Fernando 2014

Trial name or title	A pilot double‐blind randomised placebo‐controlled dose–response trial assessing the effects of melatonin on infertility treatment (MIART): study protocol
Methods	Pilot phase II cross‐over double‐blinded randomised placebo‐controlled dose–response trial Each treatment arm will be randomly allocated a letter (A, B, C or D) by way of opaque sealed envelope Randomisation will be computerised and participants will be randomised at a ratio of 1:1:1:1 to 1 of the groups, A–D, using the minimisation method.
Participants	We plan to recruit a total of 160 infertile women undergoing IVF/ICSI INCLUSION CRITERIA; 1. Undergoing first cycle of IVF or ICSI; 2. Age between 18 and 45; 3. Body mass index between 18 and 35; 4. Undergoing a gonadotrophin releasing hormone (GnRH) antagonist cycle (without oral contraceptive pill (OCP) scheduling). EXCLUSION CRITERIA 1. Current untreated pelvic pathology: moderate‐to‐severe endometriosis, submucosal uterine fibroids/polyps assessed by the treating specialist to affect fertility, pelvic inflammatory disease uterine malformations, Asherman’s syndrome and hydrosalpinx 2. Currently enrolled in another interventional clinical trial 3. Concurrent use of other adjuvant therapies (e.g. Chinese herbs, acupuncture) 4. Current pregnancy 5. Malignancy or other contraindication to IVF 6. Autoimmune disorders 7. Undergoing preimplantation genetic diagnosis 8. Hypersensitivity to melatonin or its metabolites 9. Concurrent use of any of the following medications: A. Fluvoxamine (e.g. luvox, movox, voxam); B. Cimetidine (e.g. magicul, tagamet); C. Quinolones and other CYP1A2 inhibitors (ciprofloxacin, avalox); D. Carbamazepine (e.g. tegretol), rifampicin (e.g. rifadin) and other CYP1A2 inducers; E. Zolpidem (e.g. stilnox), zopiclone (e.g. imovane) and other non‐benzodiazepine hypnotics. 10. Inability to comply with trial protocol
Interventions	1. Placebo capsule taken twice a day; 2. 2 mg melatonin capsule twice a day (4 mg/day total); 3. 4 mg melatonin capsule twice per day (8 mg/day total); 4. 8 mg melatonin capsule twice per day (16 mg/day total).
Outcomes	Primary outcome: Clinical pregnancy rate, defined as the presence of a live pregnancy in the uterine cavity at a transvaginal ultrasound at 6 – 8 weeks’ gestation Secondary outcomes: Live birth, miscarriage, adverse events, melatonin serum levels
Starting date	Recruitment will start in July 2014. This will occur over 2 years. Analysis and dissemination will occur after this period of time. The study is expected to be completed by February 2017.
Contact information	Dr Shavi Fernando; shavif@hotmail.com
Notes	Participants will be recruited from Monash IVF infertility clinics in Melbourne, Australia over a period of 2 years Ethics and dissemination: Ethical approval has been obtained from Monash Health HREC (Ref:13402B), Monash University HREC (Ref: CF14/523‐2014000181) and Monash Surgical Private Hospital HREC (Ref: 14107). Data analysis, interpretation and conclusions will be presented at national and international conferences and published in peer reviewed journals. Trial registration number: ACTRN12613001317785