Volume 6, Issue 3, June 2014, Pages 392–399
Original article
Polycystic Ovary syndrome: A Randomised feasibility and pilot study using Chinese Herbal medicine to explore Impact on Dysfunction (ORCHID)—Study protocol
Abstract
Introduction
We
aim to evaluate the feasibility of, and pilot procedures for, a
randomised study in the UK administering Chinese herbal medicine (CHM)
to women with polycystic ovary syndrome (PCOS) related oligo- and/or
amenorrhoea. Our primary aim of this feasibility study is to evaluate
how appropriate oligo- and amenorrhoea is as the primary outcome of the
main study.
Methods
A
prospective, multi-centre, randomised, patient- and practitioner-blind,
feasibility and pilot study will be conducted. 40 women with
PCOS-related oligo- and/or amenorrhoea will be randomised to one of two
parallel arms comparing standardised CHM treatment against
individualised CHM treatment as usual for 6 months. Participants will be
prescribed 8 g of CHM granulated extracts twice daily, totalling 16 g
per day. Feasibility will be determined by collecting data on menstrual
regularity, body mass index, waist hip ratio, weight, Polycystic Ovary
Syndrome Questionnaire, Measure Yourself Medical Outcome Profile,
Dermatology Life Quality Index, Morisky Medication Adherence Scale,
modified Ferriman–Gallwey scale, liver and kidney function,
practitioner-blinding questionnaire and participant feedback forms.
Process data will also inform feasibility such as recruitment rate,
completion rate and reasons for dropout. Statistical analysis will be
piloted in this study. We will present descriptive statistics for
primary and secondary variables and use analysis of variance and
Chi-squared tests where appropriate.
Results and conclusion
This
study received ethical approval in December 2012. 40 participants were
recruited between January 2013 and August 2013 and the study is expected
to complete in March 2014.
Keywords
- Chinese herbal medicine;
- Polycystic ovary syndrome;
- Feasibility study;
- Pilot;
- Menstrual disorders;
- Randomised controlled trial
Introduction
Polycystic
ovary syndrome (PCOS) affects an estimated 6–18% of women of
reproductive age and is a heterogeneous condition characterised by
endocrine and metabolic disturbances [1], [2] and [3].
Oligomenorrhoea and amenorrhoea are cardinal symptoms of PCOS and
primary care management typically involves oral contraceptives and
insulin-sensitising agents. However, there is evidence of
dissatisfaction with such treatments which has been associated with
intolerable side-effects, poor adherence rates and a potential increase
in cardiovascular and metabolic risk [4], [5], [6], [7] and [8].
This highlights a number of issues and barriers with current management
and thus warrants exploration of other potentially more effective
treatments that could be offered in primary care.
There
is anecdotal evidence and emerging evidence from randomised controlled
trials (RCTs) suggesting Chinese herbal medicine (CHM) could play an
important role in the treatment of oligo- and amenorrhoea [9].
However, such studies are conducted in China, limiting the
generalisability of findings to Western populations and which
necessitates further exploration with a fully powered RCT in a UK
setting. Prior to such a study and given the novel nature of offering
CHM in primary care, it is important to first conduct a feasibility and
pilot study to plan resources and reduce uncertainties [10], [11], [12], [13] and [14].
The aims of this study are to determine the feasibility of conducting a
randomised study in the UK administering CHM to women with PCOS-related
oligo- and/or amenorrhoea, and to pilot and evaluate the study
procedures.
Our primary feasibility question is:
- 1.
- Is oligomenorrhoea and amenorrhoea appropriate as the primary outcome measure for the main study?Our secondary feasibility questions are:
- 2.
- Are other measures more appropriate for investigation as the primary outcome measure for the main study?
- 3.
- What is the safety profile of CHM?
- 4.
- How should the CHM intervention in the main study be delivered?
- 5.
- Can a double-blind, randomised trial with CHM for PCOS be conducted?
Methods
Design
A
prospective, multi-centre, randomised, patient- and practitioner-blind,
feasibility and pilot study will be conducted. This is a pragmatic
study with two parallel arms comparing standardised CHM treatment
against individualised CHM treatment as usual for PCOS-related oligo-
or/and amenorrhoea. Although both standardised and individualised CHM
are routinely available in the UK, individualised CHM is typically
regarded as ‘gold standard’ practice, a view that is supported in the
clinical literature [15]
as well as an earlier Delphi study conducted by this research team
(unpublished results). However, we are interested in exploring
differences that may exist between the two interventions and preliminary
scientific data gathered from this present study will inform the CHM
intervention for the main study.
