Phase I Trial of an Investigational Small Pox Medication

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

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.

Study Overview

• Status: Completed
• Conditions: Smallpox; Monkey Pox; Orthopoxviral Disease
• Intervention / Treatment: Drug: ST-246 Days 1 - 3; Drug: ST-246 Days 11 - 13

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Orlando, Florida, United States, 32809
      • Orlando Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 18 to 50 years
2. Available for clinical follow-up duration of study.
3. Able/willing to give written consent.
4. Good general health; no clinically significant medical history.
5. Refrain from taking any medications from screening through 72 hours after last dose.
6. Adequate venous access.
7. PE and lab results without clinically significant findings within 28 days prior to receipt of drug.
8. Meet Lab Criteria within 28 days prior to receipt of drug.
9. Negative pregnancy test
10. Non smokers
11. No alcohol or caffeine
12. 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:

1. Marked baseline prolongation of QT/corrected QT interval (QTc) interval (
2. History of additional risk factors for Torsade de Pointes
3. Clinically significant abnormal ECG
4. Personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or prolongation of the PR interval
5. Family history of Sudden Cardiac Death not clearly due to acute myocardial infarction.

6. 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
7. Family history of idiopathic seizures
8. History or presence of neutropenia or other blood dyscrasia
9. Known Hepatitis B or Hepatitis C infection
10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome illness.
11. Current or recent history of a clinically significant bacterial, fungal, or mycobacterial infection.
12. Known clinically significant chronic viral infection (or current clinically significant viral infection
13. History of frequent or severe headaches or migraines
14. Known chronic bacterial, mycobacterial, fungal, parasitic, or protozoal infection
15. Woman who is pregnant or is breast-feeding or planning to become pregnant
16. On any concomitant medications
17. History of drug allergy that, in the opinion of the PI, contraindicates participation in the trial.
18. Inability to swallow medication
19. Body Mass Index above 35 or below 18,
20. Current drug abuse or alcohol abuse.
21. 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
22. Clinically significant lactose intolerance
23. Received experimental drug within 30 days
24. Vaccination within 30 days
25. Total of more than 350 milliliters (mL) of blood drawn in 2 months
26. Treatment with any immunosuppressant or immunomodulatory medication in 3 months
27. 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
28. History or diagnosis that would affect absorption of study medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Group ST-246 Form I (followed by Form V); 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; 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).; Other Names: Tecovirimat; Drug: ST-246 Days 11 - 13; 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.; Other Names: Tecovirimat
ACTIVE_COMPARATOR: Group ST-246 Form V (followed by Form I); 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; 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).; Other Names: Tecovirimat; Drug: ST-246 Days 11 - 13; 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.; Other Names: Tecovirimat

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: SIGA Technologies
• Collaborators: National Institutes of Health (NIH)

Publications and helpful links

General Publications

• Hatmal MM, Al-Hatamleh MAI, Olaimat AN, Ahmad S, Hasan H, Ahmad Suhaimi NA, Albakri KA, Abedalbaset Alzyoud A, Kadir R, Mohamud R. Comprehensive literature review of monkeypox. Emerg Microbes Infect. 2022 Dec;11(1):2600-2631. doi: 10.1080/22221751.2022.2132882.

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (ACTUAL): October 1, 2008
• Study Completion (ACTUAL): October 1, 2008

Study Registration Dates

• First Submitted: August 1, 2008
• First Submitted That Met QC Criteria: August 5, 2008
• First Posted (ESTIMATE): August 6, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): June 29, 2015
• Last Update Submitted That Met QC Criteria: June 22, 2015
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: Smallpox; Orthopoxviral; Monkey pox
• Additional Relevant MeSH Terms: Virus Diseases; Infections; DNA Virus Infections; Poxviridae Infections; Smallpox; Monkeypox
• Other Study ID Numbers: SIGA-246-005; DMID 08-0014 (OTHER: NIH Contract (HHSN266200600014C))