Chapter 4.A.2.
Chapter 4.A.2. Great Britain Medical Research Council Common Cold Unit 1987 Study

The British Medical Research Council (MRC) Common Cold Unit in Salisbury, England, tested zinc gluconate lozenges (23 mg zinc) against placebo in double-blinded human rhinovirus (HRV)-2 prophylaxis and therapeutic efficacy clinical trials.(10) The entire article is presented here.

In the prophylaxis study, zinc reduced the total mean clinical score from 8.2 in the placebo group to 5.7. This reduction was statistically significant on the second day after virus challenge with HRV-2.

In the therapeutic study, the mean clinical score for zinc-treated patients was consistently lower than for placebo-treated patients after day 1, reducing mean clinical score over the 6-day study from 41 in the placebo-treated group to 27.2 in the zinc-treated group. On each day of the study after day 1, mean nasal secretion weights from zinc-treated patients were less than half those of placebo-treated patients. On day 4 and afterward, nasal secretion weights in the zinc-treated group were nearly an order of magnitude lower than in the placebo-treated group. Results were statistically significant by several measurements at times during the study.

The astringent lozenges were used every two hours while awake, totaling 9 doses/day. Lozenges were soluble, pleasant-tasting, 1-gram, wet-granulated fructose-Methocel(r)-based compressed tablets. No distinguishable difference in taste or appearance between zinc and placebo lozenges was observed. The zinc gluconate lozenges produced 22 grams of zinc-laden saliva and dissolved in 19 minutes. Salivary Zn2+ ion concentration was 5 mMol or less at pH 7.4. Salivary pH was 5.4. Reduction in duration was based upon the return to normal of symptoms in all zinc-treated patients on day 6 compared with the 10.8-day historic average duration of colds. Thus, treatment reduced average duration of colds by 4.8 days. Zinc lozenges had a ZIA value of 44.

The zinc gluconate lozenges tested were made by RBS Pharma of Milan, Italy, (now part of R˘hne-Poulenc Pharma, Italia, S.P.A.). Professor Rinaldo Pellegrini, Medical-Scientific Director for RBS Pharma was the only researcher to visit with the original Texas group and follow advice concerning omitting zinc chelators from the lozenge formulation. RBS Pharma compounded zinc gluconate in fructose (a sugar), the only sweet tablet base that does not become bitter in solid state reactions with zinc gluconate.

Lozenge Composition

Lozenges contained 175 mg zinc gluconate (23 mg zinc) or placebo and weighted 1.00 gram each. Lozenges were one-half inch in diameter and 1/4 inch thick at the crown. Standard concave punches were used. Both were made using a binder with properties similar to high molecular weight hydroxypropyl methycellulose (Methocel(r) K4M) as viscosity of saliva was high, leaving the mouth with a moderately slimy feel. Both were tan in color. Saliva viscosity, tablet appearance, and very fine texture suggested the manufacturing process used to make these lozenges to have been wet granulation. Zinc gluconate carbonizes when mixed with carbohydrates at moderate temperature, requiring drying temperatures to be less than 50 C. to prevent most carbonization, consequently the lozenges had a light tan coloration.

The original 1985 flavor was very sweetly flavored. Although lozenges were made in 1985, their taste in 1992 was still sweet with no evidence of the biting bitterness normally associated with lozenges made with dextrose, sucrose, or sugar-alcohols. Lozenges were moderately astringent and had a mild chalk-like undertaste identical to pure zinc gluconate powder. The first flavor-note was sweet during dissolution tests in 1985 and later in 1992. After flavor oils had evaporated from lozenges in 1992, lozenge flavor was less sweet, slightly chalky and bland without bitterness. After dissolving lozenges for about 15 minutes, a slight chalky taste of zinc gluconate along with increased astringency developed. Both zinc and placebo lozenges were quite astringent and caused an overnight dry mouth.

The tablets showed no tendency to disintegrate at any time during dissolution from intact tablet to a tiny sliver. Oral dissolution times averaged 19 minutes. Lozenges produced an average of 22 ml of saliva during dissolution. ZIA calculations showed lozenges to have a ZIA value of 44, a modest value, because of increased salivation and more rapid dissolution rate.

