Efficacy and Safety of CR6261 in an H1N1 Influenza Healthy Volunteer Human Challenge Model

Phase 2

Completed

Conditions: H1N1 Influenza Healthy Volunteers

Interventions: Biological: Placebo
Biological: CR6261

Registration Number: NCT02371668

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: Background:

- Researchers want to see if a new drug reduces flu disease in people treated with this drug versus a placebo. The drug has an antibody that may help the immune system fight the flu. Placebo is only sugar and water. All participants will get the flu virus. They may or may not develop flu symptoms.

Objective:

- To see if the drug CR6261 reduces flu disease in people treated with this drug versus a placebo.

Eligibility:

- Healthy nonsmokers ages 18 45.

Design:

* Participants will be screened under a separate protocol.

* Participants must use contraception or abstinence for several weeks before and after the study. They must have no alcohol for 1 day before each visit. Any medicine must be approved by the study doctor until after follow-up.

* Participants will stay in a hospital isolation unit for at least 10 days.

* They will have:

* Medical history

* Physical exam

* Blood and urine tests

* Heart and lung test

* Tests for drugs and alcohol

* Throughout their stay, participants will:

* Be closely watched by a medical team

* Have nasal washes and swabs several times a day

* Participants will have the flu virus sprayed in each nostril.

* The next day, participants will get either study drug or placebo through a soft plastic tube placed in a vein by needle. It will take 2 hours. They will not know which they get.

* Participants can go home after 10 days if they test negative for the flu 2 days in a row.

* Participants will have daily questionnaires at home and 2 follow-up visits over 2 months.

Detailed Description: The high morbidity and mortality associated with both pandemic and seasonal influenza and the threat of new potentially pandemic strains emerging makes influenza an important infectious disease and public health problem. Mean annual estimates of influenza deaths due to seasonal influenza alone attributes up to 49,000 deaths in the US and 250,000 to 500,000 deaths in industrialized countries to influenza. Pandemics can have an even more devastating effect. Public health agencies must continue to be prepared by making attempts to reduce the public health impact of this important virus.

In the realm of influenza therapeutics, antiviral drugs are currently used to treat influenza infection in those who fail to be protected by current vaccines or those who do not receive a vaccine. Currently, only two classes of antivirals are FDA approved for the treatment of influenza A: neuraminidase inhibitors and matrix M2 channel blockers. Although these drugs have been shown to be effective in reducing influenza illness by 24-48 hours and reducing shedding in relatively healthy adults, as with vaccination, they have had limited effectiveness in high risk groups and those who have severe or complicated influenza infections. In addition, antiviral resistance has become very common in human influenza A viruses, as currently circulating H1N1 and H3N2 strains are resistant to the adamantane M2 channel blockers and many cases of neuraminidase inhibitor resistance have also been reported with strains of both subtypes. This resistance can develop quickly and in most cases only requires a single amino acid change. Given these significant issues with currently available treatments, novel therapies for influenza are clearly needed.

Live virus challenge studies have played a pivotal role in developing influenza therapeutics in the past, and they will be instrumental in the future. No novel therapeutic or prophylactic agent has been FDA-approved since the last influenza challenge studies ceased over a decade ago. In collaboration with the Crucell Vaccine Institute (part of Crucell which is in the Janssen family of Pharmaceutical Companies of Johnson \& Johnson) this protocol will evaluate mAb CR6261 for possible therapeutic value. Unlike the current antivirals that are compounds which interfere with some portion of the viral replicative cycle, this agent is a mAb that targets the stem of HA, neutralizing the virus by stabilizing the pre-fusion state and preventing the pH-dependent fusion of viral and cellular membranes. Pre-clinical data suggest that this mAb has good cross-protective efficacy with a variety of HA subtypes unlike current vaccines, making it potentially effective in the event of an emerging influenza virus outbreak with a novel HA subtype. In addition, the conserved nature of the HA stem region suggests that amino acid changes conferring resistance are much less likely. We will effort to demonstrate that CR6261 leads to improved outcomes compared with placebo with respect to the AUC of virus shedding as determined by qPCR in NP swabs in all treated subjects.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 104

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo, 5% dextrose (D-glucose) water
CR6261	CR6261	CR6261, Investigational monoclonal antibody against influenza A viruses

Primary Outcome Measures

Name	Time	Method
Area Under the Curve (AUC) of Viral Shedding	3 times a day for 10 days	Area under the curve (AUC) calculated from quantitative real-time RT-PCR for influenza A taken from 3 time per day nasal swab collection.

Secondary Outcome Measures

Name	Time	Method
Confirmed Influenza Infection	Evaluated daily for 10 days + 8 weeks convalescent follow up	Percentage of participants who experienced either viral shedding or symptoms + a four fold rise in convalescent HAI titer.
Days of Symptoms	Evaluated for up to 2 months	Duration in days symptoms were experienced after influenza challenge
Viral Shedding	Evaluated daily for 10 days	Percentage of participants who experienced influenza viral shedding
Symptoms	Evaluated daily for 10 days	Percentage of participants who experienced influenza symptoms
Total FLUPRO Score	Evaluated from day 0 to day 8	Objective symptoms score from patient directed FLUPRO questionnaire (inFLUenza Patient-Reported Outcome dairy) . The FLUPRO questionnaire uses a 5-point ordinal scale, with higher scores indicating a more frequent sign or symptom. Total scores can range from 0 (symptom free) to 4 (maximum severity of symptoms). Daily scores (Day 0 - Day 8) are averaged to calculate a total score for each participant, then calculated the median total FLUPRO score for each arm.
Days of Shedding	Evaluated for up to 2 months	Duration in days viral shedding was detected after influenza challenge
Mild to Moderate Influenza Disease	Evaluated daily for 10 days	Percentage of participants who experienced influenza symptoms and shedding
Number of Symptoms	Evaluated for up to 2 months	Number of unique influenza symptoms experienced after influenza challenge