Pockaj, B.A., Gallagher, J.G., Loprinzi, C.L., Stella, P.J., Barton, D.L., Sloan, J.A., … Fauq, A.H. (2006). Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG trial N01CC1. Journal of Clinical Oncology, 24, 2836–2841.

The purpose of the study was to measure the efficacy of black cohosh (one capsule, Cimicifuga racemosa 20 mg twice daily) for the treatment of hot flashes in women with and without a history of breast cancer.

Participants received four weeks of therapy with black cohosh or an identical appearing placebo. The black cohosh or placebo was given as one tablet twice per day. After completing the first four weeks, participants were crossed over to the alternative treatment arm.

• The study randomized 132 participants. 107 participants (81%) completed the first five weeks of hot flash diaries; 99 participants (75%) completed the entire nine weeks of therapy. The mean age was 56 years.
• Inclusion criteria:
  • History of breast cancer, a perceived increased risk of breast cancer, or did not want to take estrogen due to the increased risk of breast cancer.
  • Participants experienced bothersome hot flashes (14 or more per week) for at least one month.
  • Concomitant therapy with tamoxifen, raloxifene, or an aromatase inhibitor was allowed as long as patient had been on the therapy for one month.
  • Use of vitamin E and/or soy was allowed if the patient had been on a stable dose for one month or more and planned to continue the same dose during the entire study period.
• Exclusion criteria:
  • Receiving concomitant chemotherapy, androgens, or estrogens.
  • Any prior use of black cohosh; use of antidepressants within the prior two weeks (or planned use during the next nine weeks); or current or planned use of other agents for treating hot flashes (e.g., clonidine, belladonna alkaloids, dehydroepiandrosterone) 
  • Other oral herbal therapies, therapeutic herbal teas, or tinctures during the study period were not allowed because of potential interactions with black cohosh.

This was a double-blind, randomized, cross-over clinical trial with two four-week periods.

Participants completed a prospective, daily hot flash diary during the baseline week and then during the two four-week crossover treatment periods. Hot flash scores were measured by assigning points to each hot flash based on severity (1 for mild to 4 for very severe) and then adding the points for a given time period.

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. The difference between treatment week 4 (study week 5) and baseline  hot flash score (study week 1) was compared between placebo and black cohosh arms by standard two-sided Wilcoxon procedures. Confidence intervals were constructed for median reductions in hot flash frequency and score. 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. Thirty-four percent of patients preferred the black cohosh treatment, 38% preferred the placebo, and 28% did not prefer either treatment. Toxicity was minimal across both groups.

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

Limitations of the study included using a subset of participants did not have a diagnosis of breast cancer but met the eligibility criteria of a perceived increased risk of breast cancer, or did not want to take estrogen because of the increased risk of breast cancer. The numbers of participants with and without a breast cancer diagnosis were not specified.