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Trial registered on ANZCTR


Registration number
ACTRN12620001084976
Ethics application status
Approved
Date submitted
24/08/2020
Date registered
20/10/2020
Date last updated
20/10/2020
Date data sharing statement initially provided
20/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Study of a vaginal treatment in preventing Recurrent Vulvovaginal Candidiasis (thrush)
Scientific title
Efficacy of Intravaginal Combination Therapy of Acetic and Lactic Acid (ICTALA) in premenopausal women Recurrent Vulvovaginal Candidiasis – A Randomised, Double blind Placebo Controlled Clinical Trial
Secondary ID [1] 301886 0
NIL
Universal Trial Number (UTN)
Trial acronym
RVVC ICTALA study
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Recurrent Vulvovaginal Candidiasis 318393 0
Condition category
Condition code
Infection 316407 316407 0 0
Other infectious diseases
Alternative and Complementary Medicine 316408 316408 0 0
Other alternative and complementary medicine
Renal and Urogenital 316409 316409 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A 1.9gm pessary that contains 3% Acetic and 2% lactic acid in gelatin forms the investigational medicinal product. Intravaginal Combination Therapy of Acetic and Lactic Acid (ICTALA)

One ICTALA pessary, applied for 7 days following menstruation (from day 10-17 of menstrual cycle). Administration repeated every month for 6 months.

Particpant compliance:
At appointment 2 and 3 IMP compliance will be checked:
Study intervention use will be recorded, and any returned medication will be counted as a measure of compliance. Any participant with less than 60% compliance will be withdrawn.

Confirmation of recurrence and treatment.
Participants with confirmed recurrence will be instructed to seek 150mg oral fluconazole from their local pharmacy for treatment. Participants will be reimbursed for treatment cost.

Microbiome assessment (Subset of participants)
A subset of local Queensland participants will have the option to provide additional consent to provide vaginal swabs (self swabbed) for next generation sequencing microbiome analysis (fungal and bacterial). Participants self vaginal swab at Baseline, appointment 2 (3 months) and appointment 3 (6 months).

Hormonal blood draw (Subset of participants-Estradiol, FSH, LH, Progesterone):
A subset of local Queensland participants who have provided additional consent to vaginal microbiome analysis will also be asked to provide consent to a blood draw at a local pathology centre for hormonal analysis. Participants attend the blood draw at Baseline, appointment 2 (3 months) and appointment 3 (6 months).



Intervention code [1] 318177 0
Prevention
Comparator / control treatment
One placebo gelatin pessary capsule (all ingredients except acetic acid and lactic acid) intravaginally applied for 7 days following menstruation (day 10-17 of menstrual cycle). Administration will be repeated every month for 6 months.

Ingredients:
Each 1.9 gm placebo contains:
Gelatin base (gelatin, glycerine and water, PCCA) 1900mg





Control group
Placebo

Outcomes
Primary outcome [1] 324560 0
The primary outcome is a change of recurrence and severity of RVVC following standard extended Fluconazole.

Assessed via: Sobel Symptom Score, Savvy Check rapid yeast test and vaginal swab Culture/microscopy (self swabbed)
Timepoint [1] 324560 0
Anytime: Ongoing, when symptoms occur during trial during the 9 months trial period
Secondary outcome [1] 384970 0
Quality of life (QoL:assessed by the modified DLQI (dermatology Life Quality Index)
Timepoint [1] 384970 0
Every fortnight (14 days) through 9 months trial period
Secondary outcome [2] 384971 0
Economic burden: assessed by the EQ-5D
Direct costs of goods and services used in preventing and treatment of RVVC such as the medical costs, clinic charges and medication costs will be measured. Additionally, direct non-medical costs for travel and time to attend to medical appointments will be factored into cost analysis. Indirect costs such as output loss due to illness will be assessed.

Timepoint [2] 384971 0
Every fortnight (14 days) through 9 month trial period
Secondary outcome [3] 384972 0
Tolerability/side effects will be measured fortnightly over the 9 months trial period through participant diary entries including during Appointment 2 and 3.

