Clinical trial NCT03135522
Conditions: Cough
Keywords: Chronic cough Refractory cough Chronic refractory cough Zinc Zinc acetate
Sponsor: Johns Hopkins University
Start date: 2018-02-14; Completion date: 2019-12-11
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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) arm 2: 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)
Interventions: intervention 1: Zinc Acetate 50 Mg Oral Capsule intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: * 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) intervention 2: * 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)

Protocol documents:
Prot_SAP_000.pdf: 
22 Apr 2019 
 
American Lung Association 
Airways Clinical Research Centers 
 
 
 
 
Pilot of Zinc Acetate to Improve 
Chronic Cough 
(ZICO) 
 
 
 
 
Protocol 
Version 1.5 
NCT number NCT03135522 
 
 


ZICO Protocol Version 1.5 
 
Document distribution │ii 
 
 
 
 
Document history 
 
 
Version 0, draft (September 2016) 
 
Version 1.0 (17 March 2017)  
 
Version 1.1 (26 May 2017) 
 
Version 1.2 (11 Oct 2017) 
 
Version 1.3 (21 Feb 2018) 
 
Version 1.4 (04 Jan 2019) 
 
Version 1.5 (22 Apr 2019) 
 
 
 


ZICO Protocol Version 1.5 
 
Abstract │iii 
 
 
 
Abstract 
 
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, ACE inhibitors, 
or parenchymal lung disease.  It is one of the most common conditions leading to specialty 
referral, accounting for about 20% of new pulmonary consultations.  Chronic refractory cough 
can lead 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. The Pilot of Zinc Acetate to Improve Chronic Cough 
(ZICO) is a pilot study for a larger randomized clinical trial to establish the safety and tolerability 
of zinc acetate to treat cough in this population. The pilot trial will enroll 36 participants, 18 in 
each group, at 3 clinical centers. 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, 
pancreatitis, 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, after a two week washout, will help establish the 
duration of treatment effect. The primary objective of the trial is to evaluate the feasibility of a full 
scale trial including estimating the statistical properties of the Cough Specific Quality of Life 
Questionnaire (CQLQ) and other measures of cough severity and overall health.  


 
ZICO Protocol Version 1.5  
Introduction │ 4 
 
 
Confidential, not for attribution or citation. 
 
 
Contents 
 
Document history .................................................................................................................. ii 
Abstract ................................................................................................................................ iii 
1. Introduction .......................................................................................................................... 5 
1.1. Title  ........................................................................................................................... 5 
1.2. Sponsor ....................................................................................................................... 5 
1.3. Investigators and study centers .................................................................................. 5 
1.4. Background and significance ...................................................................................... 6 
2. Study design ...................................................................................................................... 10 
2.1. Trial schema ............................................................................................................. 10 
2.2. Eligibility criteria ........................................................................................................ 10 
2.3. Recruitment ............................................................................................................... 13 
2.4. Summary of visits ...................................................................................................... 13 
2.5. Study data collection schedule ................................................................................. 15 
2.6. Outcome measures ................................................................................................... 16 
2.6.1. Patient Reported Outcomes ............................................................................. 16 
2.6.2. Pulmonary function .......................................................................................... 16 
2.6.3. Other measures ............................................................................................... 17 
2.7. Specimen collection, storage and shipping ............................................................... 17 
3. Study treatment .................................................................................................................. 17 
3.1. Description of study treatment .................................................................................. 17 
3.2. Randomization .......................................................................................................... 18 
3.3. Side effects ............................................................................................................... 18 
3.4. Unmasking ................................................................................................................ 19 
4. Analysis plan ...................................................................................................................... 19 
4.1. Sample size .............................................................................................................. 19 
5. Protection of human subjects ............................................................................................. 21 
5.1. Risks to the participants ............................................................................................ 21 
5.2. Data Confidentiality ................................................................................................... 22 
5.3. Recruitment and consent procedures ....................................................................... 22 
6. Data and safety monitoring plan ........................................................................................ 23 
7. Literature cited ................................................................................................................... 24 
Appendix .................................................................................................................................. 29 
  


 
ZICO Protocol Version 1.5  
Introduction │ 5 
 
 
Confidential, not for attribution or citation. 
 
 
1. Introduction 
1.1. Title  
Pilot of Zinc Acetate to Improve Chronic Cough 
 
1.2. Sponsor 
NHLBI 
 
1.3. Investigators and study centers 
Network Chair 
Bailey, William  
 
 
University of Alabama, Birmingham  
 
Main Study Principal Investigators 
Wise, Robert  
 
 
Johns Hopkins University 
Canning, Brendan 
 
 
Johns Hopkins University 
 
Participating Centers 
Que Loretta 
 
 
 
Duke University Medical Center 
Katial, Rohit   
 
 
National Jewish Health 
Rogers, Linda  
 
 
Mt. Sinai Medical Center  
 
Data Coordinating Center 
Holbrook, Janet 
 
 
Johns Hopkins University 
Wise, Robert  
 
 


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ZICO Protocol Version 1.5  
Introduction │ 7 
 
 
Confidential, not for attribution or citation. 
 
 
treat, the impact of the condition is often underestimated and patients are told that they need to 
accept their condition. 
 
