Placebo-controlled RCT of Botulinum Toxin A as a Treatment for Provoked Vestibulodynia
Condition: Vulvodynia
MeSH terms: Vulvodynia; Vulvar Vestibulitis
Study type: Interventional
Phase: Phase 3

Summary: 
      Women with provoked vestibulodynia (PVD) suffer from severe dyspareunia and often present a
      hyperactivity of the pelvic floor muscles (PFM) which maintain the dyspareunia. The rationale
      for the study is that for women with PVD who don't succeed to restore the function of the PFM
      by physiotherapy, Botulinum Toxin A (BTA) could be an optional treatment by decreasing the
      high muscle tonus and thus possibly reduce the coital pain.
    

Detailed description: 
      Design and methodology General outline The study is an investigator- initiated phase III
      study to determine the effect of botulinum toxin A injections in the bulbocavernosus muscles
      in women with provoked vestibulodynia for reduction of the level of dyspareunia. The study
      will be a double blind, placebo-controlled RCT analyzed according to the intention to treat.
      The study will be carried out according the trial protocol, current regulations (LVFS
      2011:19, ICH GCP) and to the latest version of the Helsinki declaration. Ethical approval
      from the Stockholm regional ethic committee will also be obtained before the study begins. No
      financial support from the manufacturer of the active drug is obtained.

      Women with PVD, age 18-40 years, will be informed about the study by their gynecologist or
      via advertisement with information on how to contact the research nurse or the responsible
      gynecologists for more information. If the diagnosis of PVD needs to be clarified, a
      screening appointment will be scheduled.

      It is estimated that the project will require 4 years for recruitment and treatment of all
      participants, follow-ups, data analyses and report of results.

      During the recruitment, the patients with PVD will be asked to participate in an epigenetic
      study analyzing the grade of methylation of certain candidate genes associated to pain and
      anxiety before and after treatment and a "genome wide association study" with the aim to find
      possible genetic markers of PVD. If they accept, a venous blood sample will be taken during
      Visit 1 and Visit 5. These studies are otherwise separated from the RCT and have ethical
      approval. The blood samples will be registered in Stockholms Medicinska Biobank
      (registreringsnummer 941 hos IVO) and stored for later analyses at the research department of
      Dept. of Obstetrics and Gynecology, 182 88 Danderyd, Sweden.

      Visit 1(recruitment and baseline) If the patient is willing to participate and fulfill
      inclusion and exclusion criteria she will sign informed consent in the presence of the
      gynecologist in charge of the injections of BTA or placebo.

      Evaluation of psycho-sexual health and quality of life (QoL) The following validated
      (including the Swedish language) questionnaires will be filled in;

        -  Data on general and reproductive health including current medication and anti-conception
           method

        -  Female Sexual Function Index (FSFI)

        -  Female Sexual Distress Scale (FSDS)

        -  Quality of life (WHOQOL-BRIEF, Swedish version

        -  EQ-5

        -  PSS (perceived stress scale)

        -  Anxiety questionnaire (Spence, Swedish version).

      Evaluation of coital pain/dyspareunia

        -  The level of dyspareunia the last month will be reported at baseline using VAS 0 (no
           pain) to 100 (worst pain imaginable)

        -  Functional measure of coital impairment (Never pain, Occasional or mild pain - not
           preventing intercourse, Moderate pain - sometimes preventing intercourse, Severe pain -
           most times preventing intercourse). In addition the

        -  Pain at insertion of a normal size tampon will also be reported according to VAS 0-100.

      Vaginal pressure measurement Measurement of vaginal pressure will be performed by the use of
      a thin plastic catheter with a small pressure transducer at the top (4 mm), connected to a
      manometer. The catheter is placed in the vagina, 3 -4 cm from the vaginal opening. Vaginal
      resting pressure in mm Hg (VRP), pelvic floor muscle (PFM) strength, PFM endurance for 10s
      will be measured.

      Venous blood sample of 20 ml to separate genetic studies

      Randomization The research nurse will perform the randomization according to a computerized
      block-randomization and prepare sealed envelopes containing data of randomized treatment for
      each participant. She will also prepare a randomization list with name, personal number and
      randomization number that will be kept locked away in the research department.

