Cough
Conditions
Keywords
Chronic cough, Refractory cough, Chronic refractory cough, Zinc, Zinc acetate
Brief summary
The Pilot of Zinc Acetate to Improve Chronic Cough (ZICO) is a study of 36 patients with chronic refractory cough that will be used to (1) assess if zinc acetate (150 mg/day) will improve patient reported measures of cough, (2) to establish if treatment with zinc acetate is well tolerated, and (3) to determine if the trial logistics are feasible.
Detailed description
Chronic refractory cough in adults is defined as a cough lasting more than 8 weeks that does not resolve with treatment for asthma/eosinophilic airway disease, gastroesophageal reflux disease (GERD), or rhinosinusitis/post-nasal drip; and is not caused by smoking, angiotensin-converting-enzyme (ACE) inhibitors, or parenchymal lung disease. This is one of the most common conditions leading to specialty referral accounting for about 20% of new pulmonary consultations. Chronic refractory cough leads to severe impairment of quality of life and social isolation as well as sleep deprivation and chronic fatigue. The few available treatments have limited benefit and substantial side effects or abuse potential. While there are validated tools to measure the health-impact of chronic cough which can provide feasible clinical trial outcome measures, there have been no academic multi-center trials of chronic cough, and guidelines for treatment continue to rely largely on opinion rather than evidence. ZICO is a small scale randomized proof-of-concept clinical trial to establish the safety and tolerability of zinc in this population. The primary outcome measure will be the Cough Specific Quality of Life Questionnaire (CQLQ). Participants will be 18 years or older, with chronic cough lasting at least 3 months, which has been unresponsive to treatments for asthma, GERD or other upper airway disease. Individuals that are current smokers, use an ACE inhibitor, currently take zinc supplements (or multivitamins with zinc), or whose medical history includes primary parenchymal lung disease, congestive heart failure, chronic kidney disease, or another medical condition that could interfere with the study or are pregnant or breast-feeding will be excluded. Participants will be randomized to receive 6 weeks of treatment with either zinc acetate or placebo. Follow-up assessments will occur at 1, 3, 6 and 8 weeks after randomization; the final assessment is after a two week washout to establish the duration of treatment effect. In addition to completing a daily cough diary, participants will complete cough specific and general quality of life measures, complete spirometry testing and have serum zinc and copper levels measured.
Interventions
* Day 0 (randomization) to day 3 Zinc acetate 50 mg per day (one capsule) * Day 4 to day 7 If well tolerated: Zinc acetate 100 mg per day (two capsules) * Day 8 to V5 (6 weeks) If well tolerated: Zinc acetate 150 mg per day (three capsules)
DRUGPlacebo oral capsule
* Day 0 (randomization) to day 3 Placebo (one capsule per day) * Day 4 to day 7 If well tolerated: placebo (two capsules per day) * Day 8 to V5 (6 weeks) If well tolerated: placebo (three capsules per day)
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
American Lung Association
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* No upper or lower respiratory infection within 4 weeks * Either * Negative evaluation for: * Asthma; no symptoms of disease or no evidence of asthma based on spirometry and/or methacholine challenge test * GERD: no symptoms of acid reflux disease or negative potential of hydrogen (pH) probe * Rhinosinusitis/upper airway cough Or * Cough persists despite treatment for the following: * Asthma -treated for at least 8 weeks with at least medium dose inhaled corticosteroids or with oral corticosteroids * GERD - treated for at least 8 weeks with either a proton pump inhibitor (PPI) or H2 blocker * Upper airway disease, postnasal drip or sinusitis - treated for at least 8 weeks with nasal steroids, antihistamines or both. * Non-smoker; defined as * no smoking of any substance (e.g., tobacco, e-cigarette, marijuana) in the past 6 months, and * less than 20 pack-year smoking history * Chest x-ray or CT scan in the past 12 months; negative for parenchymal lung diseases (such as interstitial lung disease, idiopathic pulmonary fibrosis, pneumonia, or TB) and negative for lung cancer * Overall Cough Visual Analog Scale (Cough-VAS) score of 30 or higher * Willing to halt use of zinc supplements or multivitamins containing zinc for the duration of the study * Provide written informed consent
Exclusion criteria
