Homeopathic Oscillococcinum® for preventing and treating influenza and influenza‐like illness
Abstract
Background
Influenza is a highly infectious viral disease that is particularly common in the winter months. Oscillococcinum® is a patented homeopathic medicine that is made from a 1% solution of wild duck heart and liver extract, which is then serially diluted 200 times with water and alcohol.
Objectives
To determine whether homeopathic Oscillococcinum® is more effective than placebo in the prevention and/or treatment of influenza and influenza‐like illness in adults or children.
Search methods
We searched CENTRAL (2014, Issue 8), MEDLINE (1966 to August week 4, 2014), MEDLINE In‐Process & Other Non‐Indexed Citations (4 September 2014), AMED (2006 to September 2014), Web of Science (1985 to September 2014), LILACS (1985 to September 2014) and EMBASE (1980 to September 2014). We contacted the manufacturers of Oscillococcinum® for information on further trials.
Selection criteria
Randomised, placebo‐controlled trials of Oscillococcinum® in the prevention and/or treatment of influenza and influenza‐like illness in adults or children.
Data collection and analysis
Three review authors independently extracted data and assessed risk of bias in the eligible trials.
Main results
No new trials were included in this 2014 update. We included six studies: two prophylaxis trials (327 young to middle‐aged adults in Russia) and four treatment trials (1196 teenagers and adults in France and Germany). The overall standard of trial reporting was poor and hence many important methodological aspects of the trials had unclear risk of bias. There was no statistically significant difference between the effects of Oscillococcinum® and placebo in the prevention of influenza‐like illness: risk ratio (RR) 0.48, 95% confidence interval (CI) 0.17 to 1.34, P value = 0.16. Two treatment trials (judged as 'low quality') reported sufficient information to allow full data extraction: 48 hours after commencing treatment, there was an absolute risk reduction of 7.7% in the frequency of symptom relief with Oscillococcinum® compared with that of placebo (risk difference (RD) 0.077, 95% CI 0.03 to 0.12); the RR was 1.86 (95% CI 1.27 to 2.73; P value = 0.001). A significant but lesser effect was observed at three days (RR 1.27, 95% CI 1.03 to 1.56; P value = 0.03), and no significant difference between the groups was noted at four days (RR 1.11, 95% CI 0.98 to 1.27; P value = 0.10) or at five days (RR 1.06, 95% CI 0.96 to 1.16; P value = 0.25). One of the six studies reported one patient who suffered an adverse effect (headache) from taking Oscillococcinum®.
Authors' conclusions
There is insufficient good evidence to enable robust conclusions to be made about Oscillococcinum® in the prevention or treatment of influenza and influenza‐like illness. Our findings do not rule out the possibility that Oscillococcinum® could have a clinically useful treatment effect but, given the low quality of the eligible studies, the evidence is not compelling. There was no evidence of clinically important harms due to Oscillococcinum®.
PICOs
Plain language summary
Homeopathic Oscillococcinum® for preventing and treating influenza and influenza‐like illness
Review question
To determine whether homeopathic Oscillococcinum® is more effective than placebo in the prevention and/or treatment of influenza and influenza‐like illness in adults or children.
Background
Influenza ('the flu') is a highly infectious viral respiratory disease. Other than treatments for complications (such as pneumonia), the conventional medical strategies for the prevention or treatment of flu are not entirely effective or satisfactory. Oscillococcinum® is a highly diluted homeopathic preparation manufactured from wild duck heart and liver, which may be reservoirs of flu viruses. Some people take Oscillococcinum® regularly over the winter months either to prevent flu or as a treatment for flu symptoms.
Study characteristics
We included six studies, which comprised two prevention trials (a total of 327 young to middle‐aged adults in Russia) and four treatment trials (a total of 1196 teenagers and adults in France and Germany).
Key results
The findings from the two prevention trials did not show that Oscillococcinum® can prevent the onset of flu. Although the results from the four other clinical trials suggested that Oscillococcinum® relieved flu symptoms at 48 hours, this might be due to bias in the trial methods. One patient reported headache after taking Oscillococcinum®. The evidence is current to September 2014.
Quality of the evidence
The overall standard of research reporting was poor, and thus many aspects of the trials' methods and results were at unclear risk of bias. We therefore judged the evidence overall as low quality, preventing clear conclusions from being made about Oscillococcinum® in the prevention or treatment of flu and flu‐like illness.
Authors' conclusions
Summary of findings
| Oscillococcinum®compared with placebo for treatment of influenza | ||||||
| Patients/sample: participants aged over 12 years, with influenza‐like illness Settings: general or specialist practices, France and Germany Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Oscillococcinum® | |||||
| Absence of symptoms at 48 hours ‐ patient assessment | 90 per 1000 | 167 per 1000 | RR 1.86 (1.27 to 2.73) | 796 (2 studies) | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| The assumed risk is taken as that of the patients in the placebo groups of the two relevant trials. In the absence of information from other sources, calculations for low‐, medium‐ and high‐risk populations have not been calculated. | ||||||
Background
Description of the condition
Influenza is a highly infectious and prevalent viral disease that is particularly common in the autumn and winter months in temperate regions of the world; annual epidemics are associated, worldwide, with three to five million cases of severe disease and one quarter to half a million deaths per annum (WHO 2009). In high‐income countries, most deaths occur among people aged 65 or older. The 2008‐2009 pandemic strain of H1N1 ('swine flu') virus was highly infectious but of relatively low pathogenicity. However, the risk of a pandemic of a more virulent H5N1 ('avian flu') strain persists. Though several prescription‐only agents can prevent or reduce the duration of influenza, much influenza is treated in the community without the involvement of a physician.
Description of the intervention
Oscillococcinum® is a patented homeopathic medicine that is commercially available over‐the‐counter in many countries. The rationale for its use in influenza is not the standard homeopathic principle of 'let like be cured by like', but the related principle of 'isopathy': that a medicine derived from the causative agent of the disease, or from a product of the disease process, is used to treat the condition (Swayne 2000). The medicine is manufactured from wild duck's heart and liver, which may be reservoirs and vectors of influenza viruses (CDCP 2010; Watanabe 2011; Woo 2011).
