Acupuncture for menopausal vasomotor symptoms: study protocol for a randomised controlled trial
Acupuncture for menopausal vasomotor symptoms: study protocol for a randomised controlled trial
Marie Pirotta 0
Carolyn Ee 0
Patty Chondros 0
0 Department of General Practice, University of Melbourne , Australia 200 Berkeley St, Carlton, Victoria 3053 , Australia
Background: Hot flushes and night sweats (vasomotor symptoms) are common menopausal symptoms, often causing distress, sleep deprivation and reduced quality of life. Although hormone replacement therapy is an effective treatment, there are concerns about serious adverse events. Non-hormonal pharmacological therapies are less effective and can also cause adverse effects. Complementary therapies, including acupuncture, are commonly used for menopausal vasomotor symptoms. While the evidence for the effectiveness of acupuncture in treating vasomotor symptoms is inconclusive, acupuncture has a low risk of adverse effects, and two small studies suggest it may be more effective than non-insertive sham acupuncture. Our objective is to assess the efficacy of needle acupuncture in improving hot flush severity and frequency in menopausal women. Our current study design is informed by methods tested in a pilot study. Methods/design: This is a stratified, parallel, randomised sham-controlled trial with equal allocation of participants to two trial groups. We are recruiting 360 menopausal women experiencing a minimum average of seven moderate hot flushes a day over a seven-day period and who meet diagnostic criteria for the Traditional Chinese Medicine diagnosis of Kidney Yin deficiency. Exclusion criteria include breast cancer, surgical menopause, and current hormone replacement therapy use. Eligible women are randomised to receive either true needle acupuncture or sham acupuncture with non-insertive (blunt) needles for ten treatments over eight weeks. Participants are blinded to treatment allocation. Interventions are provided by Chinese medicine acupuncturists who have received specific training on trial procedures. The primary outcome measure is hot flush score, assessed using the validated Hot Flush Diary. Secondary outcome measures include health-related quality of life, anxiety and depression symptoms, credibility of the sham treatment, expectancy and beliefs about acupuncture, and adverse events. Participants will be analysed in the groups in which they were randomised using an intention-to-treat analysis strategy. Discussion: Results from this trial will significantly add to the current body of evidence on the role of acupuncture for vasomotor symptoms. If found to be effective and safe, acupuncture will be a valuable additional treatment option for women who experience menopausal vasomotor symptoms.
Acupuncture; Complementary medicine; Menopause; Hot flashes; Vasomotor symptoms; Quality of life; Placebo
Three quarters of menopausal women experience vasomotor
symptoms (VMS), or hot flushes and night sweats . VMS
last an average of 5.2 years  but persist in 10% of women
for 15 years or longer , and can cause significantly lowered
quality of life due to social embarrassment, sleep deprivation,
and physical discomfort . Risk factors for VMS include
Caucasian ethnicity , increased body mass index (BMI)
[6,7], being a smoker , feeling stressed , financial
impoverishment , and history of depression .
Hormone replacement therapy (HRT) is a highly effective
treatment for hot flushes, reducing incidence by up to
90% . However, HRT also increases the risk of
thromboembolic disease , stroke , breast cancer  and
possibly, dementia . Despite growing interest in
nonhormonal pharmacological therapies such as psychotropic
drugs and selective serotonin reuptake inhibitors (SSRIs)
and serotonin-noradrenaline reuptake inhibitors (SNRIs),
these are not as effective as HRT, and often cause
troublesome adverse events [4,13,14]. Current evidence does not
support the use of most complementary medicines (CM)
for VMS, with popular treatments such as black cohosh
shown to be ineffective [15,16] and only modest benefits
reported with soy . Yet, over half of the women
surveyed in a 2006 Sydney study reported using CM for their
menopausal symptoms, with acupuncturists being the
second most popular therapists visited .
Acupuncture is a form of Chinese medicine that involves
the insertion of fine needles into specific points on the
surface of body known as acupuncture points, or acupoints
. Acupuncture has an excellent safety profile when
practised by qualified acupuncturists, with large prospective
studies reporting that 90% of patients do not experience
any adverse events, and that serious events are rare [20,21].
Some progress has been made on understanding the
neural mechanisms of acupuncture. Acupuncture
analgesia is modulated by various transmitters, notably
endogenous opioids, serotonin and noradrenaline [22,23].
Acupuncture activates the pain matrix - areas of the brain
that have been shown to be consistently activated by
noxious stimuli  - which includes the insula, an area that
may be involved in the hot flush mechanism [25,26].
Acupuncture for VMS
The thermoneutral zone is the tolerable temperature zone
of the immediate environment within which changes in
core body temperature do not cause compensatory
sweating or flushing . Researchers propose that low
serotonin levels and subsequent high noradrenaline levels
during menopause narrow the thermoneutral zone in
women experiencing VMS. Treatments that raise central
serotonin levels, such as SSRIs or acupuncture, may reduce
hot flushes by normalising the thermoneutral zone .
