Description of studies
We identified 198 reports possibly fulfilling our inclusion criteria and retrieved 55 reports. We excluded 22 and classified one as pending translation from Polish. For descriptions see the 'Characteristics of included studies' table.
We identified 20 reports of 21 prophylaxis and safety trials fulfilling our inclusion criteria. We were unable to identify any unpublished trials, despite receiving nine letters and three electronic communications from manufacturers, authors and researchers.
The mean amantadine arm size was 327 individuals (median 140.5, 25th percentile 92.5, 75th percentile 348.2), the mean rimantadine arm size was 87 individuals (median 102, 25th percentile 63, 75th percentile 114) and the mean placebo arm size was 265 individuals (median 139, 25th percentile 99, 75th percentile 269). Differences in mean and median size were due to few bigger trials (Peckinpaugh 1970a; Peckinpaugh 1970b; Smorodintsev 1970) and several smaller ones.
The mean sample was 599 individuals (median 297, 25th percentile 202, 75th percentile 536). Mean length of follow up was 30 days (median 30 days, 25th percentile 16.5 days, 75th percentile 42 days). The duration of the epidemic was specified by only one trial (Kantor 1980) and was 49 days.
The identified trials are listed below (using the name of the first author):
We identified 13 published treatment trials (one by Máté 1970 contained both treatment and prophylaxis data). We were unable to identify any unpublished trials. The mean amantadine arm size was 80 individuals (median 63, 25th percentile 18.5, 75th percentile 90.2), the mean rimantadine arm size was 47 individuals (median 20, 25th percentile 11.5, 75th percentile 82.5) and the mean control arm size was 66 individuals (median 35.5, 25th percentile 13.5, 75th percentile 87.6). Again, differences in mean and median size were due to one bigger trial (Kitamoto 1968) and the others being smaller ones. The mean sample was 140 individuals (median 90.5, 25th percentile 29.7, 75th percentile 87.6). Mean length of follow up was 23 days (median 21 days, 25th percentile 10 days, 75th percentile 30 days).
Identified trials are listed below using the name of the first author and year of publication in the case of there being more than one trial by the same author. One trial (Hornick 1969) was broken down further into four sub-trials (see below for explanation).
van Voris 1981
We identified 10 reports related to 11 trials which had been carried out during the 1968 to 1969 pandemic (Galbraith 1971; Kitamoto 1968; Knight 1970; Máté 1970; Muldoon 1976; Nafta 1970; Oker-Blom 1970; Peckinpaugh 1970a; Peckinpaugh 1970b; Schapira 1971; Smorodintsev 1970).
Effects of interventions
We carried out nine comparisons:
Comparison A - oral amantadine compared to placebo in the prophylaxis of influenza or ILI.
Comparison B - oral rimantadine compared to placebo in the prophylaxis of influenza or ILI.
Comparison C - oral amantadine compared to oral rimantadine in the prophylaxis of influenza or ILI.
Comparison D - oral amantadine compared to placebo in the treatment of influenza.
Comparison E - oral rimantadine compared to placebo in the treatment of influenza.
Comparison F - oral amantadine compared to oral rimantadine in the treatment of influenza.
Comparison G - oral or inhaled amantadine versus placebo or aspirin in the nasal viral shedding or persistence in upper airways at two to five days.
Comparison H - oral amantadine compared to control medication in the treatment of influenza.
Comparison I - inhaled amantadine compared to placebo in the treatment of influenza.
For comparisons A, B and C we analysed the effects on 'cases', stratified either as influenza (a defined set of signs and symptoms backed up by serological confirmation and/or isolation of influenza virus from nasal fluids) or clinical criteria alone (ILI) or asymptomatic cases (serological confirmation and/or isolation of influenza virus from nasal fluids without symptoms). The effects on nasal viral shedding were assessed by single studies: Reuman 1989(amantadine) and Dolin 1982 (rimantadine). We stratified comparisons on the basis of whether participants had received vaccination or not.
Additionally we assessed adverse effects in both comparisons.
In Comparisons A and B significant heterogeneity between the trial results was evident for both types of influenza analyses, so all results quoted are average treatment effects based on random-effects models. In Comparison A, amantadine prevented 61% (95% CI 35% to 76%) of influenza cases and 25% (95% CI 13% to 36%) of ILI cases. Both of these results are highly statistically significant (P < 0.001). There was no effect on asymptomatic cases (risk ratio (RR) 0.85; 95% CI 0.40 to 1.80), nor any difference in efficacy between unvaccinated and vaccinated individuals (RR 0.45; 95% CI 0.28 to 0.74 and RR 0.10; 95% CI 0.03 to 0.34). The effectiveness in unvaccinated subjects is significantly higher than that of placebo in unvaccinated subjects (RR 0.42; 95% CI 0.07 to 2.52), but not in vaccinated individuals 0.75 (95% CI 0.62 to 0.90).