Homeopathic medicines are prepared in a flask by a process of serial dilution with succussion (vigorous shaking with impact against an elastic stop) at each stage. Oscillococcinum® is made by the 'Korsakovian' or single‐flask method. An extract of the duck liver and heart (Anas barbariae hepatis et cordis extractum HPUS) is shaken in a flask and then poured off. A water/alcohol mixture is added to dilute the liquid, which remains on the walls of the flask (approximately 1%). This new dilution is succussed and poured off. The process is carried out serially a total of 200 times, to give a '200K' dilution or 'potency' (HPUSA 2012).
The product Oscillococcinum® is manufactured only in the 200K formulation and by one company with exclusive rights to the 'Oscillococcinum®' registered trade name. A number of other preparations of Anas barbariae hepatis et cordis extractum are also available; their formulation is similar to that of Oscillococcinum® but the precise differences in extraction and preparation are unknown and so they have potentially different attributes of biological activity.
How the intervention might work
A 200K potency is so dilute that a typical dose is unlikely to contain any molecules of the starting material (Kayne 2006). The use of high dilutions, including 'ultra‐molecular' dilutions such as 200K, is the reason that homeopathy is sometimes viewed as implausible.
Nevertheless, there is some evidence from in vitro biological models that ultra‐molecular homeopathic dilutions elicit physiological effects. A total of some 1500 experiments have been reported (Clausen 2011). In a systematic review of in vitro biological experiments with ultra‐molecular dilutions, 73% showed biological effects; many of the experiments were of high quality (Witt 2007). Seventy‐three per cent of replication experiments were positive, though no positive experimental result was stable enough to be reproduced by all research groups. The best established such model is based on inhibition of basophil activation by high dilutions of histamine; there are multiple independent and multi‐centre reproductions of this model (Endler 2010; Ste Laudy 2009).
Physical research suggests that ultra‐molecular homeopathic dilutions may possess anomalous water structure. Nuclear magnetic resonance (NMR) studies suggest the presence in ultra‐molecular dilutions of stable supra‐molecular structures, involving nanobubbles of atmospheric gases and highly ordered water around them (Demangeat 2004; Demangeat 2009). Low temperature thermoluminescence experiments on the properties of ultra‐molecular dilutions show that a 'signature' of lithium is detectable in ultra‐molecular lithium chloride (Rey 2003; Van Wijk 2006). Rational hypotheses have been advanced to explain the mechanism of action of homeopathic or ultra‐low‐dose interventions on the immune system (Bellavite 2007) or in prothrombosis (Eizayaga 2011), but it remains unknown how such ultra‐dilute physical properties might enable the physiological effects noted in the other biological models above.
Why it is important to do this review
We reviewed randomised controlled trials (RCTs) of Oscillococcinum® for the prevention and treatment of influenza or influenza‐like illness (ILI). We defined ILI as symptoms of influenza, such as cough, fever, chills and muscle pain, without a need for virological confirmation of influenza virus infection. There is uncertainty as to the extent of similarity of related preparations (see above), therefore this review focuses solely on the registered product Oscillococcinum®.
Existing prevention and treatment strategies for influenza or ILI are not entirely effective or satisfactory. Immunisation provides moderately effective protection, though evidence is lacking in adults aged 65 years or older (Osterholm 2011). There is a delay of several months between identification of the epidemic strain and the vaccine becoming available in adequate amounts (WHO 2006). The adamantanes, amantadine and rimantadine, are only active against influenza A, and drug resistance is widespread (Jefferson 2009b); their use is recommended only in emergencies when all other measures have failed. Neuraminidase inhibitors (oseltamivir (Tamiflu®) and zanamivir (Relenza®) are moderately effective in reducing the duration of influenza symptoms (Jefferson 2009a; Jefferson 2014; Wang 2012). They may be effective in preventing laboratory‐confirmed influenza, but not ILI (Jefferson 2009a; Jefferson 2014). Both drugs are associated with adverse effects (Jefferson 2014). Alternative or additional prevention and treatment strategies are therefore of interest.
Objectives
To determine whether homeopathic Oscillococcinum® is more effective than placebo in the prevention and/or treatment of influenza and influenza‐like illness in adults or children.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) with a placebo control.
Types of participants
Patients of any age (adults or children) wishing to prevent, or presenting with, influenza or ILI (symptoms of influenza such as cough, fever, chills and muscle pain, in the absence of virological evidence of infection).
Types of interventions
Oscillococcinum® in any regime. All other formulations of Anas barbariae hepatis et cordis extractum and medicines made from homeopathically prepared influenza virus, influenza vaccine or avian liver, are not included. Previous versions of this review, Vickers 2000, Vickers 2004 and Vickers 2006, included one study on 'Anas barbariae 200 CH' that was not defined by the authors as Oscillococcinum® (Attena 1995); as stated above (Description of the intervention), such a preparation may have properties that differ importantly from those of true Oscillococcinum®. Previous versions of the review also included two studies on Mucococcinum (Nollevaux 1990; Rottey 1995), a preparation comprising a variety of inactivated viruses and bacteria prepared homeopathically to a 200K potency, which is clearly different from Oscillococcinum®.
Types of outcome measures
Any measure of influenza severity or duration, except laboratory findings (for example, antibody titres).