Two systematic reviews, published in 2009, found no
evidence that acupuncture is effective for VMS, and
recommended more rigorous research [27,28]. Since then,
four new clinical trials have published their results
[29-32]. Two of these were pragmatic randomised trials
and reported reductions of mean hot flush scores by 48
to 66% in treatment groups, compared with 28 to 29%
in usual care groups (total n = 451) [29,33]. However, a
contentious issue in acupuncture research is the use of
an adequate sham method in order to control for
nonspecific effects of acupuncture. One approach is
insertive sham acupuncture, which may involve needling of
acupuncture points that are considered to be irrelevant
in the treatment of the condition in question, needling
non-acupuncture points, or superficial needling without
eliciting a needle sensation. Insertive sham controls are
increasingly considered to be an inferior acupuncture
control method, with many large randomised controlled
trials (RCTs) failing to show a difference between true
and insertive sham acupuncture . Five such trials for
VMS all failed to demonstrate a difference in mean hot
flush scores between groups receiving true and insertive
sham acupuncture [35-39]. Alternatively, non-insertive
sham acupuncture controls for needling while
simulating a needle-prick sensation using a blunt needle which
does not penetrate the skin [40,41]. These sham needles
have been designed to shorten and telescope into
themselves, and have been validated as plausible simulations of
acupuncture in several studies [41-45]. Three small
trials reported true acupuncture to be more effective than
non-insertive sham, with greater reductions in VMS
frequency  and severity [30,46]. Two of these trials
were published after the 2009 systematic reviews were
Collectively, the extant literature suggests that
acupuncture treatment as practised in a community setting
can relieve the burden of hot flushes and that the
insertion of a needle may represent part of the specific effect
of acupuncture on VMS.
Pilot study of acupuncture for VMS
In 2009, CE, MP and CX undertook a pilot project to
assess feasibility of a trial of needle acupuncture compared
with non-insertive sham needle for VMS. Twenty-seven
women were randomised, and 20 completed the study.
Study outcomes and participant feedback were used to
modify the design of this current RCT protocol. Our
method was feasible and acceptable to participants (results
There is a need for safe and effective treatment of
menopausal VMS, given the negative impact that hot flushes
can have on quality of life. Acupuncture is a popular
treatment amongst midlife women and has a favourable safety
profile. However, evidence for its effectiveness in treating
VMS remains inconclusive, although results from
pragmatic studies and studies using non-insertive sham
needles are promising. We have used findings from our
feasibility study to inform the design of an adequately
powered randomised sham-controlled trial using the
noninsertive sham needle.
Aims and hypotheses
Our primary aim is to assess the efficacy of needle
acupuncture in improving hot flush severity and frequency in
menopausal women. Our hypothesis is that needle
acupuncture will result in greater improvement in the severity
and frequency of hot flushes compared to non-insertive
sham acupuncture after ten treatments given over an
The trial, also known as the Acupause trial, is a
stratified, single (participant)-blind, parallel, randomised
sham-controlled trial with equal allocation. The clinical
trial results will be reported according to the
CONSORT guidelines and the Standards for Reporting
Interventions in Clinical Trials of Acupuncture (STRICTA)
The trial is taking place in 15 private clinics of project
acupuncturists (Chinese medicine practitioners) in Australia,
located in metropolitan Melbourne, and regional Victoria,
New South Wales, and the Gold Coast, Queensland,
between September 2011 and October 2014.
The trial has been approved by the Human Research
Ethics Committees of the University of Melbourne (1135293
16/6/2011); Monash University (2011001242); RMIT
University (1135293); and Southern Cross University
(ECN-11192). It has been registered with the Australian New
Zealand Clinical Trial Registry (ACTRN12611000393954)
and is funded by a Project Grant from the National Health
and Medical Research Council, Australia (APP 1004406).
A total of 360 women in the late menopausal transition or
postmenopause, who are experiencing hot flushes, are
being recruited. A number of recruitment methods are used
including (i) advertising through social media (Facebook),
University staff and student newsletters, and a health
register in a Melbourne tabloid newspaper; (ii) flyers at
Examination Red tongue with scant coat
Each symptom is scored on a 4-point Likert scale for both frequency and severity
in the previous month. A score of 1 is given for each tongue and pulse
examination that meets the stated criteria.
aThese symptoms receive a double score as they are considered
general practitioner, menopause outpatient and allied
health surgeries and female-only fitness centres; (iii)
various strategies through Jean Hailes for Womens
Health (www.jeanhailes.org.au), an Australian national
not-for-profit education and research organisation
focusing on womens health (strategies include utilisation of the
organisations research register, media releases, social
networking connections, website features, and features in
consumer and professional newsletters); and (iv) media
exposure (radio, television and print).
