Condition category
Pregnancy and Childbirth
Date applied
08/08/2013
Date assigned
08/08/2013
Last edited
18/11/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Male infertility accounts for almost half of all referrals to the IVF clinic for assisted conception. In many cases, the male sperm are present but are either unable to fertilise his partner's egg or the embryo fails to implant or even miscarries at a later stage. It is possible to inject sperm directly into the egg [Intracytoplasmic Sperm Injection (ICSI)] and for pregnancies to be achieved as a result. Unfortunately, however, although this method is very often successful at fertilising the egg, achieving a viable pregnancy is far less successful. It is estimated that on average, once transferred to his partner's uterus, less than a quarter of all fertilised eggs will implant and develop into a baby to term. Recently, a new method for sperm selection has been developed and initial results suggest it may help pregnancy outcomes. The method relies on selecting sperm by their ability to stick to a naturally occurring substance hyaluronan that is normally found close to the surface of the egg. This material can be coated on to a special plate and if the male sperm is allowed to swim or flow over the material, the 'best' sperm will bind to the coating and can then be easily picked for injection. This study aims to show that replacing the usual sperm selection step with this method can significantly improve the live birth rate. This study also aims to assess other factors including pregnancy rate, live birth rate and pregnancy loss.

Who can participate?
This study aims to recruit 3730 couples undergoing ICSI treatment, aged over 18 years.

What does the study involve?
Couples will be randomly allocated to one of two groups: the intervention group where the specialists will select the sperm using hyaluronan binding for the ICSI procedure; the control group where they will select the sperm using the standard practice. The group to which the couple are allocated to will be decided by a process called randomisation, which is like a coin toss. The study does not involve any additional procedures, we will only collect the treatment outcomes for all participating females. At the end of the study, we will compare the live birth rate in both groups. We will also look at the miscarriage rate and clinical pregnancy rate, which reflects how many treated women with embryo(s) transferred into their womb, proceeded to pregnancy confirmed by detecting a fetal heartbeat or fetal sac.

What are the possible benefits and risks of participating?
There will be no immediate direct benefit to those taking part. This research may, however, in time improve general ICSI treatment and its outcome rates. ICSI is routinely performed and as might be expected from a naturally occurring substance that is present throughout the body, there have been no reported risks with using hyaluronan. Hyaluronan-coated plates are already approved for clinical use for that purpose. It means they went under rigorous testing and no risks to patients using them have been described by the manufacturer. There are no other risks.

Where is the study run from?
This study is run from 16 fertility centres across the UK.

When is study starting and how long is it expected to run for?
It is anticipated that recruitment will start in second half of 2013. The total study recruitment period is expected to last for a minimum of 21 months and then follow up will continue till the last pregnancy outcome is known. We plan to complete the study recruitment in 2016.

Who is funding the study?
Funding has been provided by National Institute for Health Research - Efficacy and Mechanisms Evaluation (NIHR-EME) grant, UK.

Who is the main contact?
Dr David Miller
D.Miller@leeds.ac.uk

Trial website

http://www.habselect.org.uk

Contact information

Type

Scientific

Primary contact

Dr David Miller

ORCID ID

http://orcid.org/0000-0002-1709-108X

Contact details

Reader in Molecular Andrology
Reproduction and Early Development Group
Leeds Institute of Genetics
Health and Therapeutics (LIGHT)
University of Leeds
Institute of Genetics
Health and Therapeutics
Clarendon Way
Leeds
LS2 9JT
United Kingdom
-
D.Miller@leeds.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

14845

Study information

Scientific title

Selection of sperm for Assisted Reproductive Treatment by prior hyaluronic acid binding (HABSelect): increasing live birth outcomes and reducing miscarriage rates – multicentre randomised controlled, blinded trial

Acronym

HABSelect

Study hypothesis

1. We aim to test the hypothesis that the outcome of current standard treatment for Intracytoplasmic Sperm Injection (ICSI) - an important procedure for fertility treatment - can be potentially improved by deployment of a prior sperm selection step using hyaluronan-coated plates (PICSI). The PICSI plates are thought to select more mature and 'better quality' sperm that can bind to its hyaluronan coating. This method may increase the live birth rate and correspondingly decrease miscarriage rate in pregnancies resulting from ICSI treatment.
2. We also hypothesise that hyaluronan-selected sperm have more efficiently packaged chromatin with lower levels of DNA damage that help support normal embryonic development.

