ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12623000279628

Ethics application status

Approved

Date submitted

22/02/2023

Date registered

15/03/2023

Date last updated

23/02/2024

Date data sharing statement initially provided

15/03/2023

Type of registration

Prospectively registered

Titles & IDs

Public title

Genetic predisposition in women with pelvic organ prolapse

Scientific title

Genetic and Biochemical Predictors of Pelvic Organ Prolapse

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Pelvic Organ Prolapse

Condition category

Condition code

Renal and Urogenital

Other renal and urogenital disorders

Intervention/exposure

Study type

Observational

Patient registry

False

Target follow-up duration

Target follow-up type

Description of intervention(s) / exposure

The goal of this study is to look for genetic variation in a cohort of New Zealand women with a severe pelvic organ prolapse phenotype. This is defined as pre-menopausal women (<55) with a prolapse score of 3 or 4 as defined by the POP-Q scale. This defined group of women may have a genetic cause underlying their prolapse. In this study, a gene-collapsing burden analysis of genetic variation in a defined set of genes will be performed in the experimental group as compared to the control group (pre-menopausal women, para greater or equal to 1, POP-Q score 0 or 1).
Recruitment will be ongoing over a 10 year period. This length of time is necessary to recruit an appropriately sized cohort. There are two parts to this study:
1. Surgical study: Women undergoing surgical repair of a pelvic organ prolapse will have a blood, urine and tissue sample collected alongside their surgery. They will have their genome sequenced, and the biochemistry and proteins of the urine and tissue will be analysed. The results of this analysis will be compared to the results of a control group of women who are undergoing surgical repair of an abdominal hysterectomy.
Participants recruited into this arm of the study will give one blood sample, one urine sample and one tissue sample (5 mm punch biopsy of anterior vaginal) at the time of their surgery. No follow up with participants is required post-surgery but their data will be returned to them at their request.
2. Genome-only study: Women with prolapse will be identified in the primary care setting and have only a blood sample taken and a genome sequencing performed. The results of this analysis will be compared to results from a second control group of women without prolapse identified in the primary care setting.
In this arm of the study, participants will provide one blood sample only. No follow up with participants is required but their data will be returned to them at their request.

Intervention code [1]

Early Detection / Screening

Comparator / control treatment

Control group:
- Women (including all people with female reproductive anatomy [but no history of male hormone therapy]) between 30 and 55
- Para 1 or higher (pregnancy carried to at least 24 weeks)
- POP-Q grade 0 or 1
- No first degree relatives that fit into the prolapse group
- All women who are participating as controls will give a blood sample: this will be taken during surgery for the surgical group or at a contracted phlebotomy site for the genome-only study.
- For the surgical study ONLY: women must be scheduled to undergo an abdominal hysterectomy. they will give a tissue sample and a urine sample during surgery.

Control group

Active

Outcomes

Primary outcome [1]

The proportion of participants (cases vs controls) with gene-altering, rare variants in genes relevant to pelvic floor connective tissue (identified in the surgical study) as analysed by whole genome sequencing of whole-blood DNA

Timepoint [1]

1 year post-recruitment

Secondary outcome [1]

Quantity of collagen breakdown-products in the urine of surgical cases vs controls, as measured by commercially available ELISA kits

Timepoint [1]

2-months post sample collection

Secondary outcome [2]

Expression of extracellular proteins in the connective tissue of the anterior vaginal wall, as measured by non-targeted mass-spec.

Timepoint [2]

6-months post sample collection

Secondary outcome [3]

Quantity of elastic-fibre breakdown-products in the urine of surgical cases vs controls, as measured by commercially available ELISA kits

Timepoint [3]

2 months post-sample collection

Eligibility

Key inclusion criteria

All participants (surgical and genome-only study):
1. Aged between 18 and 55
2. Women (including all people with female reproductive anatomy [but no history of male hormone therapy])
3. Able to give informed consent for participation

Prolapse group for both studies:
1. A previously or currently diagnosed POP-Q grade 3 or 4 pelvic organ prolapse

Surgical prolapse group:
1. Undergoing planned pelvic prolapse repair surgery

Surgical control group:
1. Undergoing a planned abdominal hysterectomy.

No further specific, inclusion criteria for the genome-only study

Minimum age

18 Years

Maximum age

55 Years

Sex

Females

Can healthy volunteers participate?

