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

Pulmonary Fibrosis

Sickle Cell Disease

Heart Failure

Resuscitation Outcomes Consortium

Cardiovascular Cell Therapy

Cardiothoracic Surgical Investigations

AsthmaNet

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

NHLBI

PRC DSMB

Steering Committee

DCC

Clinical Sites

Internal Committees

Regulatory Agencies

NIH AsthmaNet

AsthmaNet Protocol TimelinesAsthmaNet Protocol Timelines

• 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

Clinical Research Skills Development Core

Vitamin D add-on therapy enhances corticosteroid responsiveness in Asthma

(VIDA)

10

• 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

Rationale

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

• 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

Primary Hypothesis

Protocol Pg 13

VIDA Study Design (n=400 adults)

Protocol Pg 19

•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

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

• 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

Background

Overview

SYMPTOMS

Onset of RTI symptoms

Is azithromycin more effective than placebo for

preventing clinically significant LRT symptoms?

APRIL Treatment Failure: Progression of LRT Symptoms

Does the addition of oral corticosteroids during an acute episode reduce the

severity of the episode?

APRILOCELOT

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

• 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)

Two Separate But Linked Trials

Co-Primary HypothesesCo-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

SYMPTOMS

Onset of RTI symptoms

Begin APRIL Illness Kit:

Azithromycin or Placebo

APRIL Treatment Failure (APRIL Primary Outcome): Progression

of Symptoms

Begin OCELOT Rescue Kit:

Prednisolone or Placebo

See Child within 36-72 hrs in Center

Clinic & assess PRAM (OCELOT Primary

Outcome)

APRIL OCELOT

Clinical Care per Physician Discretion