Amantadine and rimantadine for influenza A in adults

Tom Jefferson; Vittorio Demicheli; Carlo Di Pietrantonj; Daniela Rivetti

doi:10.1002/14651858.CD001169.pub3

. 2006 Apr 19;2006(2):CD001169. doi: 10.1002/14651858.CD001169.pub3

Amantadine and rimantadine for influenza A in adults

Tom Jefferson ^1,^✉, Vittorio Demicheli ², Carlo Di Pietrantonj ², Daniela Rivetti ³

Editor: Cochrane Acute Respiratory Infections Group

PMCID: PMC7068158 PMID: 16625539

Abstract

Background

Amantadine hydrochloride (amantadine) and rimantadine hydrochloride (rimantadine) have antiviral properties, but they are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects.

This review was first published in 1999 and updated for the fourth time in April 2008.

Objectives

The objective of this review was to assess the efficacy, effectiveness and safety ('effects') of amantadine and rimantadine in healthy adults.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (1966 to April Week 4, 2008), EMBASE (1990 to April 2008) and reference lists of articles.

Selection criteria

Randomised and quasi‐randomised studies comparing amantadine and/or rimantadine with placebo, control medication or no intervention, or comparing doses or schedules of amantadine and/or rimantadine in healthy adults.

Data collection and analysis

For prophylaxis (prevention) trials we analysed the numbers of participants with clinical influenza (influenza‐like‐illness or ILI) or with confirmed influenza A and adverse effects. Analysis for treatment trials was of the mean duration of fever, length of hospital stay and adverse effects.

Main results

Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.2). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prophylaxis were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal (GI) adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with amantadine than rimantadine. Neither drug affected the rate of viral shedding from the nose or the course of asymptomatic influenza.

Authors' conclusions

Amantadine and rimantadine have comparable efficacy and effectiveness in relieving or treating symptoms of influenza A in healthy adults, although rimantadine induces fewer adverse effects than amantadine. The effectiveness of both drugs in interrupting transmission is probably low. Resistance of influenza viruses to amantadine is a serious worldwide problem as shown by recent virological surveillances. Both drugs have adverse gastrointestinal (stomach and gut) effects, but amantadine can also have serious effects on the nervous system. They should only be used in an emergency when all other measures fail.

Keywords: Adult; Aged; Humans; Middle Aged; Influenza A virus; Amantadine; Amantadine/adverse effects; Amantadine/therapeutic use; Antiviral Agents; Antiviral Agents/adverse effects; Antiviral Agents/therapeutic use; Drug Administration Schedule; Emergencies; Influenza, Human; Influenza, Human/drug therapy; Influenza, Human/prevention & control; Randomized Controlled Trials as Topic; Rimantadine; Rimantadine/adverse effects; Rimantadine/therapeutic use; Virus Shedding; Virus Shedding/drug effects

Plain language summary

Antiviral drugs amantadine and rimantadine for preventing and treating the symptoms of influenza A in adults

The drugs amantadine and rimantadine can both help prevent and relieve the symptoms of influenza A in adults, but amantadine has more adverse effects.

The flu can be caused by many different viruses. One type is influenza A, with headaches, coughs and runny noses that can last for many days and lead to serious illnesses such as pneumonia. Amantadine and rimantadine are antiviral drugs. The review of trials found that both drugs are similarly helpful in relieving the symptoms of influenza A in adults, but only when there is a high probability that the cause of the flu is influenza A (a known epidemic, for example). It is likely that neither drug will interrupt the spread of influenza A and by treating symptoms may encourage viral spread in the community by people who are feeling better but are still infectious. Resistance of influenza viruses to amantadine is a serious worldwide problem as shown by recent surveys. Both drugs have adverse gastrointestinal (stomach and gut) effects, but amantadine can also have serious effects on the nervous system. They should only be used in an emergency when all other measures fail.

Background

Description of the intervention

The M2 ion channel blocking antiviral compounds amantadine hydrochloride (amantadine) and rimantadine hydrochloride (rimantadine) were licensed in 1976 and 1993 respectively as anti‐influenza drugs in the USA. Recently the World Health Organization has encouraged member countries to use antivirals in seasonal influenza "interpandemic periods". The rationale given is as follows: "wide scale use of antivirals and vaccines during a pandemic will depend on familiarity with their effective application during the interpandemic period. The increasing use of these modalities will expand capacity and mitigate the morbidity and mortality of annual influenza epidemics. Studies conducted during the interpandemic period can refine the strategies for use during a pandemic" (WHO 2005). It is also likely that given their low cost amantadine and rimantadine may be used in epidemic or pandemic situations.

This review was first published in 1999 and updated for the fourth time in April 2008.

Objectives

To identify, retrieve and assess all studies evaluating the effects of amantadine and rimantadine on influenza A in healthy adults.
To assess the effectiveness of amantadine and/or rimantadine in preventing cases of influenza A (prophylaxis) in healthy adults, both at an individual level and to interrupt transmission.
To assess the effectiveness of amantadine and/or rimantadine in shortening or reducing the severity of influenza A in healthy adults (treatment).
To estimate the frequency of adverse effects associated with amantadine and/or rimantadine administration in healthy adults.

Methods

Criteria for considering studies for this review

Types of studies

Any randomised or quasi‐randomised studies comparing amantadine and/or rimantadine in humans with placebo, control medication or no intervention or comparing doses or schedules of amantadine and/or rimantadine. Only studies assessing protection or treatment from exposure to naturally occurring influenza were considered initially.

Types of participants

Apparently healthy individuals (with no known pre‐existing chronic pathology known to aggravate the course of influenza) aged 14 to 60.

Types of interventions

Amantadine and/or rimantadine as prophylaxis and/or treatment for influenza, irrespective of target viral antigenic configuration.

Types of outcome measures

Clinical

Numbers and/or severity (however defined) of influenza cases and/or deaths occurring in amantadine and/or rimantadine and placebo or control groups.

Infectivity of index cases (measured by variables such as length of nasal shedding of influenza viruses or persistence in the upper airways).

Adverse effects

Number and seriousness of adverse effects, including cases of malaise, nausea, fever, arthralgias, rash, headache and more generalised and serious signs.

