Bentov 2014

Methods	Double‐blind placebo‐controlled randomised trial
Participants	IVF/ICSI patients (n = 39) Inclusion criteria: infertility requiring IVF–ICSI and age 35 – 43, mean age; CoQ10 39.0 ± 0.79 and placebo 39.1 ± 0.52 Exclusion criteria: body mass index (BMI) >38 kg/m2; early follicular phase (day 2 – 4) serum FSH level 20 mIU/mL; abnormal uterine cavity as evidenced by sonohysterogram or hysterosalpingography; any current use of systemic steroid medication or any infertility treatment within 3 months of study enrolment; any contraindication to being pregnant and carrying a pregnancy to term; contraindication for the use of CoQ10, superfact, menopur, hCG, estrase, and progesterone suppositories; any ovarian or abdominal abnormality that may interfere with adequate TVS evaluation; absence of 1 or both ovaries; clinically relevant systemic disease (e.g. insulin‐dependent diabetes, adrenal dysfunction, organic intracranial lesion, PCOS, hyperprolactinemia, or hypothalamic tumor) or serious illness (neoplasia); history (within past 12 months) or current abuse of alcohol or drugs; administration of any investigational drugs within 3 months before the study enrolment; any medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the study drugs; gastrointestinal diseases; malabsorption syndromes; and liver dysfunction; unexplained gynaecological bleeding; ejaculated sperm not sufficient for ICSI; abnormal controlled ovarian hyperstimulation (COH) screening blood done for both partners, including prolactin, thyroid stimulating hormone, HIV serology, hepatitis B and C serology, rubella, group and screen, and syphilis serology before participation in the study; the concurrent use of any of the following drugs: daunorubicin, doxorubicin, blood pressure medications, warfarin, timolol, atorvastatin, cerivastatin, lovastatin, pravastatin, simvastatin, gemfibrozil, tricyclic antidepressant medications (including amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine), multivitamins, or any vitamin supplementation except folic acid
Interventions	1. CoQ10 600 mg: 1 tablet a day with breakfast (n = 17) 2. Placebo ‐ identical capsules containing rice oil and starch (n = 22) Duration of treatment up to 3 cycles if pregnancy did not occur. All participants took either CoQ10 or placebo for 2 months. On day 3 of the following cycle, they started ovarian stimulation for IVF while continuing the consumption of the supplements.
Outcomes	Primary outcome: number of euploid eggs per retrieval Secondary outcome: cumulative pregnancy rate per retrieval and cumulative livebirth rate per retrieval
Notes	12 (5 dropouts) CoQ10 group and 15 (7 dropouts) in the placebo completed the study and 10 in the CoQ10 and 14 of the placebo group completed an IVF/ICSI cycle. Overall there were 15 dropouts from recruitment until the end of the study; 6 women withdrew from the study for personal reasons, 3 for conceiving spontaneously, 2 for poor compliance, 1 for failing to achieve the target BMI, and 3 because of poor ovarian response Participant enrolment to the study began in 2010 and was terminated in June 2012 before sample size reached, due to a paper published in May 2012 by Levin et al describing the negative effects of polar body biopsy on embryogenesis. In the CoQ10 group, 30.8% of the women were treated with the long luteal GnRH agonist protocol, compared with 7.7% in the placebo group. The rest of the participants in both groups were treated with the short microdose flare protocol 2 centres Toronto, Canada Trial registration no: NCT01048385 Informed consent Ethics approval Funding; Ferring Pharmaceuticals provided Menopur Conflict of interests; one of the authors has a consultancy role with Fertility Neutraceuticals involved in the manufacturing and distribution of CoQ10 Email sent to author regarding live birth, clinical pregnancy, dropouts and allocation concealment on 24th November 2015 'bentov@lunenfeld.ca', no reply.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were assigned in chronological order according to the day of study enrolment to a computer‐generated randomization"
Allocation concealment (selection bias)	Unclear risk	"Each enrolled participant received a pre‐assigned package containing either placebo or CoQ10 for the duration of the study".
Blinding (performance bias and detection bias) All outcomes	Low risk	"The study was a double blind, placebo‐controlled, randomized trial". "Both the physician and the patient were blinded regarding assignment of the patients".
Incomplete outcome data (attrition bias) All outcomes	High risk	"At the point the study was terminated (June 2012), we had recruited a total of 39 patients who were evaluated and randomized (17 to the CoQ10 group and 22 to the placebo group). Only 27 had started the treatment with the supplements (12 of the CoQ10 group and 15 of the placebo group). In all, 24 patients completed the treatment cycle and had a polar body biopsy (PBBX) and embryo transfer done (10 of the CoQ10 group and 14 of the placebo group). Six patients withdrew from the study for personal reasons, three for conceiving spontaneously, two for poor compliance, one for failing to achieve the target BMI, and three because of poor ovarian response."
Selective reporting (reporting bias)	Low risk	Both primary and secondary outcomes reported in the Methods were reported in the results. Protocol available.
Other bias	High risk	"However, because of the premature termination of the study, the CoQ10 group had only one‐third and the control group half of the target number". Early termination of trial for embryo safety reasons may cause an overestimation of the effect of the intervention