Orthopoxviral Disease
Conditions
Keywords
Orthopoxvirus, Smallpox, This is a safety study only, ST-246 is being studied for treatment of Orthopoxviruses
Brief summary
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
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.
Interventions
DRUGST-246 400 mg
Capsules, 400 mg daily for 14 days
DRUGST-246 600 mg
Capsules, 600 mg daily for 14 days
DRUGPlacebo
Capsules, once daily for 14 days
Sponsors
SIGA Technologies
National Institutes of Health (NIH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. 18 - 75 yrs 2. Healthy volunteer 3. Ability to consent 4. Available for clinical follow-up for study 5. Not taking other medications 6. Adequate venous access 7. Using adequate birth control; negative pregnancy test 8. Able and willing to avoid alcohol for screening and study duration
Exclusion criteria
1. Inability to swallow study medication 2. Pregnant or breast-feeding 3. 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, 4. History of drug allergy that contraindicates study participation 5. 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) 6. Clinically abnormal ECG 7. Has or will participate in a clinical trial or experimental treatment within 30 days of, or during, the study 8. Cannot or will not do physical exercise 24 hrs before and after PK days 9. Will not consume grapefruit/grapefruit juice during study 10. Vaccination within 2 wks of screening, or planned before Day 42 of study 11. Treatment with prednisone or equivalent immunosuppressant/modulatory drug \<3 mths before screening 12. Clinically significant physical exam and lab results \<2weeks from 1st study drug dose
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Days 1 to 14; then 24, 48, 72, 96 and 120 hours and 4 weeks after final dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | Day 1 post-dose | Cmax: Maximum drug concentration in plasma determined directly from individual concentration-time data |
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | Day 1 post-dose | Tmax: Time to reach maximum drug concentration in plasma calculated from \[plasma\] versus time profiles |
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | Day 1 post-dose | 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 |
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½ | Day 14 post-dose | t½: Observed terminal elimination half-life determined after the last dose on Day 14 |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORThomas Marbury, MD
Orlando Clinical Research Center
PRINCIPAL_INVESTIGATORErik Ross, MD
Apex Research Institute
PRINCIPAL_INVESTIGATORJon Ruckle, MD
Hawaii Clinical Research Center
Participant flow
Recruitment details
This study was conducted at three sites: Apex Research Institute, Santa Ana, CA, Hawaii Clinical Research Center, Honolulu, HI, and Orlando Clinical Research Center, Orlando, FL. The study was conducted in male and female volunteers ages 18 - 75 years inclusive from the sites' databases.
Pre-assignment details
Following an up to 14-day Screening Period, eligible subjects were randomly assigned to receive either ST-246 400 mg (n=45) or ST-246 600 mg (n=46) or placebo (n=16). Treatment was orally administered after a light meal over a 14-day Treatment Period. There was a 28-day Follow-up Period.
Participants by arm
| Arm | Count |
|---|---|
| ST-246 400 mg 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days. | 45 |
| ST-246 600 mg 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days. | 46 |
| Placebo Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days. | 16 |
| Total | 107 |
Baseline characteristics
| Characteristic | ST-246 600 mg | Placebo | ST-246 400 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical >=65 years | 6 Participants | 3 Participants | 2 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants | 13 Participants | 41 Participants | 94 Participants |
| Age, Continuous | 43.7 years STANDARD_DEVIATION 15.81 | 42.5 years STANDARD_DEVIATION 17.03 | 41.3 years STANDARD_DEVIATION 15.22 | 42.5 years STANDARD_DEVIATION 15.64 |
| Region of Enrollment United States | 46 participants | 16 participants | 45 participants | 107 participants |
| Sex: Female, Male Female | 22 Participants | 9 Participants | 27 Participants | 58 Participants |
| Sex: Female, Male Male | 24 Participants | 7 Participants | 18 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| other Total, other adverse events | 11 / 45 | 8 / 46 | 1 / 16 |
| serious Total, serious adverse events | 0 / 45 | 0 / 46 | 0 / 16 |
Outcome results
Primary
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.
Time frame: Days 1 to 14; then 24, 48, 72, 96 and 120 hours and 4 weeks after final dose
Population: As per protocol. During the study, a total of 6 withdrawals occurred. These were due to adverse events (2) and consent withdrawal (1) in the 400 mg group, and subject request (1), lost to follow-up (1) and protocol violation (1) in the 600 mg group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ST-246 400 mg | 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. | 34 Participants |
| ST-246 600 mg | 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. | 38 Participants |
| Placebo | 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. | 15 Participants |
Secondary
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
Time frame: Day 1 post-dose
Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 23 subjects in each of the ST-246 400 mg and 600 mg groups were excluded from PK analysis due to early withdrawals or because PK data fell below the limit of quantitation (BLQ) before the 24-hour dosing interval was complete.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 400 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 11329 ng*hr/mL | Standard Deviation 4945 |
| ST-246 600 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 13895 ng*hr/mL | Standard Deviation 5702 |
Secondary
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
Time frame: Day 14 post-dose
Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 5 and 6 subjects in the ST-246 400 mg and 600 mg groups respectively, were excluded from PK analysis due to withdrawals or because PK data fell below the limit of quantitation (BLQ).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 400 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 12026 ng*hr/mL | Standard Deviation 4255 |
| ST-246 600 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 14791 ng*hr/mL | Standard Deviation 5712 |
Secondary
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax
Cmax: Maximum drug concentration in plasma determined directly from individual concentration-time data
Time frame: Day 1 post-dose
Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 2 subjects in each of the ST-246 400 mg and 600 mg groups were excluded due to early withdrawals.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 400 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 1170 ng/mL | Standard Deviation 429 |
| ST-246 600 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 1467 ng/mL | Standard Deviation 626 |
Secondary
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax
Cmax: Maximum drug concentration in plasma determined directly from individual concentration-time data
Time frame: Day 14 post-dose
Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 4 subjects in each of the ST-246 400 mg and 600 mg groups were excluded from PK analysis due to withdrawals or because PK data fell below the limit of quantitation (BLQ).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 400 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 1286 ng/mL | Standard Deviation 449 |
| ST-246 600 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 1523 ng/mL | Standard Deviation 607 |
Secondary
Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½
t½: Observed terminal elimination half-life determined after the last dose on Day 14
Time frame: Day 14 post-dose
Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 21 and 20 subjects in the ST-246 400 mg and 600 mg groups respectively, were excluded from PK analysis due to early withdrawals or because PK data fell below the limit of quantitation (BLQ).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 400 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½ | 26 hours | Standard Deviation 11 |
| ST-246 600 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½ | 24 hours | Standard Deviation 15 |
Secondary
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax
Tmax: Time to reach maximum drug concentration in plasma calculated from \[plasma\] versus time profiles
Time frame: Day 14 post-dose
Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 4 and 5 subjects in the ST-246 400 mg and 600 mg groups respectively, were excluded from PK analysis due to withdrawals or because PK data fell below the limit of quantitation (BLQ).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 400 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 4 hours | Standard Deviation 1 |
| ST-246 600 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 3 hours | Standard Deviation 1 |
Secondary
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax
Tmax: Time to reach maximum drug concentration in plasma calculated from \[plasma\] versus time profiles
Time frame: Day 1 post-dose
Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 2 subjects in each of the ST-246 400 mg and 600 mg groups were excluded due to early withdrawals.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 400 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 4 hours | Standard Deviation 1 |
| ST-246 600 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 4 hours | Standard Deviation 1 |