We include women if they:
1. Are deemed postmenopausal (at least 12 months
past the final menstrual period) or in the late
menopausal transition (Follicular Stimulating
Hormone/FSH level of 25 IU or greater, amenorrhoea
of 60 days and currently experiencing VMS) .
(Women who have had a hysterectomy are included if
an FSH level is greater than 25 IU and they are
51 years of age or older); and
2. Record a mean hot flush score of at least 14 over
7 days during the run-in period (equivalent to an
average of seven moderately-severe hot flushes a day and
assessed using a validated Hot Flush Diary) [50,51]; and
3. Meet the criteria for the Traditional Chinese
medicine (TCM) diagnosis of Kidney Yin deficiency
determined using a structured Chinese medicine
history and examination . Women are included
if they score higher for Kidney Yin deficiency than
for Kidney Yang deficiency. See Table 1 for details of
the standardised history and examination used.
Table 1 Standardised Traditional Chinese Medicine (TCM)
history and examination used in the Acupause study
Kidney Yin deficiency scale
Sensations of heat in the
body with sweatinga
Dry mouth or dry hard stool
Aching and soreness in the lower
back and knees Dizziness or tinnitus
Ache and soreness
in the lower back
Kidney Yin deficiency is the most common diagnosis
made by TCM practitioners in menopausal women who
present with hot flushes [53,54]. We use standardised
TCM diagnosis as an inclusion criterion for several
reasons. In clinical practice it is usual for an acupuncturist
to tailor an acupuncture point prescription to fit the
diagnosis that is made after history and examination.
However, individualisation of the acupuncture point
prescription did not impact on treatment outcome in
one pragmatic trial on acupuncture for VMS . By
standardising this TCM diagnostic process, we are
creating a homogenous sample according to TCM
diagnosis, simplifying the treatment protocol, and ensuring
our findings are applicable to both TCM and western
Women are excluded if they:
1. Are younger than 40 years of age (therefore
diagnosed as having Premature Ovarian Failure) or
have previously been diagnosed with premature
ovarian failure and are less than 50 years of age;
2. Have had a bilateral salpingo-oophorectomy;
3. Have any medical reason to be amenorrheic
(for example pregnancy, hyperprolactinemia,
4. Have poorly controlled hyperthyroidism or hypothyroidism;
5. Are experiencing VMS that started or became
worse after diagnosis of breast cancer or
commencing treatment for breast cancer;
6. Are currently taking HRT, with the following
washout periods to be observed: transdermal
(four weeks), oral or intrauterine HRT (eight
weeks), progestin implant/oestrogen injectable,
phytoestrogen therapy (three months), oestrogen
pellet/progestin injectable (six months);
7. Have ceased any other treatment for hot flushes within twelve weeks of screening (including complementary medicines);
8. Have commenced using any other pharmacological or complementary therapy for hot flushes in the past eight weeks;
9. Have commenced using vaginal oestrogen therapy
in the past twelve weeks;
10. Are unable to read or write sufficiently in English to
complete the outcome measures, which require a
Grade 6 reading level;
11. Have had needle acupuncture treatment in the past
12. Have relative contraindications to acupuncture (use
of anticoagulant drugs, heart valve disease, poorly
controlled diabetes mellitus);
13. Are unwilling or unable to attend for acupuncture/
sham acupuncture for ten treatments over eight
14. Are unable to give informed consent.
Changes to eligibility criteria after trial commencement
To facilitate recruitment within the funded study
period, two changes were made to the original eligibility
criteria. Originally, any previous acupuncture
experience was an exclusion criterion. From October 2011,
participants with previous acupuncture experience were
deemed to be eligible, as long as the last needle
acupuncture treatment was more than two years previously.
Use of the Park Sham Device has been validated in
non-acupuncture nave participants [43,55], and advice
from the manufacturer was that broadening the
inclusion criteria to non-acupuncture nave participants
was reasonable (personal communication, Dr Jongbae
Park). Setting a two-year period since a participants
last acupuncture experience was considered a long
enough time frame to minimise familiarity to
In July 2012, in the light of emerging evidence and
recommendations from the Stages of Reproductive Ageing
(STRAW + 10) Workshop (Harlow, Gass et al. 2012), we
expanded our criteria to include women in the late
menopausal transition (a phase now known to be characterised
by oestrogen deficiency and high risk of VMS), assessed
using FSH testing.
See Figure 1 for a flowchart of the trial procedures.
Potential participants complete an initial screening survey,
followed by a TCM questionnaire online or over the
telephone with a trained investigator (KN). All details are
stored online in a password-protected survey management
software account. Women who score higher on the Kidney
Yin scale than on the Kidney Yang scale are sent a baseline
Hot Flush Diary (HFD) to complete.