Primary outcomes
Primary outcome measures for prophylaxis studies:
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Occurrence of influenza (either symptomatic or laboratory‐confirmed)
Primary outcome measures for treatment studies:
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Patient‐reported absence of influenza symptoms at 48 hours
Secondary outcomes
Secondary outcome measures for prophylaxis studies:
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Adverse events
Secondary outcome measures for treatment studies:
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Adverse events
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Physician assessment of symptoms at 48 hours
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Patient‐reported symptom relief after more than 48 hours
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Concomitant medication
Search methods for identification of studies
Electronic searches
For this 2014 update we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 8) (accessed 5 September 2014), which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (July 2012 to August week 4, 2014), MEDLINE In‐Process & Other Non‐Indexed Citations (4 September 2014), AMED (August 2012 to September 2014), Web of Science (August 2012 to September 2014), LILACS (August 2012 to September 2014) and EMBASE (August 2012 to September 2014). Previously we searched CENTRAL (2012, Issue 7), MEDLINE (Ovid) (January 2006 to July week 4, 2012), MEDLINE In‐Process & Other Non‐Indexed Citations (6 August 2012), AMED (2006 to August 2012), Web of Science (1985 to August 2012), LILACS (1982 to August 2012) and EMBASE.com (January 2006 to August 2012). There were no language or publication restrictions. (Details of earlier searches are in Appendix 1).
We used the search strategy described in Appendix 2 to search MEDLINE and CENTRAL. We combined the MEDLINE search strategy with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐maximising version (2008 revision); Ovid format (Lefebvre 2011). We adapted the terms to search the other databases (see Appendix 3).
Searching other resources
We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov trials registries for completed and ongoing studies (latest search 8 September 2014). We contacted the manufacturers of Oscillococcinum® for information, which was provided. The manufacturers of Oscillococcinum® were aware of one paper, originally published in Russian in 2005, which is a randomised controlled trial of the preventive effects of Oscillococcinum® in influenza. This paper has been translated into English and its findings are reflected in this review update.
Data collection and analysis
Selection of studies
The three review authors independently applied prospective inclusion and exclusion criteria to the literature identified. There were no disagreements about study inclusion. In particular, there was no dissent in the decision to include only those studies that investigated trademarked Oscillococcinum®.
Data extraction and management
The three review authors independently extracted data. We extracted the following data on the trial participants from included trials: inclusion and exclusion criteria and method and place of recruitment (for example, primary care). We extracted separately, by group, the following data on trial participants: number randomised, number of withdrawals, age and gender. We recorded, by group, the number of participants and number of events, or the mean and standard deviation (SD) for each outcome measure. We turned ordinal scales into binomial variables by regarding each participant as 'improved' or 'not improved', as appropriate. If variables were reported more than once per follow‐up day, we selected the results for the evening thereof. We recorded details of the treatment given and adverse events reported for the experimental and comparison groups.
In this update, we did not attempt to contact trial authors to provide data or other information that was missing from their trial reports. 'Mean time to recovery' (the main outcome measure selected by the authors of the previous versions of this review) cannot be extracted from the original trial reports, and so 'absence of patient‐assessed influenza symptoms at 48 hours' was the most appropriate measure available to us as 'primary outcome' ‐ see Types of outcome measures. As was the case in previous versions of the review, both published and unpublished studies were eligible for data extraction (see Electronic searches); thus, our adjusted approach does not render this review update any more or less prone to publication bias than its predecessors. We contacted the manufacturers of Oscillococcinum® for trial reports. We resolved disagreements between review authors by consensus.
Assessment of risk of bias in included studies
We used the following methodological categories to appraise each paper:
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Sequence generation (was the allocation sequence adequately generated by, for example, a computerised random number generator?)
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Allocation concealment of treatment (was treatment allocation concealed until each new patient had been unambiguously entered into the trial?)
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Blinding of (a) participants and personnel; and (b) blinding of outcome assessors (was knowledge of the allocated interventions adequately prevented during the study?)
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Incompleteness of outcome data (were incomplete or missing outcome data adequately addressed? Were there systematic differences in withdrawals from the trial?)
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Free from selective reporting (have all the measures described in the paper's Methods been reported in the Results?)
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Other potential threats to validity (was the study apparently free of other problems that could put it at risk of bias? (e.g. was there extreme baseline imbalance in the groups' participants?)).
We judged each category using the Cochrane 'Risk of bias' tool (Higgins 2011). 'Low risk' of bias indicates our opinion that the plausibly postulated bias was unlikely to alter the results seriously; 'high risk' of bias, on the other hand, indicates that plausibly postulated bias seriously weakened our confidence in the results. We judged a category 'unclear risk' if there was insufficient or no information on which to assess whether or not an important risk of bias existed. Two review authors (RTM, JF) independently judged each trial. After the first independent assessments, there was 64% accord between the two review authors across all six categories for the seven eligible papers. We readily resolved the areas of disagreement by discussion, including input from the third review author (PF).
No trial was excluded from the review if we judged it 'high risk of bias', but we regarded the findings from any such trial with increased caution.
Measures of treatment effect
We used relative treatment effect (risk ratio, RR) as the measure of choice (dichotomous data). For primary outcomes (in cases for which the RR data showed a statistically significant difference), we then also examined the absolute risk reduction (risk difference, RD). We calculated number needed to treat to benefit (NNTB) in the standard way, as a reciprocal of the risk difference. At a population level, there would be significant social gains from at least a 5% difference in the proportion of individuals prevented from acquiring influenza symptoms or in the proportion of those achieving symptom relief at 48 hours (see Implications for practice). We therefore regard the minimal clinically important benefit as a difference of 5% favouring Oscillococcinum® (i.e. RD > 0.05, corresponding to NNTB < 20). Correspondingly, we regard the minimal clinically important harm as a difference of 5% favouring placebo.
Unit of analysis issues
All eligible trials were of parallel‐group design. There were no issues in connection with non‐standard designs, such as cross‐over trials and cluster‐randomised trials.
Dealing with missing data
We noted missing data in the description of each trial. In all analyses, we have used the per‐protocol sample sizes in order to remain consistent with the data presentation and analyses in the original papers.
Assessment of heterogeneity
We used the fixed‐effect meta‐analysis model by default. We used the random‐effects model in cases where statistical heterogeneity was evident (visually, where I2 statistic > 50% and/or where Chi2 > number of degrees of freedom (df)). In such cases, we applied the more conservative of the two results.
