American Botanical Council Clarifies Echinacea Trial Published in Annals of Internal Medicine

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American Botanical Council Clarifies Echinacea Trial Published in Annals of Internal Medicine ABC quoted by AP, Bloomberg News, and other major media

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December 21, 2010. Today the Annals of Internal Medicine published a clinical trial on a proprietary echinacea formulation and its potential effects on people with common cold symptoms. The trial results do not show a statistically significant benefit for the echinacea product, even though there was a “trend” toward a benefit in reduction of symptoms and duration of symptoms.1 ABC Founder and Executive Director Mark Blumenthal was interviewed about this trial last week by both the Associated Press and Bloomberg Business News.

Associated Press coverage Predictably, the AP article was widely distributed and has been posted on the websites of many leading newspapers and news outlets, including The New York Times, The Washington Post, The Los Angeles Times, USA Today, The Seattle Times, The Wall Street Journal, National Public Radio, mainstream television news sites (ABC, MSNBC, Fox News), and many others.2 The AP article says, “Barrett and other experts said the findings would probably be viewed as positive by echinacea supporters but as the ‘nail in the coffin’ by critics . "‘It's not a compelling result in either direction,’ said Mark Blumenthal, executive director of the American Botanical Council, which follows research on herbal products. He said Barrett is on the group's advisory board.

“Blumenthal said the study was well designed, used a good quality product at a reasonable dosage and tested echinacea in a real-world setting, rather than giving colds to research volunteers.”2 Bloomberg News coverage Bloomberg News reporter Nicole Ostrow quoted Blumenthal’s comments about the diversity of echinacea products and problems interpreting the clinical research: “‘Echinacea products are not all alike,’ said Mark Blumenthal, founder and executive director of the American Botanical Council, a nonprofit organization based in Austin, Texas, in a telephone interview on Dec. 15. The challenge is determining which ones have the most benefit or any benefit.’

“The studies showing the most efficacy for echinacea in fighting colds looked at formulations made from the root and leaves of Echinacea purpurea, one of three different species, he said. The tablets used in the new study contained roots of the purpurea species and another, according to the report.”3

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Perspectives on the New Echinacea Trial Blumenthal’s quotes in the AP and Bloomberg articles were based on the following points he made about this trial during the interviews: This is a large trial, possibly the largest randomized, controlled trial on echinacea published to date, including 719 subjects. These subjects were taken from the general population in 2 Wisconsin communities and the trial is based on the susceptibility to infection by a cold virus. This is in contrast to some echinacea trials in which a rhinovirus is actually inhaled in a controlled situation.

The trial tested short-term use of the echinacea preparation, mostly within 24 hours of the appearance of initial symptoms. Primary endpoints measured in the trial were cold symptom severity and duration of symptoms, while the secondary endpoints were levels of interleukin-8 and neutrophil, markers for immune response, which did not increase overall in the echinacea-treated subjects to statistical significance.

The trial used a good quality echinacea preparation, made by MediHerb (Australia) and distributed in the United States by Standard Process (Palmyra, WI). This echinacea preparation is sold to health practitioners only and is not generally available in retail outlets or on the Internet.

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The MediHerb echinacea preparation is in tablet form and contains dried, concentrated extracts of two types of echinacea, the equivalent of 675 mg of E. purpurea root and 600 mg of E. angustifolia root, each standardized to 2.1 mg of alkamides, one of the key biologically active chemical compounds found in echinacea roots. In this trial, based on the dosage regimen, the MediHerb echinacea tablet contained a daily dose equivalent of 10.2 grams of (both types) dried echinacea root during the first 24 hours after the subject noticed the first symptoms of cold, and 5.1 grams per day of dried echinacea root consumed during the next 4 days.

The trial contained 4 arms: 1 arm had no placebo pill as a control; 1 arm had a placebo pill; 1 arm used the specific echinacea product in a double-blinded manner; 1 arm received the echinacea tablet in an open label manner, unblended.

This trial was designed and conducted by people who are experts in echinacea research and have published extensively on echinacea clinical trials, particularly the lead researcher, Bruce Barrett, MD, PhD, a professor of family medicine at the University of Wisconsin in Madison. Mr. Kerry Bone, founder of MediHerb and an internationally respected author of herb books for health professionals, was also a co-author of the trial.

There was a slight trend toward benefit in symptom reduction in both echinacea groups, with a reduction in duration by about 12 hours, which, although not statistically significant, the authors note may be considered clinically significant by some patients.

