Clinical trial NCT05818124: Efficacy and Safety of Molnupiravir in Healthy Participants Inoculated With Experimental Influenza Virus (MK-4482-019)
Official title: A Phase 2a Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MK-4482 in Healthy Participants Inoculated With Experimental Influenza Virus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Influenza Infection
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2023-04-18
Enrollment: 162
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a phase 2a double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of molnupiravir (MK-4482) in healthy participants inoculated with experimental influenza virus. The primary hypotheses are that MK-4482 initiated 12 hours following intranasal inoculation of the influenza challenge virus reduces the peak viral load compared to placebo and that MK-4482 initiated 2 days following intranasal inoculation of the influenza challenge virus reduces the viral load area under the curve (AUC) compared to placebo.

Detailed description: This study has two parts. Part 1 is an open-label validation study, with a cohort of 20 untreated participants undergoing nasal inoculation with the A/France/759/21 \[H1N1\] strain on Day 0 to confirm viral infectivity and disease. Part 2 will be a randomized, double-blind placebo- and active-comparator-controlled study where participants will be inoculated on Day 0 with either the A/France/759/21 \[H1N1\] virus used in Part 1 or an alternative influenza virus. Part 2 will evaluate the antiviral efficacy, pharmacokinetics, and safety of MK-4482 in participants inoculated with the challenge virus.

Eligibility criteria: Inclusion Criteria:

* Is in good health based on medical history, physical examination, vital sign measurements, spirometry, and electrocardiograms performed before inoculation.
* Has a total body weight ≥50 kg and Body Mass Index (BMI) ≥18 kg/m\^2 and ≤35 kg/m\^2.
* For males: abstains from heterosexual intercourse as their preferred and usual lifestyle and agrees to remain abstinent OR uses contraception unless confirmed to be azoospermic.
* For participants assigned female sex at birth: is not pregnant or breastfeeding, AND is either not a person of childbearing potential (POCBP) or is a POCBP AND uses a contraceptive method that is highly effective (low user dependency method, OR a user dependent hormonal method in combination with barrier method), or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle, has a negative highly sensitive pregnancy test, abstains from breastfeeding, 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 has currently active, symptoms or signs suggestive of upper or lower respiratory tract infection within 4 weeks prior to admission to quarantine.
* Has a history of clinically significant endocrine, gastrointestinal (GI), cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological abnormalities or diseases.
* Is mentally or legally incapacitated, has significant emotional problems at the time of prestudy visit, or expected during the conduct of the study, or has a history of clinically significant psychiatric disorder of the last 5 years.
* Has a history of cancer.
* Has a history of rhinitis 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 prior to 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.
* Has a diagnosis of cluster headache/migraine or is receiving prophylaxis against migraine.
* Has a lifetime history of anaphylaxis and/or a lifetime history of severe allergic reaction. Significant intolerance to any food or drug in the last 12 months.
* Has had major surgery and/or donated or lost 1 unit of blood within 3 months prior to the prestudy visit.
* Uses or anticipates the use of concomitant medications, including vitamins or herbal and dietary supplements from approximately 2 weeks prior to the planned date of viral challenge until the poststudy visit.
* Has evidence of receipt of vaccine within the 4 weeks prior to the planned date of viral challenge.
* Intends to receive any vaccine(s) before the last day of follow-up.
* Has received any investigational drug within 3 months prior to the planned date of viral challenge.
* Has received 3 or more investigational drugs within the previous 12 months prior to the planned date of viral challenge.
* Has had prior inoculation with a virus from the same virus subtype as the challenge virus.
* Has had prior inoculation with a virus from the same virus-family as the challenge virus in the last 12 months.
* Has had prior participation in another human viral challenge study with a respiratory virus in the preceding 3 months, taken from the date of viral challenge in the previous study to the date of expected viral challenge in this study.
* Has smoked ≥10 pack-years at any time.
* Has a recent history or presence of alcohol addiction, or excessive use of alcohol.
* Consumes excessive amounts, defined as more than 6 servings of caffeinated beverages or xanthine-containing products.
* 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.
* Has had any nasal or sinus surgery within 3 months.
* Is a regular user of cannabis or any illicit drugs, or has a history of drug abuse within approximately 1 year.