Research Design

A lozenge tolerance and taste study first showed people were unable to distinguish between zinc and placebo lozenges. Two double-blind placebo controlled trials were then conducted at Harvard Hospital in Salisbury, England, to determine the prophylactic and therapeutic effects of zinc gluconate lozenges on human rhinovirus-2 (HRV-2) challenge.

In the prophylactic study, a total of 57 volunteers received lozenges of either zinc gluconate (23 mg zinc) in 29 volunteers or matched placebo in 28 volunteers every 2 hours while awake during a period of 5 days. On the second day, volunteers were challenged with 102 tissue culture infecting dose (TCID50) of HRV-2, and were monitored daily for symptoms and signs of colds and laboratory evidence of infection.

In the therapeutic study, 69 volunteers were inoculated with 102 TCID50 of HRV-2. Twelve developed cold symptoms and were randomly allocated to receive either zinc gluconate lozenges or placebo lozenges, with six receiving zinc lozenges and six receiving placebos every 2 hours while awake for 6 days. Lozenges were given from the time symptoms of a cold developed, and were continued throughout the duration of the trial. Volunteers were kept in quarantine for 48 hours before the start of the study as well as during the study.

As day zero information for the therapeutic trial is missing from the MRC article, borrowed data from the prophylactic trial (Figure 1.a. of Al-Nakib) for day zero of the study was used to bring out significant details in the therapeutic trial results. According to David A. J. Tyrrell (MRC Common Cold Unit Director and study co-author) in 1993, combination of data from the separate studies is not absolutely legitimate (as one might expect), but combination is acceptable to Tyrrell as combination gives -- in his words, "a rough idea of the sort of result one might obtain if the patients in the therapeutic study had been observed and the data analyzed as in the prophylactic study."(11)

Results of Prophylactic Trial

Treatment in the prophylactic trial showed the response to zinc treatment to have been statistically significant on the day after viral challenge, with zinc reducing total clinical scores compared to placebo (8.2 vs. 5.7), mean nasal secretion weight, and virus excretion. Even though treatment was stopped on the third day after viral challenge, mean clinical scores for the zinc-treated group on the fourth, fifth, and sixth days remained lower than for the placebo-treated group -- by 30 percent on day 4, 38 percent on day five, and 20 percent on the sixth day even though mean nasal secretion weights had risen on day 5 by 20 percent.

Results of Therapeutic Trial - Mean Clinical Scores

Mean clinical score is estimated to be 0.1 for both groups on day zero. On the second day of the prophylactic trial, mean clinical score peaked at 8.5 and 12 points for zinc and placebo treatments respectively (see Figure 5). By day 6, mean clinical score for the zinc-treated group had returned to 0.6 which is six times pre-infection, while the score for the placebo-treated group returned only to 3.3 which is 33 times pre-infection. On day 6 the mean clinical score for zinc-treated patients was 20 percent of placebo-treated patients. Relative to placebo, by the sixth day zinc-treated patients had mean clinical scores essentially identical to pre-infection scores, showing colds were essentially absent in the zinc-treated group. All of the colds continued unabated in the placebo-treated group. Had the clinical trial lasted an additional day, the mean clinical score of zinc-treated patients might have reached zero. Similar benefit in the placebo-treated patients appears quite unlikely.

Daily clinical scores of zinc and placebo treated groups

Figure 5. Daily clinical score of ZIA 44 zinc gluconate- and placebo-treated groups. (Composite from Figures 1.a. and 2.a. of Al-Nakib, courtesy of Journal of Antimicrobial Chemotherapy).

Zinc clearly reduced the mean daily clinical scorecompared with the placebo group score. Reduction in duration in the zinc-treated group compared with placebo treatment was statistically significant with only 6 patients per group on day 4 ( P < 0.01) and day 5 (P < 0.05) of treatment. Total mean clinical score (additive from day zero through day 6) was also reduced from 41 points in the placebo group to 27.2 in the zinc group.