Women recording an average of seven moderately-severe
hot flushes a day over the seven- day period are then
assessed for TCM criteria (tongue and pulse diagnosis) by a
trained acupuncturist (either CE or a project
acupuncturist). For quality assurance purposes, the first twenty
potential participants tongues assessed are photographed after
obtaining written consent and an expert Chinese medicine
practitioner and researcher (CX) views the de-identified
photographs to reconcile the diagnosis with the clinical
picture. Thereafter, photographs are only taken of participants
if their TCM diagnosis is unclear. Prior to randomisation,
women are requested to provide written informed consent
after discussing trial procedures and risks of acupuncture
with a trained acupuncture researcher (CE/JS).
Providers and standardisation of the intervention
Fifteen project acupuncturists at 15 sites administer the
study interventions. All acupuncturists have obtained a
Bachelor degree in Chinese medicine, have five or more
years of clinical experience and are registered with the
Chinese Medicine Board of the Australian Health
Practitioner Regulation Agency.
To optimise fidelity of delivery of the intervention, project
acupuncturists attend a two-hour training session delivered
by the acupuncturist researcher (CE) who developed and
administered the interventions during the pilot trial.
Acupuncturists receive a detailed training manual and a DVD
demonstrating the use of the Park Sham Device (sham
needle). The training session includes an introduction to basic
clinical research methods and a practical demonstration of
the Park Sham Device, during which acupuncturists gain
hands-on experience on how to use the sham needle.
Either the acupuncturist researcher (CE) or a trained
non-acupuncturist investigator (SM) in NSW and
Queensland, visits project acupuncturists within a few
weeks of their first study participant session to ensure
protocol adherence. During this visit, a treatment is
observed and feedback provided to the acupuncturist.
Deidentified photographs of the needling at interstate
training sessions are Emailed to CE so that point location could
Acupuncturists record details of each treatment on
individual Case Report Forms, which are kept in a locked
cupboard in the clinic and returned to the research team
every six months.
The standardised treatment protocol is based on TCM
principles and is designed to treat Kidney Yin deficiency.
The protocol was developed by consensus between two
practising acupuncturist researchers (CX and CE) after
considering a textbook, literature review and expert opinions
from three leading international acupuncture researchers
with particular expertise in womens health.
While the number of points for an adequate dose of
acupuncture is yet to be determined , this current
study protocol follows the minimum protocols used in
other positive studies of acupuncture for hot flushes. In
particular the positive study by Nir et al. used an average
of six points, and nine treatments were provided . A
literature review suggests that at least ten treatments
should be provided for hot flush treatment . The
acupuncture points chosen for this trial are included in the
group of eight core acupuncture points that were used in
one pragmatic trial  which allowed for
individualisation of the treatment protocol by acupuncturists.
However, no relation was found between choice of particular
acupuncture points and treatment outcome in that study,
suggesting that point specificity may not be of relevance
when using acupuncture to treat hot flushes.
All participants receive ten thirty-minute treatments over
eight weeks, twice weekly in the first two weeks and weekly
thereafter. Treatments are provided at no cost to
participants. All attempts are made to minimise missed sessions
and limit breaks between sessions to two weeks or less.
True acupuncture needles are standard stainless steel,
sterile and disposable, 32-gauge in thickness and 40 mm
in length. Table 2 describes the acupuncture point
prescription. A standardised prescription of six acupuncture
points is used unilaterally. Needles are inserted and
manipulated manually until needling sensation (de qi) is
obtained, and are retained for 20  minutes with manual
manipulation at 10 minutes. De qi, literally meaning
arrival of energy, is a term used in acupuncture and refers
to a sensation of numbness or distension sometimes
generated by stimulating acupuncture needles. According
to acupuncture theory, activation of de qi may be one
indication that acupuncture is exerting its beneficial effects
. Acupuncturists are trained to enquire about specific
needle sensations when providing true acupuncture.
We use a non-insertive sham control, the Park Sham
Needle, which is supported by a base unit consisting of a
plastic ring and guide tube and attached to the skin with
double-sided tape. The needle and base unit is collectively
referred to as the Park Sham Device (see Figure 2). This
sham needle has been validated in both acupuncture-nave
and acupuncture-experienced participants, and in healthy
volunteers and patients [41,43,44,55,58]. It has been
demonstrated to be less likely to induce de qi or the specific
needling sensation than a true acupuncture needle .
Participants in the control group receive bilateral
needling on three non-acupuncture points which are
not located on the same neuromuscular segments as the
prescribed points used in the true acupuncture group,
so as to minimise any segmental effects. Table 3
describes the sham points used. All other aspects of the
sham intervention (use of the Park Sham Device base
unit, needle retention time and manipulation, asking
about needle sensation, treatment schedule) are as
described above for the true acupuncture group.
