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Trial registered on ANZCTR


Registration number
ACTRN12619001003167
Ethics application status
Approved
Date submitted
2/07/2019
Date registered
15/07/2019
Date last updated
3/03/2020
Date data sharing statement initially provided
15/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Fertility In Vitro Fertilisation (IVF) and Intrauterine Insemination (IUI) trial in couples with uneXplained infertility (The FIIX Study).
Scientific title
Effect of IVF compared to Intrauterine Insemination on live birth rate in couples with uneXplained infertility (The FIIX Study).
Secondary ID [1] 298453 0
None
Universal Trial Number (UTN)
U1111-1229-2553
Trial acronym
The FIIX Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Unexplained Infertility 313197 0
Condition category
Condition code
Reproductive Health and Childbirth 311657 311657 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intrauterine insemination (IUI) followed by in vitro fertilisation (IVF) arm

Participants randomised to this arm will receive four cycles of IUI, followed by two completed cycles of IVF until pregnancy leading to live birth is achieved.
IUI treatment will begin at the start of the next menstrual cycle (day 1) following randomisation. IUI with oral ovarian stimulation will be given with five days of either oral clomiphene citrate (CC) or letrozole from cycle day 2-6. The clinicians and fertility clinics involved will determine the medication used and dose as per their normal clinic policy. The dose of Clomiphene is usually between 25mg-150mg daily and letrozole 2.5-7.5mg daily. Blood tests will be taken, and monitoring for follicular development via transvaginal ultrasound will occur, according to clinic protocol, this usually will not be more than 2-3 times per cycle. On the day of ovulation semen will be washed and prepared and then directly inserted with a catheter into the cervix.
The IUI procedure will be carried out either by a fertility clinic nurse trained in IUI or by the study co-ordinator (myself) a fertility subspecialty trainee. It will be carried out at the fertility clinics involved in the study.
If four cycles of IUI are carried out and do not lead to live birth then the patient progresses to IVF treatment.
The number of cancelled and complete cycles of IUI that have been carried out, and over what time period, will be monitored by our Data Safety Monitoring Board (DSMB) and reported back to the trial steering committee if there are concerns.

IVF will be carried out by doctors, embryologists and nurses at the involved clinics in the standard way the clinic normal carries out an IVF cycle. The study is pragmatic in that the clinic and practitioner has autonomy over the cycle type, medication dose and follow up/progress regimen. Two completed cycles of IVF will be offered until a live birth is achieved. A completed cycle includes transfer of all available frozen embryos in subsequent cycles, using a single embryo transfer policy. All frozen embryos must be transferred prior to progressing into the second IVF cycle. The two IVF cycles would be expected to be complete within a 12 month time frame.
Intervention code [1] 314699 0
Treatment: Other
Intervention code [2] 314939 0
Treatment: Drugs
Comparator / control treatment
In vitro fertilisation (IVF) arm.

Participants randomised to this arm will receive up to two completed cycles of IVF until pregnancy leading to live birth is achieved. The first cycle of IVF will run parallel to the IUI cycles in the intervention arm and we would aim to complete this cycle by six months from randomisation (including frozen embryo transfers). Both cycles should be complete by 18 months post randomisation with follow up not extending beyond 24 months.

IVF will be carried out by doctors, embryologists and nurses at the involved clinics in the standard way the clinic normal carries out an IVF cycle. The study is pragmatic in that the clinic and practitioner has autonomy over the cycle type, medication dose and follow up/progress regimen. Two completed cycles of IVF will be offered until a live birth is achieved. A completed cycle includes transfer of all available frozen embryos in subsequent cycles, using a single embryo transfer policy. All frozen embryos must be transferred prior to progressing into the second IVF cycle.
Control group
Active

Outcomes
Primary outcome [1] 320363 0
Cumulative live birth rate (CLBR), defined as any live birth conceived within 185 days of randomisation, including live birth following a treatment cycle (including any subsequent frozen embryo replacements) and following any spontaneous pregnancy or pregnancy from off protocol treatment.
Conception will be determined by a positive serum pregnancy test.
Live birth is defined as birth after 20 completed weeks of gestation of a baby which breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached. A birth weight of 400 grams or more can be used if gestational age is unknown. Live births are counted as birth events, for example, a twin or triplet live birth is counted as one birth event.
Timepoint [1] 320363 0
Measured at 185 days (six months)
Secondary outcome [1] 371350 0
CLBR defined as any conception leading to live birth measured at 550 days (18 months) from randomisation regardless of whether all potential treatment cycles are completed.

