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Trial registered on ANZCTR


Registration number
ACTRN12614001153606
Ethics application status
Approved
Date submitted
12/10/2014
Date registered
31/10/2014
Date last updated
31/10/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
The vulvo-vaginal pain study:
A study looking at the effectiveness of an intra-vaginal cream for treatment of chronic vulvo-vaginal pain. .
Scientific title
Pregabalin vaginal cream to be used in women with chronic idiopathic vulvovaginal pain: A double blind, placebo controlled randomized trial of Pregabalin cream vs placebo cream on vulvo-vaginal pain and sexual function.
Secondary ID [1] 285049 0
nil known
Universal Trial Number (UTN)
Trial acronym
The Vulvovaginal pain study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
vulvo-vaginal pain 292569 0
Condition category
Condition code
Reproductive Health and Childbirth 292878 292878 0 0
Other reproductive health and childbirth disorders
Renal and Urogenital 293605 293605 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Interventions;
Double Blinded randomized allocation of active Pregabalin(Lyrica- Registered Trademark) or placebo vaginal aqueous cream twice daily for 6 weeks . At 6 weeks the option is provided for open label use of active cream for a further 6 weeks
Randomization
Randomization numbers will be generated by the Epidemiologist and patients will be allocated numbers by a research nurse, in order to keep the chief investigators blinded. Twenty millilitre calibrated syringes of active and placebo cream will only be labelled as cream A and B. Each syringe will have am identifying number for tracking.
* Cream will be applied to vulvo-vaginal area twice daily for 2 weeks initially. It will be kept at room temperature. Dosage of cream will be increased from starting dose at 2 weeks in consultation with the investigator if no response is obtained. Cream will be applied to the point of maximal pain.
Participants will be interviewed at 2 weeks. If at or before 2 weeks side effects are experienced- subjects will be instructed to contact the investigator and discuss. Dosage reduction may be initially advised or cessation and a consultation will be organized for reassessment as soon as convenient. A different base such as Glycerine and Sorbelene might then be used. Dosage doubling will be scheduled if there is no response

* Further Labelled Pregabalin cream will be provided at 6 weeks if the participant wishes. Treatment will continue for a further 6 weeks (12 weeks in total). Dosage of cream will again be increased 1 week later (i.e. week 7) in consultation with the CI if no response is noted, or reduced , adjusted if side effects are experienced.
At the 6 week visit, any remaining cream from the 1st 6 weeks will be retrieved and examined for usage. At the 12 week point - any remaining cream will be retrieved and examined for usage.
Patients will be phoned when questionnaires are due to make sure these are completed and that cream is tolerated and being used
* The dose (Lyrica registered trademark) Pregabalin will be 2.5% in concentration. This starting dose is equivalent to 25 mg of drug in 1 ml of cream used twice daily.
If side effects are initially experienced, half the dose can be used twice daily by drawing up half the initial amount (0.5 ml). If no effect is initially observed, 2 mls can be used twice daily at 2 weeks; ie - dose is doubled.
* Participants with significantly impaired renal function will not be recruited to the study (e GFR < 60 or creatinine clearance < 60 mls/min). Those with mildly impaired renal function (e GFR >= 60) will receive the standard dosage but note will be made of this. Maximum oral dosage of (Lyrica registered trademark) Pregabalin is 300 mg . Guidelines suggest the drug is safe orally in those with renal impairment up to an oral dose of 150 mg twice daily.
If dosage doubling is required in a participant where mild renal impairment is also present (Cr Cl 30-60 ml/min); a dose adjustment will be calculated by consulting a renal physician for advice.
* Subjects will complete a set of standardized questionnaires at regular intervals. The research nurse will remind them by phone. Questionnaires may be completed on line confidentially or posted.

Intervention code [1] 289888 0
Treatment: Drugs
Comparator / control treatment
The control treatment is a placebo cream made up only of the aqueous base cream . It will be provied in unlabelled syringes identical in appearance to the active cream. It will be applied identically.
Control group
Placebo

Outcomes
Primary outcome [1] 292750 0
a) Vulvo-vaginal pain as assessed by a GRA pain scale 1. 0 (no pain) to 100 (worst possible pain)
A pain scale is the most sensitive measure of pain severity over time and is the primary measure used to determine treatment efficacy
Timepoint [1] 292750 0
4 weeks
6 weeks
12 weeks
Primary outcome [2] 292751 0
b). Patients Global impression of change scale . This is another sensitive index of treatment response over time and its inclusion is recommend in pain trials.
Timepoint [2] 292751 0
4 weeks
6 weeks
2 weeks
Primary outcome [3] 292752 0
c) Sexual activity measured for those sexually active over time .
1. Female sexual function index . This is a standardised validated measure of sexual function
Assessment of any effect of drug treatment on sexual function is relevant.

