Study A: A placebo-controlled crossover study to assess safety of intranasal administration of palivizumab
Study B: Effect of intranasal administration of palivizumab on respiratory syncytial virus-associated infection - a double-blind randomized controlled trial

Respiratory syncytial virus (RSV) is the second cause of death in the infant
period after malaria worldwide. It is estimated that RSV was associated with
33,1 million cases of acute respiratory tract infection (ARTI) in 2015.
Currently, there is no vaccine or treatment for RSV. Palivizumab, a humanized
monoclonal antibody against the surface F protein of RSV, is the only approved
preventive intervention, which is currently limited to high-risk infants due to
prohibitive costs. To prevent one RSV hospitalization the current estimated
cost for palivizumab is 100,000 euros. Not only are costs high, but prophylaxis
is now administered via monthly intramuscular injections. The proposal to
administer it via nose drops would make administration less burdensome for an
infant and reduce costs by more than 90%. From 2008 - 2010, we performed a
trial at the UMCU administering palivizumab to late preterms 32-35 weeks
gestation age (WGA) and found an 80% reduction in hospitalization in the
intervention group. We expect that local administration to the airways will be
even more effective. Furthermore, in vivo we demonstrated that palivizumab can
provide local mucosal protection when administered into the lungs to protect
against RSV infection in a dose-dependent manner for up to a week after
administration. We propose to administer palivizumab via the intranasal route
(nose drops) to make it more affordable, acceptable and effective. The
independent RSV patient advisory board (PAB) has specifically supported the
importance of this study as they find it morally unacceptable that the current
cost of RSV prevention is not only prohibitive, but also burdensome to young
children with administration through 5 intramuscular injections.

Study A: Safety of intranasal administration of palivizumab in healthy adults
Study B: Effect of local administration of palivizumab on prevention of RSV
infection

Study A: Phase I RCT: Crossover safety study in healthy adult volunteers with
14-day washout period. After favorable DSMB evaluation, study B will start.
Study B: Phase IIb RCT: Double-blind placebo controlled proof-of-concept trial
in target population.

Study A: 1 nose drop in the right nostril once daily of 1 mg/mL palivizumab or
placebo for 7 days; 14 day washout period, then crossover to other arm for 7
days.
Study B: 1 nose drop per nostril once daily of 1 mg/mL palivizumab or placebo
for a duration of 2 - 5 months during the RSV season

Study A: This study is a phase I safety study. In the proposed population
intramuscular palivizumab has been shown to be safe. There is no evidence that
there is risk of toxicity upon intranasal administration for this monoclonal
antibody that has a non-human target (RSV F protein) and has been used
clinically for over 20 years.
Study B: This study is a therapeutic study. In the proposed study population
palivizumab has been shown to reduce RSV-related hospitalization (82%),
medically-attended RSV infection (80%) and total RSV infection (67%)[1].
Palivizumab is a registered drug for intramuscular administration that has an
excellent safety profile and has been used clinically in children for more than
20 years. The burden is daily nose drops administered during the RSV season
starting in October at the earliest for a duration of 5 months during the RSV
season. The risks in this study are considered to be minimal. The possible
benefit is prevention of RSV hospitalization, medically attended RSV infection
and total RSV infection.