Vasomotor symptoms (VMS) and sleep disturbances are some of the most frequent and bothersome symptoms associated with menopause.1-4 5-7 8,9
Hormone therapy is currently the most effective treatment option approved for the management of VMS.10 11-13
Evolving evidence supports a central role of hypothalamic, estrogen-sensitive kisspeptin, neurokinin (NK)-B, and dynorphin (KNDy) neurons in thermoregulation and the etiology of VMS.14-19 14,20-23 24-27
Elinzanetant (NT-814) is a novel, selective NK-1,3R antagonist in development for the treatment of moderate-to-severe VMS associated with menopause. It is the first dual antagonist targeting both NK-1 and NK-3 receptors. NK-1R–specific antagonism has previously shown efficacy in primary insomnia and mood disorders not related to menopause.28-32 23
METHODS
Study design
SWITCH-1 was a multicenter, multicountry, double-blind, placebo-controlled, dose-range finding study with an adaptive randomization design evaluating elinzanetant in postmenopausal women aged 40 to 65 years. Menopause was defined as either (1) at least 12 months of spontaneous amenorrhea, (2) at least 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone levels of more than 40 mIU/mL and serum estradiol less than 30 pg/mL, or (3) at least 6 weeks of postsurgical bilateral oophorectomy with or without hysterectomy. The study protocol and statistical analysis plan are available in Supplemental Digital Content (Supplemental Data 1, https://links.lww.com/MENO/B68
Institutional review board and ethics committee approval was obtained for all study sites, and all participants provided written informed consent. A 3-week initial screening period was used to assess eligibility. This 3-week period included a single-blind placebo run-in in the last 2 weeks in which participants received placebo once daily. To be eligible for the study, participants needed to meet the inclusion criteria (Supplemental Table 1, https://links.lww.com/MENO/B69
Eligible participants were initially randomized 1:1:1:1:1 and stratified by region (North America [United States and Canada] versus United Kingdom) to receive either once-daily elinzanetant (40, 80, 120, or 160 mg, soft gel capsules) or matching placebo for 12 weeks followed by a 4-week off-treatment follow-up (Supplemental Fig. 1, https://links.lww.com/MENO/B69
The trial used an adaptive design algorithm based on Bayesian Emax dose-response modeling33 T statistic adaptive dose-finding design,34
Data collection
Participants recorded the frequency and severity of VMS and the number of nighttime awakenings secondary to VMS twice daily in electronic diaries (eDiaries). Severity was scored on a scale of 0 to 3, with 0 representing none; 1, mild (sensation of heat without sweating); 2, moderate (sensation of heat with sweating but able to continue activity); and 3, severe (sensation of heat with sweating, causing cessation of activity). Any VMS causing a nighttime awakening by definition was considered severe.
The Insomnia Severity Index (ISI) questionnaire and Pittsburgh Sleep Quality Index (PSQI) were used to assess participants' sleep, whereas the Menopause-specific Quality-of-Life questionnaire intervention version (MenQoL-I) assessed quality of life (Supplemental Table 2, https://links.lww.com/MENO/B69
Safety was assessed through adverse event monitoring. Other routine assessments included medical history, physical examinations, 12-lead electrocardiograms, suicide severity rating, clinical laboratory assessments, vital signs, and bone turnover markers. For changes in liver enzymes, only increases three or more times the upper limit of normal (ULN) were considered relevant, as per US Food and Drug Administration guidance.35
Endpoints
The coprimary efficacy endpoints were mean change in the frequency and severity of moderate-to-severe VMS compared with placebo from baseline to weeks 4 and 12. Secondary endpoints included the mean change from baseline compared with placebo of moderate-to-severe VMS frequency and severity at weeks 1, 2, 8, and 16; number of nighttime awakenings secondary to VMS at weeks 1, 2, 4, 8, 12, and 16; and ISI, PSQI, and MenQoL-I scores at weeks 4, 8, 12, and 16.
Statistical analysis
Assuming a common standard deviation of 4.4, n = 27 per treatment group would give approximately 95% power via trend test across all doses including placebo if the true underlying dose-response was nondecreasing from a reduction of four VMS on placebo up to eight on the highest dose of elinzanetant. Thus, the initial sample size was planned to be 33 participants per treatment group (165 in total) to allow for participants dropping out.