The only anticipated side effect is a mild burning/warmth on application of the vaginal pessary.
Timepoint [3] 384972 0
Every fortnight (14 days) through 9 months trial period.
Secondary outcome [4] 384982 0
Next Generation Sequencing Vaginal Swab: Vaginal Microbiome study
subset study

Vaginal Swab 16S: Bacteria
Vaginal Swab ITS1: Fungi
Timepoint [4] 384982 0
Appointment 1/ Day 1, Appointment 2/ Day 85, Appointment 3/Day 170
Secondary outcome [5] 387079 0
Participant characteristics/ trends (e.g. hygiene, menstruation, medication). These outcomes will be determined fortnightly over the 9 months trial period through participant diary entries including during Appointment 2 and 3.
Exploratory outcome.
Timepoint [5] 387079 0
Every fortnight (14 days) through 9 months trial period.

Eligibility
Key inclusion criteria
1. Premenopausal women
2. In good health (no serious current illness or specified chronic diseases, see exclusion criteria)
3. A history of RVVC defined as >3 episodes of Vulvovaginal Candidiasis in a 12 months period as documented in patient medical records and case history, including at least one positive vaginal culture pathology report
4. Finished/finishing a minimum of extended 3 month Fluconazole therapy for RVVC
5. Willing to answer questionnaires and comply with the study requirements.
6. Ability to apply intravaginal therapies
7. Ability to collect vaginal swabs
8. On stable medication(s) and/or Complementary medicines, other than excluded (see below), for >2 months

Minimum age
18 Years
Maximum age
60 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. >1 month gap since the last Fluconazole treatment/dose
2. Vaginal pH>4.5 at Baseline
3. Positive SavvyCheck at Eligibility screening
4. Positive Human Chorionic gonadotropin (hCG) urinalysis test at Eligibility screening (confirming pregnancy), currently pregnant and/or breastfeeding
5. Intra uterine device (hormonal or coil, ring pessary)
6. Menstrual abnormalities, defined as oligomenorrhoea, menorrhagia or amenorrhoea
7. Menstrual cycle is >7 days long
8. Women of child bearing potential who have not been using effective methods of contraception for 14 days prior to Baseline Appointment 1..
9. Individuals who are diagnosed with a significant chronic disease, including kidney, liver and autoimmune disease, sexually transmitted infection, uncontrolled Diabetes (Type 1 or Type 2, HbA1c >7.5%), vulvar or vaginal medical condition (other than RVVC), pelvic inflammatory disease, recurrent urinary tract infection
10. Current cancer or a remission diagnosis in the last 12 months (Skin cancer excision without treatment not a basis for exclusion).
11. Individuals taking any medication that addresses hormones including hormone replacement therapy (except the OCP), antiestrogens, aromatase inhibitors or any medication of a hormonal blocking nature associated with a breast cancer diagnosis
12. Individuals taking HMG-CoA reductase inhibitors, antiretroviral or immunosuppressant medication.
13. Individuals taking antifungal (other than Fluconazole) antimicrobial or anti-inflammatory medications applied for a chronic health condition (which can not be ceased)
14. Individuals using vaginal douches, taking probiotics (oral or vaginal), or complementary medicines for the management of VVC (Caprylic acid, Origanum vulgare: Oregano herb/oil, Hydrastis canadensis: Golden Seal, Saccharomyces cerevisiae, Handroanthus heptaphyllus:Pau D’arco, Allium sativum: Garlic, Pseudowintera colorata: Horopito) except for those willing and able to cease (if ceased allow a 3 week wash out)
15. Individuals who have commenced a new pharmaceutical or complementary medication < 2 months ago (and not willing or able to cease)
16. Known allergy to any of the ingredients in the formulation
17. Individuals that have participated in another clinical trial in the last 30 days

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomization will be blocked to allocate participants to the two trial arms. Block size will be 8 and 10, varying randomly. The randomization schedule will be created and allocated randomly by Griffith staff independent to the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Via online randomisation software
Individuals who qualify and consent to take part in the
study will be assigned to either active or placebo group
with a 1:1 allocation rate as per computer-generated
randomisation scheduled using random permuted block
sizes. The sequence generation will be prepared by a staff member at the clinical trial unit
not involved in the study.
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 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Data will primarily be analysed on an intention to treat basis, comparing the blinded intervention group with the control group. The key comparison will be the between-group difference between the ICTALA and placebo groups at 3, 6 and 9 months. We will examine the recurrence of vulvovaginal candidiasis according to the treatment group.