Conception will be determined by a positive serum pregnancy test.
Live birth is defined as the complete expulsion or extraction from a woman of a product of fertilization, after 20 completed weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles,irrespective of whether the umbilical cord has been cut or the placenta is attached. A birth weight of 500 grams or more can be used if gestational age is unknown. Live births refer to the individual newborn; for example, a twin delivery represents two live births.
Timepoint [1] 371350 0
550days (18months)

Any pregnancies from off protocol treatments, and spontaneous pregnancies, will be counted
Secondary outcome [2] 371351 0
CLBR at the completion of four IUI cycles or one IVF cycle.

Conception will be determined by a positive serum pregnancy test.
Live birth is defined as the complete expulsion or extraction from a woman of a product of fertilization, after 20 completed weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles,irrespective of whether the umbilical cord has been cut or the placenta is attached. A birth weight of 500 grams or more can be used if gestational age is unknown. Live births refer to the individual newborn; for example, a twin delivery represents two live births.
Timepoint [2] 371351 0
At the completion of four cycles of IUI (after fourth cycle serum pregnancy test) but no later than 12 months (365 days) following randomisation.
Secondary outcome [3] 371353 0
CLBR at the completion of all treatment cycles

Conception will be determined by a positive serum pregnancy test.
Live birth is defined as the complete expulsion or extraction from a woman of a product of fertilization, after 20 completed weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles,irrespective of whether the umbilical cord has been cut or the placenta is attached. A birth weight of 500 grams or more can be used if gestational age is unknown. Live births refer to the individual newborn; for example, a twin delivery represents two live births.
Timepoint [3] 371353 0
At the completion of all allocated or required treatment but no later than 24 months (730 days) following randomisation.
Secondary outcome [4] 371354 0
Time from randomisation to conception leading to live birth

Conception will be determined by a positive serum pregnancy test.
Live birth is defined as the complete expulsion or extraction from a woman of a product of fertilization, after 20 completed weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles,irrespective of whether the umbilical cord has been cut or the placenta is attached. A birth weight of 500 grams or more can be used if gestational age is unknown. Live births refer to the individual newborn; for example, a twin delivery represents two live births.
Timepoint [4] 371354 0
No fixed time point, measured in days, maximum will be 24 months (730 days)
Secondary outcome [5] 371355 0
Number of frozen embryos remaining at completion of treatment
Timepoint [5] 371355 0
18 months (550 days)
Secondary outcome [6] 371356 0
Ongoing pregnancy; defined as the presence of a heart beat as seen by ultrasonography 12 weeks after last menstrual period or treatment cycle start (including singleton, twin pregnancy, and higher multiples).
Timepoint [6] 371356 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [7] 371357 0
Viable pregnancy; defined as an intrauterine pregnancy diagnosed by ultrasonography of at least one fetus with a discernible heartbeat.
Timepoint [7] 371357 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [8] 371358 0
Miscarriage; the spontaneous loss of an intrauterine pregnancy with fetal heart beat prior to 20 completed weeks of gestational age.
Timepoint [8] 371358 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [9] 371359 0
Ectopic pregnancy; defined as a pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualisation or histopathology.
Timepoint [9] 371359 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [10] 371360 0
Stillbirth; defined as the death of a fetus prior to the complete expulsion or extraction from its mother after 20 completed weeks of gestational age. The death is determined by the fact that, after such separation, the fetus does not breathe or show any other evidence of life, such as heartbeat, umbilical cord pulsation, or definite movement of voluntary muscles. Note: this includes deaths occurring during labour.
Timepoint [10] 371360 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [11] 371361 0
Termination of pregnancy/ induced abortion; intentional loss of an intrauterine pregnancy, through intervention by medical, surgical or unspecified means.
Timepoint [11] 371361 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [12] 372019 0
FertiQOL (treatment related) questionnaire
Timepoint [12] 372019 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [13] 372020 0
Hospital admission for ovarian hyperstimulation syndrome that included drainage of ascites or pleural effusions.

