A Single-Center, Randomized, Observer-Blinded, Placebo-Controlled, Single-Ascending-Dose (SAD) Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO5469754, a Humanized Monoclonal Antibody, Following Intravenous or Subcutaneous Administration in Healthy Adults

The drug to be given is a new, investigational compound that may eventually be
used for the treatment of asthma.
In asthma , difficulty in breathing results from one or more different
processes including spasm of the bronchial tubes, swelling of the bronchial
tubes, mucus that is difficult to clear from the bronchial tubes, and
thickening of the bronchial wall.
The compound is expected to realise a reduction in severe asthma exacerbations
and sustained improvements in measures of asthma control, including symptoms,
lung function and use of rescue medications.
This new compound is not registered as a drug. This is the first time that this
compound is being given to humans.

Primary:
to assess the safety and tolerability of single doses of RO5469754 when
administered as an intravenous (IV) infusion or subcutaneous (SC) injection(s),
in healthy subjects

Secondary:
to determine the single-dose pharmacokinetics (PK) of RO5469754 when
administered as an IV infusion or SC injection(s), in healthy subjects

Exploratory:
to explore potential changes in pharmacodynamic (PD) endpoints after single
doses of RO5469754 in healthy subjects

Design:
an observer-blinded, randomized, placebo-controlled, single ascending dose
study in 56 healthy male and/or female subject each receiving a single dose of
RO5469754 or placebo (three active and one placebo) administered as an IV
infusion or SC injection(s) in the fasted state; IV cohorts will be staggered;
For the first three cohorts one subject will be dosed per Day, for the
remaining IV dose cohorts two subject (one active and one placebo) will be
dosed and monitored for 24 h before the remaining subjects will be dosed

Procedures and assessments
Screening and follow-up:
clinical laboratory, physical examination, 12-lead ECG (triplicate), vital
signs, pregnancy test (females only), weight; at eligibility screening: medical
history, ethanol and drug screen, HBsAg, anti HCV, anti-HIV 1/2 and TB test;
clinical laboratory, physical examination, weight, vital signs, 12-lead ECG
(triplicate), ethanol and drug screen and pregnancy test (females only) to be
repeated upon admission

Observation period:
one period in clinic from -17 h up to 72 h after drug administration on Day 1
and ambulant visits on Days 5 (SC only) and 6 (SC only) and in Weeks 2, 3, 4,
5, 7, 10, 13 and 16 (follow-up). In Groups 9 - 11 extra ambulatory visits are
possible in weeks 15, 17, 19, 21 and/or 22

Blood sampling:
for pharmacokinetics (IV cohorts): pre-dose up to 72 h post start of infusion,
and at weeks 2, 3, 4, 5, 7, 10, 13 and 16; In Groups 9 - 11 extra samples are
possible in weeks 15, 17, 19, and 21
for pharmacokinetics (SC cohorts): pre-dose and up to 120 h post-dose, and at
weeks 2, 3, 4, 5, 7, 10, 13 and 16; In Groups 9 - 11 extra samples are possible
in weeks 15, 17, 19, and 21

ADA (antibodies) sample: pre-dose on Day 1;
PD biomarker samples: pre-dose and 4 (IV cohorts only), 24, 48 and 72 h
post-dose and at weeks 2, 3, 4, 5, 7, 10, 13 and 16; In Groups 9 - 11 extra
samples are possible in weeks 15, 17, 19, and 21

for RCR (DNA): once at Day -1;
for RCR (RNA): once at Day -1 and pre-dose on Day 1;
for exploratory RNA biomarkers: pre-dose and up to 72 h post-dose and at weeks
2, 3, 4, 5, 7, 10, 13 and 16; In Groups 9 - 11 extra samples are possible in
weeks 15, 17, 19, and 21
for exploratory PD biomarkers: pre-dose and up to 72 h post-dose and at weeks
2, 3, 4, 5, 7, 10, 13 and 16;In Groups 9 - 11 extra samples are possible in
weeks 15, 17, 19, and 21

Safety assessments:
adverse events: throughout the study; at several timepoints abbreviated
physical exam, vital signs, 12-lead ECG, clinical laboratory, a pregnancy test
(females only), and tolerability of SC-injection (SC-cohorts only)

Bioanalysis:
analysis of RO5469754 samples using a validated method by Sponsor
analysis of ADA-sample using a validated method by Sponsor
analysis of PD biomarker samples using a validated method by PRA
analysis of RCR samples using a validated method by Sponsor
analysis of exploratory RNA biomarkers using a validated method by Sponsor
analysis of exploratory PD biomarkers using a validated method by Sponsor

Active substance RO5469754

Procedures: pain, light bleeding, heamatoma, possibly an infection.