Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12612000122853
Ethics application status
Approved
Date submitted
2/11/2011
Date registered
25/01/2012
Date last updated
24/08/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
The addition of naturopathic herbal medicine to a lifestyle intervention for women with polycystic ovary syndrome (PCOS), a randomised controlled trial.
Scientific title
The effectiveness of naturopathic herbal medicine and a lifestyle intervention, compared to lifestyle intervention alone for oligomenorrhoea, serum hormones, anthropometric, reproductive, blood pressure, quality of life and adverse outcomes in overweight women with polycystic ovary syndrome (PCOS).
Secondary ID [1] 273314 0
No other registrations
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Polycystic ovary syndrome (PCOS). 279087 0
Oligomenorrhoea. 279088 0
Hormone health. 279119 0
Anthropometric features. 279120 0
Quality of life. 279121 0
Engagement and adherence. 279122 0
Condition category
Condition code
Alternative and Complementary Medicine 279276 279276 0 0
Herbal remedies
Reproductive Health and Childbirth 279277 279277 0 0
Other reproductive health and childbirth disorders
Physical Medicine / Rehabilitation 279313 279313 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This was a pragmatic randomized controlled trial (RCT). Pragmatic RCTs are designed to assess clinical effectiveness and safety (as opposed to efficacy), with findings anticipated to translate into real world settings and directly meet the information needs of consumers and clinicians. (1,2) They are characterized by a degree of flexibility for the administration of complex interventions; flexibility of practitioner expertise and by broad participant eligibility criteria (3, 4).

In this pragmatic RCT, there were two interventions; lifestyle and naturopathic herbal medicine all delivered over three months. All participants received the same lifestyle intervention based on the recommendations defined in the Evidence Based Guidelines (EBG) for the management of PCOS commissioned by the National Health and Medical Research Council. (5) The lifestyle intervention in the EBG recommends reduced dietary energy (caloric) intake in the setting of healthy food choices, irrespective of diet composition (using tools such as lifescripts:www.health.gov.au/lifescripts) and exercise for at least 150 minutes per week including 90 minutes of aerobic activity (60-90% of maximum heart rate) (5).

Two trained lifestyle coaches (a nutritionist and an exercise physiologist) collaboratively introduced diet plans and a structured sequence of aerobic and progressive resistance exercises. The ‘exercise prescription’ was designed by an exercise physiologist at Western Sydney University. It included body postures which applied resistance to large skeletal muscle groups (progressive resistance training) combined with aerobic activity (brisk walking on an incline, jogging, cycling, cross trainer, circuits at the gym, dancing etc.). A degree of flexibility was embedded into the program to accommodate individual ability and exercise preferences. Exercise sessions consisted of two parts, aerobic and resistance each estimated to take 20 to 30 minutes. Participants were advised to exercise for at least 150 minutes per week. This was presented in terms of weekly time allocations for exercise for example one 60 minute session and two 45 minute sessions or three 30 minute sessions or three sessions of 50 minutes each. The first exercise session was supervised by the exercise physiologist. Subsequent sessions were either supervised by the exercise physiologist, a trainer at a gym or self-administered at a location convenient to the participant. The intensity of an individual’s exercise prescription increased at two weekly intervals in response to individual progress.

Diets were developed according to personal taste and individual requirements. Participant’s recalled their usual daily food intake over the previous two weeks during the trial entry interview. Key dietary components were identified (daily intake of vegetables and fruit (type and number of servings), overall energy content, type of diet and consumption of unhealthy foods (high energy, nutrient sparse and high glycaemic index). Written information was provided outlining the 'Lifescripts diet' for comparison with individual diets. Additional written information was provided to enable participants to identify foods with a low glycaemic index (GI). Specific diet plans were introduced on an individualized needs basis. Dietary adjustments were collaboratively discussed, based on individual energy requirements and considered with reference to participants existing diet. Women were encouraged to swap high energy, nutrient sparse foods with lower energy, nutrient dense foods and foods with a high GI to foods with a low GI. Dietary adjustments were provided in a supportive, conversational manner. Written information, recipes, menus suggestions and referrals to information based web sites enabled participants to access further information provided by the Human Nutrition Unit at the University of Sydney and the Department of Health in Queensland..

Trial participants had access to the lifestyle coaches throughout the trial, were contacted fortnightly, invited to attend supervised exercise sessions and helped to construct their own personalized lifestyle plan. The lifestyle program and its delivery were allowed to vary between participants with the aim to maximize clinical relevance of the trial findings

Participants compliance was assessed fortnightly and during an interview at week twelve. Women self-reported the intensity of exercise (mild, moderate or vigorous) and number of minutes per week. Dietary compliance was assessed through the average number of self-reported servings of vegetables and fruit per day and number of high energy, nutrient sparse and high GI foods consumed per week.

Naturopathy was provided in the form of two types of herbal medicine tablets and two 30 minute consultations with a naturopath at weeks four and eight. During the consultations, education regarding self-care and responses to questions about the menstrual cycle were provided, Women were asked about their well-being (tailored questions about general health, sleep quality, energy, pain) and assessed for adverse effects.

