Daridorexant FAQ

Question 1

What were the key INCLUSION criteria for the 301/302 trials?

Answer 1

Adults 18 years or older
Diagnosed with insomnia disorder (DSM-5 criteria)
Moderate to severe intensity (ISI score >15)
Self-reported history of disturbed sleep on at least 3 nights per week for 3 months before screening - and met on at lease 3 of the 7 nights of the placebo run-in period
30 min to fall asleep
30 awake during sleep time
< 6.5 h of total sleep time
PSG criteria met during the placebo run-in period
LPS > 20 min
WASO > 30 min
TST < 7 h

(Publication)

Question 2

What were the EXCLUSION criteria for the 301/302 trials?

Answer 2

Self-reported daytime napping (> 1 h a day; > 3 days a week)
History of suicidal ideation or attempt
Acute or chronic psychiatric condition not controlled by therapy
Severe depression
Alcohol or drug misuse
An apnea or hypopnea index > 15 events h (AASM criteria)
An apnea or hypopnea event associated with a drop in SpO2 to <80%
Periodic limb movement index > 15 events per h
Restless leg syndrome
Circadian rhythm disorder
REM disorder
Narcolepsy

(Publication)

Question 3

Was nicotine use prohibited during the 301/302 trials?

Answer 3

Nicotine use was NOT prohibited provided
It was less than 1 pack of cigarettes per day
Patients could refrain from smoking at night

(Supplement)

Question 4

Was caffeine consumption restricted during the phase 3 trials?

Answer 4

Caffeine was restricted to a maximum of 600 mg/day and consumption after 2:00 PM on PSG days and 4:00 PM on all other days was prohibited.

(Supplement)

Question 5

What were the primary endpoints in the 301/302 phase 3 trials?

Answer 5

Change from baseline to month 1 and month 3 of
LPS (latency to persistent sleep - PSG - objective measure of sleep onset)
WASO (wake after sleep onset - PSG - objective measure of sleep maintenance)
The recording times were averaged over 2 nights of PSG and averaged - the mean +/- SD was reported

(Publication)

Question 6

What were the secondary endpoints in the 301/302 phase 3 trials?

Answer 6

Change from baseline to month 1 and month 3 in:
Self-reported total sleep time (sTST - subjective measure - eDiary)
Self-reported sleepiness domain score of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ - subjective measure)

Reported values are the mean of 7 entries recorded the week before the PSG recording nights

(Publication)

Question 7

What were the exploratory endpoints for the 301/302 phase 3 trials?

Answer 7

Change from baseline to month 1 and month 3 in:
Total score of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) (subjective)
Mood domain score of the IDSIQ (subjective)
Alertness/Cognition domain score of the IDSIQ (subjective)
sWASO (subjective - eDiary)
sLPO (subjective - eDiary)
Morning Visual Analog Scale (VAS) score for quality of sleep (subjective)
Evening VAS score for ability to function and daytime alertness (subjective)

Subjective measures report the mean of daily scores averaged over the 7 nights before PSG recording

Proportion of time spent in each stage of sleep (objective - PSG)
TST (objective - PSG)
Insomnia Severity Index (ISI) score (subjective - recorded on PSG visit dates)

(Publication)

Question 8

How many patients in the studies underwent CBT/ CBT-I ? (Cognitive Behavioral Therapy - Insomnia)

Answer 8

CBT-I was allowed only if the participant began CBT-I at least 1 month before visit 3 (PSG nights 1 & 2) and the patient agreed to continue CBT-I throughout the rest of the study.

301-
3 patients - (0.3%; one in each of the 50 mg, 25 mg and placebo treatment groups)- were using CBT-I at screening
25 patients previously failed CBT-I treatment prior to entering the study (2.7% - 11 in the 50 mg; 7 in the 25 mg; and 7 in the placebo groups, respectively)

302-
0 subjects were using CBT-I at screening
9 patients previously failed CBT-I treatment prior to entering the study (1.0%; 2 in the 25 mg, 4 in the 10 mg, 3 in the placebo groups, respectively)

(Data on File)

Question 9

Was a subgroup analysis performed on subjects who received both CBT-I and daridorexant?

Answer 9

Due to the few numbers on patients using CBT-I, this subgroup analysis was not possible.

(Supplement)

Question 10

Was appetite measured in the phase 3 trials?

Answer 10

No, appetite was not measured during the phase 3 trials.

Supplement

Question 11

Was the effect of daridorexant consistent across sex?

Answer 11

Yes, the effect of daridorexant was consistent across sex. No sex differences were noted in the response to daridorexant

(Publication)

Question 12

Was the effect of daridorexant consistent across geographical locations?

Answer 12

Yes, the effect of daridorexant was consistent across geographical locations. The treatment effect of daridorexant did not differ across patient locations.

(Publication)

Question 13

Did the effect of daridorexant differ by ethnic group?

Answer 13

No subgroup analysis of daridorexant across ethnic groups was performed. Between 87 - 93% of participants were white.

