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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] 309059 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pelvic Organ Prolapse 329119 0
Condition category
Condition code
Renal and Urogenital 326091 326091 0 0
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] 325502 0
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] 333956 0
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] 333956 0
1 year post-recruitment
Secondary outcome [1] 418834 0
Quantity of collagen breakdown-products in the urine of surgical cases vs controls, as measured by commercially available ELISA kits
Timepoint [1] 418834 0
2-months post sample collection
Secondary outcome [2] 419113 0
Expression of extracellular proteins in the connective tissue of the anterior vaginal wall, as measured by non-targeted mass-spec.
Timepoint [2] 419113 0
6-months post sample collection
Secondary outcome [3] 419409 0
Quantity of elastic-fibre breakdown-products in the urine of surgical cases vs controls, as measured by commercially available ELISA kits
Timepoint [3] 419409 0
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
20
Final
Recruitment outside Australia
Country [1] 25282 0
New Zealand
State/province [1] 25282 0

Funding & Sponsors
Funding source category [1] 313264 0
University
Name [1] 313264 0
University of Otago
Country [1] 313264 0
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] 315000 0
None
Name [1] 315000 0
Address [1] 315000 0
Country [1] 315000 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312494 0
Central Health and Disability Ethics Committee New Zealand
Ethics committee address [1] 312494 0
Ethics committee country [1] 312494 0
New Zealand
Date submitted for ethics approval [1] 312494 0
23/09/2022
Approval date [1] 312494 0
13/12/2022
Ethics approval number [1] 312494 0
2022 EXP 13191

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124862 0
Dr Emma Wade
Address 124862 0
Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
258 Great King Street
Dunedin
9016
Country 124862 0
New Zealand
Phone 124862 0
+64 34797469
Fax 124862 0
Email 124862 0
[email protected]
Contact person for public queries
Name 124863 0
Emma Wade
Address 124863 0
Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
258 Great King Street
Dunedin
9016
Country 124863 0
New Zealand
Phone 124863 0
+64 34797469
Fax 124863 0
Email 124863 0
[email protected]
Contact person for scientific queries
Name 124864 0
Emma Wade
Address 124864 0
Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
258 Great King Street
Dunedin
9016
Country 124864 0
New Zealand
Phone 124864 0
+64 34797469
Fax 124864 0
Email 124864 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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.TypeCitationLinkEmailOther DetailsAttachment
18413Study protocol    385451-(Uploaded-22-02-2023-11-22-14)-Study-related document.docx
18414Informed consent form    385451-(Uploaded-22-02-2023-11-22-27)-Study-related document.docx
18415Ethical 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.