Marburg Virus Disease
Conditions
Brief summary
This is a placebo-controlled, randomized, double-blind study to evaluate the pharmacokinetics of galidesivir following administration of single doses by IV infusion
Detailed description
This single ascending dose study will evaluate the safety, tolerability, and PK of single doses of galidesivir vs. placebo administered as IV infusions in healthy subjects enrolled in up to four dose cohorts of 8 subjects each. A single dose of study drug will be administered per cohort: 6 subjects will receive galidesivir IV, and 2 subjects will receive matching placebo.
Interventions
DRUGgalidesivir
galidesivir IV infusion
DRUGplacebo
placebo IV infusion
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
BioCryst Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * written informed consent * males and non-pregnant, non-lactating females * BMI 19.0-32.0 * willing to abide by contraceptive requirements * normal vitals * willing to abide by study procedures and restrictions
Exclusion criteria
* clinically significant medical condition or medical history or psychiatric condition or history of psychiatric condition * abnormal cardiac finding, or laboratory/urinalysis abnormality at screening * known family history of sudden death or long QT syndrome, family or personal history of QT prolongation, or arrhythmia that required medical intervention * current participation in any other investigational drug study or participation in an investigational drug study within 3 months of screening visit * use of prescription, OTC, or herbal medications during study or use of any specified medications within 30 days prior to study * Recent or current history of alcohol or drug abuse * Regular use of tobacco or nicotine products * Positive serology for HBV, HCV, or HIV * history of severe adverse reaction to or known sensitivity to any drug * pregnant, lactating, or planning to become pregnant within 30 days of the study. Male subjects with pregnant female partners are excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | AEs were assessed and recorded from the time of signing the ICF through to the appropriate follow-up period, up to 23 days from IMP dosing on Day 1. | Any event reported on the subject's study record that occurred on or after the initiation of study drug was defined as treatment emergent (TEAE). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma PK - Galidesivir Cmax (Maximum Observed Concentration of Drug) | Plasma PK parameters are based on sampling over a 21 day period | Serial blood samples for PK assessment of plasma galidesivir were collected at the following time points: * Day 1 to Day 5: 0 hour (pre dose), halfway through the infusion (0.5 hour), 1 hour (end of the infusion), 1.25, 1.50, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 60, 72, and 96 hours post dose. * Day 6 (+1 day), Day 8 (+1 day), Day 14 (± 1 day) * Day 21 (+2 days) or early termination. Cmax for galidesivir was estimated using non compartmental methods with Phoenix® WinNonlin® v8.1 or higher (Certara, Inc.). |
| Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve) | Plasma PK parameters are based on sampling over a 21 day period | Serial blood samples for PK assessment of plasma galidesivir were collected at the following time points: * Day 1 to Day 5: 0 hour (pre dose), halfway through the infusion (0.5 hour), 1 hour (end of the infusion), 1.25, 1.50, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 60, 72, and 96 hours post dose. * Day 6 (+1 day), Day 8 (+1 day), Day 14 (± 1 day) * Day 21 (+2 days) or early termination. AUC0-inf (AUC from time 0 extrapolated to infinite time) and AUC0-t (AUC from time 0 to time t, where t = the last quantifiable concentration) for galidesivir was estimated using non compartmental methods with Phoenix® WinNonlin® v8.1 or higher (Certara, Inc.). |
| Galidesivir Renal Clearance | Urine PK parameters are based on sampling over a 96 hour period. | Urine was collected from subjects over a 96 hour period per protocol, analyzed for galidesivir concentrations. Urine PK parameters including CLR (renal clearance of unchanged drug cumulatively over all collection intervals or in a specific interval) were estimated in SAS for Windows v9.4 or higher (SAS Institute, Inc.) based on the recorded urine concentrations and volumes. |
Countries
United States
Participant flow
Pre-assignment details
A single dose of study drug was administered to subjects in each of cohorts 1 to 4. In each cohort, 6 subjects received galidesivir and 2 subjects received matching placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo single placebo IV infusion | 8 |
| 5 mg/kg Galidesivir Single IV infusion 5 mg/kg galidesivir | 6 |
| 10 mg/kg Galidesivir Single IV infusion 10 mg/kg galidesivir | 6 |
| 15 mg/kg Galidesivir Single IV infusion 15 mg/kg galidesivir | 6 |
| 20 mg/kg Galidesivir Single IV infusion 20 mg/kg galidesivir | 6 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | 20 mg/kg Galidesivir | 15 mg/kg Galidesivir | 10 mg/kg Galidesivir | 5 mg/kg Galidesivir |
|---|---|---|---|---|---|---|
| Age, Continuous | 31.1 years STANDARD_DEVIATION 6.88 | 35.3 years STANDARD_DEVIATION 9.87 | 31.8 years STANDARD_DEVIATION 8.98 | 41.7 years STANDARD_DEVIATION 12.04 | 33.5 years STANDARD_DEVIATION 8.76 | 39.8 years STANDARD_DEVIATION 10.76 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 12 Participants | 3 Participants | 0 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 19 Participants | 3 Participants | 6 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Female | 5 Participants | 13 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 19 Participants | 4 Participants | 4 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 2 / 8 | 0 / 6 | 0 / 6 | 4 / 6 | 1 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 6 | 1 / 6 | 1 / 6 | 0 / 6 |
Outcome results
Primary
Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events.