Despite advances in our understanding of the neurobiology of cough, there has been a paucity of 
rigorous clinical research on this condition.  For example, ClinicalTrials.gov lists only 3 clinical 
trials for chronic refractory cough, none sponsored by NIH.  This lack of evidence is particularly 
notable in that the evidence-based guidelines for chronic cough treatment must rely more on 
expert opinion than rigorous evidence, leading to an “urgent” call for multicenter trials of potential 
cough therapies.1, 14  
 
Usual OTC treatments with expectorants and antihistamines are not beneficial vs. placebo, 
although widely used at a cost of $5 Billion / year.15 Treatments such as morphine, amitriptyline, 
gabapentin, and P2X3 receptor blockers have been effective in well-designed single-site trials, but 
the treatment effects are moderate and adverse effects are common.16, 17, 18, 19, 20 In a 2013 meta-
analysis, Yancey et al., found 49 comparative studies of antitussive treatments, 13 of which were 
considered good quality.  They concluded that the only proven effective treatments were opioid 
narcotics and dextromethorphan and raised concerns about adverse effects and abuse potential, 
making them unsuited for chronic use.15  
 
The lack of evidence regarding effective treatments for chronic cough is supported by a survey of 
opinion leaders in which 82% agreed with the statement:  “There are no currently effective 
treatments for cough hypersensitivity syndrome.” 21  Despite its high morbidity and prevalence, no 
approved treatments are available for chronic refractory cough.  Indeed, the FDA has not 
approved a new treatment for cough since 1958 (benzonatate, Tesalon®).   
 
This trial takes a novel approach to chronic refractory cough that specifically targets the recently 
discovered major mechano-receptor and chemo-receptor for cough supported by strong pre-
clinical and highly supportive human data.  
 
Role of Na-K ATP-ase 
Considerable progress has been made by the Canning laboratory in defining the vagal afferent 
pathways regulating cough and this has facilitated the identification and evaluation of novel 
therapeutic strategies for cough suppression.9, 22, 23, 24 At least 2 vagal afferent nerve subtypes 
essential to cough regulation have been identified (figure 2).25, 26 Notably, the cough receptors 
express unique isozymes of Na+-K+ ATPase.27 These sodium pump isozymes play an essential 
role in regulating cough receptor excitability.  Cardiac glycosides (digoxin and ouabain) and other 
drugs known to interact with neuronal sodium pumps dose-dependently suppress cough in guinea 
pigs and in patients.26, 27, 28, 29  This work strongly suggests that neuronal sodium pump inhibition 
may be an effective antitussive strategy, prompting clinical assessments by our consultants 
Jaclyn Smith and colleagues to evaluate the actions of digoxin in chronic cough patients and a 
study by Lorcan McGarvey and colleagues to measure cough reflex sensitivity in a group of 
patients with loss of function mutations in their neuronal sodium pumps.28   
 
We found no evidence for neuronal isoform expression in structural cells of the human airways 
based on exhaustive microarray analysis of >40K genetic loci in human bronchi (n=5 lung 
donors), suggesting that neuronal selective inhibitors of this isoenzyme will have limited off target 
effects in the lung.  Unfortunately, both digoxin and ouabain are relatively nonselective inhibitors 
of sodium pump function, and have narrow therapeutic windows, thus limiting their utility as 
antitussives.  Thus, other strategies for inhibition of this isoenzyme are necessary.  Zinc is a 
strong candidate for this role. 
 


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ZICO Protocol Version 1.5  
Introduction │ 9 
 
 
Confidential, not for attribution or citation. 
 
 
 
 
In humans, zinc lozenges have been effective in reducing the duration of viral upper respiratory 
infections (URI).  The theoretical, though unproven, mechanism has been to block adhesion of 
virus to epithelial cells via ICAM1.37  Three controlled clinical trials of zinc acetate or zinc 
gluconate have demonstrated symptom reduction URI, particularly the duration of acute cough.38, 
39, 40 A meta-analysis showed a benefit with zinc therapy for URI. The summary statistics 
indicated that acute cough duration was reduced with zinc lozenges at a dose greater than 75 
mg/day.41, 42 Thus, there is sufficient evidence to support the notion that adequate doses of zinc 
can benefit humans who suffer from chronic cough. 
 
Zinc is a widely available molecule with a long safety history as a nutritional supplement, 
treatment for colds, and for therapy of Wilson’s disease that will be immediately available for 
patients should it be shown to be effective.  Zinc may be administered long-term if necessary, 
unlike narcotic antitussives. We are proposing to use the FDA-approved formulation of zinc 
acetate (Galzin®) in the approved adult dose of 150mg/day for long-term use in Wilson’s disease.   
 
Previous studies of antitussives that have shown an effect have had treatment periods of 2 
weeks to 12 weeks, with a treatment effect apparent at 2-4 weeks. The treatment duration of 6 
weeks was selected as a reasonable period to determine whether there is a treatment effect and 
to assess for tolerability, adherence, steady-state serum zinc levels, potential adverse effects, 
and persistence of treatment effects.  Longer treatment periods would not substantially augment 
the goals of this pilot/feasibility study.   
 
 
 
 


 
ZICO Protocol Version 1.5  
Analysis plan │ 10 
 
 
Confidential, not for attribution or citation. 
 
