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Trial registered on ANZCTR


Registration number
ACTRN12613001317785
Ethics application status
Approved
Date submitted
26/11/2013
Date registered
27/11/2013
Date last updated
16/06/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
MIART: Can melatonin improve the live birth rate in infertile couples undergoing assisted reproductive technologies?
Scientific title
A double-blind randomised placebo-controlled dose-response trial assessing the effects of melatonin on infertility treatment (MIART)
Secondary ID [1] 283653 0
Nil Known
Universal Trial Number (UTN)
U1111-1150-7764
Trial acronym
MIART
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infertility 290603 0
Condition category
Condition code
Reproductive Health and Childbirth 290993 290993 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial will have four arms. All capsules will be indistinguishable from each other.
1. Placebo capsule taken twice per day
2. 2mg melatonin capsule twice per day (4mg/d total)
3. 4mg melatonin capsule twice per day (8mg/d total)
4. 8mg melatonin capsule twice per day (16mg/d total)

The participant will commence taking the trial medication on the day that she begins ovarian stimulation injections (Day 2-3 of her natural menses) at 0800 and 2200 each day, with the last capsule being taken at 2200 the night before oocyte collection. Each participant will undergo an assisted reproductive technology as deemed appropriate by their treating clinician. Melatonin has a very short half-life. Consequently, no significant period of time is required for 'washout'. If a participant does not fall pregnant in her first trial cycle, she will be offered randomisation to a different treatment arm for her next cycle.

In order to ensure the integrity of study data, participant adherence to trial protocol will be assessed on a medication administration record updated daily by the participant. At oocyte collection, participants will return medication bottles and compliance will be confirmed by counting remaining tablets. This will be recorded on individual patient compliance forms and patient record forms.
Intervention code [1] 288355 0
Treatment: Drugs
Comparator / control treatment
Placebo - equivalent appearance
Control group
Placebo

Outcomes
Primary outcome [1] 290973 0
Clinical Pregnancy rate - defined as the presence of a live pregnancy in the uterine cavity at a transvaginal ultrasound after approximately 7 weeks gestation
Timepoint [1] 290973 0
3 months after randomisation
Secondary outcome [1] 305711 0
Miscarriage rate
Timepoint [1] 305711 0
At 6 months after randomisation
Secondary outcome [2] 305712 0
Follicular fluid and serum levels of melatonin
Timepoint [2] 305712 0
At 6 weeks after randomisation
Secondary outcome [3] 305713 0
Follicular fluid and serum levels of 8-OHDG
Timepoint [3] 305713 0
At 6 weeks after randomisation
Secondary outcome [4] 308242 0
Live birth rate - Birth of a live baby after 24 weeks gestation
Timepoint [4] 308242 0
2 years after randomisation
Secondary outcome [5] 308243 0
Sleepiness score - based on the Karolinska sleepiness scale
Timepoint [5] 308243 0
3 months after randomisation
Secondary outcome [6] 308244 0
Pregnancy complication rate - Including ovarian hyperstimulation syndrome (OHSS), multiple pregnancy, congenital or chromosomal abnormalities, stillbirth, preeclampsia, delivery before 34 weeks, delivery between 34 and 37 weeks, placenta praevia, gestational diabetes, low birthweight
Timepoint [6] 308244 0
2 years after randomisation
Secondary outcome [7] 308245 0
Total number of oocytes collected
Timepoint [7] 308245 0
3 months after randomisation
Secondary outcome [8] 308246 0
Biochemical pregnancy rate - Presence of serum hCG level of >25IU/l on Day 16 after embryo transfer
Timepoint [8] 308246 0
Day 16 after embryo transfer
Secondary outcome [9] 308247 0
Oestradiol and Progesterone levels - serum assays
Timepoint [9] 308247 0
3 months after randomisation
Secondary outcome [10] 308248 0
Follicular blood flow and uterine artery blood flow - pelvic Power Doppler ultrasound
Timepoint [10] 308248 0
approximately 2 weeks after randomisation
Secondary outcome [11] 308249 0
oocyte quality - graded visually using a standardised grading chart into germinal vesicle, meiosis I or meiosis II at time of oocyte collection
Timepoint [11] 308249 0
At time of oocyte colelction
Secondary outcome [12] 308250 0
total number and quality of embryos - graded visually using standardised scale into Grades 1-4
Timepoint [12] 308250 0
Just prior to embryo transfer (Day 3-5 post oocyte collection)
Secondary outcome [13] 308251 0
fertilization rate - the number of oocytes that become fertilised
Timepoint [13] 308251 0
Day 3-5 post oocyte collection
Secondary outcome [14] 310115 0
Utilisation rate = (number of embryos transferred or frozen)/(number of oocytes fertilised), assessed by count.
Timepoint [14] 310115 0
3 months after randomisation