Any event reported on the subject's study record that occurred on or after the initiation of study drug was defined as treatment emergent (TEAE).
Time frame: AEs were assessed and recorded from the time of signing the ICF through to the appropriate follow-up period, up to 23 days from IMP dosing on Day 1.
Population: The safety population included all randomized subjects who received any amount of study drug (i.e. a partial infusion).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subjects with at least 1 TEAE | 2 participants |
| Placebo | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Not related TEAEs | 2 participants |
| Placebo | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Related TEAEs | 0 participants |
| Placebo | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Mild TEAE | 2 participants |
| Placebo | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Moderate TEAE | 0 participants |
| Placebo | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Severe TEAE | 0 participants |
| Placebo | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subjects with at least 1 SAE | 0 participants |
| Placebo | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subject Discontinuation due to AE | 0 participants |
| 5 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Related TEAEs | 0 participants |
| 5 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Severe TEAE | 0 participants |
| 5 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subjects with at least 1 TEAE | 0 participants |
| 5 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Mild TEAE | 0 participants |
| 5 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Not related TEAEs | 0 participants |
| 5 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subject Discontinuation due to AE | 0 participants |
| 5 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Moderate TEAE | 0 participants |
| 5 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subjects with at least 1 SAE | 0 participants |
| 10 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subjects with at least 1 SAE | 1 participants |
| 10 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subject Discontinuation due to AE | 0 participants |
| 10 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Mild TEAE | 1 participants |
| 10 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Severe TEAE | 0 participants |
| 10 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Related TEAEs | 0 participants |
| 10 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Not related TEAEs | 1 participants |
| 10 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subjects with at least 1 TEAE | 1 participants |
| 10 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Moderate TEAE | 0 participants |
| 15 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Not related TEAEs | 2 participants |
| 15 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Related TEAEs | 2 participants |
| 15 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Mild TEAE | 3 participants |
| 15 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Moderate TEAE | 0 participants |
| 15 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Severe TEAE | 1 participants |
| 15 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subject Discontinuation due to AE | 0 participants |
| 15 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subjects with at least 1 TEAE | 4 participants |
| 15 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subjects with at least 1 SAE | 1 participants |
| 20 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Mild TEAE | 1 participants |
| 20 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subject Discontinuation due to AE | 0 participants |
| 20 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Related TEAEs | 1 participants |
| 20 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subjects with at least 1 SAE | 0 participants |
| 20 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Subjects with at least 1 TEAE | 1 participants |
| 20 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Severe TEAE | 0 participants |
| 20 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Not related TEAEs | 0 participants |
| 20 mg/kg Galidesivir | Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events. | Moderate TEAE | 0 participants |
Secondary
Galidesivir Renal Clearance
Urine was collected from subjects over a 96 hour period per protocol, analyzed for galidesivir concentrations. Urine PK parameters including CLR (renal clearance of unchanged drug cumulatively over all collection intervals or in a specific interval) were estimated in SAS for Windows v9.4 or higher (SAS Institute, Inc.) based on the recorded urine concentrations and volumes.
Time frame: Urine PK parameters are based on sampling over a 96 hour period.
Population: The PK population included subjects for whom at least 1 PK parameter was estimated. The PK population was the primary population for the PK analysis. There were only 5 subjects in the 20 mg/kg cohort as 1 subject was lost to follow-up after discharge from clinic on Day 5.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Galidesivir Renal Clearance | 9.305 L/hr | Geometric Coefficient of Variation 16.7 |
| 5 mg/kg Galidesivir | Galidesivir Renal Clearance | 11.66 L/hr | Geometric Coefficient of Variation 17.8 |
| 10 mg/kg Galidesivir | Galidesivir Renal Clearance | 11.51 L/hr | Geometric Coefficient of Variation 14.5 |
| 15 mg/kg Galidesivir | Galidesivir Renal Clearance | 7.131 L/hr | Geometric Coefficient of Variation 90.4 |
Secondary
Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve)
Serial blood samples for PK assessment of plasma galidesivir were collected at the following time points: * Day 1 to Day 5: 0 hour (pre dose), halfway through the infusion (0.5 hour), 1 hour (end of the infusion), 1.25, 1.50, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 60, 72, and 96 hours post dose. * Day 6 (+1 day), Day 8 (+1 day), Day 14 (± 1 day) * Day 21 (+2 days) or early termination. AUC0-inf (AUC from time 0 extrapolated to infinite time) and AUC0-t (AUC from time 0 to time t, where t = the last quantifiable concentration) for galidesivir was estimated using non compartmental methods with Phoenix® WinNonlin® v8.1 or higher (Certara, Inc.).
