Trial Review

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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
15/04/2024
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. Four cycles of IUI would be expected to be complete within the primary endpoint (six/seven months from the date of randomisation).

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 12/13 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 within the primary endpoint (six/seven months from randomisation) (including frozen embryo transfers). Both cycles should be complete by 20 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 185/215 days (6/7 months) 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) for participants randomised prior to and including 18th August 2021. Measured at 210 days (seven months) for participants randomised after 18th August 2021.
Secondary outcome [1] 371350 0
CLBR defined as any conception leading to live birth measured at 550/610 days (18/20 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
Measured at 550days/18months (for participants randomised prior to and including 18th August 2021). Measured at 610days/20months (for participants randomised after 18th August 2021). Any pregnancies from off protocol treatments, and spontaneous pregnancies, will be counted.
Secondary outcome [2] 371351 0
CLBR at the completion of four IUI-OS cycles or one complete 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-OS (after fourth cycle serum pregnancy test) or one complete IVF cycle 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 to pregnancy leading to live birth: defined as the time taken to conceive a pregnancy which results in a live birth, measured as calendar time from randomisation to pregnancy.
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) for participants randomised prior to and including 18th August 2021 20 months (610 days) for participants randomised after 18th August 2021.
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) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
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) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
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) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
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) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
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) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
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) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
Secondary outcome [12] 372019 0
FertiQOL (treatment related) questionnaire
Timepoint [12] 372019 0
6 months (185 days) and 18 months (550 days) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
Secondary outcome [13] 372020 0
Hospital admission for ovarian hyperstimulation syndrome that included drainage of ascites or pleural effusions - serious adverse events 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) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
Secondary outcome [14] 372021 0
Hospital admission from other treatment-related causes such as OHSS, haemorrhage, or pelvic infection requiring active treatment - serious adverse events. This excludes hospital admissions for pregnancy/obstetric related complications (e.g. admission for ectopic/miscarriage/pre-eclampsia/PPROM/postpartum complications etc.)
Timepoint [14] 372021 0
6 months (185 days) and 18 months (550 days) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
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) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
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) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
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) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
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 (185 days) and 18 months (550 days) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
Secondary outcome [19] 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 [19] 380855 0
6 months (185 days) and 18 months (550 days) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
Secondary outcome [20] 401435 0
Serious drug reaction as a result of medication taken during fertility treatment - serious adverse events
Timepoint [20] 401435 0
6 months (185 days) and 18 months (550 days) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
Secondary outcome [21] 401436 0
Maternal death at any point during study follow-up, including pregnancy and 6 weeks postnatal - serious adverse events
Timepoint [21] 401436 0
6 months (185 days) and 18 months (550 days) for participants randomised <=18/08/2021 7 months (210 days) and 20 months (610 days) for participants randomised >18/08/2021
Secondary outcome [22] 434082 0
Major congenital anomaly identified within 6 weeks of birth - serious adverse events Defined as requiring admission to NICU due to abnormality (such as, complex cardiac/congenital diaphragmatic hernia) after birth or palliative care.
Timepoint [22] 434082 0
No fixed time point, within six weeks of birth, maximum will be 24 months (730 days) post randomisation.
Secondary outcome [23] 434083 0
Neonatal death occurring within 6 weeks of delivery - serious adverse events
Timepoint [23] 434083 0
No fixed time point, within six weeks of birth, maximum will be 24 months (730 days) post randomisation.

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
Sex
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
Updated statistical analysis plan for FIIX in effect from August 2021. This came into effect after 328 participants were randomised.

This version supersedes the original statistical analysis plan dated 5/5/20.

Introduction

Rationale for update to the statistical analysis plan

The FIIX study is a multicentre, open-label, two-arm parallel non-inferiority randomised controlled trial with 1:1 allocation in New Zealand. Participants are allocated to receive either up to four cycles of IUI followed by two complete cycles of IVF, or two complete cycles of IVF. The study was conceived before the COVID-19 pandemic. Measures to control the spread of COVID-19 have affected the delivery of the study interventions in such a way that the originally planned analysis may not provide a useful answer to the study question. The planned analyses have been updated in response to the pandemic, to ensure that the study provides useful information about the relative effectiveness of the study interventions. The updated analyses have been informed by published guidance for analysis of randomised trials affected by a pandemic [1].