Defined as any admission to hospital where the working diagnosis is OHSS and drainage of ascites or a pleural effusion was required. This will be determined by the individual fertility clinic searching hospital records or identifying the discharge summary diagnosis for patients.
Timepoint [13] 372020 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [14] 372021 0
admission to hospital following a fertility cycle from other treatment related causes such as haemorrhage or pelvic infection.
Defined as any admission to hospital where the working diagnosis is likely secondary to their fertility treatment. This will be determined by the individual fertility clinic searching hospital records or identifying the discharge summary diagnosis for patients.
Timepoint [14] 372021 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [15] 372022 0
Multiple pregnancy; defined as two or more gestational sacs seen by ultrasonography.
Timepoint [15] 372022 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [16] 372104 0
Incremental cost per couple.
Unit costs will include - medication cost of the drugs in the only public clinic (Fertility Plus); intervention services (IUI and IVF) using 2020 costs as paid to the Northern Region clinics; pregnancy and delivery for singletons and multiple pregnancy sourced from the medical literature 9-11 or current birth costs in New Zealand.
Timepoint [16] 372104 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [17] 372105 0
Incremental cost per live birth.
Unit costs will include - medication cost of the drugs in the only public clinic (Fertility Plus); intervention services (IUI and IVF) using 2020 costs as paid to the Northern Region clinics; pregnancy and delivery for singletons and multiple pregnancy sourced from the medical literature 9-11 or current birth costs in New Zealand.
Timepoint [17] 372105 0
6 months (185 days) and 18 months (550 days)
Secondary outcome [18] 380853 0
biochemical pregnancy - defined as a pregnancy diagnosed only by the detection of beta hCG in serum or urine, which fails to progress to the point of ultrasound confirmation.
Timepoint [18] 380853 0
6 months (185days) and 18months (550 days)
Secondary outcome [19] 380854 0
biochemical pregnancy - defined as a pregnancy diagnosed only by the detection of beta hCG in serum or urine, which fails to progress to the point of ultrasound confirmation.
Timepoint [19] 380854 0
6 months (185days) and 18months (550 days)
Secondary outcome [20] 380855 0
Early pregnancy loss - defined as the spontaneous loss of an intrauterine pregnancy, where there is no fetal heart beat detected at the time of ultrasound at 6-8 weeks.
Timepoint [20] 380855 0
6 months (185days) and 18 months (550 days)

Eligibility
Key inclusion criteria
Inclusion criteria
1. Eligible for two packages of publicly funded fertility treatment in NZ and all of the following:
a. Age - Female <39 years 4 months and male <54 years and 4months at the time of randomisation.
b. Body mass index (BMI) - Female - BMI < /= 32.
c. Both partners are non-smokers for three months.
d. Both partners with no history of illicit drug use or alcohol abuse within the preceding 12 months.
e. Day 2 FSH <15IU for the female partner
f. Both partners must be a NZ citizen or resident, hold a NZ work visa or student visa which allows them to stay in NZ continuously for two years or more, or be an Australian citizen or resident who can prove intention to stay in NZ for two years or more.
g. Couples must have:
i. No previous children from public fertility treatment.
ii. No more than one child (including adopted children) of any age to the same relationship, or
iii. No more than one child from a previous relationship living at home (at least half of the time)
2. Female partner has a regular ovulatory cycle (21-35 days).
3. Female partner has evidence of patent fallopian tube(s) on hysterosalpingogram or at laparoscopy or recent intrauterine miscarriage (within 24 months) (tubal spasm is not considered tubal blockage).
4. Male partner has a total motile sperm count (TMSC) > 10 million, on last semen analysis or within two of the past three semen analyses.
Minimum age
18 Years
Maximum age
54 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Women with a history of stage 3 and 4 endometriosis
2. Women with submucosal fibroids or any fibroid >8cm or fibroids between 5-8cm if endometrial cavity is distorted or cavity length is >10cm.
3. Couple who require egg or sperm donation
4. Women with a past history of ectopic pregnancy or bilateral blocked tubes or tubal surgery for adhesions/hydrosalpinges.

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)
Yes there is allocation concealment.
Allocation concealment will be ensured, as the data system will not release the randomisation code until the couple has been recruited into the trial, which takes place after baseline measurements have been entered in the system.
The randomisation sequence will not be accessible to the recruiters.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Couples will be randomly assigned to either the IUI followed by IVF arm or the IVF arm with a 1:1 allocation using a variable block design via a web-based data system.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Couples will be randomly assigned to either the IUI followed by IVF arm or the IVF arm with a 1:1 allocation using a variable block design via a web-based data system. The block sizes will not be disclosed, to ensure concealment.
Allocation concealment will be ensured, as the data system will not release the randomisation code until the couple has been recruited into the trial, which takes place after baseline measurements have been entered in the system.
The randomisation sequence will not be accessible to the recruiters. The study is not blinded because of the nature of the intervention. The researchers who collect data for pregnancy outcomes will be aware of the assigned intervention.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The analysis of the primary outcome will be by logistic regression. We will perform a sensitivity analysis excluding women who were ineligible (e.g. unrecognised pregnancy at study entry) and will estimate the Complier Averaged Causal Effect, which estimates the effect of treatment in participants who comply with the protocol. If any participant has missing data for the primary outcome, we will define them as not having had a live birth.
Secondary outcomes will be analysed using logistic or linear regression according to the outcome distribution, again adjusting for the covariates listed in the primary analysis.
An exception is time to pregnancy leading to live birth; we will plot the cumulative incidence for this outcome, and will use Cox regression, adjusting for the same covariates as described above.
A cost effectiveness analysis will be undertaken including the cost per woman treated and the cost per live birth.
Exploratory subgroup analyses will be performed, but the trial is not powered to this end. These will involve tests of interaction between treatment and age (<36 vs 36 or over) and between treatment and number of previous treatment attempts.
Primary outcome assessed at p<0.05
All secondary analyses statistical significance set at 0.01 (99%). No other adjustment for multiple comparisons.

