14 CLINICAL STUDIES

Overview of the Clinical Studies

A total of 656 adults and post-menarchal pediatric females with RVVC (defined as ≥3 episodes of vulvovaginal candidiasis (VVC) in a 12-month period) were randomized in two multicenter, multinational, double-blind, placebo-controlled trials: Trial 1 (NCT#03562156) and Trial 2 (NCT#03561701). A total of 219 adults and post-menarchal pediatric females with RVVC were randomized in a multicenter, double-blind trial [Trial 3 (NCT#03840616)]. Although females of reproductive potential were included in the clinical efficacy data, VIVJOA is contraindicated in females of reproductive potential due to the risk of embryo-fetal toxicity [see Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3, 8.4)].

Trial 1 and Trial 2

Trial 1 and Trial 2 were both randomized, placebo-controlled trials evaluating the efficacy and safety of VIVJOA in the reduction of RVVC. Both trials consisted of two phases: an open-label induction phase and an 11-week maintenance phase. Patients received three sequential doses of 150 mg of fluconazole (every 72 hours) on Days, 1, 4 and 7 during the induction phase. Patients returned 14 days after the first dose of fluconazole and if the acute VVC episode was resolved (vulvovaginal signs and symptoms score < 3) they were randomized (2:1) to receive either 150 mg of VIVJOA or placebo for 7 days followed by 11 weekly doses in the maintenance phase.

In Trial 1, a total of 483 patients were enrolled in the induction phase with 326 patients entering the maintenance phase with 217 patients randomized to VIVJOA and 109 patients randomized to placebo. A total of 182 patients (84%) in the VIVJOA group and 91 patients (83%) in the placebo group completed the trial. The mean age of patients was 34 years old (range 17-78 years old) with 85% of patients aged 18-44 years and 15% of patients aged 45 years and older. Patients were 72% White, 13% Black or African American, 14% Asian, and 8% were of Hispanic or Latino ethnicity.

In Trial 2, a total of 425 patients were enrolled into the induction phase with 330 patients entering the maintenance phase with 220 subjects randomized to VIVJOA and 110 patients randomized to placebo. A total of 191 patients (87%) in the VIVJOA group and 91 patients (83%) in the placebo group completed the trial. The mean age of patients was 34 years old (range 18-73 years old) with 85% of patients aged 18-44 years and 15% of patients aged 45 years and older. Patients were 89% White, 10% Black or African American and 15% were of Hispanic or Latino ethnicity.

For both Trial 1 and Trial 2, efficacy was assessed by the proportion of patients with ≥1 culture-verified acute VVC episode (positive fungal culture for Candida species associated with a clinical signs and symptoms score of ≥3) during the Maintenance Phase through Week 48. Evaluation of clinical signs and symptoms included erythema (redness), edema (swelling), excoriation (skin picking), itching, burning and irritation. Since treatment for acute VVC was allowed to be provided to a patient if it was deemed to be clinically needed when the patient had a signs and symptoms score ≥ 3 and a positive KOH test, the proportion of patients with ≥1 culture-verified acute VVC episode or who took medication known to treat VVC during the Maintenance Phase through Week 48 is also presented.

VIVJOA was superior to placebo with reference to the proportion of patients with ≥1 culture‑verified acute VVC episode through Week 48 (Table 2) or the proportion of patients with ≥1 culture-verified acute VVC episode or who took medication known to treat VVC during the Maintenance Phase through Week 48. For both Trial 1 and Trial 2, the average percentage of patients was lower in the VIVJOA groups compared with the placebo group (Table 2).

Table 2: Trial 1 and 2 Efficacy Endpoints: ITT Population
	Trial 1		Trial 2
	VIVJOA (N=217)	Placebo (N=109)	VIVJOA (N=218)	Placebo (N=108)
Abbreviations: ITT=Intent-to-Treat (Population); VVC=vulvovaginal candidiasis.
* Average %. Missing values were imputed with multiple imputation using the following auxiliary information: region, treatment, Baseline body mass index, Baseline age, ethnicity, and visit. † The p-value was obtained using a Chi-square test comparing VIVJOA with placebo.
Proportion of Patients with ≥1 Culture-verified Acute VVC Episode (Day 1 through Week 48)*	6.7%	42.8%	3.9%	39.4%
Treatment Difference p-value†	<0.001		<0.001
Proportion of Patients with ≥1 Culture-verified Acute VVC Episode or received VVC medication (Day 1 through Week 48)*	27.3%	50.8%	21.3%	49.7%
Treatment Difference p-value†	<0.001		<0.001

Trial 3

Trial 3 was a randomized, double-blind trial evaluating the efficacy and safety of VIVJOA versus fluconazole and placebo in adults and post-menarchal pediatric females with RVVC. The trial consisted of two phases: induction and maintenance.

During the induction phase, patients received 1050 mg of VIVJOA over two days (600 mg [4×150mg] on Day 1 and 450 mg [3×150mg] on Day 2) or three sequential doses of 150 mg of fluconazole (every 72 hours) on Days, 1, 4 and 7. Patients returned 14 days after the first dose and moved to the maintenance phase if the acute VVC episode was resolved. During the maintenance phase, patients received 150 mg VIVJOA weekly or placebo weekly for 11 weeks.

A total of 219 patients were randomized (2:1) into the induction phase: 147 to VIVJOA and 72 to fluconazole/placebo. One patient in the VIVJOA group did not receive drug therefore 146 patients received VIVJOA. A total of 112 patients (76%) in the VIVJOA group and 55 patients (76%) in the fluconazole/placebo group completed the trial.

The mean age of patients was 35 years (range 16-78) with 80% of patients aged 18-44 years and 19% of patients aged 45 years and older. Patients were 59% White, 34% Black or African American, 1% Asian and 26% were of Hispanic or Latino ethnicity. The trial was conducted completely in the United States.

Efficacy was assessed by the proportion of patients with ≥1 culture verified acute VVC episode during the maintenance phase (post-randomization through Week 50) or who failed clearing their infection during the induction phase. A recurring acute VVC episode was defined as a positive culture for Candida species and a clinical signs and symptoms score of ≥3. Evaluation of clinical signs and symptoms included erythema(redness), edema (swelling), excoriation (skin picking), itching, burning and irritation. Additionally, the proportion of patients with ≥1 culture verified acute VVC episode or who took medication known to treat VVC during the maintenance phase (post-randomization through Week 50) or who failed clearing their infection during the induction phase is presented.

VIVJOA was superior to fluconazole/placebo in the proportion of patients with ≥1 culture‑verified recurring acute VVC episode during the maintenance phase (post randomization through Week 50) or failed clearing their infection during the induction phase and the proportion of patients with ≥1 culture‑verified recurring acute VVC episode or took VVC medication known to treat VVC during the maintenance phase (post randomization through Week 50) or who failed clearing their infection during the induction phase. The average percentage of patients was lower in the VIVJOA group compared with the fluconazole/placebo group (Table 3).

Table 3: Trial 3 Efficacy Endpoints ITT population
	VIVJOA (N=147)	Fluconazole/Placebo (N=72)	Treatment Difference p-value*
Abbreviations: ITT=Intent-to-Treat (Population); VVC=vulvovaginal candidiasis
* The p-value was obtained using a Chi-square test comparing VIVJOA with fluconazole/placebo. † Average %, Missing values were imputed with multiple imputation using the following auxiliary information: treatment, baseline body mass index, baseline age, ethnicity, and visit.
Proportion of Patients with ≥1 Culture-verified Acute VVC Episode through Week 50 or Unresolved VVC Episode During the Induction Phase†	10.3%	42.9%	<0.001
Proportion of Patients with ≥1 Culture-verified Acute VVC Episode or took VVC medication through Week 50 or Unresolved VVC Episode During the Induction Phase†	43.5%	59.0%	0.039