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Phase III Double-Blind, Randomized, Placebo-Controlled Crossover Trial of Black Cohosh in the Management of Hot Flashes: NCCTG Trial N01CC¹

Barbara A. Pockaj, James G. Gallagher, Charles L. Loprinzi, Philip J. Stella, Debra L. Barton, Jeff A. Sloan, Beth I. Lavasseur, Radha M. Rao, Tom R. Fitch, Kendrith M. Rowland, Paul J. Novotny, Patrick J. Flynn, Elliott Richelson, Abdul H. Fauq

From the Mayo Clinic and Mayo Foundation, Rochester; Metro-Minnesota Community Clinical Oncology Program, St Louis Park, MN; Geisinger Clinic and Medical Center Community Clinical Outreach Program (CCOP), Danville, PA; Michigan Cancer Consortium, Ann Arbor, MI; Siouxland Hematology-Oncology Associates, Sioux City, IA; Scottsdale CCOP, Scottsdale, AZ; Carle Cancer Center CCOP, Urbana, IL; and the Mayo Clinic Jacksonville, Jacksonville, FL

Address reprint requests to Charles Loprinzi, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: cloprinzi{at}mayo.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: Hot flashes can cause significant morbidity in postmenopausal women undergoing or finished with breast cancer treatment. Black cohosh has been used to treat hot flashes, but definitive clinical data about efficacy have been equivocal.

METHODS: A double-blind, randomized, cross-over clinical trial with two 4-week periods, was used to study the efficacy of black cohosh (1 capsule, Cimicifuga racemosa 20 mg BID) for the treatment of hot flashes in women. Participants kept a daily hot flash diary during a baseline week and then during two 4-week crossover treatment periods. Hot flash scores were measured by assigning points (1 to 4 for mild to very severe) to each hot flash based on severity and then adding the points for a given time period.

RESULTS: Between October 31, 2003, to March 4, 2004, 132 patients were randomly assigned. Toxicity was minimal and not different by treatment group. Patients receiving black cohosh reported a mean decrease in hot flash score of 20% (comparing the fourth treatment week to the baseline week) compared with a 27% decrease for patients on placebo (P = .53). Mean hot flash frequency was reduced 17% on black cohosh and 26% on placebo (P = .36). Patient treatment preferences were measured after completion of both treatment periods by ascertaining which treatment period, if any, the patient preferred. Thirty-four percent of patients preferred the black cohosh treatment, 38% preferred the placebo, and 28% did not prefer either treatment.

CONCLUSION: This trial failed to provide any evidence that black cohosh reduced hot flashes more than the placebo.

	INTRODUCTION

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Hot flashes are a common manifestation of diminished ovarian function as a result of natural menopause or breast cancer therapy. Hormone replacement therapy (HRT) has been the mainstay of treatment for hot flashes, but is contraindicated in women with breast cancer or at high risk for the development of breast cancer.¹ Even though HRT can be beneficial for the prevention of bone loss,² recent studies have cast doubt on the cardiovascular benefits and have observed a potential harmful effect.³ These new findings compounded with HRT being associated with an increased risk of breast cancer,¹ have caused women to seek alternative therapies.

A number of dietary supplements claim to relieve hot flashes. Of these nonprescription therapies, black cohosh is the most widely used supplement to treat hot flashes.⁴ Black cohosh or Cimicifuga racemosa, native to North America, is a member of the buttercup family. There has been a significant increase in the use of black cohosh over time, resulting in sales of $79 million in 2003.⁵

Even though women have embraced black cohosh, clinical data demonstrating its efficacy in relieving hot flashes is mixed. Small prospective trials with black cohosh conducted in Europe reported improvements of symptoms.⁶ Subsequently, larger randomized trials have been performed and have not consistently demonstrated clinical benefit.^7-10

A small Mayo Clinic (Scottsdale, AZ) pilot study of black cohosh was associated with a 50% reduction in hot flash score.¹¹ Based on this promising pilot study and contradictory results found in the literature, it was decided to perform a large randomized placebo-controlled study using a cross-over technique through the North Central Cancer Treatment Group (NCCTG) to better determine the ability of black cohosh to reduce hot flashes and whether it had any evident toxicity.