Yes

Key exclusion criteria

All participants:
1. Diagnosed primary genetic disorder affecting connective tissue or a secondary disorder that affects connective tissue such as autoimmune diseases

Control group for both surgical and genome-only studies:
1. First degree relative with a previously or currently diagnosed (prior to age 55) POP-Q grade 3 or 4 pelvic organ prolapse
2. Para 0

Surgical group (both prolapse and controls)
1. Taking anti-coagulant medications
2. Any medical condition that, in the assessment of the operating surgeon, contraindicates taking a tissue biopsy

Study design

Purpose

Screening

Duration

Cross-sectional

Selection

Case control

Timing

Both

Statistical methods / analysis

Over 10 years, we aim to recruit 500 women (250 cases and 250 controls) to the surgical study, and a further 700 (350 cases and 350 controls) to the genetics arm of the study only.

Biomarkers of connective tissue and connective tissue breakdown will be analysed in the urine and tissue biopsies from women participating in the surgical study. Briefly, a sample of urine will be collected from study participants, and analysed for the quantification of hydroxyproline (marker of collagen degradation) and of desmosine (marker of mature elastin degradation). The two biomarkers of interest will be quantified via enzyme-linked immunosorbent assay (ELISA) using commercially available kits. Also, anterior vaginal wall tissue will be processed for mass spectrometry to quantify the extracellular (EC) proteins. Protein quantification will be undertaken to identify ~80 proteins in the samples. Data will be processed using Proteome Discoverer software, by searching against the SWISS-PROT amino acid sequence database for protein identification. A comparative analysis of protein abundance will be undertaken between cases and controls, using unpaired t-tests with Bonferroni correction to find statistical differences.

For all study participants, genome sequencing will be performed by AgResearch (New Zealand). Quality checked, raw genome sequence will be returned to the researchers via secure server. Genomes will be analysed for the presence of rare, protein coding variants in genes of interest using a gene-collapsing burden analysis. The software package SKAT-O will be used to statistically compare the gene-based burden, and single-variant associations between cases and controls.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

11/04/2023

Actual

3/04/2023

Date of last participant enrolment

Anticipated

11/03/2032

Actual

Date of last data collection

Anticipated

11/02/2033

Actual

Sample size

Target

1200

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Otago

Address [1]

DSM Dean's Department
Dunedin Hospital, 2nd Floor
Great King Street
Dunedin, 9016

Country [1]

New Zealand

Primary sponsor type

University

Name

University of Otago

Address

University of Otago
362 Leith Street, Dunedin North, Dunedin 9016

Country

New Zealand

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Health and Disability Ethics Committee New Zealand

Ethics committee address [1]

Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

23/09/2022

Approval date [1]

13/12/2022

Ethics approval number [1]

2022 EXP 13191

Summary

Brief summary

The purpose of the study is to discover if certain types of variation in a person’s genes can influence whether or not they experience a pelvic organ prolapse (POP). We want to understand if your genes can change the composition of the supportive pelvic floor tissue and make it more likely that you will experience a prolapse.

Our hypothesis is that women who experience a pelvic organ prolapse before the menopause are more likely to have changes in the genes that contribute to the make-up of the pelvic floor connective tissue. We hypothesise that by specifically looking at the genes that are critical to pelvic floor connective tissue, we will more easily find this rare, genetic variation.

The study involves laboratory testing on tissue(s) removed from the body including blood, urine and a tissue biopsy in some cases. The study does not affect care or healing in any way. 

The new knowledge gained will help scientists and doctors better understand if women are predisposed to pelvic organ prolapse based on their genetics. This could allow future research to discover new treatments or to target particular women for preventative care.

This study is funded by the University of Otago. The study is approved by a research ethics committee to ensure the safety of those in the study. 

The results of the study may be published or presented in scientific journals or at conferences. No information will be disclosed that could cause you to be identified. Portions of the information collected may be used in a thesis used for the purposes of gaining a research qualification by a student researcher. Individuals will not be able to be identified from any of this information

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Emma Wade

Address

Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
258 Great King Street
Dunedin
9016

Country

New Zealand

Phone

+64 34797469

Fax

emma.wade@otago.ac.nz

Contact person for public queries

Name

Emma Wade

Address

Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
258 Great King Street
Dunedin
9016

Country

New Zealand

Phone

+64 34797469

Fax

emma.wade@otago.ac.nz

Contact person for scientific queries

Name

Emma Wade

Address

Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
258 Great King Street
Dunedin
9016

Country

New Zealand

Phone

+64 34797469

Fax

emma.wade@otago.ac.nz

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

This is a large study where data will be combined and presented as cases versus controls instead of individual by individual. Furthermore, the data generated is sensitive, genomic data which belongs to the individual being sequenced.

What supporting documents are/will be available?

Doc. No.	Type	Attachment
18413	Study protocol	385451-(Uploaded-22-02-2023-11-22-14)-Study-related document.docx
18414	Informed consent form	385451-(Uploaded-22-02-2023-11-22-27)-Study-related document.docx
18415	Ethical approval	385451-(Uploaded-22-02-2023-11-22-33)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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