Respiratory Syncytial Virus (RSV) Human Challenge Study of Molnupiravir in Healthy Participants (MK-4482-017)

Study Overview
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Brief Summary
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This is a phase 2A, double-blind, randomized, placebo-controlled study of molnupiravir (MK-4482) in healthy participants who have been inoculated with an experimental Respiratory Syncytial Virus (RSV) [RSV-A Memphis 37b]. It is hypothesized that MK-4482 will reduce the peak viral load (PVL) compared to placebo when given either before (prophylactic) or after (treatment) RSV-A Memphis 37b inoculation. Participants arrive at the study center for check-in between Day -3 and Day -1. The assigned treatment sequence (consisting of a combination of molnupiravir or placebo) begins Day -1. Participants receive viral inoculation with RSV-A Memphis 37b on Day 0, and depart on Day 12. There is a follow-up visit on Day 28.

Official Title
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A Phase 2a Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MK-4482 in Healthy Participants Inoculated With Experimental Respiratory Syncytial Virus

Conditions
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Respiratory Syncytial Virus

Intervention / Treatment
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* Drug: Molnupiravir
* Drug: Placebo
* Biological: RSV A Memphis 37b


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is in good health based on medical history, physical examination, vital sign measurements, spirometry, and electrocardiograms (ECGs) performed before randomization. Has a total body weight ≥50 kg and Body Mass Index (BMI) ≥18 kg/m^2 and ≤35 kg/m^2. For males, agrees to abstain from heterosexual intercourse OR use contraception unless confirmed to be azoospermic during the study and for 90 days after. For females, is not pregnant or breastfeeding, AND is either not a woman of childbearing potential (WOCBP) or is a WOCBP AND uses a highly effective contraceptive (low user dependency OR a user dependent hormonal method in combination with a barrier method), has a negative highly sensitive pregnancy test at screening, and has medical, menstrual, and recent sexual activity history reviewed by the investigator to decrease risk of early undetected pregnancy. Exclusion Criteria: Has a history of, or currently active, symptoms or signs suggestive of upper or lower respiratory tract infection within 4 weeks prior to the first study visit. Has a history of clinically significant endocrine, gastrointestinal (GI), cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases. Has a history of resolved depression and/or anxiety 1 or more years ago may be included at the discretion of the investigator. Has a history of cancer (malignancy). Has a history of rhinitis (including hay fever) which is clinically active or history of moderate to severe rhinitis, or history of seasonal allergic rhinitis likely to be active at the time of inclusion into the study and/or requiring regular nasal corticosteroids on an at least weekly basis, within 30 days of admission to quarantine. Has a history of atopic dermatitis/eczema which is clinically severe and/or requiring moderate to large amounts of daily dermal corticosteroids. If the reporting physician has diagnosed migraine can be included, provided there are no associated neurological symptoms such as hemiplegia or visual loss. If there is a physician diagnosed mild Irritable Bowel Syndrome not requiring regular treatment, can be included at the discretion of the investigator. Uses or anticipates use during study of herbal supplements within 7 days prior to Viral Challenge, any cytochrome P450 (CYP450)-inhibiting medications within 21 days prior to Viral Challenge, or any over-the-counter medications (eg, ibuprofen) within 7 days prior to Viral Challenge. Has evidence of receipt of vaccine within the 4 weeks prior to the planned date of viral challenge/first dosing with study medication (whichever occurs first). Intends to receive any vaccine before the last study visit. Has received any investigational drug within 3 months or 5 half-lives (whichever is greater) prior to the planned date of viral challenge/first dosing with study medication (whichever occurs first). Has received ≥3 investigational drugs in the past 12 months. Has had a prior inoculation with a virus from the same family as the challenge virus. Has smoked ≥10 pack years at any time (one pack of 20 cigarettes a day for 10 years). Has a recent history or presence of alcohol addiction, or excessive use of alcohol (weekly intake in excess of 28 units alcohol; 1 unit being a half glass of beer, a small glass of wine or a measure of spirits), or excessive consumption of xanthine-containing substances (eg, daily intake in excess of 5 cups of caffeinated drinks such as coffee, tea, cola). Has a lifetime history of anaphylaxis and/or a lifetime history of severe allergic reaction. Has any significant abnormality altering the anatomy of the nose in a substantial way or nasopharynx that may interfere with the