Farr Trial 1 1987.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: prevention Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: "We have developed a taste‐matched placebo containing denatonium benzoate (a bitter substance used to discourage thumb sucking in children) and have demonstrated in previous studies that our zinc and placebo lozenges are comparable both in palatability and in the proportion of subjects who believe they are receiving active medication (B. M. Farr and J. M. Gwaltney, Jr., J. Chronic Dis., in press)."; "On the final day of the study, each subject completed a questionnaire regarding taste, aftertaste, and any adverse effects of the medication, in addition to whether he believed he was given active medication and not placebo."; "Perceptions were not significantly different regarding predominant lozenge taste and palatability or whether medication was active (Table 3)." Duration of follow‐up: 21 days Duration of intervention: 5 days Duration of run‐in or washout period: treatment began 36 hours after viral inoculation If prevention, describe challenge if any: "Rhinovirus type 39 was administered by intranasal drops (0.25 ml per nostril) on two occasions 30 min apart just after admission to the motel in trial 1. The viral inoculum pool had a titer of 103 550% tissue culture infective doses per ml. A 1:10 (vol/vol) dilution of this pool was used for inoculation." If treatment, describe how participants were identified as having colds/URTI: NA Outcomes measured: 1) self‐report of 8 common cold symptoms (sneezing, nasal discharge, nasal congestion, malaise, headache, chilliness, sore throat, and cough), each rated for severity from 0 (none) to 3 (severe); 2) development of a cold, defined as a total symptom score of 0.5 plus either nasal discharge for 3 days or the belief of the participant that a cold had occurred; 3) nasal mucus weight collected from tissues each morning on days 1 to 7; 4) clinical laboratory tests (e.g. levels of zinc in serum) on day 7
Participants	Setting: community Country: USA Zinc gluconate 184 mg/d lozenge Number: 16 Percentage female: 50% Age (mean (SD)): 21.4 (2.4) years Placebo lozenge Number: 16 Percentage female: 69% Age (mean (SD)): 20.6 (2.0) years Overall Number: 32 Percentage female: 56% Age (mean (SD)): 21.0 (2.2) years Inclusion criteria: NR ‐ participants described as 'healthy adult volunteers'. "Healthy adult volunteers (n = 32) with titers of serum neutralizing antibody to rhinovirus type 39 of <1:2 were assigned by prior computer randomization to receive either zinc gluconate or placebo lozenge therapy in trial 1," Exclusion criteria: "Exclusion criteria included symptoms of any respiratory illness in the week before the study, a history of hayfever, any familiarity with the taste of either denatonium benzoate or zinc, a history of any chronic disease, pregnancy, lactation or an unacceptable contraceptive method in women of childbearing potential, and known abuse of habit‐forming drugs." Group differences: differences are small and appear consistent with chance and small sample size. "In trial 1, 19 (56%) of the subjects (8 zinc, 11 placebo) were women. Of the 32 volunteers, 27 were students (14 zinc, 13 placebo). Only four of the subjects were smokers (2 zinc, 2 placebo). The mean age was 21.4 (+ 0.6, standard error of the mean [SEM]) years in the zinc group and 20.6 (± 0.5, SEM) years in the placebo group." Condition studied: common cold Description of recruitment: NR Diagnostic criteria for condition: "Trial 1 subjects were interviewed in the afternoon before viral challenge (study day 0) and then each morning on study days 1 through 7 regarding eight common cold symptoms, including sneezing, nasal discharge, nasal congestion, malaise, headache, chilliness, sore throat, and cough. Subjects were interviewed each morning and afternoon in trial 2. Symptoms were rated for severity according to the following scale: 0, none; 1, mild; 2, moderate; and 3, severe. Criteria for a cold were based on a modification (6) of the criteria proposed by Jackson et al. (8) and required a total symptom score of.5 plus either nasal discharge for 3 days or the belief of the subject that a cold had occurred."; "Infection rates were determined by viral isolation in both trials and /or by documentation of a fourfold or greater rise in serum‐neutralizing‐antibody titre in paired specimens obtained on the day of viral challenge and 21 days later in trial 1." Number of study centres: 1 Number of withdrawals: 0 Total number screened/eligible/randomised: NR/NR/32