Information provided to participants about acupuncture
Participants are informed, during the process for obtaining
informed consent, that there is a control group, referred
to as a placebo group, and that there is a 50% chance of
being randomly allocated to this group or the true
acupuncture group. All participants are told that the placebo
needles are designed to stimulate different nerves
compared to the true acupuncture needles, and all participants
are aware that placebo treatment is not considered active
Heart and Liver Yin
Together with KI7,
stops night sweating
Strengthens the uterus,
nourishes the kidneys
Table 2 Acupoints used in the true acupuncture group in the Acupause study (Unilateral)
In the depression below the tip of the medial malleolus
2 cuna directly above the acupoint Kidney 3 on the anterior Tonifies Kidney Yang and up to 15 mm
border of the Achilles tendon. (Kidney 3 is located in the depression stops night sweating
between the tip of the medial malleolus and the Achilles tendon)
Spleen 6 (SP6/Sanyinjiao)
3 cun directly above the tip of the medial malleolus
Conception Vessel 4 (CV4/Guanyuan) On the anterior midline, 3 cun below the umbilicus
When the palm faces upward, the point is on the radial side
of the tendon of muscularis flexor carpi ulnaris, 0.5 cun
above the transverse crease of the wrist
On the dorsum of the foot, in the depression distal to
the junction of the first and second metatarsal bones
aA cun is is a measurement used in locating acupoints, and corresponds to the distance between the two medial ends of the creases of the interphalangeal joints,
when the patients middle finger is flexed.
Figure 2 Diagram of Park Sham device. Reproduced from Acupuncture in Medicine, Jongbae Park, Adrian White, Clare Stevinson, Edzard Ernst,
Martin James, vol 20, p 168-174, copyright 2002 with permission from BMJ Publishing Group Ltd.
treatment. If they specifically enquire, they are told that
the acupuncturists remain blinded and receive a
prespecified pack of needles and instructions as to where to
insert needles for each participant after randomisation.
Participants can withdraw from the trial at any time. The
data collected up to the time of withdrawal will be
included in the analysis unless participants specifically
request for their data to be withdrawn, in which case any
unprocessed data will be withdrawn from analysis. This
has been made explicit in the Plain Language Statement
and Consent Form. Should a participant withdraw, a
detailed reason (if provided) is recorded in the trial database.
In order to avoid confounding the results of the trial,
participants are asked to avoid commencing new pharmaceutical
co-interventions for hot flushes during the intervention
period, such as herbal treatments and HRT. If already on
treatment for hot flushes, participants are requested not to
discontinue this treatment during the trial.
Primary outcome measure
The primary outcome measure is the hot flush score at
end-of-treatment (EOT). EOT hot flush score is calculated
from the seven-day HFD which participants commence
immediately upon completing their final treatment. These
diaries have been used in multiple trials of interventions,
and have been shown to be a consistent and reliable
method of evaluating change in VMS .
Participants note daily in the diary the number and
severity (mild, moderate, severe and very severe) of hot
flushes experienced over a twenty-four hour period for
seven days. The pilot study showed that it was feasible
and acceptable for women to complete the diary over
seven days with minimal missing data. The HFD will be
used to determine three specific measurements: 1) hot
flush frequency; 2) hot flush severity; and 3) a hot flush
score comprising both frequency and severity. These
scores are calculated as follows:
Table 3 Points used in the sham acupuncture group in the Acupause study (bilateral)
Name given to point
2 cuna above and 5 cun lateral to the umbilicus
Midway between the acupoints Lung 5 and
Large intestine 11 on the cubital crease
On the bulge of the rectus femoris, 5 cun above
the middle of the superior border of the patella
aA cun is is a measurement used in locating acupoints, and corresponds to the distance between the two medial ends of the creases of the interphalangeal joints,
when the patients middle finger is flexed.
2 cun lateral and 3 cun proximal
toreal acupoint Spleen 10
Table 4 Summary of measures collected as part of the Acupause study
severity and score
Seven-day day flush diary
Menopause-Specific Quality of
Hospital Anxiety and
aPrimary Outcome Measure. VMS, vasomotor symptoms.
bImmediately after the first treatment; cEnd-of-treatment.
Hot flush frequency = total number of hot flushes
reported/Number of days reported
Hot flush severity = (1 number of mild hot flushes + 2
number of moderate hot flushes + 3 number of severe
hot flushes + 4 number of very severe hot flushes)/
Number of hot flushes reported
Hot flush score = (1 number of mild hot flushes + 2
number of moderate hot flushes + 3 number of
severe hot flushes + 4 number of very severe hot
flushes)/Number of days reported
Secondary outcome measures
i. Hot flush score at other time-points: the primary
outcome measure is the hot flush score at the EOT;
however, hot flush score will also be measured at
four weeks to assess the intermediate effect of
acupuncture and at three and six months to measure
longer-term outcomes as recommended in the two
recent systematic reviews [27,28].
ii. Health related quality of life: the Menopause-Specific
Quality of Life Questionnaire (MENQOL) is a
validated measure of quality of life and clinical
change during the menopausal transition and is
specific to women in the first eight years post
menopause . It consists of 29 items assessing
four domains: VMS, physical symptoms,
psychological symptoms, and urogenital/sexual
iii. Anxiety and Depression: Hospital Anxiety and
Depression Scale (HADS) is a validated widely-used
14-item self-report scale designed to briefly measure
current anxiety and depressive symptoms in
nonpsychiatric hospital patients. It excludes somatic
symptoms, therefore avoiding potential confounding
factors . The HADS comprises two independent
seven-item subscales for anxiety and depression.
