Phase 2a MK-4482 Influenza Human Challenge Study in Healthy Participants
Research type
Research Study
Full 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
IRAS ID
1007195
Contact name
Gillian Gillespie
Contact email
Sponsor organisation
Merck Sharp & Dohme LLC
Clinicaltrials.gov Identifier
Research summary
Research Summary
Part 1: Healthy participants will be infected with newly produced influenza virus, the various components of their blood, the lining of their noses and other samples will be tested in order to measure the effects of the virus on the body before, during and after viral infection. For this research study 20 volunteers, 18-55 years, who consent to the to the participation in this research will be invited to Quarantine unit at hVIVO to stay for 11 days and one follow up clinic visit.
Part2: The purpose is to test the effects of an experimental drug called MK-4482 that may be useful in treating patients infected with influenza, as it may be useful in the prevention of influenza or ‘the flu’. A licensed drug called Oseltamivir (Tamiflu) currently used to treat flu will also be used in the study as a comparator that will be given to some of the participants in the study. 140 healthy participants in 4 groups of 35, aged 18-55 years, who consent to the participation in this study will be orally inoculated with a study influenza virus in one of our Quarantine residential facilities for 11 days. We will then give MK-4482 or Oseltamivir or Placebo to the participants allocated at random in one of the four groups:
1. Early Group - MK-4482 administered orally twice a day, starting 12 hours after inoculation of Influenza virus on Day
2. Late Group - MK-4482 administered orally twice a day, starting 48 hours after inoculation of the influenza virus
3. Active comparator Group - Oseltamivir administered orally twice a day, starting 48 hours after inoculation of the influenza virus.
4. Placebo Group
Participants will be monitored for safety throughout the study and have assessments performed daily during the quarantine period with symptoms collected daily using symptom diary cards and FLU-PRO Plus © questionnaire. Participants will need to return for a final follow up visit approximately 28 days (±3 days) from the date they receive the study virus.Summary of results
"Study design
This study tested a new drug (MK-4482) to see if it could help prevent or treat influenza in healthy male and female participants aged 18 to 55 who were experimentally infected with A/France/759/21 [H1N1] influenza strain (the study virus). It was conducted by hVIVO Services Ltd. on behalf of the study sponsor Merck Sharp & Dohme LLC. The study was divided into two parts with 161 participants. Of the 161 participants infected with the study virus, 141 were dosed with either MK-4482, Oseltamivir (a licenced drug used to compare performance of the study drug) or placebo (a dummy drug). 140 participants completed the study medication.
Part 1: 20 participants were given the study virus (Influenza A/France/759/21 [H1N1]) to check if it was suitable for the main study. No drugs were tested in this part, and it helped confirm the study virus could be used in Part 2.
Part 2: 141 participants were split into four groups and were randomly assigned to one of three treatments or a placebo:
o Early: Took 10 doses of 800 mg MK-4482 administered orally twice a day, starting 12 hours after challenge with the study virus and for 5 consecutive days followed by placebo for 1.5 days (35 participants),
o Late: Took placebo for 1.5 days followed by 10 doses of 800 mg MK-4482 administered orally twice a day, starting 48 hours after challenge with the study virus and for 5 consecutive days (36 participants),
o Comparator: Took placebo for 1.5 days followed by 10 doses of 75 mg Oseltamivir administered orally twice a day, starting 48 hours after challenge with the study virus and for 5 consecutive days (35 participants),
o Placebo: Took a placebo administered orally twice a day, starting 12 hours after challenge with the study virus and for 6.5 consecutive days (35 participants),
To ensure the participants nor the researchers knew who was in which treatment group, all participants received either MK-4482, Oseltamivir or the placebo starting 12 hours after being infected with the study virus twice daily for 6.5 days. Participants stayed in quarantine and were monitored until discharge on Day 8.Safety
Part 1:
The study virus was generally well tolerated in participants. There were no deaths, Serious Adverse Events (SAE)s or study discontinuation due to the study virus. 13 participants (65%) experienced 1 or more Adverse Events (AEs) during the study. 9 participants (45%) experienced 14 AEs that were determined by the investigator to be related to the study virus. These included: Neutropenia (Low blood neutrophils) (1), Diarrhoea (1), Nausea (feeling sick) (1), Vomiting (3), Viral tonsillitis (1), Alanine aminotransferase increased (liver enzyme) (1), Hypophosphatemia (Low blood phosphate levels (1), Headache (4), Productive cough (cough with mucus) (1)
Part 2:
The study drug, MK-4482, given as 800 mg doses multiple times, was generally well tolerated by participants who were exposed to the flu virus used in the study. Fewer side effects were reported in the MK-4482 groups compared to the group that received a placebo. Safety tests showed no concerning changes caused by the study drug. There were no deaths, serious health problems, or severe side effects related to the drug.
1 participant in the placebo group chose to leave the study, with a last dose administered on Day 1 PM. No participants stopped taking the study drug because of side effects.
42 participants (29.8%) experienced 1 or more AEs during the study: 8 in early group; 11 in late group, 11 in comparator group and 12 in placebo group.
2 participants (1.4%) experienced 2 AEs that were determined by the investigator to be intervention related to the study drug; Abdominal pain (1) in comparator and Diarrhoea (1) in placebo.
About 8.5% of participants (12 out of 141) had 13 AEs that were determined by the Investigator to be likely caused by the flu virus. These included: Neutropenia (Low blood neutrophils) (3) and Vomiting (1), in late; Diarrhea (1), Headache (1) and Pleuritic pain (chest pain that worsens with breathing, coughing, or sneezing) (1) in comparator; Chest discomfort (1) and Platelet count decreased (1) in placebo; Neutrophil count decreased (4) 1 in early and 3 in placebo.Conclusions
Part 1 of the study investigated the infectivity rate and the safety of the influenza challenge virus, A/France/759/21 [H1N1] strain, in healthy adult participants. The study virus was deemed suitable to be used as the study virus for Part 2.
Part 2 of the study investigated whether MK-4482, could lower flu virus levels in participants. When treatment began 12 hours or 2 days after exposure, MK-4482 failed to reduce virus levels compared to a placebo.
Taking multiple 800-mg doses of MK-4482 every 12 hours was generally safe for participants who were given the flu virus. They had fewer side effects compared to those who got the placebo. The levels of the drug in the blood were similar to what was seen in earlier studies with healthy adults."REC name
Wales REC 5
REC reference
23/WA/0090
Date of REC Opinion
26 Jul 2023
REC opinion
Further Information Favourable Opinion