Interventions	Zinc gluconate 184 mg/d lozenge Study description of intervention and administration: "The lozenges were identical in size, shape, and appearance and were similar in taste, as documented in our previous studies. Both lozenges contained 2% citric acid and a lemon flavoring. The zinc gluconate lozenge (RF 2546; Bristol Myers Products, Hillside, N.J.) contained 23 mg of elemental zinc." "Each lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the number of the subject, the treatment day, and dosing instructions." "The first dose consisted of two lozenges, one followed by the other. Subsequent doses consisted of a single lozenge, and the dosage interval was 2 h. A total of eight doses was administered each day for 5 days in trial 1" "The total daily dosages of zinc were 207 mg on day 1 of treatment and 184 mg on each subsequent study day in trial 1" Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate Frequency of dose: every 2 h/8 doses Dose per day (elemental zinc in mg): 204 mg day 1 and 184 mg on days 2 to 5 Duration of treatment: 5 days Placebo lozenge Study description of intervention and administration: "The lozenges were identical in size, shape, and appearance and were similar in taste, as documented in our previous studies. Both lozenges contained 2% citric acid and a lemon flavoring." "The placebo lozenge for trial 1 (RF 2547; Bristol Myers Products) contained 0.00125 mg of denatonium benzoate" "Each lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the number of the subject, the treatment day, and dosing instructions." "The first dose consisted of two lozenges, one followed by the other. Subsequent doses consisted of a single lozenge, and the dosage interval was 2 h. A total of eight doses was administered each day for 5 days in trial 1" "The total daily dosages of zinc were 207 mg on day 1 of treatment and 184 mg on each subsequent study day in trial 1" Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: every 2 h/8 doses Duration of treatment: 5 days
Outcomes	Development of common cold/URTI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Global severity of cold symptoms (0 to 3 rating) Outcome type: dichotomous outcome Reported as: standard error (mean, SE, N) Notes: measured as "total symptom score" Severity of nasal symptoms (0 to 3 rating) Outcome type: dichotomous outcome Reported as: standard error (mean, SE, N) Notes: sum symptom scores
Identification	Author's name: Barry M. Farr Institution: University of Virginia School of Medicine Email: none Address: Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 229081 Trial registration identifier: none Year study recruitment began: NR (1987 or earlier)
Notes	Declaration of interest: NR Funding source: "This work was supported in part by Bristol Myers Products, Hillside, N.J. B.M.F. is the recipient of a Milbank Scholar Award in Clinical Epidemiology from the Milbank Memorial Fund, New York, N.Y. We acknowledge with gratitude the assistance of Katherine F. Adams, Kathleen M. Kiehl, and Pat P. Beasley in conducting the volunteer study, Deborah F. Thacker and Kate K. Engleby for technical assistance, and Madeleine Ward and Marjorie Jensen for assistance in the preparation of the manuscript. We also gratefully acknowledge the help of Joseph Armellino, Joseph Migliardi, George Blewitt, Niroo Gupta, and their colleagues at Bristol Myers Products and Denis Schisano at Pragma Biotech, Inc., Bloomfield, N.J." Contact with study authors for additional information: none Other: might be a possible source of bias: "We have developed a taste‐matched placebo containing denatonium benzoate (a bitter substance used to discourage thumb sucking in children) and have demonstrated in previous studies that our zinc and placebo lozenges are comparable both in palatability and in the proportion of subjects who believe they are receiving active medication (B. M. Farr and J. M. Gwaltney, Jr., J. Chronic Dis., in press)."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Healthy adult volunteers (n = 32) with titers of serum neutralizing antibody to rhinovirus type 39 of <1:2 were assigned by prior computer randomization to receive either zinc gluconate or placebo lozenge therapy in trial 1" Judgement comment: computer‐generated randomisation sequence.
Allocation concealment (selection bias)	Unclear risk	Quote: "Each lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the nuniber of the subject, the treatment day, and dosing instructions." Judgement comment: allocation processes not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The lozenges were identical in size, shape, and appearance and were similar in taste, as documented in our previous studies." Judgement comment: likely that participants were blinded although not explicit that personnel were also blinded.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Trial 1 subjects were interviewed in the afternoon before viral challenge (study day 0) and then each morning on study days 1 through 7 regarding eight common cold symptoms, including sneezing, nasal discharge, nasal congestion, malaise, headache, chilliness, sore throat, and cough." Judgement comment: insufficient information on outcome assessment to be certain that outcome assessment was blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The zinc gluconate and placebo groups demonstrated equivalent infection rates of 100 and 94%, respectively (Table 1). All of the infected subjects except for one placebo recipient, who only seroconverted, shed rhinovirus type 39. Only one individual, also in the placebo group, lacked any evidence of infection by viral isolation or seroconversion. The proportions of subjects who seroconverted were similar in the two treatment groups." Judgement comment: incomplete data due to lack of infection, which was measured. Appears that data were collected for all participants (32/32).
Selective reporting (reporting bias)	Unclear risk	Judgement comment: insufficient information to permit judgement of ‘low risk’ or ‘high risk’. Severity of symptoms could have been reported a bit more transparently.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.