Efficacy, Safety and Tolerability of Enteric-Coated Cholestyramine Capsules for Adult Short Bowel Syndrome

• Sponsor: Pharmascience Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04046328
• Collaborator: (none)
• Enrollment: 13
• Locations: 3
• Arms: 2
• Actual Duration (Months): 26.3
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

A new Enteric-Coated Cholestyramine (ECC) capsule has been developed to manage diarrhea associated with Short Bowel Syndrome (SBS) in adults. The formulation is expected to release cholestyramine in the remaining segment of the small intestine in SBS patients, thus binding bile acids after fat digestion, but before induction of diarrhea in the colon. The delayed-release profile is also expected to help reduce the potential for drug-drug interactions occurring in the proximal small intestine. Two doses of ECC will be studied for efficacy, safety and tolerability in this Phase IIa trial.

Condition or Disease	Intervention/Treatment	Phase
Short Bowel Syndrome	Drug: Enteric-Coated Cholestyramine (ECC) Capsule; Drug: Placebo	Phase 2

Detailed Description

A new Enteric-Coated Cholestyramine (ECC) capsule has been developed to manage diarrhea associated with Short Bowel Syndrome (SBS). SBS is usually caused by the significant resection or loss of function of the ileum, leading to reduced reabsorption of bile acids and subsequent osmotic diarrhea. The new ECC formulation could release cholestyramine in the remaining segment of the small intestine in SBS patients, delivering and binding bile acids before they induce diarrhea in the colon. The proposed advantages of this formulation are: a) to prevent drug-drug interactions in the proximal GI tract, b) to preserve the fat digestive properties of bile acids in the duodenum and 3) to offer a more palatable dosage form to patients. Moreover, since distal delivery of cholestyramine is expected to be more effective in diarrhea prevention/reduction in SBS, lower doses than the ones used with non-enteric coated cholestyramine may be sufficient. Two doses of ECC will be studied for efficacy, safety and tolerability in well-defined non fully-colectomized, adult SBS patients suffering from diarrhea.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Multiple-center, randomized, double-blind, double dummy, 2-period, 2-sequence cross-over designMultiple-center, randomized, double-blind, double dummy, 2-period, 2-sequence cross-over design
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: This study will be fully blinded, using the double dummy technique (combination of active ECC capsules and matching placebo in the low dose treatment arm).
• Primary Purpose: Treatment
• Official Title: A Phase IIa, Proof of Concept, Randomized, Double-Blind, Dose-Finding, Cross-Over Study of the Efficacy, Safety and Tolerability of a New Enteric-Coated Cholestyramine Capsule in Adult Short Bowel Syndrome Patients
• Actual Study Start Date: Oct 15, 2019
• Actual Primary Completion Date: Dec 22, 2021
• Actual Study Completion Date: Dec 22, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: "Low" Dose ECC Regimen ECC at the 1.7 g daily dose, administered BID (twice daily) as 2 capsules of ECC, plus 3 capsules of placebo, at least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before evening meal.	Drug: Enteric-Coated Cholestyramine (ECC) Capsule; Enteric-Coated Delayed Release Cholestyramine Capsules; Drug: Placebo; Enteric-Coated Delayed Release Placebo Capsules
Experimental: "High" Dose ECC Regimen ECC at the 4.25 g daily dose, administered BID (twice daily) as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal.	Drug: Enteric-Coated Cholestyramine (ECC) Capsule; Enteric-Coated Delayed Release Cholestyramine Capsules

Outcome Measures

Primary Outcome Measures

1. Change in the Weekly Frequency of Bowel Movements Measured Between Baseline and the Second Week of Treatment [Baseline and Week 2 of treatment (Days 8 to 14, and Days 36 to 42)]

   Change in the weekly frequency of bowel movements measured between baseline and the second week of treatment. Baseline is defined as the second week of screening for treatment period 1 and second week of washout for treatment period 2.