Results of Therapeutic Trial - Mean Daily Nasal Secretion Weights

Zinc lozenges also reduced mean daily nasal secretion weight (grams) and total facial tissues used. These reductions were statistically significant from days 2 (P < 0.05) and 6 (P < 0.01) for nasal secretion weights and similarly significant on days 4 through 6 of medication for tissue counts when compared with placebo (Figure 6). Mean total nasal secretion weights were also significantly lower -- 22.0 grams in the zinc-treated group compared with 51.4 grams in the placebo group.

In addition, zinc also significantly reduced the mean number of facial tissues used by volunteers compared to placebo on day 4 -- 1.42 versus 2.75 (P < 0.05), day 5 -- 0.25 versus 2.17 (P < 0.01) and day 6 -- 0.33 versus 1.67 (P < 0.05). Total mean tissue count for the 6-day period was thus reduced from 21.7 for those who received placebo to 14.3 for those who received zinc (P < 0.01).

Daily nasal secretion weights of zinc and placebo treated patients

Figure 6. Daily nasal secretion weights in grams for ZIA 43.9 zinc gluconate- and placebo-treated groups. (Composite from Figures 1.b. and 2.b. of Al-Nakib, courtesy of Journal of Antimicrobial Chemotherapy).

On day 4, zinc-treated patients in the therapeutic trial had daily nasal secretion weights essentially the same as patients in the prophylaxis trial before viral inoculation, while placebo-treated patients had nasal secretion weights nearly 10 times higher than pre-infection. By day 6, all zinc-treated patients in the therapeutic trial had daily nasal secretion weights identical to nasal secretion weights of the patients in the prophylaxis trial before viral inoculation.

MRC Conclusions

The MRC Common Cold Unit concluded 1-gram zinc gluconate lozenges containing 23 mg zinc in a fructose and Methocel base used every 2 hours while awake consistently reduced both mean daily over-all symptoms and signs of disease as reflected in clinical scores and mean nasal secretion weights, the most objective measures of clinical response to treatment. The MRC Common Cold Unit indicated their findings warranted large field trials of zinc gluconate lozenges to extend and confirm zinc gluconate lozenge efficacy against natural common colds in the community.

Generally, zinc gluconate in fructose-based lozenges was well tolerated despite the relatively large number of lozenges taken. Some volunteers commented that the taste of food was affected by lozenges, but no serious objections to either zinc or placebo lozenges were noted.

No adverse changes in hematologic and biochemical indices were noted. Zinc-treated patients all showed a marked increase in urinary zinc excretion.

Although viral excretion was about 20 percent less in the zinc-treated patients than in the placebo-treated patients in the prophylaxis trial during the first 4 days after viral challenge, the difference was not statistically significant, and the MRC indicated the mechanism of action responsible for significant benefit to cold suffers remained unknown.

Duration of Common Colds and ZIA Calculation

All placebo-treated patients had considerable symptoms remaining on day six, the end of the study. Given the data available it was not possible to know the absolute length of placebo-treated colds in this study. For zinc-treated patients, nasal drainage at days 4, 5, and 6 was estimated to be essentially the same as pre-infection. At day 6, mean clinical score and nasal secretion weights are essentially the same as pre-infection, judging from the pre-inoculation data from the prophylaxis trial.

Consequently, duration of the zinc-treated common colds was 6 days, and average duration equals duration in this case. If the average duration of zinc-treated colds is compared with 10.8 days average duration (as has been historically found to be the case), a 4.8 day average reduction in common cold duration can be deduced from this experiment.

Working backwards from average duration to half-life yields a theoretical half-life of 4.1 days for zinc-treated colds and 7.0 days for placebo-treated colds, which appears reasonably close to data shown in Figure 5.

Zinc Ion Availability

Calculation shows the ZIA value is 44. Lozenges dissolved in 19 minutes and produced 22 grams zinc-laden saliva. Salivary molar concentration of Zn2+ ion was 5 mMol, which was 50 times antirhinoviral concentration according to Korant and colleagues(7) and 100 times antirhinoviral concentration according to Merluzzi and colleagues,(8) and Geist and colleagues.(9)

A ZIA value of about 50 and a Zn2+ ion concentration of about 5.0 appear to be minimal values for strong, but less than antirhinoviral, efficacy as colds did not disappear immediately upon initiation of treatment.

Chapter 4.A.3. - McNeil 11.5-mg Zinc Gluconate Study