Two Period / Two Treatment Cross-over to Assess the Effect of Florastor® on Gastrointestinal Tolerability, Safety, and PK in Healthy Subjects Receiving Zavesca®

Study Overview
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Brief Summary
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Cross-over, tolerability study with healthy subjects taking Zavesca in combination with Florastor. Forty-two subjects will be randomized to one of two treatment sequences of Zavesca with Florastor and Zavesca with Placebo of Florastor. Gastrointestinal tolerability and PK endpoints, demographic, laboratory and safety testing, and AEs and SAEs will be collected throughout the seventy-four day study.

Detailed Description
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This is a Phase 1, single-center, double-blind, randomized, placebo-controlled, two period / two treatment, cross-over study with GI tolerability, safety, and PK assessments. A total of 42 healthy subjects will be enrolled. At least 30% of female subjects are expected to be enrolled. Subjects will participate in 2 treatment periods (Treatment Period 1 and Treatment Period 2), separated by a 10- to 14-day washout. Subjects will be randomly allocated to the treatment sequence, A-B or B-A: Treatment A: Placebo of S. boulardii 500 mg twice a day (b.i.d.) from Day 1 to Day 16 of the treatment period, and miglustat capsules 100 mg t.i.d. from Day 3 to Day 16. Treatment B: S. boulardii 500 mg b.i.d. from Day 1 to Day 16 of the treatment period, and miglustat capsules 100 mg t.i.d. from Day 3 to Day 16. To minimize possible carry-over effect, a 10 to 14-day washout period is added between Treatment Period 1 and Period 2. Steady-state PK evaluations will occur at the end of Period 1 and Period 2 requiring full-day clinic stays by each subject. The planned study duration per subject will be approximately 46 days (not inclusive of Screening and serious adverse event [SAE] follow-up periods). However, the duration may be up to 53 days if all visit windows are utilized. The Screening period may last up to 30 days prior to the first administration of study medication. Telephone follow-up will occur within 48-72 hours after last study drug dose in each treatment period to record SAEs/AEs and concomitant medications. In addition, subjects will be followed up 30 days after permanent study drug discontinuation for ongoing AEs and new SAEs via a telephone consult.

Official Title
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A Single-center, Double-blind, Randomized, Placebo-controlled, Two Period / Two Treatment Cross-over Study to Assess the Effect of Florastor® (Saccharomyces Boulardii Lyo) on Gastrointestinal Tolerability, Safety, and Pharmacokinetics of Zavesca® (Miglustat) in Healthy Subjects

Conditions
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Diarrhea

Intervention / Treatment
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* Drug: Treatment A
* Drug: Treatment B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent prior to any study-mandated procedure Healthy male and female subjects aged between 18 and 55 years (inclusive) at Screening Women must have a negative serum pregnancy test at Screening and negative urine pregnancy test at the first day of each treatment period and must use a reliable method of contraception from Screening during the entire study and up to 30 days after the last dose. Male subjects must agree to use reliable contraception throughout the study and for 4 months after study drug discontinuation Reliable methods of contraception for all subjects include the following: Barrier type devices (e.g., male and female condom, diaphragm and contraceptive sponges) used ONLY in combination with a spermicide Intrauterine devices Oral contraceptive agent Depo-Provera (medroxyprogesterone acetate) Levonorgestrel implants Abstinence, the rhythm method, and contraception by the partner alone are NOT reliable methods of contraception A BMI of 18.5 to 30 kg/m2 (inclusive) at Screening No clinically significant findings on the physical examination, laboratory assessment, electrocardiogram (ECG), and vital signs at Screening Exclusion Criteria: Ingestion of any medication within 7 days prior to study enrollment (Day 1) except contraceptives Use of anti-diarrheal medications within 30 days prior to study enrollment (e.g., loperamide) Use of oral probiotic supplements or S. boulardii within 30 days prior to study enrollment Use of oral antifungals or antibiotics within 8 weeks prior to study enrollment History of yeast allergy Current alcohol or drug dependence Renal function impairment, (i.e., creatinine clearance [C Cr]<70 mL/min/1.73m2 as per Cockroft-Gault) History of GI distress including diarrhea (more than 2 loose stools per day, for 5 or more days) within 30 days prior to study enrollment History of irritable bowel syndrome, inflammatory bowel disease, or other disease resulting in frequent or severe diarrhea Lactose intolerance Subjects on any specialized diet, including low carbohydrate diets Lactating, pregnant women or women who plan to become pregnant during the course of the study History of any neurological disease/symptom, e.g., convulsion Loss of 500 mL or more of blood within 3 months prior to Screening Positive results to HIV Ag/Ab, HBsAg or anti-HCV tests Positive results from the HIV serology at Screening History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to Screening Excessive caffeine consumption, defined as >=5 cups of coffee a day or 800mg/day at Screening Smoking within 3 months prior to Screening and inability to refrain from smoking during the course of the study Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol Legal incapacity or limited legal capacity at Screening Unplanned weight loss defined as >5% within the past month or >=10% during the last 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Treatment A<br>Treatment A: Florastor® 500 mg twice per day from Day 1 to Day 16 of the treatment period, and Zavesca® 100 mg three times per day from Day 3 to Day 16. For Period 2, subjects will receive the alternate dosing regimen. | Drug: Treatment A<br>* Florastor® placebo. Zavesca® capsules dosed at 300 mg daily (one 100 mg capsule three times per day).<br>* Other names: Zavesca® capsules.;Drug: Treatment B<br>* Florastor® capsules dosed at 1000 mg daily (two 250 mg capsules two times per day). Zavesca® capsules dosed at 300 mg daily (one 100 mg capsule three times per day).<br>* Other names: Zavesca® capsules.;|
| Experimental: Treatment B<br>Treatment B: Florastor® 500 mg twice per day from Day 1 to Day 16 of the treatment period, and Zavesca® 100 mg three times per day from Day 3 to Day 16. For Period 2, subjects will receive the alternate dosing regimen. | Drug: Treatment A<br>* Florastor® placebo. Zavesca® capsules dosed at 300 mg daily (one 100 mg capsule three times per day).<br>* Other names: Zavesca® capsules.;Drug: Treatment B<br>* Florastor® capsules dosed at 1000 mg daily (two 250 mg capsules two times per day). Zavesca® capsules dosed at 300 mg daily (one 100 mg capsule three times per day).<br>* Other names: Zavesca® capsules.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GASTROINTESTINAL TOLERABILITY ENDPOINTS | Total number of days of diarrhea defined as 3 or more loose stools within a 24-hour period (WHO criteria) that meet the criteria of Bristol Stool Score 6-7. | baseline to end of study (day 74) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GASTROINTESTINAL TOLERABILITY ENDPOINTS | Number of consecutive days of diarrhea defined as 3 or more loose stools (WHO criteria) within consecutive 24-hour periods that meet the criteria of Bristol Stool Score of 6-7. | baseline to end of study (day 74) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diarrhea