 
2. Study design 
 
Randomized, two parallel arm, placebo-controlled clinical trial (n = 36, 18/arm). 
The study aims are:  
• 
To establish if treatment with zinc acetate is well tolerated 
• 
To determine if the trial logistics are feasible 
• 
To assess statistical properties of patient reported measures of cough  
 
2.1. Trial schema 
 
 
2.2. Eligibility criteria 
 
Participants must affirm that they have multiple daily episodes of cough that have persisted for 
more than three months. Individuals with asthma/eosinophilic airway disease or 
gastroesophageal reflux may be eligible if treatment with inhaled corticosteroids and/or 
bronchodilators, or H2 blockers and/or proton pump inhibitors, respectively, did not resolve 
cough. In addition, individuals with upper airway cough and/or rhinosinusitis whose cough did not 
respond to nasal steroids, antihistamines and/or expectorants/decongestants may be eligible to 
participate.  
Individuals on treatments for cough (e.g. inhaled corticosteroids, H2 blockers, nasal steroids) 
should remain on their background treatment during the trial.  
Individuals cannot be current smokers (not smoked for at least six months), cannot be using an 
ACE inhibitor, and cannot have any parenchymal lung disease as all of these can cause cough.  
 
 
 


 
ZICO Protocol Version 1.5  
Analysis plan │ 11 
 
 
Confidential, not for attribution or citation. 
 
 
 
Inclusion criteria:  
• 
Men or women age 18 or older 
• 
Chronic cough for more than 3 months 
• 
No upper or lower respiratory infection within 4 weeks 
• 
Either 
 
o 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 pH probe  
 
Rhinosinusitis/upper airway cough 
 
Or 
 
o Cough persists despite treatment for the following potential causes: 
 
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  
o no smoking of any substance (e.g., tobacco, e-cigarette, marijuana) in the past 6 
months, and 
o less than 20 pack-year smoking history 
• 
Chest x-ray or CT scan in the past 24 months and after the onset of cough; negative for 
parenchymal lung diseases (such as interstitial lung disease, idiopathic pulmonary fibrosis, 
pneumonia, or TB) and negative for lung cancer 
• 
Overall Cough VAS score of 30 or higher at V1 
• 
Willing to halt use of zinc supplements or multivitamins containing zinc for the duration of 
the study 
• 
Provide written 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 COPD (FEV1/FVC < 0.70 and FEV1% predicted < 80%) 
• 
History of: 
o Bronchiectasis 
o Interstitial lung disease 
o Sarcoidosis 
o Pneumoconiosis 
o Asbestosis 


 
ZICO Protocol Version 1.5  
Analysis plan │ 12 
 
 
Confidential, not for attribution or citation. 
 
 
o Chronic mycobacterial infection 
o Lung cancer 
o 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 
 
 


 
ZICO Protocol Version 1.5  
Analysis plan │ 13 
 
 
Confidential, not for attribution or citation. 
 
 
2.3. Recruitment 
Patients with chronic refractory cough will be identified according to methods that have been 
successful at each participating ALA ACRC center. Methods include screening patients regularly 
seen at the participating clinical center, review of existing patient registries, response to 
advertisements approved by the local Institutional Review Board (IRB), or referral by other health 
care providers. Patients will be asked information about their cough, demographic characteristics, 
and their interest in the study. Pre-screening interviews can be conducted in person or by 
telephone. 
 
2.4. Summary of visits 
Visit 1 Screening Visit (week -1, 2 hours) 
• 
Consent 
• 
Eligibility assessment 
o Chest x-ray, if participant does not have chest x-ray or CT from within the past 2 
years 
• 
Cough Visual Analog Scales (C-VAS) 
• 
Baseline medical history 
• 
Spirometry (pre- and post-bronchodilator) 
• 
Pregnancy test for women of child-bearing potential 
• 
Blood draw for creatinine level, serum zinc and copper levels, and biospecimens 
• 
Explain and distribute cough diary 
 
Visit 2 Baseline / Randomization (week 0, 2 hours) 
• 
Interval medical history 
• 
Collect and review cough diary 
• 
Cough questionnaire completion 
o Cough Visual Analog Scales (C-VAS)  
o Cough Quality of Life Questionnaire (CQLQ) 
o Leicester Cough Questionnaire (LCQ)  
o Global Assessment of Change in Cough (GACC) 
o Cough-related Impact on Quality of Life Scale (Cough IQOLS)  
o EQ-5D 
• 
Physical examination 
• 
Eligibility review and randomization 
• 
Dispense study treatment 
 
Visit 3 Phone follow-up visit (week 1, 10 minutes) 
• 
Review study procedures 
• 
Assess for adverse events 
• 
Review and troubleshoot adherence 
 
Visit 4 On-treatment follow-up visit (week 3, 1.5 hours) 
• 
Interval medical history 
• 
Assess for adverse events 
• 
Collect and review cough diary 
• 
Cough questionnaire completion 


 
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o Cough Visual Analog Scales (C-VAS)  
o Cough Quality of Life Questionnaire (CQLQ) 
o Leicester Cough Questionnaire (LCQ)  
o Global Assessment of Change in Cough (GACC) 
o Cough-related Impact on Quality of Life Scale (Cough IQOLS)  
o EQ-5D 
 
Visit 5 On-treatment final follow-up visit (week 6, 2 hours) 
• 
Interval medical history 
• 
Assess for adverse events 
• 
Collect and review cough diary 
• 
Spirometry (pre- and post-bronchodilator) 
• 
Cough questionnaire completion 
o Cough Visual Analog Scales (C-VAS)  
o Cough Quality of Life Questionnaire (CQLQ) 
o Leicester Cough Questionnaire (LCQ)  
o Global Assessment of Change in Cough (GACC) 
o Cough-related Impact on Quality of Life Scale (Cough IQOLS)  
o EQ-5D 
• 
Drug return 
• 
Blood draw for serum zinc and copper levels  
 
