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.

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

10 weeks