aims of the study and, in particular, any of the nasal assessments or viral challenge. Has any clinically significant history of epistaxis (large nosebleeds) within the last 3 months of the first study visit and/or history of being hospitalized due to epistaxis on any previous occasion. Has had any nasal or sinus surgery within 3 months of the first study visit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel A: Molnupiravir Prophylaxis<br>Participants receive molnupiravir 800 mg every 12 hours for 5 days beginning on Day -1, and are inoculated with RSV-A Memphis 37b on Day 0. Participants then receive placebo on the evening of Day 4 to the morning of Day 10. | Drug: Molnupiravir<br>* Four molnupiravir 200 mg capsules (800 mg total dose) taken twice daily by mouth.<br>* Other names: MK-4482;Drug: Placebo<br>* Placebo capsule matched to molnupiravir taken twice daily by mouth.<br>Biological: RSV A Memphis 37b<br>* RSV A Memphis 37b viral challenge given once by intranasal administration at a dosage of  4 Log10 plaque forming units (PFUs).<br>|
| Experimental: Panel B: Molnupiravir Triggered Treatment<br>Participants receive placebo on Day -1, are inoculated with RSV-A Memphis 37b on Day 0, and continue to receive placebo until testing positive for RSV. Participants then receive molnupiravir 800 mg every 12 hours for 5 days. | Drug: Molnupiravir<br>* Four molnupiravir 200 mg capsules (800 mg total dose) taken twice daily by mouth.<br>* Other names: MK-4482;Drug: Placebo<br>* Placebo capsule matched to molnupiravir taken twice daily by mouth.<br>Biological: RSV A Memphis 37b<br>* RSV A Memphis 37b viral challenge given once by intranasal administration at a dosage of  4 Log10 plaque forming units (PFUs).<br>|
| Placebo Comparator: Panel C: Matched Placebo<br>Participants receive placebo from Day -1 to Day 10, and are inoculated with RSV-A Memphis 37b on Day 0. | Drug: Placebo<br>* Placebo capsule matched to molnupiravir taken twice daily by mouth.<br>Biological: RSV A Memphis 37b<br>* RSV A Memphis 37b viral challenge given once by intranasal administration at a dosage of  4 Log10 plaque forming units (PFUs).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Panel A: Peak Viral Load (PVL) Based on Viral Quantitative Culture | PVL is the maximum viral load determined by viral quantitative culture (plaque assay). | From Day 2 up to Day 12 | 
| Panel B: Area Under the Viral Load-time Curve (VL-AUC) Determined by Viral Quantitative Culture | VL-AUC is determined by viral quantitative culture (plaque assay). | Twice daily from Day -1 to Day 11; once on Day 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Panels A & B: Number of participants experiencing ≥1 adverse event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | From Day -1 up to Day 28 | 
| Panels A & B: Number of participants experiencing ≥1 serious AE (SAE) | An SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires hospitalization or prolongs existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly or birth defect; or is another important medical event such as invasive/malignant cancers or substance abuse/dependency. | From Day -1 up to Day 28 | 
| Panels A & B: Number of participants experiencing ≥1 viral challenge-related AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | From Day 0 up to Day 28 | 
| Panels A & B: Number of participants experiencing ≥1 viral challenge-related SAE | An SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires hospitalization or prolongs existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly or birth defect; or is another important medical event such as invasive/malignant cancers or substance abuse/dependency. | From Day 0 up to Day 28 | 
| Panel A: VL-AUC Determined by Viral Quantitative Culture | VL-AUC is determined by quantitative viral culture (plaque assay). | Twice daily from Day 2 to Day 11; once on Day 12 | 
| Panel A: VL-AUC Determined by Real-time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) | VL-AUC is determined by qRT-PCR. | Twice daily from Day 2 to Day 11; once on Day 12 | 
| Panel A: PVL Determined by qRT-PCR | PVL is determined by maximum viral load defined by qRT-PCR. | From Day 2 up to Day 12 | 
| Panel A: Area Under the Curve over Time of Total Clinical Symptoms (TSS-AUC) | TSS-AUC measured from 10 symptoms within the graded symptom scoring will be reported. Participants use a symptom diary card to record the severity of 10 symptoms on a scale ranging from 0 (absence) to 3 (bothersome and interferes with activities). | Three times daily from Day 2 to Day 11, once on Day 12 | 
| Panel A: Area Under the Curve over Time of Total Clinical Symptoms Change from Baseline (TSS-AUC-CFB) | TSS-AUC-CFB measured from 10 symptoms within the graded symptom scoring will be reported. Participants use a symptom diary card to record the severity of 10 symptoms on a scale ranging from 0 (absence) to 3 (bothersome and interferes with activities). | Baseline and three times daily from Day 2 to Day 11, once on Day 12 | 
