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| ID | Type | Description | Link |
|---|---|---|---|
| R01HL105573 | U.S. NIH Grant/Contract | View source | |
| UCD105573 | Other Identifier | UC Davis |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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The major impact of this study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy. The investigators hypothesize that a subset of adult severe asthma patients will respond to supplemental L-arginine and derive clinical benefit from the addition of this therapy to standard-of-care asthma medications. The investigators hypothesize that the patients that benefit most will have low exhaled nitric oxide concentrations (< 20 ppb) at baseline.
We hypothesize that a subset of adult severe asthma patients will respond to supplemental L-arginine and derive clinical benefit from the addition of this therapy to standard-of-care medications. We hypothesize that these patients will have lower exhaled NO concentrations (<20 ppb) and lower nitric oxide synthase 2 (NOS2)/ arginase I (Arg1) mRNA ratios in their airway epithelial cells than "non-responders." The aim is to test the hypothesis that adult severe asthma subjects with exhaled breath NO concentrations < 20 ppb will have fewer American Thoracic Society (ATS)-defined asthma exacerbations over 3 months when treated with L-arginine compared to subjects with exhaled nitric oxide concentration (FeNO) > 25 ppb. The major impact of this study will be to identify the adult severe asthma cohort that will benefit from supplemental L-arginine therapy to define the underlying mechanisms of arginine benefit in asthma. This follows our initial 20 subject trial of L-arginine in asthma subjects (Kenyon et al., Pharmaceuticals 2011) that was designed to determine how L-arginine was metabolized (by testing serum markers) and whether certain participants had clinical benefit.
To do this, we will recruit a total of 50 ATS-defined severe asthmatic subjects with ongoing asthma exacerbations in past two months and enroll them in a randomized, blinded, placebo-controlled, cross-over designed trial of L-arginine and placebo. We will compare 25 subjects with "low" FeNO < 20 with 25 subjects that have "high" FeNO > 25 ppb.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low Exhaled Nitric Oxide (NO) | Active Comparator | Subjects with a baseline exhaled NO level less than or equal to 20 ppb will be enrolled in the Low Exhaled Nitric Oxide arm. All subjects will receive L-arginine and placebo in this cross-over design study. |
|
| High Exhaled Nitric Oxide (NO) | Active Comparator | Subjects with a baseline exhaled NO level greater than or equal to 25 ppb will be enrolled in the High Exhaled Nitric Oxide arm. All subjects will receive L-arginine and placebo in this cross-over design study. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| L-Arginine | Drug | L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Acute Exacerbation at 3 Months | The primary endpoint of the study is the number of acute moderate exacerbations at 3 months. A moderate asthma exacerbation is defined as any of the following: 1) A drop in morning peak flow rate (PEFR) >30% from baseline on 2 consecutive days (1 event), 2) Need for initiation of oral steroids or am increased dose of inhaled corticosteroids on any two consecutive days (1 event), 3) Doubling of short-acting β-agonist use (e.g. number of puffs of albuterol) per day for 2 consecutive days (1 event). | 3 month |
| Measure | Description | Time Frame |
|---|---|---|
| Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) | The secondary endpoint is the change in FEV1/FVC ratio at 3 months. This calcuation is a ratio between the volume of breath exhaled in the first second divided by the total amount of breath exhaled in a vital capacity maneuver. A normal ratio is usually > 70%. | 3 month |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nicholas Kenyon, MD,MS | Univ. of California, Davis | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UC Davis CTSC Clinical Research Center | Sacramento | California | 95817 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32497023 | Derived | Liao SY, Showalter MR, Linderholm AL, Franzi L, Kivler C, Li Y, Sa MR, Kons ZA, Fiehn O, Qi L, Zeki AA, Kenyon NJ. l-Arginine supplementation in severe asthma. JCI Insight. 2020 Jul 9;5(13):e137777. doi: 10.1172/jci.insight.137777. |
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Participants were assigned to low or high exhaled nitric oxide groups based on their levels at time of Visit 1.
54 subjects consented and enrolled for the trial, but n=50 were randomized as n=4 participants declined to participate.