      Blinding and masking The research nurse who opens the randomization envelope will prepare the
      syringe with active drug or placebo according to the randomization number. The syringe will
      be marked with the patient's name, personal number and randomization number and left on a
      tray at an assigned place where it will be collected by the insertion provider (responsible
      investigator). Thus, a double blind procedure is obtained. Participation in the study and the
      patient's randomization number will be noted and kept in each patient's Clinical Research
      Format (CRF). Copies of the randomization envelopes will be kept locked away in the research
      department of the Dept. of Obstetrics and Gynecology, Danderyd Hospital. In case of emergency
      the individual envelopes can be obtained at all times and can then be accessed by all
      investigators involved in the study. Thereby the blinding of the study is not jeopardized in
      case of emergency.

      Drug administration A total amount of 50 Allergan-units BTA, diluted in sterile NaCl solution
      9 mg/ml to 0, 5 ml or 0, 5 ml of the sterile NaCl solution 9 mg/ml will be injected at two
      occasions (tree months apart) at 4 sites (2 at each side) in m. bulbocavernosus approximately
      3-4 cm from the vaginal opening by EMG guidance and the use of an EMG needle (37mm x 27G,
      Natus Manufacturing Limited, Ireland).

      Participants without a highly effective anti-conception method will undergo a pregnancy test
      before randomization and treatment. Highly anti-conception methods are defined as; combined
      hormonal method containing estrogen and progesterone (oral, intravaginal, transdermal),
      progesterone only (oral, injectable, implantable), intrauterine device, intrauterine
      hormone-releasing system, bilateral tube occlusion, vasectomized partner, sexual abstinence.

      In between visits, a web-based diary will be kept for reporting of adverse events, pain
      during sexual activity and the result of the tampon test performed once a week at home. The
      research nurse will send e-mails with the questionnaires to be filled in before each
      follow-up visit and check that all questionnaires have been completed. She will also remind
      the participants via e-mail to report adverse events and perform the tampon test as required.

      Visit 2, 4-6 weeks after baseline

      Evaluation of reported adverse events Vaginal pressure measurement

      Visit 3, 12 weeks after baseline Evaluation of reported adverse events Questionnaires for
      psycho-sexual health and QoL - same as Visit 1

      Coital pain and the tampon test (VAS 0-100) and functional measure of coital impairment
      Vaginal pressure measurement Pregnancy test of participants without highly effective
      anti-conception method The patients will be treated with the same treatment as they were
      randomized for at baseline (either 50 Allergan-units BTA (0.5 ml) or 0.5 ml placebo) injected
      in the same manner.

      Visit 4, 16-18 weeks after baseline Evaluation of reported adverse events Vaginal pressure
      measurement

      Visit 5, 24 weeks after baseline Evaluation of reported adverse events Questionnaires for
      psycho-sexual health and QoL - same as Visit 1

      Coital pain and the tampon test (VAS 0-100) and functional measure of coital impairment

      Vaginal pressure measurement Venous blood sample of 20 ml to separate genetic studies At this
      point patients will be offered, if needed, information on conventional treatment of PVD with
      exercises for desensitizing the vestibular mucosa and exercises pelvic floor muscles
      rehabilitation.

      Visit 6, 12 months from baseline Questionnaires for psycho-sexual health and QoL - same as
      Visit 1

      Coital pain and the tampon test (VAS 0-100), and functional measure of coital impairment

      Vaginal pressure measurement

      End of Trial

      The trial is completed when the last patients has come for her Visit 6.

      After the trial is completed, participants who have received placebo will be offered
      treatment with Botox injections, administered the same way as in the study, if the results
      show that Botox is more effective than placebo for PVD and that no serious adverse events
      have occurred during the trial. For the post-trial treatment, the patients have to pay for
      the medication. The treatment is otherwise free of charge. No other treatment for PVD is
      planned to be carried out and the participants will resume contact with their ordinary open
      care gynecologist if needed when the trial is completed.
    

Intervention name(s): Botulinum Toxin Type A; Sterile Saline Solution
Intervention type(s): Drug; Drug
Other intervention name(s): Botox; Sterile saline
Intervention MeSH terms: Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment