All patients were recruited during the fall using local radio and television advertisements. People with early onset common colds were invited to join a clinical study intended to determine if zinc gluconate lozenges could shorten duration of common colds. All patients were both self diagnosed and diagnosed by the physician (William W. Halcomb, a general practice physician and allergist) to have uncomplicated common colds.

Persons presenting with an allergy were not admitted to this study. Likewise, pregnant women and persons on immunosuppressive drugs were not admitted. Persons with known serious health disorders were also excluded.

Informed consent was obtained in writing after explanation of the study. Patients filled out a printed health questionnaire and were instructed in the study protocol. Patients chose a randomly coded bottle containing either 75 zinc gluconate or 75 placebo lozenges in a double-blind manner.

At the first office visit, patients were instructed to dissolve tablets slowly as lozenges. Loading dose was two tablets (46 mg zinc), taken one after another. The double-strength loading dose was considered important to rapid recovery from symptoms, and everyone was instructed to be certain the double dose was taken. Emphasis was placed upon slowly dissolving lozenges in a manner intended to maximize the amount of zinc that could be absorbed into mucosal membranes of the mouth and throat.

Adults and youths over 60 pounds were to dissolve one tablet every two hours while awake after the loading dose. Children under 60 pounds were to dissolve 1/2 tablet every two hours while awake. All were instructed to continue treatment every two hours while awake until 6 hours after the end of the last common cold symptom. All were instructed to avoid stress and include one or two treatments during the first day after cessation of symptoms as insurance against relapse.

Experience with many common colds using zinc gluconate lozenge treatment during the 4 years immediately preceding the study also showed results could be improved if certain other steps were followed. Patients were told results might be improved if patients (a) slept after the first treatment and after other treatments when possible, (b) used a lozenge at bedtime (especially important as lymph circulation stops during sleep holding Zn²⁺ ions in tissues overnight), (c) took lozenges after meals and liquids (not before or on an empty stomach to avoid nausea), (d) avoided mouthwashes or alcohol, (e) avoided aspirin, antihistamines, decongestants, or other cold remedies, and (g) avoided smoking.

Patients were instructed to eat soda crackers if nausea occurred. More recent research confirms these techniques to improve results, perhaps by helping to prevent removal of zinc from oral tissues as well as by preventing immunosuppression or complexation of Zn²⁺ ions by other drugs.

Each patient was given a "treatment response form" in which they were to record severity of ten common cold symptoms each day for 7 days at the same time of day as their initial office visit. Symptoms studied were headache, fever, muscle pain, sneezing, nasal drainage, nasal obstruction, sore throat, scratchy throat, cough, hoarseness, and other. Common cold symptoms were scored as being either severe (3 points), moderate (2 points), minor (1 point), or absent (0 points). Space was provided to record side effects and other comments about treatment.

The report was limited out of concern by the authors and journal editors for possible superimposed allergies and bacterial infections in colds of longer duration. Also, a main goal of the research was to study the effects of zinc gluconate lozenges on colds of short pre-treatment duration, not long duration. Short pre-treatment duration better assessed possible impact of Zn²⁺ ions on rhinoviruses which are believed to replicate immediately before onset of common cold symptoms and during the first day or two of symptoms. To encourage unbiased reporting of pre-treatment duration of common colds, all patients were accepted into the study regardless of how long their colds had lasted before initiation of treatment.

The second and main criticism was the possibility of unblinding because of oral side effects and taste differences between zinc and placebo. To answer unblinding criticisms, subgroups of zinc-treated patients offering comments or complaints about taste, aftertaste, and oral side effects were compared with those not offering complaints. There were no differences in response to zinc treatment between the two subgroups. Taste problems associated with zinc gluconate in sucrose, dextrose, and sugar-alcohols are absent from zinc gluconate tablets having no other soluble ingredients.

Duration of common colds was defined as presence of any one or more of these ten symptoms. Presence of any one or more common cold symptom is the main result of the study, and is also shown in Figure 3.

The two experimental groups clearly responded differently, and the effects of zinc were apparent from the beginning. In the zinc group, sizable numbers of patients became completely asymptomatic rather quickly -- 15 percent within 12 hours and 25 percent by 24 hours -- whereas no placebo-treated patient was symptom-free within 24 hours (P < 0.02 at 12 hours, P < 0.001 at 24 hours, by exact binomial calculations).

