomy (i.e., colon-in-continuity \[CIC\] or stoma) and baseline parenteral support (PS) volume (i.e., \<12 L/week or ≥12 L/week). The number of randomized participants in CIC and stoma will be monitored to ensure approximately equal numbers of CIC and stoma participants are randomized.

The study will consist of 4 periods: a Screening Period prior to randomization (including optimization and stabilization phases), a Treatment Period starting at randomization, a Safety Follow-up (SFU) Period after the last dose of IMP is completed, and an Anti-Drug Antibody (ADA) Follow-up Period beginning after the last dose of IMP.

All participants who complete the IMP treatment will be offered participation in an open label single arm apraglutide long-term extension (LTE) study. Participants who do not wish to continue onto the LTE study will be requested to complete an SFU Visit, which will occur 4 weeks (±1 week) after the last dose of IMP, after which they will transition into ADA Follow-Up period.

Вмешательства

• Препарат Apraglutide
  Apraglutide is a synthetic peptide analogue of glucagon-like peptide-2 (GLP-2), which acts as a full agonist at the GLP-2 receptor with in vitro potency and selectivity comparable with native GLP-2. Participants will be administered or will self-administer a weekly SC injection of apraglutide.
• Препарат Placebo
  Participants will be administered or will self-administer a weekly single SC injection of placebo in the matching injection volumes.

Первичные конечные точки

• Relative change from baseline in actual weekly PS volume at Week 24. [Срок оценки: At Week 24]

Вторичные конечные точки (12)

• Participants who achieve clinical response in actual weekly PS volume (at least 20% reduction from baseline) at both Week 20 and Week 24. [Срок оценки: At both Week 20 and Week 24]
• Participants who achieve a reduction of PS days per week (categorical) from baseline at Week 24. [Срок оценки: At Week 24]
• Participants who achieve a reduction of at least 1 PS day per week from baseline at Week 24. [Срок оценки: At Week 24]
• Participants reaching enteral autonomy at Week 24. [Срок оценки: At Week 24]
• Absolute change from baseline in actual weekly PS volume at Week 24. [Срок оценки: At Week 24]
• Participants who achieve clinical response (categorical) in actual weekly PS volume reduction from baseline at both Week 20 and Week 24. [Срок оценки: At both Week 20 and Week 24]
• Participants who achieve a reduction of at least 2 PS days per week from baseline at Week 24. [Срок оценки: At Week 24]
• Participants who achieve a reduction of at least 3 PS days per week from baseline at Week 24. [Срок оценки: At Week 24]
• Relative change from baseline in actual weekly PS volume at Week 12. [Срок оценки: At Week 12]
• Relative change from baseline in parenteral nutrition (PN) calories at Week 24. [Срок оценки: At Week 24]
• Improvement on Patient Global Impression of Change Version 2 (PGICv2) at Week 24. [Срок оценки: At Week 24]
• Incidence of Treatment-Emergent Adverse Events [Срок оценки: From first dose through 28 days after last dose]

Критерии участия

Критерии включения

• Participant must be ≥18 years of age, at the time of signing the informed consent.
• Male and female participants with SBS-IF, receiving PS secondary to surgical resection of the small intestine with residual length ≥10 cm to <200 cm from duodeno-jejunal flexure, based on available clinical and/or medical/surgical records, and with either: (a.) CIC remaining and neither jejunostomy nor ileostomy with the latest intestinal resection resulting in SBS-IF being at least 12 months prior to Screening OR (b.) Jejunostomy or ileostomy with the latest intestinal resection resulting in SBS-IF being at least 6 months prior to Screening.
• BMI of ≥18.5 to <30 kg/m2 at randomization.
• Individuals of any gender identity, assigned male or female at birth are eligible to participate. Male participants: Male participants with a female partner of childbearing potential must commit to practice highly effective methods of contraception (eg, condom, vasectomy) and abstain from sperm donation during the study and for 2 weeks after the EOT/Early Discontinuation (ED) Visit. Female participants: Women of childbearing potential must agree to practice effective contraception and to use a highly effective method of contraception during the study and for 4 weeks after the EOT/ED Visit. To be considered sterilized or infertile, female participants must have undergone surgical sterilization (hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or be postmenopausal (defined as at least 12 months amenorrhea without an alternative medical cause; a follicle-stimulating hormone \[FSH\] test \[with or without estradiol\] is required to confirm if there is doubt). Women who do not engage in heterosexual intercourse will be allowed to join the study without contraception following a thorough discussion with the investigator to determine if this is feasible for the participant. The following are not considered acceptable methods of contraception: calendar, ovulation, symptothermal, postovulation methods, withdrawal (coitus interruptus), spermicides only, and the lactational amenorrhea method.
• Signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.
• PS requirement of at least 3 days per week as assessed before Screening, at the end of optimization, and at the time of randomization.
• Participant is considered optimized (average drinking volume is ≥1.0 L and ≤3.5 L per day and the average urinary volume is ≥0.8 L and ≤2.5 L per day) at study Visit 2a, 2b, or 2c.
• Participant is considered stable with regard to PS volume requirement, drinking volume, and urinary output at last Stabilization Phase Visit and Visit 4 when the actual PS usage matches prescribed PS (±10% deviation in volume from the last optimization visit), average urine volume at the last stabilization visit and randomization visit match (±25% deviation from last optimization visit is acceptable), while the average drinking volume is constant (the 48-hour oral intake differs from the last optimization visit by less than 10% and minimum 1.0 and maximum 3.5 L per day) and average urine volume is ≥0.8 L and ≤2.5 L per day.
• Willingness to adhere to an individual predefined drinking menu and urine measurements during the 48-hour fluid balance periods.
• No planned restorative surgery or major intestinal surgery (more than 10% intestinal resection or surgery that changes anatomy group, ie, CIC or stoma) from the signing of informed consent through completion of the SFU visit.
• Willingness to undergo either a colonoscopy or CT/MRI colonography (if anatomically feasible and medically appropriate) and have any identified polyps removed.

