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

Phase 2a, Randomized, Doubleblind, Placebo-controlled Trial Evaluating the Antiviral Activity, Safety and Pharmacokinetics of Repeated Oral Doses of JNJ-64281802 Against Dengue-3 Infection in a Dengue Human Challenge Model in Healthy Adults

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.

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.

Inclusion Criteria for receipt of Study Drug:

1. Male or female.

2. 18 to 55 years of age, inclusive, at time of screening.

3. Healthy on the basis of physical examination, medical history, and vital signs performed at screening.

4. Healthy on the basis of clinical laboratory tests performed at screening.

5. Must pass the comprehension assessment indicating that the participant understands the purpose, procedures, and potential risks and benefits of the study, after reading the informed consent and after the investigator or designee has provided detailed information on the study and answered the potential participant's questions.

6. Must have a body mass index between 18.0 and 35.0 kg/m2, inclusive.

7. Must have a normal electrocardiogram (ECG, test which displays a person's heartbeat) at screening.

8. Must have a blood pressure (after lying face up for greater than or equal to 5 minutes) between 90 and 140 mmHg systolic and less than or equal to 90 mmHg diastolic at screening.

9. Must complete the informed consent process independently and without assistance and sign an informed consent form (ICF) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.

10. All persons of childbearing potential must have a negative pregnancy test at screening.

11. A volunteer must be:

    1. Not of childbearing potential, or
    2. Of childbearing potential and practicing a highly effective, preferably user independent method of contraception and agrees to remain on a highly effective method while receiving study drug and until 90 days after the last dose of study drug.

12. A person of childbearing potential must agree not to donate eggs for the purposes of assisted reproduction during the study and for 90 days after the last dose of study drug.

13. During the study and for 90 days after the last dose of study drug, persons who are having sexual relationships in which their partner may become pregnant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person. Persons who are having sexual relationships in which their partner may become pregnant should also be advised of the benefit for their partner to use a highly effective method of contraception as condoms may break or leak.

14. A sperm-producing participant must agree not to donate sperm for the purpose of reproduction during the study and for 90 days after the last dose of study drug.

15. Must be willing and able to adhere to the study requirements and lifestyle restrictions:

    • Do not take any restricted medications/treatments
    • Agree to follow all study requirements
    • No unusual strenuous exercise
    • Must not donate blood or blood products within 6 months after last dose of study drug
    • Must not participate in another investigational study during the study or within 90 days after last dose of study drug
    • Must not travel to any dengue-endemic region (as defined by the United States Centers for Disease Control and Prevention
    • Must limit the use of food or drinks/beverages containing alcohol to the absolute minimum from 48 hours before first dose of study drug until Day 85.
    • Must refrain from consumption of grapefruit or grapefruit juice, energy drinks, excessive use of caffeine from 7 days before first dose of study drug until Day 85
    • May not use drugs of abuse (including amphetamine, barbiturate, cocaine, methadone, and opiates) until 3 weeks after the last dose of study drug.
    • Should not consume any food containing poppy seeds or codeine-containing formulation starting 72 hours before the screening visits and before any visit during the follow-up phase (to avoid a false-positive urine drug test).
    • Should follow the instructions for the timing of the standardized meals

16. Available for the duration of the study, which is approximately 85 days after injection of the dengue virus.

Exclusion Criteria for receipt of Study Drug:

1. History of liver or renal impairment; significant cardiac, vascular, pulmonary, gastrointestinal (such as significant diarrhea, constipation lasting greater than 2 days), endocrine, neurologic, hematologic, rheumatologic, neoplastic, autoimmune, or metabolic disturbances.

2. Known allergies, hypersensitivity, or intolerance to the study drug (JNJ-64281802) or its inactive substances, or an acute, life threatening allergic reaction or swelling following study drug administration.

3. History of a severe allergic reaction or anaphylaxis (which is a severe, potentially life-threatening allergic reaction).

4. Taken any substances or therapies that are not allowed before the first dose of study drug.

5. Received an investigational intervention or participated in another investigational clinical trial (including investigational vaccines) within 6 months before first dose of study drug, or is currently enrolled in an investigational study, or is planning to be enrolled in an investigational study within 90 days after last dose of study drug. With the exception of participation in COVID-19 vaccine trials and receipt COVID-19 vaccines licensed or under Emergency Use Authorization which can be received at any time.