Time frame: Plasma PK parameters are based on sampling over a 21 day period
Population: The PK population included subjects for whom at least 1 PK parameter was estimated. The PK population was the primary population for the PK analysis. Only 5 subjects were included in the 20 mg/kg cohort for AUC0-t analysis, as 1 subject was lost to follow-up after discharge from clinic on Day 5.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve) | AUC0-inf | 21160 ng*h/mL | Geometric Coefficient of Variation 23 |
| Placebo | Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve) | AUC0-t | 17150 ng*h/mL | Geometric Coefficient of Variation 21 |
| 5 mg/kg Galidesivir | Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve) | AUC0-t | 32360 ng*h/mL | Geometric Coefficient of Variation 17.4 |
| 5 mg/kg Galidesivir | Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve) | AUC0-inf | 37080 ng*h/mL | Geometric Coefficient of Variation 14.5 |
| 10 mg/kg Galidesivir | Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve) | AUC0-inf | 65860 ng*h/mL | Geometric Coefficient of Variation 21.9 |
| 10 mg/kg Galidesivir | Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve) | AUC0-t | 59590 ng*h/mL | Geometric Coefficient of Variation 22 |
| 15 mg/kg Galidesivir | Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve) | AUC0-inf | 81230 ng*h/mL | Geometric Coefficient of Variation 14.3 |
| 15 mg/kg Galidesivir | Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve) | AUC0-t | 73350 ng*h/mL | Geometric Coefficient of Variation 14.1 |
Comparison: A model with In-transformed dose (dose continuous) as a fixed effect \& subject as a random effect was applied to In-transformed AUC0-inf Dose proportionality was assessed by restricted max likelihood using SAS PROC MIXED. The mean slope was estimated from the power model \& the corresponding 90% CI calculated. Although there was no formal statistical hypothesis tested for this secondary objective, there was evidence for dose proportionality if the 90% CI of the fixed slope for In-dose contained 190% CI: [0.872, 1.128]
Comparison: A model with In-transformed dose (dose continuous) as a fixed effect \& subject as a random effect was applied to In-transformed AUC0-t. Dose proportionality was assessed by restricted max likelihood using SAS PROC MIXED. The mean slope was estimated from the power model \& the corresponding 90% CI calculated. Although there was no formal statistical hypothesis tested for this secondary objective, there was evidence for dose proportionality if the 90% CI of the fixed slope for In-dose contained 1.90% CI: [0.952, 1.219]
Secondary
Plasma PK - Galidesivir Cmax (Maximum Observed Concentration of Drug)
Serial blood samples for PK assessment of plasma galidesivir were collected at the following time points: * Day 1 to Day 5: 0 hour (pre dose), halfway through the infusion (0.5 hour), 1 hour (end of the infusion), 1.25, 1.50, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 60, 72, and 96 hours post dose. * Day 6 (+1 day), Day 8 (+1 day), Day 14 (± 1 day) * Day 21 (+2 days) or early termination. Cmax for galidesivir was estimated using non compartmental methods with Phoenix® WinNonlin® v8.1 or higher (Certara, Inc.).
Time frame: Plasma PK parameters are based on sampling over a 21 day period
Population: The PK population included subjects for whom at least 1 PK parameter was estimated. The PK population was the primary population for the PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Plasma PK - Galidesivir Cmax (Maximum Observed Concentration of Drug) | 5540 ng/mL | Geometric Coefficient of Variation 7.8 |
| 5 mg/kg Galidesivir | Plasma PK - Galidesivir Cmax (Maximum Observed Concentration of Drug) | 10300 ng/mL | Geometric Coefficient of Variation 22.3 |
| 10 mg/kg Galidesivir | Plasma PK - Galidesivir Cmax (Maximum Observed Concentration of Drug) | 17730 ng/mL | Geometric Coefficient of Variation 17.5 |
| 15 mg/kg Galidesivir | Plasma PK - Galidesivir Cmax (Maximum Observed Concentration of Drug) | 20490 ng/mL | Geometric Coefficient of Variation 16.2 |
Comparison: A model with In-transformed dose (dose continuous) as a fixed effect \& subject as a random effect was applied to In-transformed Cmax. Dose proportionality was assessed by restricted max likelihood using SAS PROC MIXED. The mean slope was estimated from the power model \& the corresponding 90% CI calculated. Although there was no formal statistical hypothesis tested for this secondary objective, there was evidence for dose proportionality if the 90% CI of the fixed slope for In-dose contained 1.90% CI: [0.868, 1.096]