Methods
Study Design
We conducted a clinical trial at the University Women's Hospital of Bern using a four-arm, prospective, randomized study design investigating the effects of AP and Zhi Mu 14 (a standardized CHM preparation) on postmenopausal women experiencing 20 or more hot flushes per week (Fig. 1). AP treatment was sham-controlled and single-blinded, whereas treatment with CHM was placebo-controlled and double-blinded. Participants took part in the study for a total of 26 weeks, including a run-in period with diary collection (2 wk), a treatment period (12 wk), and a follow-up period after completion of treatment (12 wk). Recruitment was carried out from December 2009 to March 2011 through advertisements on pin boards and on the Web sites of the University of Bern and the University Hospital of Bern. The ethics committee of the Canton of Bern, Switzerland, formally approved the research protocol.
(Enlarge Image)
Figure 1.
Flow diagram of progress through the phases of the randomized trial based on Consolidated Standards of Reporting Trials (CONSORT) recommendations. TCM, traditional Chinese medicine.
Study Participants
Eligible study participants were postmenopausal women who met the following inclusion criteria: hot flushes for at least 1 year, at least 20 hot flushes per week during the run-in period, normal gynecologic status, at least 12 months of self-defined amenorrhea or had undergone hysterectomy, body mass index lower than 30 kg/m, initial score of at least 20 points on the Menopause Rating Scale (MRS) II, follicle-stimulating hormone serum concentration higher than 30 IU/L, and a signed informed consent form. The following exclusion criteria were applied: HT and/or treatment with TCM and/or any kind of surgical intervention within 12 weeks of recruitment; abnormal genital bleeding; abnormal liver function; bilateral ovariectomy; pregnancy; chronic and/or acute physical diseases and/or mental disorders; abuse of alcohol and/or any other addictive substances; recent or planned phytoestrogen-enriched diet; intake of herbal remedies for treating menopausal symptoms; more than 2 weeks of planned absence during the treatment period; simultaneous participation in any other clinical trial.
Procedure
Women who were interested in participating in the study underwent telephone screening to determine initial eligibility. An informed consent form was signed before the start of the trial. Initially eligible women received a complete written and oral description of the study and were invited to a clinic visit for medical examination, including heart rate, blood pressure, gynecologic examination, and laboratory blood tests. The participants received instructions on keeping a 2-week hot flush diary to document the frequency and severity of hot flushes. Diary data, gynecologic examination results, and laboratory test results were used to verify eligibility. Eligible women were randomized to one of four study groups. All study participants completed questionnaires at the end of the run-in period (baseline), 4 weeks after the start of treatment, at the end of treatment, and 12 weeks after treatment completion (follow-up). At the end of the follow-up period, participants underwent final medical examination. All participants were instructed not to take hormonal medication or to initiate other treatments for their hot flushes during their study participation.
Randomization and Blinding
An independent data manager carried out randomization by using a computer-generated random allocation sequence. Allocation concealment was achieved through sequentially numbered, opaque, sealed envelopes. After baseline examination had been completed, eligible participants were assigned to one of the four study groups by consecutively opening the envelopes as they entered the study. The probability of being allocated to the TCM AP, sham AP, verum CHM, or placebo CHM group was equal (1:1:1:1). Participants were unaware of their assignment to a treatment condition or a control condition. The study staff in charge of data collection, outcome assessment, and preliminary data analysis was also blinded. Only the acupuncturist was informed of the allocation of women to the TCM and sham AP groups. The complete randomization list was placed in a sealed envelope and kept there until the study was completed.
Interventions
AP Groups A licensed acupuncturist (P.J.) with 30 years of clinical experience performed all AP treatments in both AP study groups. Participants in the TCM and sham AP groups were scheduled for 12 weekly treatments. On the first treatment session, women received a TCM diagnosis. The standard treatment of women in the TCM AP group was composed of the following AP points: CV-4, GV-20, GB-20, PC-6, ST-36, SP-6, LI-4, and KI-3. Except for CV-4 and GV-20, which are located at the median of the body, all standard treatment points were needled bilaterally. In addition to this standardized treatment, 7 to 10 supplementary AP points were needled based on a person's TCM diagnostic category (ie, "kidney yang with spleen yang deficiency": BL-20, BL-23, SP-9, and CV-6; "kidney yin with liver yin deficiency": BL-18, BL-23, HT-6, KI-6, and LR-3) or in accordance with the physician's clinical judgment. No more than 24 points were needled during any treatment. Needles were inserted through the skin to a depth of 0.2 to 1.5 cm, depending on the target site. With each needle insertion, the acupuncturist attempted to elicit a de Qi sensation, which is characterized as a feeling of soreness, numbness, heaviness, or distention around the stimulated AP point. The retention time of the sterile, single-use, stainless-steel AP needles (needle type, SEIRIN; 0.25 × 30 mm and 0.25 × 40 mm) was 30 minutes, without any additional stimulation.
