Phase I Trial of an Investigational Small Pox Medication

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the pharmacokinetic parameters and safety of a single dose of ST-246 400mg Form I versus ST-246 400mg Form V capsules in fed normal healthy volunteers.

Detailed Description
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This was a Phase I, double-blind, cross-over, single-dose study of the orally administered anti-orthopoxvirus compound, ST-246, to 12 healthy, fed volunteers between the ages of 18 and 50 years. Subjects were randomized such that 6 subjects received either ST-246 Form I (monohydrate) followed 10 days later after a wash-out period by Form V (hemihydrate), and 6 subjects received ST-246 Form V followed by Form I, as for the previous group. Both forms of ST-246 were similar in the way they were manufactured. The only difference between Form I and Form V may be related to how it dissolves, and this may affect the way that it is absorbed in the human body. Information about any side-effects that may occur will also be collected in this study.

Official Title
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A Phase I Randomized, Double-Blind, Crossover, Exploratory Study of the Pharmacokinetics of a Single Oral Dose of Form I Versus Form V Capsules of the Anti-Orthopoxvirus Compound ST-246® in Fed Normal Healthy Volunteers

Conditions
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Orthopoxviral Disease, Smallpox, Monkey Pox

Intervention / Treatment
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* Drug: ST-246 Days 1 - 3
* Drug: ST-246 Days 11 - 13


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 50 years Available for clinical follow-up duration of study. Able/willing to give written consent. Good general health; no clinically significant medical history. Refrain from taking any medications from screening through 72 hours after last dose. Adequate venous access. PE and lab results without clinically significant findings within 28 days prior to receipt of drug. Meet Lab Criteria within 28 days prior to receipt of drug. Negative pregnancy test Non smokers No alcohol or caffeine Participant or partner has undergone surgical sterilization, or the participant agrees either to be abstinent or use two non-hormonal methods of contraception for duration of the study Exclusion Criteria: Marked baseline prolongation of QT/corrected QT interval (QTc) interval ( History of additional risk factors for Torsade de Pointes Clinically significant abnormal ECG Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or prolongation of the PR interval Family history of Sudden Cardiac Death not clearly due to acute myocardial infarction. History of any clinically significant conditions including: Asthma Diabetes mellitus History of thyroidectomy or thyroid disease Serious angioedema episodes Head trauma resulting in a diagnosis of TBI other than concussion Seizure or history of seizure Bleeding disorder diagnosed by a doctor or significant bruising or bleeding difficulties with intramuscular injections or blood draws Malignancy Family history of idiopathic seizures History or presence of neutropenia or other blood dyscrasia Known Hepatitis B or Hepatitis C infection Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome illness. Current or recent history of a clinically significant bacterial, fungal, or mycobacterial infection. Known clinically significant chronic viral infection (or current clinically significant viral infection History of frequent or severe headaches or migraines Known chronic bacterial, mycobacterial, fungal, parasitic, or protozoal infection Woman who is pregnant or is breast-feeding or planning to become pregnant On any concomitant medications History of drug allergy that, in the opinion of the PI, contraindicates participation in the trial. Inability to swallow medication Body Mass Index above 35 or below 18, Current drug abuse or alcohol abuse. Inability to refrain from physical exercise for a period of 24 hr before and after a PK day or refrain from consuming xanthines, grapefruit or grapefruit juice Clinically significant lactose intolerance Received experimental drug within 30 days Vaccination within 30 days Total of more than 350 milliliters (mL) of blood drawn in 2 months Treatment with any immunosuppressant or immunomodulatory medication in 3 months Any condition occupational reason or other responsibility that, in the judgment of the PI, would jeopardize the safety or rights of a subject participating in the trial or would render the subject unable to comply with the protocol History or diagnosis that would affect absorption of study medication