Search methods for identification of studies

Electronic searches

In the original review, published in The Cochrane Library 1999, issue 3, an electronic search of MEDLINE was carried out using the extended search strategy of the Cochrane Acute Respiratory Infections (ARI) Group (ARI Group 1998) with the following search terms or combined sets from 1966 to the end of 1997 in any language:

Influenza   Route (oral)   Route (parenteral)   Amantadine   Rimantadine

We read the bibliography of retrieved articles and of reviews of the topic in order to identify further trials. We also carried out a search of the Cochrane Controlled Trials Register (CCTR) and of EMBASE (1985 to 1997). In order to locate unpublished trials we wrote to the following:

manufacturers;
researchers active in the field;
first or corresponding authors of studies evaluated (but not necessarily included) in the review.

In the first updated review published in 2001, the Cochrane Acute Respiratory Infections Group's Trials Register was searched in March 2001, and CENTRAL (The Cochrane Library 2001, issue 2) was also searched for new trials.

In the second updated review in 2003, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2003, issue 4), MEDLINE (January 1966 to November week 2, 2003), EMBASE (1990 to November 2003) and reference lists of articles. We also contacted manufacturers, researchers and authors. There were no language restrictions.

In the third updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, issue 3), MEDLINE (2003 to August Week 4, 2005), EMBASE (October 2003 to July 2005) and reference lists of articles. We also contacted manufacturers, researchers and authors. There were no language restrictions.

In the fourth updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (2005 to April Week 4, 2008) and EMBASE (July 2005 to April 2008). There were no language or publication restrictions.

We ran the following search strategy on MEDLINE (a similar search strategy was used to search for trials on CENTRAL and EMBASE).

MEDLINE

1 exp INFLUENZA   2 influenza$   3 or/1‐2   4 exp AMANTADINE   5 amantadine   6 exp RIMANTADINE   7 rimantadine   8 or/4‐7   9 3 and 8   10 RANDOMIZED CONTROLLED TRIAL.pt.   11 CONTROLLED CLINICAL TRIAL.pt.   12 RANDOMIZED CONTROLLED TRIALS.sh.   13 RANDOM ALLOCATION.sh.   14 DOUBLE BLIND METHOD.sh.   15 SINGLE‐BLIND METHOD.sh.   16 or/10‐15   17 (ANIMAL not HUMAN).sh.   18 16 not 17   19 CLINICAL TRIAL.pt.   20 exp Clinical Trials   21 (clin$ adj25 trial$).ti,ab.   22 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.   23 PLACEBOS.sh.   24 placebo$.ti,ab.   25 random$.ti,ab.   26 or/19‐25   27 26 not 17   28 18 or 27   29 9 and 28

Data collection and analysis

Selection of studies

Two review authors (VD, TOJ) independently read all trials retrieved in the search and applied the inclusion criteria. VD and TOJ assessed trials fulfilling the review inclusion criteria for quality, and analysed results.

Data extraction and management

Two review authors (TOJ and DR) extracted data from included studies on standard forms. The procedure was supervised and arbitrated by VD. The following data were extracted, checked and recorded:

Characteristics of participants.
Number of participants.
Age, gender, ethnic group and risk category.

Characteristics of interventions

Type of antiviral, type of placebo, dose, treatment or prophylaxis schedule and length of follow up (in days).

Characteristics of outcome measures

Number and severity of influenza and ILI cases and deaths in amantadine/rimantadine and placebo groups.
Length of nasal shedding of influenza viruses or persistence in the upper airways.

Adverse effects

Four categories were used:

Gastrointestinal (GI) symptoms (nausea, vomiting, dyspepsia, diarrhoea and constipation).
Increased central nervous system (CNS) activity (insomnia, restlessness, light‐headedness, nervousness and concentration problems).
Decreased CNS activity (malaise, depression, fatigue, vertigo and feeling drunk).
Dermatological changes (urticaria and rash).

(Adverse effect data were collected as the number of participants experiencing each (or any) adverse effect).

Number of withdrawals due to adverse effects.
Date of trial.
Location of trial.
Sponsor of trial (specified, known or unknown).
Publication status.

Assessment of risk of bias in included studies

We carried out assessment of methodological quality for RCTs using criteria from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). We assessed studies according to randomisation, generation of the allocation sequence, allocation concealment, blinding and follow up. We entered extracted data into Cochrane Review Manager software (RevMan 2008). Aggregation of data was dependent on the sensitivity and consistency of definitions of exposure, populations and outcomes used.

Assessment of trial quality was made according to the following criteria:

Generation of allocation schedule (defined as the methods of generation of the sequence which ensures random allocation).
Measure(s) taken to conceal treatment allocation (defined as methods to prevent selection bias, that is to say, to ensure that all participants have the same chance of being assigned to one of the arms of the trial. It protects the allocation sequence before and during allocation).
Number of drop‐outs of allocated healthcare worker participants from the analysis of the trial (defined as the exclusion of any participants for whatever reason ‐ deviation from protocol, loss to follow up, withdrawal, discovery of ineligibility, while the unbiased approach analyses all randomised participants in the originally assigned groups, regardless of compliance with protocol ‐ known as intention‐to‐treat analysis).
Measures taken to implement double‐blinding (a single blind study is one in which observer(s) or subjects are kept ignorant of the group to which the subjects are assigned). When both the observer and the participants are kept ignorant of assignment the trial is called double‐blind. Unlike allocation concealment, double blinding seeks to prevent ascertainment bias and protects the sequence after allocation).

For criteria 2, 3 and 4 there is empirical evidence that low quality in their implementation is associated with exaggerated trial results (Schulz 1995) and it is reasonable to infer a quality link between all four items.

The four criteria were assessed by answering the following questions:

Generation of allocation schedule

Did the review author(s) use?

Random number tables.
Computer random‐number generator.
Coin tossing.
Shuffling of allocation cards.
Any other method which appeared random.

Concealment of treatment allocation

Which of the following was carried out?

There was some form of centralised randomisation scheme where details of an enrolled participant were passed to a trial office or a pharmacy to receive the treatment group allocation.
Treatment allocation was assigned by means of an on‐site computer using a locked file which could be accessed only after inputting the details of the participant.
There were numbered or coded identical looking compounds which were administered sequentially to enrolled participants.
There were opaque envelopes, which had been sealed and serially numbered, utilised to assign participants to intervention(s).
A mixture of the above approaches including innovative schemes, provided the method appears impervious to allocation bias.
Allocation by alternation or date of birth or case record or day of the week or presenting order or enrolment order.