Visit 6 Off-treatment washout visit (week 8, 2 hours) 
• 
Interval medical history 
• 
Assess for adverse events 
• 
Collect and review cough diary 
• 
Spirometry (pre- and post-bronchodilator) 
• 
Cough questionnaire completion 
o Cough Visual Analog Scales (C-VAS)  
o Cough Quality of Life Questionnaire (CQLQ) 
o Leicester Cough Questionnaire (LCQ)  
o Global Assessment of Change in Cough (GACC) 
o Cough-related Impact on Quality of Life Scale (Cough IQOLS)  
o EQ-5D 
• 
Exit interview 
• 
Provide information on treatment assignment in sealed envelope 
 
 


 
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2.5. Study data collection schedule 
Visit 
V1 
V2 
V3 
(phone) 
V4 
V5 
V6 
Target (weeks) 
-1 
0 
1 
3 
6 
8 
Consent, eligibility evaluation 
● 
Baseline medical history 
● 
Interval health history/ adverse 
events 
● 
● 
● 
● 
● 
Return cough diary 
● 
● 
● 
● 
Spirometry (pre-post BD) 
● 
● 
● 
C-VAS 
● 
● 
● 
● 
● 
CQLQ, LCQ, GACC, Cough IQOLS, 
EQ-5D 
 
● 
● 
● 
● 
Drug return 
● 
Exit interview/provided treatment 
assignment envelope 
 
● 
Physical examination 
● 
Pregnancy test 
● 
Randomization / drug dispensing 
● 
Blood for creatinine level 
● 
 
Blood for zinc and copper levels 
● 
 
● 
Blood for optional biospecimens 
● 
 
 
Chest x-ray* 
● 
 
 
Key:  (V#) Visit Number, (BD) Bronchodilator, (C-VAS) Cough visual analog scales, (CQLQ) 
Cough specific Quality of Life, (LCQ) Leicester cough questionnaire, (GACC) global assessment 
of change in cough, (EQ-5D) EuroQOL  quality of life instrument, (Cough IQOLS) Cough-related 
Impact on Quality of Life Scale 
*If needed to determine eligibility  
 
 


 
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2.6. Outcome measures 
 
2.6.1. 
Patient Reported Outcomes 
 
Cough specific Quality of Life (CQLQ):  This is a 28 item self-completed questionnaire with six 
subscales with excellent psychometric properties (Cronbach alpha = 0.92, ICC = 0.89) that is 
responsive to treatment.13, 43 The estimates of the standard deviation are consistent (12-15) across 
studies.  A minimum clinically important difference of 5 has been proposed, which is based upon a 
small single center study of idiopathic pulmonary fibrosis and has not been validated in a larger, 
multicenter cohort.44  
 
Leicester cough questionnaire (LCQ):  The LCQ is a patient reported cough outcome measure 
which has been validated and will be used to assess convergent validity for the CQLQ.  The LCQ 
has similar properties as the CQLQ with 19 items and 3 domains, with a total possible score 
ranging from 3 to 21.45, 46 The minimal important difference of the LCQ for patients with chronic 
cough is 1.3. 47 
 
Cough visual analog scales, overall, daytime, nighttime, urge to cough (C-VAS): The C-VAS is a 
patient reported cough outcome measure that provides a measure of the severity, intensity and 
noxious qualities of cough that are not as well represented on the health impact scales. Each 
element of the VAS has a possible score of 0 to 100.16  
 
EuroQol EQ-5D- 5L: The EQ-5D-5L is an overall measure of health related quality of life that that 
provides a measure of utility for calculation of Quality Adjusted Life Years (QALYs). The EQ-5D 
measures 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression graded from level 1 (i.e., no problems) to level 5 (i.e., extreme problems). Use 
of the 5-levels (EQ-5D-5L) rather than the standard 3 level EQ-5D (EQ-5D-3L) decreases the 
ceiling effect, improves discriminative ability, and potentially has more power to detect differences 
between groups.48 
 
Cough-related Impact on Quality of Life Scale (Cough IQOLS):  This is a health related quality of 
life measure that includes the impact of cough adapted from Sandra Wilson’s Asthma Impact on 
Quality of Life Survey (AQOLIS). 
 
Global assessment of change in cough (GACC): Global rating of change scales are widely used to 
measure change in self-assessed patient condition and determine the MID for other health related 
quality of life questionnaires.49, 50 The Global Assessment of Change in Cough (GACC) asks 
patients to assess changes in their quality of life related to their cough on a 7 point scale on four 
domains (activity limitation, symptoms, emotions, and overall quality of life). 
 
Cough Diary: The study will use the Cough Severity Diary to track cough symptoms. The diary is a 
simple, seven-item daily diary designed to assess patient reported outcomes regarding frequency 
and severity of cough.51) 
 
2.6.2. 
Pulmonary function 
Spirometry (pre- and post-bronchodilator): Spirometry is a common office test of lung function; 
both pre and post-bronchodilator tests will be performed. Post-bronchodilator spirometry will be 
performed after 2 inhalations of albuterol.  This will be done to exclude patients with significant 


 
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airflow obstruction or restriction that may indicate underlying parenchymal lung disease or COPD 
and to evaluate the association of lung function with cough. 
 
2.6.3. 
Other measures 
Demographic data collected includes age, gender, race, marital status and educational level. 
 
Clinical data includes height, weight, body mass index, smoking status and history of smoking in 
pack years.  Adverse events, changes in symptoms, medication use and utilization of medical care 
with also be assessed. 
 
2.7. Specimen collection, storage and shipping 
 
Serum will be collected for measurement of serum creatinine and subsequent calculation of 
creatinine clearance to determine if the participant meets the eligibility criteria. 
 
Biospecimens collected for measurement of serum zinc and copper levels will be processed at the 
clinical sites and sent to Quest Diagnostic laboratories, a CLIA approved central laboratory, for 
zinc and copper assessment. Zinc assessment will be measured to assess whether serum zinc 
levels are associated with cough and response to treatment, and whether supplementation 
increases serum zinc levels. Copper assessment will be performed to check for signs of potential 
copper deficiency. Participants should fast for at least 4 hours prior to collection of blood for zinc 
and copper analysis. Specimens for serum zinc and copper analysis must be processed within 2 
hours to ensure accurate assessment of zinc and copper levels. 
 
Additional blood will be collected and stored for future use. The ALA-ACRC maintains a 
biorepository of specimens from our studies to conduct ancillary studies of the relationship of 
biomarkers to airway and related diseases.  Permission to draw and store biospecimens for future 
ancillary studies and/or DNA testing is optional and is not a requirement for participation in this 
study. The results of future genetic testing will not be provided to study participants. Blood 
specimens for future use are stored at -70° or -80° C at the local site and shipped periodically in 
batches on dry ice for storage at the ACRC biospecimen repository at Nemours Children’s Center 
(NCC). The DCC supplies blood drawing tubes, bar-code labels, shipping labels, containers, and 
transmittal slips.  All sites are required to be certified in biosafety for handling biological 
specimens in accordance with local hospital / university policy and applicable law.  
 
 
 
3. Study treatment 
3.1. Description of study treatment 
Participants will be randomly assigned to receive a daily dose of 150 mg of zinc acetate or 
matched placebo taken in three doses of 50 mg each or placebo.  For this trial 50 mg zinc acetate 
capsules will be over-encapsulated and a matched placebo will be created. Zinc will be taken with 
the morning or evening meal. Participants will be instructed to titrate up the dose of study drug 
starting with one capsule (50 mg) in the morning on day 1, increasing to two capsules (100 mg) on 
day 4, and reaching three capsules (150 mg) on day 8.  Participants will be instructed to take the 
medication with food.   If participants are not able to tolerate the full dose, they may split the dose 


 
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into two or three doses per day taken at meal-time (e.g. two capsules in AM and one capsule in 
PM, or one capsule with breakfast, lunch, and dinner).  If a participant is not able to tolerate the full 
dose, then the dose should be titrated down to the highest tolerable dose, i.e., one or two 
capsules as tolerated. 
The study will use the FDA-approved formulation of oral zinc, Galzin®. FDA has approved 
Galzin® 150mg/day for long-term use in adults with Wilson’s disease. Zinc supplementation for 
food has been considered Generally Recognized as Safe (GRAS) by the FDA. NIH recommends 
up to 40 mg/day as a dietary supplement in adults and multivitamins used long-term for prevention 
of macular degeneration contain 80mg of elemental zinc.  OTC lozenges (Cold-eez ®) contain 
13.3 mg of zinc as zinc gluconate and are taken in doses of up to 80 mg/day for relief of URI 
symptoms.  Zinc gluconate is available as unregulated nutritional supplements in 100mg capsules.  
 
3.2. Randomization  
Participants will be randomized to zinc acetate or placebo at V2. Treatment assignment will be 
randomly allocated in a 1:1 ratio with stratification by clinic with permuted block design will be 
used. Assignments will released from the DCC after evidence that an eligible participant has 
signed consent and completed all baseline evaluations. 
Zinc acetate or placebo will be dispensed to the participant at the V2 visit. At randomization the 
participant will be assigned a unique bottle ID code and clinics will dispense that bottle to the 
participant. Each participant will receive a single bottle of 168 capsules for the 6 weeks of 
treatment. At the second to last study (V5) visit, the bottle with the unused capsules will be returned. 
3.3. Side effects 
The most common adverse effects of zinc supplementation are dyspepsia, nausea, and a metallic 
taste. These side effects can be mitigated by downward adjustment of the dose, taking the drug 
with meals, and/or spreading the dose out over the day (i.e. taking 1 capsule in the morning and 2 
capsules at night, or taking 1 capsule each at breakfast, lunch, and dinner).  
 
Elevations of liver and pancreatic enzymes have been reported in patients with Wilson’s disease, 
treated with zinc acetate, but this has not been reported in other populations and the relationship 
with zinc supplementation is unclear. Participants with a history of pancreatitis will be excluded 
from the study. Study participants experiencing abdominal pain should be evaluated for possible 
pancreatitis. With zinc gluconate nasal spray some patients have noted loss of smell, but this has 
not been reported with oral zinc. 
 
