A Study to Evaluate the Single Dose Safety, Tolerability and Pharmacokinetics of IV BCX4430

• Sponsor: BioCryst Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03800173
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 32
• Location: 1
• Arms: 2
• Actual Duration (Months): 4.6
• Patients Per Site Per Month: 6.9

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Marburg Virus Disease	Drug: galidesivir; Drug: placebo	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Double-blind, Placebo Controlled, Dose Ranging Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Galidesivir (BCX4430) Administered as Single Doses Via Intravenous Infusion in Healthy Subjects
• Actual Study Start Date: Dec 10, 2018
• Actual Primary Completion Date: Apr 30, 2019
• Actual Study Completion Date: Apr 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Galidesivir Galidesivir IV infusion	Drug: galidesivir; galidesivir IV infusion
Placebo Comparator: placebo Placebo IV infusion	Drug: placebo; placebo IV infusion

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.).

2. 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.).

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	PRA Health Sciences	Lenexa	Kansas	United States	66219

Sponsors and Collaborators

• BioCryst Pharmaceuticals
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Daniel Dickerson, MD, PhD, PRA Health Sciences

Study Documents (Full-Text)

• Study Protocol - Jan 11, 2019
• Statistical Analysis Plan - Apr 10, 2019

More Information

Publications

None provided.

• Responsible Party: BioCryst Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03800173
• Other Study ID Numbers: BCX4430-106; DMID18-0013; 272201300017C-18-0-1
• First Posted: Jan 11, 2019
• Last Update Posted: Jul 23, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Virus Diseases; Marburg Virus Disease; Galidesivir

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Placebo	5 mg/kg Galidesivir	10 mg/kg Galidesivir	15 mg/kg Galidesivir	20 mg/kg Galidesivir
Arm/Group Description	single placebo IV infusion	Single IV infusion 5 mg/kg galidesivir	Single IV infusion 10 mg/kg galidesivir	Single IV infusion 15 mg/kg galidesivir	Single IV infusion 20 mg/kg galidesivir
Period Title: Overall Study
STARTED	8	6	6	6	6
Safety Population	8	6	6	6	6
PK Population	0	6	6	6	6
COMPLETED	8	6	6	6	5
NOT COMPLETED	0	0	0	0	1

Baseline Characteristics

Arm/Group Title	Placebo	5 mg/kg Galidesivir	10 mg/kg Galidesivir	15 mg/kg Galidesivir	20 mg/kg Galidesivir	Total
Arm/Group Description	single placebo IV infusion	Single IV infusion 5 mg/kg galidesivir	Single IV infusion 10 mg/kg galidesivir	Single IV infusion 15 mg/kg galidesivir	Single IV infusion 20 mg/kg galidesivir	Total of all reporting groups
Overall Participants	8	6	6	6	6	32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.1 (6.88)	39.8 (10.76)	33.5 (8.76)	41.7 (12.04)	31.8 (8.98)	35.3 (9.87)
Sex: Female, Male (Count of Participants)
Female	5 62.5%	3 50%	1 16.7%	2 33.3%	2 33.3%	13 40.6%
Male	3 37.5%	3 50%	5 83.3%	4 66.7%	4 66.7%	19 59.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	5 62.5%	1 16.7%	3 50%	0 0%	3 50%	12 37.5%
White	2 25%	5 83.3%	3 50%	6 100%	3 50%	19 59.4%
More than one race	1 12.5%	0 0%	0 0%	0 0%	0 0%	1 3.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Galidesivir Safety and Tolerability, as Measured by the Number of Participants Experiencing Adverse Events.
Description	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.

Outcome Measure Data

Analysis Population Description

The safety population included all randomized subjects who received any amount of study drug (i.e. a partial infusion).