Assessment of reporting biases
We have not specifically addressed publication bias in view of the detailed 'Risk of bias' assessment per trial and the small number of eligible trials overall.
Data synthesis
We assumed there was sufficient clinical homogeneity in influenza symptoms and in the prescription of Oscillococcinum® in the trials to enable the fixed‐effect meta‐analysis model to be used by default (see also Assessment of heterogeneity). We usually considered a meta‐analysis was appropriate when a given type of data was available from more than a single trial report.
Subgroup analysis and investigation of heterogeneity
We analysed prophylaxis and treatment trials in two distinct categories, with the investigation of heterogeneity for each particular analysis carried out as above.
One paper presented subgroup analyses on the effect of age of patient and severity of symptoms after 48 hours of treatment (Ferley 1989); that analysis was not a planned part of the study's protocol. We undertook Chi2 analysis on these data to examine more directly the comparative influence of younger/older age and of illness severity on symptom relief at 48 hours.
Sensitivity analysis
We did not carry out sensitivity analyses.
Results
Description of studies
For this 2014 update, we obtained a total of 453 records from the electronic database searches. We identified no new trials for inclusion.
Results of the search
Each of the six eligible trials (see below) reported outcomes that reflected the presence or absence of influenza or ILI, compatible with our designated primary outcomes both for prophylaxis and treatment studies.
For prophylaxis trials, 'number of subjects who fell ill' was the common outcome identifiable across the two studies concerned (Selkova 2005a; Selkova 2005b). Neither study reported adverse events.
For treatment trials, symptom relief was reported in a number of different ways. Indeed, a primary outcome measure was defined clearly by the original authors in just one of the treatment studies (Ferley 1989): the proportion of patients that reported absence of symptoms (complete resolution of five defined cardinal symptoms and rectal temperature < 37.5 °C) within 48 hours of treatment with Oscillococcinum®. The same paper examined patient‐reported symptom relief over a period of seven days following treatment, while other treatment trials, including Papp 1998, selected two to five days or more. Physician assessments of symptoms at 48 hours were also used in one paper (Papp 1998). Both these treatment trials could be included in a meta‐analysis of the primary outcome measure: patient‐assessed absence of influenza symptoms at 48 hours after receiving Oscillococcinum® or placebo (see also Notes in Characteristics of included studies: Papp 1998).
As secondary outcomes from treatment, we have included 'proportion of patients reporting absence of symptoms by three days of treatment', 'proportion of patients reporting absence of symptoms by four days of treatment' and 'proportion of patients reporting absence of symptoms by five days of treatment'. Three trials reported outcomes for individual symptoms of influenza, such as fever, chills, aches or cough (Casanova 1984; Casanova 1988; Papp 1998).
Additional secondary outcomes from the treatment studies included: physician‐assessed absence of symptoms at 48 hours; physician‐assessed improvement at 48 hours (see also Notes in the Characteristics of included studies table: Papp 1998); use of concomitant medication (Ferley 1989; Papp 1998). Only one study assessed and reported adverse events (Papp 1998).
Included studies
We included six studies in this review: two prophylaxis trials, published in a single paper by Selkova (Selkova 2005a; Selkova 2005b), with a total of 327 participants, and four treatment trials (Casanova 1984; Casanova 1988; Ferley 1989; Papp 1998), with a total of 1196 participants. All six trials compared trademarked Oscillococcinum® (Boiron) to a placebo.
Only one of the treatment trials explicitly reported that participants were accrued during an outbreak of influenza (Ferley 1989). Participants were generally recruited from primary care settings. Some trials included both children (older than 12 years) and adults. Inclusion and exclusion criteria were sometimes not described. In two of the four treatment trials, participants had to meet a defined standard for influenza‐like illness (for example, rectal temperature greater than 38 °C and at least two episodes of headache, stiffness, lumbar and articular pain or shivers). Exclusion criteria in these two trials were prior duration of symptoms for longer than 24 hours, immune deficiency, influenza vaccination or immunostimulant treatment.
Details are given in the Characteristics of included studies table.
Excluded studies
Three studies included in the previous version of the review, Vickers 2006, have been excluded in this update because we have now focused solely on patented Oscillococcinum®. Attena 1995 used a 200C potency of extract of liver and heart from Anas barbariae (not Oscillococcinum®); it was published as a letter to the Editor of a peer‐reviewed journal. Nollevaux 1990 and Rottey 1995 used a preparation of inactivated viruses and bacteria prepared to a 200K potency.
Risk of bias in included studies
The standard of trial reporting was poor or very poor. In only two trials was there sufficient information to enable data extraction of the main outcome (defined above), though some of the necessary data were extractable solely from the graphical illustrations in those papers (Ferley 1989; Papp 1998). Four studies were published in the non‐peer‐reviewed literature, in France or in Russia (Casanova 1984; Casanova 1988; Selkova 2005a; Selkova 2005b). One of the above trials was reported in a general medical magazine rather than in a scientific journal; accordingly, this trial was reported very briefly and most of the important experimental details were missing (Casanova 1984). No details of exclusions and withdrawals were given in four trials (Casanova 1984; Casanova 1988; Selkova 2005a; Selkova 2005b). The sample sizes in the trials by Selkova 2005a, Casanova 1984 and Casanova 1988 are suspiciously round numbers (100, 100, 300 respectively).
Overall, the extent of methodological bias in this set of trials is difficult to determine, as illustrated by the high frequency of the judgement 'unclear' using the 'Risk of bias' tool in RevMan 2014 (Figure 1). Specific examples of plausible bias per assessment domain are given below.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Allocation
The procedures for sequence generation and allocation concealment were adequately reported in just one paper (Papp 1998). Allocation procedures were not reported in any of the other papers; risk of bias arising from such deficiencies of reporting and/or prosecution of the trials is therefore impossible to ascertain.
