History of NHLBI Clinical Research Networks

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History of NHLBI Clinical Research Networks
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
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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.

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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
  patientsat least 1 across-the-lifetime trial
• One or two of these trials may be long-term
  preventative trials
• 4-6 Proof of Concept studies

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Internal Committees
Steering Committee
NHLBI
Clinical Sites
PRC
DSMB
DCC
Regulatory Agencies
NIH
AsthmaNet
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AsthmaNet Protocol Timelines
We Are Here
INFANT-AVICA
Microbiome
VIDA
APRIL-OCELOT
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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

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Vitamin D add-on therapy enhances corticosteroid
responsiveness in Asthma(VIDA)
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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
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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 (lt30 ng/mL) subjects
  demonstrate
• increased airway hyperresponsiveness
• decreased lung function
• decreased steroid response in vitro

Protocol Pg 6-12
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Primary Hypothesis

• In individuals 18 years and older with persistent
  asthma who remain symptomatic despite low dose
  ICS and who are vitamin D insufficient (lt30
  ng/ml), the addition of vitamin D is superior to
  placebo in reducing treatment failures

Protocol Pg 13
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VIDA Study Design (n400 adults)

• Population adults with asthma and vitamin D
  insufficiency (lt30 ng/mL)
• Intervention vitamin D or placebo added to
  low-dose ICS
• Primary outcome post-randomization treatment
  failure
• Secondary outcomes multiple

Protocol Pg 19
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• 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

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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

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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
APRIL Treatment Failure Progression of LRT
Symptoms
Onset of RTI 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?
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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
• Participation in OCELOT once APRIL treatment
  failure is achieved (and thus APRIL participation
  is complete)

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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
• 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)
• 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)

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Treatment Strategies
APRIL
OCELOT
See Child within 36-72 hrs in Center Clinic
assess PRAM (OCELOT Primary Outcome)
APRIL Treatment Failure (APRIL Primary Outcome)
Progression of Symptoms
Onset of RTI symptoms
SYMPTOMS
Begin APRIL Illness Kit Azithromycin or Placebo
Begin OCELOT Rescue Kit Prednisolone or Placebo
Clinical Care per Physician Discretion