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Trial registered on ANZCTR


Registration number
ACTRN12624001210561p
Ethics application status
Submitted, not yet approved
Date submitted
12/09/2024
Date registered
2/10/2024
Date last updated
2/10/2024
Date data sharing statement initially provided
2/10/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised, double-blinded, placebo-controlled trial assessing the efficacy of Mi-Gel® in the treatment of women with vulval pain / entry dyspareunia.
Scientific title
Randomised, double-blinded, placebo-controlled trial assessing the efficacy of Mi-Gel® in the treatment of women with vulval pain / entry dyspareunia.
Secondary ID [1] 312954 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record
ACTRN12619001163190 was a phase II study using the same investigational product. This study is the phase III study to illustrate efficacy.

Health condition
Health condition(s) or problem(s) studied:
Entry dyspareunia 335126 0
Vulval pain 335127 0
Condition category
Condition code
Renal and Urogenital 331627 331627 0 0
Normal development and function of male and female renal and urogenital system
Neurological 331691 331691 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1 - Mi-Gel, contains amitriptyline 5 mg/g (0.5% w/w) and estriol 0.3 mg/g (0.03% w/w)] in a topical gel formulation.

Dose of 0.5mL applied twice daily, topically, to vulva for 12 weeks.

The product is shipped directly to patient from a GMP manufacturing facility and is weighed prior to sending. A return package will enable the patient to return the tubes back to the depot after 12 weeks of use for weighing and compliance calculation.
Intervention code [1] 329488 0
Treatment: Drugs
Comparator / control treatment
Arm 2 - placebo gel as a base formulation without any active ingredients (amitriptyline or estriol) comprised of lecithin, isopropyl palmitate, propylene glycol, sorbic acid and poloxamer 407
Control group
Placebo

Outcomes
Primary outcome [1] 339359 0
change from baseline in the monthly pain scores at Week 12 (End of Treatment) compared between the investigational product and the placebo.
Timepoint [1] 339359 0
The NRS is conducted at baseline (pre-treatment), week 4, week 8 and finally at week 12 post commencement of treatment (primary endpoint).
Secondary outcome [1] 439648 0
1. Responder rate: Participants with a 30% or more reduction from baseline in NRS scores for vulval pain will be defined as responders.
Timepoint [1] 439648 0
Responder rate will be evaluated at week 12 post-commencement of treatment. The rate will be calculated for both arm 1 (active) and arm 2 (placebo) and a comparison will be assessed.
Secondary outcome [2] 439649 0
2. Change from baseline at Week 12 (End of Treatment) in Vulval Pain scores compared between the investigational product and the placebo. Questionnaires will be administered at baseline (pre-treatment) week 4, week 8, and week 12 (post treatment commencement)
Timepoint [2] 439649 0
Questionnaires will be administered at baseline (pre-treatment) week 4, week 8, and week 12 (post treatment commencement)
Secondary outcome [3] 439650 0
3. Change from baseline at Week 12 (End of Treatment) in Vulval Pain scores relating to sexual health, compared between the investigational product and the placebo. Questionnaires will be administered at baseline (pre-treatment) week 4, week 8, and week 12 (post treatment commencement)
Timepoint [3] 439650 0
Questionnaires will be administered at baseline (pre-treatment) week 4, week 8, and week 12 (post treatment commencement)
Secondary outcome [4] 439841 0
4. Change from baseline at Week 12 (End of Treatment) in Bladder function scores compared between the investigational product and the placebo. Questionnaires will be administered at baseline (pre-treatment) week 4, week 8, and week 12 (post treatment commencement)
Timepoint [4] 439841 0
Questionnaires will be administered at baseline (pre-treatment) week 4, week 8, and week 12 (post treatment commencement)
Secondary outcome [5] 440086 0
5. Change from baseline at Week 12 (End of Treatment) in Quality of life scores compared between the investigational product and the placebo. Questionnaires will be administered at baseline (pre-treatment) and week 12 (post treatment commencement)
Timepoint [5] 440086 0
Questionnaires will be administered at baseline (pre-treatment) and week 12 (post treatment commencement)

