Phase I Trial of an Investigational Small Pox Medication

Phase 1

Completed

Conditions: Orthopoxviral Disease
Smallpox
Monkey Pox

Interventions: Drug: ST-246 Days 1 - 3
Drug: ST-246 Days 11 - 13

Registration Number: NCT00728689

Lead Sponsor: SIGA Technologies

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Group ST-246 Form I (followed by Form V)	ST-246 Days 1 - 3	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.
Group ST-246 Form I (followed by Form V)	ST-246 Days 11 - 13	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.
Group ST-246 Form V (followed by Form I)	ST-246 Days 1 - 3	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.
Group ST-246 Form V (followed by Form I)	ST-246 Days 11 - 13	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
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	4 weeks	Evaluated safety parameters included: 1. physical examination/vital signs 2. electrocardiograms (heart rate, PR interval, QRS duration, QT interval, and QTc Bazett) 3. laboratory safety tests (hematology, chemistry, urinalysis) 4. 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.