short bowel syndrome and intestinal failure

Primary objective • To evaluate the efficacy of weekly SC apraglutide in reducing PS dependency Secondary objectives • To evaluate selected parameters indicative of clinical efficacy • To evaluate the safety and tolerability of apraglutide compared with placebo • To assess the pharmacokinetics (PK) of apraglutide Exploratory objectives • To assess the pharmacodynamic (PD) effect of apraglutide • To evaluate additional selected parameters indicative of clinical efficacy

apraglutide

Apraglutide

注射液

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Primary efficacy endpoint
• Relative change from baseline in actual weekly PS volume at Week 24 Key secondary endpoints.
• Subjects who achieve a reduction of at least 1 day per week of PS from baseline at Week 24
• Relative change from baseline in actual weekly PS volume at Week 24 in stoma subjects.
• Subjects who achieve a reduction of at least 1 day per week of PS from baseline at Week 48 in CIC subjects.
• CIC subjects reaching enteral autonomy at Week 48 Secondary endpoints common to both strata (stoma and CIC)
• Clinical responders (20% reduction of PS volume from baseline at both Weeks 20 and 24)
• Relative change from baseline in actual weekly PS volume at Week 12
• Subjects reaching enteral autonomy at Week 24
• Calorie reduction in the parenteral nutrition (PN) at Week 24
• Change from baseline on the Pittsburgh Sleep Quality Inventory (PSQI) at Week 24
• Patient Global Impression of Change (PGIC) at Week 24
• Change from baseline on the Patient Global Impression of Severity (PGIS) at Week 24
• Apraglutide PK parameters: absorption rate constant (ka), apparent clearance (CL/F) and apparent volume of distribution (Vz/F) of apraglutide, with their intraand inter-individual variability in the subject population
Secondary endpoints for stoma population
• Clinical responders (20% reduction of PS from baseline at both Weeks 20 and 24)
• Subjects who achieve a reduction of at least 1 day per week of PS from baseline at Week 24
• Clinical ‘high’ responders (40% reduction of PS at Weeks 20 and 24)
• Change from baseline on the Short Bowel Syndrome with Intestinal Failure and Stoma - Quality of Life Questionnaire (SBS-IF-S-QOL) at Week 24
• Change from baseline on the Pittsburgh Sleep Quality Inventory (PSQI) at Week 24
• Patient Global Impression of Change (PGIC) at Week 24
• Change from baseline on the Patient Global Impression of Severity (PGIS) at Week 24
Secondary endpoints for CIC population
• Relative change from baseline in actual weekly PS volume at Week 48
• Change from baseline on the Short Bowel Syndrome with Intestinal Failure and Colon-in-Continuity -
Quality of Life Questionnaire (SBS-IF-CIC-QOL) at Week 48
• Change from baseline on the Pittsburgh Sleep Quality Inventory (PSQI) at Week 48
• Patient Global Impression of Change (PGIC) at Week 48
• Change from baseline on the Patient Global Impression of Severity (PGIS) at Week 48
• Trough plasma concentration (Ctrough) at each visit during the prolonged dosing period (Week 24 – Week 48)
Safety endpoint for stoma and CIC populations
• Adverse events of special interest (AESIs):
o Injection site reactions
o Gastrointestinal (GI) obstructions
o Gallbladder, biliary and pancreatic disease
o Fluid overload
o Colorectal polyps
o Malignancies
• Clinical chemistry, hematology, hemostasis, anti-drug antibodies (ADA) including neutralizing ADA (nAb) and cross-reactivity to endogenous GLP-2 and urinalysis
• Adverse events (system organ class, frequency severity and relatedness)