* Marijuana use (smoking or ingestion of marijuana) in the past 6 months * Use of ACE inhibitor currently or within the past 6 weeks * Use of zinc supplements or multivitamins containing zinc currently or within the past 6 weeks * Occupational exposure to dust or chemicals that may cause cough, as determined by study physician * Diagnosis or evidence of chronic obstructive pulmonary disease (COPD) as defined by forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) \< 0.70 and FEV1% predicted \< 80% * History of lung disease, such as: * Bronchiectasis * Interstitial lung disease * Sarcoidosis * Pneumoconiosis * Asbestosis * Chronic mycobacterial infection * Lung cancer * History of pancreatitis * Congestive heart failure * Chronic kidney disease (creatinine clearance \< 30ml/min) * Pregnant or breast-feeding * Other medical conditions that would interfere with participation in study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cough Quality of Life Questionnaire (CQLQ) Score by Treatment Group | Baseline and 6 weeks | Unadjusted comparison of change in CQLQ score between zinc acetate and placebo treatment groups. CQLQ scores range from 28 to 112, with lower scores indicating fewer adverse events. A minimum clinically importance difference of 5 has been proposed for this questionnaire. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Leicester Cough Questionnaire (LCQ) Score by Treatment Group | Baseline and 6 weeks | Unadjusted comparison of change in LCQ scores between zinc acetate and placebo treatment groups. LCQ scores range from 3 to 21, with lower scores indicating a greater impact of cough upon one's life. The minimum clinically importance difference for the LCQ for people with chronic cough is 1.3. |
| Change in Cough Visual Assessment Scale (C-VAS) Scores by Treatment Group | Baseline and 6 weeks | Unadjusted comparison of change in overall severity of cough as measured by C-VAS between zinc acetate and placebo treatment groups. C-VAS scores cover four domains - severity of cough in daytime, nighttime, and overall, and severity of urge to cough. Scores range from 0 to 100 for each domain with overall scores ranging from 0 to 400. Lower scores indicate less severity. Overall severity of cough is the only domain reported here. |
| Change in Global Assessment of Change in Cough (GACC) Score by Treatment Group | Baseline and 6 weeks | Unadjusted comparison of change in GACC scores between zinc acetate and placebo treatment groups. GACC scores measure change in quality of life related to cough in four domains - activity limitation, symptoms, emotions, and overall quality of life. GACC scores range from -3 (very much worse) to 3 (very much better). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zinc Acetate 50 mg Oral Capsule 50 mg zinc acetate oral capsules, over-encapsulated, administered starting at 1 capsule/day and escalated to 3 capsules/day by Day 8 post-randomization (if tolerated)
Zinc Acetate 50 Mg Oral Capsule: • Day 0 (randomization) to day 3 Zinc acetate 50 mg per day (one capsule)
* Day 4 to day 7 If well tolerated: Zinc acetate 100 mg per day (two capsules)
* Day 8 to V5 (6 weeks) If well tolerated: Zinc acetate 150 mg per day (three capsules) | 17 |
| Placebo Oral Capsule Placebo matched to zinc acetate 50 mg oral capsule active arm, administered starting at 1 capsule/day and escalated to 3 capsules/day by Day 8 post-randomization (if tolerated)
Placebo oral capsule: • Day 0 (randomization) to day 3 Placebo (one capsule per day)
* Day 4 to day 7 If well tolerated: placebo (two capsules per day)
* Day 8 to V5 (6 weeks) If well tolerated: placebo (three capsules per day) | 17 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo Oral Capsule | Total | Zinc Acetate 50 mg Oral Capsule |
|---|---|---|---|
| Acid reflux medications Histamine 2 receptor blockers | 0 Participants | 1 Participants | 1 Participants |
| Acid reflux medications None of the above | 10 Participants | 21 Participants | 11 Participants |
| Acid reflux medications Other acid reflux medications | 0 Participants | 0 Participants | 0 Participants |
| Acid reflux medications Proton pump inhibitors | 7 Participants | 12 Participants | 5 Participants |
| Age, Continuous | 62 years | 62 years | 62 years |
| Breathing medications Bronchodilators | 6 Participants | 13 Participants | 7 Participants |
| Breathing medications Inhaled corticosteroids | 1 Participants | 2 Participants | 1 Participants |
| Breathing medications None of the above | 10 Participants | 18 Participants | 8 Participants |
| Breathing medications Other medications for breathing | 0 Participants | 1 Participants | 1 Participants |
| Cough characteristics Cough during the rest of the day or night | 16 Participants | 33 Participants | 17 Participants |
| Cough characteristics Cough upon awakening | 12 Participants | 23 Participants | 11 Participants |
| Cough characteristics Persistent phlegm in chest | 5 Participants | 12 Participants | 7 Participants |
| Cough medications Benzonatate | 0 Participants | 1 Participants | 1 Participants |
| Cough medications Cough suppressants | 3 Participants | 7 Participants | 4 Participants |
| Cough medications None of the above | 11 Participants | 23 Participants | 12 Participants |
| Cough medications Other cough medications | 3 Participants | 3 Participants | 0 Participants |
| E-cigarette usage | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 30 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Frequency of cough Almost every day | 16 Participants | 30 Participants | 14 Participants |
| Frequency of cough Several days a week | 1 Participants | 4 Participants | 3 Participants |
| Has asthma based on spirometry or methacholine challenge | 6 Participants | 14 Participants | 8 Participants |
| Has gastroesophageal reflux disease based on diagnosis or a positive pH probe | 10 Participants | 20 Participants | 10 Participants |
| Has rhinosinusitis, postnasal drip, and/or upper airway disease | 6 Participants | 20 Participants | 14 Participants |
| Health insurance Don't know | 0 Participants | 1 Participants | 1 Participants |
| Health insurance Private insurance | 14 Participants | 25 Participants | 11 Participants |