Anxiety has been demonstrated to be a predictor of
a high placebo response in menopause studies .
iv. Expectancy and beliefs about acupuncture: the
Credibility/Expectancy Questionnaire is a validated,
quick and easy-to-administer six-item scale for
measuring treatment expectancy and rationale
credibility for use in clinical outcome studies .
This questionnaire is administered once,
immediately after the first treatment.
v. Success of blinding: as surveys to measure the
success of blinding may enhance participants focus
on this, we measure this aspect immediately after
the first treatment . There is currently no
validated measure to assess blinding in acupuncture
research. We will use the scale developed by Bang
, which ranges from 1 (completely not blinded)
to +1 (perfectly blinded).
Participants characteristics and risk factors for hot flushes
Participants complete a Demographics Questionnaire
upon enrolment into the trial, which collects
demographic information and information on risk factors for
hot flushes including:
xii. information on previous use of acupuncture,
including types of acupuncture used, date of last
treatment, frequency of use, conditions treated, and
perceived response to acupuncture
Data storage and access
All hard copy information that contains personal
information on participants or that can be identified is
stored in a secure locked cabinet. Electronic data that
contains personal information or that can be identified
is password-protected on a secure server and can only
be accessed by authorised researchers. Information will
be retained for a minimum of fifteen years after
publication of results.
Sample size calculation
Sample size calculations are based on a two-sample
ttest with 80% power and significance level at 5% for a
two-sided test. We assumed conservatively that the
mean hot flush score at baseline would be 14, the lowest
possible entry score for the trial. Assuming a 50%
relative reduction in the HF scores in the control group due
to the placebo effect, which is the typical response
reported in hot flush randomised controlled trials , we
anticipate that women in the sham acupuncture group
will have a mean hot flush score of 7 at EOT. To be
clinically significant, we expect that women in the true
intervention group to show at least 75% reduction in the
total HF score from baseline, with a mean HF score of 3
at EOT. Based on these assumptions, 266 women (133
per trial group) will be needed to detect hot flush score
difference of 4 (standard deviation (SD) = 11.6 )
between the two trial groups at EOT. This sample size is
sufficient to detect a difference of 0.35 of 1 SD between
the trial groups for the quality of life measures. Sample
size was inflated to 360 women (180 per study group) to
allow for attrition of 26% (experienced in the pilot study)
at the measurement of the primary outcome at the EOT.
Randomisation and allocation concealment
Participants are randomly allocated to one of two trial
groups: true acupuncture or sham acupuncture, using a
computer-generated randomisation sequence, stratified
by project acupuncturist using block sizes of either eight
or twelve (with block sizes appearing in random order)
within each stratum and an allocation ratio of 1:1. The
research assistant responsible for allocating participants
is not aware of the block sizes used. An independent
researcher with no other involvement in the trial used this
allocation sequence to create a password-protected
electronic spreadsheet which contains the covert allocation
schedule. The principal investigator (MP) holds the
Implementation and allocation concealment
Upon confirmation of eligibility of women for the trial
(that is, after completion of the baseline HFD and
clinical confirmation of diagnosis of Kidney Yin deficiency),
the unblinded research assistant (KN) uses the
spreadsheet to randomly allocate participants to receive either
real or sham acupuncture. The spreadsheet displays
sequentially only the next treatment allocation.
The research assistant informs the relevant project
acupuncturist of the allocation status by mobile phone text
messaging, Email or fax, depending on the acupuncturists
preference. Group allocation is indicated only by the list of
acupuncture points for either real or sham acupuncture,
to avoid unblinding should the participant inadvertently
see the communication. As acupoints used for needling
in real and sham acupuncture groups are different,
acupuncturists can easily identify group allocation from the
list of points provided. This process can be cross-checked
against the covert randomisation schedule code held by
the principal investigator to ensure no corruption of the
process has occurred. To prevent selection bias, all
baseline information is collected prior to the acupuncturist
being informed of the treatment allocation.
The research assistant responsible for randomisation (KN)
and the project acupuncturists who deliver the treatment
to the women are not blind to treatment allocation.
Blinding of project acupuncturists is not possible because of the
difference between real and sham acupuncture points used
and the tactile difference between real and sham needling.
