Full title: Selection of sperm for Assisted Reproductive Treatment by prior hyaluronic acid binding: increasing live birth outcomes and reducing miscarriage rates – multicentre randomised controlled, blinded trial
Research Funder: NIHR - Efficacy and Mechanism Evaluation Programme (EME)
Research status: Recruiting
HABSelect study is a collaboration between University of Leeds (UK) and its partners supported by Pragmatic Clinical Trials Unit, Queen Mary University of London (UK).
Male infertility accounts for almost half of all referrals to the IVF clinics for assisted conception. In many cases, the man's sperm are present but are either unable to fertilise his partner's egg or the embryo fails to implant or miscarries at a later stage. There are numerous reasons why these outcomes might occur, but providing the sperm are viable, it is possible to inject it directly into the egg and for pregnancies to be achieved as a result. Unfortunately, however, although this method is often successful at fertilising the egg, achieving a viable pregnancy is far less successful. It is estimated that once transferred to his partner's uterus, less than a quarter of all fertilised eggs will implant and develop to term. All the indicators are that the sperm was somehow dysfunctional, so choosing the best sperm for injection is clearly still an issue that remains unresolved. Recently, a method has been developed that preliminary tests suggest can greatly improve pregnancy outcomes. The method relies on only the 'best' sperms' ability to stick to the hyaluronan matrix that is normally found near the surface of the egg. Hyaluronan can be persuaded to coat the surface of a laboratory plate and if the man's sperm is allowed to swim or flow over that surface, the 'best' of them will stick to it allowing the embryologist or andrologist (who are the laboratory operators) to select it for injection. Scientists are not sure why the 'better' sperm selected this way appear to work or indeed what it is about these sperm that makes them the 'best' of the bunch. The purpose of this research is therefore twofold.
Firstly, we hope to introduce the method into clinics to confirm that it can indeed improve pregnancy and live birth success rates for couples where the male factor is the cause of fertility problems by reducing implantation failure and miscarriages.
Secondly, we want to find more about what makes these 'best' sperm different from the others and determine whether the difference is in their DNA or rather the way their DNA is packaged in the cell, which could be both genetic and environmental in origin. If the latter, then changes in lifestyle could potentially improve the couples' chance of achieving a pregnancy successfully
Chief Investigator & Lead Laboratory Investigator:
Dr David Miller, BSc, PhD, PGCE, Reader in Molecular Andrology Leeds Institute of Genetics and Health Therapeutics (LIGHT), University of Leeds
Dr Yacoub Khalaf (and PI for the site) – Guy's and St Thomas Hospital
Prof Arri Coomarasamy – MBChB, MRCOG,MD, Clinical Reader in Reproductive Medicine and Gynaecology, Consultant Gynaecologist, Birmingham Women Hospital;
Prof Siladitya Bhattacharya (and PI for the site) – Aberdeen Maternity Hospital
Dr Vinay Sharma MBBS, DCh, PhD, FRCOG, Consultant in Gynaecology and Reproductive Medicine,The Leeds Centre for Reproductive Medicine, Seacroft Hospital, Leeds Teaching Hospitals NHS Trust
Dr Yacoub Khalaf, MBBCh, MSc, FRCOG, MFFP, Consultant in Gynaecology and Reproductive Medicine, The Assisted Conception Unit, Guy's Hospital, Guy's and St Thomas NHS Foundation Trust
Bonnie Collins, Lead Embryologist and Laboratory Manager Centre for Reproductive Medicine, St Bartholomew's Hospital, Barts and The London NHS Trust
Prof Daniel Brison, PhD, FRCPath, Honorary Professor of Clinical Embryology and Stem Cell Biology The Department of Reproductive Medicine, Old St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust
Dr Jackson Kirkman-Brown, PhD, MBE, Reader in Human Reproductive Science Birmingham Women Fertility Centre, Birmingham Women Hospital, Birmingham Women's NHS Foundation Trust
Dr Allan Pacey BSc, PhD, Senior Lecturer in Andrology Assisted Conception Unit, Jessop Wing, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust
Prof Nicholas Macklon, MBChB, MD, FRCOG, Professor of Obstetrics and Gynaecology Complete Fertility Centre Southampton, Princess Ann Hospital, Southampton University Hospitals NHS Trust
Dr Katherine Whalley, BSc, PhD, Lead Embryologist, Assisted Conception Unit, Ninewells Hospital, NHS Tayside
