. 2021 Sep 12;38(10):5025–5045. doi: 10.1007/s12325-021-01900-w

Table 5.

Neurokinin 3 receptor antagonists (NK3Ra) study results

Clinical trial	Trial design and key participant BL data	Key outcomes	Results (p-values vs. placebo)
1a. Prague et al The Lancet (2017) [29]	DBRCT; Cross-over trial: 1 UK centre Mean age = 55 years (49–62) Mean BMI = 25.85 kg/m² 38 randomised to 4 weeks MLE4901 (40 mg BID) and 4 weeks placebo (BID) in random order separated by a 2-week washout period 37 included in ITT analysis	1°: # of weekly HFs during week 2°: HF severity, bother and interference scores at week 4 Important AEs/SAEs Discontinuations	1°: ↓ in weekly # of HFs from BL vs. placebo [ITT adjusted means: 19.35 (73%↓) vs. 49.01 (28%↓], respectively; p < 0.001] 2°: ↓ HF severity score from BL vs. placebo [3.27 (44%↓) vs. 5.70 (5%↓), p < 0.0001], ↓ bother score (2.92 vs. 5.56, p < 0.0001), and ↓ interference score (7.94 vs. 26.48, p < 0.0001) 3 developed a transaminase rise (ALT 4.5–5.9 × upper limit of normal) but normal bilirubin, occurring 28 days after starting, which normalised within 90 days Discontinuations (24%) higher than expected (mostly not MLE4901-related)
1b Prague et al Menopause (2018) [30]	Prague et al. [30] reports a post hoc time course analysis of Prague et al. [29] to define therapeutic profile of MLE4901 by comparing the mean daily total of HFs at day 3, and mean weekly total after weeks 1, 2, 3, and 4 of both Tx periods, and also compared with week 2 of the BL period Post hoc analysis of questionnaire data (minimum n = 33, maximum n = 35)	# of HFs HF severity, bother and interference Impact on sleep via: # of night-time HFs Individual MENQoL items Individual HFRDIS items	↓ # of HFs from BL vs. placebo by day 3 (72%↓ vs. 21%↓; p < 0.0001), maintained through to week 4 HF severity, bother & interference continued to improve vs. placebo. At day 3: ↓ HF severity from BL by 38% (vs. 7%↓; p < 0.0001), which ↓ to − 44% by week 4 (vs. 5%↓) ↓ HF bother from BL by 39% (vs. 5%↓; p < 0.0001), which ↓ to − 50% by week 4 ↓ HF interference from BL by 61% (vs. 24%↓; p = 0.0006), which ↓ to − 70% by week 4 Impact of sleep: ↓ night-time HFs from BL vs. placebo at week 4 (78%↓ vs. 22%↓; p < 0.0001). Improvements rapid, significant by day 3 vs. placebo (p < 0.0001) Improved MENQoL psychosocial and physical domains at week 4. Authors suggested due to improved sleep since ‘difficulty sleeping’, ‘lethargy’ and ‘tiredness’ improved at week 4 (p < 0.0001, p = 0.00128, and p = 0.0002, respectively), and ‘lethargy’ and ‘tiredness’ improved by day 3 (p = 0.0474 and p = 0.0132, respectively), whereas ‘muscle ache’ and ‘physical strength’ did not improve Improved ‘sleep’ and ‘concentration’, significant by day 3 vs. placebo (sleep: p = 0.001; concentration: p = 0.0075) (HFRDIS)
2 Depypere et al Journal of Clinical Endocrinology and Metabolism (2019) [31]	DBRCT: 8 Belgian centres Mean age = 53.5 years (44–64) Mean BMI = 25.8 kg/m² 87 randomised (1:1) to fezolinetant 90 mg BID or placebo for 12 weeks 87 included in mITT analysis (inferred from Fig. 2A but this is unclear)	1°: ∆ from BL in mean daily total VMS score (composite of # and severity) at week 12 2°: Important AEs/SAEs Discontinuation due to AEs	1°: ↓ mean daily total VMS score from BL vs. placebo at week 4, 8 and 12 [week 12: 2.7 (91%↓) vs. 14.4 (44%↓); all comparisons p < 0.001] 2°: ↑ AEs considered Tx-related vs. placebo (30.2% vs. 25%), most commonly GI disorders (23% vs. 9%) ↑ discontinuations due to AEs (2 (4.7%) vs. 0)
