Efficacy and safety of a novel dual pH-dependent delayed-release ColeseveLam for the trEatment of bile Acid diarrhoea: a Randomized, double-blind, parallel-group, placebo-controlled clinical trial – CLEAR

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Monteresearch S.r.l.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Decision date (initial)

2026-04-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Safety

Primary efficacy objective: To demonstrate the superiority of a 12-day treatment with dual pH-dependent delayed-release colesevelam vs. placebo in BAD remission rate for participants with moderate-to-severe BAD, as defined by 75SeHCAT diagnostic criteria.

Secondary objectives 3

1. Secondary efficacy objectives: To further evaluate the efficacy of a 12-day treatment with dual pH-dependent delayed-release colesevelam compared with placebo on: BAD remission rate (considering C4 criteria for BAD); BAD features (stool consistency and frequency, Complete Spontaneous Bowel Movement [CSBM], urgency of defecation); GI symptoms; Use of the rescue medication.
2. Exploratory efficacy objective: To assess the efficacy of a 12-day treatment with dual pH-dependent delayed-release colesevelam compared with placebo on BA hepatic synthesis.
3. Safety and tolerability objectives: To assess the safety and tolerability of the Investigational Medicinal Products (IMPs) throughout the trial, in terms of: Adverse events; Vital signs; Safety laboratory evaluations.

Conditions and MedDRA coding

Bile acid diarrhoea

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Signed written informed consent.
2. 2. Male or female, age ≥ 18 and < 80 years.
3. 3. 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).
4. 4. 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).
5. 5. Willingness and capability to fulfil all tasks foreseen by the trial protocol.
6. 6. 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 31

1. 1. 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).
2. 2. 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.
3. 3. Known or suspected bowel (subileus or ileus) or biliary duct obstruction.
4. 4. Known or suspected dysphagia.
5. 5. Previous major abdominal surgery, including bowel ostomy (uncomplicated appendectomy, cholecystectomy, hysterectomy or caesarean section are allowed unless within 6 months prior to Visit 1).
6. 6. Acute suspected or proven viral gastroenteritis within 4 weeks prior to Visit 1.
7. 7. Acute suspected or proven non-viral gastroenteritis within 8 weeks prior to Visit 1.
8. 8. 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.
9. 9. 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.
10. 10. History of acute myocardial infarction, or stable or unstable angina.
11. 11. History of stroke or transient ischemic attack within 6 months prior to Visit 1.
12. 12. 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.
13. 13. 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.
14. 14. Fasting triglycerides level above 3.4 mmol/L (300.9 mg/dL) at Visit 1.
15. 15. History of or known allergy or hypersensitivity or intolerance to colesevelam or its excipients.
16. 16. History of or known allergy to 75SeHCAT or its excipients.
17. 17. Prior and concomitant treatment with bile acid sequestrants (i.e., cholestyramine, colestipol, colesevelam) starting from 1 week prior to Visit 1.
18. 18. Previous unsuccessful treatment of BAD with colesevelam.
19. 19. Current treatment with oral anticoagulants, including warfarin and new oral anticoagulants.
20. 20. 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.
21. 21. Concomitant use (starting from Visit 1) of laxatives or anti-diarrheal drugs, including 5-Hydroxytryptamine 3 (5􀇦HT3) 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-
22. 22. Prior and concomitant rectal treatments (other than topical steroids for the treatment of haemorrhoids) starting from 2 weeks before Visit 1.
23. 23. Prior and concomitant treatment with antibiotics starting from 2 weeks before Visit 1.
24. 24. Prior and concomitant treatment with immunosuppressant or immunomodulator agents including monoclonal antibodies starting from 6 weeks prior to Visit 1.
25. 25. Prior and concomitant treatment with cyclosporine starting from 2 months before Visit 1.
26. 26. 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).
27. 27. Concomitant use of statins or fenofibrate.
28. 28. History of drug abuse or use of illegal drugs.
29. 29. 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).
30. 30. 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).
31. 31. Pregnancy or breastfeeding throughout the whole trial duration.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary efficacy endpoint: Proportion of participants with BAD remission, defined according to Hjortswang criteria, at the end of the stable dose treatment period (Days 6-12), considering participants with moderate-to-severe BAD defined by 75SeHCAT ≤10%.

Secondary endpoints 12

1. Secondary efficacy endopoints: Proportion of participants with BAD remission, as per Hjortswang criteria, at the end of the stable dose treatment period, considering the subgroup of participants with BAD defined by C4 >46 ng/mL.
2. Secondary efficacy endpoints: Change from screening/baseline period (i.e., Days -8 to -2) to stable dose treatment period (i.e., Days 6-12) in the mean number of stools/day with a BSFS type ≤2, ≥3 and ≤5, and ≥6, as self-assessed daily by participants up to End of Study (EOS) (e-diary), considering participants with BAD defined by either 75SeHCAT or C4 criteria.
3. Secondary efficacy endpoints: Change from screening/baseline period (Days -8 to -2) to stable dose treatment period (Days 6-12) in the average BSFS score, as self-assessed daily by participants up to EOS (e-diary), considering participants with BAD defined by either 75SeHCAT or C4 criteria.
4. Secondary efficacy endpoints: Change from screening/baseline period (Days -8 to -2) to stable dose treatment period (Days 6-12) in the mean number of stools/day (average daily frequency of defecation), as self-assessed daily by participants up to EOS (e-diary), considering participants with BAD defined by either 75SeHCAT or C4 criteria.
5. Secondary efficacy endpoints: Change from screening/baseline period (Days -8 to -2) to stable dose treatment period (Days 6-12) in the mean number of CSBM, defined as the spontaneous occurrence of a bowel movement associated with a feeling of complete evacuation, as self-assessed daily by participants up to EOS (e-diary), considering participants with BAD defined by either 75SeHCAT or C4 criteria.
6. Secondary efficacy endpoints: Change from screening/baseline period (Days -8 to -2) to stable dose treatment period (Days 6-12) in the average score for urgency of defecation, as self-assessed daily by participants up to EOS, using a 7-point Likert scale (ranging from 0 to 6, where 0 = no urgency at all and 6 = a very great deal of urgency) (e-diary).
7. Secondary efficacy endpoints: Change from baseline/randomization at End of Treatment (EOT) in the average total score for the Gastrointestinal Symptom Rating Scale (GSRS), as well as the relative scores for each symptom cluster (i.e., reflux, abdominal pain, indigestion, diarrhoea and constipation) and single item, as self-assessed by participants (e-diary).
8. Secondary efficacy endpoints: Proportion of participants who use the rescue medication.
9. Exploratory efficacy endpoint: Change from baseline/randomization at EOT of serum concentration of C4.
10. Safety and tolerability endpoints: Incidence of all Adverse Events (AEs), AEs leading to IMP discontinuation, Adverse Drug Reactions (ADRs), and Serious Adverse Events (SAEs) throughout the trial.
11. Safety and tolerability endpoints: Vital signs (systolic and diastolic blood pressure, and heart rate) at Visit 1, Visit 2, EOT and EOS.
12. Safety and tolerability endpoints: Safety laboratory evaluations at Visit 1 and EOT.

Investigational products

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

Test 2

Placebo 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Monteresearch S.r.l.

Sponsor organisation

Monteresearch S.r.l.

Address

Via 4 Novembre 94

City

Bollate

Postcode

20021

Country

Italy

Scientific contact point

Organisation

Monteresearch S.r.l.

Contact name

Stefano Selva

Public contact point

Organisation

Monteresearch S.r.l.

Contact name

Stefano Selva

Third parties 5

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Results and documents

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

Documents 13 files

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

Application history

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