Efficacy and Safety of Dual pH-Dependent Delayed-Release Colesevelam Hydrochloride in Patients with Moderate-to-Severe Bile Acid Diarrhoea
- Trial ID
- 2025-523868-20-00
- Protocol
- F106-CT01
- Sponsor
- Monteresearch S.r.l.
Trial statistics
Objectives
The primary objective is to demonstrate the superiority of a 12-day treatment with dual pH-dependent delayed-release colesevelam compared to a placebo regarding the remission rate in patients with moderate-to-severe bile acid diarrhoea, as defined by 75SeHCAT diagnostic criteria. 5, 3
Secondary objectives include:
- Evaluation of efficacy based on remission rates using C4 criteria, stool consistency, stool frequency, complete spontaneous bowel movement, urgency of defecation, gastrointestinal symptoms, and the use of rescue medication.
- Exploratory assessment of bile acid hepatic synthesis.
- Assessment of safety and tolerability through the monitoring of adverse events, vital signs, and laboratory evaluations.
Participants
The sponsor did not provide information regarding the total number of participants. The study population consists of male and female patients diagnosed with moderate-to-severe bile acid diarrhoea. Eligible participants include individuals aged between 18 and 79 years. Inclusion requires evidence of the condition as confirmed by 75SeHCAT scintigraphy, specifically a value of ≤10%. Furthermore, participants must exhibit active disease according to Hjortswang criteria, characterized by a mean of at least three stools per day or at least one watery stool per day. Females of childbearing potential are required to utilize highly effective contraception throughout the trial period.
Plans and Procedures
This is a Phase IIa, randomized, double-blind, parallel-group, placebo-controlled clinical trial designed to evaluate the efficacy and safety of a novel dual pH-dependent delayed-release colesevelam hydrochloride for the treatment of bile acid diarrhoea. The study employs a methodology to demonstrate the superiority of the test product against a placebo in achieving remission rates for participants with moderate-to-severe disease. The research protocol includes a screening period to confirm diagnosis via 75SeHCAT scintigraphy and assess symptomatic activity. Following screening, participants undergo a randomization process and a treatment period consisting of a stable dose phase from Day 6 to Day 12. The sequence of study activities concludes with an end-of-study visit to evaluate safety and efficacy endpoints. Total participant involvement is determined by the assessment of clinical outcomes and safety parameters, including the monitoring of adverse events. Early termination from the study may occur due to various clinical conditions or protocol non-compliance.
Treatment
The investigational product, SUB01423MIG, consists of colesevelam hydrochloride administered as a gastro-resistant tablet. The dosage is 1875 mg, provided via oral use.
A placebo is utilized in the study, consisting of film-coated oral tablets that are matched to the appearance of the experimental medication.
The background therapy includes DISSENTEN, which contains loperamide hydrochloride. This medication is administered as an 8 mg tablet for oral use.
Efficacy
The primary efficacy endpoint is the proportion of participants achieving bile acid diarrhoea remission, as determined by Hjortswang criteria, at the conclusion of the stable dose treatment period between days 6 and 12. This assessment applies to participants with moderate-to-severe disease, defined by 75SeHCAT levels of ≤10%.
Secondary efficacy endpoints include the following:
- Proportion of participants achieving remission according to Hjortswang criteria at the end of the stable dose treatment period within a subgroup defined by C4 levels >46 ng/mL.
- Changes from the screening/baseline period (days -8 to -2) to the stable dose treatment period (days 6-12) in the mean number of stools per day categorized by Bristol Stool Form Scale (BSFS) types ≤2, ≥3 and ≤5, and ≥6.
- Changes from the screening/baseline period to the stable dose treatment period in the average BSFS score.
- Changes from the screening/baseline period to the stable dose treatment period in the average daily frequency of defecation.
- Changes from the screening/baseline period to the stable dose treatment period in the mean number of complete spontaneous bowel movements (CSBM).
- Changes from the screening/baseline period to the stable dose treatment period in the average score for urgency of defecation, measured via a 7-point Likert scale.
- Changes from baseline or randomization at the end of treatment in the average total score for the Gastrointestinal Symptom Rating Scale (GSRS), including relative scores for symptom clusters such as reflux, abdominal pain, indigestion, diarrhoea, and constipation.
- The proportion of participants utilizing rescue medication.
