Table 2.

Clinical trials involving neurokinin B and NKB antagonism

Author	Study design	Cohort	Intervention	Results
A, NKB in healthy males
Jayasena et al (2014) (128)	Randomized single-blinded placebo-controlled trial	23 healthy men	NKB (IV infusion 0.4-5.12 nmol/kg/h over 90 min, 5.12 nmol/kg/h over 4 h)	NKB did not alter LH, FSH, or testosterone levels at all doses
Narayanaswamy et al (2016) (129)	Randomized single-blinded placebo-controlled trial	5 healthy men per group	Naltrexone (oral 50 mg) NKB (IV infusion 2.56 nmol/kg/h over 8 h) KP54 (IV infusion 0.1 nmol/kg/h over 8 h)	Whereas naltrexone and KP54 increased LH levels, NKB did not alter LH or FSH
B, NKB in healthy females
Jayasena et al (2014) (128)	Randomized single-blinded placebo-controlled trial	5-8 premenopausal women per group	NKB (IV infusion 0.32, 0.64, 1.28, 2.56, or 5.12 nmol/kg/h for 3 h) vs vehicle	No change in LH, FSH, and E2 at all doses throughout menstrual cycle
Jayasena et al (2015) (130)	Randomized, double-blinded, placebo-controlled, 2-way crossover trial	10 premenopausal women	NKB (IV infusion 5.12 nmol/kg/h over 30 min) vs vehicle during follicular phase	NKB induced hot flashes in 8/10 women, and elevated heart rate, skin temperature, and thermal imaging
C, NK3R antagonism in PCOS
George et al (2016) (131)	Double-blind, placebo-controlled, phase 2 trial	65 PCOS	AZD4901 (oral 20 mg, 40 mg, 80 mg, once daily for 28 d)	Highest dose of AZD4901 reduced: LH AUC by 52.0% (95% CI, 29.6%-67.3%) LH pulses by 3.55 LH pulses/8 h (95% CI, 2.0-5.1) Total testosterone by 28.7% (95% CI, 13.9%-40.9%)
Skorupskaite et al (2020) (98)	Prospective study	15 PCOS	MLE4901 (oral 40 mg 2×/d for 7 d) vs vehicle	MLE4901 vs vehicle reduced: LH (4.0 ± 0.4 vs 6.5 ± 0.8 IU/L) LH pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h) FSH secretion (2.0 ± 0.3 vs 2.5 ± 0.4 IU/L)
Fraser et al (2021) (132)	Phase 2a, randomized, double-blind, placebo-controlled	73 PCOS	Fezolinetant (oral 60 mg, 180 mg, 4×/d)	Highest dose of Fezolinetant reduced testosterone by 33%, LH by −10.17 IU/L and FSH by −1.46 IU/L
D, NK3R antagonism in menopausal hot flashes
Prague et al (2017) (133)	Phase 2, randomized, double-blind, placebo-controlled, crossover	28 menopausal women	MLE4901(oral 40 mg 2×/d for 4 wk) vs vehicle	MLE4901 reduced hot flash frequency vs vehicle (19.35 vs 49.01 per wk) and decreased hot flash severity vs vehicle (3.27 vs 5.70 per wk)
Depypere et al (2019) (134)	Double-blind, randomized, placebo-controlled	87 menopausal women	Fezolinetant (oral 90 mg 2×/d for 12 wk) vs vehicle	Fezolinetant reduced VMS score vs vehicle (−26.5 vs −12.2) and decreased frequency of moderate/severe VMS by 5 episodes per d
Fraser et al (2020) (135)	Phase 2b, double-blind, randomized, placebo-controlled	287 menopausal women	Fezolinetant (oral 15, 30, 60, 90 mg 2×/d or 30, 60, 120 mg 1×/d for 12 wk) vs vehicle	All doses of fezolinetant, except lowest one, reduced moderate/severe VMS (>2×/d) by 4 and 12 wk
Trower et al (2020) (136)	Double-blind, randomized, placebo-controlled	76 menopausal women	NT-814 (oral 50, 100, 150, 300 mg 1×/d for 14 d) vs vehicle	NT-814 reduced hot flash frequency by 24% (50 mg), 59% (100 mg), 84% (150 mg), and 66% (300 mg)
Lederman et al (2023) (137)	Double-blind, randomized, placebo-controlled	522 menopausal women	Fezolinetant (oral 30 mg or 45 mg 1×/d for 12 wk) vs vehicle followed by 40-wk active treatment extension	Fezolinetant reduced VMS frequency at wk 4 (difference in change in least squares mean –1.87; 30 mg, –2.07; 45 mg) and wk 12 (–2.39; 30 mg, –2.55; 45 mg) Fezolinetant 30 mg or 45 mg 1×/d, reduced severity of VMS at wk 4 (−0.15 to −0.19) and wk 12 (−0.24 to −0.2)

Abbreviations: AUC, area under the curve; E2, estradiol; FSH, follicle-stimulating hormone; IV, intravenous; KP, kisspeptin; LH, luteinizing hormone; NK3R, neurokinin 3 receptor; NKB, neurokinin B; PCOS, polycystic ovary syndrome; VMS, vasomotor symptoms.