Descriptive statistical analyses were performed on all endpoint time points using Statistical Analysis System, version 9.4. Formal statistical hypothesis testing was performed at the two-sided, 0.05 level of significance for VMS frequency, severity, and nighttime awakenings secondary to VMS at all time points up to week 12 and ISI, PSQI, and MenQoL-I scores at weeks 4 and 12. Efficacy analyses were performed on the full analysis set, which included all randomized participants who received at least one dose of the study drug and had VMS data for at least 7 days of posttreatment assessments. Endpoints were analyzed using a mixed-effect model repeated measures approach incorporating postrandomization data up to week 12. Pairwise statistical comparisons were performed for each elinzanetant dose group versus placebo and least square (LS) means, SE, and 95% CI for the treatment difference were reported. Safety endpoints were summarized in all participants who received at least one dose of study drug.
RESULTS
SWITCH-1 was conducted at 25 sites across the United States, United Kingdom, and Canada. In total, 760 participants were screened, 199 were randomized, and 180 completed treatment (Fig. 1 ). Based on emerging efficacy data, the data review committee chose to discontinue randomization to the 80 mg and 40 mg doses after 17 and 31 participants were enrolled in these groups, respectively. All randomized participants were included in both the full analysis set and safety analysis set. Baseline demographics, VMS, sleep, quality of life, and menopause characteristics were well balanced between treatment groups and indicated a high symptom burden (Table 1 ; Supplemental Tables 3 and 6-9, https://links.lww.com/MENO/B69
FIG. 1: Disposition of study participants.
Table 1 -
Baseline demographics and characteristics
Parameter/category
Elinzanetant group
Placebo group (N = 47)
40 mg (n = 31)
80 mg (n = 17)
120 mg (n = 52)
160 mg (n = 52)
Total elinzanetant (N = 152)
Demographics (safety analysis set)
Age, mean (SD) (y)
55.6 (4.1)
55.4 (4.0)
55.9 (4.2)
54.8 (4.4)
55.0 (3.8)
55.1 (4.1)
Race, n (%)
Asian
2 (4)
0
0
1 (2)
1 (2)
2 (1.3)
Black or African American
6 (13)
5 (16)
3 (18)
13 (25)
11 (21)
32 (21.1)
White
38 (81)
24 (77)
13 (77)
37 (71)
40 (77)
114 (75.0)
Other
a
1 (2)
2 (7)
1 (6)
1 (2)
0
4 (2.6)
BMI, mean (SD) (kg/m2 )
28.56 (3.83)
27.72 (4.88)
29.56 (5.02)
27.24 (4.64)
27.72 (4.87)
27.76 (4.81)
Moderate and severe VMS characteristics (full analysis set), mean (SD)
Frequency, daily
11.82 (4.42)
12.13 (8.81)
14.55 (5.87)
13.54 (7.17)
12.92 (6.90)
13.16 (7.28)
Severity, weekly
2.54 (0.20)
2.51 (0.26)
2.63 (0.24)
2.54 (0.24)
2.54 (0.26)
2.55 (0.25)
BMI, body mass index; VMS, vasomotor symptoms.
a
Vasomotor symptoms
Compared with placebo, there were statistically significant and clinically relevant reductions (improvements) in the mean daily frequency of moderate-to-severe VMS with elinzanetant 120 mg at week 4 (difference in LS means [SE], −3.93 [1.02]; P < 0.001) and week 12 (−2.95 [1.15]; P = 0.01) (Fig. 2 ). The improvements with elinzanetant 160 mg were significant at week 4 (−2.63 [1.03]; P = 0.01) but not week 12 (−1.78 [1.19]; P = 0.13). Improvements with elinzanetant 40 mg and 80 mg were observed but not statistically significant compared with placebo at either of the primary endpoint time points.
FIG. 2: Change from baseline in mean daily frequency (A , C ) and weekly severity (B , D ) of moderate and severe VMS by treatment group. EZN, elinzanetant; LS, least square; VMS, vasomotor symptoms.