Критерии исключения

• Pregnancy and/or lactation and/or plans to become pregnant or to breastfeed.
• Major abdominal surgery (more than 10% intestinal resection or surgery that changes anatomy group) in the last 6 months prior to Screening Visit. Surgery for feeding tube placement and cholecystectomy allowed, after discussion with medical monitor and appropriate documentation. Any planned surgical procedures during the study duration must be discussed with the medical monitor prior to enrollment, with appropriate documentation of approval of eligibility, if applicable.
• Ultra-short gut (residual length <10 cm from duodeno-jejunal flexure).
• A history of clinically significant intestinal adhesions increasing the risk of GI obstruction and/or GI contrast study(ies) of remaining small bowel suggesting subacute intestinal obstruction or mild stricture within 6 months prior to Screening.
• Constipation that is not adequately managed by dietary recommendations, laxatives, or cathartic medications.
• Active or untreated enterocutaneous fistula.
• History of cancer (including colon carcinoma) or clinically significant lymphoproliferative disease within ≤5 years, except for adequately treated basal cell skin cancer.
• Diagnosis of any variant of familial adenomatous polyposis or comparable polyposis syndrome.
• Active inflammatory bowel disease or any other acute or chronic related underlying medical condition that, in the opinion of the investigator, would limit the participant's ability to complete or participate in the study, or confound study results. Discussion with the medical monitor is required.
• Sepsis experienced within the previous 2 months prior to or during Screening; or a central venous catheter infection requiring the use of systemic antibiotics within 30 days prior to or during Screening, with the exception of systemic antibiotics administered for <72 hours while awaiting the results of pending blood culture(s) that turn out negative (ie, <72 hours empiric systemic antibiotics while ruling out a central venous catheter infection is allowed as long as the culture turns out negative).
• Decompensated heart failure (New York Heart Association class III-IV) and/or known coronary heart disease defined as unstable angina pectoris and/or myocardial infarction within the previous 6 months prior to Screening.
• Radiation enteritis, scleroderma, or residual evidence of intestinal dysmotility, including pseudo-obstruction and Hirschsprung's disease, coeliac disease, refractory or tropical sprue.
• History of alcohol or drug abuse within the previous 12 months prior to Screening that, in the opinion of the investigator, could interfere with study participation, compliance, and safety of participants.
• Child-Pugh scale Class C for liver disease.
• Evidence of chronic renal disease as demonstrated by inadequate renal function, which is defined as estimated glomerular filtration rate <20 mL/min/1.73 m2 (using the Chronic Kidney Disease Epidemiology formula).
• Positive results for HIV, hepatitis A, B, and/or C tests at the Screening Visit. Note: Participants recovered from hepatitis B or C can be enrolled, ie, they have markers of the infection, but the viral load is undetectable. Participants with evidence of an acute or chronically active hepatitis B or C infection should be excluded. If a participant has a positive hepatitis A immunoglobulin M test, this would indicate an acute infection and the participant is ineligible, but they may be eligible for rescreening after recovery. Participants with positive HIV test results and undetectable viral loads may be rescreened (in case the initial test was a false positive).
• Clinically significant concurrent illness (eg, uncontrolled hypertension, pancreatic or gallbladder disease) or finding on physical examination or clinical laboratory test after signing the ICF but before receiving the first dose of IMP. Note: The investigator will determine if a finding is clinically significant. The investigator will consider whether the finding 1) could prevent the participant from performing any study procedure or assessment, 2) represents a condition that would be exclusionary, 3) could represent a safety concern if the participant participated in the study, or 4) could confound any study assessment.