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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 |
| --- | --- |
| Active Comparator: Group ST-246 Form I (followed by Form V)<br>Each of six subjects receive a single oral 400 mg dose (2×200 mg) of ST-246 Form I (monohydrate) in the first intervention period, followed 10 days later (3 days post-treatment monitoring and 7 days wash-out period) in the second intervention period by a single oral 400 mg dose (2×200 mg) of ST-246 Form V (hemihydrate). Both forms of drug are orally administered within 30 minutes after a standard light meal consisting of 400-450 calories and approximately 25% fat. | Drug: ST-246 Days 1 - 3<br>* First Intervention is on Days 1 - 3, and includes 6 patients dosed once orally with ST-246 Form I (Arm 1), and 6 patients dosed once orally with ST-246 Form V (Arm 2).<br>* Other names: Tecovirimat;Drug: ST-246 Days 11 - 13<br>* Second Intervention is on Days 11 - 13 (after a 3 day post-treatment monitoring and 7 day wash-out period) where the 6 patients previously given ST-246 Form I (Arm 1) are now dosed once orally with ST-246 Form V, and the 6 patients previously given ST-246 Form V (Arm 2) are now dosed once orally with ST-246 Form I.<br>* Other names: Tecovirimat;|
| Active Comparator: Group ST-246 Form V (followed by Form I)<br>Each of six subjects receive a single oral 400 mg dose (2×200 mg) of ST-246 Form V (hemihydrate) in the first intervention period, followed 10 days later (3 days post-treatment monitoring and 7 days wash-out period) in the second intervention period by a single oral 400 mg dose (2×200 mg) of ST-246 Form I (monohydrate). Both forms of drug are orally administered within 30 minutes after a standard light meal consisting of 400-450 calories and approximately 25% fat. | Drug: ST-246 Days 1 - 3<br>* First Intervention is on Days 1 - 3, and includes 6 patients dosed once orally with ST-246 Form I (Arm 1), and 6 patients dosed once orally with ST-246 Form V (Arm 2).<br>* Other names: Tecovirimat;Drug: ST-246 Days 11 - 13<br>* Second Intervention is on Days 11 - 13 (after a 3 day post-treatment monitoring and 7 day wash-out period) where the 6 patients previously given ST-246 Form I (Arm 1) are now dosed once orally with ST-246 Form V, and the 6 patients previously given ST-246 Form V (Arm 2) are now dosed once orally with ST-246 Form I.<br>* Other names: Tecovirimat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: t½ | Mean terminal half-life (t½; hrs) for Forms I and V were calculated from [plasma] vs time profiles. | Post-dose samples at 0.5,1,2,3,4,8,12,24,36,48,72 hrs | 
| Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: AUC0-τ | Area under the drug concentration-time curve from time zero to time t, where t is the last timepoint with a drug concentration ≥ lowest obtainable quantification (AUC0-τ; ng*hr/mL). | Post-dose samples at 0.5,1,2,3,4,8,12,24,36,48,72 hrs | 
| Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: AUC0-∞ | Area under the drug concentration-time curve from time zero to infinity (AUC0-∞; ng*hr/mL). | Post-dose samples at 0.5,1,2,3,4,8,12,24,36,48,72 hrs | 
| Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: Cmax | Maximum drug concentration in plasma, determined directly from individual concentration-time data (Cmax) | Post-dose samples at 0.5,1,2,3,4,8,12,24,36,48,72 hrs | 
| Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: Tmax | Time to maximum plasma concentration(Tmax; hrs) for Forms I and V were calculated from [plasma] vs time profiles. | Post-dose samples at 0.5,1,2,3,4,8,12,24,36,48,72 hrs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Study Participants Who Tolerated a Single Dose of ST-246 Form I vs. Form V as Determined by No Clinically Significant Changes in Safety Parameters | Evaluated safety parameters included: physical examination/vital signs electrocardiograms (heart rate, PR interval, QRS duration, QT interval, and QTc Bazett) laboratory safety tests (hematology, chemistry, urinalysis) adverse events For a), b) and c), summary statistics (mean,SD, median, minm, maxm)for values, and changes from baseline(Day 1 pre-dose) to each timepoint, were measured and compared to laboratory normal reference ranges. Values for a)- d) were assigned grades according to DAIDS AE Grading Table. Any Grade of 3 or higher was considered severe and significant. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Orthopoxviral, Smallpox, Monkey pox