Secondary Outcome Measures

1. Total Number of Bowel Movements for the Whole 2-week Treatment Period [Days 1 to 14 and Days 29 to 42]

2. Mean Daily Stool Form Score According to the BSFS (Bristol Stool Form Scale), Measured During the Second Week of Treatment [Days 8 to 14, and Days 36 to 42]

   The BSFS classifies the form of human feces into seven categories (Type 1 to Type 7) based on stool shape and consistency. Types or scores of 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 tending towards diarrhea, and 6 and 7 indicate diarrhea.

3. Mean Daily Dose of Loperamide in mg, if Used, During the Second Week of Treatment [Days 8 to 14, and Days 36 to 42]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Adult, ambulatory male and female subjects

2. Provision of signed and dated informed consent form (ICF)

3. Age ≥ 18 years and ≤ 80 years

4. Stable SBS of:

5. Non-surgical origin; OR

6. Surgical origin where the last surgical ileal resection was performed at least 6 months prior to enrolment

7. Partial, Home Parenteral Nutrition and/or parenteral fluids are allowed, at a maximum frequency of 6 times a week throughout the trial, as long as the regimen has been stable for at least 2 weeks prior to screening and is expected to remain unchanged during the study

8. At least 50 % of the colon being intact

9. Intact duodenum

10. BMI ≥ 18

11. Presence of stable chronic diarrhea for at least 3 months prior to enrolment as evidenced by medical history

12. Presence of stable chronic diarrhea during the 2-week screening diary period before randomization, as evidenced by completion of a screening diary demonstrating:

13. Mean daily production of at least 3 soft or watery stools (BSFS scores 6 or 7); or

14. More than 3 bowel movements per day on average with >25% of them being BSFS type 6 or 7

15. Stated willingness and ability to comply with all study procedures, including daily recording of bowel movements and BSFS in the patient diaries, and availability for the duration of the study

16. Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be without clinical significance, as determined by the investigator

17. Female subjects must meet one of the following criteria:

1. Participant is of childbearing potential and agrees to use one of the accepted contraceptive regimens from at least 30 days prior to the first study treatment administration through to at least 30 days after the last dose of the study treatment.

An acceptable method of contraception includes one of the following:

1. Abstinence from heterosexual intercourse

2. Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)

3. Intrauterine device (with or without hormones)

4. Condom with spermicide

1. Participants of non-childbearing potential, defined as surgically sterile (i.e. has undergone complete hysterectomy or bilateral oophorectomy) or is in a menopausal state (i.e. at least 1 year without menses prior to the first study drug administration) are eligible

Exclusion Criteria:

1. Patients with known or suspected intestinal strictures of clinical relevance as judged by the Investigator

2. Active inflammatory bowel disease (IBD) or fistula during the screening period as judged by the Investigator

3. Crohn's disease patients not being in clinical remission for the last 12 weeks prior to randomization

4. Diarrhea caused by other causes than SBS

5. Presence of clinically significant steatorrhea, requiring pancreatic enzymes supplementation

6. Presence of complete biliary obstruction

7. Presence of active cancer (except resected cutaneous basal or squamous cell carcinoma and except in situ cervical cancer) and/or need to receive chemotherapy or radiotherapy during the study

8. History of allergic reaction to cholestyramine or any excipient of the investigational drug product or placebo, or packaging components

9. Females who are lactating at screening

10. Females who are pregnant according to the pregnancy test at screening or prior to the first study treatment administration

11. Significant history (at least 3 consecutive months in the year prior to Screening) of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic)

12. Subjects who took an Investigational Product (IP) in the 30 days prior to the first study drug administration

13. Any other clinically significant condition that is considered by the principal investigator as being susceptible to put the patient at greater safety risk, influence response to study product, or interfere with study assessments.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Solumed Centrum Medyczne	Poznań		Poland
2	Szpital Wielospecjalistyczny im. Stanleya Dudricka	Skawina		Poland
3	Wojewódzki Specjalistyczny Szpital im. M. Pirogowa w Łodzi	Łódź		Poland

Sponsors and Collaborators

• Pharmascience Inc.

