Monkey Pox, Orthopoxviral Disease, Smallpox
Conditions
Keywords
Orthopoxviral, Smallpox, Monkey pox
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.
Interventions
DRUGST-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).
DRUGST-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.
Sponsors
National Institutes of Health (NIH)
SIGA Technologies
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Study period was approximately 2 weeks (from August 26, 2008 to September 8, 2008), plus a 30-day post-treatment follow up. The study was conducted at a Phase I Study Unit of a Clinical Research Center in Orlando, FL.
Pre-assignment details
All participants needed to meet strict entry criteria. Sixty-three subjects were screened to randomize 12 subjects into the study.
Participants by arm
| Arm | Count |
|---|---|
| ST-246 Form I Followed by Form V Each of six subjects receive a single 400 mg dose (2×200 mg) of ST-246 Form I, followed 10 days later by a single 400 mg dose (2×200 mg) of ST-246 Form V. Both forms of drug are orally administered within 30 minutes after a standard light meal consisting of 400-450 calories and approximately 25% fat. | 6 |
| ST-246 Form V Followed by Form I Each of six subjects receive a single 400 mg dose (2×200 mg) of ST-246 Form V, followed 10 days later by a single 400 mg dose (2×200 mg) of ST-246 Form I. Both forms of drug are orally administered within 30 minutes after a standard light meal consisting of 400-450 calories and approximately 25% fat. | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout Period (Days 4 - 10) | Death in family | 1 | 0 |
Baseline characteristics
| Characteristic | ST-246 Form V Followed by Form I | ST-246 Form I Followed by Form V | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Continuous | 34.8 years STANDARD_DEVIATION 9.4 | 34.7 years STANDARD_DEVIATION 8 | 34.8 years STANDARD_DEVIATION 8.3 |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 12 | 2 / 11 |
| serious Total, serious adverse events | 0 / 12 | 0 / 11 |
Outcome results
Primary
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).
Time frame: Post-dose samples at 0.5,1,2,3,4,8,12,24,36,48,72 hrs
Population: Both groups started with 12 particpants. Outlier values were excluded from analyses for 3 subject PK profiles (one Form I and 2 Form V). Form V group lost a particpant during wash-out period due to death in the family.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 Form I | Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: AUC0-∞ | 19922.017 ng*hr/mL | Standard Deviation 6543.563 |
| ST-246 Form V | Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: AUC0-∞ | 21982.709 ng*hr/mL | Standard Deviation 9330.953 |
Comparison: A sample size of 12 subjects was chosen to provide a statistical power of 80% to detect a 25% difference of the Form V mean between the Form I and Form V doses at the 0.05 level (2-sided) for this crossover design. Firstly, a parametric (normal theory) general linear model was applied and an ANOVA for a 2-way crossover design was employed to examine the differences among the 2 forms. Secondly, AUC0-∞ was analyzed on a log scale, to assess bioequivalence between Form I and Form V.p-value: 0.0997ANOVA
Primary
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).
Time frame: Post-dose samples at 0.5,1,2,3,4,8,12,24,36,48,72 hrs
Population: Both groups started with 12 particpants. Form V group lost a particpant during wash-out period due to death in the family.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 Form I | Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: AUC0-τ | 15624.495 ng*hr/mL | Standard Deviation 5449.188 |
| ST-246 Form V | Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: AUC0-τ | 20065.316 ng*hr/mL | Standard Deviation 6744.974 |
Comparison: A sample size of 12 subjects was chosen to provide a statistical power of 80% to detect a 25% difference of the Form V mean between the Form I and Form V doses at the 0.05 level (2-sided) for this crossover design. Firstly, a parametric (normal theory) general linear model was applied and an ANOVA for a 2-way crossover design was employed to examine the differences among the 2 forms. Secondly, AUC0-τ was analyzed on a log scale, to assess bioequivalence between Form I and Form V.p-value: 0.0048ANOVA
Primary
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)
Time frame: Post-dose samples at 0.5,1,2,3,4,8,12,24,36,48,72 hrs
Population: Both groups started with 12 particpants as 'per protocol'. Form V group lost a particpant during wash-out period due to death in the family.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 Form I | Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: Cmax | 1068.9 ng/mL | Standard Deviation 294.3 |
| ST-246 Form V | Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: Cmax | 1230.2 ng/mL | Standard Deviation 348.6 |
Comparison: A sample size of 12 subjects was chosen to provide a statistical power of 80% to detect a 25% difference of the Form V mean between the Form I and Form V doses at the 0.05 level (2-sided) for this crossover design. Firstly, a parametric (normal theory) general linear model was applied and an ANOVA for a 2-way crossover design was employed to examine the differences among the 2 forms. Secondly, Cmax was analyzed on a log scale, to assess bioequivalence between Form I and Form V.p-value: 0.0422ANOVA
Primary
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.
Time frame: Post-dose samples at 0.5,1,2,3,4,8,12,24,36,48,72 hrs
Population: Both groups started with 12 particpants. Outlier values were excluded from the half-life analyses for 3 subject PK profiles (one Form I and 2 Form V). Form V group lost a particpant during wash-out period due to death in the family.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 Form I | Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: t½ | 27.446 hours | Standard Deviation 13.109 |
| ST-246 Form V | Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: t½ | 28.180 hours | Standard Deviation 21.992 |
Comparison: A sample size of 12 subjects was chosen to provide a statistical power of 80% to detect a 25% difference of the Form V mean between the Form I and Form V doses at the 0.05 level (2-sided) for this crossover design. A parametric (normal theory) general linear model was applied and an ANOVA for a 2-way crossover design was employed to examine the differences among the 2 forms.p-value: 0.4591ANOVA
Primary
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.
Time frame: Post-dose samples at 0.5,1,2,3,4,8,12,24,36,48,72 hrs
Population: Both groups started with 12 particpants. Form V group lost a particpant during wash-out period due to death in the family.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ST-246 Form I | Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: Tmax | 3.8 hours | Standard Deviation 1.5 |
| ST-246 Form V | Pharmacokinetic Parameters for a Single Dose of ST-246 Form I vs. Form V: Tmax | 3.8 hours | Standard Deviation 1.6 |
Comparison: A sample size of 12 subjects was chosen to provide a statistical power of 80% to detect a 25% difference of the Form V mean between the Form I and Form V doses at the 0.05 level (2-sided) for this crossover design. A parametric (normal theory) general linear model was applied and an ANOVA for a 2-way crossover design was employed to examine the differences among the 2 forms.p-value: 0.8581ANOVA
Secondary
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: 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.
Time frame: 4 weeks
Population: Both groups started with 12 particpants. Form V group lost a particpant during wash-out period due to death in the family.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ST-246 Form I | 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 | 12 participants |
| ST-246 Form V | 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 | 11 participants |