Zinc is listed as a class A drug for pregnancy indicating that it does not have substantial 
teratogenic potential. We are excluding pregnant and lactating women from this trial because 
pregnancy may have either beneficial or deleterious effects on chronic cough and zinc is 
transmitted in breast milk that may alter infant feeding behavior. Women of child bearing potential 
must be willing to use appropriate methods of pregnancy prevention during the duration of the 
study. Women of childbearing potential includes all female participants except those who are 
surgically sterile (both ovaries and/or uterus removed), postmenopausal (no menstrual period for 
longer than 12 consecutive months), or incapable of pregnancy.  
 
The FDA-approved prescribing information for zinc acetate states the following regarding over-
dosage: 
 
“One fatality associated with over-dosage of zinc sulfate has 


 
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been reported. The death of this adult woman followed the 
accidental ingestion of approximately 28 g of zinc sulfate. 
[Equivalent to 560 capsules of zinc acetate or 3 bottles of 
dispensed study drug].  Death occurred on the fifth day after 
ingestion and was attributed to renal failure. Hemorrhagic 
pancreatitis and hyperglycemic coma resulted from the overdose. 
The amount ingested was 500 mg/Kg of zinc sulfate, a         
value that is in the same order of magnitude as that found to be 
lethal in animals.” 
 
Drug interaction information contained in UpToDate indicates that absorption of the following 
medications might be impaired by zinc: cephalosporin antibiotics, quinolone antibiotics, 
tetracycline antibiotics, bisphosphonates, dolutegravir, deferiprone, and eltrombopag. If a 
participant is prescribed one of these medications during the study, the participant will be 
instructed to take zinc/placebo at least 1 hour prior to or 1 hour after taking that medication.   
 
In theory, prolonged consumption of zinc could lead to copper deficiency which is manifest as a 
reversible anemia and neutropenia as well as neuropathy.  Because copper is ubiquitous in the 
diet, and deficiency is rare in the absence of malabsorption syndromes or gastric bypass 
surgery, it is unlikely that the duration of treatment in this trial will lead to copper deficiency. 
However, in patients using long-term high-dose zinc, monitoring for hematologic abnormalities 
and peripheral neuropathy would be indicated.52 We will measure serum copper levels prior to 
starting study drug and after completing study drug treatment to assess for potential signs of 
copper deficiency, as well as to assess the likelihood of side effects in more long-term use of 
zinc.  
 
3.4. Unmasking 
Unmasking of treatment assignment is rarely necessary.  If adverse events occur that may be 
related to the study treatment, then the study treatment is stopped and the patient continues 
follow-up.  Envelopes with treatment assignment are provided to the clinic in the case a treating 
physician feels it is important to know the treatment assignment.  In addition, the DCC provides a 
phone number where authorized personnel can receive unmasking information.   All participants 
are provided with a wallet card that provides information that they are participating in a clinical trial 
and gives the contact numbers of personnel at the clinic. 
 
4.  Analysis plan  
4.1. Sample size 
 
The primary goals of the pilot study are to establish the feasibility of performing a randomized trial 
and to obtain preliminary estimates of the relative efficacy of zinc versus placebo and the 
statistical properties of the patient reported outcome measures. A sample size of 36 (18/arm) has 
80% power to detect a treatment effect of 0.56 standard deviations (SD) or greater, where SD is 
for the difference from baseline to 6 weeks in CQLQ score, based upon a two-sample t-test and a 
one-sided type 1 error rate of 0.20.  We are conducting a contemporaneous cohort study to 
establish the minimal important difference (MID) and SD for change in CQLQ scores in 100 
participants with chronic cough.  This analysis will not necessarily provide information whether the 
changes are clinically important, but will provide a framework for establishing changes that are 
outside of the range of variability of symptoms and would be noticeable by the patient. Thus, in 


 
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this context, the MID would be analogous to the “Just Noticeable Difference” (JND) used in 
psychophysics of perception.   
 
 
Primary Analysis 
 
The primary analysis will focus on the tolerability of zinc acetate versus placebo. These analysis 
will rely on qualitative assessments of adverse drug effects as well as unadjusted comparisons of 
the frequency of events and adherence by treatment assignment. 
 
The statistical analysis for efficacy will be an unadjusted comparison of 6-week change in CQLQ 
between treatment groups.  A linear mixed effects model will be used to model change in CQLQ 
over time. A saturated means model with indicators for each time point, treatment and treatment 
by time interaction, will be specified and a random effect for individual will be used to account for 
the repeated measurements over time. The 6-week treatment by time interaction term 
represents the difference in change in CQLQ between the treatment groups, i.e. the primary 
outcome. If the data are non-normal, then transformations and non-parametric alternatives (e.g. 
Wilcoxon Rank-Sum test comparing the raw differences from baseline to 6-weeks between 
treatment groups) will be explored. Using the methods described by Cocks and Torgerson, we 
will test whether or not the upper boundary of the 1-sided 80% confidence interval of the 
treatment effect excludes the MID.53 For example, a total sample size of 36 would be sufficient to 
exclude a MID of 5 or higher for a 1-sided 80% confidence interval if the standard deviation for 
the change in CQLQ was 15. Sensitivity analyses using alternate mean and covariance 
structures will also be performed.  Analyses will be done based upon principles of intention to 
treat, i.e. all data from all randomized participants will be included in the analysis. 
 