The authors provided an interesting, cautiously worded, and reasonable conclusion: This dose regimen of the echinacea formulation did not have a large effect on the course of the common cold, compared with either blinded placebo or no pills. However, the trends were in the direction of benefit, amounting to an average half-day reduction in the duration of a weeklong cold, or an approximate 10% reduction in overall severity.1 Illness duration and severity were not statistically significant with echinacea compared with placebo.

These results do not support the ability of this dose of the echinacea formulation to substantively change the course of the common cold.1 Unlike some previous echinacea clinical trials which turned out negative,4 these authors do not represent themselves as having produced the definitive study on echinacea, and they carefully craft their language to show that the conclusions, although not showing a statistically significant beneficial effect, did show trends toward benefit, which are of therapeutic value to some consumers.

There are many clinical trials on numerous types of echinacea preparations in the clinical literature and recent systematic reviews of some of these trials have concluded that there is benefit or trend towards benefit for the echinacea preparations used in the selected trials.5,6 Blumenthal also noted that conducting a meta-analysis of clinical trials on echinacea preparations is difficult, if not impossible, since so many different types of echinacea preparations are on the market and have been used in the many clinical trials. The heterogeneity of these preparations is based on the fact that there are three species of echinacea found in commerce: i.e., Echinacea angustifolia, E. pallida and E. purpurea, with the latter being the most popular.

In addition, the echinacea preparations found in the US market generally contain either dried herb material or alcoholic extracts from either the root or the above-ground part of the plant (aerial part), or even fresh-pressed juice from the fresh aerial parts. And, to further complicate matters for researchers who are attempting conducted systematic review or meta-analysis of clinical trials on these preparations, there are mixtures of these echinacea materials from two or three species. Since echinacea species and their plant parts contain different chemical profiles, these various products can have different activities and benefits—as reflected in some of the clinical trials.

Blumenthal also told the AP that the most compelling clinical literature published to date supports the clinical efficacy of two different brands of extracts of Echinacea purpurea root and aerial parts. For the first, there have been 3 clinical trials on the EchinaforceÂŽ extract produced by A. Vogel in Switzerland, imported into the US and distributed in health food stores by Bioforce USA.6 The second brand, called EchinamideÂŽ, on which 2 published clinical trials7 have shown some benefit for cold symptoms is produced in Canada by Natural Factors and sold in the US in health food stores.

Additional coverage of this trial not based on the AP story was done by CNN (online), NBC Nightly News, and other outlets, although the AP story is dominant.

Additional perspectives Australian herbalist and co-author Kerry Bone, one of the trials co-authors wrote in an email to Standard Process, the importer of the MediHerb product used in the trial: This is a well designed and conducted study delivering a robust result. It demonstrated that initiating treatment with a traditional Echinacea root product has only limited value in altering the course of the common cold once it has taken hold. Perhaps a study with higher doses might have delivered a better result. Nonetheless, it should not be a surprise to many herbal clinicians like myself who have been mainly using Echinacea root as a preventative in their practices. It might be contrary to popular thinking, but animal experiments have shown that Echinacea root takes time to induce its immune effects. This is why any benefit once an infection takes hold is probably marginal and it is best suited

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as a preventative. I have been involved in several clinical trials (either as co-author or advisor) that have demonstrated the long-term use of Echinacea root boosts immunity and prevents infections. One such positive trial of Echinacea root in reducing infections in long-haul airline travellers is currently in press (K. Bone, e-mail, December 21, 2010).

Francis Brinker, ND, a respected herbal expert and author of Herb Contraindications and Drug Interactions 4th Edition (2011), and a member of the ABC Advisory Board*, wrote: Once again, a good opportunity was lost. If the open label portion of the study had been done with an equivalent liquid echinacea extract, or even solid extract in lozenge form, I expect the beneficial results would have reached statistical significance.

For years I have noticed that clinical studies done on echinacea that include extracts of fresh Echinacea purpurea whole plant or aerial plant, especially in liquid form, are consistently positive compared to those using dried echinacea species extracts (or powdered herbs), especially in solid forms (tablets or capsules) to treat viral URTIs [upper respiratory tract infections]. It makes eminently good sense to treat locally when possible, and contact of echinacea extracts with the oropharangeal lymphatic tissue is extremely important in acute URTI conditions. Use of solid extracts requires systemic distribution that is useful as an adjunct, but not as the sole therapeutic intervention when echinacea is concerned. Use of whole powdered echinacea parts and species should be reserved for such or as a preventive measure. I understand the preference when doing research to use a solid form, since it makes a placebo-control much easier to make and administer, but it deprives the study of utilizing a factor of known empirical efficacy (local tissue exposure) (F. Brinker, e-mail, December 21, 2010).