	METHODS

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Patients
Patients considered for this study, similar to patients that participated in several prior randomized clinical trials,^12-14 were women with a history of breast cancer, a perceived increased risk of breast cancer, or who did not want to take estrogen due to the increased risk of breast cancer. All patients had to be free of clinically evident malignant disease. They must have had bothersome hot flashes ( 14 per week) for at least 1 month and desired therapeutic intervention. They could not have been receiving concomitant antineoplastic chemotherapy, androgens, or estrogens. Concomitant therapy with tamoxifen, raloxifene, or an aromatase inhibitor was allowed as long as the patient had been on the therapy for 1 month and was not planning to alter this therapy during the study. Patients were ineligible if they had any prior use of black cohosh; use of antidepressants within the prior 2 weeks (or planned use during the next 9 weeks); or current or planned use of other agents for treating hot flashes (eg, clonidine, belladonna alkaloids, DHEA). Use of vitamin E and/or soy was allowed if the patient had been on a stable dose for 1 month and planned to continue the same dose during the entire study period. The use of other oral herbal therapies, therapeutic herbal teas, or tinctures during the study period were not allowed due to potential interactions with black cohosh.

All patients gave written consent following federal guidelines, and the protocol was approved by the institutional review board at each treating location. The patients were then stratified on the basis of age, current tamoxifen use, current raloxifene use, current aromatase inhibitor use, duration of hot flashes, and average frequency of hot flashes per day using a dynamic allocation procedure that balances the marginal distributions.^15,16

Protocol Treatment
During the first week, no treatment was given and this served as baseline data. Patients were asked to complete a prospective, daily hot flash diary for the 9 weeks of the study. The hot flash diaries have been previously validated in several previous studies.¹² Participants received 4 weeks of therapy with black cohosh or an identical appearing placebo. The black cohosh, or placebo, was given as one tablet twice per day. For the next 4 weeks, patients were crossed over to the alternative treatment arm. All treatments were double-blinded. Participants also completed a weekly symptom experience diary asking for a 0 to 10 rating of their experience during the prior week of the following items: nausea, excessive sweating, joint or muscle pain, chills, headache, nervousness, stomach cramps, dizziness, negative mood swings, heaviness in legs, quality of life, how much hot flashes interfered with their quality of life, and how satisfied they were with their hot flash control. These single items were scored individually; no summation was done. In addition, the Greene Climacteric Scale was completed at the end of the baseline week and following 4 weeks of both treatments.

Black Cohosh Details
For this study, capsules of black cohosh contained 20 mg Cimicifuga racemosa and rhizome extract standardized to contain 1 mg of triterpene glycosides as calculated by 27-deoxyacetin mixed in dicalcium phosphate, whey, microsystalline cellulose, stearic acid, peppermint flavor, silica and magnesium stearate. The dose chosen was based on the recommended dose of the most commonly marketed black cohosh product in the United States (Remifemin; GlaxoSmithKline, Research Triangle Park, NC). Being unable to obtain remifemin and placebos from GlaxoSmithKline, another source of black cohosh was obtained. The product and matching placebos for this study were supplied by Hi-Health Corporation, Scottsdale, Arizona. In order to verify that this product was similar to the most commonly studied commercially available black cohosh product, Remifemin, proton nuclear magnetic resonance and high performance liquid chromatography (HPLC) analyses were performed. To perform the proton nuclear magnetic resonance (HNMR) analysis, 10 mg of powdered remifemin and the study black cohosh tablets were dissolved by vortexing the samples in 0.5 mL of dimethyl sulfoxide (DMSO.d6; six deuterium atoms). The proton nuclear magnetic resonance spectra of the resulting solutions were measured and were found to be almost identical for the two extracts. Then 10 mg of each compound were separately extracted from 1 mL methanol and 40% aqueous isopropanol alcohol. A total of 20 microliters of each was injected into a 126-Beckman HPLC instrument with 166 ultraviolet detector (flow rate 1.5 mL/min; maximum, 254 nm; linear gradient 10% B to 100% B in 30 minutes where B = 0.1% trifluoroacetic acid and A = 80% acetonitrile in 0.1% trifluoroacetic acid). Again, the general HPLC profiles were found to be very nearly identical. During the HPLC, three prominent peaks were manually collected and analyzed by infusion of methanolic and aqueous isopropanolic extracts on a Sciex-265 Triple Quadrupole mass spectrometer (Applied Biosystems, Forest City, CA). The fingerprint spectra were measured under two different orifice and ring voltages (400 and 200 for orifice and 74 and 35 for the ring). The mass spectrometry spectra showed very similar peak pattern under both conditions of measurement. Based on this analysis, both compounds had very similar HNMR and HPLC profiles.