The secondary endpoints regarding stool frequency, Bristol Stool Form Scale, CSBM, urgency, and GSRS scores are collected through daily participant self-assessment using an e-diary up to the end of study. An exploratory endpoint involves evaluating the change from baseline or randomization at the end of treatment in the serum concentration of C4.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed written informed consent.
- Male or female, age ≥ 18 and < 80 years.
- Evidence of moderate-to-severe BAD, as confirmed by 75SeHCAT scintigraphy (i.e., 75SeHCAT ≤10%) (during the study screening/baseline period or within two calendar years prior to Visit 1).
- Active disease according to Hjortswang criteria, i.e., symptomatic BAD, defined as follows: mean of ≥ 3 stools/day or mean of ≥ 1 watery stool (BSFS of type 6 or 7)/day over the study screening/baseline period (Days -8 to -2, i.e., the last week prior to baseline/randomization).
- Willingness and capability to fulfil all tasks foreseen by the trial protocol.
- Female of childbearing potential must have a negative urine pregnancy test (dipstick) prior to the first IMP administration, and currently using or agree to use consistently and correctly (i.e., perfect use) a highly effective method of contraception for the individual participant and her partner(s) throughout the trial and for at least one full contraceptive cycle (when applicable). Highly effective methods of contraception include the following: a) implantable progestogen-only hormone contraception associated with inhibition of ovulation; b) Intrauterine Device (IUD); c) Intrauterine Hormone-releasing System (IUS); d) combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral; intravaginal; transdermal), provided the participant has been using that hormonal contraceptive for an adequate period of time to ensure effectiveness; e) progestogen-only hormone contraception associated with inhibition of ovulation (oral; injectable), provided the participant has been using that hormonal contraceptive for an adequate period of time to ensure effectiveness; f) vasectomized partner, provided that the partner is the sole participant’s sexual partner and the absence of sperm has been confirmed; g) bilateral tubal occlusion or tubal ligation; h) sexual abstinence, defined as refraining from heterosexual intercourse during the entire period of risk associated with the IMP (i.e., up to 24h after the end of treatment). Barrier contraceptives (i.e., diaphragm or cervical cap with spermicide and/or condoms [male or female] with or without a spermicidal agent) are not considered highly effective methods of contraception, and thus must not be used as sole method of contraception. Of note, the use of an oral contraceptive is allowed only if a properly separate administration from it of the IMP (i.e., at least four hours before or at least four hours after the oral contraceptive) can be ensured. Of note, females who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal (at least 12 months of amenorrhea following cessation of all exogenous hormonal treatment) are not considered of childbearing potential.
Exclusion Criteria
- Ascertained organic GI diseases, including celiac disease or inflammatory bowel diseases (i.e., Crohn's Disease [CD], ulcerative colitis, diverticular disease, infectious colitis, ischemic colitis, microscopic colitis).
- Presence of other severe GI motility disorders, or diseases that could affect the ileum and the enterohepatic circulation of bile acids or the colon, including biliary dyskinesia, gastroparesis, intestinal pseudo-obstruction, narcotic bowel syndrome, gastric and ileal resection or bypass, short bowel syndrome, radiation enteritis, chronic pancreatitis, known small intestine bacterial overgrowth, diverticulitis, collagenous colitis, colonic resection, toxic megacolon, fistula, perforation or abscess. Of note, patients who have undergone cholecystectomy are eligible for the trial.
- Known or suspected bowel (subileus or ileus) or biliary duct obstruction.
- Known or suspected dysphagia.
- Previous major abdominal surgery, including bowel ostomy (uncomplicated appendectomy, cholecystectomy, hysterectomy or caesarean section are allowed unless within 6 months prior to Visit 1).
- Acute suspected or proven viral gastroenteritis within 4 weeks prior to Visit 1.
- Acute suspected or proven non-viral gastroenteritis within 8 weeks prior to Visit 1.
- Active malignancy of any type (except for non-invasive basal or squamous cell carcinoma of the skin), or history of a malignancy other than non-invasive basal or squamous cell carcinoma of the skin. Patients with a history of malignancies that have been surgically removed with no evidence of recurrence for at least five years and no treatment prior to Visit 1 are allowed to participate in the trial.