In a follow-up email on December 23, Dr. Brinker added these comments about the trial: Having now read the article in toto, I would like to share some further thoughts and address points made by the authors.

I do applaud the care and consideration with which the study by Barret et al. 2010 was developed and executed. I personally know one of the clinicians involved, Dr. Dave Rakel, a former residential fellow in the University of Arizona's Program in Integrative Medicine. Dave is an excellent example of what is right in medicine's pursuit of viable alternative practices to integrate as adjuncts with conventional practice. All medical research is good to the degree that it can teach us something about how patients can be treated effectively or not. The important thing is to accurately interpret and apply the results.

Unfortunately, this study failed in helping to demonstrate the efficacy of a particular echinacea preparation for treating acute colds (though this does not imply that the product may not be useful for other purposes), but it did provide further evidence on the type of product that is not optimally effective in this condition. This also serves an important purpose.

In deconstructing the article I would like to begin by excerpting the last sentence: "Individual choices about whether to use echinacea to treat the common cold should be guided by personal health values and preferences, as well as by the limited evidence available.� What is the nature of the limited evidence? On the first page of the article the authors describe 2 main types of echinacea preparations in general:

(1) stabilized fresh juice of aerial parts of E. purpurea rich in hydrophilic derivatives such as polysaccharides/glycoproteins, and (2) aqueous-ethanolic extracts or the roots of E. purpurea or E. angustifolia richer in hydrophobic constituents such as alkamides.

However, they did not distinguish liquid versus solid versions of each of these, e.g., whether the aerial juice is stabilized by 22% ethanol or by drying. This distinction is demonstrably important as shown by the studies they cited of positive and negative studies, and by their choice of the dried root extract for this study.

In the introduction they note 3 positive studies and 5 negative studies. The positive studies and preparations used all include liquid extracts of E. purpurea aerial plant as follows: Cohen et al 2004 used liquid extracts of E. purpurea aerial plant and E. angustifolia root along with vitamin C and propolis; Goel et al 2004 used a liquid extract of E. purpurea whole fresh plant; Sperber et al 2004 used liquid E. purpurea aerial plant juice. These studies support the use of the first type of preparation noted by the authors, if liquid extracts of the aerial parts are included along with its liquid expressed juice. (Another positive study they did not mention, Lindemuth & Lindemuth 2000, used tea made from E. purpurea herb and dry root extract plus E. angustifolia herb. Use of E. angustifolia preparations as adjuncts seems entirely appropriate.)

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In the 5 negative studies noted, none used liquid E. purpurea aerial plant extracts, but the preparations used are the following: Barrett et al 2002 dried powders of E. angustifolia root and E. purpurea root and herb in capsules; Taylor et al 2003 dried E. purpurea juice in a syrup vehicle; Turner et al 2000 solid extract of uncharacterized echinacea (identified by the authors in a follow-up letter as being labeled as containing "E. purpurea and E. angustifolia"); Turner et al 2005 liquid extracts of E. angustifolia root; Yale & Liu 2004 freeze-dried juice of E. purpurea aerial plant in capsules.

Now future authors will add another "negative" study of echinacea preparations to their lists: dried extracts of E. purpurea and E. angustifolia roots. The authors of this article defend their choice of preparations by stating: "When we designed this study in 2002, we decided to use a root-based, alkamide-rich preparation. Research published since that time (32-38) has tended to support our decision."

However, the studies to which they refer are in vitro research, except for 2 human pharmacokinetic studies that demonstrate absorption of alkamides from the MediHerb product. They do not point to any human clinical studies indicative of the efficacy of such preparations, though they did cite several negative studies that used echinacea root preparations. (A positive study using a solid extract that should be noted is Brinkeborn et al. 1999 using Echinaforce, a fresh E. purpurea whole plant extract, while a solid extract of E. purpurea root in this same study was not effective.)

An interesting corollary to this is that all of the published studies to date using echinacea for the prevention of URTIs have utilized liquid extracts. It should be recognized from an empirical rationale and the evidence that acute infections can best be treated by concentrating the appropriate therapy locally, i.e., with frequent use of liquid E. purpurea aerial/whole plant extracts (as a gargle to maximize exposure to oropharyngeal tissue and then swallowed), while prevention may be accomplished with less frequent dosing of powdered echinacea roots, herb, or solid extracts used for enhancing systemic resistance over a prolonged period. If dosage (species, part, form, size, and frequency) is not optimized, then neither are the results.

Combining both approaches by the internal use of good quality echinacea powdered root, herb, and/or solid extracts as an adjunct to the local and internal use of a liquid fresh E. purpurea plant preparation for treating acute URTIs therefore seems entirely appropriate and advisable.