Primary outcomes:
measure: Part 1: Infectivity Rate Based on Quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR) Day 1 to Discharge
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 1: Infectivity Rate Based on qRT-PCR Day 2 to Discharge
timeFrame: From Day 2 afternoon up to Day 8
measure: Part 1: Number of participants experiencing ≥1 viral challenge-related adverse event (AE)
timeFrame: From Day 0 to Day 31
measure: Part 2, Panel A: Peak Viral Load (PVL) by Quantitative Viral Culture
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel B: Area Under the Viral Load-Time Curve (VL-AUC) by Quantitative Viral Culture
timeFrame: From Day 2 morning up to Day 8
Secondary outcomes:
measure: Part 1: Quantitative Viral Culture-Confirmed Influenza Infection Day 1 to Discharge
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 1: Quantitative Viral Culture-Confirmed Influenza Infection Day 2 to Discharge
timeFrame: From Day 2 afternoon up to Day 8
measure: Part 1: VL-AUC by Quantitative Viral Culture Day 1 to Discharge
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 1: VL-AUC by qRT-PCR Day 1 to Discharge
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 1: VL-AUC by Quantitative Viral Culture Day 2 to Discharge
timeFrame: From Day 2 afternoon up to Day 8
measure: Part 1: VL-AUC by qRT-PCR Day 2 to Discharge
timeFrame: From Day 2 afternoon up to Day 8
measure: Part 1: PVL by qRT-PCR Day 1 to Discharge
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 1: PVL by Quantitative Viral Culture Day 1 to Discharge
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 1: PVL by qRT-PCR Day 2 to Discharge
timeFrame: From Day 2 afternoon up to Day 8
measure: Part 1: PVL by Quantitative Viral Culture Day 2 to Discharge
timeFrame: From Day 2 afternoon up to Day 8
measure: Part 1: Duration of Quantifiable Influenza by qRT-PCR Day 1 to Discharge
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 1: Duration of Quantifiable Influenza by Quantitative Viral Culture Day 1 to Discharge
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 1: Duration of Quantifiable Influenza by qRT-PCR Day 2 to Discharge
timeFrame: From Day 2 afternoon up to Day 8
measure: Part 1: Duration of Quantifiable Influenza by Quantitative Viral Culture Day 2 to Discharge
timeFrame: From Day 2 afternoon up to Day 8
measure: Part 1: Area Under the Total Symptom Score-Time Curve (TSS-AUC) Day 1 to Discharge
timeFrame: From Day 1 morning up to Day 8
measure: Part 1: TSS-AUC Day 2 to Discharge
timeFrame: From Day 2 middle of the day to up to Day 8
measure: Part 1: Peak Total Symptom Score (TSS) Day 1 to Discharge
timeFrame: From Day 1 morning up to Day 8
measure: Part 1: Peak TSS Day 2 to Discharge
timeFrame: From Day 2 middle of the day up to Day 8
measure: Part 1: Duration in Days of Grade ≥2 Symptoms Day 1 to Discharge
timeFrame: From Day 1 morning up to Day 8
measure: Part 1: Duration in Days of Grade ≥2 Symptoms Day 2 to Discharge
timeFrame: From Day 2 middle of the day up to Day 8
measure: Part 1: Time in Days to Symptom Resolution Day 1 to Discharge
timeFrame: From Day 1 morning up to Day 8
measure: Part 1: Time in Days to Symptom Resolution Day 2 to Discharge
timeFrame: From Day 2 middle of the day up to Day 8
measure: Part 1: Time in Days to Peak Daily Maximum TSS Day 1 to Discharge
timeFrame: From Day 1 morning up to Day 8
measure: Part 1: Time in Days to Peak Daily Maximum TSS Day 2 to Discharge
timeFrame: From Day 2 middle of the day up to Day 8
measure: Part 2, Panel A: VL-AUC by Quantitative Viral Culture
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel A: VL-AUC by qRT-PCR
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel A: PVL by qRT-PCR
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel A: qRT-PCR-Confirmed Influenza Infection
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel A: qRT-PCR-Confirmed Symptomatic Influenza Infection
timeFrame: From Day 1 morning up to Day 8
measure: Part 2, Panel A: qRT-PCR-Confirmed Moderately Severe Symptomatic Influenza Infection
timeFrame: From Day 1 morning up to Day 8
measure: Part 2, Panel A: qRT-PCR-Confirmed Febrile Influenza Infection
timeFrame: From Day 1 morning up to Day 8
measure: Part 2, Panel A: Quantitative Viral Culture-Confirmed Influenza Infection
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel A: Quantitative Viral Culture-Confirmed Symptomatic Influenza Infection
timeFrame: From Day 1 morning up to Day 8
measure: Part 2, Panel A: Duration of Quantifiable Influenza by qRT-PCR
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel A: Duration of Quantifiable Influenza by Quantitative Viral Culture
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel A: Time in Days to Confirmed Negative Test by qRT-PCR