Statistically significant improvements compared with placebo in the mean daily frequency of moderate-to-severe VMS were achieved by week 1 for both elinzanetant 120 mg (difference in LS means [SE], −1.80 [0.67]; P = 0.008) and 160 mg (−1.69 [0.67]; P = 0.01) (Fig. 2 ). Improvements tended to increase throughout treatment and returned toward baseline 4 weeks after treatment discontinuation (Supplemental Table 4, https://links.lww.com/MENO/B69
Reductions in mean weekly severity of moderate-to-severe VMS followed a similar trend; however, reductions were only significant compared with placebo for elinzanetant 160 mg at week 12 (0.27 [0.13]; P = 0.048) (Fig. 2 ; Supplemental Table 5, https://links.lww.com/MENO/B69
Sleep and quality of life
Reductions (improvements) in the frequency of nighttime awakenings secondary to VMS were significantly larger compared with placebo for elinzanetant 120 mg at weeks 1, 2, 4, and 8 (P = 0.006 to P = 0.049) but not at week 12 (Supplemental Table 6, https://links.lww.com/MENO/B69
Compared with placebo, there were statistically significant improvements in ISI score at weeks 4 and 12 for elinzanetant 120 mg (differences in LS means [SE], −3.41 [0.92]; P < 0.001 and −4.27 [1.01]; P < 0.001, respectively) and 160 mg (−3.28 [0.95]; P < 0.001 and −4.85 [1.05]; P < 0.001, respectively) (Fig. 3 A). Clinically meaningful improvements of at least a 6-point reduction were achieved at weeks 8 and 12 for elinzanetant 120 mg and week 12 for elinzanetant 160 mg (Supplemental Table 7, https://links.lww.com/MENO/B69 36 P = 0.008).
FIG. 3: Change from baseline in ISI (A ), PSQI (B ), and MenQoL-I (C ) score by treatment group at weeks 4 and 12. EZN, elinzanetant; ISI, Insomnia Severity Index questionnaire; LS, least square; MenQoL-I, Menopause-specific Quality-of-Life questionnaire intervention version; PSQI, Pittsburgh Sleep Quality Index.
Compared with placebo, there were statistically significant improvements in PSQI total score at weeks 4 and 12 for elinzanetant 120 mg (difference in LS means [SE], −2.05 [0.51]; P < 0.001 and −2.46 [0.67]; P < 0.001, respectively) and 160 mg (−1.90 [0.52]; P < 0.001 and −2.14 [0.69]; P = 0.002, respectively) (Fig. 3 B; Supplemental Table 7, https://links.lww.com/MENO/B69
Improvements in overall MenQoL-I score were statistically significant compared with placebo at weeks 4 and 12 for elinzanetant 120 mg (difference in LS means [SE], −0.87 [0.20]; P < 0.001 and −0.80 [0.22]; P < 0.001, respectively) and 160 mg (−0.61 [0.21]; P = 0.004 and −0.77 [0.23]; P < 0.001, respectively) (Fig. 3 C). Clinically meaningful improvements of at least a 1-point reduction were seen for elinzanetant 120 mg and 160 mg at weeks 4, 8, 12 and 16 (Supplemental Table 9, https://links.lww.com/MENO/B69 37
Improvements in sleep and quality of life returned toward baseline 4 weeks after treatment discontinuation (Supplemental Tables 6-9, https://links.lww.com/MENO/B69
Safety
Overall, 235 treatment-emergent adverse events (TEAEs) were reported in 67.8% (103 of 152) of participants in the elinzanetant groups, and 80 TEAEs were reported in 60% (28 of 47) of participants in the placebo group (Table 2 ). Most TEAEs were mild or moderate. The most frequently reported TEAEs across all treatment groups were headache, somnolence, and diarrhea. Seven of 152 elinzanetant-treated participants (4.6%) (2 of 17 [12%] for elinzanetant 40 mg and 5 of 52 [10%] for elinzanetant 160 mg) and 1 of 47 (2%) placebo-treated participants discontinued treatment because of adverse events; there were no discontinuations in the 120-mg dose group. Reasons for treatment discontinuation were prolonged QT and bradycardia; increased liver function test; headache; somnolence, abdominal distension, and dyspepsia; fatigue; depression and anxiety; and erythema multiforme in the elinzanetant groups and headache in the placebo group. The apparent prolonged QT leading to withdrawal of a participant was found to be erroneous (QTc was within normal limits) on expert review. There was no obvious relationship between elinzanetant dose and the number of TEAEs. Somnolence was reported more frequently in the 160-mg dose and 40-mg dose groups compared with other doses, at a similar incidence in each group. Dizziness was only reported at higher doses of elinzanetant (120 and 160 mg); however, all incidences of dizziness were considered unrelated to treatment by the investigators.
