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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 116
- 试验地点
- 1
- 主要终点
- Panel A vs Panel C: Peak Viral Load (PVL) Determined by Viral Quantitative Culture
研究概览
简要总结
This is a 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 treatment with the drug MK-4482 (molnupiravir) will reduce the peak viral load (PVL) in the participant compared to placebo when given either before or after RSV-A Memphis 37b inoculation.
详细描述
Participants arrive at the study center for check-in between Day -3 and Day -1. Participants receive the assigned treatment beginning on Day -1. On Day 0, all participants receive viral inoculation with RSV-A Memphis 37b. All participants depart on Day 12 and follow-up is continued until Day 28.
The study is designed with the following arms:
- Panel A: Molupiravir Prophylaxis - in this arm, participants receive molupiravir beginning on Day -1, are incoluated with RSV-A Memphis 37b on Day 0, and continue receiving molnupiravir for a total of 5 days before switching to placebo through Day 10.
- Panel B: Molupiravir Triggered Treatment - in this arm, participants receive placebo beginning on Day -1 until testing positive for RSV. Participants are inoculated with RSV-A Memphis 37b on Day 0. When participants test positive for RSV, they switch to molnupiravir for a total of 5 consecutive days before switching back to placebo through Day 10. If participants in this arm do not test positive for RSV by Day 5, they automatically switch to molnupiravir through Day 10.
- Panel C: Placebo - in this arm, all participants receive placebo beginning on Day -1, are inoculated with RSV-A Memphis 37b on Day 0, and continue receiving placebo through Day 10.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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^
- •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.
排除标准
- •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, any over-the-counter medications (eg, ibuprofen) within 7 days prior to Viral Challenge, or any systemic anti-viral administration within 4 weeks of Viral Challenge/first dosing of study medication.
- •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.
研究组 & 干预措施
Panel A: Molnupiravir Prophylaxis
Participants received 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 switch to placebo beginning on the evening of Day 4 to the morning of Day 10.
干预措施: Molnupiravir (Drug)
Panel A: Molnupiravir Prophylaxis
Participants received 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 switch to placebo beginning on the evening of Day 4 to the morning of Day 10.
干预措施: Placebo (Drug)
Panel A: Molnupiravir Prophylaxis
Participants received 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 switch to placebo beginning on the evening of Day 4 to the morning of Day 10.
干预措施: RSV A Memphis 37b (Biological)
Panel B: Molnupiravir Triggered Treatment
Participants received 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 received 800 mg of molnupiravir every 12 hours for 5 days.
干预措施: Molnupiravir (Drug)
Panel B: Molnupiravir Triggered Treatment
Participants received 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 received 800 mg of molnupiravir every 12 hours for 5 days.
干预措施: Placebo (Drug)
Panel B: Molnupiravir Triggered Treatment
Participants received 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 received 800 mg of molnupiravir every 12 hours for 5 days.
干预措施: RSV A Memphis 37b (Biological)
Panel C: Matched Placebo
Participants received placebo beginning on Day -1, are inoculated with RSV-A Memphis 37b on Day 0, and continue receiving placebo until the morning of Day 10.
干预措施: Placebo (Drug)
Panel C: Matched Placebo
Participants received placebo beginning on Day -1, are inoculated with RSV-A Memphis 37b on Day 0, and continue receiving placebo until the morning of Day 10.
干预措施: RSV A Memphis 37b (Biological)
结局指标
主要结局
Panel A vs Panel C: Peak Viral Load (PVL) Determined by Viral Quantitative Culture
时间窗: From Day 2 up to Day 12
PVL was defined as the maximum viral load during a specified time period. PVL determined by viral quantitative culture (plaque assay) was measured from Day 2 up to Day 12 (end of participant quarantine). PVL (on the log10 scale) of RSV A Memphis 37b determined by viral quantitative culture (plaque assay) between Day 2 and Day 12 am after intranasal inoculation (Day 0) was analyzed using a linear model with treatment group as a fixed categorical effect. Per protocol, only Panel A (prophylaxis) and Panel C (placebo) were included in the model.
