The common cold is recognized as the most frequent disease in Western civilization and the number one cause of primary health care consultations [
Colds comprise a syndrome of symptoms, typically with nasal complaints, cough, sore throat, and sometimes constitutional complaints, like headache, malaise, and fever [
The development of effective cold preventives is hampered by the multiplicity of viruses and the complex interplay between host and virus [
Vaccination presents an effective method for managing seasonal influenza and respiratory, syncytial virus (RSV) in children. However, the efficacy of vaccination depends on the immunological fitness of the recipient and primarily in older individuals or those with chronic heart disease only insufficient immunity can be built up, resulting in a reduced immunity in this vulnerable population [
Another method for preventing cold infections is to modulate the immune system [
On the other hand, a good safety profile is mandatory for therapies that are designed to be taken over several months [
The present study aimed to examine safety parameters of
This study was a randomized, double-blind, parallel, placebo-controlled clinical trial conducted at the Common Cold Center in Cardiff University (United Kingdom). The study was conducted according to the declaration of Helsinki (2000), the international conference on harmonization, good clinical practice regulations, the association of the British Pharmaceutical Industry, and the human tissue authority. The trial received ethical approval from the local ethics committee by 28th July 2009 and, finally, from the medicines and healthcare products regulatory agency (MHRA) on the 2nd July 2009. The study was registered under the Eudra-CT number, 2009-012297-12. From October to November 2009, healthy participants were included in the study and were randomly allocated to receive either
The
The therapy regimen was in accordance with the recommendation by the manufacturer. Participants swallowed
Participants were recruited via advertisements around the university campus. At first contact, respondents received an info-leaflet describing the trial. The study inclusion criteria were adults (≥18 years old) of good physical condition, that experienced ≥2 colds per year. The exclusion criteria were ineffective contraception; participation in another study; women that were pregnant or breast feeding; current cold infection; currently taking antimicrobial or antiviral medication; alcohol or drug abuse; psychiatric disorders; epilepsy; attempted suicide; planned surgical intervention; serious chronic disease that could influence absorption, metabolism, or elimination of the medication; known AIDS or other autoimmune diseases; diabetes type 1; corticosteroid-treated asthma; medicinally treated atopy or allergy; a known allergy to plants of the composite family (Asteraceae). Volunteers with clinically relevant laboratory abnormalities were dropped out after inclusion. All participants provided signed, informed consent.
A total of 755 subjects were included. Subjects were randomly allocated to receive treatment or placebo. The randomization code was prepared in block-sizes of 6 with the “RANCODE Professional 3.6” program. Each participant received treatment based on his/her identification number, which was allocated according to the time point of inclusion. Drugs were personally dispensed by the investigator or personnel authorized by the investigator. The randomization procedure was prepared by a statistician. The original randomization code was retained by the statistician in a sealed envelope, and one copy was conveyed to the investigator. Only in a case of emergency the investigator was permitted to open the envelope that contained the identification of a treatment.
The blinding of the study treatment was found to be adequate, when pretested in 79 test persons. In both treatment groups, nearly half of the participants believed that they were given the Echinaforce preparation (17 of 38 subjects (45%) with placebo and 19 of 41 subjects (46%) with verum). A total of 15 recipients of placebo (39%) and 17 (42%) with verum stated that they did not know which preparation they were given.
With at least 300 evaluable subjects in each group, assuming a 0.2 proportion of individuals with adverse drug reactions (ADRs) within each group, the upper limit of the observed one-sided 97.5% confidence interval of the difference between the placebo proportion,
Over the entire study period, all participants retained a diary to record AEs by answering the question “Did you have any unusual or unexpected symptoms today?” Moreover, at the monthly study visits, participants were interviewed about acute or experienced events by the study physician. The AE analysis included all AEs with a date/time of onset on or after the start date of the study treatment. The analysis excluded AEs with a date/time of onset that occurred before the start date or when information on the date/time of onset was missing. All AEs were coded with the lowest level terms from the latest installed version of the MedDRA Dictionary (V. 13.1).
For AEs described by a physician(s), the lowest level term was chosen that best matched the physician’s actual description. These lowest level terms were translated into preferred terms (PTs) and classified into a system organ class (SOC) employing the latest installed version of the MedDRA Dictionary (V. 13.1). Primary analysis was performed on the basis of the per protocol population.