Impact of the pandemic on the conduct of the trial

Due to pandemic control measures, the study treatments were paused in two periods while the study was active. This means that some participants who had been recruited to the study and randomised to one of the study arms faced a considerable delay to the start of their treatment. Some participants who had not yet received any study treatment did not commence treatment during this period, while participants who had commenced treatment but were not yet pregnant had to wait to undergo further attempts (further frozen embryo transfers in the IVF arm, or further insemination cycles in the IUI arm). Moreover, treatments in the two arms were paused for differing lengths of time, such that there were periods where clinics continued to perform IVF, but did not perform IUI. This means that there are periods where participants received IVF if they were randomised to the IVF arm, but received no treatment if they were randomised to the IUI arm. We therefore have periods in the study where the difference in outcomes between the groups reflects a comparison of ‘IVF versus no IUI’. While this might yield useful information about the relative effectiveness of these two interventions during a pandemic, the goal of the study is to provide information about the relative effectiveness of the two interventions outside of a pandemic.


We anticipate that an additional consequence of the pandemic, albeit one that is harder to quantify, is that there will have been delays to treatments in both arms throughout the study period. This could arise due to illness in clinic staff or in patients, for example. This could plausibly affect the two arms in the study differently.

In the following sections, we describe the updated statistical analysis plan, highlighting departures from the previous version.

Study methods

Estimand

We are interested in the effect of IVF and IUI as treatment policies [2]. This would usually mean that we are interested in the outcome measures in all participants, regardless of whether they are adherent to the intended treatment protocols. Moreover, participants would be analysed in their allocated groups, regardless of what they actually received. These two principles amount to a description of what has traditionally, albeit inconsistently, referred to as the ‘intention to treat effect’. However, in light of the COVID-19 pandemic, this description requires further elaboration [1]. Specifically, given the impact of the pandemic on the trial, we must indicate whether our interest is in estimating the relative effect of the study interventions within or outside of a pandemic context. Anticipating that the delivery of care will not continue to be interrupted in the same manner (or at least, not the same extent) by the COVID-19 pandemic in future, our primary interest is in estimating the relative effect of IUI compared to IVF outside of a pandemic context (or, more accurately, in a scenario where the treatments are not seriously disrupted by a pandemic). We have updated our primary analysis to reflect this estimand (estimand 1). An additional analysis of the outcome ‘live birth’ is planned corresponding to a different estimand: the relative effect of IUI compared to IVF in the context of an ongoing pandemic (estimand 2).

Trial design

The overall trial design remains unchanged. A multicentre, open label, two-arm parallel non-inferiority randomised controlled trial with 1:1 allocation. Participants are allocated to receive either up to four cycles of IUI followed by two complete cycles of IVF, or two complete cycles of IVF.

Randomisation

Randomisation remains unchanged. Couples are randomly assigned to either the IUI followed by IVF arm or the IVF arm with a 1:1 allocation using a variable block design. The block sizes are not disclosed, to ensure concealment. The randomisation is stratified by centre and by age (<36 OR >=36).

Timing of the primary outcome

The timing of the primary outcome has been changed for participants randomised from 19th August 2021 onwards. For these participants, the primary outcome, cumulative live birth rate (CLBR), will be assessed at 7 months (215 days) post-randomisation. Specifically, any live birth arising from a pregnancy initiated in the first 7 months from randomisation will be included. For participants randomised prior to this date, the timing of the primary outcome assessment remains unchanged (6 months/185 days). This change was made to accommodate the delays to treatment in both arms of the trial which was evident before and exacerbated by COVID-19. This amendment was approved by HDEC (reference code: 2022 AM 8410) February 2022.
Sample size

The originally planned sample size was 580 participants. This was based on the primary outcome, CLBR at 6 months from randomisation, using the following estimates from the literature:
• Estimated cumulative live birth rate (CLBR) of 30% after four cycles of IUI at 185 days (6 months).
• Estimate CLBR of 30% for a single completed IVF cycle at 185 days (6 months).
• Sample size calculated based on the hypothesis of noninferiority for CLBR at 6 months. Estimated CLBR is 30% in each group, and requires 580 patients (290 in each arm) for 80% power to reject the null hypothesis that the groups differ by more than 10 percentage points in favour of IVF at the 5% level, allowing for 10% withdrawals.

