Study design
IIPCOS-2 is an international, multi-centre, comparative cohort study of non-randomised design, which was conducted between October 1998 and April 2000. Patients suffering from acute respiratory and ear complaints were recruited by physicians in 57 primary care practices in Austria (8), Germany (8), the Netherlands (7), Russia (6), Spain (6), Ukraine (4), United Kingdom (10) and USA (8). The physicians belonged to 3 different groups: providing homeopathic treatment only (22), providing either homeopathic or conventional treatment (9), and providing conventional treatment only (12). The physicians, prescribing primarily homeopathic single remedies, had in addition to their conventional medical qualifications, graduated from a homeopathic training program and at least 5 years experience using homeopathy in their medical practice. The protocol was approved by the International Ethics Committee in Freiburg, Germany. The study was conducted in accordance with the declaration of Helsinki, Good Clinical Practice (GCP) guidelines and national legal requirements.
Patients
Patients older than one month, presenting themselves with at least one of five chief complaints (runny nose, sore throat, ear pain, sinus pain or cough), and onset of symptoms not more than 7 days before, were eligible to participate. Each chief complaint comprised of 5 to 9 individual symptoms, which were rated by the physicians with scores from 0 – not present to 4 – very severe. The mean score for each chief complaint was used to measure severity at baseline. Patients meeting the inclusion criteria, respectively in case of children their parents/legal guardians, were informed by the physician about the nature of the study. Prior to enrolment into the trial each patient/parent had to provide written informed consent to participate. Exclusion criteria were among others severe mental impairment, severe chronic diseases such as spinal cord injuries and alcohol or drug abuse. At centres providing both therapies (mixed centres) the treatment was chosen by the physicians and/or following the patients' preference.
Study protocol
During the initial patient contact the physician documented the onset of chief complaint, severity of symptoms, clinical diagnosis, concomitant medical problems and medication and primary treatment prescribed. Patients completed a questionnaire asking for demographic and health-related information. Additionally some general questions addressed the patients' willingness to pay, patient confidence in health care provider and therapy, treatment preference, willingness to be randomized (at mixed centres only) etc. The patient follow-up was carried out by telephone 7, 14 and 28 days after the initial contact. Independent external study collaborators performed the calls. According to the study protocol they were blinded for the patient's treatment. The following parameters were documented: severity of complaint-related symptoms, time until occurrence of first improvement, therapy outcome (assessed with complete recovery, major improvement, slight improvement, no change or deterioration), patient's satisfaction with the treatment (very satisfied, satisfied, neutral, dissatisfied or very dissatisfied) and general health condition. In case any adverse events had occurred, the physician was informed in order to collect more information and medically assess the case.
The response rates were defined as the proportion of patients assessing themselves as 'completely recovered' or 'major improved' after 7, 14 and 28 days of treatment. The main outcome criterion was the response rate after 14 days. Other outcome criteria were the response rates after 7 and 28 days, time to onset of first improvement (patients' assessments after how many days they had experienced a first improvement), patient satisfaction with treatment and health care provider and the occurrence of adverse events. Adverse events were coded by using the WHO-ART terminology.
A total of 72 selected homeopathic medications in potencies of 12C and higher (manufactured according to the German Homeopathic Pharmacopoeia), were given to the physicians as the basic set of study medication. Nevertheless, the physicians were free to prescribe any other remedy, any other potency or dosage form. Conventional treatment, registered in each participating country, was prescribed by the investigator and picked from a pharmacy.
Data collection and monitoring
Data were collected with a validated remote data entry system that was accessed via the Internet. The physicians entered their data online into electronic case report forms. The remote data entry system checked each entry for completeness and consistency. It recorded all data values with date and time of entry as well as all changes in the database in an audit trail. Access to the database was protected by password identification. Each user had a unique password that was provided in a sealed envelope. After entering was completed, data were transferred via Internet to the data collection centre at the former Institute for Numerical Statistics (IFNS, acquired by Omnicare Inc. in 1999) in Cologne, Germany. Monitoring was performed adherent to GCP-guidelines by an independent clinical monitor. Monitoring visits took place at least twice in order to inspect the course of the trial and to carry out source data verification. A data review tool enabled the monitor to identify missing data values, data values deviating from the normal range and among other things, data needing source verification.
Statistical methods
Data analysis was conducted by ClinResearch, Cologne, Germany, using the statistical software package SAS 9.1.3 under Windows XP Professional. The study was designed to confirm non-inferiority of the primary outcome criterion in the total patient population after homeopathic treatment in comparison to conventional treatment, using the one-sided equivalence test at the 2.5% significance level. The non-inferiority margin was defined by 5%-points. Subgroup analyses were performed on age groups (children:
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