At inclusion and exclusion visits, participants provided blood samples. These were processed to determine clinical chemistry, hematology parameters, and differential blood cell counts. Clinically relevant abnormalities that deviated from the normal range were flagged by the laboratory. The final safety criterion was the assessment, by participants and physicians, of therapy tolerability.
Causal relationship between recorded AEs and the study medication was rated by the physician as either “not related,” “unlikely,” “possible,” “probable/likely,” “certain,” “not assessable/unclassifiable,” “unknown,” or “not applicable.” AEs that were at least “possibly” related to the medication were considered adverse drug reactions (ADRs); these were included in the primary analysis of the per protocol collective (PP). With this respect, the proportion of patients with any ADRs was compared between groups to determine the non-inferiority of the treatment. To prove safety, there should be less than a 10% (non-inferiority limit) difference between the proportions of patients with ADRs in the Echinaforce and placebo groups. The alternative hypothesis (HA) of interest was to show non-inferiority by determining that the proportion of patients with ADRs in the Echinaforce group (
The second question the participant answered in the diary, “Do you believe you have a cold today?” was answered yes or no. During acute colds, the symptoms “headache,” “chilliness,” “sneezing,” “nasal obstruction,” “nasal discharge,” “sore throat,” “cough,” and “malaise” were rated on a 4-point Likert scale with 0 or no entry = absence, 1 = mild, 2 = moderate, and 3 = severe symptoms. In addition, the participant indicated in the diary the daily intake of concomitant medication and/or therapy. This matrix was based on the work by Jackson and colleagues, who described the clinical features and symptoms of a virally induced common cold [
Nasal secretions were collected during acute stages of colds. Samples were inserted into a transport vial and stored at the study site at −70°C. At the end of the clinical trial, the samples were analyzed for the presence of respiratory viruses (Provincial Health Services Authorities, PHSA; BC Center for Disease Control, Vancouver Canada). Briefly, RNA was isolated from the nasal secretions using MagMax Express 96 Nucleic Acid Extractor (Applied BioSystems, Foster City CA) and screened with a Respiratory Virus Panel. The FAST Multiplex panel (Roche Diagnostics, Basel, Switzerland) could detect the following viruses (Virus Type/Subtype): Influenza A H1/H3, Influenza B, Respiratory Syncytial Virus, Coronavirus 229E/OC43/NL63/HKU1, Parainfluenza virus 1–4, human Metapneumovirus, Entero-rhinovirus, Adenovirus, and human Bocavirus. Frequency ratios of every virus and of membranous virus infections between treatment groups were compared to the underlying group sizes using a chi-square test.
All statistical analyses were performed with the SAS system (Version 9.2) and Testimate 6.4 (IDV, Datenanalyse und Versuchsplanung, Gauting/München).
A total of 755 study subjects were screened and allocated into one of the treatment groups between October and November 2009. Of these, 673 subjects completed the study; the last patient visit was conducted in late April 2010. Eighty-two (10.9%) subjects discontinued the trial prematurely; of these, 38 were out of contact after randomization, 16 withdrew consent, 3 terminated the study due to technical reasons, 3 terminated due to intolerable AEs or deterioration of the participant’s health, and 22 withdrew for no documented reason. A complete flow diagram of participant disposition is shown in Figure
Flow diagram of participant disposition.
The two groups were comparable with regard of age, gender, body weight, height, and body mass index (BMI). There was no noticeable difference between groups in anamnestic variables, including blood pressure or heart rate. The only variable that was significantly different between groups was the susceptibility to colds, measured as the number of colds experienced in the past. Participants in the placebo group were significantly less susceptible to infections than those in the
Demographic and anamnestic data from participants in the safety collective at the inclusion visit.
Variables | Echinaforce |
Placebo |
|
---|---|---|---|
Age (years) (SD) | 23.6 (7.8) | 23.2 (7.2) |
|
Body weight (kg) (SD) | 67.7 (13.1) | 69.5 (13.1) |
|
Body height (cm) (SD) | 167.5 (9.0) | 168.1 (8.9) |
|
Body mass index (SD) | 24.1 (4.0) | 24.5 (3.9) |
|
Gender | |||
Female |
244 (68.7) | 227 (62.7) |
|
Male |
111 (31.3) | 135 (37.3) | |
Colds in the past; |
|
|
|
A total of 25 subjects in the Echinaforce group (9.0%) and 30 subjects in the placebo group (10.0%) experienced 27 and 30 ADRs, respectively. The percentage difference was −0.97%, with an upper limit of the one-sided 97.5% confidence interval of 3.6%, which is less than 10%. Consequently, Echinaforce was demonstrated to be noninferior to placebo in the incidence of ADRs as per protocol population.
