Dysport in Vulvodynia Phase II Study

Study Overview
=================
Brief Summary
-----------------
This study is designed to define optimal doses of Dysport and evaluate its efficacy and safety compared with placebo for the treatment of vulvodynia. The study will consist of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2). Both Stage 1 and Stage 2 will consist of a double-blind period (with treatment cycle 1; Dysport or placebo) followed by an open label treatment period. One or two optimally safe and effective doses of Dysport selected from Stage 1 will be further investigated in the Stage 2.

Official Title
-----------------
A Phase II, Multicentre, Double-blind, Randomised, Placebo Controlled, Dose Escalation and Dose Finding Study to Evaluate the Efficacy and Safety of Dysport in Vulvodynia Patients

Conditions
-----------------
Vulvodynia

Intervention / Treatment
-----------------
* Biological: Botulinum toxin type A
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Premenopausal Have vulvodynia for at least 6 months and for no more than 15 years Have provoked pain at the vestibule on a Q tip test Exclusion Criteria: Deep pain during intercourse Have genitourinary or gastrointestinal conditions which may interfere with the study Previous surgery that according to investigator's judgement may impact on study outcome (including but not limited to hysterectomy, vestibulectomy, urologic surgery, perianal surgery) or genital trauma or mutilation/cutting

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dysport - Dose Escalation stage 1<br>Intramuscular injection of Dysport on day 1 of each cycle. | Biological: Botulinum toxin type A<br>* Botulinum Toxin Type A (Dysport) using a vial of 500 U will be injected intramuscularly across pelvic floor muscles.<br>* Other names: AbobotulinumtoxinA (Dysport®);|
| Placebo Comparator: Placebo - Dose Escalation stage 1 and Dose Expansion stage 2<br>Intramuscular injection on day 1 of cycle 1. | Drug: Placebo<br>* The reconstituted solution will be injected intramuscularly across pelvic floor muscles.<br>|
| Active Comparator: Dysport - Dose Expansion stage 2<br>Depending upon the results from Stage 1 one or two doses of Dysport will be selected. Intramuscular injection of Dysport on day 1 of each cycle. | Biological: Botulinum toxin type A<br>* Botulinum Toxin Type A (Dysport) using a vial of 500 U will be injected intramuscularly across pelvic floor muscles.<br>* Other names: AbobotulinumtoxinA (Dysport®);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the DB Treatment Period (Stage 1) | For Stage 1, the primary endpoint was safety during the DB treatment period as assessed by the incidence of adverse events (AEs). An AE was the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition could have been symptoms, signs or abnormal results of an investigation. A TEAE was an event with start date on or after the date of the first investigational medicinal product (IMP). Relatedness to treatment was assessed by the investigator. TEAEs of special interest included events suggesting a possible remote spread of effect of the toxin, events related to urinary incontinence or faecal incontinence and events assessed as a potential hypersensitivity reaction. Results for this outcome are reported as the number of participants experiencing at least one TEAE in each specified category. | From Baseline (Cycle 1 Day 1) to Cycle 1 Week 12 (DB treatment period, Stage 1) | 
| Mean Change From Baseline in Vaginal Dilator Induced Pain During the DB Treatment Period at Week 6 (Stage 2) |  | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 (DB treatment period, Stage 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Vaginal Dilator Induced Pain as Reported on an 11-point Numeric Rating Scale (NRS) During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | For the dilator test, a vaginal dilator was used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. The dilator test was used to assess the change from Baseline in the vaginal dilator induced pain (using the DMTS reported at Baseline). Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as change from Baseline during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Number of Participants Who Reported at Least a 50% Decrease From Baseline in Vaginal Dilator Induced Pain as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | For the dilator test, a vaginal dilator was used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. The dilator test was used to assess the change from Baseline in the vaginal dilator induced pain (using the DMTS reported at Baseline). Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a ≥50% decrease from Baseline during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Number of Participants Who Reported at Least a 30% Decrease From Baseline in Vaginal Dilator Induced Pain as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | For the dilator test, a vaginal dilator was used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. The dilator test was used to assess the change from Baseline in the vaginal dilator induced pain (using the DMTS reported at Baseline). Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a ≥30% decrease from Baseline during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Number of Participants Who Reported at Least a 2-point Decrease From Baseline in Vaginal Dilator Induced Pain as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | For the dilator test, a vaginal dilator was used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. The dilator test was used to assess the change from Baseline in the vaginal dilator induced pain (using the DMTS reported at Baseline). Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a ≥2-point decrease from Baseline during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Mean Change From Baseline in the DTMS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | For the dilator test, a set of 8 vaginal dilators of increasing diameter (#1 being the smallest and #8 being the largest) were used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. Based on the subjective pain threshold, the largest sized dilator that the participant accepted/tolerated for the test, was defined as the DMTS. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as change from Baseline in the DTMS during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Mean Change From Baseline in the Composite Score for the Vaginal Dilator Induced Pain and Dilator Size During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | For the dilator test, a set of 8 vaginal dilators of increasing diameter (#1 being the smallest and #8 being the largest) were used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. The composite score for the vaginal dilator induced pain and dilator size was the sum of all pain measurements across the full range of dilator sizes. For any dilator size that was beyond the DMTS, the pain score was 10. There was to be at least 6 pain scores (recorded by the investigator) to calculate the composite score. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as change from Baseline in the composite score for the dilator test during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Mean Change From Baseline in Pain During Insertion of Vaginal Dilator Number 6 Size as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | From 2 weeks prior to the next planned visit, all participants rated in the electronic diary (eDiary) once a week the level of the corresponding pain following insertion of the number 6 vaginal dilator into the vagina. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the change from Baseline in participant reported pain score for the number 6 dilator test during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Number of Participants Who Reported at Least a 50% Decrease From Baseline in Pain During Insertion of Vaginal Dilator Number 6 Size as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | From 2 weeks prior to the next planned visit, all participants rated in the eDiary once a week the level of the corresponding pain following insertion of the number 6 vaginal dilator into the vagina. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a ≥50% decrease from Baseline in participant reported pain score for the number 6 dilator test during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Number of Participants Who Reported at Least a 30% Decrease From Baseline in Pain During Insertion of Vaginal Dilator Number 6 Size as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | From 2 weeks prior to the next planned visit, all participants rated in the eDiary once a week the level of the corresponding pain following insertion of the number 6 vaginal dilator into the vagina. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a ≥30% decrease from Baseline in participants reported pain score for the number 6 dilator test during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Number of Participants Who Reported at Least a 2-point Decrease From Baseline in Pain During Insertion of Vaginal Dilator Number 6 Size as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | From 2 weeks prior to the next planned visit, all participants rated in the eDiary once a week the level of the corresponding pain following insertion of the number 6 vaginal dilator into the vagina. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a 2-point decrease from Baseline in participant reported pain score for the number 6 dilator test during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Mean Change From Baseline in Pain During Intercourse as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | From the Screening visit, and then 2 weeks prior to the next planned visit, participants recorded on a daily basis in the eDiary if they had intercourse and if yes, the level of the corresponding pain during each intercourse instance. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. The 2-week average was used, which was calculated as the average of the score over the last 2 weeks (14 days) prior to the visit. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the change from Baseline in participant reported pain score during intercourse (over the last 2 weeks prior to each visit) during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Mean Change From Baseline in the Number of Intercourse Instances in Participants With Partners During the DB Treatment Period at Week 6 and Week 12 (Stage 1) | From the Screening visit, and then 2 weeks prior to the next planned visit, participants recorded on a daily basis in the eDiary if they had intercourse and if yes, the number of intercourse instances in the previous 24-hour period. The number of intercourse instances over the 2 weeks preceding the visit was calculated as the total recorded number of intercourse instances over 14 days prior to the visit. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the change from Baseline in number of intercourse instances (over the last 2 weeks prior to each visit) during the DB treatment period at Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) | 
| Use of Pain Rescue Medication Associated With Intercourse During the DB Treatment Period at Week 6 and Week 12 | From the Screening visit, and then 2 weeks prior to the next planned visit, participants recorded on a daily basis in the eDiary if they had intercourse and also details of any pain rescue medication consumed for each intercourse instance to prevent or treat the vestibular pain. If a participant used the rescue medication associated with at least one instance during the 2-week prior to a visit, the participant was considered as having used the rescue medication for that visit. Results for this outcome are reported as the number of participants using pain rescue medication associated with intercourse (over the last 2 weeks prior to each visit) during the DB treatment period at Baseline, Week 6 and Week 12. | Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1) |