An Evaluation of Repeated Oral Doses of JNJ-64281802 Against DENV-3 Challenge

Phase 2

Completed

Conditions: Dengue

Interventions: Drug: Cohort 1 - Group 1 JNJ High Dose
Drug: Cohort 1 - Group 2 JNJ Medium Dose
Drug: Cohort 1 - Group 2 JNJ Low Dose
Drug: Cohort 1 - Group 1/2 Placebo

Registration Number: NCT05048875

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: The investigational study drug, JNJ-64281802, is being developed for the prevention and treatment of dengue infection. This study is hypothesizing that the highest dose of the investigational study drug is superior to receiving a placebo with respect to its antiviral activity in healthy adult participants inoculated with Dengue Serotype 3.

Detailed Description: This study is a multicenter, randomized, placebo-controlled, double-blind, interventional Phase 2a, study in normal healthy adult subjects 18 - 55 years of age, inclusive, recruited from the metropolitan Baltimore/Washington, DC area \& Burlington/Vermont. The study follows an adaptive 2-stage design consisting of 2 cohorts, each with up to 3 groups. The 2 cohorts will be enrolled in a staggered manner. As a safety measure, a sentinel group of 4 participants will be enrolled in Cohort 1 (Group 1a) before enrolling the remaining participants (Group 1b and Group 2) in the cohort.

The purpose of this study is to evaluate the clinical and virologic response to repeated doses of investigation product JNJ-64281802 when administered orally in healthy, DENV and ZIKV-naïve, non-pregnant, adult volunteers who are subsequently inoculated with rDEN3delta30, a recombinant DENV-3 strain, to explore the antiviral activity of repeated oral doses of JNJ-64281802 versus placebo. The safety, tolerability, PK, and the relationship between the PK and antiviral activity of JNJ-64281802 will also be evaluated. Placebo recipients are included in the study as a control to better assess study agent associated versus non-study agent associated AEs and to act as infectivity controls following administration of rDEN3delta30.

After providing written informed consent, subjects will undergo eligibility screening, including medical history, physical examination, hematology testing, liver and renal function testing, human immunodeficiency virus (HIV) screening, hepatitis B and C screening, urinalysis, urine toxicology screening, ECG screening, alcohol breath test screening (per PI/provider discretion), COVID-19 testing (if determined necessary by the clinician or per guidelines), and serology screening for previous infection of DENV and ZIKV (Cohort 1) and DENV, ZIKV, West Nile virus, and SLEV (Cohort 2).

Serum or urine pregnancy testing will be performed on applicable persons of childbearing potential. All screening tests must be performed within 60 days of initiation of JNJ-64281802 study agent at Study Day -5 (Cohort 1) or Study Day -2 (Cohort 2). HIV screening must be performed within 2 weeks of JNJ-64281802 study agent administration. Pregnancy screening will occur at applicable screening visit(s), be repeated on the first day of JNJ-64281802 administration prior to administration, and on the day of inoculation with rDEN3delta30 prior to inoculation with rDEN3delta30. All clinically significant abnormalities will be reviewed with subjects and referral for follow-up care will be provided. Subjects will be determined to be eligible based on the inclusion and exclusion criteria for this protocol. For subjects who are eligible, the Study Day -5 (Cohort 1) or Study Day -2 (Cohort 2) visit will be scheduled for initiation of JNJ-64281802.

For Cohort 1: Subjects will present to the inpatient unit on Study Day -6. After eligibility criteria have been reviewed and confirmed, subjects will be admitted during this period of intensive PK sampling. Dosing with JNJ-64281802 or placebo will begin on Study Day -5. Discharge will occur on Study Day -4. Dosing with JNJ-64281802 will be observed in-clinic on Days -5, -4, -1, 1, 3, 5, 7, 9, 11, 14, 16, 18, and 21. Subjects will have phone contact on Days -3, -2, 2, 4, 6, 8, 10, 12, 13, 15, 17, 19, and 20 to record time of dose, time of last food intake, and review AEs and concomitant therapy. Daily dosing with JNJ-64281802 or placebo will occur from Study Day -5 through Study Day 21. On Study Day 21 subjects will present to the unit for a second intensive PK sampling period for a full day. On Study Day 1, all subjects will be challenged with rDEN3delta30.

For Cohort 2: Subjects will present to the inpatient unit on Study Day -3. After eligibility criteria have been reviewed and confirmed, subjects will be admitted during this period of intensive PK sampling. Dosing with JNJ-64281802 or placebo will begin on Study Day -2. Discharge will occur on Study Day 1. Dosing with JNJ-64281802 will be observed in-clinic on Days -2, -1, 1, 4, 6, 8, 11, 13, 15, 18, and 21 for the daily dosing regimen and on Days -2, -1, 1, 8 and 15 for the weekly dosing regimens. In the daily dosing regimen with JNJ-64281802 or placebo, twice daily dosing will occur from Study Day -2 to Study Day -1, and daily dosing from Study Day 1 to Study Day 21. In the weekly dosing regimens, twice daily dosing will occur from Study Day -2 to Study Day -1, and weekly dosing which will occur on Study Day 1, Study Day 8, and Study Day 15. On Study Day 21 for the daily regimen, and on Study Day 15 for the weekly regimens, subjects will present to the unit for a second intensive PK sampling period for a full day. On Study Day 1, all subjects will be challenged with rDEN3delta30.

During the inpatient visits on Study Day -6 to -4 (Cohort 1) and Study Day -3 to 1 (Cohort 2), the subjects will be evaluated by a clinician and will have blood drawn for clinical laboratory studies, virologic assays, and immunologic assays. During the outpatient visits subjects will return to the clinic for evaluation and for blood draw as specified in the Schedule of Procedures. Study Day 85 will be the final visit for Cohort 1. Study Day 85 will be the final visit for Cohort 2\*. Subjects will have their temperature measured in clinic or measure their temperatures at home twice daily from Study Day 1 through Study Day 29.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 56

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1 - Group 1 JNJ High Dose	Cohort 1 - Group 1 JNJ High Dose	Sentinel high-dose. Four participants will be enrolled in Group 1a before enrolling the remaining participants to Group 1b (12 participants total in Group 1, all same dosing regimen). Note group 1a and group 1b are combined into one arm, because the dosing regimen is the same and they were not separated during final statistical analysis.
Cohort 1 - Group 2 JNJ Medium Dose	Cohort 1 - Group 2 JNJ Medium Dose	Group 2 includes Medium and low dose, 14 participants total. Enrolled after completion of Group 1a.
Cohort 1 - Group 2 JNJ Low Dose	Cohort 1 - Group 2 JNJ Low Dose	Group 2 includes Medium and low dose, 14 participants total. Enrolled after completion of Group 1a.
Cohort 1 - Group 1/2 Placebo	Cohort 1 - Group 1/2 Placebo	Matching placebo. Note Group 1 placebo and group 2 placebo are combined per sponsor data analysis.

Primary Outcome Measures

Name	Time	Method
Assess the Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo in Terms of Reduction of Dengue Infection.	28 days	Area under the DENV-3 RNA viral load (VL) concentration-time curves from immediately before inoculation (baseline on Day 1) until Day 29. Cohort 2 was recently unblinded (data analysis is in process) and Cohort 2 is not part of the primary outcome assessment. Therefore, it cannot yet be fully represented in the record (i.e., results).

