Supplementing L-citrulline to Overweight Late Asthma oNset Phenotypes (SANDIA)

• ClinicalTrials.gov Identifier: NCT03885245
• Recruitment Status: Recruiting
• First Posted: March 21, 2019
• Last Update Posted: March 6, 2023
• Sponsor: University of Colorado, Denver
• Collaborators: National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (NHLBI); Duke University
• Information provided by (Responsible Party): University of Colorado, Denver

Tracking Information

• First Submitted Date: March 6, 2019
• First Posted Date: March 21, 2019
• Last Update Posted Date: March 6, 2023
• Actual Study Start Date: October 1, 2021
• Estimated Primary Completion Date: June 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 19, 2019)

• Change in Asthma Control Questionnaire [ Time Frame: Through study completion, up to 32 weeks ]
  to determine L-citrulline efficacy, reduction in questionnaire scores determined by administering the questionnaires before, mid-way, and after during each treatment phase to see if there's a change in scores.
• Change in Asthma Control Test [ Time Frame: Through study completion, up to 32 weeks ]
  To determine L-citrulline efficacy, reduction in questionnaires scores determined by administering the questionnaires before, mid-way, and after during each treatment phase to see if there's a change in scores.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Supplementing L-citrulline to Overweight Late Asthma oNset Phenotypes
• Official Title: Supplementing L-citrulline to Overweight Late Asthma oNset Phenotypes to Increase Airway L-arginine/ADMA Ratio and Improve Asthma Control
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment

Condition

• Asthma
• Obesity

Intervention

• Drug: L-ctirulline
  7 weeks of treatment with 15 g/day of orally administered (powder form mixed with water) L-citrulline
  Other Name: L-citrulline
• Drug: Matching Placebo
  7 weeks of treatment with orally administered matching placebo (to 15 g/day of L-citrulline)

Study Arms

• Experimental: 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.
  Intervention: Drug: L-ctirulline
• Placebo Comparator: 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.
  Intervention: Drug: Matching Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 19, 2019): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 30, 2024
• Estimated Primary Completion Date: June 30, 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Asthma Research; 1 (844) 365-0852; asthmaresearch@ucdenver.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03885245
• Other Study ID Numbers: 19-0219; R01HL146542 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Colorado, Denver
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Colorado, Denver
• Original Study Sponsor: Same as current

Collaborators

• National Institutes of Health (NIH)
• National Heart, Lung, and Blood Institute (NHLBI)
• Duke University

Investigators

• Principal Investigator: Fernando Holguin, MD, MPH; University of Colorado Denver- Anschutz Medical Campus

• PRS Account: University of Colorado, Denver
• Verification Date: March 2023