3a Fraser et al VESTA Menopause (2020) [32]	DBRCT; Dose-ranging: 51 US centres Mean age = 54.6 years (41–65) Mean BMI = 28.4 kg/m² 356 randomised (1:1) to fezolinetant BID 15, 30, 60, or 90 mg, or fezolinetant QD 30, 60, or 120 mg or placebo for 12 weeks 349 included in mITT analysis	1°: Mean ∆ in # of mod/severe HFs from BL at weeks 4 and 12 Mean ∆ in mod/severe HF severity from BL at weeks 4 and 12 2°: Important AEs/SAEs Discontinuation due to AEs	1°: All doses ↓ # of mod/severe HFs from BL vs. placebo at week 4 (ranging 62–81%↓ vs. 39%) and week 12 (ranging 74–87%↓ vs. 55%); all p ≤ 0.024 All doses ↓ mod/severe HF severity from BL vs. placebo at week 4 (ranging 29–54%↓ vs. 12%↓; all p ≤ 0.0322) and 60 mg BID, 90 mg BID, and 60 mg QD at week 12 ranging (52–53%↓ vs. 32%↓; all p ≤ 0.016) 2°: AEs similar across Tx groups, with no indication of a dose effect. Most commonly nausea, diarrhoea, fatigue 2 severe (but not serious) AEs considered Tx-related (both 60 mg QD): 1 cholelithiasis, 1 drug-induced liver injury (ALT [14.1xULN] and AST [9.5xULN] in a woman with obesity and NASH) 9 had ALT or AST > 3xULN, and 3 (60 mg BID, 90 mg BID, and 60 mg QD) had ALT or AST > 8xULN. None had total bilirubin > 2xULN ∴no cases met criteria for Hy’s law. ALT/AST levels rapidly returned to BL values after discontinuation/trended toward normalization while on drug Discontinuations due to AEs vs. placebo: Numerical ↑
3b Santoro et al VESTA Menopause (2020) [33]	Santoro et al. [33] reports results of 2° endpoints from VESTA [32]	% achieving 50%, 70% and 90% ↓ from BL in # of mod/severe HFs	Responder analyses ↑ ≥ 50% responder rate (all doses p < 0.05). All doses numerical ↑ in 70% and 90% responder rates (with magnitude and sig varying by dose and responder rate) Shorter time to 50% ↓ in HFs vs. placebo (2.2–8.4 days vs. 15.1 days; no p-value given)
4 Trower et al RELENT-1 Menopause (2020) [34]	DBRCT; multiple-ascending-dose study: 3 US centres Mean age = 55 years Mean BMI = 28.18 kg/m² 76 randomised (3:1) to NT-814 vs. placebo within each of 4 sequential dose cohorts; 50, 100, 150, and 300 mg/day for 2 weeks 76 included in mITT analysis	Pre-specified exploratory efficacy endpoints: ∆ from BL in daily # of mod/severe HFs at week 2 ∆ from BL in avg. daily HF severity at week 2 ∆ from BL in daily #. of waking due to night sweats Important AEs/SAEs Discontinuation due to AEs	50 mg and 100 mg no significant ↓ in HF endpoints. (With 50 mg vs. placebo, mean HF frequency actually higher (p = 0.048) although median HF frequency no difference) ↓ # of mod/severe HFs from BL vs. placebo [150 mg 84%↓ (p < 0.001), 300 mg 66%↓ (p = 0.022) vs. 37%↓] Doses ≥ 150 mg improved symptoms early (within week 1 of Tx) ↓HF severity vs. placebo with 150 mg [41%↓ vs. 13%↓ (p < 0.001)]; 300 mg no sig. difference ↓waking due to night sweats vs. placebo [150 mg 81%↓ (p < 0.001), 300 mg 63%↓ (p = 0.031) vs. 32%↓)]. AEs similar with placebo, 50 mg, 100 mg and 150 mg groups (slightly higher in 300 mg group) Most common: mild somnolence and headache No discontinuation due to AEs

