History of NHLBI Clinical Research Networks
1993
1995
1997
1999
2001
2003
2005
2007
2009
2011
Adult Asthma
Acute Respiratory Distress Syndrome
Childhood Asthma
Thalassemia
Pediatric Heart Disease
Blood and Marrow Transplant
Transfusion Medicine Hemostasis
COPD
Resuscitation Outcomes
Consortium
Pulmonary Fibrosis
Sickle Cell Disease
Heart Failure
Cardiovascular Cell
Therapy
Cardiothoracic Surgical
Investigations
AsthmaNet
2013
AsthmaNet Mission Statement
• The mission of AsthmaNet is to break new ground by providing evidence
which enables advances in asthma treatment that will have high impact on
patient management through clinical trials that seek to fill gaps in
knowledge, to personalize asthma therapy, and to identify new therapies.
• The unification of prior NIH investment in separate pediatric and adult
networks into one AsthmaNet will enhance scientific exchange and stimulate
research that addresses questions about the similarities, differences, and
relationships between childhood and adult asthma.
• AsthmaNet will provide experience and opportunities to develop new
investigators.
AsthmaNet Approach
• AsthmaNet protocols will include large-scale Clinical Management trials to
carefully evaluate existing or new therapeutic approaches to asthma
management. These protocols may be accompanied by mechanistic studies.
• Proof-of-concept studies also will be conducted to identify promising agents
or approaches to asthma therapy which might be considered for subsequent
larger scale testing.
• Over the 7-year project period, we will conduct 6-8 Clinical Management trials
– at least 3 protocols focused on questions in adult patients
– at least 3 protocols directed towards pediatric patients
at least 1 across-the-lifetime trial
– One or two of these trials may be long-term preventative trials
– 4-6 Proof of Concept studies
Internal
Committees
Steering
Committee
NHLBI
Clinical
Sites
PRC
DSMB
Regulatory
Agencies
NIH
DCC
AsthmaNet
AsthmaNet Protocol Timelines
We Are
Here
INFANT-AVICA
Microbiome
VIDA
APRIL-OCELOT
Development
Execution
Analysis
Clinical Research Skills
Development Core
• To provide junior clinical investigators with
outstanding opportunity to refine their
research skills through:
– One-on-one mentoring
– Participation in AsthmaNet activities
– Preparation of ancillary protocols
– Involvement in conduct of clinical trials
Vitamin D add-on therapy enhances
corticosteroid responsiveness in Asthma
(VIDA)
10
Rationale
• Significant variability in response to inhaled
corticosteroids (ICS) has been reported
• Optimal asthma control is often not achieved
with ICS, necessitating add-on therapy
• Emerging data suggest vitamin D may
modulate asthma phenotypes, among them
glucocorticoid response
Protocol Pg 6-12
Vitamin D Deficiency & Asthma
• CAMP participants with Vit D insufficiency had ↓lung
function and ↑risk for exacerbations
• Children: increase in Vit D levels associated with reduced:
– hospitalization
– anti-inflammatory medications
– airway hyperresponsiveness
• Adults: Vit D insufficient (<30 ng/mL) subjects demonstrate:
– increased airway hyperresponsiveness
– decreased lung function
– decreased steroid response in vitro
Protocol Pg 6-12
Primary Hypothesis
• In individuals 18 years and older with persistent
asthma who remain symptomatic despite low dose
ICS and who are vitamin D insufficient (<30 ng/ml),
the addition of vitamin D is superior to placebo in
reducing treatment failures
Protocol Pg 13
VIDA Study Design
(n=400 adults)
•Population: adults with asthma and vitamin D insufficiency (<30 ng/mL)
•Intervention: vitamin D or placebo added to low-dose ICS
•Primary outcome: post-randomization treatment failure
•Secondary outcomes: multiple
Protocol Pg 19
APRIL - Azithromycin for Preventing the
development of upper Respiratory tract
Illness into Lower respiratory tract
symptoms in children
And
OCELOT - Oral Corticosteroids for treating
Episodes of significant LOwer respiratory
Tract symptoms in children
Background
•
•
•
•
Severe episodes of lower respiratory tract
symptoms are common in early childhood
Disproportionate amount of health-care
resources used in this age group
Little evidence to guide practitioners for
episode prevention
Controversy as to the efficacy of oral
corticosteroids at decreasing symptom
burden during severe wheezing episodes
Overview
2 separate but linked trials conducted in 600 children 12-71 months of
age with a history of a clinically significant wheezing in the prior year
Onset of RTI
symptoms
APRIL Treatment
Failure: Progression
of LRT Symptoms
APRIL
OCELOT
SYMPTOMS
Is azithromycin more
effective than placebo for
preventing clinically
significant LRT symptoms?
Does the addition of oral corticosteroids
during an acute episode reduce the
severity of the episode?
Two Separate But Linked Trials
•
•
•
2 separate and unique interventions at
differing stages of RTI progression
Factorial design
Maximizes trial efficiency


Recruitment of a single “cohort” of children
Two trials that function independently
o
Participation in OCELOT once APRIL treatment
failure is achieved (and thus APRIL participation
is complete)
Co-Primary Hypotheses
Co-PRIMARY HYPOTHESES: Among preschool-aged children
with recurrent wheezing episodes and one or more clinically
significant wheezing episode in the year prior to enrollment:
1. The risk of progression to clinically significant lower
respiratory tract symptoms is lower if azithromycin is
given at the early signs of an RTI compared with
placebo. (APRIL - Prevention Trial)
2. The severity of clinically significant lower respiratory
tract symptoms is lower if oral corticosteroids are given
for rescue due to symptom progression compared with
placebo. (OCELOT - Treatment Trial)
Treatment Strategies
OCELOT
APRIL
Onset of RTI
symptoms
APRIL Treatment
Failure (APRIL Primary
Outcome): Progression
of Symptoms
See Child within
36-72 hrs in Center
Clinic & assess PRAM
(OCELOT Primary
Outcome)
SYMPTOMS
Begin APRIL
Illness Kit:
Azithromycin or
Placebo
Begin OCELOT
Rescue Kit:
Prednisolone or
Placebo
Clinical Care per
Physician
Discretion