Summary statistics will be described using either mean (standard deviation) or median (25th-75th percentile) for continuous variables, according to distribution, or as frequency (percentage) for categorical variables. The between-group differences at baseline for participant will be compared using linear regression (continuous data) or logistic regression (binary data), and if any characteristic differs at p<0.005 it will be included as a co-variable in all regression models that consider outcomes.

Between group differences for the primary outcome measure (recurrence of vulvovaginal candidiasis; binary data) will be compared using logistic regression analysis. Treatment group will be included as the main effect, and no covariables will be included. Secondary analyses considering interval data will compare the groups using linear regression, considering count data will compare groups using Poisson regression, and considering time-to-event data will use Cox regression. Statistical significance will be set at p<0.05.

We will compare microbiome composition, quality of life as well as physiological markers using mixed-effects models treating 'participant' as a random effect and adjusting baseline variables if necessary. P-values of less than 0.05 will be considered significant. There will be secondary analyses "per protocol" and comparing the intervention group with the control group.

An economic evaluation comprising both cost-effectiveness and cost-utility analyses will be undertaken to quantify the additional costs and health benefits if the intervention compared to usual care. The analysis will have a time horizon of nine months, consistent with the trial intervention.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 306305 0
University
Name [1] 306305 0
Griffith Univeristy
Address [1] 306305 0
Clinical Trial Unit Ian O'Connor Building Level 4, Building G40 Griffith University Gold Coast Campus, Parklands Drive, Southport QLD 4215
Country [1] 306305 0
Australia
Primary sponsor type
University
Name
Griffith Univeristy
Address
Clinical Trial Unit Ian O'Connor Building Level 4, Building G40 Griffith University Gold Coast Campus, Parklands Drive, Southport QLD 4215
Country
Australia
Secondary sponsor category [1] 306801 0
None
Name [1] 306801 0
Address [1] 306801 0
Country [1] 306801 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306520 0
Griffith University Human Research Ethics Committee
Ethics committee address [1] 306520 0
Griffith University Gold Coast Campus, Parklands Drive, Southport, QLD 4215
Ethics committee country [1] 306520 0
Australia
Date submitted for ethics approval [1] 306520 0
17/01/2020
Approval date [1] 306520 0
23/02/2020
Ethics approval number [1] 306520 0
2020/065

Summary
Brief summary
Recurrent Vulvovaginal Candidiasis (RVVC) is a dermatological and sexual health disorder impacting 5-10% of the female population. The management of RVVC often requires ongoing drug management called maintenance therapy. Even with maintenance regimes, up to 57% of women may experience a relapse of symptoms within 3-6 months of therapy completion. The ongoing and recurrent symptom presentations associated with RVVC have significant impacts on health status and quality of life, as well as pose an economic burden. The proposed trial will assess whether "Intravaginal Combination Therapy of Acetic and Lactic Acid" (ICTALA) is effective and well-tolerated for the prevention of RVVC. ICTALA will be utilised to ultimately provide an intervention that can reduce antimicrobial drug usage and decrease post fluconazole therapy relapse.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104146 0
Prof Evelin Tiralongo
Address 104146 0
Clinical Trial Unit Ian O'Connor Building Level 4, Building G40 Griffith University Gold Coast Campus, Parklands Drive, Southport, QLD 4215
Country 104146 0
Australia
Phone 104146 0
+61 756780366
Fax 104146 0
NA
Email 104146 0
e.tiralongo@griffith.edu.au
Contact person for public queries
Name 104147 0
Mrs Moira Bradfield Strydom
Address 104147 0
Clinical Trial Unit Ian O'Connor Building Level 4, Building G40 Griffith University Gold Coast Campus, Parklands Drive, Southport, QLD 4215
Country 104147 0
Australia
Phone 104147 0
+61 756780364
Fax 104147 0
NA
Email 104147 0
moira.bradfieldstrydom@griffithuni.edu.au
Contact person for scientific queries
Name 104148 0
Mrs Moira Bradfield Strydom
Address 104148 0
Clinical Trial Unit Ian O'Connor Building Level 4, Building G40 Griffith University Gold Coast Campus, Parklands Drive, Southport, QLD 4215
Country 104148 0
Australia
Phone 104148 0
+61 756780364
Fax 104148 0
NA
Email 104148 0
moira.bradfieldstrydom@griffithuni.edu.au

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 other documents available
Summary results
No Results