Clinical trial

Trial design and key participant BL data

Key outcomes

Results (p-values vs. placebo)

1a.

Prague et al

The Lancet (2017) [29]

DBRCT; Cross-over trial: 1 UK centre

Mean age = 55 years (49–62)

Mean BMI = 25.85 kg/m²

38 randomised to 4 weeks MLE4901 (40 mg BID) and 4 weeks placebo (BID) in random order separated by a 2-week washout period

37 included in ITT analysis

1°:

# of weekly HFs during week

2°:

HF severity, bother and interference scores at week 4

Important AEs/SAEs

Discontinuations

1°:

↓ in weekly # of HFs from BL vs. placebo [ITT adjusted means: 19.35 (73%↓) vs. 49.01 (28%↓], respectively; p < 0.001]

2°:

↓ HF severity score from BL vs. placebo [3.27 (44%↓) vs. 5.70 (5%↓), p < 0.0001], ↓ bother score (2.92 vs. 5.56, p < 0.0001), and ↓ interference score (7.94 vs. 26.48, p < 0.0001)

3 developed a transaminase rise (ALT 4.5–5.9 × upper limit of normal) but normal bilirubin, occurring 28 days after starting, which normalised within 90 days

Discontinuations (24%) higher than expected (mostly not MLE4901-related)

Prague et al

Menopause

(2018) [30]

Prague et al. [30] reports a post hoc time course analysis of Prague et al. [29] to define therapeutic profile of MLE4901 by comparing the mean daily total of HFs at day 3, and mean weekly total after weeks 1, 2, 3, and 4 of both Tx periods, and also compared with week 2 of the BL period

Post hoc analysis of questionnaire data (minimum n = 33, maximum n = 35)

# of HFs

HF severity, bother and interference

Impact on sleep via:

# of night-time HFs

Individual MENQoL items

Individual HFRDIS items

↓ # of HFs from BL vs. placebo by day 3 (72%↓ vs. 21%↓; p < 0.0001), maintained through to week 4

HF severity, bother & interference continued to improve vs. placebo. At day 3:

↓ HF severity from BL by 38% (vs. 7%↓; p < 0.0001), which ↓ to − 44% by week 4 (vs. 5%↓)

↓ HF bother from BL by 39% (vs. 5%↓; p < 0.0001), which ↓ to − 50% by week 4

↓ HF interference from BL by 61% (vs. 24%↓; p = 0.0006), which ↓ to − 70% by week 4

Impact of sleep:

↓ night-time HFs from BL vs. placebo at week 4 (78%↓ vs. 22%↓; p < 0.0001). Improvements rapid, significant by day 3 vs. placebo (p < 0.0001)

Improved MENQoL psychosocial and physical domains at week 4. Authors suggested due to improved sleep since ‘difficulty sleeping’, ‘lethargy’ and ‘tiredness’ improved at week 4 (p < 0.0001, p = 0.00128, and p = 0.0002, respectively), and ‘lethargy’ and ‘tiredness’ improved by day 3 (p = 0.0474 and p = 0.0132, respectively), whereas ‘muscle ache’ and ‘physical strength’ did not improve

Improved ‘sleep’ and ‘concentration’, significant by day 3 vs. placebo (sleep: p = 0.001; concentration: p = 0.0075) (HFRDIS)

Depypere et al

Journal of Clinical Endocrinology and Metabolism

(2019) [31]

DBRCT: 8 Belgian centres

Mean age = 53.5 years (44–64)

Mean BMI = 25.8 kg/m²

87 randomised (1:1) to fezolinetant 90 mg BID or placebo for 12 weeks

87 included in mITT analysis (inferred from Fig. 2A but this is unclear)

1°:

∆ from BL in mean daily total VMS score (composite of # and severity) at week 12

2°:

Important AEs/SAEs

Discontinuation due to AEs

1°:

↓ mean daily total VMS score from BL vs. placebo at week 4, 8 and 12 [week 12: 2.7 (91%↓) vs. 14.4 (44%↓); all comparisons p < 0.001]

2°:

↑ AEs considered Tx-related vs. placebo (30.2% vs. 25%), most commonly GI disorders (23% vs. 9%)

↑ discontinuations due to AEs (2 (4.7%) vs. 0)

Fraser et al

VESTA

Menopause (2020) [32]

DBRCT; Dose-ranging: 51 US centres

Mean age = 54.6 years (41–65)

Mean BMI = 28.4 kg/m²

356 randomised (1:1) to fezolinetant BID 15, 30, 60, or 90 mg, or fezolinetant QD 30, 60, or 120 mg or placebo for 12 weeks

349 included in mITT analysis

1°:

Mean ∆ in # of mod/severe HFs from BL at weeks 4 and 12

Mean ∆ in mod/severe HF severity from BL at weeks 4 and 12

2°:

Important AEs/SAEs

Discontinuation due to AEs

1°:

All doses ↓ # of mod/severe HFs from BL vs. placebo at week 4 (ranging 62–81%↓ vs. 39%) and week 12 (ranging 74–87%↓ vs. 55%); all p ≤ 0.024

All doses ↓ mod/severe HF severity from BL vs. placebo at week 4 (ranging 29–54%↓ vs. 12%↓; all p ≤ 0.0322) and 60 mg BID, 90 mg BID, and 60 mg QD at week 12 ranging (52–53%↓ vs. 32%↓; all p ≤ 0.016)

2°:

AEs similar across Tx groups, with no indication of a dose effect. Most commonly nausea, diarrhoea, fatigue

2 severe (but not serious) AEs considered Tx-related (both 60 mg QD): 1 cholelithiasis, 1 drug-induced liver injury (ALT [14.1xULN] and AST [9.5xULN] in a woman with obesity and NASH)

9 had ALT or AST > 3xULN, and 3 (60 mg BID, 90 mg BID, and 60 mg QD) had ALT or AST > 8xULN. None had total bilirubin > 2xULN ∴no cases met criteria for Hy’s law. ALT/AST levels rapidly returned to BL values after discontinuation/trended toward normalization while on drug

Discontinuations due to AEs vs. placebo: Numerical ↑

Santoro et al

VESTA

Menopause

(2020) [33]

Santoro et al. [33] reports results of 2° endpoints from VESTA [32]

% achieving 50%, 70% and 90% ↓ from BL in # of mod/severe HFs

Responder analyses

↑ ≥ 50% responder rate (all doses p < 0.05). All doses numerical ↑ in 70% and 90% responder rates (with magnitude and sig varying by dose and responder rate)

Shorter time to 50% ↓ in HFs vs. placebo (2.2–8.4 days vs. 15.1 days; no p-value given)

Trower et al

RELENT-1

Menopause

(2020) [34]

DBRCT; multiple-ascending-dose study: 3 US centres

Mean age = 55 years

Mean BMI = 28.18 kg/m²

76 randomised (3:1) to NT-814 vs. placebo within each of 4 sequential dose cohorts; 50, 100, 150, and 300 mg/day for 2 weeks

76 included in mITT analysis

Pre-specified exploratory efficacy endpoints:

∆ from BL in daily # of mod/severe HFs at week 2

∆ from BL in avg. daily HF severity at week 2

∆ from BL in daily #. of waking due to night sweats

Important AEs/SAEs

Discontinuation due to AEs

50 mg and 100 mg no significant ↓ in HF endpoints. (With 50 mg vs. placebo, mean HF frequency actually higher (p = 0.048) although median HF frequency no difference)

↓ # of mod/severe HFs from BL vs. placebo [150 mg 84%↓ (p < 0.001), 300 mg 66%↓ (p = 0.022) vs. 37%↓]

Doses ≥ 150 mg improved symptoms early (within week 1 of Tx)

↓HF severity vs. placebo with 150 mg [41%↓ vs. 13%↓ (p < 0.001)]; 300 mg no sig. difference

↓waking due to night sweats vs. placebo [150 mg 81%↓ (p < 0.001), 300 mg 63%↓ (p = 0.031) vs. 32%↓)].

AEs similar with placebo, 50 mg, 100 mg and 150 mg groups (slightly higher in 300 mg group)

Most common: mild somnolence and headache

No discontinuation due to AEs

DBRCT double-blind, randomised, placebo-controlled trial, XR extended release, mod moderate, # number, HFs hot flushes/flashes, VMS vasomotor symptoms, ≥ greater than or equal to, ≤ less than or equal to, > greater than, < less than, mg/d milligrams/day, (m)ITT (modified) intention-to-treat, BL baseline, 1° primary, 2° secondary, avg. average, ∆ change, sig. significant, ns not significant, ↑ increase, ↓ reduced, diff. difference, Tx treatment, (S)AEs (serious) adverse events, (S) or (D) BP (systolic) or (diastolic) blood pressure, LFTs liver function tests, ALT alanine aminotransferase, AST aspartate aminotransferase, NASH non-alcoholic steatohepatitis, ULN upper limit of normal, MENQoL Menopause-Specific Quality of Life questionnaire, HFRDIS Hot Flash-Related Daily Interference Scale, PEG The Pain Enjoyment of Life and General Activity scale, PHQ-9 9-item Patient Health Questionnaire, GAD-7 7-item Generalized Anxiety Disorder questionnaire, PSS Perceived stress scale