CLINICAL OBJECTIVES:
1. Primary
To determine if hyaluronan-selected, Intracytoplasmic Sperm Injection (PICSI) results in more term (37 or above weeks’ gestation ) live birth deliveries in comparison with the current standard treatment (PVP ICSI).
2. Secondary
To determine the impact on:
2.1. increasing clinical pregnancy rate (CPR) based on detection of fetal heartbeat or presence of fetal sac
2.2. reducing miscarriage rate defined as pregnancy loss after confirmation of clinical pregnancy
2.3. increasing pre-term live birth rate (below 37 weeks' long).

MECHANISTIC OBJECTIVES:
1. Primary
To evaluate if PICSI can compensate for poor sperm quality and investigate how sperm binding to hyaluronan (assessed by testing for hyaluronan binding score - HBS) relates to their genetic material and to live birth rate.
To evaluate the differences in chromatin (genetic material) architecture in ICSI- prepared sperm with high and low hyaluronan binding scores (HBS) including any correlation with DNA damage.
2. Secondary
The primary mechanistic evaluation will be extended to selected sperm samples collected from the density gradient (DGC) interface layer of prepared sperm that is not used for the fertility treatment. We wish specifically to determine the relationship between genetic material packaging and the level of its damage in these interface samples with the HBS of the corresponding pellets used for treatment.

Ethics approval

Yorkshire and The Humber REC: Sheffield, 11/06/2013, ref: 13/YH/0162

Study design

Parallel-group two-arm multicentre blinded randomised controlled clinical trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Treatment

Patient information sheet

Currently not available in web format. Please use the contact details below to request for couple information sheet with informed consent form.

Condition

Male-related fertility treatment

Intervention

PICSI - hyaluronan-based sperm selection system has been approved for clinical use but not introduced into wider practice yet.
Hyaluronan is a natural substance in the body and is currently used for different medical and non-medical purposes. It is also found close to the surface of the egg and thought to be involved into process of sperm selection by the egg for subsequent fertilisation.
1. Hyaluronan coated plates (used in the Intervention Group) make use of that hyaluronan property - the coating binds selectively more mature sperm allowing the embryologist or andrologist to easily pick a sperm for injection.
2. The control (non-intervention) group will receive the current standard treatment, where the sperm is visually selected by the embryologist or andrologist.
The participating couples and their clinical team will be blinded to the study allocation as well as research nurses who follow up the pregnancy outcome of participating females. The study will also collect the sperm left (residual) after ICSI treatment. The research team will perform a series of additional tests on these samples looking in more depth at the way genetic material is packaged in the cell and how its damage correlates with the sperms' ability to bind to hyaluronan and to live birth rate. All the tests performed are established techniques used to research DNA structure and damage in sperm cells.

Intervention type

Procedure/Surgery

Phase

Drug names

Primary outcome measures

1. Clinical: Live birth at ≥37 weeks' gestation following the first fresh ICSI treatment
2. Mechanism: HBA score will be recorded on the day of PICSI / PVP-ICSI procedure and DGC washed sperm will be examined, retrospectively for disruption of chromatin architecture and DNA damage

Secondary outcome measures

Clinical:
1. Clinical pregnancy rate based on detection of a fetal heartbeat or the presence of fetal sac at 6-9 weeks' gestation
2. Miscarriage, defined as pregnancy loss after confirmation of clinical pregnancy
3. Live birth <37 weeks' gestation

Mechanism: Chromatin disruption in relation to DNA damage and DNA packaging anomalies in 45:90 interface samples and correlation between clinical and post-clinical HBA scores in relation to initial sperm concentration. The relationship between the tests of chromatin and DNA integrity with live birth outcome and miscarriage will be dynamically assessed by statistical modelling