Prof Siladitya Bhattacharya, MBBS, MD, FRCOG, Professor of Reproductive Medicine and Fertility Aberdeen Fertility Centre, Aberdeen Maternity Hospital, NHS Grampian
Central Research Team:
Dr David Miller – Chief Investigator and Laboratory Lead, Leeds
Dr Jackson Kirkman – Brown – Laboratory Co-Lead, Birmingham
Dr Sue Pavitt – Trial Design & Operations, Leeds
Prof Robert West – Senior Trial Statistician (mechanistic side), Leeds
Coordinating Centre: Pragmatic Clinical Trials Unit (PCTU), Queen Mary University of London
Karolina Witt – Trial Coordinator
Richard Hooper – Senior Trial Statistician (clinical side)
Miland Joshi – Trial Statistician
Sandy Smith - Data Manager
Tom Power – Trial Database Developer
Anitha Manivannan – Quality Assurance Manager
Amy Hoon - Trial Monitor
Ms Karolina Witt – Trial Coordinator Pragmatic Clinical Trials Unit, Yvonne Carter Building, 58 Turner Street, Whitechapel, E1 2AB
Phone: 0207 882 2526
Study Design: The HABSelect study is a multicentre, prospective randomised controlled, parallel-group trial of PICSI (hyaluronan binding) versus PVP-ICSI procedures for the treatment of male infertility
Setting: at least 10 HFEA-registered Fertility Centres, which perform IVF-ICSI procedures across UK
Study Main Objectives:
To determine efficacy of hyaluronan –selected ICSI versus standard ICSI in a randomised controlled trial where the primary
outcome will be live birth rate ≥ 37 weeks' gestation after ICSI procedure with first fresh embryo transfer. We will also determine impact of the intervention on live birth rate < 37 weeks' gestation, clinical pregnancy and miscarriage rate.
To evaluate if PICSI can compensate for poor sperm quality; evaluate differences in genetic material integrity in sperm with different hyaluronan – binding score including any correlation with DNA damage.
Sample size: 3730 couples undergoing ICSI procedure recruited over the period of 21 months.
1) Inclusion criteria for randomisation
- Couples able to provide informed consent
- Couples undergoing ICSI procedure
- BMI: 19.0-30.0 kg/m2
- AMH level 0.8 – 2.5 ng/ml (5.7 – 17.9 pmol/l ) and/or FSH level 3 – 10 miU/ml
- Age: 18 – 43
- Age: 18-55
- Able to produce freshly ejaculated sperm for the treatment cycle
2) Exclusion criteria for randomisation
- Couples who have not consented prior to ICSI willbe ineligible.
- Couples using non-ejaculated sperm.
- Couples using donor gametes.
- Men with vasectomy reversal; cancer treatment involving any chemotherapy and/or radiotherapy in the past two years.
- Previous participation in the HABSelect trial.
- Split IVF/ICSI procedures.
Study start and anticipated finish: 01st July 2013 – 31st December 2016
Intervention: The clinical trial will involve approaching and consenting to the study couple who were referred by their GP to Fertility Centre and who, based on the performed semen assessment, were recommended ICSI (Intra-Cytoplasmic Sperm Injection) procedure as the most recommended form of fertility treatment.
All participating couples, after providing written informed consent, will be randomised on an equal basis to either receive interventional (hyaluronan-based ICSI or PICSI) or control procedure (standard ICSI). The couple will not know which procedure they were allocated to (it is a process called 'blinding').
For the study protocol, fresh semen will be obtained on the day of ICSI at each centre and an adequate proportion taken for treatment purposes and to determine the samples' hyaluronan binding score (HBS). The remainder of the semen sample will be aliquoted, frozen and stored locally until transferred to those centres undertaking the mechanistic (laboratory) investigations. The
mechanistic study will analyse the patients' sperm for DNA fragmentation index (Belfast), chromatin compaction status and nuclear integrity (Leeds and Sheffield) and cytology index (Birmingham).
There are no additional study procedures once PICSI/ ICSI are performed; however, participating couples will be followed for up to 42 weeks to fully determine pregnancy outcome including live birth rate (LBR), clinical pregnancy rate (CPR) and miscarriage rate.
Outcomes: The collection of pregnancy outcomes is mandatory for IVF clinics as per HFEA Code of Practice and HABSelect will make use of these data once collected.
Project Milestones: We anticipate starting recruitment 01st October 2013; it will last till the end of June 2015 and the follow-up of participants will end in July 2016. Data analysis, report writing and dissemination of findings will last till the end of 2016. The total length of the study will be therefore 42 months.