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

Primary Purpose

Asthma, Obesity

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
L-ctirulline
Matching Placebo
Sponsored by
University of Colorado, Denver
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Asthma

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Duke University (Asthma, Allergy and Airway Center)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

L-citrulline

Matching Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Change in Asthma Control Questionnaire
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
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.

Secondary Outcome Measures

Full Information

First Posted
March 6, 2019
Last Updated
March 2, 2023
Sponsor
University of Colorado, Denver
Collaborators
National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), Duke University
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1. Study Identification

Unique Protocol Identification Number
NCT03885245
Brief Title
Supplementing L-citrulline to Overweight Late Asthma oNset Phenotypes
Acronym
SANDIA
Official Title
Supplementing L-citrulline to Overweight Late Asthma oNset Phenotypes to Increase Airway L-arginine/ADMA Ratio and Improve Asthma Control
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 1, 2021 (Actual)
Primary Completion Date
June 30, 2024 (Anticipated)
Study Completion Date
June 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver
Collaborators
National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), Duke University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asthma, Obesity

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
L-citrulline
Arm Type
Experimental
Arm Description
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.
Arm Title
Matching Placebo
Arm Type
Placebo Comparator
Arm Description
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 Type
Drug
Intervention Name(s)
L-ctirulline
Other Intervention Name(s)
L-citrulline
Intervention Description
7 weeks of treatment with 15 g/day of orally administered (powder form mixed with water) L-citrulline
Intervention Type
Drug
Intervention Name(s)
Matching Placebo
Intervention Description
7 weeks of treatment with orally administered matching placebo (to 15 g/day of L-citrulline)
Primary Outcome Measure Information:
Title
Change in Asthma Control Questionnaire
Description
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.
Time Frame
Through study completion, up to 32 weeks
Title
Change in Asthma Control Test
Description
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.
Time Frame
Through study completion, up to 32 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Adequate completion of informed consent process Male and female patients Physician diagnosis of asthma Able to perform reproducible spirometry according to ATS criteria Pre-bronchodilator FEV1 >/= 50% of predicted at Visit 0 Confirmation of asthma All racial/ethnic backgrounds may participate. BMI >/= 30 Regular treatment with ICS or ICS/LABA or LAMA combination medication for at least 1 month; participants can be on biologics. Smoking history </= 10 pack years and no smoking in the last 3 months Age of asthma onset (diagnosis) >/= 12 years FeNO </= 30 ppb ACQ >/= 0.50 or ACT </=19 Exclusion Criteria: Respiratory tract infection within the 4 weeks prior to Visit 1 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) Asthma-related ER visit within the previous 4 weeks of Visit 0 History of ICU admission/intubation due to asthma in the past 1 year 3 or more asthma exacerbations requiring treatment with systemic corticosteroids for more than three days in the past year consistent with severe asthma Asthma exacerbation requiring systemic corticosteroids within the 4 weeks prior to Visit 0. Chronic renal failure Positive urine cotinine or THC test on the day of the bronchoscopy visit Positive urine (or serum) pregnancy test at Visit 0 or at any time during the study Intolerance or allergy to L-arginine or L-citrulline Concomitant use of PDE5 drugs or oral mononitrates Untreated sleep apnea 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Asthma Research
Phone
1 (844) 365-0852
Email
asthmaresearch@ucdenver.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fernando Holguin, MD, MPH
Organizational Affiliation
University of Colorado Denver- Anschutz Medical Campus
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University (Asthma, Allergy and Airway Center)
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Antoinette Santoro, MS, BSRT
Phone
919-479-0731
Email
maria.santoro@duke.edu
First Name & Middle Initial & Last Name & Degree
Catherine Foss, BS, RRT
Phone
(919) 613 - 7627
Email
catherine.foss@duke.edu
First Name & Middle Initial & Last Name & Degree
Loretta Que, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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Supplementing L-citrulline to Overweight Late Asthma oNset Phenotypes

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