The plot for the zinc group is roughly an exponential decay with a half-life of about 2.2 days; this is to say, half of the remaining symptomatic patients became symptom free about every 2.2 days. In contrast, half of the placebo group required 7 days to become asymptomatic, in agreement with generally accepted durations for common colds. In our zinc-treated population, 90 percent were asymptomatic by day 7 compared with 51 percent of the placebo-treated population (P << 0.0001).

The experiment was too short to measure fully average duration of cold symptoms, especially in the placebo group. Even if all symptoms remaining on day 7 had ended by day 8 for both groups (extremely unlikely), the effect of zinc lozenges on average duration would have been statistically highly significant (average duration would be 3.0 days in the zinc group and 5.9 days in the placebo group, P<< 0.0001). Improved estimates of average duration of these colds can, in this case, be based on average duration for an exponential decay curve (half-life/ln 2) and on half-lives. This method of extrapolation leads to average durations of 3.2 days and 10 days and to an estimated 7-day reduction in the average duration attributable to zinc gluconate lozenges.

Figure 3. Duration of common colds in ZIA 100 zinc gluconate- and placebo-treated groups.

*Group sums of severity scores in points divided by number of patients N having symptom at start of treatment (severe = 3 points, moderate = 2 points, minor = 1 point, absent = 0 points).

An initial abrupt decrease in reported severity occurred in both groups at hour 1 (not shown), perhaps partly because of changed circumstances and expectations following enrollment in the study. Then the two groups diverge convincingly at 12 hours and thereafter (P<0.01 to 0.001 through day 7). Whereas the zinc group recorded a 50 percent drop in severity scores in less than 1 day, the placebo group required 3 days for the same reduction. In the zinc group, total severity scores continued to fall rapidly and nearly exponentially from hour 6 through day 7, with a half-life of 1.5 days, compared to a half-life of 5 days in the placebo group after hour 6.

Figure 4. Average total severity of colds in ZIA 100 zinc gluconate and placebo-treated groups.

On the other hand, most of the dropouts from the zinc group resulted from oral side effects including tablet grittiness. Reaction to zinc gluconate tablets was quite varied. A few patients had strong reactions to their taste while the majority of patients had no comment, accepting the bland, chalky taste as a reasonable and acceptable part of treatment. Some oral side effects are now primarily attributed to the nonsoluble formulation of lozenges. Unpalatable taste was a result of zinc gluconate and dicalcium phosphate. Irritation of mouth, tongue, and throat may also be caused by abrasive non-soluble tablet excipients. Three-fourths of all complaints were from women. Most side effects were accepted as a normal part of therapy by patients, and were considered a trade-off for a quick recovery. A complete listing of side effects and complaints is found in Table 4.

Among 64 patients in the zinc-treated group who returned response reports, 20 (31 percent) are considered dropouts because they stopped treatment and/or stopped recording symptoms before cessation of symptoms. Three other reports were rejected because of lack of usable data or because notation by patients that lozenges were swallowed rather than dissolved. Most zinc drop-outs (14 patients) occurred within 24 hours of starting treatment; 13 resulted from objections to treatment, 8 from side effects, and 5 from taste. Three blamed lack of benefit. At the time of dropping out, 13 zinc-treated patients had improved, two were worse, and five were unchanged or change was unknown based on severity scores.

Drop-outs in the placebo group were rather different. Among 44 reports from placebo-treated patients, 15 (34 percent) dropped out (10 prematurely stopped treatment and five stopped recording symptoms). Seven stopped within 24 hours of starting treatment, and only one noted objection to the treatment as reason. Ten placebo-treated patients blamed lack of benefit. At the time of stopping, three placebo-treated patients' severity scores were improved, six were worse, and six were unchanged. Ten patients who stopped treatment but who recorded adequate symptom data were included in the placebo group analysis, because their stopping placebo "treatment" could not benefit their colds and because their omission might distort sampling of the group.

The tablets required about 20 minutes to dissolve in flowing water bath tests and about 30 minutes to dissolve in the mouth. This difference results from the differences in dynamics between the two methods. For example, patients often pigeon-hole lozenges in their cheeks with little dissolution occurring. Because lozenges were small, bland, hard tablets that dissolved slowly, little zinc-laden saliva was generated (15 ml) resulting in a high Zn²⁺ ion molar concentration (7.4 mMol) which was 74 times antirhinoviral concentration according to Korant and co-workers(7) and 148 times antirhinoviral concentration according to Merluzzi and co-workers(8) and Geist and co-workers.(9)

Tablets had a ZIA value of 100 and reduced the average duration of all common cold symptoms by 7 days. ZIA 100 lozenges may produce antirhinoviral effects, judging from the very rapid initial response from these lozenges not seen in any study with lower ZIA values.