Concealment methods were described as 'adequate' for (1), (2), (3), (4) or (5). Method (6) was regarded as 'inadequate',as were trials using a system of random numbers or assignments. For some trials allocation was regarded as 'unclear' if only terms such as 'lists' or 'tables' or 'sealed envelopes' or 'randomly assigned' were mentioned in the text.

Exclusion of allocated participants from the analysis of the trial

Did the report mention explicitly the exclusion of allocated participants from the analysis of trial results?
If so did the report mention the reason(s) for exclusion? (if yes, specify).

Measures to implement double blinding

Did the report mention explicitly measures to implement and protect double blinding?
Did the author(s) report on the physical aspect of amantadine/rimantadine administration, that is, appearances, colour, route of administration.

Arbitration procedure

There was no disagreement between TOJ and VD on the quality of trials, but DR was appointed as arbitrator.

Measures of treatment effect

The risk ratios (RR) of events comparing prophylaxis and placebo groups from the individual trials were combined using the DerSimonian and Laird (DerSimonian 1986) random‐effects model to include between‐trial variability. We carried out a sensitivity analysis of methods used, comparing our results obtained using the fixed‐effect and random‐effects models. In the prophylaxis trials efficacy was derived as 1‐RR x 100 or the RR when not significant. Odds ratios (OR) were used to estimate association of adverse effects with exposure to antivirals. In treatment trials the choice of methods for combining the estimates of severity of influenza depended on the format in which the data were presented. We made comparisons between the mean duration of symptoms in the two groups, and methods for combining differences in means were used. Specifically, where the data were presented as the number of subjects with duration of symptoms beyond a cut‐off time period these were presented as 'cases with fever at 48 hours'. The bewildering array of outcomes used in the treatment trials prevented us from using more than the 'cases with fever' outcome.

Results

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.

Prophylaxis trials

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):

Brady 1990   Callmander 1968   Dolin 1982   Hayden 1981   Kantor 1980   Máté 1970   Millet 1982   Monto 1979   Muldoon 1976   Nafta 1970   Oker‐Blom 1970   Payler 1984   Peckinpaugh 1970a   Peckinpaugh 1970b   Pettersson 1980   Plesnik 1977   Quarles 1981   Reuman 1989   Schapira 1971   Smorodintsev 1970   Wendel 1966

Treatment trials

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).

Galbraith 1971   Hayden 1980   Hayden 1986   Hornick 1969a   Hornick 1969b   Hornick 1969c   Hornick 1969d   Ito 2000   Kitamoto 1968   Kitamoto 1971   Knight 1970   Máté 1970   Rabinovich 1969   Younkin 1983   van Voris 1981   Wingfield 1969

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).

Risk of bias in included studies

Two review authors (VD, TOJ) assessed allocation method, allocation concealment, blinding and completeness of follow up. There were 30 trials in all, 28 of which considered either amantadine and/or rimantadine efficacy and two (Hayden 1981; Millet 1982) which considered adverse effects only. Twelve prophylaxis trials and seven treatment trials reported sufficient data on adverse effects. The quality of the prophylaxis trials was relatively good, considering their age. Among the 20 prophylaxis trials, 17 stated that the allocation method was randomised, although only four mentioned a particular method (Brady 1990; Monto 1979; Pettersson 1980; Reuman 1989) and two did not mention random allocation at all (Plesnik 1977; Schapira 1971). These two trials have therefore been classified as controlled clinical trials (CCTs) rather than RCTs. All prophylaxis trials were stated to be double‐blind, with the exception of Payler 1984 which was open and had no placebo group (the comparison group was no intervention other than influenza vaccine at the beginning of the season). Among the 13 treatment trials, 11 stated that the allocation method was randomised and no trials mentioned a particular method. For Hornick's trials (Hornick 1969a; Hornick 1969b; Hornick 1969c; Hornick 1969d) there was no mention of random allocation at all. Very limited information was available for one trial (Ito 2000).

Major flaws in the reporting of trials were:

Lack of information on the completeness of follow up. In many trials there was a large difference between the number randomised and the number who actually participated.
Lack of detailed description of methods to conceal allocation with many trials just describing a "double‐blind" procedure.
Frequent inconsistencies in the reporting of numerators and denominators in various arms of trials.
In the treatment trials, the use of a bewildering variety of outcomes, such as severity scores, of which none were alike.

A full description of all trials is available in the 'Characteristics of included studies' table.

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.

