Safety and Preliminary Efficacy of BGP345A in Constipation Due to Opioid-based Medications

Study Overview
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Brief Summary
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The purpose of this study is to assess safety and preliminary efficacy of BGP345A in patients with constipation due to the use of opioid-based medications for the management of chronic non cancer pain.

Official Title
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A Randomized Placebo-controlled Study to Assess Safety and Preliminary Efficacy of BGP345A in Patients With Constipation Due to the Use of Opioid-based Medications for the Management of Chronic Non Cancer Pain

Conditions
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Opioid-Induced Constipation

Intervention / Treatment
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* Biological: Lactobacillus gasseri BGP345A
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: I1. Age over 18 years (limit included), I2. Diagnosed with OIC according to the adapted ROME IV criteria (Mearin F et al, 2016) previously used in clinical evaluation of patients with OIC (Webster LR et al, 2017) and self-reported symptoms assessed by a physician (daily diary check at V1 visit): Fewer than three (<3) spontaneous bowel movements (SBMs) per week. A SBM is defined as a bowel movement without the use of laxatives in the previous 24 hours as recorded in the daily diary. And one or more of the following symptoms in at least 25% of bowel movements: straining, feeling of incomplete evacuation, and/or hard/small stools, defined as Bristol Stool Scale (BSS) score lower than 3 (<3). I3. With chronic non-cancer pain since at least three months, including the following indications but not limited to: back-pain, rheumatisms and post-operative pain, I4. Patients received opioids for chronic analgesia (intended treatment ≥6 Weeks) for 1 week or more prior to study start and a stable regimen of opioids for 3 or more days before study entry (V0 visit) and during the whole study , I5. Subjects must be willing to discontinue laxative use at screening and only use the rescue laxatives permitted throughout the study duration, I6. For women: Non menopausal with the same reliable contraception since at least 2 cycles before the beginning of the study and agreeing to keep it during the entire duration of the study (condom with spermicide gel, any oral contraceptive, intrauterine device, subcutaneous contraceptive implant, vaginal ring, surgical intervention (bilateral tubal ligation or ovariectomy or hysterectomy), ESSURE system), Menopausal without or with hormone replacement therapy, I7. Good general and mental health with in the opinion of the investigator: no clinically significant and relevant abnormalities of medical history or physical examination, I8. Able and willing to participate to the study by complying with the protocol procedures as evidenced by his dated and signed informed consent form, I9. Affiliated with a social security scheme. Exclusion Criteria: E1. Involvement in any investigational drug or device study within 30 days prior to this study, E2. Unable to withdraw other OIC treatments (any kind of laxative other than provided in the study), E3. History of chronic constipation prior to starting analgesic medication or any potential non-opioid cause of bowel dysfunction that may be a major contributor to the constipation upon investigator judgment, E4. Surgery planned within the whole study period, E5. Evidence of active medical diseases affecting bowel transit, E6. Antibiotic treatment intake within the last month prior the study start (V0), E7. Unwilling to withdraw probiotic supplements, yoghurts without supplemented bacteria are permitted, E8. Any history of drug addiction in the past five years, E9. Pregnant or lactating women or intending to become pregnant, E10. Unwilling to maintain food habits and current physical activity for the whole study duration, E11. With a personal history of anorexia nervosa, bulimia or significant eating disorders according to the investigator, E12. Having a lifestyle deemed incompatible with the study according to the investigator including drug and alcohol abuse, E13. Taking part in another clinical trial or being in the exclusion period of a previous clinical trial, E14. Under legal protection (guardianship, wardship) or deprived from his rights following administrative or judicial decision, E15. Presenting a psychological or linguistic incapability to sign the informed consent, E16. Impossible to contact in case of emergency.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active arm<br> | Biological: Lactobacillus gasseri BGP345A<br>* Active and placebo capsules for oral use<br>* Other names: BGP345A;|
| Placebo Comparator: Placebo arm<br> | Biological: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the average weekly number of Spontaneous Bowel Movements (SBMs) (expressed in number of stools/week) | A SBM (Spontaneous Bowel Movement) is defined as a bowel movement without the use of laxatives in the previous 24 hours as recorded in the daily diary (Webster LR et al, 2017). | Over the 4 week treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of responders over the 4-weeks of treatment period defined by subjects reporting an average weekly number of SBMs ≥ 3 and an increase of the average weekly number of SBM ≥1 from baseline | SBM responders | Average over the last two weeks of treatment | 
| Change in the average weekly number of BMs (Bowel Movements) | BM (Bowel Movements) expressed in number of stools/week | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Change in the average weekly number of CSBMs (Complete Spontaneous Bowel Movement) | CSBMs (Complete Spontaneous Bowel Movement) expressed in number of stools/week is defined by as a bowel movement without the use of laxatives in the previous 24 hours as recorded in the daily diary and the feeling of complete emptying after bowel movement. | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Change in the average weekly number of SBMs | SBMs expressed in number of stools/week | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Change in the average weekly number of SBMs with no straining (straining score 1) | SBMs expressed in number of stools/week | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Time to first SBM and CSBM after the last recorded stool before the randomisation | Expressed in hours | Over 4 week treatment period | 
| Change in the number of days with presence of SBMs | SBMs expressed in days/week | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Change in the number of days with presence of CSBMs | CSBMs expressed in days/week | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Change in the average weekly number of SBMs rated 3 or 4 on the BSS (Bristol Stool Scale) | Expressed in stools/week | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Change of stool consistency assessed by the BSS (Bristol Stool Scale) | Expressed in arbitrary units/stool from 1-7. | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Change of the overall BFI (Bowel Function Index) score | Expressed in arbitrary units, range 0-100 | Over 4 week treatment period | 
| Change in the average daily abdominal bloating score | Expressed in arbitrary units/day (this score will be assessed daily for the past 24hours and could range from 0 to 4, where 0 = absent or no bloating, 1 = mild, 2 = moderate, 3= severe, and 4 =very severe bloating) | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Change in the average daily abdominal discomfort score | Expressed in arbitrary units/day (this score will be assessed daily for the past 24hours and could range from 0 to 4, where 0 = no abdominal discomfort, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe discomfort) | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Change in average daily pain at defecation assessed by the Visual Analogic Scale for pain at defecation (VAS) | Expressed in arbitrary units/day with stool, range 0-100 | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Change in the weekly frequency of rescue laxative use assessed by the daily diary | expressed in average of days/week | Over 4 week treatment period; during each week of the treatment period; and up to 8 weeks at study completion. | 
| Frequency of rescue laxative use assessed by the daily diary. | Expressed in number of laxative uses | Over the 4 week treatment period | 
| General health state measuring vital parameters assessed - Body weight | Body weight (kg) | Through study completion, 10 weeks | 
| General health state measuring vital parameters assessed- Diastolic Blood Pressure | Diastolic Blood Pressure (mmHg) | Through study completion, 10 weeks | 
| General health state measuring vital parameters assessed- Systolic Blood Pressure | Systolic Blood Pressure (mmHg) | Through study completion, 10 weeks | 
| General health state measuring vital parameters assessed- Vital signs | Vital signs (BPM) | Through study completion, 10 weeks | 
| the frequency of adverse events (AE), serious adverse events (SAE), Treatment-Emergent Adverse events (TEAE), Serious treatment-emergent adverse events (STEAE) | Frequency and nature of events | Through study completion, 10 weeks |