Timepoint [3] 292752 0
4 weeks
6 weeks
12 weeks
Secondary outcome [1] 309605 0
A) to document prevalence of local side effects, Non validated questions will be asked .Local irritation-will be documented by questionnaire in a qualitative fashion. Results can be quantified later in a meaningful way depending on nature of responses
Timepoint [1] 309605 0
4 weeks
6 weeks
12 weeks
Secondary outcome [2] 309606 0
B). Systemic effects and somnolence; oral administration of pregabalin causes somnolence rates of ~ 20% . The first scale is ;
1. Drowsiness / somnolence/fatigue 0-100 GRA scale .

The main rationale for using Pregabalin as topical cream is to avoid drowsiness. Therefore a key secondary aim is to assess somnolence with use of the cream compared to placebo.
Timepoint [2] 309606 0
4 weeks
6 weeks
12 weeks
Secondary outcome [3] 310982 0
Sexual function is included here as a secondary outcome measure even though it will form a primary outcome measure as because no space is available for the Marinoff scale under primary outcome measures.
The Marinoff sexual pain scale is another brief, validated measure of sexual function that will form a primary outcome measure.
Sexual function is impacted upon by vaginal pain and is a primary complaint for most sexually active women.
Timepoint [3] 310982 0
4 weeks
6 weeks
12 weeks
Secondary outcome [4] 310983 0
B). Systemic effects and somnolence; oral administration of pregabalin causes somnolence rates of ~ 20% . The second measure is ;

2. Sedation also using Karolinska sleepiness scale
Timepoint [4] 310983 0
4 weeks
6 weeks
12 weeks
Secondary outcome [5] 310984 0
Vaginal examination when clinically indicated will be performed to document prevalence of local side effects,
Results will be recorded in a qualitative fashion. Results can be quantified later in a meaningful way depending on nature of responses
Timepoint [5] 310984 0
4 weeks
6 weeks
12 weeks
Secondary outcome [6] 310985 0
Urinary tract infection will be tested for at enrollment using a midstream urine sample and again throughout the study if there are suggestive symptoms of new onset frequency, urgency, incontinence, malodorous or cloudy urine. . Urinary tract infection will be tested for at baseline and later more because it could confound results- and not as a n outcome measure . Use of cream could possibly also cause infection and would be a possible secondary outcome measure

Timepoint [6] 310985 0
4 weeks
6 weeks
12 weeks
Secondary outcome [7] 311022 0
complaints of local side effects to the cream will be recorded qualitatively and later quantified for analysis as a secondary outcome measure.
Timepoint [7] 311022 0
4 weeks
6 weeks
12 weeks

Eligibility
Key inclusion criteria
*INCLUSION; Unable to insert tampon or have penetrative vulvo-vaginal intercourse or to tolerate regular vulvo-vaginal examination
*There may be also discomfort wearing tight clothing, discomfort sitting, mobilizing
*Other causes of pain must have been excluded by swab, biopsy and / or skin scraping if necessary. Participants will be reviewed by a female dermatologist with a clinical and research interest in vaginal pain. Diagnoses of local trauma, scarring, candida, HSV, other dermatoses- lichen simplex etc will only exclude participation if appropriate treatment for these diagnoses has been provided but has not resolved the symptom substantially.

* Pain must be present persistently for greater or equal to 6 months
* Maximum Pain Severity was / is > 50 on Gra scale 1-100 on greater or equal to 2 occasions in 1 week

*Other associated pelvic pain conditions do not exclude inclusion; such as interstitial cystitis/ painful bladder syndrome), endometriosis, rectal pain, provided focal vulvo-vaginal examination is also uncomfortable
Can include past use of oral Gabapentin or Pregabaln with or without side effects.
Participants may come from clinics at RPAH or from elsewhere

Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
*Vulvo-vaginal or vulval pain of known and effectively treatable cause ie it is not refractory to other treatment
*Pregnancy or risk of pregnancy (unprotected intercourse). If risk suspected HCG testing prior to randomization
Age 17 or under
*Lichen planus/sclerosis will exclude participation
*Untreated pelvic malignancy, past or current radiation therapy.
*Known allergy to Gabapentin , Pregabalin

*Pain present persistently for less than 6 months
* If the maximum Pain Severity was never > 50 on Gra scale 1-100 on < 2 occasions in 1 week.

