A Phase 1, Single-Ascending-Dose Study of BT051 in Healthy Subjects

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled study to assess the safety and tolerability of single ascending doses of BT051 in healthy male or female volunteers aged 18 to <50 years. A total of 50 subjects will be randomized to receive a single oral dose of BT051 or matching placebo in a ratio of 4 active:1 placebo in 5 ascending dose cohorts (10 subjects per cohort) at active dose levels of 100mg, 300mg, 700mg, 1500mg or 3500mg. The study Safety Review Committee (SRC) will evaluate if any dose-limiting adverse events (AEs) occurred in a cohort through Day 3, as well as review cumulative safety data for all previous cohorts and any available pharmacokinetic (PK) data before proceeding to dosing in the next cohort.

Detailed Description
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BT051-1-001 is a phase 1, randomized, double-blind, single center, single-ascending-dose study in which healthy subjects will receive a single oral dose of BT051 or placebo while confined to the clinical unit. Approximately 50 subjects will be enrolled in 5 sequential, ascending dose cohorts. Healthy male and female adult subjects will be enrolled and screened for participation within 28 days before the scheduled administration of study drug. After written informed consent is obtained, the screening procedures will include: medical history, documentation of prior medications (i.e., medications taken within 30 days before the scheduled dose of study drug), viral serology tests, clinical laboratory testing, pregnancy testing (for women of childbearing potential), 12 lead electrocardiograms (ECGs), vital sign measurements, and physical examination. After confirmation of inclusion and exclusion criteria, subjects eligible for randomization will be admitted to the clinical unit 1 day before the scheduled administration of study drug (Day -1) and will be confined in the clinical unit until the morning of Day 3. All subjects will return to the clinical unit on Day 7 (-1 or +2 days) and for the last follow-up on Day 30 (±3 days) for study assessments. A total of 10 subjects will be randomized to receive BT051 or placebo (8 active:2 placebo) in each of the following sequential dose escalating cohorts: 100mg, 300mg, 700mg. 1500mg and 3500mg. Administration of a single dose of study medication on Day 1 will occur under fasted conditions (i.e., no food allowed overnight before dosing until at least 4 hours after dosing). Except for approximately 240-480 mL of water given with study drug, no fluid will be allowed from 1 hour before dosing until 1 hour postdose; water will be provided ad libitum at all other times. The study Safety Review Committee (SRC) will evaluate if any dose-limiting adverse events (AEs) through Day 3 occurred in a cohort before proceeding to dosing in the next cohort. In addition, cumulative safety data will be reviewed for all previous cohorts along with any available pharmacokinetic (PK) data. A lower dose may be explored in case dose-limiting AEs are observed at a higher dose level. For PK analyses, blood, urine, and fecal samples will be collected from each subject. Blood samples will be collected on Day 1 at predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 48 hours postdose. Urine samples will be collected at the following intervals (pooled for each collection interval): 0-4, 4-8, 8-24, and 24-48 hours postdose. One stool sample will be collected prior to dose (from Days -2 to Day 1). Following dosing on Day 1, all stool samples will be collected through Day 3 (48 hours postdose) while the subject is confined to the clinical unit. In addition, a stool sample will be collected on Day 7 (-1 or +2 days). Safety assessments will include monitoring of AEs, clinical laboratory testing, vital sign measurements, physical examinations, and ECGs at select time points for 30 days following the dose of study drug. Potential systemic pharmacologic T-cell immunosuppressive activity will be evaluated.