A total of 293 AEs were reported by 177 subjects treated with Echinaforce and 306 AEs were reported by 172 subjects in the placebo group (safety collective). Four AEs in the Echinaforce group and 3 in the placebo group led to discontinuation of treatment (Table
Overview of adverse events (AEs) and adverse drug reactions (ADRs) that occurred during the study period in the safety collective.
Echinaforce |
Placebo |
Total |
|
---|---|---|---|
Number (%) of participants with | |||
(i) adverse events | 177 (49.9) | 172 (47.5) | 349 (48.7) |
(ii) drug-related AEs1 | 35 (9.9) | 35 (9.7) | 70 (9.8) |
(iii) serious AEs | 0 (0.0) | 1 (0.3) | 1 (0.1) |
(iv) AEs leading to treatment discontinuation | 3 (0.8) | 2 (0.6) | 5 (0.7) |
Number of events2 | |||
(i) adverse events | 293 | 306 | 599 |
(ii) drug-related AEs1 | 39 | 36 | 75 |
(iii) serious adverse |
0 | 1 | 1 |
(iv) AEs leading to treatment discontinuation | 4 | 3 | 7 |
1AEs that were causally related to the study medication with ratings of certain, probable/likely, or possible.
2AEs were based on the Preferred Terms (PTs), each PT counted only once per participant.
Overall, no significant difference could be identified in the occurrence of AEs between groups, whether related or unrelated to the study drug (Fisher’s exact test). This did not change when considering the total numbers, the system organ class, or the preferred terms (data not shown).
In the hematological or biochemical measures no significant or clinically relevant changes from before to after Echinaforce treatment and in comparison to placebo were detected. No abnormalities were found after the 4-month exposure to Echinaforce. Previously reported safety concerns like induction of allergic reactions, leucopenia, or autoimmune diseases were not observed under
About 64% of participants in the Echinaforce group and 71% in the placebo group assessed the tolerability of the medicine to be “good” or “very good.” There was no significant difference between groups.
Efficacy was assessed concurrent with the safety variables during the long-term treatment with Echinaforce. A priori case definitions were made for sample size (calculation), statistical methodology, and measurements of probability or clinical end point.
The placebo group had a total of 188 cold episodes, with a collective duration of 850 episode days; in comparison, the Echinaforce group had 149 episodes with a collective duration of 672 episode days (ITT population). The difference of cumulated events (episodes and episode days) between the treatment groups each of 26% reached statistical significance for episode days (
Concurrent medication was a significant factor in the present study. In the
A total of 201 nasal secretion samples were collected in the study; 86 in the
In long-term studies (here, 4 months), compliance represents a sensible factor. Therefore, we specifically examined a population that took ≥100% of the recommended study medication for the entire study period. Eighty-eight compliant subjects in the
Prevention of mild-to-moderate diseases, like the common cold, requires therapies with satisfactory safety and efficacy profiles. The common cold is particularly in need of preventive treatments, due to its high frequency and high associated costs of illness [
In the present study, safety and efficacy variables were analyzed over a collective total of 11,472 weeks or 2,868 months of prophylaxis from 717 subjects. We used a highly sensitive method to detect AEs, and we included the physician’s experience to assess causality (ADRs). In addition, extensive laboratory tests were conducted to examine hematologic and metabolic parameters.
The overall safety profile of Echinaforce was very good, based on the total AEs, the ADRs, and the laboratory measurements, within the treatment group and in comparison with placebo. In addition, the global tolerability assessments by the physicians and participants were quite positive. The fact that more than 75% mentioned that they would take the medicine again indicated that a 4-month treatment with Echinaforce was well accepted. Although the present data did not indicate any safety concern with
The study also assessed cold episodes using a highly accepted method developed by Jackson et al. [
A difference of 26% between groups in an open-field, long-term prevention study was comparable with a previous study on the effects of nasally administered interferons, and this difference can be considered clinically relevant [
Previous studies have described the problems associated with assessing cold infections purely on subjective symptomatic grounds [
The present work described the largest clinical trial to date that tested the safety and efficacy of
Overall, the risk/benefit results from this clinical study suggested that long-term treatment with
Professor R. Eccles, Dr. M. Jawad and P. Klein have no conflict of interests.