Differentiated Evaluation of Extract-Specific Evidence on Cimicifuga racemosa's Efficacy and Safety for Climacteric Complaints

Table 2

Clinical studies between 2000 and 2012 on the efficacy of Cimicifuga racemosa in neurovegetative and psychic climacteric complaints, differentiated by extract and regulatory status (registered medicinal product-not registered as medicinal product).

Extract DER; extractant/standardization; brand name; manufacturer	Regulatory status	First author, year of publication	Design	Number of patients	Dose (Cimicifuga-drug/day or control/day); duration of application	Main results	Impact on evidence
Isopropanolic special extract (iCR) DER 6–11 : 1; 40% Isopropanol Remifemin; Schaper & Brümmer, Germany	Medicinal product (EU and outside EU)	Liske, 2002	RCT	76: standard dose; 76: high dose	39 mg; 127 mg; 3 months (𝑛=152); up to 6 months; (𝑛=149)	Significant improvement of the KMI; responder rate (KMI < 15) after 3 months approx. 70%; high dose during menopausal transition significantly superior; no influence on hormones and vaginal cytology	⊕
		Osmers, 2005	RCT	153: iCR; 151: placebo	40 mg; 3 months	Significant improvement of the MRS-total score versus placebo; strongest effect in vasomotor complaints (hot flushes, sweatings, and sleep disorders) and higher superiority during menopausal transition	⊕ ⊕
		Nappi, 2005	RCT	32: iCR; 32: HT (TTSE2)	40 mg; 25 𝜇g + Progesterone; 3 months	In both groups comparably strong, significant improvement of vasomotor complaints, anxiety, and depression; no influence of iCR on hormones, liver function, and endometrium	⊕
		Bai, 2007	RCT	122: iCR; 122: tibolone	40 mg; 2.5 mg; 3 months	Comparably strong, significant reduction of the KMI in both groups; with better safety of iCR: superiority of iCR in the benefit-risk ratio	⊕ ⊕
		Schmidt, 2005	ONC	502	40 mg; 3 months	Significant improvement of the modif. KMI, most pronounced reduction of hot flushes and sweatings	⊕
		Vermes, 2005	ONC	2,016	40 mg; 3 months	Significant improvement of the KMI, strongest for hot flushes, sweatings, sleeping difficulties, and anxiety	⊕
		Julia Molla, 2009	ONC	122	40 mg; 3 months	Significant increase in quality of life (Cervantes-HR-QoL-Scale), especially in the domains menopause/health and psyche	⊕
Isopropanolic special extract (iCR) (see previously) with Hypericum perforatum extract; standardized to 1 mg triterpene glycosides and 0.25 mg total hypericin Remifemin plus; Schaper & Brümmer, Germany	Medicinal product (EU)	Uebelhack, 2006	RCT	151: iCR + Hyp; 150: placebo	120 mg (week 1–8); 60 mg (week 9–16); 4 months	Significant superiority versus placebo in the improvement of MRS- and HAMD-Scores	⊕ ⊕
		Briese, 2007	OC	3,114: iCR + Hyp; 3,027: iCR	60–120 mg; 40 mg; 6 months (𝑛=6,141); up to 12 months; (𝑛=736)	In both groups, significant improvement of the MRS-total score and -subscore Psyche; for psychic complaints iCR + Hyp is significantly more effective than iCR monotherapy	⊕ ⊕
No data on extractant and DER Cimicifuga-extract with hypericum extract, standardized to 1 mg terpene glycosides and 0.25 mg hypericin Gyno-plus; Jin-Yang Pharm, Korea	Medicinal product (Korea)	Chung, 2007	RCT	47: CR + Hyp; 42: placebo	According to SPC; 3 months	Significant superiority in the improvement of the KMI versus placebo; no influence on hormones and vaginal cytology; significant increase of HDL in the CR + Hyp-group	⊕ ⊕