In Comparison B rimantadine was not effective against either influenza (RR 0.28; 95% CI 0.08 to 1.08) or ILI (RR 0.65; 95% CI 0.35 to 1.20), however, analysis using a fixed-effect model shows significant protection against influenza and ILI in unvaccinated participants. Whilst these results are conventionally not statistically significant (P = 0.07 and P = 0.17, respectively), the estimates are based on only 688 individuals, and are of a very similar magnitude to those for amantadine. There was no effect on asymptomatic cases (RR 1.39; 95% CI 0.45 to 4.27), although this observation is based on one study only (Dolin 1982).
In Comparison C there is no evidence of a difference in efficacy between amantadine and rimantadine, although the confidence interval is quite wide (RR amantadine versus rimantadine 0.88. 95% CI 0.57 to 1.35). In comparisons B and C there were insufficient data to stratify by vaccine status of participants.
The 'all adverse effects' category includes all types and was derived from those trials which either did not report sufficient information to allow a more detailed classification or which presented aggregate data. Adverse effects incidence is reported in our meta-analysis as the number of participants with at least one event, thus the incidence of individual adverse effects cannot be summed to give the total with any adverse effect as more than one adverse event is likely to have taken place in the same individual during the trial.
In Comparison A gastrointestinal symptoms (mainly nausea, odds ratio (OR) 2.56; 95% CI 1.37 to 4.79), insomnia and hallucinations (OR 2.54; 95% CI 1.50 to 4.31) and withdrawals from the trials because of adverse events (2.54; 95% CI 1.60 to 4.06) were significantly more common in participants who received amantadine than placebo. Analysis using a fixed-effect model shows a significant association with depression, insomnia and the 'all adverse events' category.
In Comparison B, rimantadine recipients were also more likely to experience 'all adverse effects' than placebo recipients (OR 1.96; 95% CI 1.19 to 3.22). However, there was no evidence of an increase in CNS-related effects with rimantadine, and withdrawal rates were similar in both groups.
The direct comparison of amantadine with rimantadine (Comparison C) confirmed that CNS adverse effects and withdrawal from trials were significantly more frequent among amantadine recipients than rimantadine recipients (CNS effects, OR 3.11; 95% CI 1.67 to 5.78; withdrawals OR 2.49; 95% CI 1.26 to 4.93).
Thus rimantadine may be no less efficacious but safer than amantadine in preventing cases of influenza in healthy adults. Readers should bear in mind that the study sizes of the safety trials of rimantadine are considerably smaller than those of amantadine, so that the conclusions that can be drawn for rimantadine are somewhat less certain than those for amantadine.
We considered meta-analysing symptoms outcome data to further inform the assessment of the effects of amantadine and rimantadine in the treatment role. When we tabulated the outcome typology we discovered that such a meta-analysis would be impossible as can be seen from Table 1.
Table 1. Trial symptom outcomes used
|Galbraith 1971||Average time to clearance of symptoms|
|Hayden 1980||Aggregate scores of systemic and respiratory symptoms|
|Hayden 1986||Aggregate scores of systemic and respiratory symptoms|
|Hornick 1969a||Percentage of patients in three symptoms clearance time periods|
|Kitamoto 1968||No symptoms|
|Kitamoto 1971||No symptoms|
|Knight 1970||Between arms symptoms concordance. Aggregate data only|
|Máté 1970||Duration of fever (aggregate) and length of stay in infirmary|
|Togo 1970*||Percentage of patients in three symptoms clearance time periods|
|Younkin 1983*||Significance of the difference of symptoms scores|
|van Voris 1981||Percentage of improvement of symptom scores at different time periods|
|Wingfield 1969||Significance of difference of proportions of patients in three symptoms clearance time periods|
We resorted to using duration of fever (defined as a temperature greater than 37 °C) as the only common outcome. One obvious cost of this approach is the possible confounding effect of the presence of fever for a variable length of time prior to and after entry to the study (and hence at the moment of commencement of treatment). However, if random allocation had been properly carried out, this effect should disappear.
In Comparison D amantadine significantly shortened duration of fever compared to placebo (by 0.99 days; 95% CI 0.71 to 1.26). The meta-analysis is based on 542 subjects (250 in the amantadine and 292 in the placebo arm). Where time to fever clearance data were not available (as in van Voris 1981 and Wingfield 1969), a dichotomous outcome was used (cases with fever at 48 hours). This comparison showed that amantadine was significantly better than placebo (RR 0.21; 95% CI 0.07 to 0.66). However, there was no effect on nasal shedding or persistence of influenza A viruses in the upper airways after up to five days of treatment (RR 0.97; 95% CI: 0.76 to 1.24).