Official Title
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A Phase 1, Randomized, Double-Blind, Single-Ascending-Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of BT051 in Healthy Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: BT051 100mg
* Drug: BT051 300mg
* Drug: BT051 700mg
* Drug: BT051 1500mg
* Drug: BT051 3500mg
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all the following criteria to be considered eligible to participate in the study: Male or female subjects age ≥18 years and <50 years In good health with no clinically significant abnormalities as determined by medical history, physical exam, and laboratory values Able and willing to provide written informed consent Be able to understand the study procedures and agree to participate in the study For male subjects, be surgically sterile or agree to use an appropriate method of contraception (i.e., condom) or have a female sexual partner who is surgically sterile or using an insertable, injectable, transdermal, or combination oral contraceptive with a barrier method approved and deemed highly effective by the United States Food and Drug Administration (FDA) through 30 days after the dose of study drug For female subjects of childbearing potential, be using an insertable, injectable, or transdermal hormonal contraceptive, or combination oral contraceptive with a barrier method approved and deemed highly effective by the FDA through 30 days after the dose of study drug and have negative results on pregnancy tests done at Screening and on Day -1. NOTE: women who are surgically sterile or postmenopausal (i.e., no menses for at least 2 years or documented by follicle stimulating hormone) are also eligible to participate. Availability to volunteer for the entire study duration and willing to adhere to all protocol requirements, including confinement in the clinical unit through Day 3 Body mass index (BMI) >18.5 and <32.0 kg/m^2 Ability to fast for at least 10 hours and consume standard meals Willingness to discontinue concomitant medications Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from participating in the study: Pregnant, breast feeding, or seeking pregnancy while on study Have, as determined by the investigator, a history or clinical manifestations of significant neurologic, renal, hepatic, hematologic, cardiac, pulmonary, metabolic, endocrine, psychiatric, gastrointestinal (GI) disorders (including infectious, ischemic, inflammatory bowel disease, irritable bowel syndrome, known lactose intolerance, or immunological diseases) or other condition that would preclude participation in the study Have a history of a malignancy (or active malignancy), with the exception of subjects with basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the cervix who have been treated and cured Have had any symptoms of cold, flu, or febrile illness within 2 weeks prior to dosing Have received any live attenuated vaccine within 30 days of dosing Have received cyclosporine A within the last 1 month, including Restasis® (cyclosporine ophthalmic emulsion) for dry eye syndrome or any other cyclosporine ophthalmic preparation Participation in a clinical trial of an investigational drug or medical device within 30 days before Screening In the opinion of the Investigator, unable to comply with the study protocol Have a history of alcoholism or illicit drug use within 2 years before the scheduled dose of study drug A positive test result for any of the following: human immunodeficiency virus (HIV), hepatitis B virus (HBV) surface antigen, hepatitis C virus (HCV) antibody, drugs of abuse (marijuana, amphetamines, barbiturates, cocaine, opiates, phencyclidine and benzodiazepines), and alcohol. Have donated more than 500 mL of blood within 60 days before the scheduled dose of study drug Have taken prescription medications within 5 half-lives of the specific substance (or, if half-life is not known, within 48 hours) before the scheduled administration of study drug Have taken over-the-counter medication or supplements, including nutritional supplements, stool softeners (e.g., Miralax), or colon preparations within 7 days before dosing History of any hypersensitivity or allergic reaction to cyclosporine History of GI surgery or any part of GI tract removed excluding appendectomy and cholecystectomy Use of tobacco or marijuana products within the previous 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BT051 100 mg<br>Participants will receive a single oral dose of 100mg BT051. | Drug: BT051 100mg<br>* Single oral dose of 100mg BT051<br>|
| Experimental: BT051 300 mg<br>Participants will receive a single oral dose of 300mg BT051. | Drug: BT051 300mg<br>* Single oral dose of 300mg BT051<br>|
| Experimental: BT051 700 mg<br>Participants will receive a single oral dose of 700mg BT051. | Drug: BT051 700mg<br>* Single oral dose of 700mg BT051<br>|
| Experimental: BT051 1500 mg<br>Participants will receive a single oral dose of 1500mg BT051. | Drug: BT051 1500mg<br>* Single oral dose of 1500mg BT051<br>|
| Experimental: BT051 3500 mg<br>Participants will receive a single oral dose of 3500mg BT051. | Drug: BT051 3500mg<br>* Single oral dose of 3500mg BT051<br>|
| Placebo Comparator: Placebo<br>Participants will receive a single oral dose of Placebo matching BT051 dose. | Drug: Matching Placebo<br>* Placebo Matching BT051<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of BT051 based on the difference of proportions between treatment groups of subjects experiencing treatment-emergent adverse events (TEAEs). | Proportion of subjects experiencing a TEAE will be summarized using the MedDRA system organ class and preferred term. | Baseline to Day 30 | 
| Evaluate the safety and tolerability of BT051 based on the difference of proportions between treatment groups of subjects experiencing clinically significant changes from baseline in clinical laboratory tests. | Proportion of subjects with a change from baseline from normal to abnormal in clinical laboratory tests (hematology with differential, serum chemistry, coagulation, and urinalysis) will be summarized. | Baseline to Day 30 | 
| Evaluate the safety and tolerability of BT051 based on the difference of proportions between treatment groups of subjects observed with a change from baseline in physical examinations, vital signs, and electrocardiograms (ECG). | Proportion of subjects with a change from baseline from normal to abnormal in physical examinations, vital signs, and ECGs will be summarized. | Baseline to Day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve (AUC) in whole blood | Difference between treatment groups of mean AUC of BT051 and BT070 (BT051 cleavage product) in whole blood | Baseline to Day 3 | 
| Maximum observed concentration (Cmax) in whole blood | Difference between treatment groups of mean Cmax of BT051 and BT070 (BT051 cleavage product) in whole blood | Baseline to Day 3 | 
| Time to maximum observed concentration (Tmax) in whole blood | Difference between treatment groups of mean Tmax of BT051 and BT070 (BT051 cleavage product) in whole blood | Baseline to Day 3 | 
| Half-life (t1/2) in whole blood | Difference between treatment groups of mean t1/2 of BT051 and BT070 (BT051 cleavage product) in whole blood | Baseline to Day 3 | 
| Stool concentration of BT051 and BT070 | Difference between treatment groups in mean stool concentration of BT051 and BT070 (BT051 cleavage product): Total mg and Total mg/g of stool | Baseline to Day 7 | 
| Urine concentration of BT051 and BT070 | Difference between treatment groups in mean urine concentration of BT051 and BT070 (BT051 cleavage product) | Baseline to Day 3 |