*Severe renal impairment (Cr Cl or e GFR < 60) or recent (less than 12 months) acute myocardial infarct.
* They live more than 200 km from Sydney


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)
The trial will recruit in the Sydney area within 200 km radius and also women attending a gynaecology clinic at RPAH. They will attend private rooms of Professor Benness – Carillion Ave Newtown to participate

Potential participants identified among the existing patient population will be approached to participate. Because this can present ethical problems, these patients will be directed to the web site and any questions they may have will be directed to a doctor who is not an investigator so that there is no possibility of coercion.
Respondents will call the investigator Dr Manning or the research nurse Sr S Brokenshire, for screening according to a screening questionnaire checklist; listing inclusion/ exclusion criteria and to obtain further information. They will be invited to ring us with further enquiries. Informed consent forms will be posted or emailed. (see appendices in this document for checklist).
Potential participants will be booked to be seen in rooms for a 1st visit. A 24 hour bladder voiding diary will have been mailed out with the consent and completion of this will be explained by the research nurse over the phone for clarity. The completed diary will be brought in at the time of first clinic visit.
The visit will include full history and physical examination including a vulvo-vaginal examination. Demographic data will be obtained. PTSD and catastrophizing scales will be completed on this occasion only.
If inclusion criteria are satisfied and the participant feels informed and willing; informed consent will be signed. Further investigations to verify the diagnosis will be performed if needed prior to enrollment.
Randomization will be achieved through a computer-generated randomization sequence held distantly by Professor Attia (Hunter Medical Resaerch Institute).
This will determine if cream A or B is to be administered Only Australian custom pharmaceuticals will know which cream contains active Lyrica. This information will be kept from participants , investigators and statistical staff -Professor Attia. Of the 2 creams, labelled A and B , only one of which will contain active Lyrica drug. The bottles will have a patient identifying number attached to the label. The dug will be administered according to the allocated letter by the research nurse.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization numbers will be generated by the Statistician Professor Attia using computer generated 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
nil
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
A power calculation (Prof John Attia; Hunter Medical research institute) used the only available observational clinical study, by Boardman to calculate a sample size based on their Gabapentin cream’s pain effectiveness on a GRA scale when compared to a placebo cream. This is the main primary outcome measure. Sedation is a secondary outcome measure
The minimal clinically significant difference in the
Visual Analogue Scale is 10 points,. We powered to detect t 20 points difference between the placebo arm and active arm on a 100 point visual analog scale. Assuming 80% and p=0.05 and SD for difference score of 25, we require 26 people in each arm. A total of 52 participants.
We will aim to recruit 70 subjects to allow for participant drop out and missing data.

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)
NSW
Recruitment hospital [1] 2769 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 8468 0
2050 - Missenden Road

Funding & Sponsors
Funding source category [1] 289660 0
Charities/Societies/Foundations
Name [1] 289660 0
International Urogynaecology Society
Address [1] 289660 0
2030 M Street NW
Suite# 701
Washington, DC 20036
Country [1] 289660 0
United States of America
Primary sponsor type
Individual
Name
Dr Jane Manning
Address
Private practice. Address: 317 Parkway Ave Hamilton NSW 2303
Country
Australia
Secondary sponsor category [1] 288351 0
Individual
Name [1] 288351 0
Professor Christopher Benness
Address [1] 288351 0
Ste 404, RPAH Medical Ctr
100 Carillon Ave
Newtown
Sydney
NSW 2042
Country [1] 288351 0
Australia
Secondary sponsor category [2] 288784 0
Individual
Name [2] 288784 0
Dr Elizabeth Willsteed
Address [2] 288784 0
Ste 6, Jarrett St Specialist Cntr, 14-18 Jarrett St, Gosford North NSW 2250
Country [2] 288784 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291794 0
Sydney Local Health District (RPAH ZONE)
Ethics committee address [1] 291794 0
The Ethics Officer
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 291794 0
Australia
Date submitted for ethics approval [1] 291794 0
Approval date [1] 291794 0
01/08/2014
Ethics approval number [1] 291794 0
X14- 0129 HREC /14/RPAH/166

Summary
Brief summary
A randomised, placebo-controlled study looking at the effectiveness of an intravulvo-vaginal cream Lyrica (registered trademark) for treatment of chronic pain in the vulvo-vagina.
A research project is being conducted by Professor Chris Benness, Dr Elizabeth Willsteed and Dr Jane Manning to investigate a treatment for chronic vulvo-vaginal pain.

