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MASTER study

 

Cost-effectiveness of IUI, IVF and ICSI for male subfertility. MAle Subfertility Treatment Effectiveness Rcts / The MASTER study

 

Go to the MASTER website

 

Objective
In one third of subfertile couples male subfertility is diagnosed. Current treatments for male subfertility, IUI, IVF and ICSI, have, despite their widespread use, not been compared on their cost-effectiveness. The primary aim of this project is to assess the cost-effectiveness of therapies for male subfertility. We hypothesize that less invasive therapies are equally effective as more invasive therapies.

 

Study design
Two multicentre randomized controlled clinical trials with each two treatment arms, i.e. IUI versus no treatment (expectant management) and ICSI versus IVF. As in each comparison the treatment will be more invasive, the inclusion criteria for this study will be based on total motile sperm count, in which in couples with mild male subfertility minimally invasive treatments will be evaluated (i.e. IUI versus expectant management), whereas in couples with severe male subfertility more invasive treatments will be evaluated.

 

Study population
Subfertile couples with male subfertility.
Inclusion criteria:
-  Age female partner 18-42 years
-  Failure to conceive for at least 12 months
-  Male subfertility: Pre-wash TMSC < 10.10^6
-  No major uterine or ovarian abnormalities detected by TVS
-  Couple who start treatment for a first, or first after a succesful pregnancy, cycle
Exclusion criteria:
-  Severe male subfertility: Post-wash TMSC < 300.10^3
-  Female partner with polycystic ovary syndrome or any other anovulation, severe endometriosis, double-sided tubal pathology, endocrinopathological disease (Cushing syndrome, adrenal hyperplasia, hyperprolactinemia, acromegaly, imminent ovarian failure, premature ovarian failure, hypothalamic amenorrhea and diabetes mellitus (type I)


Intervention
RCT 1 (pre-wash TMSC 3-10 million) : 3 cycles of IUI, followed by 3 cycles of IUI-COH. Control: expectant management. Treatment time horizon 6 months.
RCT 2 (pre-wash TMSC < 3 million, post-wash TMSC > 0.3 million): 3 cycles of ICSI, including transfer of cryoembryos. Control: 3 cycles of IVF, including transfer of cryopreserved embryos. Treatment time horizon 12 months.


Outcome measures
Primary outcome: ongoing pregnancy leading to live birth within the treatment time horizon. Ongoing pregnancy is defined as a visible embryonic heartbeat at ultrasound from 12 weeks of gestation onwards.
Secondary outcome: time to pregnancy, defined as the time between randomization and reaching ongoing pregnancy, miscarriage, defined as a non-vital intra-uterine pregnancy before 16 weeks of gestation or ectopic pregnancy, multiple pregnancy, defined as registered heartbeat of at least two fetuses at 12 weeks of gestation onwards and live birth rate are secondary outcomes. Further secondary outcomes are neonatal mortality, pregnancy complications (preterm birth < 37 weeks, birth weight < 2.500 gram, Pregnancy Induced Hypertension (PIH), (pre-) eclampsia, HELLP) costs of reproductive treatments, perinatal care and adverse events. Also patients' quality of life and preferences will serve as secondary outcomes.

 

Power/data analysis
This study will be designed as a superiority trial with respect to ongoing pregnancy leading to a live birth. Analysis will be by intention to treat.
The sample size calculation for RCT 1 (TMSC 3-10 million, IUI vs expectant management) is based on a non-inferiority design. We expect a 25% live birth conceived within 6 months after both IUI and expectant management. With an alpha of 5% and a beta of 20%, 434 couples will be required to exclude a difference of 10% or more to the detriment of expectant management. To account for a 5% loss to follow-up we need to include 458 couples.
The sample size calculation for RCT 2 (TMSC < 3 million, IVF vs ICSI) is based on a superiority design. We assume the ongoing pregnancy rate leading to a live birth after 12 months will be 45% after IVF and ICSI and want to be able to prove an absolute difference of 15%. With a two-sided alpha of 5% and a beta of 20%, 176 couples per group are required. Accounting for 5% loss to follow-up and cross-over, we will  need to include 372 couples in RCT 2, 186 couples per group.
 
Economic evaluation
A cost-effectiveness analysis of ICSI versus IVF, IVF versus IUI and IUI versus expectant management will be performed. The primary outcome measure will be given as the costs per ongoing pregnancy, resulting in live birth. Budget impact analysis will then be performed to estimate the financial impact on national level. In a priori budget impact analysis a possible cost saving of 7 million Euros was estimated at an implementation rate of 80%.

 

Subsidy
ZonMW


Contact (researcher)
Drs. M. Cissen/ Dr. J.P. de Bruin
Jeroen Bosch Ziekenhuis
PO Box 90153
5200 ME 's-Hertogenbosch
Tel: 073-5532444
m.cissen@jbz.nl/ j.d.bruin@jbz.nl