Estradiol softgel inserts for the treatment of VVA symptoms: an expert opinion

Figures & data

Figure 1. REJOICE trial efficacy data: Change in co-primary endpoints over time from baseline to week 12: (a) superficial cells, (b) parabasal cells, (c) vaginal pH, and (d) severity of dyspareunia [16]. ^ap < 0.05, ^bp < 0.01, ^cp < 0.001 for TX-004 HR versus placebo. Figure modified from Simon et al 2017 [18]

Table 1. Visual assessments in the REJOICE trial: LS mean change from baseline to weeks 2 and 12 [22]

Vaginal Parameters	TX-004 HR 4 µg		TX-004 HR 10 µg		TX-004 HR 25 µg		Placebo
Vaginal color Baseline score, mean ± SD LS Mean (SE) Week 2 Week 12	n 186 185 171	1.8 ± 0.61 –0.69 (0.05)^b -0.97 (0.05)^b	n 188 187 173	1.7 ± 0.59 –0.77 (0.05)^b -1.06 (0.05)^b	n 186 184 175	1.8 ± 0.60 –0.78 (0.05)^b -0.96 (0.05)^b	n 187 186 175	1.7 ± 0.64 –0.40 (0.05) -0.60 (0.05)
Vaginal epithelial integrity Baseline score, mean ± SD LS Mean (SE) Week 2 Week 12	n 186 185 171	1.6 ± 0.84 –0.85 (0.05)^b -0.97 (0.05)^b	n 188 187 173	1.4 ± 0.83 –0.87 (0.05)^b -1.07 (0.05)^b	n 186 184 175	1.5 ± 0.77 –0.93 (0.05)^b -1.01 (0.05)^b	n 187 186 175	1.5 ± 0.84 –0.53 (0.05) -0.60 (0.05)
Vaginal epithelial surface thickness Baseline score, mean ± SD LS Mean (SE) Week 2 Week 12	n 186 185 171	1.9 ± 0.67 –0.76 (0.05)^b -0.98 (0.05)^b	n 188 187 173	1.8 ± 0.63 –0.76 (0.05)^b -1.03 (0.05)^b	n 186 184 175	1.9 ± 0.59 –0.76 (0.05)^b -0.94 (0.05)^b	n 187 186 175	1.9 ± 0.65 –0.40 (0.05) -0.61 (0.05)
Vaginal secretions Baseline score, mean ± SD LS Mean (SE) Week 2 Week 12	n 186 185 171	1.8 ± 0.68 –0.79 (0.05)^a -1.01 (0.05)^b	n 188 187 173	1.7 ± 0.66 –0.83 (0.05)^b -1.06 (0.05)^b	n 186 184 175	1.7 ± 0.63 –0.86 (0.05)^b -1.04 (0.05)^b	n 187 186 175	1.8 ± 0.63 –0.54 (0.05) -0.64 (0.05)

LS: least square; SD: standard deviation; SE: standard error.

^ap < 0.001; ^bp < 0.0001 vs placebo.

Figure 2. Women’s (a) satisfaction with TX-004 HR; (b) likelihood of using TX-004 HR again; (c) treatment preference over previously used vulvar and vaginal atrophy treatments. P-value vs placebo. Figure modified from Kingsberg et al, 2017 [30]

Figure 3. Phase 2 studies: baseline-corrected mean plasma concentration versus time curve for estradiol after treatment with TX-004 HR (a) 10 µg and (b) 25 µg versus comparator. AUC_0-24 comparison is significantly different for both doses (p < 0.001). Figure modified from Pickar et al, 2017 [31]

Table 2. Mean estrogen values in pharmacokinetic trials and ANOVA results for comparisons between TX-004 HR (TherapeuticsMD, Boca Raton, FL) and Vagifem (Novo Nordisk, Plainsboro, NJ) [31]

	AUC0-24 (pg·hr/mL)				Cmax (pg/mL)				tmax (hr)
Dose (µg)	TX-004 HR	Vagifem	p-value	Ratio*	TX-004 HR	Vagifem	p-value	Ratio*	TX-004 HR	Vagifem
Estradiol 10 25	49.62 89.21	132.92 292.1	< 0.0001 < 0.0001	38% 31%	14.38 23.08	20.38 42.70	0.0194 < 0.0001	72% 54%	1.75 1.85	9.28 11.18
Estrone 10 25	24.24 50.22	48.24 165.5	0.0002 < 0.0001	46% 31%	5.15 10.69	6.98 23.58	0.0127 0.0002	75% 51%	5.87 5.14	9.07 11.48
Estrone sulfate 10 25	66.6 (ng·hr/dL) 4290	121.6 (ng·hr/dL) 7330	0.0091 0.0031	67% 58%	12.2 (ng/dL) 497.6	16.9 (ng/dL) 730.6	0.0366 0.0042	75% 58%	5.5 11.75	8.8 15.87

Data represented as baseline adjusted geometric mean. *Ratio of TX-004 HR to Vagifem. P-values between TX-004 HR and Vagifem

Figure 4. REJOICE trial PK substudy: unadjusted mean serum estradiol concentrations over time after treatment with TX-004 HR (A) 4 µg (n = 18), (B) 10 µg (n = 19), or (C) 25 µg (n = 18) versus placebo (n = 16) at days 1, 14, and 84 (approximately 4 h after the last TX-004 HR dose); ^a4 days post-dosing. Figure modified from Archer et al, 2017 [32]

Constantine G, Simon JA, Pickar JH, et al. The REJOICE trial: a phase 3 randomized, controlled trial evaluating the safety and efficacy of a novel vaginal estradiol soft-gel capsule for symptomatic vulvar and vaginal atrophy. Menopause. 2017;24(4):409–416.

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