Panel B vs. Panel C: Area Under the Viral Load-time Curve (VL-AUC) Determined by Viral Quantitative Culture
时间窗: From Day 2 up to Day 12
VL-AUC between Day 2 and Day 12 after intranasal inoculation (Day 0) was computed for each participant, based on RSV viral load determined by viral quantitative culture (plaque assay) from nasal wash samples collected twice daily (morning and evening). In order to calculate the AUC, the actual time that the assessment was collected was used within the AUC calculation. VL-AUC (on the log10 scale) was analyzed using a linear model with treatment group as a fixed categorical effect. Per protocol, only Panel B (treatment) and Panel C (placebo) were included in the model. For both panels, only the participants with RSV infection were included.
次要结局
- All Panels: Number of Participants Who Experienced ≥1 Adverse Event (AE)(From Day -1 up to Day 28)
- All Panels: Number of Participants Who Experienced ≥1 Serious AE (SAE)(From Day -1 up to Day 28)
- All Panels: Number of Participants Who Experienced ≥1 Viral Challenge-Related AE(From Day 0 up to Day 28)
- All Panels: Number of Participants Using Concomitant Medications From Viral Challenge Through Day 28(From Day 0 up to Day 28)
- All Panels: Number of Participants Who Experienced ≥1 Viral Challenge-Related SAE(From Day 0 up to Day 28)
- Panel A vs. Panel C: VL-AUC Determined by Real-time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR)(Day 2 up through Day 12)
- Panel A vs. Panel C: Percentage of Participants With Culture-Confirmed Symptomatic RSV Infection(From Day 2 up to Day 12)
- Panel A vs. Panel C: VL-AUC Determined by Viral Quantitative Culture(From Day 2 up to Day 12)
- Panel A vs. Panel C: PVL Determined by qRT-PCR(Day 2 up through Day 12)
- Panel A vs. Panel C: Area Under the Curve Over Time of Total Symptom Scores (TSS-AUC)(From Day -1 up to Day 12)
- Panel A vs. Panel C: Area Under the Curve Over Time of Total Symptom Scores Change From Baseline (TSS-AUC-CFB)(Baseline (Day -1) and up to Day 12)
- Panel A vs. Panel C: Peak Total Symptom Scores(From Day -1 up to Day 12)
- Panel A vs. Panel C: Peak Daily Symptom Score(From Day 2 up to Day 12)
- Panel A vs. Panel C: Percentage of Participants With Respiratory Syncytial Virus (RSV) Infection Based on qRT-PCR(From Day 2 up to Day 12)
- Panel A vs. Panel C: Percentage of Participants With RSV Infection Based on Cell Culture Measurement of Nasal Sample(From Day 2 up to Day 12)
- Panel A vs. Panel C: Percentage of Participants With qRT-PCR Confirmed Symptomatic RSV Infection(From Day 2 up to Day 12)
- Panel A vs. Panel C: Percentage of Participants With qRT-PCR Confirmed Moderately Severe Symptomatic RSV Infection(From Day 2 up to Day 12)
- Panel B vs. Panel C: PVL Determined by Viral Quantitative Culture(From Day 2 up to Day 12)
- Panel B vs. Panel C: Time to Negative Test by Viral Quantitative Culture(From Day 2 up to Day 12)
- Panel B vs. Panel C: VL-AUC Determined by qRT-PCR(From Day 2 up to Day 12)
- Panel B vs. Panel C: PVL Determined by qRT-PCR(From Day 2 up to Day 12)
- Panel B vs. Panel C: Time to Negative Test by qRT-PCR(From Day 2 up to Day 12)
- Panel B vs. Panel C: TSS-AUC(From Day -1 up to Day 12)
- Panel B vs. Panel C: Area Under the Curve Over Time of Total Symptom Scores Change From Baseline (TSS-AUC-CFB)(Baseline (Day -1) and up to Day 12)
- Panel B vs. Panel C: Peak TSS(From Day -1 up to Day 12)
- Panel B vs. Panel C: Peak Daily Symptom Score(From Day -1 up to Day 12)
- Panel B vs. Panel C: Time to Symptom Resolution(From Day -1 up to Day 12)
- Panels A & B: Maximum Plasma Concentration (Cmax) of N-Hydroxycytidine (NHC)(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(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 Under the Plasma Concentration Curve From 0 to 12 Hours Postdose (AUC0-12) of NHC(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: Trough Concentration (Ctrough) of NHC(Day 2 at 12 hours predose (Panel A) or Day 6 at 12 hours predose (Panel B))