Healthy
Conditions
Keywords
Healthy Volunteers
Brief summary
The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of a single, daily, oral dose of ST-246 (either 250, 400 or 800mg) administered for 21 days to 30 healthy, fed volunteers.
Detailed description
This was a double-blind, placebo-controlled, dose-escalating, multiple-dose study of orally administered ST-246 to 30 healthy volunteers ages 18-50 years, randomized to receive either active drug (8 subjects) or placebo (2 subjects) in 1 of 3 dosing groups (250, 400 or 800mg groups). Each dose group of 10 was divided into two cohorts of 5 subjects (4 active and 1 placebo). The first cohort was dosed approximately 4-8 weeks before the second cohort of each dose group. Dose groups completed the study treatment approximately 5 weeks prior to the start of the following dose group. Study procedures included several overnight stays, medical history/exam, laboratory testing done by blood draw, and electrocardiograms.
Interventions
DRUGST-246
250 mg, 400 mg or 800 mg capsules given once daily for 21 days
DRUGPlacebo
Capsules to match experimental drug
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
SIGA Technologies
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
Subject Inclusion Criteria: * Healthy volunteers * Ability to Consent * Not taking any other medication * Adequate venous access * Using adequate birth control Subject
Exclusion criteria
* Inability to swallow study medication. * Pregnant or breastfeeding * Received experimental drug within 30 days of study entry or will participate in any experimental study during the study period. * Current drug abuse, alcohol abuse, or homelessness. * Taking concomitant medication * Lactose Intolerance * Medical condition; e.g., asthma, diabetes, thyroid disease, angioedema, BMI \>35 or \<18, hypertension, bleeding disorder, malignancy, seizure, neutropenia, Hepatitis B or C, HIV or AIDS. * Any condition, occupational reason or other responsibility that, in the judgment of the Investigator, would jeopardize the safety or rights of a volunteer, or render the subject unable to comply with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Study Participants Who Tolerated ST-246 (250, 400 or 800mg) as Determined by Changes in Safety Parameters, According to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Adverse Events (AE) Grading Table | Days 1, 6, 14-16, 21-24, 28-31, and 51-53 | 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 (AEs) For a)-c), statistical values (mean, standard deviation, median, minimum, maximum) and changes from baseline (Day 1 pre-dose) to each time-point, were compared to laboratory normal reference ranges. If values for a)-d) were a Grade 3 or higher (in DAIDS AE Table)and ST-246-related, they were considered severe and significant, respectively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | Day 1 | Cmax: Maximum drug concentration in plasma determined directly from individual concentration-time data |
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | Day 1 | Tmax: Time to reach maximum drug concentration in plasma calculated from \[plasma\] versus time profiles. |
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½ | Day 21 | t½: Observed terminal elimination half-life determined after the last dose on Day 21 |
| Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | Day 1 | 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: Ae(0-24) | Day 1 | Ae(0-24): Cumulative amount of drug excreted unchanged in urine over 24 hours (three 8-hour collection periods), determined on Days 1 and 21 |
Countries
United States
Participant flow
Recruitment details
This study was conducted at one site, Orlando Clinical Research Center, Orlando, FL. The study was conducted in healthy volunteers from the site's database.
Pre-assignment details
After a 28-day screening and 1-day enrollment period, study drug was administered on Day 1. Ten participants (8 drug:2 placebo) were randomized in each of three dosing groups (250, 400, and 800 mg ST-246). Each group was divided into 2 cohorts of 5 subjects (4 drug:1 placebo), with one cohort receiving drug 4-8 weeks before the other cohort.