Blinding
Blinding of participants and personnel was generally adequate overall, explicitly so in two trials (Ferley 1989; Papp 1998). Homeopathic medicines are generally impossible to distinguish from matching placebos because they have no inherent taste, smell or obvious adverse effects such as dry mouth, and this also is the case for Oscillococcinum®. Thus it is unlikely that bias from this source was introduced during the trials. Adequacy of blinding of outcome assessment was unclear for all trials.
Incomplete outcome data
We judged only one trial at low risk of bias in this domain (Ferley 1989). In one study, up to 10% of participants did not complete the trial; moreover, the paper did not describe details of the group‐specific reasons for drop‐out and attrition numbers throughout the paper are confused and confusing (Papp 1998). We assessed Papp 1998 as having 'unclear' risk of attrition bias, as well as all the remaining studies.
Selective reporting
All studies were 'unclear' risk of bias in this assessment domain. Amongst other areas of lack of clarity, in one of the papers the authors state that statistical analysis was "based on the mean date of elimination of symptoms" but their graphical and statistical data do not reveal such a time point; nor is it possible to extract data from the information provided in the paper (Papp 1998). Without making a number of assumptions about the precise data, it is also not possible to derive 'mean time to recovery from symptoms' from the other trial that presented time‐related information (Ferley 1989). Other concerns about statistical analysis/presentation in those two papers are summarised in the Characteristics of included studies table.
Another research group conducted two trials (Casanova 1984; Casanova 1988). The first of those trials reported data for patient assessment, chills, aches, rhinitis, night cough, day cough and fever; the second trial reported data only for temperature, chills and aches. We do not know if data on rhinitis, cough and patient assessment were recorded in the second trial but not reported. Moreover, the length of follow‐up varied between the two trials. The first reported data for day eight; the second for day four. We do not know if data were recorded daily but only the most favourable comparisons were reported. Given those considerations, the outcomes for individual symptoms are more likely to be biased than those for presence or absence of influenza or use of concomitant medication.
Other potential sources of bias
Only two of the trials presented baseline information about the study participants (Ferley 1989; Papp 1998). We nevertheless labelled Papp 1998 'unclear' risk of bias in this domain because of shortfalls in the clarity of its statistical presentation (see also Characteristics of included studies table).
Effects of interventions
See: Summary of findings for the main comparison
Prophylaxis trials
Primary outcome
Occurrence of influenza
The data on occurrence of influenza‐like illness displayed considerable heterogeneity between trials (Chi2 = 1.49, df = 1; I2 statistic = 33%). Using a random‐effects model for statistical analysis, the mean risk ratio (RR) of influenza‐like illness occurring in participants receiving treatment was 0.48 (95% confidence interval (CI) 0.17 to 1.34; P value = 0.16) (Analysis 1.1; Figure 2).
Forest plot of comparison: 1 Prevention: Oscillococcinum versus placebo. Outcome 1: Occurrence of influenza‐like illness.
Secondary outcome
Adverse events
Adverse events were not reported in either of the eligible trials.
Treatment trials
Primary outcomes
Patient‐reported absence of symptoms at 48 hours
Data from two trials showed that the mean RR for symptom absence was 1.86 (95% CI 1.27 to 2.73) (Analysis 2.1), statistically significant in favour of Oscillococcinum® (P value = 0.001; Figure 3). The two trials comprised a total of 796 participants. The mean proportion of patients who reported absence of influenza symptoms was 36/401 (= 9.0%) in the placebo groups and 66/395 (= 16.7%) in the Oscillococcinum® groups (Ferley 1989; Papp 1998), a mean difference of 7.7%. Correspondingly, the risk difference (RD) was 0.077 (95% CI 0.03 to 0.12) and so the number needed to treat to benefit (NNTB) was 13 (95% CI 9 to 34); the 95% confidence limits include the pre‐defined minimal clinically important benefit (RD 0.05, NNTB 20) ‐ see Measures of treatment effect.
Forest plot of comparison: 2 Treatment: Oscillococcinum versus placebo. Outcome 1: Absence of symptoms at 48 hours ‐ patient assessment.
Subgroup analysis
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Effect of age of patient (Analysis 2.2): for participants aged 12 to 29 years, the effect of Oscillococcinum® was RR 3.08, 95% CI 1.32 to 7.23, whereas for participants aged > 30 years, the effect was RR 1.26, 95% CI 0.59 to 2.70. Direct comparison between the two groups of participants showed that the higher frequency of symptom absence in younger participants did not reach the level of statistical significance (Chi2 = 3.188; P value = 0.07).
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Effect of severity of illness (Analysis 2.3): for participants with mild to moderate symptoms, the effect of Oscillococcinum® was RR 2.08, 95% CI 1.19 to 3.61, whereas for participants with severe symptoms, the effect was RR 0.88, 95% CI 0.33 to 2.32. Direct comparison between the two groups of participants showed that symptom relief did not occur significantly more frequently in the subgroup with mild to moderate symptoms compared to those with severe symptoms (Chi2 = 1.784; P value = 0.18).
Patient‐reported absence of specified symptoms at 48 hours
Data are derived from the trials reported by Casanova 1984, Casanova 1988 and/or Papp 1998.
Fitness for work at day two is presented in Analysis 2.4 (RR 1.80, 95% CI 0.99 to 3.26; P value = 0.05). Fitness for work at day four is shown in Analysis 2.5 (RR 1.04, 95% CI 0.83 to 1.30; P value = 0.74).
