Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001666819
Ethics application status
Approved
Date submitted
3/11/2021
Date registered
3/12/2021
Date last updated
3/10/2023
Date data sharing statement initially provided
3/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
NuLIFE study: investigating the effect of uterine copper chloride on endometrial cytokine production in healthy woman
Scientific title
NuLIFE: A prospective placebo-controlled trial investigating the ability of uterine application of a copper chloride containing gel to modulate endometrial cytokine production in healthy woman
Secondary ID [1] 305716 0
IQMV001
Universal Trial Number (UTN)
Trial acronym
NuLIFE study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
infertility
 324183 0
Condition category
Condition code
Reproductive Health and Childbirth 321662 321662 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In the first experimental phase participants receive a single application of the control gel. After a “wash-out” period of one month and one menstrual period, the same participants will receive a single dose of the active trial medication, copper chloride 100 uM (first four participants) or 200 uM (last four participants, if no severe adverse advents have been reported for the use of 100 uM) suspended in gel (ExEm Gel, ARTG identifier 207276) , to the uterine cavity in the late proliferative phase of the menstrual cycle. The gel (both control and CuCl2) will be applied by the PI of the study.
Intervention code [1] 322104 0
Treatment: Drugs
Comparator / control treatment
application of a gel without copper. The participant will first start with the control treatment and after a wash out period, will receive the copper containing gel.
Control group
Placebo

Outcomes
Primary outcome [1] 329438 0
The primary efficacy endpoint is endometrial production of Leukemia Inhibitory Factor (LIF) and Vascular Endothelial Growth Factor (VEGF). This will be assessed by molecular and immunohistochemical means in the endometrial biopsy samples, plus by ELISA in the uterine fluid samples
Timepoint [1] 329438 0
The primary efficacy endpoint: one month after the last treatment
Primary outcome [2] 329439 0
The primary safety endpoint is the number of adverse adverse events documented in accordance with the Common Terminology Criteria for Adverse Events (CTCAE5.0)
Timepoint [2] 329439 0
The primary safety endpoint: two weeks after the last treatment
Secondary outcome [1] 402629 0
Endometrial morphology post gel exposure, presence of uterine fluid, endometrial echotexture and thickness on ultrasound assessment
Timepoint [1] 402629 0
5 days after application of the gel
Secondary outcome [2] 402630 0
Molecular evidence of impaired endometrial function assessed by RT-qPCR using a panel of genes involved in endometrial proliferation
Timepoint [2] 402630 0
5 days after the application of the gel
Secondary outcome [3] 402631 0
Copper concentration in uterine fluid after CuCl2 gel treatment
Timepoint [3] 402631 0
5 days after gel application
Secondary outcome [4] 402632 0
Impact of day 5 luteal phase uterine fluid on mouse embryo development . one-cell embryos are retrieved and cultured in medium with or without the uterine fluid in small groups until day 5.
Timepoint [4] 402632 0
Monitored over a period of 5 days at one month after gel application
Secondary outcome [5] 403349 0
histological evidence of impaired endometrial function , histological assessment looking for adverse endometrial changes
Timepoint [5] 403349 0
5 days after the application of the gel

Eligibility
Key inclusion criteria
• Woman between 18 and 42 years old
• BMI between 19 and 29 kg/m2
• Regular menstrual cycle every 26-32 days
• Normal “baseline” pelvic ultrasound
• Normal pap smear and STD screen
• Written and signed informed consent
Minimum age
18 Years
Maximum age
42 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• inflammatory condition requiring systemic treatments (e.g. corticosteroids, NSAID) or acute infection (virus etc).
• medical contraindications to the combined contraceptive pill (focal migraine, DVT, smoke > 10/day, BP> 135/85, past adverse response COCP)
• known allergy to metals (copper, bronze and nickel especially)
• Past surgery to the cervix (LLETZ, cone biopsy)
• Past difficult embryo transfer, thereby increasing the risk of a difficult or impossible endometrial biopsy.
• Pregnancy or wishing to attempt pregnancy in the next 3 months.
• History of undiagnosed abnormal uterine bleeding or chronic pelvic pain.
• History of significant menstrual pain or heavy bleeding
• Recent abnormal cervical cytology/ high risk HPV screen
• Abnormal renal or liver function tests, inflammatory markers (WCC, CRP) and serum copper/ ceruloplasmin
• Contraindication to the use of copper (Wilsons Disease, allergy copper).
• Unwilling to use barrier contraception or abstain during the study menstrual cycle (in the absence of tubal ligation or partner with vasectomy).

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 0
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Statistical power calculations suggest a sample size of 2 subjects would be adequately powered to detect a 4-fold difference in LIF levels after copper treatment, However, the enrolment is doubled to 4 subjects in order to increase the statistical power in case the observed effect in vivo is less than that observed in vitro. However, we have made a decision to double the enrolment to 4 subjects in order to increase the statistical power in case the observed effect in vivo is less than that observed in vitro. The total sample size is 8 , 4 subjects in the initial phase (control/ 100?M Copper chloride) and 4 subjects in the second arm (control and second dose copper chloride determined by effect in first arm).

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
expiry date study medication
Date of first participant enrolment
Anticipated
4/08/2022
Actual
4/08/2022
Date of last participant enrolment
Anticipated
30/12/2022
Actual
24/03/2023
Date of last data collection
Anticipated
30/03/2023
Actual
9/09/2023
Sample size
Target
12
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 21011 0
Repromed Day Surgery - Dulwich
Recruitment postcode(s) [1] 35846 0
5065 - Dulwich

Funding & Sponsors
Funding source category [1] 310074 0
Commercial sector/Industry
Name [1] 310074 0
NuLIFE BV
Country [1] 310074 0
Netherlands
Primary sponsor type
University
Name
Flinders University
Address
Sturt Road, Bedford Park
South Australia, 5042
Country
Australia
Secondary sponsor category [1] 311127 0
Commercial sector/Industry
Name [1] 311127 0
NuLIFE BV
Address [1] 311127 0
Veerkade 5 F
3016DE Rotterdam
The Netherlands
Country [1] 311127 0
Netherlands

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309765 0
Bellberry Human Research Ethics Committee, Bellberry Limited
Ethics committee address [1] 309765 0
Ethics committee country [1] 309765 0
Australia
Date submitted for ethics approval [1] 309765 0
04/11/2021
Approval date [1] 309765 0
03/02/2022
Ethics approval number [1] 309765 0
2021-11-1285

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

Contacts
Principal investigator
Name 115310 0
Prof Kelton Tremellen
Address 115310 0
Repromed
180 Fullarton Rd, Dulwich SA 5065
Country 115310 0
Australia
Phone 115310 0
+61 8 8333 8113
Fax 115310 0
Email 115310 0
[email protected]
Contact person for public queries
Name 115311 0
Kelton Tremellen
Address 115311 0
Repromed
180 Fullarton Rd, Dulwich SA 5065
Country 115311 0
Australia
Phone 115311 0
+61 8 8333 8113
Fax 115311 0
Email 115311 0
[email protected]
Contact person for scientific queries
Name 115312 0
Kelton Tremellen
Address 115312 0
Repromed
180 Fullarton Rd, Dulwich SA 5065
Country 115312 0
Australia
Phone 115312 0
+61 8 8333 8113
Fax 115312 0
Email 115312 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
No individual data will be available due to privacy reasons


What supporting documents are/will be available?

No Supporting Document Provided



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.