This
study received ethical approval in December 2012 from the Register of
Chinese Herbal Medicine (RCHM) and University of Southampton ethics
committees (Approvals ID 3977) and is registered with Current Controlled
Trials. It is conducted in accordance with the Declaration of Helsinki
(1964) and International Conference on Harmonization (ICH) Good Clinical
Practice (GCP) (1996).
Eligibility criteria
Participants
will be included if they: (1) are females aged 18–44, (2) present with
oligo- and/or amenorrhoea with oligomenorrhoea defined as intervals
between periods of >35 days and <200 days and amenorrhoea as
intervals between periods of ≥200 days, (3) have received a diagnosis of
PCOS consistent with the Rotterdam criteria [16].
Participants
will be excluded if they: (1) present with other causes of
hyperandrogenism or menstrual irregularities, (2) are currently
pregnant, suspected to be pregnant, or actively trying to conceive, (3)
are breastfeeding within 6 months of joining the study, (4) are
receiving prohibited treatments such as hormonal contraceptives, (5)
have a history of liver or kidney pathologies such as cirrhosis,
glomerulonephritis, pyelonephritis, (6) have a history of psychotic
illness or have been diagnosed with an eating disorder, (7) have
currently active major depression, (8) are currently at risk of harmful
and hazardous drinking, (9) have allergies to any of the following
common herbal ingredients that are contained within the standardised CHM
treatment: nuts, citrus fruit peel, goji berry, licorice or cinnamon,
(10) do not have the spoken or written language skills necessary to take
part, (11) are unable to attend the proposed study visits, (12) present
with abnormal liver and/or kidney function at screening.
Recruitment and setting
Recruitment
will take place in the community inviting self-referrals and using a
study website, posters and flyers, online forums, social media and press
releases and which have been used in similar studies [17], [18], [19] and [20]. Recruitment methods and literature were ethically approved prior to study commencement.
Eligibility
will be initially assessed via a self-completed screening questionnaire
or telephone interview with a member of the study team. Final
eligibility criteria will be checked at the screening visit by the study
practitioner who will explain in full the study procedures before
asking for written informed consent.
Study
visits will take place in UK-based CHM clinics and conducted by CHM
practitioners who will be required to have a minimum 5 years in
practice, be registered with a professional CHM organisation, be fully
insured, have access to liver and kidney function testing and agree to
carry out the study procedures as stated in the protocol. A list of
active study sites can be obtained from the lead author.
This
feasibility study requires a sample size of 40, based on requiring data
from 15 participants per arm to calculate an estimate of the treatment
effect and associated variability of the treatment effect to inform the
power calculation for a main study [14]. Accounting for a 25% dropout rate based on similar studies [21] and [22],
20 participants will be required from each group, totalling 40
participants. A feasibility search conducted at a Wiltshire general
practice surgery suggested a 10% eligibility rate and 400 enquiries will
therefore be required to meet our recruitment target.
Study visits and assessments
Participants
will undergo 8 study assessments in total at weeks 0, 2, 4, 8, 12, 16,
20 and 24. Of these assessments, the participant will be asked to
physically attend visits at weeks 0, 4, 8, 12 and 24 whilst other
assessments may be conducted by telephone or email at the practitioner's
discretion. A participant flow diagram can be seen in Fig. 1.
- Fig. 1.
Participant flow diagram.Abbreviations: CHM = Chinese herbal medicine; PCOSQ = Polycystic Ovary Syndrome Questionnaire; DLQI = Dermatology Life Quality Index; MYMOP = Measure Yourself Medical Outcome Profile; CEQ = Credibility/Expectancy Questionnaire; MMAS = Morisky Medication Adherence Scale.
Randomisation, allocation concealment and blinding
Prior
to the study, an independent statistician (PP) will use
computer-generated random numbers with allocation ratio 1:1 to provide
an irregular block allocation sequence. Allocation codes describing
group allocation will be transferred to sealed opaque envelopes and sent
to the dispensary prior to recruitment. Prior to and during the study,
practitioners and members of the study team will have no knowledge of
the randomisation sequence generated or of treatment allocation.