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

Date	Event	Description
30 April 2008	Amended	Converted to new review format.
26 April 2008	New search has been performed	Searches conducted.
14 February 2006	New citation required and conclusions have changed	Substantive amendment.
15 September 2005	New search has been performed	Searches conducted.
26 April 2004	Feedback has been incorporated	Feedback and reply added.
9 November 2003	New search has been performed	Searches conducted.
29 March 2001	New search has been performed	Searches conducted.
29 April 1998	New search has been performed	Searches conducted.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Influenza cases	11	4645	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.24, 0.65]
1.1 Unvaccinated population	10	4109	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.28, 0.74]
1.2 Vaccinated population	1	536	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.03, 0.34]
2 ILI cases	14	17496	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.64, 0.87]
2.1 Unvaccinated population	13	14901	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.62, 0.90]
2.2 Vaccinated population	2	2595	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.07, 2.52]
3 Adverse effects	13		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Gastrointestinal	5	3336	Odds Ratio (M‐H, Random, 95% CI)	2.56 [1.37, 4.79]
3.2 Increased CNS activity	9	5002	Odds Ratio (M‐H, Random, 95% CI)	2.54 [1.50, 4.31]
3.3 Decreased CNS activity	7	3797	Odds Ratio (M‐H, Random, 95% CI)	1.73 [0.86, 3.45]
3.4 Dermatological changes	3	918	Odds Ratio (M‐H, Random, 95% CI)	1.55 [0.39, 6.20]
3.5 All adverse effects	6	4274	Odds Ratio (M‐H, Random, 95% CI)	1.70 [0.99, 2.93]
3.6 Withdrawals due to adverse effects	6	2276	Odds Ratio (M‐H, Random, 95% CI)	2.54 [1.60, 4.06]
4 Viral nasal shedding or persistence in upper airways at 2 to 5 days	1	79	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.53, 0.87]
5 Influenza cases (asymptomatic)	4	963	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.40, 1.80]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Influenza cases	3	688	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.08, 1.08]
1.1 Unvaccinated population	3	688	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.08, 1.08]
1.2 Vaccinated population	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 ILI cases	3	688	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.35, 1.20]
2.1 Unvaccinated population	3	688	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.35, 1.20]
2.2 Vaccinated population	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Adverse effects	5		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Gastrointestinal	2	357	Odds Ratio (M‐H, Random, 95% CI)	4.39 [1.43, 13.52]
3.2 Increased CNS activity	3	652	Odds Ratio (M‐H, Random, 95% CI)	1.58 [0.78, 3.19]
3.3 Decreased CNS activity	2	243	Odds Ratio (M‐H, Random, 95% CI)	1.31 [0.23, 7.50]
3.4 Dermatological changes	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.5 All adverse effects	3	558	Odds Ratio (M‐H, Random, 95% CI)	1.96 [1.19, 3.22]
3.6 Withdrawals due to adverse effects	3	625	Odds Ratio (M‐H, Random, 95% CI)	1.10 [0.48, 2.51]
4 Influenza cases (asymptomatic)	1	265	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.45, 4.27]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Influenza cases	2	455	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.48, 1.65]
1.1 Unvaccinated populations	2	455	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.48, 1.65]
1.2 Vaccinated populations	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 ILI cases	2	455	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.57, 1.35]
2.1 Unvaccinated populations	2	455	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.57, 1.35]
2.2 Vaccinated populations	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Adverse effects	3		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Gastrointestinal	1	130	Odds Ratio (M‐H, Random, 95% CI)	1.28 [0.51, 3.16]
3.2 Increased CNS activity	2	422	Odds Ratio (M‐H, Random, 95% CI)	3.11 [1.67, 5.78]
3.3 Decreased CNS activity	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.4 Dermatological changes	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.5 All adverse effects	2	339	Odds Ratio (M‐H, Random, 95% CI)	1.60 [0.28, 9.26]
3.6 Withdrawals due to adverse effects	3	631	Odds Ratio (M‐H, Random, 95% CI)	2.49 [1.26, 4.93]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of fever (37 degrees centigrade or more) in days	10	542	Mean Difference (IV, Random, 95% CI)	‐0.99 [‐1.26, ‐0.71]
2 Cases with fever at 48 hours	2	85	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.07, 0.66]
3 Adverse effects	4		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Gastrointestinal	3	494	Odds Ratio (M‐H, Random, 95% CI)	1.34 [0.32, 5.61]
3.2 Increased CNS activity	2	465	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.23, 2.53]
3.3 Decreased CNS activity	3	491	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.31, 1.38]
3.4 Dermatological changes	2	465	Odds Ratio (M‐H, Random, 95% CI)	1.40 [0.14, 13.78]
3.5 Withdrawals due to adverse effects	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Duration of hospital stay (in days)	1	36	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐2.20, 0.40]
5 Viral nasal shedding or persistence in upper airways at 2 to 5 days	3	170	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.76, 1.24]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of fever (37 degrees centigrade or more) in days	3	82	Mean Difference (IV, Random, 95% CI)	‐1.24 [‐1.71, ‐0.76]
2 Cases with fever at 48 hours	4	122	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.05, 0.53]
3 Adverse effects	2		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Gastrointestinal	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Increased CNS activity	1	14	Odds Ratio (M‐H, Random, 95% CI)	1.0 [0.10, 10.17]
3.3 Decreased CNS activity	1	31	Odds Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 5.24]
3.4 Dermatological changes	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.5 Withdrawals due to adverse effects	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Viral nasal shedding or persistence in upper airways at 2 to 5 days	3	152	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.30, 1.53]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of fever (37 degrees centigrade or more) in days	1	40	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.56, 0.96]
2 Cases with fever at 48 hours	2	73	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.23, 4.37]
3 Adverse effects	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Gastrointestinal	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Increased CNS activity	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 Decreased CNS activity	1	33	Odds Ratio (M‐H, Random, 95% CI)	22.58 [1.13, 452.21]
3.4 Dermatological changes	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.5 Withdrawals due to adverse effects	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of fever (37 degrees centigrade or more) in days	2	78	Mean Difference (IV, Random, 95% CI)	0.25 [‐0.37, 0.87]
2 Adverse effect ‐ insomnia	1	47	Odds Ratio (M‐H, Random, 95% CI)	0.92 [0.26, 3.20]
3 Viral nasal shedding or persistence in upper airways at 2 to 5 days	1	47	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.44, 1.13]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Symptoms score in confirmed cases (respiratory illness)	1	20	Mean Difference (IV, Random, 95% CI)	‐1.0 [‐3.64, 1.64]
2 Symptoms score in confirmed cases (constitutional illness)	1	20	Mean Difference (IV, Random, 95% CI)	‐2.0 [‐16.98, 12.98]
3 Adverse effects ‐ local ‐ nasal irritation	1	20	Odds Ratio (M‐H, Random, 95% CI)	12.50 [1.09, 143.43]
4 Viral nasal shedding or persistence in upper airways at 2 to 5 days	1	20	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.58, 4.05]