Participants and all other investigators are blinded,
including the study statistician. As outcomes are
selfassessed, outcome assessment is blinded. Data analysis will
be performed where the treatment groups will be identified
as Group A and B. The codes for the treatment groups will
be revealed after the all outcome data collection is
completed at six months.
Prior to providing consent to participate, participants
are informed of potential adverse events from
acupuncture. Common adverse events include fainting,
drowsiness, tiredness, temporary increase in symptoms, bruising
and soreness. A practitioner guide to preventing and
managing common adverse events is provided in the
Practitioner Training Manual. Participants report adverse events
either to the project acupuncturist delivering the
intervention or the acupuncturist researcher. The project
acupuncturist refers to the acupuncturist researcher in the event of
ongoing or unresolved concerns. Serious adverse events
(defined as potentially life-threatening, permanently
incapacitating or resulting in hospitalisation) are notified to the
study chief investigator (MP) and the Human Research
Ethics Committee within 24 hours. Informed by the pilot
project, it is anticipated that telephone advice from a
general practitioner (MP/CE) and/or acupuncturist researcher
(JS) will be adequate in most cases. If participants require
additional medical advice, they are directed to their
general practitioner. The expert acupuncturist (CX), who
chairs the Chinese Medicine Board in Australia, is also
available for advice.
Participants who score higher than 15 on the baseline
depression and/or anxiety scales will be contacted by a
general practitioner investigator (CE/MP) to be assessed for
suicide risk and referred to relevant services as required.
Both the relevant project acupuncturist and the
participant complete an Adverse Event Form should the need
arise. The form records the dates and times that the event
began and resolved; a description of the event; the
intensity of the event (mild/moderate/severe); an assessment of
the possible relationship to acupuncture, on a four-point
Likert scale ranging from unrelated to definitely related;
the outcome on a five-point Likert scale ranging from
completely resolved to persistent; and whether the event
was considered serious (potentially life-threatening,
permanent incapacitating or resulting in hospitalisation).
The Credibility/Expectancy Questionnaire, Case Report
Form, TCM Diagnosis Form and Adverse Events Form are
completed on paper copies. All other outcome measures,
participant characteristics and risk factors for hot flushes
are completed online using a survey management website
(Survey Methods www.surveymethods.com), with paper
copies available for those who prefer to use them. Online
surveys have the advantage of minimising missing data if
completion of survey questions is made mandatory prior
to submitting the survey online. Range checks are also
built into online surveys, and automated reminders are
Emailed. The study acupuncturist and research assistant
(CE and KN) oversee this data management. A reminder
letter/Email is sent after two weeks, followed by a courtesy
telephone call two weeks later by the research assistant
should questionnaires not be returned. Details of
treatment dates and follow-up are recorded in a custom-built
All paper-based data are entered into the same survey
management website by staff blinded to group allocation
at the University of Melbourne. Ten percent of all data
entry will be audited by an independent investigator for
quality assurance purposes.
Descriptive statistics will be used to summarise baseline
measures and participant characteristics between the two
trial groups and to assess for chance imbalance of
important prognostic factors. Primary outcome is the hot flush
score at EOT. Analysis will account for repeated outcome
measures taken on the same women over 12 months and
stratification by project acupuncturists. Mixed-effects
linear regression model will be used to compare the
continuous outcomes between the trial groups and marginal
logistic regression model using generalised estimating
equations with robust standard errors will be used for the
binary outcomes. Where appropriate the baseline measure
of the outcome will be included as a covariate in the
regression model. In addition, factors strongly associated with the
outcome and are found to be imbalanced between the trial
groups at baseline will also be adjusted in the regression
models. Estimates of the intervention effect will be reported
as the difference in means between trial groups for
continuous outcomes and odds ratios for binary outcomes, with
respective 95% confidence intervals and P-values. Stata 13.0
 will be used for the data analyses.
An intention-to-treat analysis strategy will be employed
where all participants will be analysed in the trial group in
to which they were allocated . In the first instance, we
will strive to minimise the extent of missing outcome data
for participants, where all efforts will be made to collect
the primary outcome on participants who withdraw,
discontinue their treatment or do not respond to the online
survey. However, in the presence of incomplete data,
information collected on the reasons for missing data will be
used to inform the appropriate statistical analysis
approach to handle the missing data. Sensitivity analyses that
capture departures from the assumption of the missing
data mechanism for the primary analysis will also be
considered to assess the robustness of the results.
Additional secondary analyses are planned. These will
include (1) exploring the effect acupuncture had on womens
quality of life, (2) identifying factors that are associated
with a placebo response, (such as anxiety/depression levels
and demographic characteristics such as socioeconomic
status), (3) the association between expectancy and beliefs
and womens response to acupuncture treatment, and (4)
the credibility of the Park Sham Device.
As acupuncture has an excellent safety profile, and is
not considered an experimental treatment, no data
monitoring committee is required.