Statistical Methodology
The primary end point was the average intrapatient hot flash score (which is a construct of average daily hot flash severity and frequency) difference between the baseline week and the last study week of the first treatment period. Hot flash activity was analyzed in a number of ways. First, the difference between treatment week 4 (study week 5) and baseline activity (study week 1) in terms of hot flash score was compared between placebo and black cohosh arms by standard two-sided Wilcoxon procedures.¹⁷ CIs were constructed for median reductions in hot flash frequency and score. Further analysis was undertaken by use of repeated measures analysis of variance and generalized estimating equations (GEE) modeling of appropriately transformed frequency and score data.^18,19 A square root transformation of the hot flash frequency and a logarithmic transformation of the hot flash score data induced normality sufficiently for the use of the ANOVA/GEE procedures.²⁰ Results of this confirmatory analysis were consistent with the primary analysis. To further validate the hot flash data, patients were asked weekly how satisfied they were with the control of their hot flashes on a scale of 0 to 10 (0 = very satisfied, 10 = very dissatisfied).

Crossover analyses were designed to be supplemental to the primary analysis described above. They were performed using the classic two-stage crossover test supplemented by graphical routines and linear models.²¹

Toxicity incidence was compared between treatment groups using Fisher's exact tests and by Wilcoxon procedures. Correlations between covariates were assessed with Spearman correlation coefficients.

A two-sided comparison of the primary end points with 50 patients per treatment group at the end of the first treatment period had the required 80% power and 5% type I error rate to detect a difference of 0.6 standard deviations or 1.2 hot flash per day, 3.0 units of hot flash score, or a drop in hot flash score of 21% from the last week of the first treatment period compared with the baseline week score. Missing data were handled by analyzing the results using the last value carried forward, minimum value carried forward, and mean value carried forward. There were no differences in results using any of these imputation methods.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
There were 132 patients randomly assigned on this study between October 31, 2003 and March 4, 2004. There were no ineligible patients and only one cancellation (a patient decided to not participate in this trial after being entered, but before study medication had been administered) on this study. Sixteen patients (12%), including the one who cancelled, did not provide any hot flash information after baseline. One hundred and seven patients (81%) finished the first 5 weeks of hot flash diaries while 99 patients (75%) completed the entire 9 weeks of therapy. Patient flow on this study is illustrated in Figure 1. Baseline data from the 116 assessable patients are presented in Table 1.

View larger version (20K): [in this window] [in a new window]   Fig 1. Patient flow diagram.

The overall efficacy of the two treatments is shown in Figure 2 and Table 2. Both treatments show a small decrease in hot flash scores over the first two weeks of treatment which then stabilized over the remainder of the trial, including the crossover period. Patients on black cohosh reported a 15% (CIs of 2% to 29%) mean decrease in hot flash scores during the fourth treatment week compared with a decrease of 31% (CIs of 18% to 44%) for patients on placebos (P = .10). As is evident in Figure 2, the crossover analysis did not suggest any benefit for black cohosh (P = .98).

View larger version (7K): [in this window] [in a new window]   Fig 2. Hot flash score reductions from baseline over the study period. Week 0 represents the baseline week.

When patients were asked which treatment arm they preferred, after completion of the 9 week study and while they were still blinded, 32% of patients preferred the black cohosh treatment, 37% preferred placebo, and 31% did not prefer either treatment. These data are not indicative of any difference in treatment preference. To further validate this finding, patients were asked weekly, as a question on their symptom experience diary, how satisfied they were with the control of their hot flashes on a scale of 0 to 10 (0 = very satisfied, 10 = very dissatisfied). During the fourth treatment week, patients receiving black cohosh perceived their hot flash control to be improved an average of 1.3 points compared with those patients receiving placebo who felt their hot flash control to be improved by 2.0 points (P = .20).