In Comparison E rimantadine shortened duration of fever compared to placebo (by 1.24 days; 95% CI -0.76 to -1.71). There were a significantly higher number of afebrile cases 48 hours after commencing rimantadine treatment (RR 0.16; 95% CI 0.05 to 0.53). However, there was no effect on nasal shedding or persistence of influenza A viruses in the upper airways after up to five days of treatment (RR 0.68; 95% CI 0.30 to 1.53), although this finding may be due to the small number of observations in this comparison (152) and is sensitive to analysis using a fixed-effect model.
The few data available directly comparing amantadine and rimantadine for treatment (Comparison F) showed that the efficacy of the two drugs was comparable, although the confidence intervals are very wide (for example, cases with fever at 48 hours RR 0.99; 95% CI 0.23 to 4.37).
In contrast to the increased adverse effect rates for prophylaxis, there was no evidence that amantadine recipients had higher adverse effect rates than placebo recipients (Comparison D), but data were only available from three trials (Kitamoto 1968; Kitamoto 1971; van Voris 1981 with combined denominator of 491) and the association with decreased CNS activity is sensitive to the application of a fixed-effect model. There were very few data available for the assessment of adverse effects of rimantadine for treatment (45 participants in Hayden 1986 and van Voris 1981) or the direct comparison between amantadine and rimantadine (33 participants in van Voris 1981).
In comparison G the effects of oral or inhaled amantadine on shedding of influenza A viruses are still not significant (RR 0.94; 95% CI 0.74 to 1.19), despite meta-analysis of five studies with a combined denominator of 237 observations.
Readers of this review should bear in mind that the difference in incidence of adverse effects is of importance, rather than the estimated incidence itself, as the adverse effects reported with these drugs are very similar to the clinical manifestations of influenza infection.
Overall both drugs appear to be effective and well-tolerated, but the evaluation of the effects of rimantadine was carried out on a very small population.
Insufficient data were available to analyse the relationships of dose (or duration) of treatment and clinical or virological effects. However, other data suggest that equivalent doses of amantadine and rimantadine at steady-state are associated with similar plasma concentrations and similar total clearance values (Aoki 1998).
We carried out further comparisons (H and I).
In Comparison H, based on Younkin 1983 and Ito 2000, standard medications (aspirin and other antipyretic or anti-inflammatory drugs or antibiotics were equally effective compared with amantadine in reducing the length of fever (mean difference (MD) random-effects model 0.25; 95% CI - 0.37 to 0.87). This observation is based on 78 individuals and in the trial by Ito 2000 amantadine was given at the lower dose of 100 mg. Aspirin and the other antipyretic drugs appear to be as potent as amantadine in treating symptoms, however they do not inhibit viral replication and as such remain a symptomatic remedy.
In comparison I (based on the Hayden 1980 trial) inhaled amantadine was no more efficacious than placebo in bringing down the respiratory or constitutional symptom score (MD -1.00; 95% CI -3.64 to 1.64 and -2.00; 95% CI -16.98 to 12.98, respectively). This comparison is based on small numbers of participants (20). Not surprisingly, amantadine caused significantly more nasal irritation (RR 12.50; 95% CI 1.09 to 143.43). Inhaled amantadine does not appear to be particularly effective but has a high incidence of local adverse effects, which would make compliance difficult.
Neither comparison showed an effect on nasal shedding or persistence of influenza A viruses in the upper airways after up to five days of treatment, although the interpretation of Comparisons H and I is made difficult by the small numbers involved and the absence of multiple trials.
All trials tested the effects of amantadine and rimantadine on a wide variety of influenza A viruses. None tested the effects on influenza B, on which the molecules are known to be ineffective. No trial tested the role of the compounds on workplace outbreak control, which is a pity considering the trial settings (prisons, factories, schools, barracks).
Some trials are likely to have included individuals who took aspirin to relieve symptoms (especially in the treatment trials). However the effects of this potential confounder should have been eliminated by the process of randomisation.
All trials commenced administration of the compounds within a reasonable time frame. Treatment started at the latest 48 hours after positive identification of the first case in the population and prophylaxis when the results of surveillance made it reasonable to do so.
No trials assessed onset of resistance, but data in one study demonstrated that 10% to 27% of patients treated with amantadine secreted drug-resistant virus within four to five days of commencing treatment (Aoki 1998).
Separate analysis of the 11 pandemic trials did not affect our findings. Finally, we considered carrying out sub-analysis by dose (100, 200, 300 mg daily), but decided against this given the small size of the resulting meta-analysis. We will re-consider this policy if any further data become available.