We have safely conducted a clinical trial of a drug not routinely used during pregnancy. Sildenafil in the escalating dose regimen 20-80 mg tid was well tolerated, with no increase in maternal or fetal morbidity or mortality but did not prolong pregnancy duration in women with preeclampsia. (ClinicalTrials.gov number, NCT 00141310).

Objective: Menopausal vasomotor symptoms (VMS) may result from altered thermoregulatory control in brain regions innervated by neurokinin 3 receptor-expressing neurons. This phase 2b study evaluated seven dosing regimens of fezolinetant, a selective neurokinin 3 receptor antagonist, as a nonhormone approach for the treatment of VMS. Methods: Menopausal women aged >40-65 years with moderate/severe VMS (≥50 episodes/wk) were randomized (double-blind) to fezolinetant 15, 30, 60, 90 mg BID or 30, 60, 120 mg QD, or placebo for 12 weeks. Primary outcomes were reduction in moderate/severe VMS frequency and severity ([number of moderate VMS × 2] + [number of severe VMS × 3]/total daily moderate/severe VMS) at weeks 4 and 12. Response (≥50% reduction in moderate/severe VMS frequency) was a key secondary outcome. Results: Of 352 treated participants, 287 completed the study. Fezolinetant reduced moderate/severe VMS frequency by −1.9 to −3.5/day at week 4 and −1.8 to −2.6/day at week 12 (all P < 0.05 vs placebo). Mean difference from placebo in VMS severity score was −0.4 to −1 at week 4 (all doses P < 0.05) and −0.2 to −0.6 at week 12 (P < 0.05 for 60 and 90 mg BID and 60 mg QD). Response (50% reduction) relative to placebo was achieved by 81.4% to 94.7% versus 58.5% of participants at end of treatment (all doses P < 0.05). Treatment-emergent adverse events were largely mild/moderate; no serious treatment-related treatment-emergent adverse events occurred. Conclusions: Fezolinetant is a well-tolerated, effective nonhormone therapy that rapidly reduces moderate/severe menopausal VMS. Video Summary: http://links.lww.com/MENO/A572; video script available at http://links.lww.com/MENO/A573.

Objective: In the primary analysis of the phase 2b VESTA study, oral fezolinetant reduced frequency and severity of menopausal vasomotor symptoms (VMS) compared with placebo. This secondary analysis evaluates effects of fezolinetant on responder rates and patient-reported outcomes (PROs). Methods: In this 12-week, double-blind study, postmenopausal women with moderate/severe VMS were randomized to fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo. Proportion of responders was based on reductions in VMS from daily diary records. P values for comparisons between active treatment and placebo were calculated using logistic regression. Changes from baseline in PROs (Menopause-Specific Quality of Life questionnaire, Hot Flash-Related Daily Interference Scale, Greene Climacteric Scale) were conducted using a mixed model for repeated measurements and compared post hoc with published minimally important differences (MIDs). Results: Of 356 women randomized, 352 were treated and analyzed. A greater proportion of women receiving fezolinetant versus placebo met definitions of response at week 12. For all doses, mean changes from baseline in Menopause-Specific Quality of Life questionnaire VMS scores exceeded the MID (1.2) at weeks 4 (placebo: −1.8; fezolinetant: range, −1.9 to −3.6) and 12 (placebo: −2.3; fezolinetant: range, −2.9 to −4.4). Mean changes in Hot Flash-Related Daily Interference Scale at weeks 4 (placebo: −2.2; fezolinetant: range, −2.5 to −3.8) and 12 (placebo: −2.9; fezolinetant: range, −3.3 to −4.3) exceeded the MID (1.76). Greene Climacteric Scale-VMS domain scores improved for most fezolinetant doses versus placebo (week 4, placebo: −1.7; fezolinetant: range, −2.1 to −3.3; week 12, placebo: −2.1; fezolinetant: range, −2.7 to −3.6). Conclusions: Oral fezolinetant was associated with higher responder rates than placebo and larger improvements in QoL and other PRO measures, including a reduction in VMS-related interference with daily life.

No abstract