Hot flushes are a common and potentially disabling
symptom during the menopause. While HRT is an effective
treatment, it does not suit all women either because of
concerns over potentially serious adverse events, or
because of relative contra-indications. Many women also
prefer to use natural or complementary therapies where
available. There is a paucity of effective and safe
nonhormonal treatments for VMS. However, preliminary
evidence suggests that acupuncture, a popular and safe
treatment for a wide range of conditions, may be
effective for VMS.
We are conducting a randomised sham-controlled trial
on acupuncture for VMS, which builds on the results from
our earlier pilot project during which feasibility of
methods was demonstrated. This robustly designed study
meets methodological benchmarks of adequate
randomisation and allocation concealment procedures, blinding of
outcome assessors and statisticians and utilising
intentionto-treat analysis strategy. The trial method also allows for
Traditional Chinese Medicine diagnosis in the eligibility
criteria and a dose of acupuncture reflecting clinical
practice to ensure results are applicable to a broad range of
health practitioners. The trial is appropriately powered to
determine a clinically relevant treatment effect. Our
results will determine the efficacy of acupuncture for
treating VMS in postmenopausal women. In particular, we will
assess the specific effect of insertion of the acupuncture
needle and its contribution to the entire treatment effect.
Our results will inform women suffering with
menopausal symptoms and both conventional and Traditional
Chinese Medicine health care professionals on the
potential role, if any, of acupuncture in the treatment of
VMS. This will advance the field significantly and, if
effective, will offer an important treatment option to
reduce VMS and potentially improve quality of life in
women at this important life stage. Future research may
explore the optimal treatment regimen for acupuncture
The trial has received funding and recruitment commenced
in late 2011. At the time of submission of this protocol,
project acupuncturists had been trained, participant
enrolment was progressing well and data collection was well
underway. Trial enrolment closed in March 2014. We
anticipate that all data will be collected by late 2014.
BMI: body mass index; CM: complementary medicines; CONSORT: Consolidated
Standards of Reporting Trials; EOT: end-of-treatment; FSH: follicular stimulating
hormone; HADS: Hospital Anxiety and Depression Scale; HFD: Hot Flush Diary;
HRT: hormone replacement therapy; MENQOL: Menopause-specific Quality of
Life questionnaire; STRICTA: Standards for reporting interventions in
acupuncture trials; RCT: randomised controlled trial; SD: standard deviation;
SNRIs: serotonin-noradrenaline reuptake inhibitors; SSRIs: selective serotonin
reuptake inhibitors; TCM: Traditional Chinese Medicine; TNZ: thermoneutral
zone; VMS: vasomotor symptoms.
CE conceived of the idea and designed the pilot project with input from MP
and CX. CE, MP, HT, CX, PC, SM and SF contributed to the design of the RCT.
CE and MP wrote the first draft of the manuscript. All authors have
contributed to, read and approved the final manuscript.
MP - MS BS, M Med, FRACGP, DRANZCOG, PhD. CE - MB BS, B.Appl.Sci
(Human Bio/Chinese Medicine), M Med, FRACGP, GradCertMedAcup.
HT - MBBS, FRACP, PhD. PC - B Sc, GradDipEpi&Biostat, MSc(Stat), PhD.
SF - BAppSc, MPH, PhD. SM - PhD BMed ND. CX - BMed, PhD.
The study is funded by a project grant from the National Health and Medical
Research Council (NHMRC), Australia.
MP is supported by an NHMRC Career Development Fellowship.
CE is supported by an NHMRC Postgraduate Scholarship.
HT is supported by a NHMRC Practitioner Fellowship.
We thank the following people: our research assistants Kitty Novy, Mary
Kyriakides and Melanie Charity for their hard work and dedication to the
day-to-day running of the project; Melanie Gibson for assistance with
recruitment and survey management; the staff at Jean Hailes for Womens
Health (especially Aleeza Zohar and James Shirvill) for assistance with
recruitment; Annie Rahilly also for assistance with recruitment; Ben Metcalf for
designing the randomisation spreadsheet; Dr Zhen Zheng, Dr Caroline Smith
and Prof Lixing Lao for providing expert opinions on the treatment protocol;
Johannah Shergis for acting as the acupuncturist researcher from January to
August 2013; Vincent Cheong for producing the DVD on the Park Sham Device;
Dr Vicki Kotsirilos for providing a consultation space for TCM interviews. Our
thanks to the project acupuncturists: Nelson Alingcastre, Phil Baxter, Mary-Jo
Bevin, George Dellas, Catherine Farchione, Lauren Lanzoni, Suzy McCleary, John
McDonald, Janette Pannacio, Stephen Pate, Tina Song, Melanie Wells, Tanya
Wilson, Richard Yates, Richard Zeng; and deep gratitude to the women involved
in our study.
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