• Elevated liver enzymes during the screening period: (a.) ALT or AST >5 × upper limit of normal (ULN); (b.) ALT or AST >3 × ULN and total bilirubin (TBL) >2 × ULN or international normalized ratio (INR) >1.5 for a person not using anticoagulant drug and INR >3 for a person on anticoagulant therapy such as warfarin; (c.) ALT or AST >3 × ULN and clinical signs of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia; (d.) Participants with serum conjugated bilirubin >34 μmol/L during 2 consecutive measurements.
• Use of diuretics, anti-diarrheals, and other common concomitant medications used in SBS-IF if dosing is not stable within 14 days prior to randomization.
• New drug treatment other than biologic therapies, or a change to the dose or dosing interval of an existing drug treatment other than a biologic, within 1 month prior to randomization. In cases of weight loss or weight gain, dose adjustments that enable the same drug unit/kg dosing (eg, mg/kg) for weight-based dosing are permitted within 1 month prior to randomization after discussion with the medical monitor and proper documentation.
• New biologic therapy or changes to dose or dosing interval of existing biologic therapy within 3 months prior to Screening, unless the dose adjustment was due to a change in weight and maintained the same drug-unit/kg (eg, mg/kg) weight-based dosing. Switching from a reference biologic product to a biosimilar, while maintaining the same dose and dosing interval, is permitted outside the 3 months prior to the screening window and/or during the study.
• Use of dipeptidyl peptidase-4 inhibitors within 3 months prior to Screening.
• At least 2 weeks of treatment with growth factors, such as growth hormone, glutamine, native GLP-2, GLP-1, short acting GLP-2 analogs (eg, teduglutide) or GLP-1 analogs within 3 months before Screening; or treatment with longer acting experimental GLP-2 analogs in the previous 6 months before Screening. Note: Prior discontinuation of GLP-2 analog treatment due to safety concerns or lack of efficacy is an exclusion criterion regardless of wash-out period. For prior discontinuation due to intolerance, the patient may be eligible based on discussion with the medical monitor. The nature of the intolerance must be clearly documented and discussed with the medical monitor.
• Citrulline supplements within less than 30 days prior to Screening.
• Prior use of apraglutide, or prior randomization in this study. Note: Randomization to placebo in a prior study of apraglutide is not an exclusion criterion.
• Known or suspected hypersensitivity to GLP-1 or GLP-2 analogs or any apraglutide excipients.
• Known antidrug antibodies (ADAs) against GLP-1 or GLP-2 analogs.
• Participation in another interventional clinical study in the last 3 months before screening and during this study (studies with catheter locks or observational studies, which are not a burden on the participant and do not interfere with the participation in this study, are allowed after discussion with the medical monitor).
• Incapable of understanding or unwilling to adhere to the study visit schedules and/or other protocol requirements.
• Inability to prepare and/or administer the dose of the study intervention or inability to have the dose prepared and/or administered by an appropriately trained care provider.
• Any condition, underlying disease, or circumstance, including psychosocial or environmental that, in the opinion of the investigator, could reduce the participant's adherence with the study visit schedule, dosing regimen, or other study requirements.
• Participant is directly or indirectly involved in the conduct and administration of this study as an investigator, subinvestigator, study coordinator, study staff member, or employee of the sponsor; or the participant is a direct relative of an individual involved in the study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 17 центров

• Ronald Reagan UCLA Medical Center, Center for the Health Sciences — Los Angeles
• Denver Health Medical Center — Denver
• MedStar Georgetown University Hospital — Washington D.C.
• University of Florida Health (UF Health) — Gainesville
• GI Pros — Naples
• Cleveland Clinic Florida — Weston
• Loyola University Medical Center — Maywood
• UofL Physicians - Colon & Rectal Surgery — Louisville
• … и ещё 9 центров

Германия · 8 центров

• University Hospital Heidelberg, Department of Endocrinology and Metabolism — Heidelberg
• University Hospital Erlangen — Erlangen
• Asklepios Clinic St. Georg — Hamburg
• University Hospital Bonn — Bonn
• University Duisburg-Essen, University Hospital Essen — Essen
• University Hospital Muenster — Münster
• University Hospital Aachen AoeR — Aachen
• Charite - University Hospital Berlin — Berlin