Participants
and practitioners will be blinded throughout this study. Participants
will be informed they will be randomised to one of two active CHM
treatments but will remain blind to the difference between treatments
during the study. At the final visit, this information will be revealed
to the participants although their allocation will not be disclosed
until the study is complete.
Practitioners
will be informed of the difference between the two interventions but
will remain blind to allocation to minimise performance bias. As
practitioners will also be conducting assessments during the study,
practitioner-blinding will be required to minimise measurement bias.
Following each assessment, the practitioner will write an individualised
prescription and send this to the dispensary. Upon receipt of an
individualised prescription for a new participant, a member of the
dispensary team will open the next randomisation envelope containing the
allocation codes, note the participant's allocation and dispense the
corresponding prescription. Where a participant is allocated to
standardised CHM, all future individualised prescriptions provided by
the practitioner for that participant will be ignored by the dispensary.
Unblinding
is permissible when a compelling medical need arises such as a serious
adverse event. Unblinding will be conducted by a member of the research
team not involved in data collection or analysis.
Interventions
All
information presented fulfils the requirements of the elaborated
CONSORT statement for reporting RCTs of herbal interventions [23].
Usual
CHM practice combines a number of single herbs to produce a CHM
prescription that is individualised to the patient. In this pragmatic
comparative study, standardised treatment will be compared against
individualised treatment as usual. Although a placebo-controlled study
in primary care was initially planned, the time required by the herbal
manufacturer to collect the required information for clinical trials
approval was inconsistent with project deadline commitments and which
necessitated a revision of the initial study design to our present
protocol. The reason for our present choice of interventions is that we
are interested in exploring potential differences between these two
groups in clinical and safety effects and, should this study progress to
a main study, to inform the design of a CHM intervention in primary
care.
Standardised
treatment consists of a pre-defined prescription of 14 single CHM
granulated extracts, the contents of which can be seen in Table 1.
This prescription is based on frequently occurring Chinese medicine
presentations and treatment strategies extrapolated from a Delphi study,
and on herbs used in RCTs for PCOS-related menstrual irregularities
from a systematic review conducted by this study team (unpublished
results). This prescription is not licensed for purchase over the
counter and is available in the UK through registered CHM practitioners
following a one-to-one consultation.
- Table 1. Contents of standardised Chinese herbal medicine prescription.
Chinese Pinyin name Common name Family name Part used Botanical name Dried herbal daily dosage (g) Percentage (%) Bai Shao (Chao) Peony (dry fried) Paeoniaceae Root Paeonia lactiflora Pall. 15 10.64 Chai Hu Bupleurum Umbelliferae Root Bupleurum chinense DC. 9 6.38 Chen Pi Tangerine peel Rutaceae Peel Citrus reticulatata Blanco 9 6.38 Chuan Xiong Szechwan lovage rhizome Umbelliferae Rhizome Ligusticum chuanxiong Hort. 9 6.38 Dang Gui Wei Angelica extremitas Umbelliferae Root tail Angelica sinensis (Oliv.) Diels 9 6.38 Gan Cao (Mi Zhi) Liquorice root (honey-fried) Fabaceae Root Glycyrrhiza uralensis Fisch. 6 4.26 Gou Qi Zi Goji berry Solanaceae Fruit Lycium barbarum L. 9 6.38 Gui Zhi Cinnamon twig Lauraceae Twig Cinnamomum cassia Presl. 9 6.38 Hong Hua Safflower Asteraceae Flower Carthamus tinctorius L. 9 6.38 Tao Ren Peach kernel Rosaceae Seed Prunus persica (L.) Batsch. 9 6.38 Tu Si Zi Chinese dodder seed Convolvulaceae Seed Cuscuta chinensis Lam. 12 8.52a Xiang Fu (Cu Zhi) Purple nutsedge (vinegar-fried) Cyperaceae Rhizome Cyperus rotundus L. 12 8.52a Yi Mu Cao Motherwort Lamiaceae Top Leonurus japonicus Houtt. 15 10.64 Zhi Ke Bitter orange Rutaceae Mature fruit Citrus aurantium L. 9 6.38 Total prescription weight 141 -
- a
- Rounded up for column total to equal 100%.
Individualised
treatment will follow usual practice whereby the study practitioner
will write an individualised prescription following an assessment with a
participant, containing details of the base formulae if relevant, and
details of the single herbs and dosages.