Investigators

• Principal Investigator: Marek Kunecki, MD, PhD, Wojewódzki Specjalistyczny Szpital im. M. Pirogowa w Łodzi
• Principal Investigator: Konrad Matysiak, MD, PhD, Solumed Centrum Medyczne
• Principal Investigator: Kinga Szczepanek, MD, Szpital Wielospecjalistyczny im. Stanleya Dudricka

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 16, 2021

More Information

Publications

None provided.

• Responsible Party: Pharmascience Inc.
• ClinicalTrials.gov Identifier: NCT04046328
• Other Study ID Numbers: PMS-2018-002; 2018-004419-32
• First Posted: Aug 6, 2019
• Last Update Posted: Jul 19, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Short Bowel Syndrome; Syndrome; Cholestyramine Resin

Study Results

Participant Flow

Pre-assignment Detail	This was a multiple center, randomized, double-blind, double dummy, 2-period, 2-sequence cross-over study design planned to evaluate 18 patients at three study centers. Due to early study termination only 13 patients were randomized and received treatment with ECC.

Arm/Group Title	"Low" Dose ECC Regimen, Then "High" Dose ECC Regimen	"High" Dose ECC Regimen, Then "Low" Dose ECC Regimen
Arm/Group Description	"Low" Dose: ECC at the 1.7 g daily dose, administered BID as 2 capsules of ECC, plus 3 capsules of placebo, at least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before evening meal. "High" Dose: ECC at the 4.25 g daily dose, administered BID as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules Placebo: Enteric-Coated Delayed Release Placebo Capsules	"High" Dose: ECC at the 4.25 g daily dose, administered BID as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal. "Low" Dose: ECC at the 1.7 g daily dose, administered BID as 2 capsules of ECC, plus 3 capsules of placebo, at least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules Placebo: Enteric-Coated Delayed Release Placebo Capsules
Period Title: First Intervention (14 Days)
STARTED	6	7
COMPLETED	6	7
NOT COMPLETED	0	0
Period Title: First Intervention (14 Days)
STARTED	6	7
COMPLETED	6	7
NOT COMPLETED	0	0
Period Title: First Intervention (14 Days)
STARTED	6	7
COMPLETED	6	7
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Intent-to-Treat (ITT Population)
Arm/Group Description	Demographics and baseline characteristics were assessed for the overall ITT Population
Overall Participants	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.9 (15.98)
Sex: Female, Male (Count of Participants)
Female	6 46.2%
Male	7 53.8%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%
Black	0 0%
Caucasian	13 100%
Other	0 0%
Region of Enrollment (participants) [Number]
Poland	13 100%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	24.1 (3.84)

Outcome Measures

1. Primary Outcome

Title	Change in the Weekly Frequency of Bowel Movements Measured Between Baseline and the Second Week of Treatment
Description	Change in the weekly frequency of bowel movements measured between baseline and the second week of treatment. Baseline is defined as the second week of screening for treatment period 1 and second week of washout for treatment period 2.
Time Frame	Baseline and Week 2 of treatment (Days 8 to 14, and Days 36 to 42)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	"Low" Dose ECC Regimen	"High" Dose ECC Regimen
Arm/Group Description	ECC at the 1.7 g daily dose, administered BID as 2 capsules of ECC, plus 3 capsules of placebo, at least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules Placebo: Enteric-Coated Delayed Release Placebo Capsules	ECC at the 4.25 g daily dose, administered BID as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules
Measure Participants	13	13
Mean (Standard Deviation) [Weekly bowel movements]	-11.5 (11.38)	-13.4 (9.73)

2. Secondary Outcome

Title	Total Number of Bowel Movements for the Whole 2-week Treatment Period
Time Frame	Days 1 to 14 and Days 29 to 42