	DISCUSSION

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A trial was reported by a German group in 1987 which randomly assigned 80 postmenopausal women to black cohosh (Remifemin) 80 mg per day versus conjugated estrogen 0.625 mg per day versus placebo for 12 weeks.⁷ Women receiving black cohosh were reported to have a significantly improved Kupperman Menopausal Index and Hamilton Anxiety Scale compared with women receiving conjugated estrogen or placebo. There was no difference in vaginal proliferation among the three groups. Of note, the Kupperman Menopausal Index is a measure of general menopause, which includes weightings not based on psychometric studies. It is not a measure of hot flash frequency²²

A subsequent German trial randomized 62 postmenopausal women to black cohosh (CR BNO 1055; Klimadynon/Menofem; Bionorica AG, Neumark, Germany) 40 mg per day versus conjugated estrogen 0.6 mg/d versus placebo for 12 weeks.⁹ The black cohosh administered was a preparation of dried aqueous/ethanolic extract of the rhizome of Cimicifunga racemosa. All groups reported an improvement in the Menopause Rating Scale. Those women receiving black cohosh or conjugated estrogen observed a marginal improvement compared to placebo (P = .05, for both comparisons). When the Menopause Rating Scale was broken down into its three factors (hot flashes, psyche, and atrophy), black cohosh administration caused an improvement in atrophy (disorders of sexuality, urinary symptoms, vaginal dryness, and joint/muscle symptoms; P = .02), but not hot flushes (hot flashes, heat complaints, and sleep disorders) or psyche (depressed mood, nervousness, or impaired memory).

Another recently reported German trial randomly assigned 304 women to black cohosh (remifemin) 40 mg per day versus placebo for 12 weeks.¹⁰ The black cohosh was an isopropanolic extract of the root stock of Cimicifunga racemosa. The analysis of the data was based on changes in the Menopause Rating Scale analyzed in a linear regression model considering the following cofactors and covariates; age at study onset, Menopause Rating Scale at baseline, follicle stimulating hormone (FSH) at baseline, pooled centers, interaction treatment by FSH, and interaction treatment at pooled centers. Using this method of analysis, black cohosh was reported to be significantly better than placebo, P = .027. It is important to note that in this study the primary end point was a subscale of the Menopause Rating Scale that included one question on hot flash and sweating severity and one question on sleep, which asked the participant to rate the severity of their sleep problem to include difficulty falling asleep, staying asleep, and waking up early. Therefore, this end point did not specifically look at numbers of daily hot flashes nor sleep disturbance specifically related to hot flashes.

A recent Italian trial randomly assigned 64 women to black cohosh (Remifemin) versus low-dose transdermal estradiol for 12 weeks.²³ The black cohosh was an isopropanolic extract of the root stock of Cimicifunga racemosa at a dose of 40 mg per day. The transdermal estradiol dosage was 25 µg per week. Women filled out a diary regarding their number of hot flashes per day. Other assessments included the Greene scale measuring menopausal symptoms and the Symptom Rating Test (SRT) measuring anxiety and depression. Both black cohosh and transdermal estrogen were reported to significantly reduce hot flashes vasomotor symptoms (Greene scale), anxiety (SRT), and depression (SRT). There was no significant difference between the black cohosh and transdermal estrogen. Interestingly, neither black cohosh nor transdermal estrogen had any effect on urogenital symptoms. Endometrial thickness, FSH, and luteinizing hormone (LH) were not influenced by either therapy.

Even though these aforementioned cited studies have suggested that black cohosh is a potential treatment for menopause, it is worth noting that the mechanisms of action of black cohosh have not clearly been elucidated. Early studies suggested that black cohosh was a phytoestrogen, but modern studies have demonstrated no estrogenic activity by a variety of methods.^11,24,25 In his study, Wuttke⁹ found that his compound of black cohosh demonstrated selective estrogen receptor modulator properties but this has not been demonstrated in other studies and conflicts with current literature. Administration of black cohosh has not caused changes in hormonal or vaginal cytologic variables.⁴ In addition, it does not change serum FSH or LH concentrations.²⁶

A review of 15 animal and 15 in vitro studies analyzing the pharmacology of black cohosh observed that the older studies are problematic due to possible contaminants in their preparations.²⁷ This review concluded that black cohosh most likely has a central neurologic effect (suggested to be dopaminergic) as opposed to a hormonal one. Burdette et al²⁸ found that black cohosh works as a partial agonist to serotonin receptors in vitro, but there is no information if black cohosh can cross the blood-brain-barrier to reach serotonin receptors in the brain.

A well-conducted, double-blind, placebo-controlled, randomized trial was performed by investigators at Columbia University (New York City, NY), who randomly assigned 85 women after completion of primary breast cancer therapy (although continued tamoxifen therapy was allowed) to black cohosh (Remifemin) 20 mg twice per day versus placebo for 60 days.⁸ FSH and LH levels did not change with either treatment. Symptom outcomes were measured using a menopausal symptom index and visual analog scale of overall health and well being. No significant difference was observed between the two groups for hot flashes, although a decrease in sweating was observed (P = .04).