Both
CHM treatments will be offered as granulated extracts for 6 months (24
weeks). Following good practice guidelines developed from our Delphi
study, granulated extracts have been regarded by our panel of UK CHM
practitioners as suitably effective in the treatment of PCOS, and 6
months deemed an appropriate length of treatment to observe improvements
in oligo- and amenorrhoea (unpublished results).
Following
each assessment, participants will receive a bottled container
containing sufficient CHM until the next scheduled assessment.
Participants will be instructed to use a measuring spoon provided to mix
five level spoons (8 g) of granules with hot water and to take morning
and evening after meals, totalling 16 g per day.
CHM dispensary and manufacturer
Phoenix
Medical Direct Limited will dispense all CHM granulated extracts which
are manufactured in China by Jiangyin Tianjiang Pharmaceutical Company
Limited, a certified Good Manufacturing Practice (GMP) company. The
solvent used for extraction is purified water to generate an 8:1 source
to product extraction ratio. Authentication of raw materials and of the
finished product is conducted using macroscopic and microscopic
examination, and chemical methods such as thin layer chromatography for
product identity and high-pressure liquid chromatography for potency
which are checked for conformity to specifications in the Chinese
Pharmacopoeia. Heavy metal testing and microbiological testing is
conducted to confirm absence of microorganisms and pesticide residue.
For each batch of single CHM granulated extract used, certificates of
analysis and voucher specimens will be retained.
Dispensing
procedures and quality assurance measures follow the standards set by
the RCHM and are compliant with and the European Directive on
Traditional Herbal Medicinal Products (THMPD) 2004/24/EC. No animal or
mineral products will be dispensed and only plant materials will be
used.
Concomitant care
Permitted
medications and interventions prior to, and at any point during, the
study include analgesics, antidepressants, vitamin and mineral
supplements, weight loss interventions and selected natural supplements
such as evening primrose oil, milk thistle and mint.
Medications
and interventions that are permitted only after 6 months’ use include
insulin-sensitising agents, anti-androgens and acupuncture. 6 months is
deemed a sufficient period of time to have lapsed in order for clinical
improvements from such treatments to have stabilised prior to
administering CHM.
Medications
and interventions that are not permitted at any time during the study
due to potential interactions with study medication or potential effects
on the study outcome measures include: hormonal contraceptives,
anticoagulants such as heparin and warfarin, anti-hypertensives,
diuretics, cardiac glycosides, ciprofloxacin, corticosteroids, lithium,
ovulation-inducing agents, laparoscopic ovarian cauterization and
fertility procedures. CHM and other herbal supplements that have a
potential action on symptoms of PCOS or could interact with the study
medication will also not be permitted and include St. Johns wort, black
cohosh, vitex agnus castus and saw palmetto.
Practitioners
will be permitted to provide participants with additional advice such
as lifestyle, stress-management or general wellbeing according to
Chinese medicine theory. It is acknowledged that offering such advice
could be a potential confounder but since it will be offered to both
treatment groups as part of pragmatic practice, we consider this to be
an acceptable co-intervention. Practitioners will be asked not to offer
advice outside of routine CHM practice.
Study restrictions
There
is no available safety data regarding CHM use during pregnancy and
participants will be strongly advised against trying to conceive whilst
participating in this study. Participants will be asked not to change
their diet or activity level during the study other than what their
practitioner has recommended. To maintain participant-blinding,
practitioners will be asked not to disclose information to participants
regarding individualising prescriptions during the study.
Modifications, discontinuation and post-trial care
Modification
to the standard 16 g daily dosage is permitted in response to adverse
effects or at the participant's request and a daily dose range of 5–25 g
is considered adherent to the protocol. Temporary discontinuation of
CHM treatment is permitted for reasons such as experiencing side-effects
or whilst on holidays and should be for a maximum period of 7 days each
time to be considered adherent to the protocol. Changes in study
practitioner and to the prescription between scheduled assessments are
not permitted owing to resource constraints.
Should
a compelling medical need arise for any participant, subsequent medical
treatment will take precedent. Since this study has been approved by
our sponsor and study interventions are routinely available and provided
by fully qualified practitioners, study participants are insured both
in terms of treatments provided as well as for research-related
activities.
