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. 2023 Apr 11;9(2):00678-2022.
doi: 10.1183/23120541.00678-2022. eCollection 2023 Mar.

Efficacy and tolerability of zinc acetate for treatment of chronic refractory cough: pilot randomised futility trial

Aparna Balasubramanian  1 , Janet T Holbrook  2 , Brendan J Canning  1 , Loretta G Que  3 , Mario Castro  4 , Barry J Make  5 , Linda Rogers  6 , Michael F Busk  7 , Alexis Rea  2 , Ashley A McCook-Veal  2 , Jiaxian He  2 , Meredith C McCormack  1 , Robert A Wise  1
Affiliations

Efficacy and tolerability of zinc acetate for treatment of chronic refractory cough: pilot randomised futility trial

Aparna Balasubramanian et al. ERJ Open Res. .

Abstract

Background: Cough is the most reported symptom in the United States, with chronic refractory cough representing significant morbidity to patients. Zinc acetate may have beneficial effects in the cough reflex pathway. We sought to assess the safety and efficacy of zinc acetate in the management of chronic refractory cough.

Study design and methods: This was a randomised, placebo-controlled, parallel-design pilot trial of individuals with chronic refractory cough. The effects of 6 weeks of zinc acetate versus placebo on quality of life and symptoms as measured by the Cough Quality-of-Life Questionnaire (CQLQ), Leicester Cough Questionnaire (LCQ), cough visual analogue score (C-VAS) and Global Assessment of Change in Cough (GACC) scores were evaluated. A futility analysis plan with a one-sided 80% confidence interval was used to compare treatment effect to published minimum clinically important differences (MCID) for each outcome.

Results: 34 participants, 17 in each group, were enrolled and randomised. Participants were primarily white females with moderate-severe cough. Participants assigned to zinc acetate had a significant increase in serum zinc levels after 6 weeks, while those assigned to placebo did not. Both groups showed improvement in CQLQ, LCQ, C-VAS and GACC scores, but the treatment effects of zinc acetate versus placebo were small with confidence intervals that did not include the MCIDs.

Interpretation: We observed no benefit of zinc therapy over placebo on cough symptoms or quality of life and conclude that larger trials of zinc for chronic cough are not warranted.

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Conflict of interest statement

Conflict of interest: M. Castro reports grant funding from the National Institutes of Health, American Lung Association and the Patient-Centered Outcomes Research Institute, pharmaceutical grant funding from AstraZeneca, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi, is a consultant for Genentech, Teva, Sanofi-Aventis, Merck, Novartis, a speaker for for Amgen, AstraZeneca, Genentech, GSK, Regeneron, Sanofi-Aventis, Teva, and receives royalties from Elsevier. Conflict of interest: Authors A. Balasubramanian, J.T. Holbrook, B.J. Canning, L.G. Que, B.J. Make, L. Rogers, M.F. Busk, A. Rea, A.A. McCook-Veal, J. He, M.C. McCormack report no conflicts of interest related to this manuscript. Conflict of interest: R.A. Wise reports personal fees for consultation from Merck relevant to the content of this manuscript.

Figures

FIGURE 1
FIGURE 1
The Zinc Acetate to Improve Chronic Cough trial design included a baseline screening period (study week −1 to 0), at the end of which participants were randomised. They then underwent titration over weeks 0 to 1. The schema for titration is shown, with one pill, of either 50 mg zinc acetate or placebo on days 0–3, two pills on days 4–7 and three pills from day 8 onwards. Participants remained on this dose through the treatment period to week 6 and subsequently had a washout period from weeks 6 to 8.
FIGURE 2
FIGURE 2
Consolidated Standards of Reporting Trials diagram. #: ineligible due to respiratory infection within 4 weeks.
FIGURE 3
FIGURE 3
Serum zinc levels at baseline and follow-up by treatment group. Boxplots of a) serum zinc and b) serum copper levels at baseline and follow-up (week 5) by treatment group. Data are presented as individual values, median, interquartile range (IQR) and the minimum value or 1.5×IQR if there are outliers.
FIGURE 4
FIGURE 4
Cough Quality-of-Life Questionnaire (CQLQ) scores at baseline, during follow-up, and after washout by treatment group. Boxes represent the distribution of CQLQ scores at different time points: baseline (week 0), during follow-up (weeks 3, 6) and after the washout period (week 8). The values at week 8 were at the end of the washout period after the assigned treatment was stopped. Data are presented as individual values, median, interquartile range (IQR) and the minimum value or 1.5×IQR if there are outliers.
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