(Publication)

Question 14

What was the level of drug compliance in the 301/302 studies?

Answer 14

Treatment compliance was calculated based on study treatment accountability (number of tablets dispensed/number of tablets returned) and treatment duration (excluding treatment interruptions).

In the placebo run-in period, median treatment compliance was 100% in all treatment groups.

During the double-blind treatment period, median treatment compliance was 100% with some balanced variability across treatment groups
In study 301 - treatment compliance was < 70% for 4 patients (1.3%) on 50 mg, 15 patients (4.8%) on 25 mg, and 12 patients (3.9%) on placebo.
In study 302 - treatment compliance was < 70% for 13 patients (4.2%) on 25 mg, 17 patients (5.5%) on 10 mg, and 10 patients (3.2%) on placebo.

In the placebo run-out period median treatment compliance was 100%

(Data on file)

Question 15

Were nightmares reported in the 302/302 phase 3 trials?

Answer 15

Yes, nightmares were reported in both studies

In 301, 0 patients on 50 mg daridorexant, 2 patients (1%) on 25 mg daridorexant and 1 patient (< 1%) on placebo reported nightmares

In 302, 1 patient (<1%) on 25 mg daridorexant, 0 patients on 10 mg daridorexant, and 1 patient (<1%) on placebo reported nightmares

(Data on file)

Question 16

Were cataplexy events reported in the 301/302 phase 3 trials?

Answer 16

No, no cataplexy events were reported in the phase 3 trials

Publication

Question 17

Were complex sleep behaviors reported in the 301/302 phase 3 trials?

Answer 17

No, no reports of complex sleep behaviors were noted.

Publication

Question 18

Were hallucinations reported in the phase 3 trials?

Answer 18

Yes, there were isolated reports of hallucinations in the phase 3 trials.

In 301 - 1 patient (<1%) on 25 mg of daridorexant reported hallucinations

In 302 - 1 patient (<1%) on 25 mg of daridorexant reported hallucinations

(Publication)

Question 19

Was sleep paralysis reported in the phase 3 trials?

Answer 19

Yes, isolated incidents of sleep paralysis were reported in the phase 3 trials.

In 301 - 1 patient (<1%) on 50 mg and 1 patient (<1%) on 25 mg daridorexant, respectively, reported sleep paralysis

In 302 - 2 patients (1%) on 25 mg daridorexant reported sleep paralysis

(Publication)

Question 20

Was somnolence reported in the phase 3 trials?

Answer 20

Somnolence was reported in both studies in all groups.

In 301 - 5 patients (2%) taking 50 mg; 11 patients (4%) taking 25 mg; and 6 patients (2%) taking placebo

In 302 - 10 patients (3%) taking 25 mg; 6 patients (2%) taking 10 mg; and 4 (1%) patients taking placebo

(Publication)

Question 21

Was somnolence reported more often in the elderly vs. younger patients in the phase 3 trials?

Answer 21

301 - Somnolence was reported by older adults taking 50 mg or placebo at a similar frequency as younger adults:
50 mg - 1 patient (0.8% vs. 2%)
25 mg - 6 patients (5% vs. 4%)
Placebo - 1 patient (0.8% vs. 2%)

302 - 25 mg - 6 patients (5% vs. 3%)
10 mg - 3 patients (2.5% vs. 2%)
Placebo - 2 patients (1.7% vs. 1%)

(Supplement)

Question 22

Were falls reported in the phase 3 trials?

Answer 22

Falls were reported by patients in both studies

301 - 	1 patient (< 1%) on 50 mg
		1 patient (< 1%) on 25 mg
		8 patients (3%) on placebo

302 - 	3 patients (1%) on 25 mg
		4 patients (1%) on 10 mg
		3 patients (1%) on placebo

(Publication)

Question 23

Did falls occur more frequently in the elderly than in younger adults in the phase 3 trials?

Answer 23

301 - 	1 patient (0.8 % vs. <1%) on 50 mg
		1 patient (0.8% vs. < 1%) on 25 mg
		4 patients (3.3% vs. 3%) on placebo

302 - 	3 patients (2.5% vs. 1%) on 25 mg
		2 patients (1.7% vs 1%) on 10 mg
		2 patients (1.7% vs 1%) on placebo

(Supplement)

Question 24

Was dizziness reported in the phase 3 trials?

Answer 24

Dizziness was reported by patients in both studies.

301 - 	7 patients (2%) on 50 mg
		6 patients (2%) on 25 mg
		2 patients (1%) on placebo

302-	6 patients (2%) on 25 mg
		4 patients (1%) on 10 mg
		4 patients (1%) on placebo

(Publication)

Question 25

Did dizziness occur more frequently in the elderly compared to younger adults in the phase 3 trials?

Answer 25

Among older adults, dizziness was reported at a similar frequency in the 50 mg and placebo groups compared to younger adults.

301-	1 patient (0.8% vs. 2%) for 50 mg
		4 patients (3.3% vs 2%) for 25 mg
		1 patient (0.8% vs. 1%) for placebo

302-	3 patients (2.5% vs. 2%) for 25 mg
		2 patients (1.7% vs. 1%) for 10 mg
		4 patients (3.3% vs. 1%) for placebo

(Supplement)

Question 26

What were the most common adverse events reported in the phase 3 trials?

Answer 26

Nasopharyngitis and headache in all groups across both studies

(Publication)

Question 27

Was the safety of daridorexant consistent between older and younger adults?

Answer 27

Yes, the safety profile was consistent across all populations and across all doses in the phase 3 trials

(Publication)

Question 28

Is the efficacy of daridorexant consistent between older and younger adults?

Answer 28

Yes, efficacy was consistent across both age groups.

Publication

Question 29

Was REM sleep affected in the phase 3 trials?

Answer 29

Yes. Time spent in REM sleep was preserved across all treatment groups and did not change at 1 month or 3 months of daridorexant use.

(Publication)

Question 30

Were NREM sleep stages affected by daridorexant?

Answer 30

No, time spent in all NREM sleep stages was consistent across treatment groups and did not change at 1 month or 3 months.

(Publication)

Question 31

What was the study design of the phase 3 trials?

Answer 31

Studies 301 and 302 were two international, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 trials

Evaluating the safety and efficacy of daridorexant in patients with moderate-to-severe chronic insomnia

Studies were conducted simultaneously, but independently (i.e. at different hospitals, with no overlap)

Trial included adults (<65 years, ~60%) and older adults (> 65 years, ~40%)

Daridorexant doses in trial 301 were 50 mg/nightly, 25 mg/nightly and placebo
Daridorexant doses in trial 302 were 25 mg/nightly, 10 mg/nightly and placebo

7-18 day screening period - with PSG performed on visit 1
13-24 day single-blind placebo run-in period - all patient received placebo - 2 nights of PSG performed on visit 3
Patients were then randomized - with 2 nights of PSG performed on visit 6 (1 month after randomization) and visit 8 (3 months after randomization, also the end of DBT)
Patients then underwent a 7-day, single-blind placebo run out (all patients received placebo)
Patients could then choose to join the placebo-controlled 9-month extension study.

(Publication)

Question 32

What were the adverse events in the phase 3 trials (summarize)?

Answer 32

Both phase 3 studies reported:
Similar rates of treatment-emergent adverse events between placebo and all doses of daridorexant
Were consistent across adult and elderly subgroups
Were NOT dose dependent

Nasopharyngitis and headache were the most commonly reported TEAEs
Somnolence and fatigue were infrequent

Discontinuations were higher in the placebo group than any of the daridorexant groups

(Publication)

Question 33

What were the reasons why patients discontinued on the phase 3 trials?

Answer 33

Discontinuations:
301 - 22 in 50 mg; 24 in 25 mg; 28 in placebo
302 - 23 in 25 mg; 23 in 10 mg; 18 in placebo

Withdrawal of consent, Adverse events, Lack of efficacy, Lost to follow-up, Other, Death (1 - determined not to be treatment related).

(Publication)

Question 34

What is the effect of food on the PK of QUVIVIQ ?

Answer 34

In the presence of a high fat, high calorie meal, the Tmax was delayed by 1.3 hrs and the Cmax was decreased by 16%. The half-life (t1/2) was shortened by 1 hr. There was no effect on total exposure (AUC).

Administration of daridorexant, alone or in combination with food, was well tolerated.

Question 35

Can you administer QUVIVIQ concomitantly with BCRP substrates (i.e. rosuvastatin)?

Answer 35

A single dose of rosuvastatin and multiple doses of 25 mg daridorexant (4 days of treatment) was well tolerated. No change in PK parameters (Cmax, AUC, t1/2) were observed. Tmax was slighly prolonged by 15 minutes. No dose adjustments are needed. Drug-drug interactions between daridorexant and concomitant drugs whose disposition is mediated by BCRP is unlikely.

The same can be inferred though modeling for the 50 mg dose. There would be a high predictibility, in view of the clear lack of interaction at the 25 mg dose, and only a two-fold increase in daridorexant dose, that no relevant DDIs would occur.

Rosuvastatin - used as a model for all BCRP substrates

Question 36

Can alcohol be consumed while taking QUVIVIQ

Answer 36

Avoid alcohol consumption with QUVIVIQ

Concomitant use of alcohol or other CNS depressants with QUVIVIQ may lead to additive impairment of psychomotor performance and risk of CNS depression. If coadministration is necessary, dose reductions of QUVIVIQ may be necessary.

In a phase I trial, coadministration of a 50 mg dose of QUVIVIQ with 0.6 g/L ethanol lead to less-than additive effects on impairment (postural stability and altertness).

Daridorexant did not affect alcohol concentrations and alcohol did not affect daridorexant concentrations. PK parameters were unchanged except for a 75 min prolongation in tmax.