Results for individual symptoms (each reported at 48 hours) are presented in Analyses 2.6 to 2.17. Most analyses showed symptom changes in favour of Oscillococcinum®: Analysis 2.6 (no chills: 1.30, 95% CI 1.04 to 1.63; P value = 0.02); Analysis 2.7 (no fever: 1.98, 95% CI 1.34 to 2.92; P value = 0.0006); Analysis 2.9 (no general aches: 1.73, 95% CI 1.16 to 2.59; P value = 0.007); Analysis 2.11 (no backache: 1.27, 95% CI 1.00 to 1.61; P value = 0.05); Analysis 2.12 (no spinal pain: 1.27, 95% CI 1.02 to 1.58; P value = 0.03); Analysis 2.13 (no muscle pain: 1.47, 95% CI 1.10 to 1.97; P value = 0.01); Analysis 2.14 (no articular pain: 1.40, 95% CI 1.09 to 1.80; P value = 0.009); Analysis 2.16 (no day cough: 2.00, 95% CI 1.20 to 3.31; P value = 0.008); Analysis 2.17 (temperature: mean difference ‐0.50 degrees, 95% CI ‐0.67 to ‐0.33; P value < 0.00001). The remaining analyses showed symptom changes in favour of placebo: Analysis 2.8 (no rhinitis: RR 1.33, 95% CI 0.66 to 2.70; P value = 0.42); Analysis 2.10 (no headache: 1.20, 95% CI 0.88 to 1.63; P value = 0.25); Analysis 2.15 (no night cough: 1.44, 95% CI 0.73 to 2.84; P value = 0.29).
Secondary outcomes
Adverse events
One patient taking Oscillococcinum® reported a headache that 'might' have been due to the trial medication (Papp 1998). None of the other eligible trials of Oscillococcinum® reported adverse events (Casanova 1984; Casanova 1988; Ferley 1989).
Physician assessment of symptoms at 48 hours
Physician assessment of improvement in symptoms at 48 hours was reported in one paper (Papp 1998): mean RR in favour of Oscillococcinum® was 1.07, 95% CI 0.98 to 1.18, which is not statistically significant (P value = 0.13) (Analysis 2.18). Physician assessment of participants' absence of symptoms at 48 hours was reported in one paper (Papp 1998): mean RR in favour of Oscillococcinum® was 1.28, 95% CI 0.79 to 2.06, which is not statistically significant (P value = 0.31) (Analysis 2.19).
Patient‐reported symptom relief after more than 48 hours
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Day 3 (Analysis 2.20; Figure 4): the RR of relief from influenza symptoms was 1.27, 95% CI 1.03 to 1.56, statistically significantly in favour of Oscillococcinum® (P value = 0.03).
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Day 4 (Analysis 2.21; Figure 5): the RR of relief from influenza symptoms was 1.11, 95% CI 0.98 to 1.27, which is not statistically significant (P value = 0.10).
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Day 5 (Analysis 2.22; Figure 6): the RR of relief from influenza symptoms was 1.06, 95% CI 0.96 to 1.16, which is not statistically significant (P value = 0.25).
Forest plot of comparison: 2 Treatment: Oscillococcinum versus placebo. Outcome 20: Absence of symptoms at 3 days ‐ patient assessment.
Forest plot of comparison: 2 Treatment: Oscillococcinum versus placebo. Outcome 21: Absence of symptoms at 4 days ‐ patient assessment.
Forest plot of comparison: 2 Treatment: Oscillococcinum versus placebo. Outcome 22: Absence of symptoms at 5 days ‐ patient assessment.
Concomitant medication
There was less increased use of concomitant medication over the trial period in the Oscillococcinum® group compared with the placebo group: RR 0.61, 95% CI 0.40 to 0.92; P value = 0.02 (Analysis 2.23). Medication use for pain or fever was significantly less in the Oscillococcinum® group: RR 0.82, 95% CI 0.67 to 1.00; P value = 0.05 (Analysis 2.24). There was no inter‐group difference in the use of medication for cough or coryza: RR 0.96, 95% CI 0.76 to 1.21; P value = 0.72 (Analysis 2.25) or of antibiotics: RR 0.87, 95% CI 0.47 to 1.62; P value = 0.67 (Analysis 2.26).
Discussion
Overall, the risk of bias in the six included trials was unclear, and so the statistical findings from this systematic review must be viewed with caution. Only two treatment trials contained some domains that we judged to have low risk of bias (Ferley 1989; Papp 1998), but each of those trials also included domains in which lack of clarity prevented clear judgement. Due to this unclear reporting, we felt obliged to judge even these two studies 'low quality of evidence' (GRADE Working Group ‐ see summary of findings Table for the main comparison).
The evidence, which is limited to two studies with unclear risk of bias, did not support a preventive effect of Oscillococcinum® in influenza and influenza‐like illness (risk ratio (RR) 0.48, 95% confidence interval (CI) 0.17 to 1.34; P value = 0.16). The results were skewed by the extremely diverse data reported in the two prophylaxis studies (Selkova 2005a; Selkova 2005b); the larger of the two trials (n = 227) obtained positive findings. Further prophylaxis research on Oscillococcinum® might thus be indicated. Since the single eligible prophylaxis paper to date did not report adverse events, any new research in this area should include such assessment. This is especially important given the high frequency of adverse reactions reported in a non‐eligible prophylaxis trial on an Oscillococcinum‐like homeopathic product (Attena 1995).
Oscillococcinum® appeared to have a modest effect on influenza and influenza‐like illness in the first two days of treatment (as assessed by the patient). At 48 hours, the RR of 1.86 (95% CI 1.27 to 2.73) indicated a statistically significant effect of Oscillococcinum®, and the 95% CIs of the risk difference (RD) (0.03 to 0.12) and the number needed to treat to benefit (NNTB) (9 to 34) suggested that the additional treatment benefit would potentially be of clinical importance at population level (limits defined as RD 0.05, NNTB 20). Four to five days after the start of treatment, the difference between Oscillococcinum® and placebo dwindled to statistical non‐significance, which may be deemed consistent with the self limiting natural course of the illness.
The limited available evidence suggested that, at 48 hours, the following symptoms were most responsive to treatment: chills, fever, general aches, backache, spinal pain, muscle pain, articular pain and day cough. A key limitation in interpreting these findings is that one of the trials was not published in a standard medical journal, contained little experimental detail, did not report withdrawals and analysed a suspiciously rounded number of participants (Casanova 1984).