Overall trial start date

01/07/2013

Overall trial end date

30/09/2017

Reason abandoned

Eligibility

Participant inclusion criteria

Current exclusion criteria as of 13/01/2015:
1. Couples able to provide informed consent.
2. Couples undergoing first fresh ICSI procedure.
3. Women:
3.1. BMI: 19.0 – 35.0 kg/m2
3.2. FSH level 3.0 – 20.0 miU/ml and/or AMH ≥1.5 pmol/L
3.3. Age: 18 to 43
4. Men:
4.1. Age: 18 to 55
4.2. Able to produce freshly ejaculated sperm for the treatment cycle

Previous exclusion criteria:
1. Couples able to provide informed consent.
2. Couples undergoing first fresh ICSI procedure
3. Women :
3.1. BMI: 19.0-30.0 kg/m2
3.2. Hormonal level: Anti-Mullerian Hormone (AMH) level 0.8 , 2.5 ng/ml and/or Follicle-Stimulating Hormone (FSH) level 3 , 10 miU/ml
3.3. Age: 18 to 43
4. Men:
4.1. Age: 18 to 55
4.2. Able to produce freshly ejaculated sperm for the treatment cycle

Target Gender: Male & Female; Upper Age Limit 55 years ; Lower Age Limit 18 years

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 7460; UK Sample Size: 7460 (3730 couples)

Participant exclusion criteria

Current exclusion criteria as of 13/01/2015:
1. Couples who have not consented prior to ICSI will be ineligible
2. Couples using non-ejaculated sperm
3. Couples using donor gametes
4. Men with vasectomy reversal; cancer treatment involving any chemotherapy and/or radiotherapy in the previous two years
5. Previous participation in the HABSelect trial
6. Split IVF/ICSI
7. If both FSH and AMH are tested and either of them falls outside the accepted range

Previous exclusion criteria:
1. Couples using non-ejaculated sperm
2. Couples using donor gametes
3. Men with vasectomy reversal; cancer treatment involving any chemotherapy and/or radiotherapy in the previous two years
4. Previous participation in the HABSelect trial
5. Split IVF/ICSI

Recruitment start date

17/12/2013

Recruitment end date

31/08/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Assisted Conception Centres at http://www.habselect.org.uk/recruitment-sites/index.html
-
United Kingdom

Sponsor information

Organisation

University of Leeds (UK)

Sponsor details

c/o Clare Skinner
Faculty Head of Research and Innovation Support
Medicine and Health
Worsley Building
Leeds
LS2 9NL
United Kingdom

Sponsor type

University/education

Website

http://researchsupport.leeds.ac.uk/index.php/about_us/contacts_whos_who/

Funders

Funder type

Government

Funder name

National Institute of Health Research - Efficacy and Mechanisms Evaluation (NIIHR-EME) Grant: Ref: 11-14-34-Miller

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

The Trial Steering Committee will agree a publication plan and be consulted prior to release or otherwise publish any study data. We anticipate that in addition to the interim final report required by the funder in September 2017 (open access), all outcomes from the study will be submitted for peer review in the appropriate, open access journals. Communications will also be delivered at key international meetings associated with relevant reproductive societies and groupings. Patients and other stakeholders will also be able to obtain information on their arm allocation after accessing a website that will be set up specifically for this purpose. As per the funder’s requirements all materials to be submitted for publication will be sent to the NIHR Coordinating Centre for EME (NCCEMEM) for approval and prior to publication.

All participant-level data will be made available to the scientific community and other interested parties once the database has been closed, cleaned and analysed and steps taken to ensure that all data with respect to patient participation remain confidential and anonymous. The main outcomes of the study reported via the usual peer-reviewed process. On request, patient participants will be able to ask which arm of the study they were in although exactly how we shall implement this service is under discussion.

Intention to publish date

Participant level data

Available on request

Results - basic reporting

Publication summary

2016 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/27855103

Publication citations

Additional files

Editorial Notes

18/11/2016: Publication reference added. 13/05/2016: The overall trial end date was changed from 30/06/2017 to 30/09/2017. 13/01/2015: The overall trial end date was changed from 31/12/2016 to 30/06/2017.