Secondary outcomes include, but are not limited to, LCQ, diary data, C-VAS, GACC, quality of 
life measures, and safety data.  Continuous variables will be analyzed similarly to the primary 
outcome.  Event outcomes will be analyzed in two ways: negative binomial regression for rates 
and Kaplan-Meier curves and Cox proportional hazards models for time to first event. 
 
Assessment of futility for a definitive trial will not rest with any single measure but will depend on 
a synthesis of the overall study feasibility and treatment tolerability as well as magnitude and 
consistency of the observed treatment effect.  However, in line with formal futility designs in 
neuroscience and oncology, we will not likely proceed with a definitive trial if the upper boundary 
of the one-sided 80% confidence interval of the treatment effect excludes the minimally important 
difference for the CQLQ, which we will validate in the concurrent cohort study. 
 
Descriptive statistics will be computed for baseline clinical and demographic characteristics by 
treatment group. Results will be displayed as means with standard deviations, medians with 1st 
and 3rd quartiles, and proportions as appropriate. 


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5. Protection of human subjects 
 
5.1.  Risks to the participants 
 
Study procedures present minor risks: 
 
Spirometry: Participants will undergo spirometry at V1, V5 and V6. This procedure involves 
forceful respiratory maneuvers. Occasionally people develop light-headedness during the 
procedure or soreness of the chest for a few days afterward. In the Lung Health Study, in 
approximately 25,000 tests, one individual sustained a serious cervical injury from syncope 
during spirometry while standing. The risk of syncope in this study is minimized by having 
participants sit during the maneuvers. 
Questionnaires and assessments: Participants will be asked to provide information about their 
psychological, physical, and medical functioning on questionnaires. While we will make every 
effort to protect privacy and keep data confidential, there is a risk that information can be 
disseminated in ways that can risk the privacy of a person. To minimize risk, we will use only 
study codes to identify data and study records, store study data and records in a secure place, 
and personal information such as names, addresses, and telephone numbers will not be in the 
central database. 
 
Chest x-ray: Participants without a chest x-ray or CT scan from within the past 2 years will have 
a chest x-ray taken to determine eligibility. Chest x-ray is a standard medical procedure for 
imaging of the lung. Risks to the volunteers are minimal. Participants undergoing chest x-ray for 
this study will be exposed to a small amount of radiation as part of the study. The effective dose 
equivalent for a chest x-ray is 7.2 millirem (mrem), or 0.072 millsieverts (mSv). This compares to 
the average background radiation dose a U.S. resident receives yearly from natural sources of 
310 mrem, or 3.1 mSv. 
We are requiring that all x-rays taken as part of the study be interpreted by a certified radiologist 
on site. The scans will be inspected for image quality and inclusion of all parts of the chest. It 
may occur that other findings are found on these images that may represent clinically significant 
findings (e.g. lung nodules). If any incidental findings are discovered during the study, the 
clinical site study physician will be notified, the information will be given to the participant and, 
with their permission, the information will also be transmitted to the participant’s usual caregiver 
for appropriate medical care or follow-up. 
 
Specimens will be obtained for serum creatinine, serum zinc and copper levels, and future 
research.  Risks of blood draw are minimized by limiting the amount drawn to no more than 
about 70 mL over the course of the study. Patients have venipuncture in the seated or lying 
position to minimize syncopal events and pressure is applied after the procedure.  
The risks of genome and other ancillary analyses of specimens are primarily related to the 
possibility that an outside agency not approved by the participant might obtain and use the 
information in such a way that it would harm the participant. To minimize this risk, specimens 
will be identified only by a numeric identifier. The results will not be a part of a participant’s 
general medical record. Genetic information or other information obtained from participants will 
not be supplied to any outside agency except as authorized by the consent statement. Genetic 
and biomarker data will not be linked to the participants’ personal identifiers and will be shared 


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with other investigators in the network through study ID codes. Results may be presented in 
publications and meetings but individual names will not be identified. 
 
5.2. Data Confidentiality 
Data which includes identifiable protected health information (PHI) are collected at each of the 
clinical sites.  PHI is stored at each of the clinical sites in accordance with HIPAA regulations and 
local university and hospital policies. This includes the storage of PHI in locked cabinets or rooms, 
limited access to secure data areas by certified participating study personnel, password 
protection for electronic medical records, and explanation of HIPAA regulations on the study 
consent form. Data such as lung function or laboratory tests that are collected as part of this study 
may be transmitted to the participants’ treating physicians with the consent of the participant.  
Participants are informed in the consent that PHI may also be disclosed for auditing purposes by 
the FDA or other regulatory bodies and is subject to subpoena. 
Date of birth and gender of participants must be shared with the central laboratory to determine 
zinc and copper reference values. The resulting data is shared only between the originating site, 
central laboratory, and DCC through a HIPAA-compliant results application run by the central 
laboratory. Personal identifiers are not otherwise transmitted to the DCC or central laboratory. 
All data are identified by study ID, and other identifying information is not entered into the 
central study database.  Source records that are transmitted to the DCC for data quality audits 
have identifying information redacted, however on-site inspections may involve access by DCC 
personnel to medical records.  
 
5.3. Recruitment and consent procedures 
Participants will be recruited by each participating clinic using their own IRB approved methods. 
These methods may include local American Lung Association campaigns, solicitation in 
physician offices, clinics, workplaces, and public media advertisements. All public 
advertisements are subject to approval by the local Institutional Review Board (IRB) and must 
indicate that it is a research study. The DCC will help coordinate recruitment among clinics and 
promote sharing of effective recruitment strategies within the network. 
 