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	"Low" Dose ECC Regimen	"High" Dose ECC Regimen
Arm/Group Description	ECC at the 1.7 g daily dose, administered BID as 2 capsules of ECC, plus 3 capsules of placebo, at least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules Placebo: Enteric-Coated Delayed Release Placebo Capsules	ECC at the 4.25 g daily dose, administered BID as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules
Measure Participants	13	13
Mean (Standard Deviation) [Bowel movements]	52.5 (20.12)	55.1 (25.18)

3. Secondary Outcome

Title	Mean Daily Stool Form Score According to the BSFS (Bristol Stool Form Scale), Measured During the Second Week of Treatment
Description	The BSFS classifies the form of human feces into seven categories (Type 1 to Type 7) based on stool shape and consistency. Types or scores of 1 and 2 indicate constipation, with 3 and 4 being the ideal stools as they are easy to defecate while not containing excess liquid, 5 tending towards diarrhea, and 6 and 7 indicate diarrhea.
Time Frame	Days 8 to 14, and Days 36 to 42

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	"Low" Dose ECC Regimen	"High" Dose ECC Regimen
Arm/Group Description	ECC at the 1.7 g daily dose, administered BID as 2 capsules of ECC, plus 3 capsules of placebo, at least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules Placebo: Enteric-Coated Delayed Release Placebo Capsules	ECC at the 4.25 g daily dose, administered BID as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules
Measure Participants	13	13
Mean (Standard Deviation) [Score on BSFS scale]	3.6 (1.42)	3.7 (1.76)

4. Secondary Outcome

Title	Mean Daily Dose of Loperamide in mg, if Used, During the Second Week of Treatment
Time Frame	Days 8 to 14, and Days 36 to 42

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	"Low" Dose ECC Regimen	"High" Dose ECC Regimen
Arm/Group Description	ECC at the 1.7 g daily dose, administered BID as 2 capsules of ECC, plus 3 capsules of placebo, at least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules Placebo: Enteric-Coated Delayed Release Placebo Capsules	ECC at the 4.25 g daily dose, administered BID as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules
Measure Participants	7	7
Mean (Standard Deviation) [mg]	72.9 (43.05)	68.9 (53.19)

Adverse Events

Time Frame	From patient randomization to the end of study visit, approximately 44 days
Arm/Group Title	"Low" Dose ECC Regimen		"High" Dose ECC Regimen
Arm/Group Description	ECC at the 1.7 g daily dose, administered BID as 2 capsules of ECC, plus 3 capsules of placebo, at least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules Placebo: Enteric-Coated Delayed Release Placebo Capsules		ECC at the 4.25 g daily dose, administered BID as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal. Enteric-Coated Cholestyramine (ECC) Capsule: Enteric-Coated Delayed Release Cholestyramine Capsules
All Cause Mortality
	"Low" Dose ECC Regimen		"High" Dose ECC Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Serious Adverse Events
	"Low" Dose ECC Regimen		"High" Dose ECC Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	"Low" Dose ECC Regimen		"High" Dose ECC Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)		4/13 (30.8%)
Gastrointestinal disorders
Abdominal pain upper	1/13 (7.7%)		1/13 (7.7%)
General disorders
Oedema peripheral	1/13 (7.7%)		1/13 (7.7%)
Infections and infestations
Pulpitis dental	1/13 (7.7%)		1/13 (7.7%)
Investigations
C-reactive protein increased	0/13 (0%)		1/13 (7.7%)
Metabolism and nutrition disorders
Hypokalaemia	1/13 (7.7%)		0/13 (0%)
Hypomagnesaemia	0/13 (0%)		1/13 (7.7%)
Decreased appetite	0/13 (0%)		1/13 (7.7%)

Limitations/Caveats

Early termination leading to small numbers of subjects analyzed and abbreviated statistical analyses.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Publication of the study results by the Investigator, the Center and by any member of the Investigational Team shall require a prior express approval of Pharmascience in writing.