Participants by arm
| Arm | Count |
|---|---|
| ST-246 250 mg 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. | 8 |
| ST-246 400mg 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. Blood and urine samples for PK taken on Days 1, 6, and 21. | 8 |
| ST-246 800 mg 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. Blood and urine samples for PK taken on Days 1, 6, and 21. | 8 |
| Placebo Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent). Blood and urine samples for PK taken on Days 1, 6, and 21. | 6 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 |
| Overall Study | Inability to follow study procedures | 1 | 0 | 1 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | ST-246 250 mg | ST-246 400mg | ST-246 800 mg | Placebo |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 8 Participants | 8 Participants | 8 Participants | 6 Participants |
| Age, Continuous | 33.9 years STANDARD_DEVIATION 8.8 | 36.5 years STANDARD_DEVIATION 8.2 | 27.6 years STANDARD_DEVIATION 7.8 | 37.5 years STANDARD_DEVIATION 7.6 | 34.8 years STANDARD_DEVIATION 8.9 |
| Region of Enrollment United States | 30 participants | 8 participants | 8 participants | 8 participants | 6 participants |
| Sex: Female, Male Female | 10 Participants | 3 Participants | 4 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 20 Participants | 5 Participants | 4 Participants | 7 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 8 | 2 / 8 | 5 / 8 | 4 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 6 |
Outcome results
Primary
Number of Study Participants Who Tolerated ST-246 (250, 400 or 800mg) as Determined by Changes in Safety Parameters, According to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Adverse Events (AE) Grading Table
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 (AEs) For a)-c), statistical values (mean, standard deviation, median, minimum, maximum) and changes from baseline (Day 1 pre-dose) to each time-point, were compared to laboratory normal reference ranges. If values for a)-d) were a Grade 3 or higher (in DAIDS AE Table)and ST-246-related, they were considered severe and significant, respectively.
Time frame: Days 1, 6, 14-16, 21-24, 28-31, and 51-53
Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each, and one placebo group with 6 subjects. A total of 7 withdrawals during the entire study were due to inability to follow procedure (4), lost to follow-up (1), requested due to concomitant medication (1), and an adverse event (1)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ST-246 250 mg | Number of Study Participants Who Tolerated ST-246 (250, 400 or 800mg) as Determined by Changes in Safety Parameters, According to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Adverse Events (AE) Grading Table | 8 Participants |
| ST-246 400mg | Number of Study Participants Who Tolerated ST-246 (250, 400 or 800mg) as Determined by Changes in Safety Parameters, According to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Adverse Events (AE) Grading Table | 8 Participants |
| ST-246 800 mg | Number of Study Participants Who Tolerated ST-246 (250, 400 or 800mg) as Determined by Changes in Safety Parameters, According to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Adverse Events (AE) Grading Table | 7 Participants |
| Placebo | Number of Study Participants Who Tolerated ST-246 (250, 400 or 800mg) as Determined by Changes in Safety Parameters, According to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Adverse Events (AE) Grading Table | 6 Participants |
Secondary
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24)
Ae(0-24): Cumulative amount of drug excreted unchanged in urine over 24 hours (three 8-hour collection periods), determined on Days 1 and 21
Time frame: Day 21
Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. Between Days 6 and 21, there were 4 (out of 7 total) withdrawals due to inability to follow procedure (2; 250mg and placebo groups), lost to follow-up (1; 400mg group), and adverse event (1; 800mg group).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24) | 0.049 mg | Standard Deviation 0.026 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24) | 0.108 mg | Standard Deviation 0.046 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24) | 0.213 mg | Standard Deviation 0.165 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24) | 0 mg | Standard Deviation 0 |
Secondary
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24)
Ae(0-24): Cumulative amount of drug excreted unchanged in urine over 24 hours (three 8-hour collection periods), determined on Days 1 and 21
Time frame: Day 1
Population: Post-screening, 30 healthy subjects were randomized on Day 1 into three active drug groups with 8 subjects each and one placebo group with 6 subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24) | 0.041 mg | Standard Deviation 0.031 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24) | 0.110 mg | Standard Deviation 0.066 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24) | 0.157 mg | Standard Deviation 0.048 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24) | 0 mg | Standard Deviation 0 |
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 21
Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. Between Days 6 and 21, there were 4 (out of 7 total) withdrawals due to inability to follow procedure (2; 250mg and placebo groups), lost to follow-up (1; 400mg group), and adverse event (1; 800mg group).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 10083 ng*hr/mL | Standard Deviation 2843 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 16182 ng*hr/mL | Standard Deviation 5534 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 22684 ng*hr/mL | Standard Deviation 4579 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 0 ng*hr/mL | Standard Deviation 0 |
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 6
Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. By Day 6 there were 3 (out of 7 total) withdrawals from the study due to inability to follow procedure (2; 800mg and placebo groups), and requested due to concomitant medication (1; 400mg group)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 11892 ng*hr/mL | Standard Deviation 4389 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 15432 ng*hr/mL | Standard Deviation 4708 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 23352 ng*hr/mL | Standard Deviation 4696 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 0 ng*hr/mL | Standard Deviation 0 |
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
Population: Post-screening, 30 healthy subjects were randomized on Day 1 into three active drug groups with 8 subjects each and one placebo group with 6 subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 9101 ng*hr/mL | Standard Deviation 3492 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 13146 ng*hr/mL | Standard Deviation 3626 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 20959 ng*hr/mL | Standard Deviation 6091 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau | 0 ng*hr/mL | Standard Deviation 0 |
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 6
Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. By Day 6 there were 3 (out of 7 total) withdrawals from the study due to inability to follow procedure (2; 800mg and placebo groups), and requested due to concomitant medication (1; 400mg group)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 1212 ng/mL | Standard Deviation 350 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 1298 ng/mL | Standard Deviation 277 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 2337 ng/mL | Standard Deviation 437 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 0 ng/mL | Standard Deviation 0 |
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
Population: Post-screening, 30 healthy subjects were randomized on Day 1 into three active drug groups with 8 subjects each and one placebo group with 6 subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 985 ng/mL | Standard Deviation 346 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 1392 ng/mL | Standard Deviation 411 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 2279 ng/mL | Standard Deviation 395 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 0 ng/mL | Standard Deviation 0 |
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 21
Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. Between Days 6 and 21, there were 4 (out of 7 total) withdrawals due to inability to follow procedure (2; 250mg and placebo groups), lost to follow-up (1; 400mg group), and adverse event (1; 800mg group)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 1101 ng/mL | Standard Deviation 378 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 1457 ng/mL | Standard Deviation 451 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 2437 ng/mL | Standard Deviation 496 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax | 0 ng/mL | Standard Deviation 0 |
Secondary
Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½
t½: Observed terminal elimination half-life determined after the last dose on Day 21
Time frame: Day 21
Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. Between Days 6 and 21, there were 4 (out of 7 total) withdrawals due to inability to follow procedure (2; 250mg and placebo groups), lost to follow-up (1; 400mg group), and adverse event (1; 800mg group).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½ | 18.8 hours | Standard Deviation 10.4 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½ | 19.9 hours | Standard Deviation 8.9 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½ | 20.7 hours | Standard Deviation 8.4 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½ | 0 hours | Standard Deviation 0 |
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 21
Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. Between Days 6 and 21, there were 4 (out of 7 total) withdrawals due to inability to follow procedure (2; 250mg and placebo groups), lost to follow-up (1; 400mg group), and adverse event (1; 800mg group)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 2.9 hours | Standard Deviation 1.1 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 2.7 hours | Standard Deviation 1 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 3.2 hours | Standard Deviation 1.3 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 0 hours | Standard Deviation 0 |
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 6
Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. By Day 6 there were 3 (out of 7 total) withdrawals from the study due to inability to follow procedure (2; 800mg and placebo groups), and requested due to concomitant medication (1; 400mg group)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 2.6 hours | Standard Deviation 1.2 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 3.7 hours | Standard Deviation 2.1 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 3.6 hours | Standard Deviation 2.3 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 0 hours | Standard Deviation 0 |
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
Population: Post-screening, 30 healthy subjects were randomized on Day 1 into three active drug groups with 8 subjects each and one placebo group with 6 subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 250 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 3.0 hours | Standard Deviation 1.1 |
| ST-246 400mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 3.3 hours | Standard Deviation 1 |
| ST-246 800 mg | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 2.9 hours | Standard Deviation 1.3 |
| Placebo | Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax | 0 hours | Standard Deviation 0 |