Vulvar Vestibulitis Clinical Trial: Desipramine-Lidocaine
Condition: Vulvar Disease
MeSH terms: Vulvar Vestibulitis; Vulvar Diseases
Study type: Interventional

Summary: 
      The Vulvar Vestibulitis Clinical Trial (VVCT) a randomized, placebo-controlled, double
      blinded clinical trial. We will study the clinical efficacy of four medical treatments for
      vulvar vestibulitis: topical lidocaine, oral desipramine, combined lidocaine and desipramine,
      and placebo cream and capsules. Desipramine is a tricyclic antidepressant commonly used by
      clinicians for treatment of several chronic pain conditions that demonstrates an optimal side
      effect profile compared to other tricyclic antidepressants. Topical lidocaine has also been
      found to be beneficial for vulvar vestibulitis treatment in small studies. It is hypothesized
      that the combined use of oral desipramine and topical lidocaine will be more therapeutically
      effective than either one by itself and better than placebo.
    

Detailed description: 
      The Vulvar Vestibulitis Clinical Trial (VVCT) is a randomized, placebo-controlled,
      double-blinded clinical trial to study the clinical efficacy of four medical treatments for
      vulvar vestibulitis: 1) topical lidocaine, 2) oral desipramine, 3) combined lidocaine and
      desipramine, and 4) placebo cream and capsules. The duration of study drug will last 12 weeks
      with post-intervention follow-up at 6 and 12 months. We plan to enroll 128 subjects from the
      university-based clinical program at the University of Rochester (UR).Primary outcome
      variable will compare the reported pain of the "Tampon Test" (mean of Weeks -2, -1, and 0),
      prior to randomization to the reported pain of "Tampon Test" (mean of Weeks 10, 11, and 12).
      The dependent (primary outcome) variable will be defined as the percent change of mean
      "Tampon test" pain of Weeks (10, 11, and 12) from Weeks (-2, -1 and 0). The primary analysis
      of this 2X2 factorial design will involve fitting an Analysis of Covariance (ANCOVA)
      regression model to the percent change of mean "Tampon test" pain with the two treatment
      variables as the predictors while adjusting for the covariate age. We will test if the
      interaction between the two treatments in the ANCOVA model is significant at the .05 level.
      If the interaction effect is not significant, it will be dropped from the model and the
      conclusion will be drawn from the model with main effects only. If significant, the model
      with interactions will be adopted. SAS PROC GLM will be used in the analysis.

      In the case of non-significant interaction, the primary analysis will be based on the ANCOVA
      model with main effects of treatments and adjusting for age. Since there are two treatments
      under investigation, the primary analysis will use the Bonferroni correction, i.e. will set
      alpha level of 0.025 (two-sided) to determine statistical significance. The significance of
      the main effect of each treatment will be assessed by t-tests in the ANCOVA model. The aim of
      the primary analysis is to determine whether each treatment is superior to placebo, and if
      both hypotheses hold, the double treatment therapy will be most effective under the additive
      effect assumption of the ANCOVA model. The ANCOVA model compares all subjects who receive
      that treatment with all subjects who do not, irrespective of whether they receive the other
      treatment, after adjusting for the other treatment and age of subject, and is more powerful
      in finding individual treatment effects in the study.

      If interaction between treatments is significant, the ANCOVA model with interaction will
      estimate the treatment effects for each of the four groups. This model is able to test all 6
      contrasts between the four combinations. A hierarchical (gatekeeping) testing strategy to
      maintain a family-wise error rate will be adopted as the following: the first stage will
      compare desipramine or lidocaine individually to placebo with multiplicity-adjusted p-values.
      If a significant difference (one or both null hypotheses rejected) is found for either or
      both individual agents, then the analysis will proceed to the second-stage of hypothesis
      which will compare the effects of the active desipramine/active lidocaine treatment to the
      double placebo. If a significant difference (null hypothesis rejected) is found for combined
      therapy over placebo based on the multiplicity-adjusted p-value, then the final (tertiary)
      stage of comparison will be performed comparing combined therapy to individual therapy. In
      the hierarchical (gatekeeping) testing procedures, inferences in each stage depend on the
      acceptance or rejection of null hypotheses in all previously stages, and each stage serves as
      a gatekeeper for the stages later in the sequence. In our strategy for the model with
      significant interaction effect, if at least one hypothesis has been rejected, then the next
      stage of hypotheses will be tested, and the family-wise error rate is controlled at the .05
      level.

      Secondary analyses will include subset analysis, comparison of the double-active treatment
      group against the others (placebo and the single-treatment groups) on percent change of mean
      "Tampon test" as well as standardized pain measures such as the Brief Pain Inventory and the
      McGill Pain Questionnaire. This is to explore if the active desipramine/active lidocaine
      treatment has more advantages that may not be shown in the ANCOVA model. The secondary
      analysis is to explore supportive evidence to the primary objective of this trial, and no
      confirmatory conclusions are needed. In the secondary analysis, confidence intervals and
      statistical tests are of exploratory nature and no claims are intended.

      Primary and secondary outcome variables will be analyzed according to a modified "intention
      to treat" with "last observation carried forward". The sample analyzed for the primary
      outcome will include the first three or fewer pre-randomization Tampon Test measures and the
      last three or fewer post-randomization Tampon Test measures, up to and including study Week
      12. The subject sample analyzed for drug safety/side effects will include all subjects who
      have taken at least one dose of study drug.
    

Intervention name(s): topical lidocaine + oral desipramine, and/or placebo
Intervention type(s): Drug
Intervention MeSH terms: Lidocaine; Desipramine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Keywords: Vulvar vestibulitis; Vulvodynia; Desipramine; Lidocaine; Genetics