Methods	Prophylaxis, randomised, double‐blind, controlled trial of rimantadine during an epidemic of influenza A/Leningrad/87 [H3N2] virus
Participants	228 healthy, not previously vaccinated, adult volunteers aged 18 to 55
Interventions	Participants were randomised to receive either rimantadine 100 mg daily or placebo for 6 weeks
Outcomes	Laboratory: paired sera were taken from all participants at the beginning and the end of the study. Within‐trial surveillance was carried out on a weekly basis and cases were defined on the basis of seroconversion and a pre‐defined list of symptoms and signs. The study reports separately on the efficacy of asymptomatic cases of influenza (diagnosed from a rise in antibody titres). Viral isolation took place by nasal washout
Notes	Brady is a clearly written and well‐reported trial (with the exception of the minor discrepancy between text and tables on the affiliation of drop‐outs). Randomisation was computer‐generated and allocation was concealed with a centralised scheme. Additionally, intention‐to‐treat analysis is clearly stated in the text
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Methods	Randomised controlled trial conducted in a community, including some military personnel. During the period of the trial there was considerable influenza A2 (Leningrad) activity
Participants	The age range of the 94 volunteer participants is 20 to 60 years (44 male and 50 female)
Interventions	The intervention arm received 100 mg of amantadine hydrochloride twice daily and the control arm (a not further described placebo)
Outcomes	Efficacy: ILI cases (from a symptoms list) in each arm and a symptom score (reported in Table 1 without an indication of time of intensity). Surveillance for adverse effects (systemic) was carried out. A list of symptoms (without a denominator) is reported in Table 2
Notes	The practices of randomisation, allocation and concealment are not further defined, making it impossible to assess methodological rigour although as the distribution of sex and age was checked and found to be similar, randomisation is likely to have been satisfactory
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Prophylaxis, randomised, double‐blind, placebo controlled trial carried out in Burlington Vermont, USA. The trial was commenced on 10 January 1981 during an outbreak of influenza A/Bangkok/1/79H3N2 and A/Brazil/11/78H1N1 detected by surveillance (see Figure 1 in the text of the trial report)
Participants	Participants initially were 450 healthy non‐vaccinated volunteers aged 18 to 45 (mean age 25.6 + 0.45 years). The final total of participants was 378 (132 in the placebo arm, 133 in the rimantadine arm and 113 in the amantadine arm)
Interventions	Amantadine 200 mg daily or rimantadine 200 mg or placebo
Outcomes	Efficacy: case definition was based on a list of symptoms plus virus isolation or a rise in serum antibody titres to influenza A. Table 1 presents both ILI cases and cases defined on the basis of laboratory confirmation. The study reports separately the efficacy on asymptomatic cases of influenza (diagnosed from a rise in antibody titres)
Notes	Although a well‐written report, no real information is given on random allocation, blinding and concealment. Intention‐to‐treat analysis was not carried out
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Treatment trial carried out in December 1969 to January 1970, at the time of an epidemic (possible pandemic) caused by a variant of A2/Hong Kong/68
Participants	Participants were unvaccinated family members aged more than 2 years recruited by 57 family doctors in the United Kingdom
Interventions	153 participants with laboratory‐confirmed diagnosis of influenza A2 were randomised to receive either doses appropriate to their ages: for adults amantadine 200 mg a day (n = 72, mean age 37.4 years), or placebo (n = 81, mean age 39.1). Treatment was commenced within 48 hours of symptoms and continued for 7 days
Outcomes	Efficacy: outcomes are clinical (Tables 2 and 3) and serological (Table 4 and 5). In our meta‐analysis, we have included the time of duration of fever (in days after commencement of treatment (Table 2) approximating the standard deviation of duration (not reported in the text) from the P value reported in the table. No adverse effect is mentioned or reported in the text
Notes	The authors conclude that amantadine treatment was effective in controlling fever, but no other symptoms, possibly due to lack of sensitivity of surveillance methods. Although randomisation is clearly mentioned, no detailed description of allocation and concealment is given, making its assessment impossible
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Randomised, double‐blind, placebo controlled treatment trial of inhaled (20 mg daily) amantadine
Participants	20 participants
Interventions	Participants were randomised to receive either amantadine (n = 9, mean 19.1 years) or diluted water placebo (n = 11, mean age 20.3 years) within 48 hours of developing symptoms for a duration of 4 days
Outcomes	Laboratory: influenza A/Texas/77[H3N2] and influenza A/USSR/77[H1N1] caused infection in the participants Efficacy : cases were ascertained clinically and immunologically and outcomes in all cases are presented as scores at day 2 of follow up for “respiratory illness” and “constitutional illness” which does not include ILI symptoms (Figures 1 and 2). Adverse effects reported in Table 2 are all local and due to the aerosol. We only included nasal burning as the most significant The study reported data on persistence and shedding of influenza A viruses from the upper airways. Viral titres were significantly lower in the treatment arm
Notes	The trial was clearly randomised, but no description of allocation and concealment is given making its assessment impossible. Additionally the rationale for distinguishing between constitutional and respiratory illness is unclear, results of outcomes are not clearly reported (mean scores only are given) and reasons for drop‐outs are not explained
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	A toxicity study reporting a randomised controlled trial undertaken in an unspecified period in USA and published in 1981
Participants	The setting is that of a state farm insurance company and the participants were 251 adult volunteers, aged between 18 to 65 (mean age of 32)
Interventions	Two trials were carried out simultaneously, both involving rimantadine and amantadine. One was a low dose (200 mg daily of each drug, n = 52) and the other a higher dose trial (300 mg daily of each drug, n = 199). The low dose trial, however, has been excluded due to the absence of any 'cases' data, and the lack of outcomes
Outcomes	Safety: systemic symptoms only with no other classification were noted, although not specified
Notes	The practices of randomisation, allocation and concealment are not further defined, although all doses were stated as being administered by a project nurse. This is a poorly reported trial as no detailed classification of adverse effects is given, which is a strange practice for a toxicity study. Additionally, data reported in the text are not consistent with that in Table 1.c. Overall 41 out of 67 (61%) in the amantadine arm, 13 out of 66 in the placebo arm (20%) and 18 out of 63 in the rimantadine arm (29%) experienced adverse effects
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Randomised double‐blind, placebo controlled treatment trial of oral rimantadine   The trial took place in the universities of Virginia and Michigan in 1983
Participants	14 adults with confirmed A/Bangkok/1/79(H3N2) influenza
Interventions	Participants were randomised to receive either rimantadine 200 mg once daily (mean age 28 years) or placebo (mean age 23 years) for 5 days. Treatment started within 48 hours of symptom onset
Outcomes	Efficacy: nasal virus shedding, duration of fever (in hours) and symptom scores (presented broken down into systemic – headache, chills, malaise, etc. and respiratory). Average duration of fever in the rimantadine arm was 31 hours (SD 22 hours) and 68 (SD 8 hours) in the placebo group
Notes	Although the trial is extremely clearly reported, no description of allocation and concealment is given
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Placebo controlled, double‐blind treatment comparison of amantadine 100 mg with lactose placebo twice daily for 10 days. 94 inmates were randomised to receive amantadine and 103 placebo in January 1968, during an epidemic of influenza A2
Participants	Participants were 153 inmates of 4 prisons: Jessup, Richmond, Walls and Wynne. Hornick 1969a reports results from the Jessup site (renamed Jessup/Maryland)
Interventions	Amantadine n = 15 mean duration 66 hours, placebo n = 15, duration 92 hours, duration SD = 35 hours (for both arms). We transformed the duration data into 24‐hour days
Outcomes	Efficacy: influenza diagnosis was made on the basis of clinical and laboratory findings. The study reported data on persistence and shedding of influenza A viruses from the upper airways
Notes	The word “randomised” in not visible in the text, however denominators in each of the arms are highly suggestive of randomisation. No mention of the allocation procedure is made in the text, nor are drop‐outs mentioned. Overall results show that participants could be divided into "rapid resolvers" to treatment (whose illness resolved within 36 hours or less), medium resolvers (whose illness resolved within 24 to 36 hours) and slow resolvers (whose illness resolved in more than 36 hours) in both arms of the trial
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Controlled treatment trial of the efficacy of amantadine during the 1999 A/Sidney/05/97 influenza season. The trial was carried out in Japan among clinic attenders within 48 hours of testing positive for influenza. Allocation is described only as semi‐randomised. Follow up is not described
Participants	49 people aged 35.6 (mean) with influenza took part   No drop‐outs are mentioned
Interventions	Participants were assigned to either oral amantadine 100 mg daily and standard medication (combination of antibiotics, NSAIDs, antihistamines and cough mixtures) or standard medication only for 4.2 + 1.2 days
Outcomes	Efficacy: maximum body temperature (in degrees C) after treatment in days   Duration of fever > 37 ºC and > 38 in days   Duration of aching in days   Duration of fatigue in days
Notes	The authors conclude that amantadine hastens significantly the resolution of fever > 38 ºC by 0.7 a day. Assessment of the trial was hampered by the limited information available in English
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	C ‐ Inadequate