Secondary Outcome Measures

Name	Time	Method
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo by Reviewing the Peak of Detectable DENV-3 RNA (log10 VL).	99 weeks
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo for Duration in Days of Detectable DENV-3 RNA.	99 weeks
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo Time to First Onset by Days of Detectable DENV 3 RNA.	99 weeks
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo Based on Presence of Detectable DENV-3 RNA as Measured by PCR (log10 VL) or Culture (log10 VL).	99 weeks
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo on Area Under the Infectious Viremia Curves From Immediately Before Inoculation (Baseline on Day 1) Until Day 29.	99 weeks
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo on the Area Under the log10-transformed Viremia Curves.	99 weeks
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo Peak of Detectable Viremia Level	99 weeks
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo on the Duration of Detectable Viremia.	99 weeks
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo on Time to First Onset of Detectable Viremia.	99 weeks
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo on Presence of Detectable Viremia.	99 weeks
FI: Percentage Fluctuation (Variation) Between Maximum and Minimum Analyte Concentration at Steady-state, Calculated as 100 x ([Cmax - Cmin] / Cavg) of JNJ-64281802	99 weeks
AUCτ: Area Under the Plasma Concentration-time Curve During the Dosing Interval (t Hours); Calculated by Linear-linear Trapezoidal Summation of JNJ-64281802	99 weeks
Occurrence and Magnitude of Anti-DENV-3 Total IgM Antibody Titers to Assess the Anti-Dengue Immune Response.	99 weeks
Occurrence and Magnitude of Anti-DENV-3 Total IgG Antibody Titers to Assess the Anti-Dengue Immune Response.	99 weeks
Time to First Onset of Anti-DENV-3 Total IgM Antibody Titers to Assess the Anti-Dengue Immune Response.	99 weeks
Time to First Onset of Anti-DENV-3 Total IgG Antibody Titers to Assess the Anti-Dengue Immune Response.	99 weeks
Number of Adverse Events to Assess the Safety and Tolerability of the Study Drug (JNJ 64281802).	85 Days
Physical Examinations to Assess the Safety and Tolerability of the Study Drug (JNJ 64281802).	99 weeks
Recording of Vital Signs to Assess the Safety and Tolerability of the Study Drug (JNJ 64281802).	99 weeks	Body temperature will be recorded twice daily by study staff and/or by the participants from Day 1 up to and including Day 29; pulse (bpm), systolic and diastolic blood pressure (mmHg) measured on each clinic visit.
12-lead ECG With Measurement of QTcF to Assess the Safety and Tolerability of the Study Drug (JNJ 64281802).	99 weeks
12-lead ECG With Measurement of QRS Interval to Assess the Safety and Tolerability of the Study Drug (JNJ 64281802).	99 weeks
12-lead ECG With Measurement of PR Interval to Assess the Safety and Tolerability of the Study Drug (JNJ 64281802).	99 weeks
Clinical Laboratory Assessments to Assess the Safety and Tolerability of the Study Drug (JNJ 64281802).	99 weeks
Assess the Dengue Infection-associated Adverse Events (Unwanted Medical Occurrence).	99 weeks	Occurrence and severity of DENV infection associated AEs.
Antiviral Activity of the Study Drug (JNJ 64281802) Versus Placebo by Reviewing the Area Under the log10-transformed DENV 3 RNA VL Concentration-time Curves From Immediately Before Inoculation (Baseline on Day 1) Until Day 29 (AUCD1 D29 [log10 VL])	99 weeks
Assess How the Body Handles the Study Drug (JNJ-64281802) Following Repeated Oral Dosing. Using Pharmacokinetic Analysis From Repeated Blood Samples Taken at Specified Time Points After Drug Administration During 2 Inpatient Stays.	99 weeks	Blood samples will be taken for measurement of plasma concentrations of JNJ-64281802 at specific time points in the study. Additional PK sampling may be performed on the non-intensive PK days (eg, in the event of an overdose) on other time points, in consultation with the JNJ drug development team. Plasma samples will be analyzed to determine concentrations of JNJ-64281802 using a validated, specific, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method under the supervision of the DDT's Bioanalytical Laboratory Department of Bioanalysis.
Cmax: Maximum Observed Analyte Concentration of JNJ-64281802	99 weeks
Cmin: Minimum Observed Analyte Concentration of JNJ-64281802	99 weeks
Ctrough: Observed Analyte Concentration Just Before the Beginning or at the End of a Dosing Interval of JNJ-64281802	99 weeks
Cavg: Average Analyte Concentration Over the Dosing Interval (τ) Calculated as AUCτ/τ of JNJ-64281802	99 weeks
Tmax: the Actual Sampling Time to Reach the Maximum Observed Analyte Concentration of JNJ-64281802	99 weeks

Trial Locations

Locations (2): Johns Hopkins University, Bloomberg School of Public Health
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Baltimore, Maryland, United States
University of Vermont Medical Center (UVMMC), Clinical Research Center
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Burlington, Vermont, United States