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| ID | Title | Description |
|---|---|---|
| FG000 | Low Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Subjects with a baseline exhaled NO level less than or equal to 20 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients. |
| FG001 | High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Subjects with a baseline exhaled NO level greater than or equal to 25 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients. |
| FG002 | Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Subjects with a baseline exhaled NO level less than or equal to 20 ppb Receive Placebo first, then L-arginine L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients. |
| FG003 | High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Subjects with a baseline exhaled NO level greater than or equal to 25 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (12 Weeks) |
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| Washout (6 Weeks) |
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| Second Intervention (12 Weeks) |
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| ID | Title | Description |
|---|---|---|
| BG000 | Low Exhaled Nitric Oxide (NO) | Subjects with a baseline exhaled NO level less than or equal to 20 ppb will be enrolled in the Low Exhaled Nitric Oxide arm. Baseline characteristics at the enrollment |
| BG001 | High Exhaled Nitric Oxide (NO) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Acute Exacerbation at 3 Months | The primary endpoint of the study is the number of acute moderate exacerbations at 3 months. A moderate asthma exacerbation is defined as any of the following: 1) A drop in morning peak flow rate (PEFR) >30% from baseline on 2 consecutive days (1 event), 2) Need for initiation of oral steroids or am increased dose of inhaled corticosteroids on any two consecutive days (1 event), 3) Doubling of short-acting β-agonist use (e.g. number of puffs of albuterol) per day for 2 consecutive days (1 event). | Several patients dropped after the first intervention | Posted | Mean | Standard Deviation | Events | 3 month |
|
Adverse events were collected for the duration of the trial,8 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Low Exhaled Nitric Oxide (NO) Phase 1, Treatment Arm | ow Exhaled Nitric Oxide (NO) Phase 1, L-Arginine arm |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hospitalization | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Subject was admitted to the hospital for exacerbation or flare of asthma either on placebo or L-arginine. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastroesophageal reflux disease | Gastrointestinal disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Nicholas Kenyon | UC Davis | 916-734-3564 | njkenyon@ucdavis.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 15, 2019 | Dec 16, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001249 | Asthma |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
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| ID | Term |
|---|---|
| D001120 | Arginine |
| ID | Term |
|---|---|
| D024361 | Amino Acids, Basic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000599 | Amino Acids, Diamino |
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|
| Placebo | Drug | Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients. |
|
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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Subjects with a baseline exhaled NO level greater than or equal to 25 ppb will be enrolled in the High Exhaled Nitric Oxide arm. Baseline characteristics at the enrollment |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Spirometry | Mean | Standard Deviation | Litters |
|
| Weight | Mean | Standard Deviation | Kg |
|
| Asthma Control Test Score | The total Asthma Control Test score is reported. It is on a scale of 5 to 25. The higher the score, the better the asthma control. A score of 20 or more suggests good asthma control. A score of less than 20 suggests inadequate asthma control. | Mean | Standard Deviation | units on a scale |
|
| OG001 | High Exhaled Nitric Oxide (NO), L-Arginine First, Then Placebo | Subjects with a baseline exhaled NO level greater than or equal to 25 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients. |
| OG002 | Low Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Subjects with a baseline exhaled NO level less than or equal to 20 ppb Receive Placebo first, then L-arginine L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients. |
| OG003 | High Exhaled Nitric Oxide (NO), Placebo First, Then L-Arginine | Subjects with a baseline exhaled NO level greater than or equal to 25 ppb Receive L-arginine first, then Placebo L-Arginine: L-arginine tablets containing 1 g of elemental L-arginine (1204 mg of L-arginine HCL) developed by Jarrow Formulas in Los Angeles. Placebo: Matching placebo tablets do not contain L-arginine. Placebo tablets were manufactured by Jarrow Formulas and contain cellulose and other excipients. |
|
|
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| Secondary | Forced Expiratory Volume in One Second (FEV1)/Forced Vital Capacity (FVC) | The secondary endpoint is the change in FEV1/FVC ratio at 3 months. This calcuation is a ratio between the volume of breath exhaled in the first second divided by the total amount of breath exhaled in a vital capacity maneuver. A normal ratio is usually > 70%. | Several patients dropped after the first intervention | Posted | Mean | Standard Deviation | ratio | 3 month |
|
|
|
|
| 0 |
| 11 |
| 0 |
| 11 |
| 0 |
| 11 |
| EG001 | Low Exhaled Nitric Oxide (NO) Phase 1, Placebo Arm | Low Exhaled Nitric Oxide (NO) Phase 1, placebo arm | 0 | 13 | 0 | 13 | 1 | 13 |
| EG002 | Low Exhaled Nitric Oxide (NO) Washout Phase | Low Exhaled Nitric Oxide (NO) Washout Phase | 0 | 19 | 0 | 19 | 0 | 19 |
| EG003 | Low Exhaled Nitric Oxide (NO) Phase 2, Treatment Arm | Low Exhaled Nitric Oxide (NO) Phase 2, L-Arginine arm | 0 | 10 | 0 | 10 | 1 | 10 |
| EG004 | Low Exhaled Nitric Oxide (NO) Phase 2, Placebo Arm | Low Exhaled Nitric Oxide (NO) Phase 2, placebo arm | 0 | 9 | 0 | 9 | 0 | 9 |
| EG005 | High Exhaled Nitric Oxide (NO) Phase 1, Treatment Arm | High Exhaled Nitric Oxide (NO) Phase 1, L-Arginine arm | 0 | 12 | 2 | 12 | 1 | 12 |
| EG006 | High Exhaled Nitric Oxide (NO) Phase 1, Placebo Arm | High Exhaled Nitric Oxide (NO) Phase 1, placebo arm | 0 | 14 | 1 | 14 | 0 | 14 |
| EG007 | High Exhaled Nitric Oxide (NO) Washout Phase | High Exhaled Nitric Oxide (NO) Washout Phase | 0 | 22 | 1 | 22 | 0 | 22 |
| EG008 | High Exhaled Nitric Oxide (NO) Phase 2, Treatment Arm | High Exhaled Nitric Oxide (NO) Phase 2, L-Arginine arm | 0 | 16 | 0 | 16 | 0 | 16 |
| EG009 | High Exhaled Nitric Oxide (NO) Phase 2, Placebo Arm | igh Exhaled Nitric Oxide (NO) Phase 2, Placebo arm | 0 | 6 | 0 | 6 | 0 | 6 |
|
| Hives | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
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| D012130 |
| Respiratory Hypersensitivity |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D000601 | Amino Acids, Essential |
| Title | Measurements |
|---|---|
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| Second Intervention |
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