Eligibility
Key inclusion criteria
1. Female sex recorded at birth.
2. Aged 30 years or over at consent.
3. Vulval pain /entry dyspareunia diagnosis of at least 3 months at time of consent.
4. Have been pregnant and delivered one or more babies.
5. Willing to apply cream/gel to the vulva twice daily for the 12 week treatment period.
6. Experiencing either:
a: Grade 2 or 3 Entry Dyspareunia based on the Marinoff Entry Dyspareunia Classification Scale OR
b: Grade 1 Entry Dyspareunia based on the Marinoff Entry Dyspareunia Classification Scale AND
• Experiencing pain at the level of the vulva (NRS at screening of greater than or equal to 4)
• Experiencing pain with penetration or attempted penetration (finger, penis or instrument) into the vaginal entry (NRS at screening of greater than or equal to 4)
7. Normal genital physical examination by a registered health practitioner in the past 90 days.
8. Willing to treat mild thrush, if present at screening and any occurrence during the treatment period with oral medication (fluconazole).
9. Willing and able to use a smartphone for regular study data collection (questionnaires) for the duration of the study.
10. Capable of providing consent (understand English and have the cognitive ability to provide consent).
Minimum age
30 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known history of ongoing serious mental health issue.
2. Known allergy or contraindication to amitriptyline or estriol.
3. Known history of breast cancer less than 10 years before consent.
4. Known history of genital cancer less than 10 years before consent.
5. Not sexually active (self or with partner).
6. Currently using or has used in the last 6 weeks prior to treatment, amitriptyline, nortriptyline or estriol in any way (oral or topical) and not willing to cease before baseline data collection.
7. History of hyperemesis gravidarum.
8. Prior diagnosis of provoked vulvodynia (before pregnancy and/or before the age of 30)
9. Uncontrolled or excessive menstrual bleeding that is not able to be controlled.
10. Pudendal Nerve Block procedure within the last 90 days before baseline or planning on having a Pudendal Nerve Block procedure during the course of the trial.
11. Pregnant (as determined by a urine pregnancy test as applicable), breastfeeding or unwilling to use methods to avoid potential pregnancy for the study duration and for 30 days after the last treatment application.
12. Current peri-vaginal infections or vulvovaginal disorders, including current moderate-severe untreated candidiasis, such as active desquamative inflammatory vaginitis/psoriasis/lichen sclerosis, or other similar conditions in the opinion of the investigator.
13. Uncontrolled health conditions that could affect the lubrication or contribute to vulval pain/entry dyspareunia, such as Sjogren’s Syndrome, scleroderma or other similar conditions in the opinion of the investigator.
14. Prior participation in a Mi-Gel® clinical trial.
15. Current participation in a clinical trial, or participation in a clinical trial within 12 weeks prior to consent.
16. The investigator believes the candidate would not make a good clinical trial participant.

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)
Computerised randomisation list of numbers for active and placebo. Number ID only on investigational product and allocation is only provided upon request per protocol.
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 administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analysis Populations
• Intent-to-Treat (ITT) Analysis Population: The ITT analysis population will include all randomized subjects regardless of whether a study medication was taken. The ITT analysis population will be used for all summaries of baseline characteristics, demographics, and efficacy endpoints. Subjects will be analysed according to the treatment groups to which they were randomised.
• Per-Protocol (PP) Analysis Population: The PP analysis population will include all randomised subjects who (i) did not have a major protocol deviation which could bias the study outcomes, (ii) had an >= 50% treatment compliance, and (iii) had at least one efficacy data point (including any primary or secondary endpoints) after baseline. Subjects will be analysed according to the treatment groups to which they were randomised. Analysis based PP population will be used to provide supportive evidence for findings from the ITT population.
• Safety Analysis Population: The Safety analysis population will include all subjects who received at least 1 dose of the study medication (Mi-Gel® or placebo). All safety endpoints and treatment exposure will be listed and summarised using the Safety analysis population. Subjects will be analysed according to the treatment groups to which they actually received.
Data Analyses:
The general analytical approach for this study will be descriptive in nature. For continuous variables, descriptive statistics will include the number of non-missing values, mean, standard deviation (SD), median, minimum, and maximum. For categorical variables, descriptive statistics will include frequency counts and percentages per category. In general, missing values will not be imputed. The details of the analyses will be documented in a separate Statistical Analysis Plan (SAP).
Demographics, baseline characteristics, concomitant medication, and subject disposition will be summarised descriptively.
The primary endpoint will be measured using monthly NRS scores for vulval pain at time points of Baseline, Week 4, Week 8, and Week 12. The observed, absolute change from baseline, and percentage change from baseline will be summarised descriptively by study visit and treatment group. The change from baseline in NRS score at each study visit will be compared between Mi-Gel® and placebo by a mixed model for repeated measures (MMRM) model. The treatment effect, the difference of the least squares means between Mi-Gel® and placebo, its 95% CI, and p-value comparing the treatment effect at Week 12 and at other visits will be estimated from the model.
Subjects could withdraw early from the study and result in missing data. Every effort should be made to reduce the missing data. A sensitivity analysis will be conducted to assess the treatment effect on the primary endpoint when missing data are imputed.
Subjects with a 30% or more reduction in NRS score from baseline will be defined as responders. The response rate will be summarised at each post-dosing study visit by treatment group, along with its 95% CI which will be estimated by Clopper-Pearson exact method. The difference in response rate between Mi-Gel® and placebo will be compared by Fisher’s exact method at Week 12 and other visits. A logistic regression will also be used to compare the odds of response between treatment groups at Week 12 and other visits.
The same MMRM model will also be used to analyse scores reported from the secondary endpoints.
Each category of Patient Global Impression of Change (PGIC) at the end of treatment will be summarized descriptively by treatment group. PGIC categories will be dichotomised as ‘Improvement’ and ‘non-improvement’ for binary data summary. PGIC improvement rate (response) will be summarized by treatment group, along with its 95% CI estimated by the Clopper-Pearson exact method. The difference in improvement rates between treatment groups will be compared by Fisher’s exact method. A logistic regression will also be used to compare the odds (chance) of improvement between treatment groups at the end of treatment.
Safety data will be summarised descriptively and listed. Adverse events (AEs) will be coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA). Treatment-Emergent AEs (TEAEs) are defined as AEs which commence, or worsen in severity, on or after the first use of investigational product. TEAEs will be summarised by System Organ Class (SOC) and Preferred Term (PT). The frequency and percentage of subjects by reported SOC/PT will be summarised, with the number of AEs counted as well. Adverse events will also be summarised by AE severity/grade and AE relationship to the investigational product. A subject with two or more AEs within the same level of summarisation (in terms of SOC or PT) will be counted only once in that level.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/11/2024
Actual
Date of last participant enrolment
Anticipated
31/05/2025
Actual
Date of last data collection
Anticipated
30/08/2025
Actual
Sample size
Target
174
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 317385 0
Commercial sector/Industry
Name [1] 317385 0
TA Pharma Pty Ltd
Country [1] 317385 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
TA Pharma Pty Ltd
Address
Country
Australia
Secondary sponsor category [1] 319678 0
None
Name [1] 319678 0
Address [1] 319678 0
Country [1] 319678 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 316114 0
Bellberry Human Research Ethics Committee H
Ethics committee address [1] 316114 0
Ethics committee country [1] 316114 0
Australia
Date submitted for ethics approval [1] 316114 0
21/08/2024
Approval date [1] 316114 0
Ethics approval number [1] 316114 0

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

Contacts
Principal investigator
Name 136834 0
Dr Karen Chan
Address 136834 0
WHRIA, Level 12, 97-99 Bathurst Street – Sydney NSW 2000
Country 136834 0
Australia
Phone 136834 0
+61 2 8197 4400
Fax 136834 0
Email 136834 0
karenkhchan@gmail.com
Contact person for public queries
Name 136835 0
Liz Howard
Address 136835 0
WHRIA, Level 12, 97-99 Bathurst Street – Sydney NSW 2000
Country 136835 0
Australia
Phone 136835 0
+61 1300 722 206
Fax 136835 0
Email 136835 0
lizzahoward@gmail.com
Contact person for scientific queries
Name 136836 0
Liz Howard
Address 136836 0
WHRIA, Level 12, 97-99 Bathurst Street – Sydney NSW 2000
Country 136836 0
Australia
Phone 136836 0
+61 1300 722 206
Fax 136836 0
Email 136836 0
lizzahoward@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.