Recruitment
Recruitment status
Recruiting
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 outside Australia
Country [1] 21598 0
New Zealand
State/province [1] 21598 0

Funding & Sponsors
Funding source category [1] 302999 0
Government body
Name [1] 302999 0
Northern Regional Fertility Service
Address [1] 302999 0
Northern Region Fertility Service
37 Taharoto Road
Private Bag 93503
Takapuna 0622
Country [1] 302999 0
New Zealand
Funding source category [2] 303152 0
Charities/Societies/Foundations
Name [2] 303152 0
Auckland DHB Charitable Trust (A+ Research Grant)
Address [2] 303152 0
Auckland DHB Charitable Trust Office
Level 15.
Support Building
Auckland City Hospital
3 Park Road
Grafton
Auckland 1023
Country [2] 303152 0
New Zealand
Funding source category [3] 303153 0
Charities/Societies/Foundations
Name [3] 303153 0
Auckland Medical Research Foundation
Address [3] 303153 0
89 Grafton Road
Grafton
Auckland 1023
Country [3] 303153 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
The University of Auckland
Private Bag 92019
Auckland 1142
New Zealand
Country
New Zealand
Secondary sponsor category [1] 302998 0
None
Name [1] 302998 0
Address [1] 302998 0
Country [1] 302998 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303548 0
Health and Disability Ethics Committee
Ethics committee address [1] 303548 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 303548 0
New Zealand
Date submitted for ethics approval [1] 303548 0
08/03/2019
Approval date [1] 303548 0
15/04/2019
Ethics approval number [1] 303548 0
NZ/1/CB42113

Summary
Brief summary
The FIIX study is a randomised controlled trial that will be carried out across NZ involving couples with unexplained infertility who are eligible for public funding. They will receive either four intrauterine insemination (IUI) cycles (washed sperm placed into the uterus) or one in vitro fertilisation (IVF) cycle (embryos made in the laboratory by mixing eggs with sperm) to determine if the treatments have similar live birth rates (LBR). The trial will continue to completion of public treatment for these couple (which is two IVF cycles) and compare LBR and cost at the end. Our hypothesis is that for couples with unexplained infertility, (1) four cycles of IUI is comparable to one completed cycle of IVF for CLBR and is more cost effective; and (2) four cycles of IUI followed by two cycles of IVF will result in more live births at lower total cost than two cycles of IVF alone.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94046 0
Prof Cindy Farquhar
Address 94046 0
Department of Obstetrics and Gynaecology
University of Auckland
Level 12 Auckland City Hospital
2 Park Road
Grafton
Auckland 1023
New Zealand
Country 94046 0
New Zealand
Phone 94046 0
+6421995414
Fax 94046 0
Email 94046 0
c.farquhar@auckland.ac.nz
Contact person for public queries
Name 94047 0
Dr Lucy Prentice
Address 94047 0
Department of Obstetrics and Gynaecology
University of Auckland
Level 12 Auckland City Hospital
2 Park Road
Grafton
Auckland 1023
New Zealand
Country 94047 0
New Zealand
Phone 94047 0
+64 2102497362
Fax 94047 0
Email 94047 0
prentice.lucy@gmail.com
Contact person for scientific queries
Name 94048 0
Dr Lucy Prentice
Address 94048 0
Department of Obstetrics and Gynaecology
University of Auckland
Level 12 Auckland City Hospital
2 Park Road
Grafton
Auckland 1023
New Zealand
Country 94048 0
New Zealand
Phone 94048 0
+64 2102497362
Fax 94048 0
Email 94048 0
prentice.lucy@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
no consent for this
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 2343 0
Study protocol
Citation [1] 2343 0
Link [1] 2343 0
Email [1] 2343 0
Other [1] 2343 0
Type [2] 2344 0
Informed consent form
Citation [2] 2344 0
Link [2] 2344 0
Email [2] 2344 0
Other [2] 2344 0
Type [3] 2345 0
Ethical approval
Citation [3] 2345 0
Link [3] 2345 0
Email [3] 2345 0
Other [3] 2345 0
Summary results
No Results