Methods	Prophylaxis, double‐blind, randomised controlled trial of the efficacy and safety of oral amantadine compared to a (not further defined) placebo. The trial took place over the period 20 February to 7 March 1978 in the military barracks at Fort Sam Houston (FSH), Texas and the target serotype was A/USSR/77
Participants	Trial participants were 139 healthy paramedic recruits (mean age 22 years)
Interventions	Participants were randomised to receive either amantadine 100 mg tablets twice daily (n = 64) or placebo (n = 62)
Outcomes	Laboratory: paired sera were obtained at the beginning of the study and 5 weeks later Efficacy: case definition consisted of a list of recognised symptoms by severity, with serological confirmation and adverse effects were recorded in the questionnaires
Notes	Although the trial was randomised and allocation concealment was protected through a system of sealed envelopes, the difficulty in reconciling figures and understanding what actually happened during the trial makes this a very poorly reported study. No reason for the loss of 20 participants to follow up is given
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Methods	Randomised, double‐blind treatment trial comparison, took place during a A2/Hong Kong influenza pandemic in January 1969
Participants	29 unvaccinated male inmates aged 22 to 42 years of 2 units of the Texas Department of Corrections. Only participants with both serological and culture (nasal shedding of the virus) confirmation of illness took part: of the 37 original participants only 29 were included Illness had become manifest an average of 42 hours before for amantadine‐treated patient and 36 hours for placebo (the authors report that the differences were not significant)
Interventions	Amantadine compared to placebo. Participants were randomised to receive either amantadine 100 mg (n = 13) or placebo capsules (n = 16) twice daily for at least 6 days
Outcomes	Efficacy: outcomes were clinical (duration of fever and symptom score) or serological and laboratory‐based (antibody titre and viral shedding). Illness had become manifest an average of 42 hours before for amantadine‐treated patient and 36 hours for placebo (the authors report that the differences were not significant)
Notes	Although randomisation was clearly applied and no drop‐outs are reported, no description of allocation and concealment is given making its assessment impossible
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

PERMALINK

Amantadine and rimantadine for influenza A in adults

Tom Jefferson

Vittorio Demicheli

Carlo Di Pietrantonj

Daniela Rivetti

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the intervention

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Clinical

Adverse effects

Search methods for identification of studies

Electronic searches

MEDLINE

Data collection and analysis

Selection of studies

Data extraction and management

Characteristics of interventions

Characteristics of outcome measures

Adverse effects

Assessment of risk of bias in included studies

Generation of allocation schedule

Concealment of treatment allocation

Exclusion of allocated participants from the analysis of the trial

Measures to implement double blinding

Arbitration procedure

Measures of treatment effect

Results

Description of studies

Prophylaxis trials

Treatment trials

Risk of bias in included studies

Effects of interventions

1. Trial symptom outcomes used.

Discussion

Authors' conclusions

Implications for practice.

Implications for research.

Feedback

Missing study?

Summary

Reply

Contributors

What's new

History

Notes

Acknowledgements

Data and analyses

Comparison 1. Oral amantadine versus placebo (prophylaxis).

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

Comparison 2. Oral rimantadine versus placebo (prophylaxis).

2.1. Analysis.

2.2. Analysis.

2.3. Analysis.

2.4. Analysis.

Comparison 3. Oral amantadine versus oral rimantadine (prophylaxis).

3.1. Analysis.

3.2. Analysis.

3.3. Analysis.

Comparison 4. Oral amantadine versus placebo (treatment).

