This phase III, prospective, randomized, double-blind, placebo-controlled clinical trial enrolled volunteers recruited by means of posters displayed in Hospital de Clínicas de Porto Alegre (HCPA) and in primary care centres in the city of Porto Alegre, Brazil, and of ads placed in local newspapers.
Inclusion criteria
This study included volunteers of both genders, aged 18 to 60 years, with a duration of symptoms no longer than 72 hours. The common cold was defined by the presence of at least two of the following 10 symptoms: sneezing, rhinorrhoea, nasal congestion, headache, myalgia, throat discomfort, sore throat, dysphonia, cough and fever. Symptoms should be moderate to severe on a four-point, Likert-type symptom severity scale (0 = no symptoms; 1 = mild; 2 = moderate; 3 = severe). Flu-like syndrome should include fever of at least 38.1°C and moderate to severe headache or moderate to severe myalgia or arthralgia in the Likert-type symptom severity scale described above.
Exclusion criteria
Volunteers were excluded from the study if they met any of the following criteria: pregnancy or breastfeeding; known hypersensitivity to any component of the study formulation; use of alcohol or illicit drugs; use of monoamine oxidase (MAO) inhibitors or barbiturates; perennial or seasonal allergic rhinitis confirmed at screening; any current acute disease or uncontrolled exacerbation of chronic disease; clinical evidence of immunosuppression; vaccination against influenza up to 1 week before inclusion; need for antiviral therapy to treat influenza A or B infection; need for antibacterial therapy to treat acute respiratory infection; use of medication to treat conditions acquired before inclusion for a time shorter than two time intervals of administration of these drugs; and participation in another clinical trial less than 1 year before.
Sample size calculation
For a statistical power of 80%, a random error of 5% and a response rate of 30% in the treatment group in comparison with the placebo group, and a 50% reduction in symptom scores after the second day of follow-up in the placebo group, the sample size was calculated as 132 patients (66 in each group) [22]. To account for a possible loss to follow-up of 10% of the volunteers, 146 patients were included in the study (73 in each group).
Statistical analysis
All variables were collected and entered into the database before randomization codes were opened. The database was created using the Epi-INFO 3.5.1 software. SPSS 14.0 was used for statistical analyses.
All variables of interest were expressed as absolute and relative frequencies. The Student t-test for independent samples was used for the comparison of means for all continuous, symmetrically distributed variables. Repeated-measures analysis of variance (ANOVA) was used for the analysis of variance of overall score means in 11 measurements.
All randomized patients were included in the analysis of efficacy (intention to treat). For all analyses, the level of significance was set at p = 0.05.
Randomization and blinding
Randomization for this clinical trial was performed using the Random Allocation Software and simple randomization into two groups by means of a table of random numbers, which generated a simple randomization spreadsheet.
The list of random numbers was placed in a sealed envelope kept by the statistician responsible for analyses. None of the authors had access to the randomization table. The active drug and placebo capsules had identical organoleptic characteristics. A standard label, designed for use with both groups, contained the following information: name of the study, study registration number with of HCPA Research Ethics Committee, bottle number/randomization number, and instructions for use and storage.
Intervention
Study drug: One capsule of a fixed-dose combination of 400 mg paracetamol, 4.0 mg chlorphenamine and 4.0 mg phenylephrine was administered according to manufacturer instructions [23] every 4 hours during waking hours between 7 a.m. and 11 p.m. (five daily doses) for 2 to 3 consecutive days. Patients were instructed to use the drug for no fewer than 2 and no more than 3 days as this reflects best clinical practice, in which users decide the maximum duration of use according to the intensity of their symptoms.
Placebo: One capsule was administered every 4 hours during waking hours between 7 a.m. and 11 p.m. (five daily doses) for 2 to 3 consecutive days.
Each participant included in the study received a bottle containing 15 capsules of the study drug or placebo, depending on group allocation, and one bottle containing 12 tablets of rescue medication (500 mg paracetamol).
Procedures
The study lasted 10 days and included three clinical visits (V1, V2 and V3) and two rounds of laboratory tests (baseline and V2).
In addition to medical history and physical examination, the participants underwent laboratory tests and electrocardiograms (ECG). Immediately afterwards, they were randomly allocated to one of the two groups and received the study drug or placebo, a diary to keep note of symptoms and adverse events, and the rescue medication.
At the end of treatment, which lasted 2 to 3 days, the patients returned for re-evaluation. The second visit included medical history, clinical and physical examination, ECG and laboratory tests, as well as an analysis of the following aspects: symptoms, using pre-defined scales; adverse events; duration of symptoms; time to return to usual activities; and drug intake, by counting the capsules and tablets used.
The third and last follow-up visit took place 7 days after the end of the treatment, when the following parameters were evaluated: persistent symptoms, according to predefined scales; duration of symptoms; time to return to usual activities; adverse events; and use of other medications after stopping use of the study drug.
Group allocation was disclosed only after data had been collected and entered into the study database, by double and independent entry followed by a comparison of the two datasets. The envelope containing the randomization table was opened in the presence of representatives of the study sponsor and the principal investigator.
Data were collected for this clinical trial from June 2, 2009 to July 7, 2009. The clinical visits were conducted at the HCPA Clinical Drug Research Center (NUCLIMED). The database was checked and analysed and the final report was written from August 8 to October 31, 2009.
Efficacy analysis
The primary endpoint was the sum of the scores of 10 common cold or flu-like syndrome symptoms evaluated on a four-point Likert-type scale for intensity (severity): 0 = no symptoms; 1 = mild; 2 = moderate; and 3 = severe. The maximum and minimum scores for each measurement were 40 and zero respectively. This scale was used by the physician during visits and also by the patients for daily self-evaluation using the study diary. Participants rated their symptoms at home before each administration of the study drug or placebo throughout the treatment period, so that a total of 10 to 15 measurements were obtained.
Secondary endpoints were overall symptom duration, time to return to usual activities, and use of rescue medication.
Safety analysis
Drug safety was evaluated by the occurrence of adverse events detected in clinical history, physical examination findings, or abnormal lab results during treatment or up to 7 days after the last dose of the medication.
All serious and non-serious adverse events were fully documented using clinical charts, original documents, and specific forms. In addition, all adverse events occurring within 7 days of the treatment were investigated, recorded and compared between groups. Adverse events were followed until their resolution or until follow-up was classified (in writing) as complete by the investigators.
Bioethical issues
This study was approved by the Ethics Committee of the Graduate Studies and Research Group of Hospital de Clínicas de Porto Alegre (HCPA). All participants were volunteers, and all procedures for this study were started only after participants had read and signed an informed consent form approved by the HCPA Research Ethics Committee.