Participants
will be withdrawn from the study either at their own request for
personal reasons, or for other reasons without their consent, including
situations in which continuing the study could be harmful to the
participant's health, becoming pregnant or requiring treatment that is
prohibited during the study. Participants will be invited to attend an
end of study visit to collect final outcome data. Where appropriate,
participants may be withdrawn from the interventional aspect but invited
for monitoring of safety and other outcomes for the remainder of the
study. Participants withdrawn from this study will not be replaced.
Upon
study completion, participants will be offered a final telephone
consultation with their practitioner within 4 weeks of their final
visit.
Data management
Standardised
online questionnaires will be used where possible to maximise
completeness of data collection, and standardised electronic or
paper-based forms where this is not possible. All source data will be
transferred to standardised case report forms (CRFs) which will be
anonymised.
Access to, and
handling of, data will be restricted to delegated study staff who must
comply with the requirements of the Data Protection Act 1998. Disclosure
of confidential information can only be made during routine procedures
such as monitoring and auditing by the study sponsor or in emergency
situations such as when a compelling medical need arises.
Outcome measures
The
clinical outcome of primary interest is regularity of menses measured
as the number of days between menses. As there will be no run-in period,
participants will be asked to recall data for a minimum of 3 menstrual
cycles preceding the baseline visit. These will be used to calculate a
baseline mean cycle length and standard deviation which will be compared
with menstrual data obtained during the 6-month study period. An
improvement is determined as a reduction from baseline in standard
deviation to reflect stability in the variability of cycle length, and a
reduction from baseline in the mean number of days between menses
towards a 21–35 days interval which is clinically accepted as a regular
cycle length. On-study menstrual data will be analysed from the first
menses since randomisation onto the study. Self-reported confidence in
the accuracy of baseline menstrual data using a 4-point Likert scale
will be recorded.
Secondary
outcomes of interest will be measured at baseline and at end of study.
These include anthropometric measurements such as body mass index [24];
weight (kg) where a clinically significant loss in weight for
overweight and obese patients is determined as a loss of ≥5% of initial
weight [25];
waist circumference (WC) where risk of metabolic complications is
increased with a WC >80 cm and substantially increased with a WC
>88 cm [26]; and waist hip ratio (WHR) where WHR ≥0.85 is considered to substantially increase risk of metabolic complications [26].
Clinically validated instruments will be used for anthropometric
measurements such as a constant-tension stretch-resistant measuring
tapes and weighing scales that are minimum class III. Quality of life
questionnaires administered include Polycystic Ovary Syndrome
Questionnaire (PCOSQ), where a minimally important difference in the
score of 0.5 on the 1–7 scale represents the smallest change in score
that is important to women [27]; Measure Yourself Medical Outcome Profile (MYMOP), where the minimal important difference for change in score is 1.0 [28] and [29];
and Dermatology Life Quality Index (DLQI) where the minimal important
difference for general skin conditions is a change in DLQI score of ≥3.2
points [30] and [31].
Hirsutism will be assessed by the practitioner using the validated
modified Ferriman–Gallwey Questionnaire (mFG), that scores 9 body areas
between 1 and 4 and where an mFG score of >6 is indicative of
hirsutism [32].
Safety
will be assessed by monitoring liver and kidney function at week 4 and
end of study using serum blood tests or the validated point-of-care
device Reflotron Desktop Analyzer [21] and [33].
We will also examine frequency and type of adverse events (AEs) and
serious adverse events (SAEs) which will be captured at each study
assessment from time of consent until the last study assessment.
Monitoring will be conducted by asking non-leading questions such as
‘How are you feeling?’ or ‘Since you were last asked, have you felt
unwell or different from usual?’ Such events will be recorded in
clinical notes and using a standardised adverse event form. Relevant
documentation such as laboratory reports relating to the event will be
collected and will include an assessment of type of event, onset date,
severity and causality, expectedness, date of resolution as well as
treatment required and outcome. AEs will be evaluated as routine study
data and will not need to be reported to the study sponsor. SAEs should
be reported immediately by telephone or by email to the study sponsor
within 24 hours of learning of the event and an SAE form completed
providing all available details of the event. After recording an AE, or
recording and reporting an SAE, the study team will make all attempts to
follow up each participant until resolution.