There were two different herbal tablets. The first was a new formulation that contained a total of 3 grams of dried herbal medicine,, constructed from four different herbal extracts commonly used by trained naturopaths and herbalists (Cinnamomum species, Glycyrrhiza glabra, Hypericum perforatum and Paeonia lactiflora). The exact formulation of the novel herbal tablet was subject to confidentiality. Participants took three herbal tablets per day for three months. The second herbal tablet, Mediherb Tribulus forte was taken during the pre-ovulation phase of the menstrual cycle, (days 5 to 14) only (three tablets per day in addition to herbal tablet one ). The Tribulus Forte tablet contains Tribulus terrestris extract equivalent to 13.5 g dried aerial parts.
Participant compliance was assessed by tablet count with the return of contents of herbal bottles at week 12.
1. Rothwell, P.M., External validity of randomised controlled trials:“to whom do the results of this trial apply?”. The Lancet, 2005. 365(9453): p. 82-93.
2. Zwarenstein, M., et al., Improving the reporting of pragmatic trials: an extension of the CONSORT statement. Bmj, 2008. 337.
3. Sullivan, P. and D. Goldmann, The promise of comparative effectiveness research. JAMA, 2011. 305(4): p. 400-401.
4. Thorpe, K.E., Zwarenstein, M.,Oxman, A.D.,Treweek, S.,Furberg, C., and D.G. Altman, Tunis, S.,Bergel, E.,Harvey, I.,Magid, D.J., A pragmatic–explanatory continuum indicator summary (PRECIS): a tool to help trial designers. Journal of clinical epidemiology, 2009. 62(5): p. 464-475.
5. AAPCOS, Evidence-based guideline for the assessment and management of polycystic ovary syndrome., NHMRC, Editor 2011, Jean Hailes Foundation for Women's Health on behalf of the PCOS Australian Alliance: Melbourne, Australia.
Intervention code [1] 283664 0
Lifestyle
Intervention code [2] 284083 0
Rehabilitation
Intervention code [3] 284111 0
Behaviour
Comparator / control treatment
The control group will receive standard care which is lifestyle intervention. This consists of structured diet and exercise advice according to the evidence based guideline.
Control group
Active

Outcomes
Primary outcome [1] 279897 0
Time to menstruation (reduced oligomenorrhoea).
Timepoint [1] 279897 0
At the commencement of the trial and at 12 weeks.
Secondary outcome [1] 294719 0
Hormone and endocrine markers tested with blood tests, and ovulation urine tests indicated on a menstrual diary.
Timepoint [1] 294719 0
Baseline and at 12 weeks.
Secondary outcome [2] 294792 0
Anthropometric features.
Timepoint [2] 294792 0
Baseline and at 12 weeks.
Secondary outcome [3] 294793 0
Quality of life questionnaire.
Timepoint [3] 294793 0
Baseline and at 12 weeks.
Secondary outcome [4] 294794 0
A subset of 30 oligomenorrhiec women will be asked to provide blood for analysis of hormones including follicle stimulating hormone (FSH); luteinising hormone (LH); oestradiol (E2); progesterone (P4); testosterone (T4); free androgen index; insulin plus sex hormone binding globulin (SHBG). Metabolic tests will include glucose.
Timepoint [4] 294794 0
Baseline and at 12 weeks.
Secondary outcome [5] 295661 0
Anxiey and depression measured using the depression and anxiety scale questionairre.
Timepoint [5] 295661 0
Baseline and at 12 weeks.
Secondary outcome [6] 327082 0
Pregnancy assessed by serum measurements of ß HCG over 10mIU/mol, ultrasound reports, antenatal screening.
Timepoint [6] 327082 0
Assessed at three months.
Secondary outcome [7] 327083 0
Live birth outcomes assessed as post natal reports of delivery of live baby.
Timepoint [7] 327083 0
Post natal reports one month following estimated due date.
Secondary outcome [8] 327084 0
Safety of the herbal medicine. Assessment of well-being by asking direct questions. Brachial arterial pressure was measured using a sphygmomanometer and stethoscope.
Timepoint [8] 327084 0
Assessed during naturopathic consultations at weeks 4 and 8 through direct questioning. Brachial artery pressure was measured using a sphygmomanometer and stethoscope.

Eligibility
Key inclusion criteria
Women aged between 18 and 44 years, with a diagnosis of PCOS according to the European Society of Hormone and Reproductive Endocrinology (ESHRE) diagnostic criteria detailed at Rotterdam in 2004. Women with a body mass index (BMI) greater that 25 kg/m2.
A basic level of literacy.
Availability for about 30 minutes to complete questionairres at the beginning and at the conclusion of the trial.
The physical ability and time availability to exerercise three times per week for 40-60 minutes.
Willingness to attend a pathology clinic and to provide a specimen of blood for analysis.
Ability to swallow 3-4 tablets per day.
Time to attend a naturopathic consultation for 30 minutes every 4 weeks for 12 weeks.
Minimum age
18 Years
Maximum age
44 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Women with PCOS and a BMI of 24 or less.
Women with conditions characterised by similar reproductive symptoms to PCOS.