There were data from only one trial on the effects of Oscillococcinum® with respect to age of patient or severity of illness (Ferley 1989). Though Ferley 1989 found a better response to treatment at 48 hours in people aged less than 30 years and in participants with less severe symptoms, these findings were based on unplanned subgroup analyses; our Chi2 test analyses did not support the researchers' original conclusions.
Although there were insufficient data to determine clearly the effect of Oscillococcinum® on concomitant medication, one trial noted a lesser increase in the overall use of concomitant medication during the study period (Papp 1998), while another trial reported a decreased use of analgesic and antipyretic medication (Ferley 1989).
It is obvious that doubts remain about the reliability and the clinical importance of the findings reported. A question as scientifically controversial as whether or not a highly diluted homeopathic medicine is equivalent to placebo will require many more statistically robust data. As adjudged above, further research is very likely to have an important impact on the confidence in, and the magnitude of, the estimate of treatment effects (GRADE Working Group grade of evidence: low quality). To confirm or refute the existing evidence, it is therefore concluded that additional research on Oscillococcinum® prevention and/or treatment is necessary ‐ see Authors' conclusions below.
Summary of main results
The evidence from two studies with unclear risk of bias did not support a significant preventive effect of Oscillococcinum® (RR 0.48, 95% CI 0.17 to 1.34; P value = 0.16). Two studies with low quality of evidence suggested that 48 hours after commencing treatment, the effect of Oscillococcinum® on patient‐reported symptom relief was significantly greater than that of placebo (RR 1.86, 95% CI 1.27 to 2.73; P value = 0.001); the RD was 0.077, 95% CI 0.03 to 0.12, indicating that at population level the symptom improvement in early influenza‐like illness (ILI) might potentially be clinically useful. There was no evidence of clinically important harms. Adverse effects of the intervention have been reported by one patient in one study.
Overall completeness and applicability of evidence
The trials reviewed here were sampled from general primary care populations and did not specifically focus on target sub‐populations for treatment of influenza, such as individuals with severe disease or at high risk of complications, including older people, pregnant and post‐partum women and those with chronic medical conditions. The incidence of complications of ILI in such groups, and indeed the general population, is of interest but was not investigated in the trials reviewed.
As discussed above, the intervention covered by this review is narrower than in the previous versions: it includes only trademarked Oscillococcinum®, whereas the earlier versions included other, similar, products. However, Oscillococcinum® is the most widely used product and has been the subject of considerable research. In one of the papers included in the previous versions (but which we have excluded), there was ambiguity about the precise nature of the medicinal product (Attena 1995). By removing such uncertainty, we therefore believe we have included only exactly relevant interventions.
From the viewpoint of external validity (generalisability), it is important to note that the majority of ILIs are not true, virologically confirmed, influenza (Jefferson 2009a). Furthermore, ILI and laboratory‐confirmed influenza are clinically indistinguishable (Call 2005). In the 2009‐2010 influenza season in the USA, which included the H1N1 'swine flu' pandemic, overall only 21% of specimens tested positive for influenza viruses, rising to around 40% at the peak of the pandemic (CDCP 2011). Clinical trials of neuraminidase inhibitors tend to include a higher proportion of true influenza than is encountered in routine practice. For people exposed to influenza, neuraminidase inhibitors reduce their chance of developing true, laboratory‐confirmed, influenza, but not ILI (Jefferson 2009a; Jefferson 2014). However, as stated, true influenza is a small component of ILI (Jefferson 2009a). Neuraminidase inhibitors are moderately effective in shortening the duration of influenza symptoms (Jefferson 2009a; Jefferson 2014; Wang 2012). Regarding neuraminidase inhibitors in epidemic and pandemic situations, there are concerns about the availability of adequate supplies and, in low‐income countries, their affordability. Given those limitations of conventional drugs, and that the studies included in the current review investigated ILI, not virologically confirmed influenza, the advent of higher‐quality data on alternative or additional options, such as Oscillococcinum®, would be of interest.
Quality of the evidence
The two prophylaxis trials comprised a total of 327 participants; the quality of their reporting was poor and the studies may have been underpowered. The two treatment trials in which our ascribed 'primary outcome measure' was reported (patient‐reported absence of symptoms at 48 hours) comprised a total of 796 participants: overall, these trials were of unclear risk of bias (GRADE Working Group: 'low quality of evidence' ‐ summary of findings Table for the main comparison). The available body of evidence therefore does not enable robust conclusions about the impact of Oscillococcinum® in preventing and/or treating influenza or influenza‐like illness.
Potential biases in the review process
Some trials of homeopathy are published in the 'grey' literature, which is not indexed in medical bibliographic databases; such was the case with several of the trials reviewed here. We have made efforts to search comprehensively and have identified and included two new trials (Selkova 2005a; Selkova 2005b), which are not indexed in the standard medical bibliographic databases. Nevertheless it remains possible that we have missed some trials, though we consider it unlikely that we have failed to identify any study of sufficient quality that would influence our findings importantly. We assessed the eligible trials rigorously for risk of bias. We identified all five original studies (six trials) as lacking clarity in some or all assessment domains. We rated no trial overall as low risk of bias and so the conclusions about trial results drawn from this review are necessarily cautious in nature.
Agreements and disagreements with other studies or reviews
Three other reviews have appraised the evidence of Oscillococcinum® or Oscillococcinum‐like homeopathic preparations (Bornhöft 2006; Marrari 2012; Ulbricht 2011). The first review cited Ferley 1989 and Papp 1998 as showing 'significance for homeopathy' and categorised each of those studies as having unclear external validity. The second review appraised the evidence both from the original randomised controlled trials and the earlier reviews: its findings and conclusions are broadly in line with this Cochrane Review, though it regarded the paper by Papp 1998 as "well‐designed and well‐reported". The third review concluded that, given the available evidence including its high benefit/risk ratio, Oscillococcinum® should be assigned the classification "generally proven". None of these three reviews cited the paper by Selkova (Selkova 2005a; Selkova 2005b). The present review is less positively positioned than any of those above.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Prevention: Oscillococcinum versus placebo. Outcome 1: Occurrence of influenza‐like illness.
