Efficacy and Safety of Vaginal Suppositories Containing Combination of Natamycin and Lactulose in Treatment of Vulvovaginal Candidiasis: International, Randomized, Controlled, Superiority Clinical Trial (Combination of Natamycin and Lactulose for Treatment of Vulvovaginal Candidiasis)

Background: The study aimed to assess the efficacy and safety of Natamycin + Lactulose vaginal suppositories (100 mg natamycin and 300 mg lactulose) (AVVA RUS JSC, Russia) in adult females with vulvovaginal candidiasis. Methods and Results: An international, randomized, controlled, assessor-blinded clinical trial enrolled 218 females who were randomized into three groups: Natamycin + Lactulose (92 patients), Lactulose (36 patients), and Pimafucin® (90 patients). The study drug and comparator drugs had an identical dosing regimen (one suppository intravaginally once daily at bedtime for six days). The study involved four visits to the study site with the examination at Visits 2 and 3. Fixed combination of Natamycin + Lactulose was superior to both comparator drugs for the primary efficacy endpoint defined as percentage of patients who achieved a clinical recovery: the absence of symptoms of vulvovaginal candidiasis. At Visit 2, clinical recovery was reported in 81.6% of females in Natamycin + Lactulose group compared to 42.9% in Lactulose group and 62.3% of patients in Pimafucin group. The difference in proportions was 38.8% and 18.4%. In Natamycin + Lactulose group, microscopic recovery (Visit 2) was observed in 75.9% of patients at Visit 2 and in 90.8% of patients at Visit 3. In Lactulose group, 45.7% and 74.3% subjects responded positively at Visits 2 and 3. In Pimafucin group, 71.3% and 88.5% of patients showed microscopic recovery at Visits 2 and 3. For the microscopic recovery, no differences were reported between Natamycin + Lactulose and Pimafucin groups at both visits. At Visit 3, the number of vaginal lactobacilli was significantly higher in Natamycin + Lactulose group. In females with low baseline values of vaginal lactobacilli, the study combination increased the vaginal levels of lactobacilli to the reference values in 15.4% of patients at Visit 2, and in 20.9% of patients at Visit 3. Conclusions: The fixed combination Natamycin + Lactulose 100 mg + 300 mg vaginal suppositories (AVVA RUS JSC, Russia) demonstrated superior efficacy compared to 1) Pimafucin 100 mg and 2) Lactulose 300 mg vaginal suppositories in adult females with vulvovaginal candidiasis. Trial registration: NCT06411314, retrospectively registered on May, the 13 ^th , 2024.