Reflux Disease Therapy in the Management of Childhood Asthma-data Entry and Analysis Only
Condition: Asthma; Gastroesophageal Reflux Disease
MeSH terms: Gastroesophageal Reflux; Esophagitis, Peptic; Asthma
Study type: Observational

Summary: 
      There have been a number of studies which attribute causality between reflux disease and
      asthma. In addition, clinicians typically treat chronic asthmatics with high dose acid
      suppressing medications (e.g. lansoprazole). However, clinical trials only recently have shed
      some light on this dilemma, with recent studies suggesting that the association is not as
      clear. This "retrospective" analysis of a prospective study which treated mod-severe
      asthmatics with lansoprazole or placebo will enter the collected raw data into a database,
      then perform statistical analyses to determine if children with asthma treated with acid
      suppression improved their asthma compared to those receiving placebo.
    

Detailed description: 
      Asthma and gastroesophageal reflux disease (GERD) are common disorders, which are usually
      non-lethal and both have high morbidity and healthcare costs. Asthma occurs in about 4% - 7%
      of the US population, and about one-third of active asthmatics are children. There is no
      universally accepted definition of asthma; it may be regarded as a diffuse, obstructive lung
      disease with 1) hyper-reactivity of the airways to a variety of stimuli (e.g., acid refluxate
      via direct exposure and indirect mechanisms; i.e., vagal innervation pathways) and 2) a high
      degree of reversibility of the obstructive process, which may occur either spontaneously or
      as a result of treatment. Gastroesophageal reflux (GER) symptoms, which often result in GERD,
      occur daily in approximately 7% - 20% of the United States adult population; yet
      population-based studies defining the prevalence of GERD in ambulatory pediatric populations
      do not exist. Conversely, recent hospital-based data demonstrate that GERD, the intra- and
      supra-esophageal disease which occurs as a result of GER, is a common pediatric condition
      resulting in 4% of pediatric hospital discharges across the country. Therefore, asthma and
      GERD are both common diseases that often appear to co-exist. Moreover, the co-existence of
      asthma and GERD is far more frequent than chance association. GERD symptoms, although usually
      mild, occur in up to 65% - 77% of asthmatics. In addition, GERD is common in asthmatics, and
      is often "silent", i.e. lacking typical symptoms of heartburn. Thus, studies which
      characterize the relationship between these two conditions and more importantly,
      interventions which may impact positively on both are critically needed. Moreover, there is
      data to suggest that both GERD and asthma are life-long conditions that may have childhood
      origins. A major unanswered question is whether severity or frequency of asthma is related to
      the response to anti-reflux treatment.

      It is also known that acute intermittent reflux, while not meeting established criteria for
      pathologic GER, can precipitate cough and presumably bronchospasm. Although 1 in 5 asthmatics
      use bronchodilators to treat symptoms which are interpreted as episodes of heartburn, it is
      not clear if they are treating bronchospasm or esophageal symptoms. Therefore, one of the
      aims of this trial was to see if we could demonstrate a significant response to
      acid-suppression therapy in a group of poorly controlled childhood asthmatics using the
      number of asthma exacerbations as outcome variables. If there is a causal link between GERD
      and poor asthma control, one would expect that treatment of GERD would improve asthma. The
      Cochrane review of evidence-based medicine concluded as follows: "In subjects who had both
      asthma and GER 51, treatment for GER did not produce a consistent improvement in asthma
      symptom A subgroup of subjects was reported to gain benefit but it appears difficult to
      predict responders. At present it is not possible to recommend medical treatment of GER as a
      means to control asthma. The Cochrane database analysis went on to recommend that "…future
      research is warranted to examine the effects of therapy for GER on asthma control.
      Additionally, "…a parallel group, randomized placebo controlled trial (RCT) using a proton
      pump inhibitor for up to 6 months would be appropriate. Such trials should include assessment
      and standardized reporting of asthma symptoms, quality of life, lung function, symptom and
      asthma medication diary, and an assessment of the effects of therapy on GER". Moreover, if
      GERD and asthma are both lifelong conditions, then one might speculate that overall
      improvement in health outcomes in adulthood can be achieved by successful detection and
      intervention in the pediatric age group. Therefore, results from a randomized placebo,
      controlled treatment trial such as the one we completed and have yet to analyze can surely
      achieve major health benefit for both children and adults suffering from asthma and GERD, and
      ultimately change clinical practice that will result in a reduction of the overall public
      health burden incurred by these chronic human conditions.

      It is important for the Institutional Review Board Committee to recognize that the actual
      "clinical trial" part of the study is complete. This IRB proposal is being submitted to
      perform perhaps the most critical aspect of the study; the data entry of all of the raw data
      into secure electronic databases, and then the statistical analysis and interpretation - the
      final step which we feel the patients and their parents are eager to have completed, and one
      which we hope will have significant impact in the scientific community - advancing the
      science behind understanding the relationship between asthma and GERD. More importantly, we
      feel that by completing the objectives of this new concept proposal - analyzing and
      interpreting the data obtained in the clinical trial, we will prove our hypothesis - that the
      treatment of GERD in moderate to severe childhood asthmatics will actually help asthma
      outcomes - thereby demonstrating that childhood is the critical period in which to intervene
      in modifying and successfully altering the natural history of these two devastating, chronic
      diseases with life-long morbidity and healthcare impact (i.e. asthma and GERD).

      The actual clinical trial which has been completed is the first investigator initiated trial
      for the principal investigator and the co-investigators. After IRB approval was obtained IRB
      #1107-2005, the study enrolled its first patient in March of 2006 and the last patient in
      December of 2008. The study was also registered with www.clinical trials.gov on October 11,
      2005. A Data Safety and Monitoring Board (DSMB) was chartered and formed and met a total of 2
      times with one final meeting to be arranged. An external study monitor performed monitoring
      visits during the first year of the study in order to assure proper protocol compliance,
      regulatory compliance and study procedure conductance.

      The study was completed largely due to the incredible efforts of the GPPA coordinators and
      Co-investigator. At present, the study is closed, no more patients are being enrolled, and as
      mentioned, all patients have either completed the study, withdrawn (early termination) or
      dropped out of the study due to lack of ability to follow up. The study currently retains its
      "blind" in that all of the raw data has been collected, all of the data remains in source
      documents (i.e. CRFs) but the data has not been entered into the secure electronic database,
      and subsequently, thus, no data analysis has occurred, interpretation provided or study
      conclusions drawn.
    

Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        This is a retrospective study. The study will simply be taking data collected during a
        prospective study and analyzing that data. There will be no subjects enrolled in this
        retrospective study. The subjects enrolled in the prospective study were children, ages 4
        to 11 years of age.
      
Keywords: asthma; children; gastroesophageal reflux; retrospective; data analysis