Arm/Group Title	Placebo	5 mg/kg Galidesivir	10 mg/kg Galidesivir	15 mg/kg Galidesivir	20 mg/kg Galidesivir
Arm/Group Description	single placebo IV infusion	Single IV infusion 5 mg/kg galidesivir	Single IV infusion 10 mg/kg galidesivir	Single IV infusion 15 mg/kg galidesivir	Single IV infusion 20 mg/kg galidesivir
Measure Participants	8	6	6	6	6
Subjects with at least 1 TEAE	2 25%	0 0%	1 16.7%	4 66.7%	1 16.7%
Not related TEAEs	2 25%	0 0%	1 16.7%	2 33.3%	0 0%
Related TEAEs	0 0%	0 0%	0 0%	2 33.3%	1 16.7%
Mild TEAE	2 25%	0 0%	1 16.7%	3 50%	1 16.7%
Moderate TEAE	0 0%	0 0%	0 0%	0 0%	0 0%
Severe TEAE	0 0%	0 0%	0 0%	1 16.7%	0 0%
Subjects with at least 1 SAE	0 0%	0 0%	1 16.7%	1 16.7%	0 0%
Subject Discontinuation due to AE	0 0%	0 0%	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Plasma PK - Galidesivir Cmax (Maximum Observed Concentration of Drug)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	5 mg/kg Galidesivir	10 mg/kg Galidesivir	15 mg/kg Galidesivir	20 mg/kg Galidesivir
Arm/Group Description	Single IV infusion 5 mg/kg galidesivir	Single IV infusion 10 mg/kg galidesivir	Single IV infusion 15 mg/kg galidesivir	Single IV infusion 20 mg/kg galidesivir
Measure Participants	6	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	5540 (7.8)	10300 (22.3)	17730 (17.5)	20490 (16.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 5 mg/kg Galidesivir, 10 mg/kg Galidesivir, 15 mg/kg Galidesivir
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.982
	Confidence Interval	(2-Sided) 90%; 0.868 to 1.096
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Plasma PK - Galidesivir AUC (Area Under the Concentration vs. Time Curve)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	5 mg/kg Galidesivir	10 mg/kg Galidesivir	15 mg/kg Galidesivir	20 mg/kg Galidesivir
Arm/Group Description	Single IV infusion 5 mg/kg galidesivir	Single IV infusion 10 mg/kg galidesivir	Single IV infusion 15 mg/kg galidesivir	Single IV infusion 20 mg/kg galidesivir
Measure Participants	6	6	6	6
AUC0-inf	21160 (23.0)	37080 (14.5)	65860 (21.9)	81230 (14.3)
AUC0-t	17150 (21.0)	32360 (17.4)	59590 (22.0)	73350 (14.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 5 mg/kg Galidesivir, 10 mg/kg Galidesivir, 15 mg/kg Galidesivir
	Comments	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 1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	1.000
	Confidence Interval	(2-Sided) 90%; 0.872 to 1.128
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, 5 mg/kg Galidesivir, 10 mg/kg Galidesivir, 15 mg/kg Galidesivir
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	1.086
	Confidence Interval	(2-Sided) 90%; 0.952 to 1.219
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Galidesivir Renal Clearance
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	5 mg/kg Galidesivir	10 mg/kg Galidesivir	15 mg/kg Galidesivir	20 mg/kg Galidesivir
Arm/Group Description	Single IV infusion 5 mg/kg galidesivir	Single IV infusion 10 mg/kg galidesivir	Single IV infusion 15 mg/kg galidesivir	Single IV infusion 20 mg/kg galidesivir
Measure Participants	6	6	6	5
Geometric Mean (Geometric Coefficient of Variation) [L/hr]	9.305 (16.7)	11.66 (17.8)	11.51 (14.5)	7.131 (90.4)

Adverse Events

Time Frame	AEs were assessed and recorded from the time of signing the ICF through to the appropriate follow-up visit, up to 23 days from IMP dosing on Day 1. All AEs were graded for severity using the modified 2014 DMID Adult Toxicity Grading Scale. Any AEs not covered by the DMID criteria were assessed and classified into 1 of 3 clearly defined categories (mild, moderate, or severe).
Arm/Group Title	Placebo		5 mg/kg Galidesivir		10 mg/kg Galidesivir		15 mg/kg Galidesivir		20 mg/kg Galidesivir
Arm/Group Description	single placebo IV infusion		Single IV infusion 5 mg/kg galidesivir		Single IV infusion 10 mg/kg galidesivir		Single IV infusion 15 mg/kg galidesivir		Single IV infusion 20 mg/kg galidesivir
All Cause Mortality
	Placebo		5 mg/kg Galidesivir		10 mg/kg Galidesivir		15 mg/kg Galidesivir		20 mg/kg Galidesivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Serious Adverse Events
	Placebo		5 mg/kg Galidesivir		10 mg/kg Galidesivir		15 mg/kg Galidesivir		20 mg/kg Galidesivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/6 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
gastrooesophageal cancer	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/8 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		5 mg/kg Galidesivir		10 mg/kg Galidesivir		15 mg/kg Galidesivir		20 mg/kg Galidesivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/8 (25%)		0/6 (0%)		0/6 (0%)		4/6 (66.7%)		1/6 (16.7%)
Blood and lymphatic system disorders
Iron deficiency anaemia	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Leukocytosis	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Gastrointestinal disorders
Abdominal Distension	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Abdominal pain	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Nausea	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Vomiting	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Hepatobiliary disorders
Hepatic lesion	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Infections and infestations
Gastroenteritis	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Back pain	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Nervous system disorders
Headache	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/6 (33.3%)	2	1/6 (16.7%)	1
Syncope	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Upper airway cough syndrome	1/8 (12.5%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Urticaria	0/8 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.