Safety, Tolerability, Pharmacokinetics (PK) of the Anti-Orthopox Drug, ST-246

Study Overview
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Brief Summary
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The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of two clinical doses of the anti-orthopoxvirus drug, ST-246, administered as a single daily oral dose for 14 days to healthy, fed volunteers. The results of this trial determine which dose will be used in expanded pivotal safety trials.

Detailed Description
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This study is a Phase II, double-blind, randomized, placebo-controlled, multi-center (3 sites) trial to assess the safety, tolerability, and pharmacokinetics of 400 mg and 600 mg Form I ST-246 when administered as a single daily oral dose for 14 days to 107 healthy, fed volunteers between 18 and 74 years of age. Safety parameters included adverse events, vital signs, physical examinations, laboratory tests (hematology, blood chemistry, and urinalysis) and electrocardiograms.

Official Title
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Double-Blind, Randomized, Placebo-Controlled, Multi-Center Trial to Assess Safety, Tolerability, and PK of the Anti-Orthopoxvirus Compound ST-246 When Administered as a Single Daily Oral Dose for 14 Days in Volunteers in the Fed State

Conditions
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Orthopoxviral Disease

Intervention / Treatment
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* Drug: ST-246 400 mg
* Drug: ST-246 600 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 - 75 yrs Healthy volunteer Ability to consent Available for clinical follow-up for study Not taking other medications Adequate venous access Using adequate birth control; negative pregnancy test Able and willing to avoid alcohol for screening and study duration Exclusion Criteria: Inability to swallow study medication Pregnant or breast-feeding Medical condition, e.g., asthma, hypertension, angioedema, traumatic brain injury other than concussion, bleeding disorder, blood dyscrasia, idiopathic seizures, cardiac disease that limits activity, diabetes, active malignancy, Hepatitis B or C, HIV or AIDS, chronic microbial infection, History of drug allergy that contraindicates study participation Medical, psychiatric, social, occupational or other reason that jeopardizes the safety/rights of participant or renders he/she unable to comply with the protocol (including drug or alcohol abuse, or homelessness) Clinically abnormal ECG Has or will participate in a clinical trial or experimental treatment within 30 days of, or during, the study Cannot or will not do physical exercise 24 hrs before and after PK days Will not consume grapefruit/grapefruit juice during study Vaccination within 2 wks of screening, or planned before Day 42 of study Treatment with prednisone or equivalent immunosuppressant/modulatory drug <3 mths before screening Clinically significant physical exam and lab results <2weeks from 1st study drug dose

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ST-246 400 mg<br>ST-246 400mg (2 x 200 mg Capsules) Orally Once Daily for 14 days | Drug: ST-246 400 mg<br>* Capsules, 400 mg daily for 14 days<br>* Other names: Tecovirimat;|
| Experimental: ST-246 600 mg<br>ST-246 600 mg (3 x 200 mg Capsules) Orally Once Daily for 14 days | Drug: ST-246 600 mg<br>* Capsules, 600 mg daily for 14 days<br>* Other names: Tecovirimat;|
| Placebo Comparator: Placebo<br>Matching Placebo capsules, Orally Once Daily for 14 days | Drug: Placebo<br>* Capsules, once daily for 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Study Participants Who Tolerated a Single Daily Oral ST-246 Dose as Determined by Safety Parameter Changes According to the DAIDS (Division of Acquired Immunodeficiency Syndrome) Adverse Events (AE) Grading Table. | Subjects were administered a single, daily oral dose of ST-246 (400 or 600 mg)and changes in safety parameteres were monitored. Safety parameters included adverse events, vital signs, physical examinations, laboratory tests (hematology, blood chemistry, and urinalysis) and electrocardiograms. The DAIDS AE grading table is a list of common terms and severity (intensity) of parameters used to describe adverse events occurring in NIAID-sponsored clinical studies/trials. | Days 1 to 14; then 24, 48, 72, 96 and 120 hours and 4 weeks after final dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | Cmax: Maximum drug concentration in plasma determined directly from individual concentration-time data | Day 1 post-dose | 
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | Cmax: Maximum drug concentration in plasma determined directly from individual concentration-time data | Day 14 post-dose | 
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | Tmax: Time to reach maximum drug concentration in plasma calculated from [plasma] versus time profiles | Day 1 post-dose | 
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | Tmax: Time to reach maximum drug concentration in plasma calculated from [plasma] versus time profiles | Day 14 post-dose | 
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | AUCtau: Area under the plasma concentration-time curve for each dosing interval (from time 0 to 24 hours sample) determined using the linear trapezoidal rule | Day 1 post-dose | 
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | AUCtau: Area under the plasma concentration-time curve for each dosing interval (from time 0 to 24 hours sample) determined using the linear trapezoidal rule | Day 14 post-dose | 
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½ | t½: Observed terminal elimination half-life determined after the last dose on Day 14 | Day 14 post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Orthopoxvirus, Smallpox, This is a safety study only, ST-246 is being studied for treatment of Orthopoxviruses