Daridorexant for the Treatment of Insomnia Disorder in Older Adults

Study Design

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Subgroup analysis of Study 1, a 3-month, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of daridorexant 50 mg and 25 mg versus placebo

Screening

20-31 days

Treatment Period

84 days

Safety Follow-up

30 days

Single-blind placebo run-in period

Daridorexant 50 mg and 25 mg vs placebo

Single-blind placebo run-out period (7 days)

Additional 23 days of observation

(or enrollment in an optional extension study for subset of patients [40 weeks])

Outcomes

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In these secondary subgroup post hoc analyses, data were descriptive, not controlled for type 1 error rate, and not specifically powered for the analysis conducted in the study. Tests for interactions between the treatment groups and age were not conducted.

Latency to Persistent Sleep (LPS)

Measures the time between the start of the PSG recording and the first 10 consecutive minutes of sleep¹

Wake After Sleep Onset (WASO)

Measures the total amount of time a person is awake between first falling asleep and the end of the PSG recording¹

Self-Reported Total Sleep Time (sTST)

Total sleep time as estimated by the participant¹

PSG, polysomnography.

1. Sateia MJ et al. J Clin Sleep Med. 2017;13:307-349.

In these secondary subgroup post hoc analyses, data were descriptive, not controlled for type 1 error rate, and not specifically powered for the analysis conducted in the study. Tests for interactions between the treatment groups and age were not conducted.

Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) Sleepiness Domain Score

Novel validated patient-report questionnaire completed daily to assess daytime impairment. Developed per FDA guidance to assess impact of insomnia and treatments¹

Total IDSIQ Score

≥17-point reduction from baseline in the Total score indicates a clinically meaningful improvement

Example Question

How mentally tired did you feel today? Scale 0-10 with 0=not at all mentally tired and 10=very mentally tired

FDA, US Food and Drug Administration.

^aEndpoints refer to Study 1.

1. Hudgens S et al. Patient. 2021;14:249-268.

In these secondary subgroup post hoc analyses, data were descriptive, not controlled for type 1 error rate, and not specifically powered for the analysis conducted in the study. Tests for interactions between the treatment groups and age were not conducted.

Visual Analog Scale (VAS) for Sleep and Daytime Measures

In the morning, the VAS is used to measure depth of sleep (0-100) and quality of sleep (0-100). In the evening, the VAS is used to measure the ability to function (0-100) and daytime alertness (0-100)

Insomnia Severity Index (ISI)

The ISI is used to measure the severity of sleep disturbance by a 7-item scale¹

ISI (0-28):

absence of insomnia (0–7);

sub-threshold insomnia (8–14);

moderate insomnia (15–21);

and severe insomnia (22–28)

A change of 10 in ISI score indicates a clinically meaningful difference

For additional details on study 1 design, please refer to 301/302 infographic

1. Morin CM et al. Sleep. 2011;34(5):601-608.

Participant Demographics and Characteristics

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Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Characteristics	<65 Years n = 566	≥65 Years n = 364
WASO, mean (SD), minutes	91.6 (38.1)	109.5 (38.5)
LPS, mean (SD), minutes	67.5 (38.9)	63.3 (38.0)
TST, mean (SD), minutes	328.0 (54.2)	315.4 (51.2)
sTST, mean (SD), minutes	314.3 (55.2)	310.9 (59.8)
Time since insomnia diagnosis, mean (SD), years	8.9 (8.8)	13.3 (12.0)
ISI score,^a mean (SD)	19.5 (4.2)	18.5 (3.9)

ISI, Insomnia Severity Index; LPS, latency to persistent sleep; SD, standard deviation; sTST, self-reported total sleep time; TST, total sleep time; WASO, wake after sleep onset.

^aISI score 0-7 = absence of insomnia; 8-14 = sub-threshold insomnia; 15-21 = moderate insomnia; and 22-28 = severe insomnia.¹

1. Morin CM et al. Sleep. 2011;34(5):601-608.

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

IDSIQ scores,^a mean (SD)	<65 Years n = 566	≥65 Years n = 364
IDSIQ Sleepiness domain score (range: 0-40)	22.9 (6.9)	21.3 (7.0)
IDSIQ Mood domain score (range: 0-40)	20.1 (8.7)	18.2 (8.5)
IDSIQ Alert/Cognition domain score (range: 0-60)	33.1 (10.1)	30.4 (10.4)
IDSIQ Total score (range: 0-140)	76.2 (24.4)	69.9 (24.8)

IDSIQ, Insomnia Daytime Symptoms and Impacts Questionnaire; SD, standard deviation.

^aLower IDSIQ scores indicate better patient-perceived daytime functioning.

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

VAS scores,^a mean (SD)	<65 Years n = 566	≥65 Years n = 364
VAS quality of sleep (range: 0-100)	34.0 (17.4)	38.6 (17.4)
VAS depth of sleep (range: 0-100)	34.3 (17.4)	38.8 (17.8)
VAS daytime alertness (range: 0-100)	37.5 (19.8)	43.4 (20.0)
VAS ability to function (range: 0-100)	38.1 (19.3)	43.3 (19.5)
VAS morning sleepiness (range: 0-100)	35.1 (18.3)	41.4 (19.1)

SD, standard deviation; VAS, visual analog scale.

^aHigher VAS scores indicate better scores.

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Safety and Tolerability

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Overall safety profile was comparable in older and younger adults
Incidence of serious adverse events were low across both age groups
One death was reported. A 78-year-old patient who received daridorexant 25 mg died of cardiac arrest that was determined not to be related to daridorexant treatment^a

^aPatient had a history of multiple cerebrovascular and cardiovascular conditions, including stroke and hypertension, and the event was assessed by the investigator as not related to treatment.

Adverse Events n (%)
Adverse Events n (%)	Daridorexant 50 mg n = 189	Daridorexant 25 mg n = 189	Placebo n = 187
Patients who experienced ≥1 TEAE
Patients who experienced ≥1 TEAE	74 (39)	78 (41)	67 (36)
Patients who experienced ≥1 serious TEAE
Patients who experienced ≥1 serious TEAE	3 (2)	1 (<1)	4 (2)
TEAEs leading to treatment discontinuation
TEAEs leading to treatment discontinuation	2 (1)	6 (3)	4 (2)
Patients who experienced a TEAE^a (≥2% in any group)
Patients who experienced a TEAE^a (≥2% in any group)
Nasopharyngitis
Nasopharyngitis	13 (6.9)	19 (10.1)	16 (8.6)
Headache
Headache	13 (6.9)	11 (5.8)	7 (3.7)
Nausea
Nausea	3 (1.6)	1 (0.5)	2 (1.1)
Fatigue
Fatigue	4 (2.1)	3 (1.6)	1 (0.5)
Accidental overdose
Accidental overdose	5 (2.6)	3 (1.6)	5 (2.7)
Dizziness
Dizziness	6 (3.2)	2 (1.1)	1 (0.5)
Back pain
Back pain	5 (2.6)	0	3 (1.6)
Somnolence
Somnolence	4 (2.1)	5 (2.6)	5 (2.7)
Diarrhea
Diarrhea	1 (0.5)	6 (3.2)	3 (1.6)
Fall
Fall	0	0	4 (2.1)
Influenza
Influenza	4 (2.1)	3 (1.6)	3 (1.6)
Upper abdominal pain
Upper abdominal pain	0	0	0

TEAE, treatment-emergent adverse event.

^aTEAEs that occurred during the double-blind treatment period presented with their preferred term; TEAEs are sorted by descending frequency in the daridorexant 50-mg group in adults aged ≥65 years, followed by age <65 years listed in order.

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Adverse Events n (%)
Adverse Events n (%)	Daridorexant 50 mg n = 119	Daridorexant 25 mg n = 121	Placebo n = 122
Patients who experienced ≥1 TEAE
Patients who experienced ≥1 TEAE	42 (35)	39 (32)	38 (31)
Patients who experienced ≥1 serious TEAE
Patients who experienced ≥1 serious TEAE	0	1 (1)	3 (3)
TEAEs leading to treatment discontinuation
TEAEs leading to treatment discontinuation	1 (1)	1 (1)	6 (5)
Patients who experienced a TEAE^a (≥2% in any group)
Patients who experienced a TEAE^a (≥2% in any group)
Nasopharyngitis
Nasopharyngitis	7 (5.9)	2 (1.7)	4 (3.3)
Headache
Headache	6 (5.0)	5 (4.1)	5 (4.1)
Nausea
Nausea	4 (3.4)	0	1 (0.8)
Fatigue
Fatigue	3 (2.5)	4 (3.3)	1 (0.8)
Accidental overdose
Accidental overdose	3 (2.5)	1 (0.8)	0
Dizziness
Dizziness	1 (0.8)	4 (3.3)	1 (0.8)
Back pain
Back pain	1 (0.8)	2 (1.7)	1 (0.8)
Somnolence
Somnolence	1 (0.8)	6 (5.0)	1 (0.8)
Diarrhea
Diarrhea	1 (0.8)	0	1 (0.8)
Fall
Fall	1 (0.8)	1 (0.8)	4 (3.3)
Influenza
Influenza	0	0	2 (1.6)
Upper abdominal pain
Upper abdominal pain	0	3 (2.5)	1 (0.8)

TEAE, treatment-emergent adverse event.

^aTEAEs that occurred during the double-blind treatment period presented with their preferred term; TEAEs are sorted by descending frequency in the daridorexant 50-mg group in adults aged ≥65 years, followed by age <65 years listed in order.

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

No adverse events of special interest related to suicidal ideation/self-injury or cataplexy were reported in either age group

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

No adverse events of special interest related to suicidal ideation/self-injury or cataplexy were reported in either age group

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Daytime Functioning: IDSIQ Total and Domain Scores

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Among older adults, daridorexant 50 mg improved the IDSIQ Total score from baseline to a greater extent than both 25 mg and placebo
Among younger adults, both daridorexant doses improved the IDSIQ Total score from baseline in a dose-dependent relationship

IDSIQ, Insomnia Daytime Symptoms and Impacts Questionnaire.

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Among older adults, daridorexant 50 mg improved the IDSIQ Sleepiness domain score from baseline to a greater extent than both 25 mg and placebo
Among younger adults, both daridorexant doses improved the IDSIQ Sleepiness domain score from baseline in a dose-dependent relationship

IDSIQ, Insomnia Daytime Symptoms and Impacts Questionnaire.

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Among older adults, daridorexant 50 mg improved the IDSIQ Mood domain score from baseline to a greater extent than both 25 mg and placebo
Among younger adults, both daridorexant doses improved the IDSIQ Mood domain score from baseline in a dose-dependent relationship

IDSIQ, Insomnia Daytime Symptoms and Impacts Questionnaire.

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Among older adults, daridorexant 50 mg improved the IDSIQ Alert/Cognition domain score from baseline to a greater extent than both 25 mg and placebo
Among younger adults, both daridorexant doses improved the IDSIQ Alert/Cognition domain score from baseline in a dose-dependent relationship

IDSIQ, Insomnia Daytime Symptoms and Impacts Questionnaire.

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Visual Analog Scale (VAS)

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Both daridorexant 50 mg and 25 mg led to greater improvements from baseline in VAS Depth of Sleep score than placebo in a dose-dependent relationship across both age groups

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Both daridorexant 50 mg and 25 mg led to greater improvements from baseline in VAS Quality of Sleep score than placebo in a dose-dependent relationship across both age groups

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Among older adults, daridorexant 50 mg led to greater improvements from baseline in the VAS Daytime Alertness score than both daridorexant 25 mg and placebo
Among younger adults, both doses led to greater improvements from baseline in the VAS Daytime Alertness score than placebo

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Both daridorexant 50 mg and 25 mg led to greater improvements from baseline in VAS Abilty to Function score than placebo in a dose-dependent relationship across both age groups

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Among older adults, daridorexant 50 mg led to greater improvements from baseline in VAS Morning Sleepiness score than both daridorexant 25 mg and placebo
Among younger adults, both doses led to greater improvements from baseline in the VAS Morning Sleepiness score than placebo

Adapted from Fietze, I, et al. Drugs Aging. 2022;39:795-810. This article is licensed under a Creative Commons Attribution NonCommercial 4.0 International License: http://creativecommons.org/licenses/by-nc/4.0/.

Daridorexant for the Treatment of Insomnia Disorder in Older Adults:

Exploring the Results of a Subgroup Analysis in Patients Aged ≥65 Years

Background

Methods

Results

Summary