In the sham AP group, AP needles were inserted superficially, without attempting to elicit a de Qi sensation, into seven bilateral target sites that did not correspond to established TCM AP points (see Table, Supplemental Digital Content 1, http://links.lww.com/MENO/A53, which describes sham AP points in detail). These sham AP points have been previously defined and used in large clinical trials.
CHM Groups Participants in the verum and placebo CHM groups were scheduled for clinic visits on weeks 1, 4, 8, and 12 of the treatment period. During these visits, a licensed TCM therapist (L.T.) with 20 years of clinical experience set a TCM diagnosis, observed the course of menopausal symptoms, inquired whether treatment-related adverse effects occurred, and assessed treatment compliance by controlling the participants' daily diary entries and weighing the remaining capsules. Women in both CHM groups were instructed to take three capsules orally with water twice per day (ie, postprandial in the morning and in the evening) and to report daily medication intake in their hot flush diary. Women in the CHM group received Zhi Mu 14, a standardized CHM preparation comprising 14 plant materials (see Table, Supplemental Digital Content 2, http://links.lww.com/MENO/A54, which describes the composition of the CHM formula Zhi Mu 14 in detail) that has been approved by the Swiss Agency for Therapeutic Products (Swissmedic) for therapeutic use. The formulation of Zhi Mu 14 is based on two modified classic formulas—"Gan Mai Da Zao Tang" and "Qing Hao Bie Jia Tang"—designed to treat hot flushes, night sweats, insomnia, mood swings, irritability, and emotional instability resulting from kidney yin deficiency. The dose of herbal extract granules (3 g/d) administered is equivalent to 15 g of dry herb. Participants in the placebo CHM group received placebo capsules containing starch (Amylum maydis) and caramel as color tracer. This placebo mixture has no known effects on menopausal symptoms. Both placebo and CHM capsules were identical in appearance and were prepared by Sheng Foong Pharmaceutical Ltd (Taiwan) on behalf of China Medical Ltd (Aesch, Switzerland). In accordance with herbal Good Manufacturing Practice, the genuineness and quality of each herbal component were controlled by conducting thin-layer chromatographic analysis and tests for heavy metal contamination, microbial traces, and pesticide residues.
Outcome Measures
The primary outcome measures were hot flush severity and frequency per week. An adapted form of a daily hot flush diary frequently used in prior studies was used for data collection. Hot flush severity score was calculated as the sum of the number of self-reported hot flushes multiplied by severity. The applied hot flush severity rating scale scores were as follows: 1 = mild (heat sensation without sweating and disruption of activity); 2 = moderate (heat sensation accompanied by sweating but with no disruption of activity); 3 = severe (heat sensation accompanied by sweating and disruption of activity). Participants were asked to record the occurrence and severity of each hot flush during the run-in and treatment periods, and on the 4th, 8th, and 12th weeks of the follow-up period of the trial. During the follow-up period, participants were reminded by telephone call to reuptake their diary entries.
As a secondary outcome measure, menopause-related quality of life was assessed using the validated MRS II. This self-report instrument comprises 11 items and assesses the presence and intensity of menopausal symptoms on a 5-point rating scale ranging from 0 (no symptom) to 4 (very severe symptom). The MRS II sum score represents the overall index of severity of climacteric-related complaints (ie, 0-4 = none to little; 5-8 = mild; 9-16 = moderate; ≥17 = severe). In addition to the MRS II sum score, three independent subscales (ie, psychological, somatovegetative, and urogenital) indicate domain-specific symptom severity.
The mean reference values for MRS II scores in European populations are 7.2 for MRS II sum score, 2.9 for the psychological subscale, 3.3 for the somatovegetative subscale, and 1.0 for the urogenital subscale. These values are comparable to the mean MRS II reference values for North America.
Statistical Analyses
Data analysis was conducted using SPSS (version 20) statistical software package for Macintosh (IBM SPSS Statistics, Somers, NY). The level of significance was set at P < 0.05. Differences in group characteristics and baseline values were analyzed using the following: χ test for dichotomous variables, Kruskal-Wallis test for continuous variables with skewed distributions, and analysis of variance for normally distributed continuous variables. To compare treatment effects on the primary and secondary outcome measures between the TCM group and the sham AP group, between the verum CHM group and the placebo CHM group, and between the TCM AP group and the verum CHM group, we calculated the mean change values for each study group by subtracting pretreatment baseline values from posttreatment values and from follow-up values. Between-group differences in mean change values were analyzed using Mann-Whitney U test. Within-group changes in outcome measures were analyzed using Wilcoxon test.