However, both of the planned analyses in the updated SAP will reduce power, either by excluding some of the randomised participants from the analysis, or by including data from participants during periods in which IUI was paused but IVF was not (such that we anticipate participants in the IUI arm to have inferior outcomes during these periods). We increased the recruitment target as a result, although anticipate that this may not be achieved due to resource limitations (cost and time). We targeted a sample size of 730.

Confidence and Significance

Type 1 error of the primary analysis will be controlled at 5%, by comparing the lower limit of a 90% two-sided confidence interval to the inferiority margin. A significance threshold of 1% will be used for secondary outcomes, which will be analysed using 99% confidence intervals.
No adjustment for multiplicity will be made for sensitivity analyses or for the alternative analyses of the primary outcome variable, CLBR, added in response to COVID-19 pandemic.

Compliance and protocol violation

This section details major changes to the planned analysis due to COVID-19 interruption. The primary analysis of CLBR will exclude all participants during periods where treatment was impacted by COVID-19 lockdowns. This means 151 participants will be removed from the analysis. March 2020 lockdown affected participants randomised between 22/09/2019 – 25/03/2020. August 2021 lockdown affected participants randomised between 14/02/2021 – 18/08/2021. The exclusions are based on date of randomization. Participants randomized in these periods will be excluded regardless of whether their individual treatment was or was not successful, and whether it was or was not significantly delayed. This decision is intended to prevent the introduction of bias, which would be a concern if we implicitly selected participants to exclude on the basis of their outcome (if we opted to include participants if they fell pregnant, for example). This analysis is intended to target the relative effect of IUI compared to IVF as treatment policies outside of a pandemic context (or more specifically, in a scenario where there are not major disruptions to the treatments due to a pandemic (estimand 1)).
A secondary analysis of CLBR will include all randomised participants, regardless of COVID interruptions. This analysis is intended to target the relative effect of IUI compared to IVF in the context of an ongoing pandemic (estimand 2).

Interim analysis

No formal interim analysis is planned. Summaries of outcome data to date will be included in reports for the DMC.

Timing of analysis

Statistical analysis for the final report will commence following the end of follow up of the final participant. However, analysis of 6/7 month (185/215 days) data (the primary outcome timepoint) may commence once the 6/7 month outcome has been obtained in all participants.


Missing Data
Missing covariate data

Since only the stratification variables are to be adjusted for in analyses, and these are anticipated to be complete (since they are required for randomisation), no action is required for missing covariate data.

Missing outcome data

Missing outcome data are anticipated due to the duration of the study. Any analysis in the presence of missing data will be subject to assumptions. We will conduct the primary analysis under one set of assumptions, but will perform sensitivity analyses allowing the assumption to vary.
For the analysis of CLBR at 6 and 7 months, we will perform analyses assuming:
- That the data are ‘missing at random’ given site and age (complete case analysis).
- That the patients with missing outcome data did not have a live birth, unless they were pregnant at the time of loss to follow up.

Assumptions

The specified primary analysis is not contingent on checking of assumptions.


Study population
Screening data
No formal analysis of factors associated with participation are planned.
Eligibility
The proportion of eligible participants from those screened, and reasons for ineligibility, will be tabulated.
Recruitment and Attrition
The numbers screened, eligible, consenting, participating and contributing outcome data at each point (6/7 and 18/20 month assessments) will be presented in the form of a CONSORT flow diagram.
Baseline Characteristics
The following table will be presented to summarise baseline characteristics of all randomised participants.

Total Group A Group B
Randomized N N N
Age Mean Mean Mean
Age by strata <36yo % % %
Age by strata >/= 36yo % % %
BMI (kg/m2) mean mean mean
Duration of infertility (mo) Median Median Median
Ethnicity % % %
Maori
Pacific
Asian
MELAA
Other European
NZ European
Previous births % % %
Previous IVF % % %
Previous IUI % % %
Sperm Concentration Mean/median Mean/median Mean/median
Sperm Motility Mean/median Mean/median Mean/median
Total motile sperm count Mean/median Mean/median Mean/median
Prediction score (Hanualt) Mean Mean Mean
AMH level Mean Mean Mean

Analysis
Data manipulation

All data will be captured in a central database[3], such that merging of multiple datasets by the trial statistician will not be required. Time to event variables will be collected using date of randomisation and date of event variables. Data will be checked for internal coherence prior to analysis.