English language familiarity. The outcome measures require participants with the ability to write and understand English to provide written consent and complete questionnaires.
The research focuses on improving menstrual regularity for women with PCOS and excludes women who are pregnant.
Children and young people have been excluded due to the infrequent diagnosis of PCOS in children and young people.
The pre-exercise screening required for entry onto the trial would exclude people highly dependant on medical care from being recruited into the trial due to the need for participation in regular exercise.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Recruitment will involve networking with primary health clinicians and medical specialists in the Western Sydney area, networking with consumer groups and PCOS support groups, placement of information on internet chat rooms and through advertisement in complementary medicine journals, around the university campuses and newsletters.

Women responding to information about the study and expressing an interest to participate will be provided with an information sheet explaining the study. An appointment will be arranged with PI Susan Arentz to provide additional information about the study. Women will be made aware that their participation is voluntary. There will be an opportunity to discuss the study with a family member prior to obtaining consent. Written consent will be sought at the end of the appointment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be computer generated and provided in the form of sealed envelopes.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?

The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Pragmatic randomized controlled trial with 2 arms. One arm received lifestyle intervention alone, the other arm received lifestyle intervention combined with naturopathic herbal medicine tablets.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
We estimated that a sample size of 110 women completing the study would have 80% statistical power (two tailed test, significance level a = 0.05) to detect a clinical difference determined a priori as a mean percentage reduction in the number of days in the menstrual cycle (oliomenorrhoea) of 55% for the group receiving herbal medicine plus lifestyle intervention, compared with a reduction of 30% in the control group. This estimation was based on studies reporting similar outcomes in women with PCOS for lifestyle interventions. Based on attrition rates from other studies, we estimated a 25% loss to attrition and calculated the necessary sample size at 148. As the trial progressed, it became apparent that attrition was approximately 10% and the minimum sample size was recalculated to 122 participants.
Analyses was undertaken using the statistical software SPSS, version 21. Differences between groups at three months were analysed using student t tests (continuous variables and for binary outcomes analysed using Chi square tests and relative risks. Analyses of covariance (ANCOVA) was additionally used to investigate differences in outcomes between groups at three months after controlling for baseline variation. The effect size was estimated using partial Eta squared. Results were presented as the adjusted mean difference between groups at endpoint and associated 95% confidence intervals. The effect of loss of body weight and on the primary outcome after controlling for baseline menstrual cycle variation and study group was examined with partial eta squared.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
31/03/2012
Actual
1/07/2012
Date of last participant enrolment
Anticipated
12/03/2014
Actual
12/03/2014
Date of last data collection
Anticipated
Actual
25/06/2014
Sample size
Target
122
Accrual to date
Final
122
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC

Funding & Sponsors
Funding source category [1] 284145 0
University
Name [1] 284145 0
Western Sydney University
Country [1] 284145 0
Australia
Funding source category [2] 284146 0
Commercial sector/Industry
Name [2] 284146 0
Mediherb Australia which is owned by Integria Healthcare (Australia) Pty Ltd
Country [2] 284146 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Douglas Hanly Moir
Address
14 Giffnock Avenue
Macquarie Park NSW
2113
Country
Australia
Secondary sponsor category [1] 283473 0
University
Name [1] 283473 0
Western Sydney University
Address [1] 283473 0
Locked Bag 1797 Penrith South NSW 2751
Country [1] 283473 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 272107 0
University of Western Sydney Human Research Ethics Committee
Ethics committee address [1] 272107 0
Ethics committee country [1] 272107 0
Australia
Date submitted for ethics approval [1] 272107 0
04/11/2011
Approval date [1] 272107 0
20/12/2011
Ethics approval number [1] 272107 0
HREC: EC00314
Project approval reference number H9407

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33344 0
Dr Susan Arentz
Address 33344 0
National Institute for Complementary Medicine
University of Western Sydney
Locked Bag 1979
Penrith South NSW 2751
Country 33344 0
Australia
Phone 33344 0
61 2 4620 3284
Fax 33344 0
61 2 4620 3291
Email 33344 0
[email protected]
Contact person for public queries
Name 16591 0
Susan Arentz
Address 16591 0
National Institute for Complementary Medicine
Western Sydney University
Locked Bag 1797
Penrith South NSW Australia 2751
Country 16591 0
Australia
Phone 16591 0
61 2 46203777
Fax 16591 0
61 2 46203291
Email 16591 0
[email protected]
Contact person for scientific queries
Name 7519 0
Susan Arentz
Address 7519 0
National Institute for Complementary Medicine, Western Sydney University, Locked Bag 1797, Penrith South, NSW Australia 2751
Country 7519 0
Australia
Phone 7519 0
61 2 46203777
Fax 7519 0
61 2 46203291
Email 7519 0
[email protected]

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