Ethanolic extract (CR BNO 1055) DER 5–10 : 1; 58% ethanol Klimadynon; Bionorica, Germany	Medicinal product (EU and outside EU)	Wuttke, 2003	RCT	20: CR; 22: HT (CE); 20: placebo	40 mg; 0.6 mg; 3 months	CR: comparable improvement of the MRS score to CE and superiority versus placebo, however, not significant; CR without effects on the endometrium, positive influence on bone markers and vaginal cytology	⊕
		Wuttke, 2006	RCT-Reana-lysis	See Wuttke, 2003	See Wuttke, 2003	Exploratory reanalysis: significant superiority of CR versus placebo in regard to improvement of daily sweats, nightly waking, and MRS subscores major climacteric complaints, somatic complaints, and mental score	⊕
		Rauš, 2006	ONC	400	40 mg; 12 months	No influence on the endometrium; significant improvement of MRS II and MRS II 4-week weighted score of hot flushes	⊕
Ethanolic extract (Cr 99) 4.5–8.5 : 1; 60% Ethanol Cimicifuga Generic, Klimadynon Uno; Kolkmann, Bionorica, Germany	Medicinal product (EU)	Frei-Kleiner, 2005	RCT	83: CR; 44: placebo	42 mg; 3 months	Superiority versus placebo in KMI and weekly weighted score of hot flushes, which is significant in patients with baseline KMI > 20	⊕
Ethanolic extract No information on DER, 50% ethanol Remixin, Mikro-Gen, Turkey	Medicinal product (Turkey)	Oktem, 2007	RCT	60: CR; 60: Fluoxetine	40 mg; 20 mg; 6 months	Significant improvement in modified KMI, Beck’s Depression Scale, and RAND-36 QoL in both groups; CR: significant superiority versus Fluoxetine in KMI and monthly scores for hot flushes and night sweats	⊕
Ethanolic extract (Ze 450) DER 4.5–8.5 : 1; 60% ethanol Cimifemin; Zeller, Switzerland	Medicinal product (Switzerland)	Kaiser, 2008	RCT	60: standard dose; 60: high dose; 60: placebo	40 mg; 80 mg; 3 months	CR: significant superiority versus placebo in KMI; high dose: significant superiority versus standard dose in KMI	⊕
Ethanolic extract; No information on DER, 70% ethanol, 2.5% triterpene glycosides Pure World, USA	No medicinal product (USA)	Newton, 2006	RCT	80: CR; 76: Multibotanical; 79: Multibotanical + Soy; 32: CEE + MPA; 84: placebo	160 mg extract?; 200 mg + 9 further; ingredients; 0.625 mg + 2.5 mg; 12 months	No significant differences between CR and placebo for vasomotor symptoms per day, symptom intensity, Wiklund Vasomotor Symptom Subscale Score	⊖
Ethanolic extract 20 : 1; 75% ethanol, standardized to 3.64 mg triterpene glycosides University of Illinois/National Institutes of Health, USA	No medicinal product, only study medication (USA)	Geller, 2009	RCT	22: CR; 22: red clover; 23: CEE/MPA; 22: placebo	128 mg; 120/378 mg; 0.625/2.5 mg; 12 months	No significant improvement of the frequency of vasomotor complaints by CR versus placebo	⊖
No information on extractant and DER CimiPure 2.5%, Pure World, Inc., USA	No medicinal product, food supplement (USA)	Ruhlen, 2007	ONC	61	80 mg extract?; 3 months plus 3 months wash out	Significant improvement of the KMI by CR, increase after wash out; no effects in serum estrogen markers, pS2, or cellular morphology of NAF	⊕

CE: conjugated estrogens; CEE: conjugated equine estrogens; CR: Cimicifuga racemosa; DER: drug-extract ratio; HAMD: Hamilton Rating Scale for Depression; HR-QoL: Health-Related Quality of Life; HT: hormone therapy; Hyp: Hypericum perforatum; iCR: isopropanolic Cimicifuga racemosa special extract; KMI: Kupperman Menopause Index; MPA: medroxy progesterone acetate; MRS: Menopause Rating Scale; NAF: nipple aspirate fluid; OC: open controlled; ONC: open noncontrolled; RAND-36 QoL: RAND-36 measure of Health-Related Quality of Life; pS2: pS2 gene; RCT: randomised controlled trial; SPC: summary of product characteristics; TTSE₂: transdermal estradiol.
Impact on Evidence for efficacy: ⊕ ⊕: confirmatory evidence; ⊕: exploratory evidence; ⊖: no evidence.