6. Persons of childbearing potential only: Pregnant as determined by a positive pregnancy blood test, breastfeeding, or planning to become pregnant during the study or within 90 days after last dose of study drug.

7. Plans to impregnate and help conceive a child during the study or within 90 days after last dose of study drug.

8. Any condition for which, in the opinion of the study doctor, participation would not be in the best interest of the participant.

9. Blood test confirming current infection with human immunodeficiency virus type 1 or 2 (HIV-1 or HIV-2), hepatitis B virus (HBV), or hepatitis C virus (HCV), or blood test confirming past or current infection with any of the following flaviviruses: dengue, Zika virus (ZIKV), West Nile virus, or St. Louis Encephalitis (SLE) virus or vaccination for dengue, Zika virus, or Japanese Encephalitis virus (JEV) Note: Blood laboratory testing will assess the presence of antibodies at screening.

10. Recent (in the past 4 weeks) travel to any dengue-endemic region (as defined by the US CDC) or having definite plans to travel to a dengue endemic region, during the study. Potential participants may be eligible for enrollment greater than or equal to 4 weeks after their return from a dengue-endemic region.

11. Received or plans to receive:

    1. Licensed live attenuated vaccines - within 28 days before first dose of study drug until 28 days after last dose of study drug.
    2. Other licensed (not live) vaccines - within 14 days before first dose of study drug until 14 days after last dose of study drug.
    3. COVID-19 vaccines, either licensed or under EUA, are allowed at any time during the study however every effort will be made to avoid the above windows of time of administration.

    Note: Vaccinations against DENV and Zika virus are not allowed until 90 days after last dose of study drug.

12. Employee of the study doctor or study site with direct involvement in the proposed study or other studies under the direction of that study doctor or study site, as well as family members of the employees or the investigator.

13. Any clinically relevant skin disease in the past 6 months, such as active dermatitis, active eczema, drug rash, psoriasis, and urticaria.

14. Having donated or lost greater than 1 unit of blood (500 mL) within 30 days or greater than 1 unit of plasma (250 mL) within 7 days before first dose of study drug or having the intention to donate blood or blood products during the study and within 6 months after last dose of study drug.

15. Receipt of blood products within the past 6 months of initiation of study drug or anticipated receipt of any blood products during the 28 days following dengue virus injection.

16. Known or suspected congenital or acquired immunodeficiency or use of immunosuppressive corticosteroids (excluding topical and nasal) or immunosuppressive drugs within 28 days before first dose of study drug until 28 days following the last dose of study drug.

    a. An immunosuppressive dose of corticosteroids is defined as greater than or equal to10 mg prednisone equivalent per day for grater than or equal to 14 days.

17. Use of any strong cytochrome P450 (CYP) 3A4 inhibitors (eg, clarithromycin, itraconazole), CYP3A4 inducers (eg, phenytoin, rifampin), or substrates for CYP3A4 (eg, midazolam, triazolam), CYP2C8 (eg, repaglinide), CYP2C9 (eg, warfarin, tolbutamide), BCRP (eg Pravastatin and folic acid), or CYP2C19 (eg, S-mephenytoin, omeprazole) within 14 days before first dose of study drug. Certain other medications are allowed including metformin, levothyroxine, H1 and H2 receptor antagonists, weak CYP3A4 inhibitors, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic anti-depressants, anxiolytics, and benzodiazepines.

18. Any significant alcohol or drug abuse in the past 12 months that has caused medical, occupational, or family problems, as indicated by participant history, or positive test result(s) for drugs of abuse (including amphetamine, barbiturate, benzodiazepine, cocaine, methadone, and opiates) at screening.

19. Behavioral, cognitive, or psychiatric disease that affects the subject's ability to understand and cooperate with the requirements of the study protocol.

20. Severe asthma (emergency room visit or hospitalization within the last 6 months).

21. Asplenia (the absence of a spleen).

22. Refusal to allow specimen storage for future research.

23. History of risk factors for life-threatening heart rhythm disturbance which includes heart failure, low potassium levels in the blood, family history of fast, chaotic heartbeats known as Long QT Syndrome.

Exclusion Criteria for dengue virus injection:

1. Body temperature greater than or equal to 38.0°C (100.4°F), confirmed by repeat measurements at least 10 minutes after the first measurement.
2. Acute illness.
3. Any other clinical or laboratory finding that would exclude the participant from inoculation (including, but limited to, a positive urine/serum pregnancy test), as assessed by the study doctor.