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel A: Time in Days to Confirmed Negative Test by Quantitative Viral Culture
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel A: Time in Days to Peak Viral Load by qRT-PCR
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel A: Time in Days to Peak Viral Load by Quantitative Viral Culture
timeFrame: From Day 1 afternoon up to Day 8
measure: Part 2, Panel C: VL-AUC by Quantitative Viral Culture
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel B & C: VL-AUC by qRT-PCR
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel B & C: PVL by qRT-PCR
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel B & C: PVL by Quantitative Viral Culture
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel B & C: Duration of Quantifiable Influenza by qRT-PCR
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel B & C: Duration of Quantifiable Influenza by Quantitative Viral Culture
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel B & C: Time in Days to Confirmed Negative Test by qRT-PCR
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel B & C: Time in Days to Confirmed Negative Test by Quantitative Viral Culture
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel B & C: Time in Days to Peak Viral Load by qRT-PCR
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel B & C: Time in Days to Peak Viral Load by Quantitative Viral Culture
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel A: TSS-AUC Day 1 to Discharge
timeFrame: From Day 1 morning up to Day 8
measure: Part 2, Panel B & C: TSS-AUC Day 2 to Discharge
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel A: Peak TSS Day 1 to Discharge
timeFrame: From Day 1 morning up to Day 8
measure: Part 2, Panel B & C: Peak TSS Day 2 to Discharge
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel A: Daily Maximum TSS Day 1 to Discharge
timeFrame: 3 times daily from the morning of Day 1 through Day 8
measure: Part 2, Panel B & C: Daily Maximum TSS Day 2 to Discharge
timeFrame: 3 times daily from the morning of Day 1 through Day 8
measure: Part 2, Panel A: Duration in Days of Grade ≥2 Symptoms Day 1 to Discharge
timeFrame: From Day 1 morning up to Day 8
measure: Part 2, Panel B & C: Duration in Days of Grade ≥2 Symptoms Day 2 to Discharge
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel A: Time in Days to Symptom Resolution Day 1 to Discharge
timeFrame: From Day 1 morning up to Day 8
measure: Part 2, Panel B & C: Time in Days to Symptom Resolution Day 2 to Discharge
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panel A: Time in Days to Peak Daily Maximum TSS Day 1 to Discharge
timeFrame: From Day 1 morning up to Day 8
measure: Part 2, Panel B & C: Time in Days to Peak Daily Maximum TSS Day 2 to Discharge
timeFrame: From Day 2 morning up to Day 8
measure: Part 2, Panels A & B: Number of Participants with One or More AE
timeFrame: Up to 31 days
measure: Part 2, Panels A & B: Number of Participants who Discontinue Study Drug Due to an AE
timeFrame: Up to day 8
measure: Part 2, Panels A & B: Number of Participants with One or More Viral Challenge-Related AE
timeFrame: Up to 31 days
measure: Part 2, Panels A & B: Number of Participants with Viral Challenge-Related Concomitant Medication Use
timeFrame: Up to 31 days
measure: Part 2, Panels A & B: Maximum Plasma Concentration (Cmax) of N-hydroxycytidine (NHC)
timeFrame: Day (D) 0, D2, D4: predose D5: predose, 0.5, 1.5, 4, 8, 12, 24, 48, 72 hours post morning dose
measure: Part 2, Panels A & B: Time to Maximum Plasma Concentration (Tmax) of NHC
timeFrame: Day (D) 0, D2, D4: predose D5: predose, 0.5, 1.5, 4, 8, 12, 24, 48, 72 hours post morning dose
measure: Part 2, Panels A & B: Half Life (t1/2) of NHC
timeFrame: Day (D) 0, D2, D4: predose D5: predose, 0.5, 1.5, 4, 8, 12, 24, 48, 72 hours post morning dose
measure: Part 2, Panels A & B: Area Under the Plasma Concentration From 0 to 12 Hours Postdose (AUC0-12) of NHC
timeFrame: Day (D) 0, D2, D4: predose D5: predose, 0.5, 1.5, 4, 8, 12, 24, 48, 72 hours post morning dose
measure: Part 2, Panels A & B: Area Under the Plasma Concentration From 0 to Time of the Last Quantifiable Concentration after Dosing (AUC0-last) of NHC
timeFrame: Day (D) 0, D2, D4: predose D5: predose, 0.5, 1.5, 4, 8, 12, 24, 48, 72 hours post morning dose
measure: Part 2, Panels A & B: Trough Concentration (Ctrough) of NHC
timeFrame: Day (D) 0, D2, D4: predose D5: predose, 0.5, 1.5, 4, 8, 12, 24, 48, 72 hours post morning dose
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: hVIVO Services ( Site 0001)
state: London, City Of
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: