The efficacy and safety of a single dose of Clindesse vaginal cream versus a seven-dose regimen of Cleocin vaginal cream in patients with bacterial vaginosis.

OBJECTIVE: To determine whether a single dose of Clindesse vaginal cream is comparable in efficacy and safety to Cleocin vaginal cream administered once daily for 7 days in the treatment of bacterial vaginosis. STUDY DESIGN: This multicenter, randomized, single-blind, parallel-group study enrolled 540 patients with BV infections. Treatment consisted of either a single intravaginal dose of Clindesse or 7 daily doses of Cleocin. Efficacy and safety were assessed 21-30 days after the start of treatment. The efficacy endpoints were Investigator Cure, Clinical Cure (a composite of all 4 Amsel's criteria and Investigator Cure), Nugent Cure (Nugent score < 4), and Therapeutic Cure (a composite of Clinical Cure and Nugent Cure). Resolution of individual Amsel's criteria was also evaluated. Treatment-emergent adverse events were monitored throughout the study. RESULTS: There were no significant differences in cure rates between the Clindesse and Cleocin treatment groups in Investigator Cure (P=0.702), Clinical Cure (P=0.945), Nugent Cure (P=0.788), or Therapeutic Cure (P=0.572). Results were also similar for 3 of 4 and 2 of 4 Amsel's criteria and for each individual Amsel's criterion (all P-values >0.200). Ninety-five percent confidence intervals for each endpoint were consistent with equivalence between the 2 products. There was no significant difference between the treatment groups in the incidence of treatment-emergent adverse events (P=0.386). CONCLUSIONS: A single dose of Clindesse vaginal cream is equivalent in safety and efficacy to a 7-dose regimen of Cleocin vaginal cream in the treatment of bacterial vaginosis. This represents a significant advance in the treatment of bacterial vaginosis.


Introduction
Bacterial vaginosis (BV) continues to be one of the most common vaginal disorders in reproductive-age women. It represents 40-50% of all cases of vaginitis, surpassing both vaginal candidiasis and vaginal trichomoniasis [1]. It causes significant patient discomfort and has been associated with many disorders of the female reproductive tract, including recurrent urinary tract infections, adnexal tenderness, postpartum endometritis, increased risk of infection after gynecologic surgery, pelvic inflammatory disease, and adverse pregnancy outcomes. BV results from replacement of the normal Lactobacillusdominant vaginal flora with polymicrobial, primarily anaerobic, bacteria. The cause of this microbial shift is not fully understood [2,3].
Recommended antimicrobial treatments for nonpregnant women often include oral or intravaginal therapy with clindamycin. While both oral and intravaginal administrations are effective, intravaginal medications may result in fewer of the adverse side effects associated with oral antibiotic therapy such as nausea, vomiting, and taste perversion [4,5]. In addition, patients treated with intravaginal therapies report increased treatment satisfaction compared with those treated with oral therapies [6]. Most intravaginal therapies for BV, like oral therapies, require the inconvenience of daily use for multiple days, and this inconvenience may have a negative effect on treatment compliance and satisfaction [7]. Thus, an effective single-dose vaginal treatment for BV might be beneficial to women from a number of different points of view. Clindesse TM (clindamycin phosphate) vaginal cream 2% is a single-dose intravaginal therapy recently approved for use in the treatment of BV in nonpregnant women. Clindesse TM uses a patented, sustained-release, single-dose, topical cream emulsion. In vitro studies with this cream technology have shown that in an acetate buffer of pH 4.3, which simulates normal vaginal fluid, the sustained release cream is highly stable and remains intact for a prolonged period of time. Under the same conditions, a conventional cream rapidly disintegrates and releases the active ingredient into the medium (data on file, KV Pharmaceutical Company, St. Louis, Missouri). Clinical studies demonstrated that butoconazole nitrate 2% in this sustained-release formulation remains in the vagina 63% longer than butoconazole nitrate 2% in a conventional formulation (median retention time 4.2 days versus 2.6 days) [8].
Given the ability of Clindesse TM to maintain therapeutic levels of clindamycin in the vagina for a prolonged period of time, we hypothesize that a single dose of Clindesse TM would be equivalent to a 7-day course of a conventional clindamycin phosphate intravaginal cream. Such reductions in dosing frequency have been shown to increase treatment compliance, patient satisfaction, and quality of life [7]. Thus, the purpose of the current study was to determine whether a single dose of Clindesse TM is equivalent in safety and efficacy to a 7-day regimen of Cleocin 1 vaginal cream in the treatment of BV.

Material and methods
The study was designed in accordance with the United States Food and Drug Administration FDA Center for Drug Evaluation and Research (CDER) 1998 draft guidelines for developing effective treatments for BV [2]. This was a multicenter, single (Investigator)-blind, active-controlled study. Patients were recruited at 28 clinics in the United States, each with its respective IRB/ethics board approval. All patients provided signed informed consent before any study-related procedure was performed. Eligible patients were nonpregnant women at least 18 years of age with a clinical diagnosis of BV, which was defined as meeting all of Amsel's criteria [9] ( 5 20% clue cells, off-white [milky or gray], thin, homogenous vaginal discharge, vaginal pH 4 4.5, a fishy amine odor upon the addition of 10% KOH to vaginal fluid [''whiff'' test]). Patients were excluded if they were pregnant or nursing; had sexually transmitted infections, had vulvovaginal infections other than BV, had vulvovaginal or cervical abnormalities or disorders; were actively menstruating; had received antifungal or antimicrobial treatment within 14 days of the study; were using intrauterine devices (IUDs); were taking anticoagulants, lithium, disulfiram, or neuromuscular blocking agents; or were hypersensitive to clindamycin, lincomycin, or to any excipient in the drug formulation.
Eligible patients were randomly assigned to 1 of 2 treatment arms (Clindesse TM or Cleocin 1 ) in a single (Investigator)-blind fashion according to a computergenerated randomization schedule. Patients were instructed in the appropriate study medication administration techniques, which were to be performed or started within 48 hours after leaving the clinic. Clindesse TM vaginal cream consisted of 2% clindamycin phosphate formulated in 5 g of the sustained-release vaginal cream, for a total of 100 mg clindamycin phosphate. Clindesse TM was self-administered by patients in a single dose. Cleocin 1 vaginal cream also consisted of 2% clindamycin phosphate, but formulated in 5 g of a conventional vaginal cream. Cleocin 1 was self-administered by the patient once daily for 7 consecutive days. Treatment effectiveness was evaluated and compared at a Test-Of-Cure (TOC) visit 21-30 days following the start of treatment, using several clinical and microbiologic indices. Investigator Cure was based on the Investigator's response (Yes/No) to a question at the TOC visit regarding the need for additional BV treatment. Clinical Cure was a composite endpoint including resolution of all 4 Amsel's criteria and Investigator Cure. Nugent Cure was defined as a Gram stain Nugent score [10] 5 4 (on a 10-point scale). Therapeutic Cure was a composite endpoint defined as both Clinical Cure and Nugent Cure. In addition, the 4 Amsel's criteria were each evaluated individually. The TOC visit was selected to demonstrate both status and duration of outcome. The per-protocol (PP) population was selected for the efficacy analyses in accordance with demonstration of equivalence between treatments.
The safety of the 2 treatments was evaluated by monitoring treatment-emergent adverse events (AEs) throughout the study.

Statistical methods
Efficacy endpoints were analyzed using the centerstratified Cochran-Mantel-Haenszel (CMH) estimate of the difference in cure rates and corresponding confidence interval [11]. Clindesse TM was to be considered equivalent to Cleocin 1 if the 2sided 95% confidence interval (CI) for the difference in cure rates (Clindesse TM minus Cleocin 1 ) had a lower limit greater than 7 20% and an upper limit less than + 20%. Efficacy analyses were performed using a PP population, which included patients who administered study medication, had baseline Nugent scores 5 4, had assessment results at the TOC visit or discontinued participation in the study prior to the TOC visit due to lack of efficacy, had no antimicrobial therapy for conditions other than BV during the study, started study medication within 48 hours of the entry visit, and had no major violations of the study protocol. All patients who administered at least 1 dose of study medication were included in the safety analyses.

Results
Of the 540 patients enrolled in the study (271 in the Clindesse TM group and 269 in the Cleocin 1 group), 253 (46.9%) were considered evaluable for the PP population (128 in the Clindesse TM group and 125 in the Cleocin 1 group). Of the 287 patients who were not evaluable in the PP population, 92 had baseline Nugent scores 5 4, 64 participated in the study for less than 21 days but were not treatment failures, and 52 did not start study medication within 48 hours of the Entry Visit. These 3 reasons account for approximately 75% of the patients who were not evaluable in the PP population. The percentages of patients with each primary reason for non-evaluability were similar between the treatment groups. A complete listing of the primary reasons for nonevaluability in the PP population by treatment group is in Table I. Cure of BV was evaluated by a number of different measures. Frequencies of Investigator Cure, Clinical Cure, Nugent Cure, and Therapeutic Cure are presented in Table II.
The Investigator Cure represents the Investigator's assessment of the need for additional therapy for BV at the TOC Visit. Investigator Cure (no additional therapy required for BV) was achieved in 89.1% of Clindesse TM patients and 86.4% of Cleocin 1 patients at the TOC visit. There were no statistically significant differences in Investigator Cure rates between treatment groups (P = 0.702) and the 95% CIs for the differences were consistent with equivalence with regard to the need for additional treatment of BV as assessed by the Investigator. Clinical Cure, which represents both alleviation of BV signs and symptoms and alleviation of the need for additional BV therapy at the TOC visit, was achieved in 64.3% of Clindesse TM patients and 63.2% of Cleocin 1 patients. There were no statistically significant differences in Clinical Cure rates between treatment groups (P = 0.945). Similar cure rates were also observed in the 2 treatment groups when less stringent criteria were used to define cure. If 3 of the 4 Amsel's criteria are used to define cure, 87.5% of Clindesse TM patients and 83.2% of Cleocin 1 patients are cured (P = 0.399). When 2 of the 4 Amsel's criteria are used to define cure, cure rates increase to 90.6% of Clindesse TM patients and 91.2% of Cleocin 1 patients (P = 0.792). There were no statistically significant differences in cure rates between treatment groups and the 95% CIs for the differences were consistent with equivalence in the alleviation of BV signs using both 2 and 3 of the 4 Amsel's criteria.
In addition, there were no statistically significant differences in resolution of Amsel's criteria between the treatment groups when the criteria for clue cells ( 5 20%) and a negative ''whiff'' test were evaluated together (P = 0.965) or when the criteria for clue cells, ''whiff'' test, and vaginal pH ( 5 4.7) were evaluated together (P = 0.539). The cure rates associated with each Amsel's criterion and selected groups of criteria are presented in Table III. Table I. Primary reasons for non-evaluability in the per-protocol population by treatment group. were discontinued due to Vaginal Yeast Infections. There was 1 serious AE (cellulitis) reported by a patient receiving Cleocin 1 during the study. The event was judged to be unrelated to the study medication by the investigator.

Discussion
As we hypothesized, analyses of interpretive, symptomatic, and diagnostic efficacy variables revealed no statistically significant differences between use of clindamycin phosphate 2%, administered in a singledose vaginal cream (Clindesse TM ), and in a standard 7-day vaginal cream (Cleocin 1 ).
Investigator Cure is an interpretive measure representing the requirement for additional therapy  N) and to have achieved cure if data for 1 Amsel's criterion were missing, but all other criteria were consistent with cure.  [5].
Although there may be some differences between these studies (e.g., study populations, inclusion criteria, patient evaluability), the cure rates observed were comparable to the 87.5% and 83.2% rates observed using the same definition of cure with Clindesse TM and Cleocin 1 , respectively, in this study. Previous clinical studies performed with Cleocin 1 defined BV cure as resolution of 2 of Amsel's criteria (the ''whiff'' test and clue cell criteria) and reported a cure rate of 86% for a 7day dosing regimen [12]. This is comparable to the 84.4% and 84.0% cure rates observed using these 2 criteria with Clindesse TM and Cleocin 1 , respectively, in this study.
In the study reported here, there were no significant differences in the incidence of AEs between the treatment groups, and AEs commonly associated with oral therapy (e.g., nausea, taste perversion) were reported in less than 1% of the patients in either treatment group.

Conclusions
Overall, a single-dose regimen of Clindesse TM was shown to be comparable with respect to both efficacy and safety to Cleocin 1 . Clindesse TM , however, provides equivalent efficacy and safety in a single dose, compared with a 7-dose regimen of Cleocin 1 .
It has been shown that reducing dose frequency increases the patient's compliance with treatment, symptom control, satisfaction with treatment, and quality of life in a number of disease states [7]. Clindesse TM offers these advantages, and therefore represents an important therapeutic advance in the treatment of BV. non-missing data in the PP population for each treatment group. n and % denote the frequency of patients cured in the PP population within each endpoint for each treatment group; | P-value was derived using FET to determine if rates of events differed between treatment groups.
Safety and efficacy of Clindesse TM versus Cleocin 1