Practitioner-blinding
will be assessed at weeks 4, 12 and at end of study by administering a
3-item standardised questionnaire that asks practitioners: ‘(1). Given
the information that you have received about the participant to date,
which treatment group do you feel this participant was assigned to?
(Response: Standardised/Individualised), (2). How certain are you of
your answer? (Response: Not at all sure, just guessed/Fairly
sure/Entirely sure), (3). Why do you think this participant was assigned
to this treatment group? Please provide as much information as you
would like (Response: Free text)’ [34].
Adherence
will be monitored using the Morisky Medication Adherence Scale (MMAS-8)
administered at week 4 and at end of study, where a score of >2 is
indicative of low adherence, 1–2 medium adherence and 0 high adherence [35]. Adherence will also be measured by calculating total CHM usage by weighing prescription containers during the study.
Baseline
comparisons will be checked for characteristics such as age, history of
conventional medication and complementary and alternative medicine use,
time since diagnosis, education level and smoking status. Baseline
comparisons will also be made for treatment expectations using the
Credibility/Expectancy Questionnaire [36] (CEQ) administered once via online questionnaire after the baseline visit but prior to CHM administration.
Clinical
treatment data will be collected including CHM diagnoses,
individualised prescription details and concomitant advice.
Practitioners will be asked to provide an assessment at baseline on
expected effectiveness of the standardised prescription for each
participant based on a 7-point Likert score. This data will inform the
CHM intervention for the main study by, for example, assessing frequency
and rank order of individual CHM prescribed, frequency and rank order
of diagnoses of study participants and doses prescribed. Comparison of
treatment effects and of safety between individualised and standardised
CHM will also provide further information regarding the choice of CHM
intervention for the main study. Other process data such as recruitment
rate, dropout rate, reasons for dropout, resource usage will be
collected. Evaluation of study participation will be collected via
feedback questionnaires administered to participants, practitioners and
dispensary at study close.
Analysis
Descriptive
statistics will be calculated for primary and secondary variables.
Principles of intention-to-treat will be adopted by analysing available
data from all randomised participants, regardless of completion and
compliance rates. Owing to the feasibility nature of this study, formal
data imputation will not be conducted.
Statistical
analysis will be piloted in this feasibility study to check suitability
of statistical methods for the main study based on the proposed
outcomes. The analysis will test for within-patient and between-group
differences in measurements taken at baseline and at end of study.
Continuous variable comparisons will be assessed at end of study
adjusted for baseline assessments for the two groups using analysis of
variance, or an analysis of covariance to include the effects of body
mass index, waist hip ratio, severity of menstrual disorder, demographic
variables, CEQ score and adherence. Categorical data will be analysed
using Chi-squared tests. Where assumptions of normality are not met
nonparametric methods will be used.
As
no formal power calculations have been carried out, results from the
statistical analysis should be considered preliminary and must be
interpreted cautiously [11].
Textual
data that is collected from sources such as clinical notes and
evaluation questionnaires will be analysed using content analysis.
Dissemination and discussion
The recruitment period lasted from January 2013 until August 2013. The final study visit is expected in March 2014.
Disseminated
findings shall contain no participant-identifiable data. On completion
of the study and regardless of the findings, a clinical study report
will be prepared for presentation at scientific meetings and for
publication in a peer-reviewed and topically relevant journal.
Publications will be reported in accordance with the Consolidated
Standards of Reporting Trials (CONSORT) statement.
At
the end of this study, we will examine the feasibility of conducting
such a study in the UK, discuss piloting the procedures, and provide
comment as to whether or not progression to a main study is recommended.
Conflict of interest
None.
Acknowledgements
The
ORCHID study is supported by a PhD research training fellowship awarded
to the main author by the National Institute for Health Research (NIHR)
School for Primary Care Research, a partnership between the
Universities of Birmingham, Bristol, Keele, Manchester, Nottingham,
Oxford, Southampton and University College London. The views expressed
are those of the authors and not necessarily those of the NHS, the NIHR
or the Department of Health.
We
are grateful to the University of Southampton Department of Primary
Care and Population Sciences for providing financial support towards the
cost of clinical equipment and medical tests. We would like to
acknowledge Phoenix Medical Direct Limited for supplying discounted
herbs and Dr. Trevor Wing for advice on the study design and for medical
imaging and phlebotomy services. Other than the role stated, those
named have had no other contribution to the study design, analysis or
writing of the protocol and of this report.
References
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