- Patients with known (as previously documented) severe heart failure (New York Heart Association [NYHA] class IV), severe renal impairment (estimated Glomerular Filtration Rate [eGFR] <30 mL/min), or severe hepatic impairment (Child-Pugh class C) or clinically significant liver enzyme abnormality, as evidenced by elevated Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) >3 times Upper Limit of Normal (ULN) or total direct bilirubin >2 times ULN at Visit 1.
- History of acute myocardial infarction, or stable or unstable angina.
- History of stroke or transient ischemic attack within 6 months prior to Visit 1.
- Clinically significant or unstable concurrent disease whose sequelae or treatment might contraindicate trial participation or interfere with the trial evaluation parameters, as judged by the Investigator.
- Any major psychiatric unstable disorder, including eating disorders, and use of antidepressant or anxiolytic agents, unless used at a stable dose for at least 6 weeks prior to baseline/randomization.
- Fasting triglycerides level above 3.4 mmol/L (300.9 mg/dL) at Visit 1.
- History of or known allergy or hypersensitivity or intolerance to colesevelam or its excipients.
- History of or known allergy to 75SeHCAT or its excipients.
- Prior and concomitant treatment with bile acid sequestrants (i.e., cholestyramine, colestipol, colesevelam) starting from 1 week prior to Visit 1.
- Previous unsuccessful treatment of BAD with colesevelam.
- Current treatment with oral anticoagulants, including warfarin and new oral anticoagulants.
- Current chronic treatment with drugs affecting intestinal pH (i.e., Proton Pump Inhibitors [PPIs]*, histamine H2-receptor antagonists, and antiacids) and/or altering the GI motility (i.e., drugs that act as prokinetics to stimulate GI motility, Glucagon-Like Peptide-1 (GLP-1) receptor agonists, and drugs that cause constipation or diarrhoea), as well as any modified-release or prolonged release drugs. *For PPIs, a wash-out from treatment of at least 4 weeks prior to Visit 1 is also required. Of note, concomitant probiotics are allowed if taken at a stable dosage throughout the trial.
- Concomitant use (starting from Visit 1) of laxatives or anti-diarrheal drugs, including 5-Hydroxytryptamine 3 (5HT3) receptor antagonists, such as alosetron and ondansetron, and eluxadoline (except for loperamide allowed as rescue medication starting from randomization), as well as opioids and antispasmodics for pain. Of note, antispasmodics are allowed to manage pain during the post-treatment follow-
- Prior and concomitant rectal treatments (other than topical steroids for the treatment of haemorrhoids) starting from 2 weeks before Visit 1.
- Prior and concomitant treatment with antibiotics starting from 2 weeks before Visit 1.
- Prior and concomitant treatment with immunosuppressant or immunomodulator agents including monoclonal antibodies starting from 6 weeks prior to Visit 1.
- Prior and concomitant treatment with cyclosporine starting from 2 months before Visit 1.
- Concomitant use of medications whose bioavailability is affected by colesevelam (i.e., olmesartan, glyburide, glimepiride, levothyroxine, anti-epileptics, ursodeoxycholic acid and oral contraceptives), except when their therapeutic regimen allows a properly separate administration of colesevelam (i.e., at least four hours before or at least four hours after such medication).
- Concomitant use of statins or fenofibrate.
- History of drug abuse or use of illegal drugs.
- Alcohol abuse, i.e., regular use of more than 2 units of alcohol per day or 10 units per week or a history of alcoholism (one unit of alcohol equals 250 ml beer, 125 ml wine or 25 ml spirits).
- Participation in other clinical trials or investigations at the same time or within 90 days prior to Visit 1 (calculated from the date of the final examination of the previous study).
- Pregnancy or breastfeeding throughout the whole trial duration.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Yet Recruiting | 02 Mar 2026 | 50 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SUB01423MIG | Test | GASTRO-RESISTANT TABLET | ORAL USE | 1875 | 12 | PRD13088722 |
DISSENTEN 2 mg compresse | Other | COMPRESSE | ORAL USE | 8 | 22 | PRD443230 |
Colesevelam-matching placebo film-coated oral tablets (Unit Dose D). | Placebo | N/A | — | — | — | N/A |
Colesevelam-matching placebo film-coated oral tablets (Unit Dose C). | Placebo | N/A | — | — | — | N/A |
SUB01423MIG | Test | GASTRO-RESISTANT TABLET | ORAL USE | 1875 | 12 | PRD13090692 |