Reviewed : Goel V, Lovlin R, Barton R, et al. Efficacy of a standardized echinacea preparation (Echinilin™) for the treatment of the common cold: a randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2004;29:75–83.

Summary: In a randomized, double-blind, placebo-controlled trial, 282 males and females aged 18-65 years with a history of two or more colds in the previous year, but otherwise in good health, were recruited to study the efficacy of a standardized Echinacea purpurea liquid extract (40% alcohol) in treating the common cold. Manufactured by Natural Factors, Burnaby, British Columbia, Canada, the extract Echinilin (sold in the U.S. as Echinamide™) is made from flowering tops of freshly harvested plants and is standardized to contain alkamides/cichoric acid/polysaccharides at concentrations of 0.25/2.5/25.5 mg/ml, respectively. Subjects were randomized to receive either echinacea extract or placebo for 7 days and were instructed to begin treatment at the onset of the first symptom related to a common cold. Treatment consisted of 10 doses the first day and 4 doses per day for the next 6 days. A dose was 4 ml of the echinacea extract or placebo diluted in a half glass of water.

Participants were asked to complete a daily log documenting the severity of their symptoms. Self-assessment was made on a 10-point scale: 0 = no symptom, 1–3 = a mild symptom, 4–6 = a moderate symptom, and 7–9 = a severe symptom. The following cold symptoms were assessed daily: sore throat, runny nose, sneezing, stuffy nose, watery eyes, chills, malaise, fever, headache, sore muscles, hoarseness, shortness of breath, and cough. Total Daily Symptom Scores (TDSS) were calculated by summing the daily scores of all symptoms. The primary efficacy end point was the change in TDSS over the 7-day treatment period. The secondary efficacy parameters were the change in total symptom scores (overall mean) of specific symptoms, duration of symptoms (number of days for which the total score was > 3), and response rate to the treatments. Response rate was calculated as the percentage of subjects demonstrating at least a 50% reduction in their maximum TDSS. In addition to self-assessments, participants were also required to see a nurse on days 3 and 8.

Of the 282 subjects entered in the trial, 128 contracted a common cold (59 received echinacea and 69 placebo) and were included in the intent-to-treat (ITT) population. Participants who followed all elements of the trial (“PP” group) were also separately analyzed. Throughout treatment, the TDSS were significantly lower in patients taking echinacea compared to those taking placebo (p < 0.05). The TDSS scores were found to be 23.1% lower in the echinacea group than in the placebo group for those participants who followed all elements of the trial (p < 0.01). All symptoms, with the exception of cough, had significantly lower scores in the echinacea group compared to the placebo group (p <0.05). In the PP group, 50% of subjects in the echinacea group showed at least a 50% reduction of their maximum TDSS by day 4. This reduction in TDSS was not evident in the placebo group until day 5.5. By day 7, the response rate increased to 95% in the echinacea group, but only to 63% in the placebo group. These results were similar but less pronounced in the ITT group. Gastrointestinal side effects (nausea, heartburn) were reported by 13% of those taking echinacea compared to 9% taking placebo. Other mild side effects such as itching, burning sensation and numbness of the tongue were reported by 13% of the echinacea group and 11% of the placebo group, respectively. However, no subjects withdrew due to these side effects.

Comments/Opinions: Completed at the University of Alberta in Edmonton, Canada, this is the first North American clinical trial to report efficacy for echinacea in the acute treatment of the common cold. In addition to early intervention, another possible key to this trial is the use of a higher dose on day one (40 ml) than on the remaining days. In contrast to a negative U.S. pediatric trial published last year (reviewed in this column in HerbalGram 62),¹ this trial uses a dosing schedule similar to a positive European trial that also used a liquid preparation made from the fresh-pressed aerial parts of E. purpurea (Echinaguard^®, another trademark for Echinacin^®, Madaus AG, Cologne, Germany).² In that trial, subjects were treated with 20 drops of the liquid every 2 hours during the first day of their symptoms and then 20 drops 3 times per day for the remaining 9 days of the trial. Interestingly, a second, negative U.S. echinacea trial did use a higher dose on day 1 of the trial,³ but comparison is difficult due to variations in the different preparations used in the trials. The product in the negative U.S. trial was an encapsulated dried powder made from the aerial parts and roots of E. purpurea and roots of E. angustifolia. Three other trials, Goel et al,⁴ Taylor et al, and Hoheisel et al, used an alcohol-based, liquid preparation made from the fresh juice. The preparation in the Taylor et al trial was a syrup prepared from the dried fresh-pressed juice of E. purpurea aerial parts. (The presence of the alcohol at about 22% is for preservation only; the alcohol is not used as a solvent as is the case with many commonly available echinacea extracts.) It may be beneficial to compare different dosing regimens as well as higher doses in future echinacea trials.

Because the preparation administered to subjects was a liquid, this study may not have been truly double blind. This criticism was pointed out by HerbalGram reviewer Bruce Barrett, PhD, professor at the University of Wisconsin Medical School and author of several critical reviews and clinical trials on echinacea. Unfortunately, this problem is inherent in any study using liquid preparations because it may be possible for blind participants to distinguish the identity of the true, active preparation from the placebo. If subjects in this trial were able to correctly identify echinacea as the active ingredient being administered, they may have over-reported positive outcomes. However, the trial authors point out that “The placebo was made to look, taste, and smell like echinacea extract but contained no detectable alkamides, cichoric acid, or polysaccharides.” They further note that “Blinding was also maintained adequately during the treatment period. On completion of the study, approximately 50% of the subjects in both groups could not guess correctly whether they had received echinacea or placebo.” Thus, insofar as this trial is concerned, double-blinding of participants using liquid preparations appears to have been successfully accomplished.

In his review, Dr. Barrett also noted that the magnitude of the apparent treatment effect may be overstated in this trial. The use of the term “response rate” is inappropriate for describing responses to the common cold, an ailment for which everyone recovers eventually. The primary outcomes instrument, while reasonable at face value, has not been tested for reliability, responsiveness, and validity. Therefore, the choice of cutoff for response rate is retrospective, and may overstate a modest effect size, i.e., the significance of the improvement in the echinacea group may not be quite as great as suggested by the results of the study.

The preparation in this trial is unique in its standardization of three groups of constituents considered to be active in both the aerial and root parts of echinacea. The investigators point to oral dose-response studies in rats showing enhanced alveolar macrophage function after 4 days of treatment.1 As respiratory macrophage activity is thought to be an important first defense against viral respiratory infection, they speculate that this may explain the efficacy of the product in this trial. It would be constructive if the manufacturers of this product were to produce human data in a future trial to support these speculations.

Practice Implications: The results of this trial place echinacea back on the list of considerations for treating the common cold in adults. It is important to note that the trial used a dose on the first day of treatment that was 2.5 times higher than the dose used on the following 6 days of treatment. In contrast to the negative pediatric trial published in the Journal of the American Medical Association,¹ there were no reports of skin rash in this trial.

Note: This online version contains a clarification edit to the original article related to the product name in the U.S.

References:

1. Taylor JA, Weber W, Standish L, et al. Efficacy and safety of echinacea in treating upper respiratory tract infections in children. JAMA. 2003;290(21):2824–2830.

2. Hoheisel O, Sandberg M, Bertram S, et al. Echinagard™ treatment shortens the course of the common cold: a double-blind, placebo-controlled clinical trial. Eur J Clin Res. 1997;9:261–268.

3.Barrett B, Brown R, Locken K, et al. Treatment of the common cold with unrefined echinacea: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2002;137(12):939–946.

4. Goel V, Chang C, Slama JV, et al. Echinacea stimulates macrophage function in lung and spleen of normal rats. J Nutr Biochem. 2002;13:487–492.