1. Signed informedonsent for this tria
1. Signed informed consent for this trial prior to any trial specific assessment.
2. Male and female subjects with SBS-IF, receiving PS, secondary to surgical resection of the small intestine with <200 cm from duodeno-jejunal flexure, based on
available medical/surgical records and with either: a. CIC and neither jejunostomy nor ileostomy with the latest intestinal resection being at least 12 months prior to screening OR b. Jejunostomy or ileostomy with the latest intestinal resection being at least 6 months prior to screening.
3. Subject is considered optimized (drinking volume is between ≥1.0 L and ≤3.5 L per day and the urinary volume is between ≥0.8 L and ≤2.5 L per day) at trial
Visit 2a, 2b, or 2c and 4.
4. Subject is considered stable with regard to PS volume requirement, drinking volume and urinary output.
5. Parenteral support requirement of at least 3 days per week as assessed before screening and at the time of randomization.
6. Willingness to adhere to an individual pre-defined drinking menu and urine measurements during the 48-hour fluid balance periods.
7. No restorative surgery intended to change PS requirements planned in the trial period
8. Age ≥18 years at screening.
9. Women of childbearing potential must agree to practice effective contraception and to use a highly effective method of contraception during the trial and
for 4 weeks after the EOT visit. Such methods include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of
ovulation (oral, intravaginal, transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner. To be considered sterilized or infertile, females must have undergone surgical
sterilization (bilateral tubectomy, hysterectomy or bilateral ovariectomy) or be post-menopausal (defined as at least 12 months amenorrhea may be confirmed
with follicle-stimulating hormone test if there is doubt).
Women who do not engage in heterosexual intercourse will be allowed to join the trial without contraception following a thorough discussion with the Investigator to determine if this is feasible for the subject.
10.Male subjects with a female partner of childbearing potential must commit to practice highly effective methods of contraception (e.g., condom, vasectomy,
etc.) and abstain from sperm donation during the trial and for 2 weeks after the EOT Visit.

1. Pregnancy or lactation.
2. Major abdominal surgery (more than 10% intestinal resection or surgery that changes anatomy group) in the last 6 months prior to screening. Surgery for
feeding tube placement allowed.
3. A history of clinically significant intestinal adhesions increasing the risk of GI obstruction and/or GI contrast study(s) of remaining small bowel suggesting
subacute intestinal obstruction or mild stricture within 6 months prior to screening.
4. Severe constipation which is not managed by dietary recommendations, laxatives or cathartic medications.
5. Enterocutaneous fistula.
6. History of cancer (including colon carcinoma) or clinically significant lymphoproliferative disease within ≤5 years, except for adequately treated basal cell skin cancer.
7. History of cholecystitis or biliary obstruction, unless cholecystectomy was performed prior to screening.
8. Subjects with Inflammatory Bowel Diseases (IBD) who have NOT been on a stable drug treatment regimen for at least the previous 12 weeks prior to screening and randomization.
9. Evidence of active IBD in the previous 6 months.
10.Visible blood in the stool within the last 12 weeks.
11.Central venous catheter sepsis experienced within the previous 8 weeks, prior to screening and randomization, or use of systemic antibiotics within
the last 30 days prior to screening due to catheter infection.
12.Decompensated heart failure (New York Heart Association class III–IV) [NYHA] and/or known coronary heart disease defined as unstable angina pectoris and/or myocardial infarction within the previous 6 months prior to Screening.
13.Radiation enteritis, scleroderma or other condition of intestinal dysmotility, coeliac disease, refractory or tropical sprue.
14.History of alcohol and/or drug abuse within the previous 12 months prior to screening.
15.Child-Pugh scale Class C.
16.Inadequate renal function as defined by estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology (CKD-EPI) formula at last stability visit.
17.Unplanned hospitalization of >24 hours duration within 4 weeks before initial screening and during screening period.
18.Changes in systemic corticosteroids, methotrexate, cyclosporine, tacrolimus, sirolimus, infliximab, or other biologic therapy/immune modifiers within 30 days of
Screening.
19.Any previous use of growth factors such as growth hormone (GH), native GLP-2, GLP-1, or GLP-2 or GLP-1 analogues in the previous 12 months before
randomization for CIC subjects and 6 months for stoma subjects.
20.Known or suspected hypersensitivity to GLP-1 or GLP-2 analogues or apraglutide excipients.
21.Known neutralizing antibodies (nAb) against GLP-1 or GLP-2 analogues.
22.Participation in another clinical trial within the last 12 weeks and during this trial (studies with catheter locks and observational trials, which are not a burden
on the subject and do not interfere with the participation in this trial, are excluded).
23.Loss of blood or donation of blood or plasma >500 mL within 12 weeks prior to screening.
24.Positive results for human immunodeficiency virus, hepatitis A, B and/or C tests*.
25.Subject not capable of understanding or not willing to adhere to the trial visit schedules and other protocol requirements.
26.Judged not eligible by the Investigator for any otherreason.