In addition to Dr. Brinker’s comments, A. Vogel Bioforce AG, the manufacturers of the Bioforce echinacea product noted above, released a statement on December 23 in which it offered an analysis of the new trial by Barrett et al.: Statement from Med. Dept. A.Vogel Bioforce AG on the Article by Barrett et al., Annals of Internal Medicine (2010): “Echinacea for Treating the Common Cold Barrett and colleagues have published a clinical study, which questions the efficacy of echinacea in the treatment of the common cold. The study was published in a scientific journal of high impact and can be found at Barrett B, et al. Echinacea for treating the common cold. Annals of Internal Medicine. 2010;153:769-777.

Study Methods 719 subjects (age > 12 years) with very mild signs and the personal impression of an upcoming common cold were assigned to four groups of interventions, unless their complaints existed for longer than 36 hours:

Interventions

Number of Participants

None

164

Echinacea (unblinded)

171

Placebo (unblinded)

168

Echinacea (unblinded)

170

Subjects received 8 tablets on the first day and on subsequent 4 days 4 tablets per day each containing the equivalent of: 675 mg of Echinacea purpurea root (alcoholic extract of dried roots); 600 mg of Echinacea angustifolia root (alcoholic extract of dried roots**); or the same number of Placebo tablets;

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or no treatment.

The primary endpoint was defined as the “area under the curve” (AUC) for global severity with duration and severity. Severity was assessed by WURSS-21 questionnaire and the duration by the participants impression of having a cold.

The results showed only a statistically insignificant trend in: reduction of the cold duration by half a day and a; reduction of severity of approximately 10%***.

The study was designed assuming a relative benefit of 20%, deduced from clinical trials with other echinacea preparations.

Comments to the study From a technical point of view the study by Barrett is of high quality (placebo-control, randomization, blinding).

However, from the medicinal and therapeutical point of view there are too many severe shortcomings, which completely dismantle the relevance and validity of this study.

Method of Assessment For the assessment of the primary endpoint the authors used a WURSS-21 questionnaire to measure the severity of the common cold. This questionnaire queries cold-unrelated symptoms like the ability to think clearly or walk/climb stairs aside of the classical cold-related symptoms. The WURSS-21 is a highly uncommon and rather unspecific tool (global) to assess the course of cold infections accurately. It has been established by the author himself and so far could not demonstrate significant efficacy for any well-established cold remedy at all. Or in other words: “You cannot measure the acceleration of a Porsche via using a thermometer on the wheel”.

Patient Selection Only volunteers with a minimal Jackson score of 2 were included in the study. The Jackson score is the mostly used score to assess cold symptoms during a common cold and focuses only on common cold symptoms. To our knowledge there is no data available to substantiate this criteria for inclusion. A Jackson score of 2 represents a day with moderate headache or a day with mild malaise and chilliness. Jackson who actually tried to differentiate virally induced colds from any other unspecific complaints (transitionally causing isolate complaints of the whole picture the cold syndrome) defined a score of more than 14 over 5 days as the minimal requirement for a cold infection.

Therefore it cannot be excluded that the study in fact included participants without cold infection and the study sample must be considered unsuitable. As demonstrated by Schoop et al. (2006) Echinacea helps in common cold infections, when applying the Jackson’s criteria appropriately.

Statistical Concerns Although it has been claimed that this study represents a very large study population, we notice that 4 groups and different interventions were studies. Thereby the actual particular groups were much smaller (N=164 – 171). Moreover, the sample size calculation was again based on the assumption of a 20% effect while using the WURSS-21. Again we notice that WURSS-21 has never demonstrated any kind of effect for echinacea in any study and therefore the statistical fundament of the whole trial is null.

Interestingly the authors themselves challenged the power of the study, admitting that their calculation basis was performed before 2004 would be outdated today. A minimal number of 200 subjects would have been required to see significance.

Investigational Products Barrett used the dried roots of two echinacea species, Echinacea purpurea and angustifolia.

A very recent well-designed clinical trial investigated various extracts of Echinacea angustifolia dried roots in a fairly large population (N=437) and could only demonstrate an insignificant trend in prevention and treatment of clinically induced common colds. We do not understand why Barrett used a very similar and highly specific extract, which before was never rigorously tested in a clinical setting. Much evidence exists for the efficacy of Echinacea purpurea above-ground parts which, supplemented with 5% of Echinacea purpurea roots yield statistically significant effects (Goel V et al, 2005; Goel et al, 2004; Brinkeborn et al, 1999).