The consent form will be subject to approval by the clinical center IRB. A copy of the consent 
form will be given to each participant, and the signed original will be kept in the participant’s 
research chart.  
 
 


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6. Data and safety monitoring plan 
A Data and Safety Monitoring Board (DSMB) is appointed and chartered by the American Lung 
Association to monitor ALA-ACRC trials. The DSMB will serves in a consultative capacity to 
ALA and will make recommendations regarding the initiation and continuation of ACRC studies. 
The NIH program officer is invited to attend review meetings, and recommendations and 
minutes will be forwarded to the NIH program officer and to all IRBs involved in the oversight of 
the study. The primary responsibility of the DSMB is to protect participants but they may also 
make recommendations regarding the scientific conduct of the study.14 The DSMB will meet to 
review the protocol and consent prior to study initiation and then periodically throughout the 
study to review the progress of the trial.  Typically the meetings take place twice a year. The 
investigators will present the DSMB with study performance data including screening and 
enrollment data, and measures of data quality and timeliness.  Safety data will include reporting 
of adverse events, protocol deviations, and unexpected or unusual events that may affect the 
safety or scientific validity of the study.  Because of the nature of this study, we are not 
proposing interim efficacy analyses or stopping guidelines. At the end of each DSMB meeting, 
the board will vote whether to continue the study as planned or whether to recommend changes 
to the study. 
 
Dr. Wise serves as the medical monitor for the research group and reviews all serious adverse 
event or unusual event reports to determine whether any immediate local or study-wide actions 
are indicated.  Because Dr. Wise reviews patient events, he will remain masked to the coded 
treatment assignments.  Interim serious adverse events or significant protocol deviations are 
transmitted to the DSMB as they occur with concurrent notification of the clinical site IRBs and, 
if appropriate to the FDA. The DSMB is given the option of having an interim meeting to review 
the event. 
 
The DSMB reports will be masked with respect to treatment assignments groups by using codes 
to identify the zinc acetate and placebo groups.  The DSMB may elect to maintain the masking 
or they can be unmasked at any time. They may also decide to be unmasked for an individual 
case if there is a serious adverse event that may be related to a specific treatment. 
 
ClinicalTrials.gov Registration 
 
The trial will be registered with ClinicalTrials.gov under the Johns Hopkins University account. 
 
 


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7. Literature cited 
 
1. 
Morice, A.H., L. McGarvey, I. Pavord, and G. British Thoracic Society Cough Guideline, 
Recommendations for the management of cough in adults. Thorax, 2006. 61 Suppl 1: p. 
i1-24. 
2. 
Irwin, R.S. and J.M. Madison, The diagnosis and treatment of cough. The New England 
journal of medicine, 2000. 343(23): p. 1715-1721. 
3. 
Ford, A.C., D. Forman, P. Moayyedi, and A.H. Morice, Cough in the community: a cross 
sectional survey and the relationship to gastrointestinal symptoms. Thorax, 2006. 
61(11): p. 975-979. 
4. 
McGarvey, L.P., L.G. Heaney, J.T. Lawson, et al., Evaluation and outcome of patients 
with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax, 
1998. 53(9): p. 738-743. 
5. 
Pavord, I.D., Chronic cough: a rational approach to investigation and management. The 
European respiratory journal, 2005. 25(2): p. 213-215. 
6. 
Lee, J.K. and S. Mintz, Chronic cough as a sign of laryngeal sensory neuropathy: 
diagnosis and treatment. The Annals of Otology, Rhinology, and Laryngology, 2006. 
115(11): p. 871. 
7. 
Morice, A.H., L.P. McGarvey, and P.V. Dicpinigaitis, Cough hypersensitivity syndrome is 
an important clinical concept: a pro/con debate. Lung, 2012. 190(1): p. 3-9. 
8. 
Chung, K.F., Chronic 'cough hypersensitivity syndrome': a more precise label for chronic 
cough. Pulmonary pharmacology & therapeutics, 2011. 24(3): p. 267-271. 
9. 
Canning, B.J., A.B. Chang, D.C. Bolser, et al., Anatomy and neurophysiology of cough: 
CHEST Guideline and Expert Panel report. Chest, 2014. 146(6): p. 1633-1648. 
10. 
Chung, K.F., Approach to chronic cough: the neuropathic basis for cough 
hypersensitivity syndrome. Journal of thoracic disease, 2014. 6(Suppl 7): p. S699-707. 
11. 
Young, E.C. and J.A. Smith, Quality of life in patients with chronic cough. Therapeutic 
advances in respiratory disease, 2010. 4(1): p. 49-55. 
12. 
French, C.L., R.S. Irwin, F.J. Curley, and C.J. Krikorian, Impact of chronic cough on 
quality of life. Archives of Internal Medicine, 1998. 158(15): p. 1657-1661. 
13. 
French, C.T., R.S. Irwin, K.E. Fletcher, and T.M. Adams, Evaluation of a cough-specific 
quality-of-life questionnaire. Chest, 2002. 121(4): p. 1123-1131. 


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14. 
Irwin, R.S., C.T. French, S.Z. Lewis, et al., Overview of the management of cough: 
CHEST Guideline and Expert Panel Report. Chest, 2014. 146(4): p. 885-889. 
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Appendix