4.1. Analysis.

Methods	Randomised, double‐blind safety trial of amantadine alone or in combination with chlorpheniramine (an anti‐histaminic compound), rimantadine alone or chlorpheniramine. The trial was conducted between October 1979 and January 1980
Participants	52 healthy adult volunteers recruited from the University of California at Los Angeles (USA)
Interventions	Amantadine 100 mg and chlorpheniramine placebo (n = 10), amantadine 100 mg and chlorpheniramine 4 mg (n = 11), chlorpheniramine 4 mg and antiviral placebo (n = 11), rimantadine 100 mg and chlorpheniramine placebo (n = 10) or antiviral placebo and chlorpheniramine placebo (n = 10) twice daily for 3 to 4 days
Outcomes	Safety: subjective side effects (from a predefined list) with a grading of 1 (mild) to 3 (severe) and performance testing
Notes	The study was randomised and certainly double‐blind, with centralised preparation of active and placebo tablets
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Methods	Cross‐over, prophylaxis, controlled trial conducted in a school near Chicago (USA) between 2 December and 20 December 1968 (period 1). The study took place during the pandemic of A/Hong Kong/1/68 (H3N2)
Participants	105 unvaccinated volunteer students aged around 21 years old took part
Interventions	At the beginning and the end of period 1 blood samples were taken from participants. During the 18 days of period 1 the 53 individuals in the intervention arm received 100 mg of amantadine hydrochloride twice daily and the control arm (a not further described oral placebo). After a 'holiday' period of 16 days (period 2) the participants were crossed over to assess whether withdrawal of amantadine rendered participants more or less susceptible to infection. The procedure was inverted and students were followed up for a further 10 days (period 3)
Outcomes	Efficacy: ILI cases (from a symptom score coupled with virus‐specific antibody rise). This allowed the authors to distinguish non‐influenza related illness during periods 1 and 2 (reported in Table 1 without an indication of intensity of symptoms). During period 1 (Table 2) 6 students had influenza (5 with serological confirmation) out of the 53 in the intervention arm and 10 (2 with serological confirmation) out of the 52 in the placebo arm Adverse events are described as insignificant but no data are reported
Notes	The authors conclude that amantadine is effective in a preventive role. The practices of randomisation, allocation and concealment are not defined, making it impossible to assess methodological rigour, although the similar numbers of participants in each arm led us to consider this a randomised trial. No drop‐outs are reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Cluster randomised, placebo controlled prevention and treatment trial of amantadine during the 1969 Hong Kong influenza epidemic in 7 military units in Hungary. Treatment was started as soon as the outbreak was recognised and lasted for up to 3 weeks. Randomisation was carried out by dormitory within the same barrack block
Participants	4740 healthy male soldiers aged 18 to 21 from seven different military units
Interventions	Participants were randomised to oral placebo or amantadine 100 mg twice daily as soon as the outbreak became clear. However in the units 1 to 4 the allocation procedure worked well but in the remaining units (5 to 7) the outbreak was only recognised later and some soldiers were partially treated or not treated at all. Surveillance showed that in units 5 and 7 influenza A activity was minimal and mixed with that of other agents, whereas in units 1 to 4 and 6 influenza activity was high. Because of uneven exposure to amantadine, only data for units 1 to 4 were extracted
Outcomes	Serological/laboratory: viral isolation or antibody response   Paired sera (from 25 subjects from each arm) Effectiveness: cases of influenza and cases of ILI (no clear definition was given)   Fever (duration and peak)   Admission to infirmary   Complications   In the results section outcomes relating to complications and duration of fever are reported by 3 subgroups of soldiers admitted to hospital/infirmary during the trial. These groups are 'V' (amantadine recipients), 'U' (placebo recipients) and 'P' (recipients of no intervention). The complications data are reported in 'U' + 'P' groups with no breakdown, leading to loss of the data As the data relate to soldiers who are already admitted to the infirmary with influenza symptoms, this part of the trial is treatment. ILI outcome data are unclearly reported Safety: the text mentions a pre‐trial test for safety on 50 soldiers in which no adverse effects were detected but no further data are reported
Notes	The authors conclude that amantadine failed to affect morbidity but reduced peak and duration of fever, duration of stay in infirmary and the incidence of complications, especially lower respiratory tract infections. Considering its age the trial is reported reasonably but lack of clarity over allocation schedules, outcome definition and amantadine coverage has led to loss of data. In practice the trial is a mix of prevention and treatment. The analysis presented in the report did not account for the clustering of allocation by dormitory, and inadequate information is provided to allow a post‐analysis adjustment for clustering
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Prophylaxis randomised open trial of 536 members of Malvern Boys School in the UK. A/H1N1 was the prevalent viral strain
Participants	Boys aged 13 to 19 years had been previously immunised in the autumn of 1982 (viral strain not reported)
Interventions	Boys were randomised to receive either amantadine 100 mg daily (n = 267 or no treatment n = 269) for 14 days. The trial started on 18 February 1983, as soon as the cases of laboratory‐confirmed influenza were described
Outcomes	Efficacy: case definition is unclear but from the results (Table 2) it would appear that clinical definitions and laboratory isolates were used
Notes	Although the trial was randomised, the design is open and the analysis was not carried out on an intention‐to‐treat basis. Additionally, length of follow up is not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	C ‐ Inadequate

