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

INTERVENTION: Product Name: SUB01423MIG, Product Code:PRD13090692, Pharmaceutical Form: GASTRO‐RESISTANT TABLET, Other descriptive name: , Strength: , Product Name: SUB01423MIG, Product Code:PRD13088722, Pharmaceutical Form: GASTRO‐RESISTANT TABLET, Other descriptive name: , Strength: , Product Name: Colesevelam‐matching placebo film‐coated oral tablets (Unit Dose C)., Product Code:N/A, Pharmaceutical Form: N/A, Other descriptive name: N/A , Strength: , Pharmaceutical form of the placebo: N/A , Product Name: Colesevelam‐matching placebo film‐coated oral tablets (Unit Dose D)., Product Code:N/A, Pharmaceutical Form: N/A, Other descriptive name: N/A , Strength: , Pharmaceutical form of the placebo: N/A , Product Name: DISSENTEN 2 mg compresse, Product Code:PRD443230, Pharmaceutical Form: TABLET, Other descriptive name: , Strength: CONDITION: Bile acid diarrhoea Therapeutic area: Diseases [C] ‐ Digestive System Diseases [C06] PRIMARY OUTCOME: Main Objective: 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. Primary end point(s): 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 Objective: 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., 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., 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. SECONDARY OUTCOME: Secondary end point(s):Exploratory efficacy endpoint: Change from baseline/randomization at EOT of serum concentration of C4. Secondary end point(s):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. Secondary end point(s):Safety and tolerability endpoints: Safety laboratory evaluations at Visit 1 and EOT. Secondary end point(s):Safety and tolerability endpoints: Vital signs (systolic and diastolic blood pressure, and heart rate) at Visit 1, Visit 2, EOT and EOS. Secondary end point(s):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. Secondary end point(s):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). Secondary end point(s):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. Secondary end point(s):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). Secondary end point(s):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. Secondary end point(s):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. Secondary end point(s):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. Secondary end point(s):Secondary efficacy endpoints: Proportion of participants who use the rescue medication. INCLUSION CRITERIA: 1. Signed written informed consent., 2. Male or female, age = 18 and < 80 years., 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. 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. Willingness and capability to fulfil all tasks foreseen by the trial protocol., 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 lea