Table 2 -
Treatment-emergent adverse events by treatment group
AE category (preferred term)
a
Elinzanetant group, n (%)
Placebo group, n (%) (N = 47)
40 mg (n = 31)
80 mg (n = 17)
120 mg (n = 52)
160 mg (n = 52)
Total (N = 152)
Any TEAEs
28 (60)
17 (55)
14 (82)
34 (65)
38 (73)
103 (67.8)
Serious TEAEs
2 (4)
0
1 (6)
1 (2)
1 (2)
3 (2)
TEAEs leading to discontinuation of study treatment
1 (2)
0
2 (12)
0
5 (10)
7 (4.6)
Most common TEAEs (occurring in ≥3 participants in any treatment group)
Headache
6 (13)
3 (10)
2 (12)
6 (12)
4 (8)
15 (9.9)
Somnolence
1 (2)
3 (10)
1 (6)
2 (4)
6 (12)
12 (7.9)
Dizziness
0
0
0
3 (6)
3 (6)
6 (3.9)
Nasopharyngitis
4 (9)
1 (3)
0
3 (6)
0
4 (2.6)
Diarrhea
3 (6)
2 (6)
2 (12)
3 (6)
3 (6)
10 (6.6)
Blood creatine phosphatase increased
1 (2)
1 (3)
1 (6)
3 (6)
1 (2)
6 (3.9)
Fatigue
0
3 (10)
1 (6)
1 (2)
4 (8)
9 (5.9)
AE, adverse event; TEAEs, treatment-emergent adverse events.
a
There were sporadic increases in transaminases during treatment of no more than three times the ULN, but these were of equal frequency and magnitude in placebo- and elinzanetant-treated participants (11% and 8.8%, respectively) and were not considered clinically relevant. Two participants randomized to elinzanetant (both 80 mg) showed increases in transaminases three or more times the ULN; however, these participants had no detectable elinzanetant in plasma samples drawn at the same time as the enzyme increases and were considered to be noncompliant with study medication. In one of the two, there was also a marked increase in creatine kinase, suggesting that the transaminase increase in this participant was likely to have been of muscle origin. There was no evidence of drug-related liver toxicity. No safety concerns were seen in any other routine safety assessments.
DISCUSSION
SWITCH-1 is the first phase 2b study to demonstrate significant improvements in menopause-related symptoms, such as VMS and sleep disturbance, and improved quality of life with a selective NK-1,3R antagonist in postmenopausal women. Although improvements were observed in placebo-treated participants, consistent with other studies of VMS treatments,38-41 38-42
The findings of this study further support the potential of NK signaling for the rapid treatment of VMS. Elinzanetant 120 mg and 160 mg led to meaningful reductions in VMS frequency after only 1 week of treatment. This is consistent with results from RELENT-1, in which similarly rapid reductions in VMS frequency were shown with a 150-mg dose of elinzanetant, and studies of NK-3R antagonists that demonstrate maximum efficacy within weeks.38,39,43
In some of our analyses, elinzanetant 120 mg seems to have a greater benefit than elinzanetant 160 mg, particularly for VMS frequency. However, findings for elinzanetant 160 mg were skewed by a single participant in this group whose VMS frequency increased by more than 200% from baseline at times during the study. In a prespecified nonparametric analysis (data not shown) and an exploratory analysis excluding high outliers (ie, the one participant in the 160-mg group), reductions in mean VMS frequency were similar to that of the 120-mg dose and statistically significant compared with placebo.
Although VMS severity showed marked reductions across the higher elinzanetant doses, reductions were only significant compared with placebo at week 12 for elinzanetant 160 mg. Despite VMS severity being used to assess efficacy of VMS treatments by some regulatory authorities, it is recognized as a problematic endpoint because average severity takes no account of the number of VMS episodes overall.44
VMS that occur at night can be particularly distressing for women and disrupt sleep. This study did not require sleep disturbance for eligibility and participants recorded a low baseline number of nighttime awakenings. Reductions in nighttime awakenings secondary to VMS therefore were small and generally did not reach statistical significance. However, many women with little VMS interference report experiencing sleep disturbance during the menopause.45 46
In a recent survey, sleep disturbances were rated as more bothersome than VMS as measured by the MenQoL questionnaire and had a greater impact on work productivity and day-to-day activities.1 37
Elinzanetant was well tolerated with no TEAEs of concern at any doses tested. There were no clear differences in the incidences of TEAEs between the treatment groups, although a slightly higher incidence of somnolence was reported for elinzanetant 160 mg (Table 2 ). Owing to previous reports of increases in liver enzymes with some single-mechanism NK-3R antagonists,38,39
The strengths of the study include its randomized, placebo-controlled adaptive design and the standardization of procedures across all study sites. The 2-week single-blind placebo run-in before the 12-week treatment period allowed 1 week for participants to familiarize themselves with the eDiaries and 1 week of baseline efficacy assessments. The inclusion of the placebo run-in, which has been used in similar studies previously, allowed for recording of baseline assessments under similar conditions to the treatment period and may provide the additional benefit of screening out participants with a high placebo response who would not have benefitted further from treatment.47
CONCLUSIONS
Taken together, findings from our study suggest that, relative to other elinzanetant doses tested, the 120-mg dose offers clinically important efficacy across a range of menopause-related symptoms with the most favorable benefit/risk profile. Elinzanetant demonstrated a generally dose-ordered response across all efficacy outcomes with no additional benefit observed with the 160-mg dose, suggesting a plateau of effect at 120 mg. The efficacy and safety of elinzanetant 120 mg will be further evaluated in a phase 3 program (NCT05042362, NCT05099159, NCT05030584).
Acknowledgments: The study was sponsored by NeRRe Therapeutics. Medical writing support was provided by Highfield with sponsorship from Bayer.
Data sharing statement: see Supplemental Digital Content, Supplemental Data 2, https://links.lww.com/MENO/B70
REFERENCES
1. Nappi RE, Kroll R, Siddiqui E, et al. Global cross-sectional survey of women with vasomotor symptoms associated with menopause: prevalence and quality of life burden.
Menopause 2021;28:875–882. doi: 10.1097/GME.0000000000001793
2. Thurston RC. Vasomotor symptoms: natural history, physiology, and links with cardiovascular health.
Climacteric 2018;21:96–100. doi: 10.1080/13697137.2018.1430131
3. Thurston RC, Chang Y, Buysse DJ, Hall MH, Matthews KA. Hot flashes and awakenings among midlife women.
Sleep 2019;42:zsz131. doi: 10.1093/sleep/zsz131
4. Thurston RC, Joffe H. Vasomotor symptoms and menopause: findings from the Study of Women's Health across the Nation.
Obstet Gynecol Clin North Am 2011;38:489–501. doi: 10.1016/j.ogc.2011.05.006
5. Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition.
JAMA Intern Med 2015;175:531–539. doi: 10.1001/jamainternmed.2014.8063
6. Freeman EW, Sammel MD, Lin H, Liu Z, Gracia CR. Duration of menopausal hot flushes and associated risk factors.
Obstet Gynecol 2011;117:1095–1104. doi: 10.1097/AOG.0b013e318214f0de
7. Freeman EW, Sammel MD, Sanders RJ. Risk of long-term hot flashes after natural menopause: evidence from the Penn Ovarian Aging Study cohort.
Menopause 2014;21:924–932. doi: 10.1097/GME.0000000000000196
8. Gold EB, Colvin A, Avis N, et al. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women's health across the nation.
Am J Public Health 2006;96:1226–1235. doi: 10.2105/AJPH.2005.066936
9. Williams RE, Kalilani L, DiBenedetti DB, et al. Frequency and severity of vasomotor symptoms among peri- and postmenopausal women in the United States.
Climacteric 2008;11:32–43. doi: 10.1080/13697130701744696
10. de Villiers TJ, Gass ML, Haines CJ, et al. Global consensus statement on menopausal hormone therapy.
Climacteric 2013;16:203–204. doi: 10.3109/13697137.2013.771520
11. Biglia N, Bounous VE, De Seta F, Lello S, Nappi RE, Paoletti AM. Non-hormonal strategies for managing menopausal symptoms in cancer survivors: an update.
Ecancermedicalscience 2019;13:909. doi: 10.3332/ecancer.2019.909
12. Constantine GD, Graham S, Clerinx C, et al. Behaviours and attitudes influencing treatment decisions for menopausal symptoms in five European countries.
Post Reprod Health 2016;22:112–122. doi: 10.1177/2053369116632439
13. Neves-E-Castro M, Birkhauser M, Samsioe G, et al. EMAS position statement: the ten point guide to the integral management of menopausal health.
Maturitas 2015;81:88–92. doi: 10.1016/j.maturitas.2015.02.003
14. Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes.
Front Neuroendocrinol 2013;34:211–227. doi: 10.1016/j.yfrne.2013.07.003
15. Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion.
Endocrinology 2010;151:3479–3489. doi: 10.1210/en.2010-0022
16. Rance NE, McMullen NT, Smialek JE, Price DL, Young WS 3rd. Postmenopausal hypertrophy of neurons expressing the estrogen receptor gene in the human hypothalamus.
J Clin Endocrinol Metab 1990;71:79–85. doi: 10.1210/jcem-71-1-79
17. Rance NE, Young WS 3rd. Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women.
Endocrinology 1991;128:2239–2247. doi: 10.1210/endo-128-5-2239
18. Rometo AM, Krajewski SJ, Voytko ML, Rance NE. Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys.
J Clin Endocrinol Metab 2007;92:2744–2750. doi: 10.1210/jc.2007-0553
19. Padilla SL, Johnson CW, Barker FD, Patterson MA, Palmiter RD. A neural circuit underlying the generation of hot flushes.
Cell Rep 2018;24:271–277. doi: 10.1016/j.celrep.2018.06.037
20. Borsay BA, Skrapits K, Herczeg L, et al. Hypophysiotropic gonadotropin-releasing hormone projections are exposed to dense plexuses of kisspeptin, neurokinin B and substance p immunoreactive fibers in the human: a study on tissues from postmenopausal women.
Neuroendocrinology 2014;100(2-3):141–152. doi: 10.1159/000368362
21. Hrabovszky E, Borsay BA, Racz K, et al. Substance P immunoreactivity exhibits frequent colocalization with kisspeptin and neurokinin B in the human infundibular region.
PLoS One 2013;8:e72369. doi: 10.1371/journal.pone.0072369
22. Navarro VM, Bosch MA, Leon S, et al. The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction.
Endocrinology 2015;156:627–637. doi: 10.1210/en.2014-1651
23. Trower M, Anderson RA, Ballantyne E, Joffe H, Kerr M, Pawsey S. Effects of NT-814, a dual neurokinin 1 and 3 receptor antagonist, on vasomotor symptoms in postmenopausal women: a placebo-controlled, randomized trial.
Menopause 2020;27:498–505. doi: 10.1097/GME.0000000000001500
24. Andersen ML, Nascimento DC, Machado RB, Roizenblatt S, Moldofsky H, Tufik S. Sleep disturbance induced by substance P in mice.
Behav Brain Res 2006;167:212–218. doi: 10.1016/j.bbr.2005.09.008
25. Lieb K, Ahlvers K, Dancker K, et al. Effects of the neuropeptide substance P on sleep, mood, and neuroendocrine measures in healthy young men.
Neuropsychopharmacology 2002;27:1041–1049. doi: 10.1016/S0893-133X(02)00369-X
26. Schaffalitzky De Muckadell OB, Aggestrup S, Stentoft P. Flushing and plasma substance P concentration during infusion of synthetic substance P in normal man.
Scand J Gastroenterol 1986;21:498–502. doi: 10.3109/00365528609015169
27. Wong BJ, Minson CT. Neurokinin-1 receptor desensitization attenuates cutaneous active vasodilatation in humans.
J Physiol 2006;577(Pt 3):1043–1051. doi: 10.1113/jphysiol.2006.112508
28. Kramer MS, Winokur A, Kelsey J, et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression.
Neuropsychopharmacology 2004;29:385–392. doi: 10.1038/sj.npp.1300260
29. Ratti E, Bellew K, Bettica P, et al. Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder.
J Clin Psychopharmacol 2011;31:727–733. doi: 10.1097/JCP.0b013e31823608ca
30. Ratti E, Bettica P, Alexander R, et al. Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies.
J Psychopharmacol 2013;27:424–434. doi: 10.1177/0269881113480990
31. Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors.
Science 1998;281:1640–1645. doi: 10.1126/science.281.5383.1640
32. Ratti E, Carpenter DJ, Zamuner S, et al. Efficacy of vestipitant, a neurokinin-1 receptor antagonist, in primary insomnia.
Sleep 2013;36:1823–1830. doi: 10.5665/sleep.3208
33. Cytel.
Compass User Manual . Cambridge, MA: Cytel Inc; 2012.
34. Ivanova A, Bolognese JA, Perevozskaya I. Adaptive dose finding based on t-statistic for dose-response trials.
Stat Med 2008;27:1581–1592. doi: 10.1002/sim.3209
35. US Food and Drug Administration.
Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation . Washington DC: US Department of Health and Human Services; 2009.
36. Yang M, Morin CM, Schaefer K, Wallenstein GV. Interpreting score differences in the Insomnia Severity Index: using health-related outcomes to define the minimally important difference.
Curr Med Res Opin 2009;25:2487–2494. doi: 10.1185/03007990903167415
37. Lewis JE, Hilditch JR, Wong CJ. Further psychometric property development of the Menopause-Specific Quality of Life questionnaire and development of a modified version, MENQOL-Intervention questionnaire.
Maturitas 2005;50:209–221. doi: 10.1016/j.maturitas.2004.06.015
38. Fraser GL, Lederman S, Waldbaum A, et al. A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause.
Menopause 2020;27:382–392. doi: 10.1097/GME.0000000000001510
39. Prague JK, Roberts RE, Comninos AN, et al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial.
Lancet 2017;389:1809–1820. doi: 10.1016/s0140-6736(17)30823-1
40. Lobo RA, Archer DF, Kagan R, et al. A 17β-estradiol-progesterone oral capsule for vasomotor symptoms in postmenopausal women: a randomized controlled trial.
Obstet Gynecol 2018;132:161–170. doi: 10.1097/AOG.0000000000002645
41. Pinkerton JV, Utian WH, Constantine GD, Olivier S, Pickar JH. Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial.
Menopause 2009;16:1116–1124. doi: 10.1097/gme.0b013e3181a7df0d
42. US Food and Drug Administration. Brisdelle Cross Discipline Team Leader Review. Silver Spring, MD: Center for Drug Evaluation and Research; 2013.
43. Prague JK, Roberts RE, Comninos AN, et al. Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action.
Menopause 2018;25:862–869. doi: 10.1097/GME.0000000000001090
44. US Food and Drug Administration. Clinical review of Brisdelle for the treatment of moderate to severe vasomotor symptoms associated with the menopause. Silver Spring, MD: Center for Drug Evaluation and Research; 2013.
45. Woods NF, Hohensee C, Carpenter JS, et al. Symptom clusters among MsFLASH clinical trial participants.
Menopause 2016;23:158–165. doi: 10.1097/GME.0000000000000516
46. Carpenter JS, Andrykowski MA. Psychometric evaluation of the Pittsburgh Sleep Quality Index.
J Psychosom Res 1998;45:5–13. doi: 10.1016/s0022-3999(97)00298-5
47. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials.
Menopause 2013;20:1027–1035. doi: 10.1097/GME.0b013e3182a66aa7