Methods	Randomised trial of the effects of oral amantadine for 28 days. Individuals in each arm, 3 days after commencing treatment were assigned to be injected with either influenza vaccine (2059 individuals) or subcutaneous saline placebo (2124 individuals). Peckinpaugh/1 was a randomised, factorial, double‐blind, controlled trial conducted between 5 December 1967 and 1 June 1968 during the 1968 to 1969 pandemic
Participants	4183 US Naval trainees. Data for those who received vaccine were not extracted
Interventions	Comparison of the effects of oral amantadine (200 mg daily) on 2079 individuals and oral placebo on 2104 individuals with and without the addition of vaccine
Outcomes	Efficacy: outcomes are presented in histogram form (Figure 3) by intervention arm (amantadine and influenza vaccine ‐ 1039 individuals, influenza vaccine and oral placebo ‐ 1020 individuals, amantadine and subcutaneous placebo ‐ 1040 and subcutaneous and oral placebo ‐ 1084 individuals). Outcomes in the figure are: % of participants who did not seek treatment, sought treatment as outpatients or were admitted to local hospital. Adverse events are described as nil
Notes	Both studies report no effect, probably because of low influenza circulation. The study was definitely randomised and arrangements to conceal allocation appear adequate. The standard of reporting is poor with outcomes reported in histogram form, making estimation of their incidence necessary.   Additionally contradictory statements in the text (concerning the definition of cases and serological outcomes) make interpretation of the text difficult
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Methods	Peckinpaugh 2 reports the results of a study conducted from December 1968 to May 1969 during the 1968 to 1969 pandemic
Participants	US Naval recruits
Interventions	Recruits were randomised to receive either amantadine 200 mg daily (n = 1329) or placebo (n = 1321) orally for 20 days
Outcomes	As in Peckinpaugh 1, serological assessment was carried out on one fourth of participants (416 sera pairs). Outcome definition and presentation (Figure 6) were similar to those in Peckinpaugh 1, as is our transformation of them
Notes	Both studies report no effect, probably because of low influenza circulation. The study was definitely randomised and arrangements to conceal allocation appear adequate. The standard of reporting is poor with outcomes reported in histogram form, making estimation of their incidence necessary.   Additionally contradictory statements in the text (concerning the definition of cases and serological outcomes) make interpretation of the text difficult
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Methods	Prophylaxis randomised double blind placebo‐controlled trial carried out at the University of Texas
Participants	Participants were 444 healthy students aged 18 to 24 who were followed up for 6 weeks on the basis weekly of self‐reporting. The trial was commenced on week 7 (? mid‐February) 1978 during an epidemic of influenza A/USSR/90/77 virus
Interventions	Students were randomised to receive either amantadine (100 mg), or rimantadine (100 mg), or placebo (not specified) tablets twice daily
Outcomes	Efficacy: cases were defined on the basis of paired sera and clinical symptoms. Viral isolation from throat swabs was additionally carried out
Notes	The practices of randomisation, allocation and concealment are not defined, making it impossible to assess methodological rigour. Analysis on the basis of intention‐to‐treat was not carried out and the overall quality of reporting is poor (with no complete details of reasons for drop‐out). This study was probably commenced at of just after the peak of influenza transmission with a consequent possible underestimation of the efficacy of prophylaxis interventions (due to late commencement of prophylaxis)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Randomised, placebo controlled treatment trial of the efficacy of rimantadine during the 1967 A2/Iowa/1/67 influenza season. The trial was carried out in the Iowa state penitentiary, USA. Treatment was started as soon as the outbreak was recognised and lasted 10 days. Randomisation is not described in detail but allocation concealment was centralised using coded bottles
Participants	22 unvaccinated inmates of the penitentiary took part. 19 had a retrospective diagnosis of influenza infection (through antibody titre assessment), 1 dropped out of the trial of the placebo arm and no further details are given of the 3 participants who had ILI symptoms but no serological confirmation of infection. All participants were enrolled if they had ILI symptoms of less than 48 hours duration. All 18 influenza cases had fever, chills, malaise and fatigue, nasal stuffiness, sore or dry throat and nasal mucosal swelling
Interventions	Participants were randomised to oral placebo or rimantadine 150 mg twice daily for 10 days. No symptomatic medication was given
Outcomes	Serological/laboratory: viral isolation antibody response (paired sera) Effectiveness: cases of influenza (symptoms of ILI plus antibody response); duration of symptoms (fever ‐ oral temp > 37 ºC ‐ nasal stuffiness, headache, sneezing, chills, sore throat, sweats, cough, malaise, sputum, myalgia, chest pain, eye pain, anorexia, apathetic appearance, hyperemic nasal mucosa, nasal discharge, nasal mucosa swelling, pharyngitis); severity of symptoms (4‐point scale 0 = not present, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe) The text does not mention any safety outcome data
Notes	The authors conclude that rimantadine hastens significantly the resolution of symptoms (50% difference in 36 hours). A well‐reported trial considering its age
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Methods	Reuman is the report of a double‐blind, prophylaxis, randomised controlled trial. The study was conducted in Cincinnati Christ Hospital, Ohio, USA during the 1985 to 1986 influenza season. Participants were followed up weekly for 6 weeks through symptom diaries and visits and all those reporting with influenza‐like illness (pre‐defined from a list of signs and symptoms) were seen on 2 consecutive days for examination and collection of nasal washouts
Participants	Participants were 476 healthy hospital personnel aged 18 to 55
Interventions	There were 3 arms to the trial: a) 159 subjects randomly allocated to receive amantadine 100 mg/day   b) 159 subjects randomly allocated to receive amantadine 200 mg/day   c) 158 subjects randomly allocated to receive identical looking placebo capsules each day To test compliance with the schedule random blood test were carried out on 48 subjects (all results were consistent with compliance)
Outcomes	Laboratory: paired sera were collected at the beginning and end of the trial and tested for antibodies against A/Chile/1/83 (H1N1), A/Philippines/1/82 (H3N2) and B/USSR/100/83, the 3 prevalent viruses during the study period. Viral assays were performed from nasal washouts Efficacy: ILI and influenza. 5 participants were infected in the placebo group, 2 subjects in the 100 mg group and 1 in the 200 mg group. The number of participants with at least 1 (systemic) adverse effect was 49 in the placebo arm, 47 in the 100 mg arm and 71 in the 200 mg arm, indicating a clear dose‐adverse effect relationship (Table 1)
Notes	The authors conclude that influenza activity was too low to be detected by the study (which was powered for a 30% incidence). The study is of good quality with computer‐generated randomisation, checks on allocation concealment and good blinding procedures. No drop‐outs are reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Methods	The study is a placebo‐controlled trial of amantadine conducted in the Northern English village of Keighly by one general practitioner during the pandemic of the winter of 1968 to 1969. Follow up was 10 days
Participants	297 healthy volunteers from firms, schools, a newspaper, a bank and families. Participants' mean age was evenly matched at 38 years (active arm) and 38.5 years (placebo arm). All participants' sera were screened prior to commencement and those who complained of symptoms of influenza underwent a second antibody titre estimation against A2/Hong Kong/1/68, the prevalent strain at the time. As it is likely that some participants were already infected prior to commencement the authors point out that the trial is both prophylaxis and treatment
Interventions	Participants were allocated to receive either amantadine 100 mg every 12 hours (157 participants) or an oil‐based placebo capsule (140 participants), identified only by a code
Outcomes	Laboratory: paired sera Efficacy: ILI or influenza Adverse effects are not reported
Notes	The authors conclude that the trial provides "marginal" evidence of prophylactic effect of amantadine. The practices of randomisation and allocation are not described, making it impossible to assess methodological rigour, although the similar numbers of participants in each arm led us to consider this a randomised trial. Allocation concealment appeared adequate. 49 out of the 157 volunteers in the treatment arm suffered influenza symptoms compared to 39 out 140 on the placebo arm. However, only 8 and 15 cases respectively were serologically confirmed as influenza (Table 3). 12 paired sera were unavailable for the 49 symptomatic volunteers in the treatment arm and 3 paired sera were unavailable although the authors do not explain the reason for the drop‐outs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear