Effect of intranasal administration of palivizumab on experimental respiratory syncytial viral infection * a human challenge study

Globally respiratory syncytial virus (RSV) is the second cause of death after
malaria in infants. RSV immunoprophylaxis with palivizumab is prohibitively
expensive and only administered to high risk children in developed countries.
There is a need to make palivizumab affordable through local administration. We
established preclinical proof of concept in mice: intranasal (IN) palivizumab
provides full protection against RSV for at least a week after administration.
We tested the stability and shelf-life of a of palivizumab in nose drop
formulation. In a phase I double-blind RCT we showed safety in healthy adult
volunteers. This study will provide clinical proof of concept that IN
administration will block RSV at the point of entry (Bouncer Hypothesis) in
experimental human infection. To mitigate the risks of large and costly
late-stage trials, an RSV controlled human infection model (CHIM) allows for a
rapid proof of concept that is also cost-effective to test for efficacy of the
proposed IN administration at an earlier stage. The World Health Organization
(WHO) has determined that CHIM contributes vital scientific knowledge and can
significantly accelerate clinical development.

Study A: Validation of productive infection of RSV CHIM
Study B: Effectiveness and immunogenicity of local administration of
palivizumab on prevention of experimental RSV infection

Study A: Validation of RSV CHIM in healthy adult volunteers: Productive
infection in RSV CHIM; If there are 2/6 productive infections, then study B
will start
Study B: Phase II RCT: Non-therapeutic double-blind placebo-controlled
proof-of-concept trial of RSV prevention through IN administration of
palivizumab or placebo in healthy adult volunteers

Study A: No intervention, only viral challenge.
Study B: 0,2mL nose drops per nostril (1mg/mL palivizumab or placebo)
administered one time each as a prophylaxis 2 hours before the viral challenge

This is a validation study. There are two main risks of CHIM that should be
considered (1) risk of severe infection in study subjects and (2) risk of
transmission from experimentally-infected individuals to researchers or the
broader public. Healthy young adults do not suffer from severe RSV infection,
but at most develop mild-to-moderate common cold symptoms after experimental
RSV infection. RSV CHIM has been used safely in clinical trial settings to test
antivirals. The potential risk of transmission of RSV from
experimentally-infected individuals to research staff and the wider public will
be addressed using infection control standard procedures and will be monitored.
These SOP*s will be developed and designed with the support of the Department
of Infection Control at UMCU (Dr. Annet Troelstra and Dr. Herman Wunderink).
The burden of the study includes 10 days of inpatient quarantine as well as
minimally invasive study procedures including viral inoculation, daily nasal
sampling (nasal lavage, scrape, nasopharyngeal swabs).
There is no direct benefit to patients who participate in the study.
Study B:
This is a non-therapeutic study. The safety risks of CHIM are mitigated by
evaluation of Study A to continue to Study B. The main difference is that Study
B will occur in the outpatient setting. Measures will be taken to understand
and carefully limit transmission risk in Study A.
Furthermore, volunteers will undergo self-quarantine for a period of 10 days,
be trained in transmission prevention measures as outlined above in the
protocol, and will be screened for children <3 years of age in the household to
limit transmission of RSV. Minimal risk is associated with the IMP which have
been previously evaluated by the Ethics Committee in the Narsyn trial.
Additional safety data has been collected in the phase I and IIB trial. Risks
are described in more detail in section 10.4. We have shown the intranasal
formulation to be safe in a phase I trial in healthy adults. The burden of the
study includes 10 days of self-quarantine. Study procedures are non-invasive
(nasal washes, nasosorption, lung function measurements, nasal scrapes) except
for 7 blood draws. There is no direct benefit to patients who participate in
the study.