History of NHLBI Clinical Research Networks

2. 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 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

5. 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.

6. 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

7. Internal Committees Steering Committee NHLBI Clinical Sites PRC DSMB Regulatory Agencies DCC NIH AsthmaNet

8. AsthmaNet Protocol Timelines We Are Here INFANT-AVICA Microbiome VIDA APRIL-OCELOT

9. 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

10. Vitamin D add-on therapy enhances corticosteroid responsiveness in Asthma(VIDA)

11. 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 Rationale Protocol Pg 6-12

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

13. 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

14. 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

15. 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

16. 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

17. 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?

18. 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) Two Separate But Linked Trials

19. 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)

20. Treatment Strategies OCELOT APRIL 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