Pilot of Zinc Acetate to Improve Chronic Cough

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.

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