| Health insurance Public insurance | 3 Participants | 8 Participants | 5 Participants |
| Highest level of education completed Graduate of four-year college | 8 Participants | 11 Participants | 3 Participants |
| Highest level of education completed Graduate of two year college or technical school | 0 Participants | 3 Participants | 3 Participants |
| Highest level of education completed High school graduate or equivalent | 1 Participants | 4 Participants | 3 Participants |
| Highest level of education completed More than eighth grade but not high school grad | 1 Participants | 1 Participants | 0 Participants |
| Highest level of education completed Post-graduate studies | 4 Participants | 10 Participants | 6 Participants |
| Highest level of education completed Some college | 3 Participants | 5 Participants | 2 Participants |
| Household Income, yearly $30,001 - 50,000 | 0 Participants | 0 Participants | 0 Participants |
| Household Income, yearly $50,001 - 75,000 | 2 Participants | 5 Participants | 3 Participants |
| Household Income, yearly Declined to answer | 0 Participants | 4 Participants | 4 Participants |
| Household Income, yearly Less than $30,000 | 3 Participants | 7 Participants | 4 Participants |
| Household Income, yearly Over $75,000 | 12 Participants | 18 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 28 Participants | 14 Participants |
| Region of Enrollment United States | 17 Participants | 34 Participants | 17 Participants |
| Rhinosinusitis medications Nasal steroids | 5 Participants | 13 Participants | 8 Participants |
| Rhinosinusitis medications None of the above | 11 Participants | 15 Participants | 4 Participants |
| Rhinosinusitis medications Oral antihistamines | 0 Participants | 2 Participants | 2 Participants |
| Rhinosinusitis medications Other runny nose or postnasal drip medications | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Female | 16 Participants | 28 Participants | 12 Participants |
| Sex: Female, Male Male | 1 Participants | 6 Participants | 5 Participants |
| Smoking Status Former | 3 Participants | 5 Participants | 2 Participants |
| Smoking Status Never | 14 Participants | 29 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 17 |
| other Total, other adverse events | 1 / 17 | 3 / 17 |
| serious Total, serious adverse events | 2 / 17 | 1 / 17 |
Outcome results
Primary
Change in Cough Quality of Life Questionnaire (CQLQ) Score by Treatment Group
Unadjusted comparison of change in CQLQ score between zinc acetate and placebo treatment groups. CQLQ scores range from 28 to 112, with lower scores indicating fewer adverse events. A minimum clinically importance difference of 5 has been proposed for this questionnaire.
Time frame: Baseline and 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zinc Acetate 50 mg Oral Capsule | Change in Cough Quality of Life Questionnaire (CQLQ) Score by Treatment Group | -5.00 score on a scale |
| Placebo Oral Capsule | Change in Cough Quality of Life Questionnaire (CQLQ) Score by Treatment Group | -6.00 score on a scale |
Secondary
Change in Cough Visual Assessment Scale (C-VAS) Scores by Treatment Group
Unadjusted comparison of change in overall severity of cough as measured by C-VAS between zinc acetate and placebo treatment groups. C-VAS scores cover four domains - severity of cough in daytime, nighttime, and overall, and severity of urge to cough. Scores range from 0 to 100 for each domain with overall scores ranging from 0 to 400. Lower scores indicate less severity. Overall severity of cough is the only domain reported here.
Time frame: Baseline and 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zinc Acetate 50 mg Oral Capsule | Change in Cough Visual Assessment Scale (C-VAS) Scores by Treatment Group | -15.24 score on a scale |
| Placebo Oral Capsule | Change in Cough Visual Assessment Scale (C-VAS) Scores by Treatment Group | -17.82 score on a scale |
Secondary
Change in Global Assessment of Change in Cough (GACC) Score by Treatment Group
Unadjusted comparison of change in GACC scores between zinc acetate and placebo treatment groups. GACC scores measure change in quality of life related to cough in four domains - activity limitation, symptoms, emotions, and overall quality of life. GACC scores range from -3 (very much worse) to 3 (very much better).
Time frame: Baseline and 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zinc Acetate 50 mg Oral Capsule | Change in Global Assessment of Change in Cough (GACC) Score by Treatment Group | 0.50 score on a scale |
| Placebo Oral Capsule | Change in Global Assessment of Change in Cough (GACC) Score by Treatment Group | 0.25 score on a scale |
Secondary
Change in Leicester Cough Questionnaire (LCQ) Score by Treatment Group
Unadjusted comparison of change in LCQ scores between zinc acetate and placebo treatment groups. LCQ scores range from 3 to 21, with lower scores indicating a greater impact of cough upon one's life. The minimum clinically importance difference for the LCQ for people with chronic cough is 1.3.
Time frame: Baseline and 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zinc Acetate 50 mg Oral Capsule | Change in Leicester Cough Questionnaire (LCQ) Score by Treatment Group | 2.55 score on a scale |
| Placebo Oral Capsule | Change in Leicester Cough Questionnaire (LCQ) Score by Treatment Group | 2.59 score on a scale |