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Trial registered on ANZCTR


Registration number
ACTRN12623000675628
Ethics application status
Approved
Date submitted
19/04/2023
Date registered
22/06/2023
Date last updated
27/10/2023
Date data sharing statement initially provided
22/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
The Womens wellness through Intrauterine Neuroimmune modulation study: The effect of a new intrauterine device on pelvic pain in women.
Scientific title
A Phase 1B, single-centre, Initial Group, randomised, double-blind, parallel-group study to investigate the tolerability and pharmacokinetics of the new Alyra Device (IUD) compared with the commonly used Mirena'Trademark' Device.
Secondary ID [1] 308130 0
Sponsor Protocol Number: AB-WIN-001

Sponsor: Alyra Biotech Pty Ltd
Universal Trial Number (UTN)
U1111-1285-1039
Trial acronym
WIN study
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Pelvic Pain 327846 0
Dysmenorrhoea 327847 0
Reproductive Health and Childbirth 330430 0
Condition category
Condition code
Reproductive Health and Childbirth 324924 324924 0 0
Menstruation and menopause
Reproductive Health and Childbirth 327272 327272 0 0
Contraception

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The Alyra intrauterine device – contains ~37mg of levonorgestrel releasing approximately 9.6 micrograms per 24 hours and ~27 mg of amitriptyline releasing approximately 0.35 mg per 24 hours. The device will be inserted by a specialist Gynaecologist highly experienced in the placement of IUDs in the general population. The Alyra intrauterine device is placed in exactly the same way, and by the same procedures and practices, as that with a standard Mirena 'Trademark' device. Only study approved Gynaecologists are able to place the Alyra device. The total duration of IUD placement is 84 days (~ 3 months). Throughout the duration of the study, you will attend onsite visits for frequent safety and monitoring checks. These checks will ensure that the device is positioned correctly and are designed to answer any queries that you may have as the study arises. You will also be given a participant information card containing the contact details of your study Gynaecologists, should you need to contact them at any time in regard to your study IUD. Following insertion of the device, participants will complete a daily study specific APP to monitor their experiences of the device.
Intervention code [1] 324590 0
Prevention
Intervention code [2] 324591 0
Treatment: Devices
Intervention code [3] 324592 0
Treatment: Drugs
Comparator / control treatment
This study will investigate the in-vivo pharmacokinetics of the Alyra device compared with the currently approved TGA standard Mirena IUD as a market comparator, and provide initial safety data for the Alyra device. The Mirena device releases levonorgestrel (a progesterone hormone) as a component of the contraceptive method. In this device levonorgestrel is released at 20 micrograms into the uterine cavity per 24 hours following insertion. Following insertion of the Alyra or Mirena devices, participants will complete a daily study specific APP to monitor their experiences of the device. As this device is the comparator, it will also be monitored for the drug release rate levels of levonorgestrel, over 84 days (~ a 3 month period).

Control group
Active

Outcomes
Primary outcome [1] 332744 0
Among participants with pre-existing dysmenorrhea-related pelvic pain, the objectives of this study are as follows: To confirm that blood assays for amitriptyline and levonorgestrel are sufficiently sensitive to guide further pharmacokinetics investigations
Timepoint [1] 332744 0
PK samples will be collected and compared at 3, 6, 9, and 12 hours post-insertion, then daily for 7 days, then again on day 14, 28, 56 and 84, after intervention commencement. PK samples of amitriptyline and levonorgestrel will be collected as whole blood samples however they will be analysed as plasma concentrations. Parameters to be examined are: Cmax, tmax, AUC0-last, Cav.
Primary outcome [2] 332933 0
To investigate the tolerability of the Alyra Device when compared with the Mirena 'Trademark' Device
Timepoint [2] 332933 0
At device removal on day 84 the following will be compared:
- number of days of pelvic pain reported per 28-day time periods post device insertion.
- average daily severity of pelvic pain (derived from days when pain was reported) for each of the three 28-day time periods post insertion.
- number of days of uterine bleeding/spotting per 28-day time periods post insertion.
- pelvic pain AUC28day for each of the three 28-day time periods post insertion.
Secondary outcome [1] 415200 0
To compare the release of amitriptyline and levonorgestrel from the Alyra Device and the Mirena 'Trademark' Device by measuring the amount of amitriptyline and levonorgestrel left in the devices after removal at completion of the study.
Timepoint [1] 415200 0
At device removal on day 84. THF extraction to be carried out on remaining amitriptyline, nortriptyline and levonorgestrel concentrations present in study devices at study end.
Secondary outcome [2] 428275 0
To investigate the effect of the Alyra Device on the endometrium using endometrial biopsies
Timepoint [2] 428275 0
Endometrial biopsies will be compared from baseline, to device removal day and then to one menstrual cycle post device removal.

Eligibility
Key inclusion criteria
*Is in good general health.
*Agrees to have an IUD for ~84 days.
*Agrees to take oral temperature recordings.
*Has a history of regular menstrual cycles (i.e. every 21-35 days).
*Has a uterus with no significant abnormalities.
*Has a minimum of one vaginal birth
*Agrees to record their symptoms daily and use of medications on a study specific APP.
*Does not plan to become pregnant during their study involvement.
Minimum age
18 Years
Maximum age
45 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
*Know sensitivity, intolerance, or allergy to non-steroidal anti-inflammatory drugs, paracetamol, ibuprofen, levonorgestrel, amitriptyline, or any components of the intrauterine device.
*Has a positive urine drug screen.
*Has a significant gynaecological condition.
*Has undergone a hysterectomy or oophorectomy.
*Has recurrent or current pelvic infections.
*Has severe arterial disease.
*Has uncontrolled epilepsy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e., computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
For each individual participant, one gynaecologist will insert the device and another gynaecologist will care for the participant post insertion and assess outcomes.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Statistical planning has been undertaken in consultation with Dr Elisa Young from Accelagen.

Pharmacokinetics participants:
Plasma amitriptyline, nortriptyline and levonorgestrel parameters to be analysed as: Cmax, tmax, AUC0-last, Cav.

Pharmacokinetics devices:
THF extraction of remaining amitriptyline, nortriptyline and levonorgestrel present in study devices at study end.

Participant Tolerability Outcomes:
Mixed model for repeated measure (MMRM) analyses to compare the change from baseline over the treatment period between the two treatment groups for the following:
- number of days of pelvic pain reported per 28-day time periods post device insertion at 4, 8. and 12 weeks.
- average daily severity of pelvic pain (derived from days when pain was reported) for each of the three 28-day time periods post insertion.
- number of days of uterine bleeding/spotting per 28 days time periods post insertion.
- pelvic pain AUC28day for each of the three 28-day time periods post insertion.
The model for each parameter will include treatment, time (4,8 and 12 weeks) and an interaction between treatment and time, as fixed effects baseline values as a covariate and subject as a random effect. Treatment differences will be estimated using least square means difference and 95% two-sided confidence intervals. The treatment effect will be estimated for each timepoints as well as the overall study period, with the same weight applied to the treatment effects for each timepoints.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
11/09/2023
Actual
Date of last participant enrolment
Anticipated
28/06/2024
Actual
Date of last data collection
Anticipated
30/09/2024
Actual
Sample size
Target
12
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 23465 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 38865 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 312387 0
Commercial sector/Industry
Name [1] 312387 0
CUREator Grant Funding
Country [1] 312387 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Alyra Biotech Pty Ltd
Address
5 Hauteville Terrace
Eastwood
Adelaide, 5063
Country
Australia
Secondary sponsor category [1] 313959 0
None
Name [1] 313959 0
Address [1] 313959 0
Country [1] 313959 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311744 0
Central Adelaide Local Health Network Inc.
Ethics committee address [1] 311744 0
SA Health, Level 3 Roma Mitchell Building
136 North Terrace, Adelaide
South Australia, 5000
Ethics committee country [1] 311744 0
Australia
Date submitted for ethics approval [1] 311744 0
24/10/2022
Approval date [1] 311744 0
17/02/2023
Ethics approval number [1] 311744 0
2022/HRE00231

Summary
Brief summary
Alyra Biotech Pty Ltd is an Australian-owned biopharma company that wishes to develop an optimal intrauterine contraceptive device (IUD) for people with period or pelvic pain. The use of IUDs globally is increasing, however some people experience increased pelvic pain in the 3-6 months following insertion, causing them to have the device removed. They then miss out on the benefits that IUDs can provide, such as; reducing your lifetime exposure to synthetic hormones; decreasing the amount of blood loss at each period; as well as decreasing intense period pain, over time with continual use.

Alyra Biotech Pty Ltd has developed and patented a novel IUD designed to reduce the severity of post-insertion pain in those that experience it, giving them access to the benefits of IUD use.

The objectives of this study are:
1. To determine how the device performs at releasing the appropriate medicinal drugs (pharmacokinetics).
2. To compare the tolerability of the new Alyra device with the currently approved for use in Australia, the Mirena 'Trademark" device.
3. To determine how much of the medicinal drugs are remaining in the device at study end.
4. To determine the effects of the Alyra Device on the endometrium using endometrial biopsies.
Trial website
https://www.alyrabiotech.com/join-our-clinical-trial/
Trial related presentations / publications
Public notes
Alyra Biotech has developed a novel IUD that provides sustained release of the TLR4 inhibitor, amitriptyline, to modulate immune activation within the uterus to reduce pelvic pain in women. (those who have pelvic pain experience increased activation). It is thought that by adding a small amount of amitriptyline directly to an IUD, that there may be reduced pain experienced after the device is inserted. It is also thought that as the dose of amitriptyline released to the body each day will be low, so that fewer people will experience the side effects usually seen when given an oral dose. The dose of amitriptyline released from the Alyra Device each day is estimated to be between 0.3 and 1.0mg per day. Taken orally for pain relief, the prescribed dose would usually be between 10 and 100 mg per day. As standard IUDs use levonorgestrel (a progesterone hormone as a contraceptive method), the Alyra Device will also release levonorgestrel. A study APP will be used by participants to gain frequent insight into their experiences using the device. As this device is new, this study will be used to test the drug release rates (of both amitriptyline and levonorgestrel) into the user for a period of 84 days (3 months), as well measuring the amount that is left over in the device after device removal at 84 days.


Phase 1B Initial (Adelaide) entry to study survey link:

https://www.surveymonkey.com/r/8FH5WYC

Contacts
Principal investigator
Name 122218 0
Prof Louise Hull
Address 122218 0
PARC Clinical Research
Level 4C, Royal Adelaide Hospital
Port Road, Adelaide, South Australia, 5000
Country 122218 0
Australia
Phone 122218 0
+61 403 993 312
Fax 122218 0
Email 122218 0
[email protected]
Contact person for public queries
Name 122219 0
Rachael Tippett
Address 122219 0
Assoc Prof Susan Evans
Alyra Biotech Pty Ltd
5 Hauteville Terrace
Eastwood, Adelaide, South Australia, 5063
Country 122219 0
Australia
Phone 122219 0
+61 414 334 583
Fax 122219 0
Email 122219 0
[email protected]
Contact person for scientific queries
Name 122220 0
Louise Hull
Address 122220 0
PARC Clinical Research
Level 4C, Royal Adelaide Hospital
Port Road, Adelaide, South Australia, 5000
Country 122220 0
Australia
Phone 122220 0
+61 403 993 312
Fax 122220 0
Email 122220 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
The study is sponsored research and the privacy of the product must be maintained.


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.