| Panel A: Peak Total Clinical Symptoms (TSS) | Peak TSS measured from 10 symptoms within the graded symptom scoring will be reported. Participants use a symptom diary card to record the severity of 10 symptoms on a scale ranging from 0 (absence) to 3 (bothersome and interferes with activities). | From Day 2 up to Day 12 | 
| Panel A: Peak Daily Symptom Score | Peak individual daily sum of symptom score measured from 10 symptoms within the graded symptom scoring will be reported. Participants use a symptom diary card to record the severity of 10 symptoms on a scale ranging from 0 (absence) to 3 (bothersome and interferes with activities). | From Day 2 up to Day 12 | 
| Panel A: Incidence of Respiratory Syncytial Virus (RSV) Infection Based on qRT-PCR | RSV infection is defined as 2 quantifiable (> LLOQ) qRT-PCR measurements reported on 2 or more days. | From Day 2 up to Day 12 | 
| Panel A: Incidence of A Nasal Swab Positive Test for RSV | The incidence of a positive (> LLOQ) cell culture measurement in nasal swab samples. | From Day 2 up to Day 12 | 
| Panel A: Incidence of RT-PCR Confirmed Symptomatic RSV Infection | Incidence of symptomatic RSV infection is defined as 2 quantifiable (≥LLOQ) qRT-PCR measurements reported on 2 or more days and a symptom of ≥2 at a single time point. | From Day 2 up to Day 12 | 
| Panel A: Incidence of RT-PCR Confirmed Moderately Severe Symptomatic RSV Infection | Incidence of symptomatic RSV infection is defined as 2 quantifiable (≥LLOQ) qRT-PCR measurements reported on 2 or more days and any symptoms of grade ≥2 at a single time point. | From Day 2 up to Day 12 | 
| Panel A: Incidence of Culture Lab Confirmed Symptomatic RSV Infection | Incidence of culture lab confirmed RSV infection is defined by 1 quantifiable (≥LLOQ) cell culture measurement from Day 2 up to Day 12, and symptom of ≥2 at a single time point. | From Day 2 up to Day 12 | 
| Panel B: PVL Determined by Viral Quantitative Culture | VL-AUC is determined by quantitative viral culture (plaque assay). | From Day -1 up to Day 12 | 
| Panel B: Time to Negative Test by Viral Quantitative Culture | The time to a negative test (result < low limit of quantification [LLOQ]) by viral quantitative culture (plaque assay) in days will be reported. | From Day -1 up to Day 12 | 
| Panel B: VL-AUC Determined by qRT-PCR | VL-AUC is determined by qRT-PCR. | Twice daily from Day -1 to Day 11; once on Day 12 | 
| Panel B: PVL Determined by qRT-PCR | PVL is determined by qRT-PCR. | From Day -1 up to Day 12 | 
| Panel B: Time to Negative Test by qRT-PCR | The time in days to a negative test (result < LLOQ) by viral quantitative culture (plaque assay) will be reported. | From Day -1 up to Day 12 | 
| Panel B: TSS-AUC | TSS-AUC measured from 10 symptoms within the graded symptom scoring will be reported. Participants use a symptom diary card to record the severity of 10 symptoms on a scale ranging from 0 (absence) to 3 (bothersome and interferes with activities). | Three times daily from Day 2 to Day 11, once on Day 12 | 
| Panel B: TSS-AUC-CFB | TSS-AUC-CFB measured from 10 symptoms within the graded symptom scoring will be reported. Participants use a symptom diary card to record the severity of 10 symptoms on a scale ranging from 0 (absence) to 3 (bothersome and interferes with activities). | Baseline and three times daily from Day 2 to Day 11, once on Day 12 | 
| Panel B: Peak TSS | Peak TSS measured from 10 symptoms within the graded symptom scoring will be reported. Participants use a symptom diary card to record the severity of 10 symptoms on a scale ranging from 0 (absence) to 3 (bothersome and interferes with activities). | From Day 2 up to Day 12 | 
| Panel B: Peak Daily Symptom Score | Peak individual daily sum of symptom score measured from 10 symptoms within the graded symptom scoring will be reported. Participants use a symptom diary card to record the severity of 10 symptoms on a scale ranging from 0 (absence) to 3 (bothersome and interferes with activities). | From Day 2 up to Day 12 | 
| Panel B: Time to Negative Test by Symptom Resolution | The time in days to symptom resolution, as measured from 10 symptoms within the graded daily symptom scoring system, will be reported. | From Day 2 up to Day 12 | 
| Panels A & B: Maximum plasma concentration (Cmax) of N-hydroxycytidine (NHC) | The Cmax of NHC will be reported. | Day -1: Predose and 12 hours postdose; Days 2, 5, and 6: 12 hours postdose; Days 4 and 7: predose and 0.5, 1.5, 4, 8, and 12 hours postdose | 
| Panels A & B: Time to maximum plasma concentration (Tmax) of NHC | The Tmax of NHC will be reported. | Day -1: Predose and 12 hours postdose; Days 2, 5, and 6: 12 hours postdose; Days 4 and 7: predose and 0.5, 1.5, 4, 8, and 12 hours postdose | 
| Panels A & B: Area uncer the plasma concentration from 0 to 12 hours postdose (AUC0-12) of NHC | The AUC0-12 of NHC will be reported. | Day -1: Predose and 12 hours postdose; Days 2, 5,Day 7: predose and 0.5, 1.5, 4, 8, and 12 hours postdose | 
| Panels A & B: Trough concentration (Ctrough) of NHC | The Ctrough of NHC will be reported. | Day -1: Predose and 12 hours postdose; Days 2, 5,Day 7: predose and 0.5, 1.5, 4, 8, and 12 hours postdose |