Supplementing L-citrulline to Overweight Late Asthma oNset Phenotypes
Status:
Recruiting
Trial end date:
2024-06-30
Target enrollment:
Participant gender:
Summary
Patients with obese late onset (after childhood) asthma can have lower FeNO levels, yet be
highly symptomatic and poorly responsive to inhaled steroids. This is a common asthma
phenotype, particularly among females. This reduction of NO occurs through increased arginase
activity and uncoupling of NO synthase (NOS), by accumulation of asymmetric di-methyl
arginine (ADMA), which further lowers the L-arginine/ADMA ratio, preferentially promoting
reactive oxygen species (ROS) formation and inflammation at the expense of NO. Indeed, in
patients with obese late onset asthma, lower L-arginine/ADMA plasma ratios are associated
with reduced FeNO, increased bronchial hyperreactivity, and greater asthma morbidity. In our
pilot studies, the administration of L-citrulline, as an L-arginine donor, to patients with
obese late onset asthma increased the L-arginine/ADMA ratio, FeNO levels, and improved asthma
control and lung function. Therefore, the objectives of the protocol are to: a) determine the
efficacy of L-citrulline, as an add-on treatment to improve the asthma control and lung
function in obese late onset asthmatics; b) leverage the use of asthmatic and control cells
to further understand obesity-related changes in epithelial airway NO metabolism, and how
these changes relate to bronchoconstriction and lung function, c) determine airway epithelial
changes in mitochondrial function and bioenergetics in obese late onset asthmatics and how
these are modified by L-citrulline. To do this, 54 obese late onset asthmatics with
suboptimal control will be blindly randomized, in a cross over study, comparing 15g/day of
L-citrulline vs. placebo, in two 8-week treatment periods with a 6-week washout in between.
The co-primary study outcomes are asthma control (ACQ, ACT) and FeNO, and secondary endpoints
plasma L-arginine/ADMA, FEV1 and PC20 methacholine. Parallel to this study, a small study of
10 healthy obese controls will receive open label L-citrulline for 7 weeks to establish
comparative reference values for the study aims. During the initial treatment phase, 50% of
study participants will be randomly allocated to undergo pre and post L-citrulline treatment
bronchoscopy to obtain BAL and airway epithelial cells. The research group proposing this
study is highly experience in asthma clinical trials, implementation of cross over design
studies, and in the use of research bronchoscopies.
Phase:
Phase 2
Details
Lead Sponsor:
University of Colorado, Denver
Collaborators:
Duke University National Heart, Lung, and Blood Institute (NHLBI) National Institutes of Health (NIH)