Supplementing L-citrulline to Overweight Late Asthma oNset Phenotypes

NCT ID: NCT03885245

Last Updated: 2025-06-10

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-10-01
• Study Completion Date: 2026-06-30

Brief 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.

Conditions

Asthma; Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

L-citrulline

L-citrulline with a dose of 15 g/day will be administered in powder form that is mixed with water and taken orally, continuously and daily for at least 7 weeks. Dispensed at Visits 1 and 1a (if needed). Washout period of at least 5 weeks and then enter crossover phase of an additional 7 weeks. Drug will be dispensed at Visit 4.

Group Type: EXPERIMENTAL

L-ctirulline

Intervention Type: DRUG

7 weeks of treatment with 15 g/day of orally administered (powder form mixed with water) L-citrulline

Matching Placebo

Administered in powder form that is mixed with water and taken orally, continuously, and daily for at least 7 weeks. Dispensed at Visits 1 and 1a (if needed). Washout period of at least 5 weeks and then enter crossover phase of an additional 7 weeks. Drug will be dispensed at Visit 4.

Group Type: PLACEBO_COMPARATOR

Matching Placebo

Intervention Type: DRUG

7 weeks of treatment with orally administered matching placebo (to 15 g/day of L-citrulline)

Interventions

L-ctirulline

7 weeks of treatment with 15 g/day of orally administered (powder form mixed with water) L-citrulline

Intervention Type: DRUG

Matching Placebo

7 weeks of treatment with orally administered matching placebo (to 15 g/day of L-citrulline)

Intervention Type: DRUG

Other Intervention Names

L-citrulline

Eligibility Criteria

Inclusion Criteria

1. Adequate completion of informed consent process

2. Male and female patients

3. Physician diagnosis of asthma

4. Able to perform reproducible spirometry according to ATS criteria

5. Pre-bronchodilator FEV1 >/= 50% of predicted at Visit 0

6. Confirmation of asthma

7. All racial/ethnic backgrounds may participate.

8. BMI >/= 30

9. Regular treatment with ICS or ICS/LABA or LAMA combination medication for at least 1 month; participants can be on biologics.

10. Smoking history </= 10 pack years and no smoking in the last 3 months

11. Age of asthma onset (diagnosis) >/= 12 years

12. FeNO </= 30 ppb

13. ACQ >/= 0.50 or ACT </=19

Exclusion Criteria

1. Respiratory tract infection within the 4 weeks prior to Visit 1

2. Oral or systemic corticosteroid burst (for any indication) within the 4 weeks prior to Visit 0. (One-time doses, such as intra-articular injections into a shoulder or knee joint, require a 4-week washout prior to Visit 0)

3. Asthma-related ER visit within the previous 4 weeks of Visit 0

4. History of ICU admission/intubation due to asthma in the past 1 year

5. 3 or more asthma exacerbations requiring treatment with systemic corticosteroids for more than three days in the past year consistent with severe asthma

6. Asthma exacerbation requiring systemic corticosteroids within the 4 weeks prior to Visit 0.

7. Chronic renal failure

8. Positive urine cotinine or THC test on the day of the bronchoscopy visit

9. Positive urine (or serum) pregnancy test at Visit 0 or at any time during the study

10. Intolerance or allergy to L-arginine or L-citrulline

11. Concomitant use of PDE5 drugs or oral mononitrates

12. Untreated sleep apnea

13. Participant in an interventional drug study or use of investigative drugs within the past 30 days or plans to enroll in such a trial during the study

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Fernando Holguin, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Colorado Denver- Anschutz Medical Campus

Locations

Duke University (Asthma, Allergy and Airway Center)

Durham, North Carolina, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Asthma Research

Role: CONTACT

asthmaresearch@ucdenver.edu

1 (844) 365-0852

Facility Contacts

Antoinette Santoro, MS, BSRT

Role: primary

maria.santoro@duke.edu

919-479-0731

Catherine Foss, BS, RRT

Role: backup

catherine.foss@duke.edu

(919) 613 - 7627

Other Identifiers

R01HL146542

Identifier Type: NIH

Identifier Source: secondary_id

View Link

19-0219

Identifier Type: -

Identifier Source: org_study_id