A randomized controlled trial comparing lifestyle intervention to letrozole for ovulation in women with polycystic ovary syndrome: a study protocol

Background Polycystic ovary syndrome (PCOS) affects between 8 and 18% of women and is the leading cause of female anovulatory infertility. Unfortunately, common treatments for women trying to conceive can be ineffective as well as disruptive or harmful to patients’ quality of life. Despite evidence that women with PCOS have expressed the need for alternative fertility treatments, lifestyle interventions incorporating a nutritional plan with supplementation, increased physical activity, and techniques for stress management have not been combined as a program and studied in this population. Literature suggests that each of these individual components can positively influence reproductive hormones and metabolic health. Methods/design This is a randomized controlled trial which will include 240 women diagnosed with PCOS, according to the Rotterdam criteria, who are trying to conceive. Participants will be randomized to either a comprehensive lifestyle intervention program or prescribed an oral fertility medication, letrozole. These two groups will be further randomized to consume either myo-inositol or a placebo. Participants will be between the ages of 18 and 37 years. Exclusion criteria include women who have already begun fertility treatment, who are currently using myo-inositol or have taken it within the past 3 months, or who are being treated for, or have a history of, an eating disorder. The primary outcome will be the ovulation rate, the secondary outcome will be conception. Other outcomes include miscarriage rates, validated rating measures of overall quality of life (including social, relational, mind/body and emotional sub-categories) and mental health scores (depression, anxiety, and stress). Discussion This trial will determine the effectiveness of a structured lifestyle-based comprehensive intervention program for women with PCOS experiencing infertility. In addition, it will determine whether supplementing with myo-inositol provides any further benefit. The objective of this study is to assess a possible non-pharmacological solution to ovulatory dysfunction in these patients and perhaps improve other associated features of PCOS. Trial registration ClinicalTrials.gov, ID: NCT02630485. Registered on 15 December 2015. Electronic supplementary material The online version of this article (10.1186/s13063-018-3009-5) contains supplementary material, which is available to authorized users.


Background and rationale 6a
Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention ______3-6____ 6b Explanation for choice of comparators ______4-5_____ Objectives 7 Specific objectives or hypotheses ______6______ Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory) ______6______

Methods: Participants, interventions, and outcomes
Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained ______7______ Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

Interventions 11a
Interventions for each group with sufficient detail to allow replication, including how and when they will be administered Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) 7-10 ( Fig 1&2)

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions _____7_______ Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned ______7______ Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions _______7____ Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how ______7______ 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial ______7_____

Methods: Data collection, management, and analysis
Data collection methods 18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol _____8-10____ 18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) ___10-11_____

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed _____7_____ 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial ____7-8______