Similarly, this current double-blind randomized cross-over study did not demonstrate any improvement in hot flashes, nor did it report any improvement of quality of life. The conduct of this current trial is consistent with the methods used in the trial performed by Columbia University, which used hot flash frequency as the primary end point.

The results of this current double-blind randomized trial do not confirm the preliminary promising-appearing information provided by the pilot trial that supported the conduct of this trial.¹¹ The positive pilot trial results appear to be likely due to placebo effects, as have been seen repeatedly in clinical trials.¹² It may be that the enthusiasm regarding the promise of natural products can enhance the usual 20% to 30% placebo effect.¹² This may also explain what was seen with soy products. Despite considerable enthusiasm, based on anecdotal experiences, the bulk of data from randomized clinical trials have not suggested that soy products work any better than do placebos.²⁹ This reinforces the need to follow-up pilot trial results with a properly conducted placebo-controlled clinical trial.

It should be noted that this trial does not in and of itself prove that there is not a black cohosh dose or schedule that might help relieve hot flashes or other menopausal symptoms. While it is possible that higher doses of black cohosh might work better, this is currently hypothetical and should be demonstrated by randomized, double-blinded trials before recommending its use in practice.

The NCCTG and others have performed several randomized controlled studies demonstrating clinical efficacy of various nonestrogenic agents for treating hot flashes.^13,14,30,31 Progestational agents, various antidepressants agents, and gabapentin have been associated with hot flash reductions of 50% to 85%. With these alternatives available to women for the treatment of hot flashes today, the use of black cohosh is not currently recommended.

	Appendix

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Additional participating institutions include: Meritcare Hospital Community Clinical Oncology Program (CCOP), Fargo, ND, 58122 (Preston D. Steen, MD); Upstate Carolina CCOP, Spartanburg, SC, 29303 (James D. Bearden III, MD); Missouri Valley Cancer Consortium, Omaha, NE, 68106 (James A. Mailliard, MD); Duluth CCOP, Duluth, MN, 55805 (Daniel A. Nikcevich, MD); Iowa Oncology Research Association CCOP, Des Moines, IA, 50309 (Roscoe F. Morton, MD); Toledo Community Hospital Oncology Program CCOP, Toledo, OH 43623 (Paul L. Schaefer, MD); Wichita Community Clinical Oncology Program, Wichita, KS, 67214 (Shaker R. Dakhil, MD); Quain and Ramstad Clinic, Bismarck, ND, 58506 (Edward K. Wos, MD); Hematology and Oncology of Dayton Inc, Dayton, OH, 45415 (Howard M. Gross, MD); Hawaii Minority-Based CCOP, Honolulu, HI (William S. Loui, MD).

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Barbara A. Pockaj, Charles L. Loprinzi, Debra L. Barton, Jeff A. Sloan, Paul J. Novotny Administrative support: Charles L. Loprinzi Provision of study materials or patients: Barbara A. Pockaj, James G. Gallagher, Charles L. Loprinzi, Philip J. Stella, Beth I. Lavasseur, Radha M. Rao, Tom R. Fitch, Kendrith M. Rowland, Patrick J. Flynn, Elliott Richelson, Abdul H. Fauq Collection and assembly of data: Charles L. Loprinzi, Debra L. Barton, Jeff A. Sloan, Paul J. Novotny Data analysis and interpretation: Barbara A. Pockaj, Charles L. Loprinzi, Debra L. Barton, Jeff A. Sloan, Paul J. Novotny Manuscript writing: Barbara A. Pockaj, Charles L. Loprinzi, Debra L. Barton, Jeff A. Sloan, Paul J. Novotny, Elliott Richelson, Abdul H. Fauq Final approval of manuscript: Barbara A. Pockaj, James G. Gallagher, Charles L. Loprinzi, Philip J. Stella, Debra L. Barton, Jeff A. Sloan, Beth I. Lavasseur, Radha M. Rao, Tom R. Fitch, Kendrith M. Rowland, Paul J. Novotny, Patrick J. Flynn, Elliott Richelson, Abdul H. Fauq

 

	NOTES

 
Supported in part by Public Health Service Grants No. CA-25224, CA-37404, CA-35103, CA-63849, CA-63848, CA-35195, CA-35272, CA-35269, CA-35101, CA-60276, CA-52352, CA-37417, and CA-35448. This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted December 21, 2005; accepted April 17, 2006.

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