Forest plot of comparison: 2 Treatment: Oscillococcinum versus placebo. Outcome 1: Absence of symptoms at 48 hours ‐ patient assessment.
Forest plot of comparison: 2 Treatment: Oscillococcinum versus placebo. Outcome 20: Absence of symptoms at 3 days ‐ patient assessment.
Forest plot of comparison: 2 Treatment: Oscillococcinum versus placebo. Outcome 21: Absence of symptoms at 4 days ‐ patient assessment.
Forest plot of comparison: 2 Treatment: Oscillococcinum versus placebo. Outcome 22: Absence of symptoms at 5 days ‐ patient assessment.
Comparison 1 Prevention: Oscillococcinum versus placebo, Outcome 1 Occurrence of influenza‐like illness.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 1 Absence of symptoms at 48 hours ‐ patient assessment.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 2 Absence of symptoms at 48 hours ‐ patient assessment ‐ by age.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 3 Absence of symptoms at 48 hours ‐ patient assessment ‐ by severity of symptoms.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 4 Fitness for work at 2 days.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 5 Fitness for work at 4 days.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 6 No chills at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 7 No fever at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 8 No rhinitis at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 9 No general aches at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 10 No headache at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 11 No backache at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 12 No spinal pain at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 13 No muscle pain at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 14 No articular pain at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 15 No night cough at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 16 No day cough at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 17 Temperature at 48 hours.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 18 Improvement in symptoms at 48 hours ‐ physician assessment.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 19 Absence of symptoms at 48 hours ‐ physician assessment.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 20 Absence of symptoms at 3 days ‐ patient assessment.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 21 Absence of symptoms at 4 days ‐ patient assessment.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 22 Absence of symptoms at 5 days ‐ patient assessment.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 23 Increased use of concomitant medication during trial.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 24 Medication used for pain or fever.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 25 Medication used for cough or coryza.
Comparison 2 Treatment: Oscillococcinum versus placebo, Outcome 26 Antibiotics used.
| Oscillococcinum®compared with placebo for treatment of influenza | ||||||
| Patients/sample: participants aged over 12 years, with influenza‐like illness Settings: general or specialist practices, France and Germany Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Oscillococcinum® | |||||
| Absence of symptoms at 48 hours ‐ patient assessment | 90 per 1000 | 167 per 1000 | RR 1.86 (1.27 to 2.73) | 796 (2 studies) | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| The assumed risk is taken as that of the patients in the placebo groups of the two relevant trials. In the absence of information from other sources, calculations for low‐, medium‐ and high‐risk populations have not been calculated. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Occurrence of influenza‐like illness Show forest plot | 2 | 327 | Risk Ratio (M‐H, Random, 95% CI) | 0.48 [0.17, 1.34] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Absence of symptoms at 48 hours ‐ patient assessment Show forest plot | 2 | 796 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.86 [1.27, 2.73] |
| 2 Absence of symptoms at 48 hours ‐ patient assessment ‐ by age Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Absence of symptoms at 48 hours ‐ patient assessment ‐ by severity of symptoms Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4 Fitness for work at 2 days Show forest plot | 1 | 334 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.8 [0.99, 3.26] |
| 5 Fitness for work at 4 days Show forest plot | 1 | 334 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.83, 1.30] |
| 6 No chills at 48 hours Show forest plot | 2 | 418 | Risk Ratio (M‐H, Random, 95% CI) | 1.30 [1.04, 1.63] |
| 7 No fever at 48 hours Show forest plot | 1 | 88 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.98 [1.34, 2.92] |
| 8 No rhinitis at 48 hours Show forest plot | 1 | 51 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.33 [0.66, 2.70] |
| 9 No general aches at 48 hours Show forest plot | 1 | 83 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.73 [1.16, 2.59] |
| 10 No headache at 48 hours Show forest plot | 1 | 334 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.2 [0.88, 1.63] |
| 11 No backache at 48 hours Show forest plot | 1 | 334 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [1.00, 1.61] |
| 12 No spinal pain at 48 hours Show forest plot | 1 | 334 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [1.02, 1.58] |
| 13 No muscle pain at 48 hours Show forest plot | 1 | 334 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.47 [1.10, 1.97] |
| 14 No articular pain at 48 hours Show forest plot | 1 | 334 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.4 [1.09, 1.80] |
| 15 No night cough at 48 hours Show forest plot | 1 | 58 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.44 [0.73, 2.84] |
| 16 No day cough at 48 hours Show forest plot | 1 | 73 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.00 [1.20, 3.31] |
| 17 Temperature at 48 hours Show forest plot | 1 | 300 | Mean Difference (IV, Fixed, 95% CI) | ‐0.5 [‐0.67, ‐0.33] |
| 18 Improvement in symptoms at 48 hours ‐ physician assessment Show forest plot | 1 | 334 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.98, 1.18] |
| 19 Absence of symptoms at 48 hours ‐ physician assessment Show forest plot | 1 | 334 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.79, 2.06] |
| 20 Absence of symptoms at 3 days ‐ patient assessment Show forest plot | 2 | 796 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.27 [1.03, 1.56] |
| 21 Absence of symptoms at 4 days ‐ patient assessment Show forest plot | 2 | 796 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.98, 1.27] |
| 22 Absence of symptoms at 5 days ‐ patient assessment Show forest plot | 2 | 796 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.96, 1.16] |
| 23 Increased use of concomitant medication during trial Show forest plot | 1 | 334 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.40, 0.92] |
| 24 Medication used for pain or fever Show forest plot | 1 | 462 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.67, 1.00] |
| 25 Medication used for cough or coryza Show forest plot | 1 | 462 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.76, 1.21] |
| 26 Antibiotics used Show forest plot | 1 | 462 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.47, 1.62] |