Study Conduct

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Enrollment started in January 2004 and ended in August 2008 and 3321 subject were screened to find 719 suitable subjects. With the very broad inclusion criteria (age, definition of a cold) it is more than astonishing why only every fifth subject fulfilled the requirements of inclusion. Also we wondered how the last patient was enrolled in August – in the mid of summer – and whether the stability of the Echinacea product was monitored over the 4-years study period.

Conclusion The study – although under the surveillance of the government – raises more questions than it answers and due to many serious flaws provides us with uncertain conclusions about the general efficacy of echinacea. However, a statement about the generalization of the new study results were given by the founder and executive director of the American Botanical Counsil (ABC) Mark Blumenthal: “the most compelling clinical literature published to date supports the clinical efficacy of two different brands of extracts of Echinacea purpurea root. For the first, there have been 3 clinical trials on the Echinaforce® extract produced by A. Vogel in Switzerland, imported into the US and distributed in health food stores by Bioforce USA. The second brand, called Echinamide®, on which 2 published clinical trials have shown some benefit for cold symptoms is produced in Canada by Natural Factors and sold in the US in health food stores.”

The clinical study by Barrett deserves attention because it primarily highlights the importance to: Investigate echinacea products of documented clinical efficacy; Use appropriate measures to detect clinical effects; Correctly define cases of common colds; Plan the size of the trial not on the grounds of misconceptions.

More information on echinacea from the extensive ABC online archives are available at an echinacea webpage on the ABC website.

The trial was funded by the National Center for Complementary and Alternative Medicine (NCCAM). *Disclosure statement: Dr. Brinker is also a consultant to Eclectic Institute, a manufacturer of echinacea-based dietary supplements. **The echinacea product was manufactured by MediHerb Company (Warwick, Queensland, Australia). ***A theoretical interpretation of confidence intervals allowed for estimation of maximal benefit of 20%.

References 1. Barrett B, Brown R, Rakel D, Mundt M, Bone K, Barlow S, Ewers T. Echinacea for Treating the Common Cold: A Randomized Trial. Ann Intern Med. 2010;153:769-777.

2. Nano S. Got a cold? Study says Echinacea won’t help much. Associated Press, Dec. 20, 2010. http://hosted.ap.org/dynamic/stories/U/US_MED_COLD_REMEDIES_ECHINACEA?SITE=NYONI& SECTION=HOME&TEMPLATE=DEFAULT. Accessed Dec. 20, 2010.

3. Ostrow N. Echinacea Shows Little Benefit as Remedy for Treating Colds, Study Finds. http://www.bloomberg.com/news/2010-12-20/echinacea-shows-little-benefit-as-remedy-for-treatingcolds-study-finds.html. Accessed Dec. 21, 2010.

4. Turner RB, Bauer R, Woelkart K, Hulsey TC, Gangemi DJ. An evaluation of Echinacea angustifolia preparations in experimental rhinovirus infections. N Engl J Med. 2005;353:341-348.

5. Shah SA, Sander S, White CM, Rinaldi M, Coleman CI. Evaluation of echinacea for the prevention and treatment of the common cold: a meta-analysis. Lancet Infect Dis. July 2007;7(7):473-480.

6. Schoop R, Klein P, Suter A, Johnston S. Echinacea in the prevention of induced rhinovirus colds: a meta-analysis. Clin Ther. 2006;28(2):174-183.

7. Goel V, Lovlin R, Barton R, Lyon MR, Bauer R, Lee TD, et al. Efficacy of a standardized echinacea preparation (Echinilin) for the treatment of the common cold: a randomized, double-blind, placebocontrolled trial. J Clin Pharm Ther. 2004;29:75-83.

8. A. Vogel Bioforce AG. Statement from Med. Dept. A.Vogel Bioforce AG on the Article by Barrett et al., Annals of Internal Medicine (2010): “Echinacea for Treating the Common Cold”. Roggiwil, Switzerland. Dec. 23, 2010. ### home | about us | support ABC | privacy policy | contact us | site map

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American Botanical Council, 6200 Manor Rd, Austin, TX 78723 Phone: 512-926-4900 | Fax: 512-926-2345 | Email: abc@herbalgram.org The information on this site is intended for educational purposes only and is not a substitute for the advice of a qualified healthcare professional. The American Botanical Council does not endorse or test products, nor does it verify the content or claims made, either implicit or explicit. ABC does not accept responsibility for the consequences of the use of this information or its most up-to-date accuracy. ABC is an independent, nonprofit, tax-exempt research and education organization under IRS section 501(c)(3). All text, images and content Copyright Š 2013 American Botanical Council, unless otherwise noted.

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