Бразилия · 7 центров

• Hospital Sao Marcos — Teresina
• Caxias Do Sul University / Clinical Research For Multicenter Studies Institute — Caxias do Sul
• Porto Alegre Clinical Hospital (HCPA) — Porto Alegre
• Pontifical University Of Rio Grande Do Sul (PUCRS) - St. Luke Hospital — Porto Alegre
• Regional Medical School Foundation (CIP HB/FAMERP) — São José do Rio Preto
• QualiVida Higienopolis - Hapvida NotreDame — São Paulo
• University of São Paulo Faculty of Medicine Clinics Hospital — São Paulo

Италия · 6 центров

• Polyclinic San Matteo, IRCCS — Pavia
• University Hospital of Padova — Padova
• IRCCS University Hospital of Bologna, Polyclinic S. Orsola-Malpighi — Bologna
• Careggi University Hospital — Florence
• Maggiore Polyclinic Hospital, Foundation IRCCS Ca' Granda — Milan
• University Hospital City of Health and Science of Turin - Hospital Molinette — Torino

Таиланд · 6 центров

Список центров уточняется — проверьте первичный протокол.

Франция · 5 центров

• Beaujon Hospital - APHP — Clichy
• Hospices Civils de Lyon - Lyon Sud — Lyon
• Nantes University Hospital Center - Hotel Dieu Hospital — Nantes
• Bordeaux University Hospital Center - Haut-Leveque Hospital, Haut-Leveque Hospital — Pessac
• Nancy Regional University Hospital Center - Brabois Hospital — Vandœuvre-lès-Nancy

Израиль · 5 центров

• Rambam Health Care Campus, Institute of Gastroenterology, Nutrition Clinic — Haifa
• Shaare Zedek Medical Center, Digestive Diseases Institute, Nutrition Clinic — Jerusalem
• Meir Medical Center, Institute of Gastroenterology and Liver Diseases — Kfar Saba
• The Tel Aviv Sourasky Medical Center, Institute of Gastrointestinal and Liver Diseases, Nu — Tel Aviv
• Chaim Sheba Medical Center, Institute of Gastrointestinal Diseases, Nutrition Unit — Tel Litwinsky

Великобритания · 5 центров

Список центров уточняется — проверьте первичный протокол.

Аргентина · 4 центра

• Buenos Aires Italian Hospital — Buenos Aires
• Allende Sanatorium — Córdoba
• San Martin General La Plata Acute General Regional Hospital — La Plata
• CDC Medical Center — Luján

Австралия · 4 центра

• St Vincent's Hospital (Melbourne) Ltd — Fitzroy
• Austin Hospital — Heidelberg
• Royal Brisbane and Women's Hospital, Gastroenterology and Hepatology — Herston
• Fiona Stanley Hospital, Harry Perkins Medical Research Institute — Perth

Чехия · 4 центра

• University Hospital Brno, Clinic of Internal Medicine - Gastroenterology — Brno
• University Hospital Hradec Kralove, 3rd Internal Clinic of Geronto-Metabolic — Hradec Králové
• University Hospital Kralovske Vinohrady, Internal Clinic — Prague
• General University Hospital in Prague — Prague

Япония · 3 центра

• Yokohama Municipal Citizen's Hospital — Yokohama
• Saga-Ken Medical Centre Koseikan — Saga
• Kagawa University Hospital — Kagawa

Польша · 3 центра

• Non-Public Healthcare Facility Stadmedica, Ambulatory Specialist Care — Bydgoszcz
• Medrise Sp. z o.o. (LLC) — Lublin
• Jerzy Gromkowski Provincial Specialist Hospital — Wroclaw

South Korea · 3 центра

• Asan Medical Center — Seoul
• Samsung Medical Center — Seoul
• The Catholic University of Korea, Seoul St. Mary's Hospital — Seoul

Тайвань · 3 центра

Список центров уточняется — проверьте первичный протокол.

Австрия · 2 центра

• Order Hospital Linz Ltd. - Hospital of Sisters of Mercy, Department of Surgery — Linz
• University Hospital Graz — Graz

Бельгия · 2 центра

• University Hospital Antwerp (UZA), Department of Gastroenterology and Hepatology — Edegem
• University Hospitals Leuven, Campus Gasthuisberg, Department of Gastroenterology — Leuven

Канада · 2 центра

• Pacific Gastroenterology Associates — Vancouver
• CHUM - University of Montreal Hospital Centre — Montreal

Венгрия · 2 центра

• Semmelweis University, Department of Surgery, Transplantation and Gastroenterology — Budapest
• University of Szeged, Department of Internal Medicine- Western Site — Szeged

Дания · 1 центр

• Rigshospitalet - University Hospital Copenhagen — Copenhagen

Нидерланды · 1 центр

• Radboud University Medical Center (Radboudumc) — Nijmegen

Испания · 1 центр

• University Hospital Virgen del Rocio (HUVR) — Seville

Идентификаторы

NCT: NCT07742735 · TA799-025 · 2026-526274-16-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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