Why is the research being done?
The purpose of this project is to establish whether a prescription drug, Pregabalin (Lyrica - registered trademark) when applied topically as a vulvo-vaginal cream is a safe and effective means of treating vulvo-vaginal pain.
Previous research has suggested that it may be effective. We hope it causes fewer side effects than Pregabalin when taken orally which is a standard treatment for the condition. This drug is not experimental or new, and is approved to treat chronic neuropathic pain.
Method:
Two creams, A and B will be prepared. One of which will contain pregabalin . Treatment allocation will be double blind and randomized. Participants who satisfy inclusion criteria will apply the cream for 6 weeks with dose adjustment allowed. They will then have the option to receive the active pregabalin cream (open label) for a further 6 weeks if they wish. They will complete questionnaires designed to detect relevant demograohic factors and factors that may potentially confound results. They will complete questionnaires on line or by mail at 0, 2 4 ,6 and 12 weeks.

Participants:
Those with vulvo-vaginal pain that has stopped tampon use or intercourse or regular internal examination for 6 months or more.
Those over 17
Those not pregnant and are not planning to become pregnant (that is, you must be currently using effective contraception)
Those with no known allergy to Pregabalin.

Those whose pain is not due to cancer or past radiation treatment or to lichen planus or lichen sclerosis, or other treatable causes.
Those who have time to participate over 6 weeks and who live within 200 km of Sydney NSW Australia Area
Those who don’t have significant kidney disease.

What would participants be asked to do?
They will need to be available for a minimum of 2 visits over a minimum 6 weeks to assess response to a blinded treatment cream. The first visit will take approximately 1 hour. Participating in the study will involve:
A vulvo-vaginal examination at the first visit
Attending for a first visit and a possible visit at 2 weeks
Completing five (5) Questionnaires which will be provided at visit 1, and again at weeks 2, 4, 6 and also week 12 if they wish to continue. These questions will ask about general health and the nature of the vulvo-vaginal pain. Some of these are sensitive questions asking about sexual function and possible abuse history.
They will complete a 24 hour voiding diary (how often you go to the toilet) prior to the first visit.
After the initial visit, online questionnaires or postal questionnaires will be possible to complete for all subsequent review, or if they wish they can attend in person.
They will collect a study drug package, labelled either A or B at the 1st visit.
All participants will apply cream throughout the 6 week study, but the contents of the cream will be either Lyrica (registered trademark) pregabalin or a placebo (not active medication). Participants will not be told which cream they receive.

What are the risks and benefits of participating?
Benefits
Participating in this study may benefit your condition (vulvo-vaginal pain).
Risks
Although the cream base is neutral - local irritation may still occur Irritation with use of this vulvo-vaginal cream may occur for 14% of women.
Sedation may still occur even though it has not been reported using this cream. Tiredness, dizziness, confusion is common with many oral medications used to treat vulvo-vaginal pain.

How will privacy be protected?
All information gained will be treated confidentially. It will be accessed, used, managed and stored in accordance with the NSW Health Records and Health Information Privacy Act 2002
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 50186 0
Dr Jane Manning
Address 50186 0
Private Practice address
PO Box 648
The Junction 2291 NSW Australia
Country 50186 0
Australia
Phone 50186 0
+61 2 49408069
Fax 50186 0
Email 50186 0
jma14246@bigpond.net.au
Contact person for public queries
Name 50187 0
Dr Jane Manning
Address 50187 0
Private practice
317 Parkway Ave Hamilton 2303 NSW Australia
Postal address: PO Box 648,
The Junction NSW 2291
Country 50187 0
Australia
Phone 50187 0
+ 61 2 49408069
Fax 50187 0
+ 61 2 49610599
Email 50187 0
jma14246@bigpond.net.au
Contact person for scientific queries
Name 50188 0
Dr Jane Manning
Address 50188 0
Private Practice
PO Box 648
The Junction 2291 NSW

Study will be conducted at the following address:

Street Address. Ste 404, RPAH Medical Ctr 100 Carillon Ave Newtown 2942 NSW
Country 50188 0
Australia
Phone 50188 0
+ 61 2 49408069
Fax 50188 0
+ 61 2 49610599
Email 50188 0
jma14246@bigpond.net.au

No information has been provided regarding IPD availability
Summary results
No Results