Statistical methods

Primary outcome (CLBR at 6 or 7 months/185 or 215 days)

Primary analysis of CLBR will be conducted using logistic regression. The outcome of any ongoing pregnancies at 6 months/185 days (7 months/215 days), following the change of the primary endpoint date) post randomisation will be included. This will be adjusted for the stratification variables: age and centre. For the purpose of comparison with the non-inferiority margin, a risk difference will be obtained from the fitted model, by predicting risk under both allocations for each patient. A bootstrap procedure will be used to calculate the 95% confidence interval, which will be used to test the hypothesis of non-inferiority.

Secondary outcomes

For continuous and binary outcomes, linear and logistic regression will be employed, adjusting for the stratification variables. For time to pregnancy leading to live birth, a Cox regression model will be used, and cumulative incidence will be plotted. Analyses of the secondary outcomes will be performed using the analysis sets corresponding to estimands 1 and 2 (see Compliance and protocol violation).

Because women have multiple chances at conception in the study, miscarriage and live birth are not mutually exclusive events. For example, a woman could have a miscarriage in one attempt, and a live birth in a subsequent attempt. In this case, she would be included both as having a miscarriage and as having a live birth in the respective analyses of these outcomes. Because a woman may have several pregnancies and miscarriages in this study, we will report these outcomes both as ‘any per woman’ (a binary outcome) and as ‘number per woman’ (a count outcome).
Subgroup analyses

Exploratory subgroup analyses for CLBR will be performed, but the trial is not powered to this end. These will involve tests of interaction between treatment and age and between treatment and number of previous treatment attempts. These analyses will be considered hypothesis generating.


Sensitivity analyses

Sensitivity analyses will be conducted around the missing data assumptions used in the analysis of the primary outcome (see section, Missing outcome data).

Safety data

Serious adverse events will be analysed descriptively, by treatment group.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/08/2019
Actual
2/08/2019
Date of last participant enrolment
Anticipated
30/11/2023
Actual
15/03/2024
Date of last data collection
Anticipated
15/03/2026
Actual
Sample size
Target
730
Accrual to date
Final
737
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
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)
Country [2] 303152 0
New Zealand
Funding source category [3] 303153 0
Charities/Societies/Foundations
Name [3] 303153 0
Auckland Medical Research Foundation
Country [3] 303153 0
New Zealand
Funding source category [4] 309791 0
Charities/Societies/Foundations
Name [4] 309791 0
Mercia Barnes
Country [4] 309791 0
New Zealand
Funding source category [5] 309792 0
Charities/Societies/Foundations
Name [5] 309792 0
Maurice and Phyllis Paykel Trust
Country [5] 309792 0
New Zealand
Funding source category [6] 309793 0
Government body
Name [6] 309793 0
Health Research Council
Country [6] 309793 0
New Zealand
Funding source category [7] 316312 0
Government body
Name [7] 316312 0
Te Puna Tahua Lottery Grants Board
Country [7] 316312 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
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
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
[email protected]
Contact person for public queries
Name 94047 0
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
[email protected]
Contact person for scientific queries
Name 94048 0
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
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No IPD sharing reason/comment: no consent for this



What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
2343Study protocolPrentice L, Sadler L, Lensen S, Vercoe M, Wilkinson J, Edlin R, Chambers GM, Farquhar CM. IVF and IUI in couples with unexplained infertility (FIIX study): study protocol of a non-inferiority randomized controlled trial. Hum Reprod Open. 2020 Sep 22;2020(3):hoaa037. doi: 10.1093/hropen/hoaa037. PMID: 32995562; PMCID: PMC7508023.   Study-related document.pdf
2344Informed consent form    Study-related document.docx
2345Ethical approval    Study-related document.pdf
17308Ethical approval    Copy of all HDEC letters of ethic approval from 15... [More Details] Study-related document.pdf
24113Statistical analysis plan    SAP with COVID changes FINAL.docx



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseIVF and IUI in couples with unexplained infertility (FIIX study): Study protocol of a non-inferiority randomized controlled trial.2020https://dx.doi.org/10.1093/HROPEN/HOAA037
N.B. These documents automatically identified may not have been verified by the study sponsor.