Eligibility
Key inclusion criteria
- Requiring first cycle of IVF or ICSI for infertility treatment
- Age between 18 and 45
- Undergoing a GnRH antagonist cycle (without OCP scheduling)
Minimum age
18 Years
Maximum age
45 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Current untreated pelvic pathology – Stage 3 or 4 endometriosis, large submucosal uterine fibroids/polyps thought by the specialist to affect fertility, diagnosed current pelvic inflammatory disease, uterine malformations (i.e uterine didelphys, bicornuate uterus and septate uterus), Asherman's syndrome and the current diagnosis of a hydrosalpinx (not treated).
2. Currently enrolled in another investigational trial
3. Concurrent use of other adjuvant therapies (eg. Co Enzyme Q10, acupuncture)
4. Current pregnancy
5. Malignancy or other contraindication to IVF
6. Autoimmune disorders
7. Will not have regular blood tests with Monash IVF (because of distance from Monash IVF)
8. Undergoing preimplantation genetic diagnosis (PGD)
9. Hypersensitivity to melatonin or its metabolites
10. Concurrent use of any of the following medications
a. Fluvoxamine (eg. Luvox, Movox, Voxam)
b. Cimetidine (eg. Magicul, Tagamet)
c. Quinolones and other CYP1A2 inhibitors (Ciprofloxacin, Avalox)
d. Carbemazepine (eg. Tegretol), rifampicin (eg.Rifadin) and other CYP1A2 inducers
e. Zolpidem (eg Stilnox), zopiclone (eg. Imovane) and other non-benzodiazepine hypnotics

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)
Participating clinicians will flag suitable patients to the primary investigator. The primary investigator will approach identified patients at the time of attendance for treatment with IVF and obtain informed consent for inclusion in the trial.
Each treatment arm will be randomly allocated a letter (A, B, C or D) by way of opaque sealed envelope (allocation concealment). Randomisation will be computerised and patients will be randomised at a ratio of 1:1:1:1 to one of the groups, A-D, using the minimisation method, which is a method of randomisation based on factors known to affect the outcome used in small trials to prevent selection bias. Participants will be blinded by receiving identical-appearing unmarked capsules. No trial researchers will be aware of participant allocation until after analyses are performed at the completion of the trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Minimisation method. Ad hoc allocation based on characteristics of the patient and relative numbers in each group.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
As this is a pilot dose-finding study, without precedence on which to base accurate power calculations, a power calculation has not been performed. Part of our aim is to provide clarification allowing for larger randomised trials to be designed in the future. We have chosen to recruit 160 participants, 40 in each group in order to assess biochemical and sonographic secondary outcomes as well as to provide an indication of effect size with our primary outcome, clinical pregnancy rate. Statistical analyses will be performed using Chi-square tests for categorical outcome variables. Clinical and demographic data will be analysed with parametric tests if they are normally distributed, otherwise appropriate non-parametric tests will be used. SPSS v20 (IBM, Armonk, New York 2011) will be used for data analysis. P <0.05 will be considered statistically significant. Adjustments will be made for confounding factors where this is statistically sound.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 1763 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 1764 0
Epworth Richmond - Richmond
Recruitment hospital [3] 1765 0
Monash Surgical Private Hospital - Clayton

Funding & Sponsors
Funding source category [1] 288331 0
Hospital
Name [1] 288331 0
Monash IVF Research and Education Foundation
Address [1] 288331 0
Monash Surgical Private Hospital, Clayton Rd, Clayton VIC 3168
Country [1] 288331 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Monash University
Victoria 3800
Country
Australia
Secondary sponsor category [1] 287047 0
Hospital
Name [1] 287047 0
Monash Medical Centre
Address [1] 287047 0
246 Clayton rd
Clayton
VIC 3168
Country [1] 287047 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290223 0
Monash Health Human Research Ethics B
Ethics committee address [1] 290223 0
246 Clayton rd
Clayton
VIC 3168
Ethics committee country [1] 290223 0
Australia
Date submitted for ethics approval [1] 290223 0
29/11/2013
Approval date [1] 290223 0
04/02/2014
Ethics approval number [1] 290223 0
13402B

Summary
Brief summary
The aim of this project is to determine whether melatonin supplementation has a dose response effect on clinical pregnancy rates, together with numerous important clinical, biochemical and sonographic secondary outcome measures. This will be achieved by a series of experiments designed to investigate the effect of melatonin on follicular fluid, serum, embryo and oocyte parameters as well as assessing clinical pregnancy rates and delivery rates
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 44562 0
Dr Shavi Fernando
Address 44562 0
Department of Obstetrics and Gynaecology
Level 5
Monash Medical Centre
246 Clayton Rd Clayton
VIC 3168
Country 44562 0
Australia
Phone 44562 0
+61395946666
Fax 44562 0
Email 44562 0
shavif@hotmail.com
Contact person for public queries
Name 44563 0
Dr Shavi Fernando
Address 44563 0
Department of Obstetrics and Gynaecology
Level 5
Monash Medical Centre
246 Clayton Rd Clayton
VIC 3168
Country 44563 0
Australia
Phone 44563 0
+61395946666
Fax 44563 0
Email 44563 0
shavif@hotmail.com
Contact person for scientific queries
Name 44564 0
Dr Shavi Fernando
Address 44564 0
Department of Obstetrics and Gynaecology
Level 5
Monash Medical Centre
246 Clayton Rd Clayton
VIC 3168
Country 44564 0
Australia
Phone 44564 0
+61395946666
Fax 44564 0
Email 44564 0
shavif@hotmail.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary