Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer’s disease: a 6-month, randomized, placebo-controlled, multicenter trial

Figures & data

Figure 1 Overall study design.

Notes: The study was comprised of a 2-week, single-blind, placebo run-in period, followed by randomization (1:1) to add-on PRM 2 mg or placebo for 24 weeks. Once the treatment period was over, the patients underwent a 2-week placebo run-out period.
Abbreviation: PRM, prolonged-release melatonin.

Figure 2 Overall study patient disposition.

Abbreviations: AE, adverse event; FAS, full analysis set; PRM, prolonged-release melatonin; SAE, serious adverse event.

Table 1 Changes from baseline in cognitive outcome, as assessed by ADAS-Cog, IADL, and MMSE after 24 weeks of treatment

	PRM				Placebo
	N	Mean ± SD	Median	P*	N	Mean ± SD	Median	P*	P**
ADAS-Cog
FAS
Baseline	29	24.59±5.57	23.0		26	27.35±8.11	25.5
24 weeks	29	25.03±8.85	24.0		26	27.54±10.87	26.5
Changes 24 weeks	29	0.45±5.00	−2.0	0.670	26	0.19±6.28	0.5	0.877	0.448+++
Insomnia subpopulation
Baseline	6	20.50±3.99	22.0		5	26.6±4.67	26.0
24 weeks	6	18.00±6.51	19.5		5	27.6±7.73	26.0
Changes 24 weeks	6	−2.50±3.08	−3.5	0.125	5	1.0±6.04	3.0	0.875+	0.045***
IADL
FAS
Baseline	31	3.29±2.64	3.0		29	3.93±2.39	4.0
24 weeks	31	4.06±2.34	4.0		29	5.55±2.15	6.0
Changes 24 weeks	31	0.77±1.41	0.0	0.005	29	1.62±1.57	2.0	<0.001	0.004
Insomnia subpopulation
Baseline	6	0.83±1.33	0.0		5	4.00±3.81	5.0
24 weeks	6	1.50±1.52	1.5		5	5.80±2.59	7.0
Changes 24 weeks	6	0.67±1.75	0.0	0.750	5	1.80±1.30	2.0	0.500	0.031
MMSE
FAS
Baseline	32	22.1±3.5	22.0		29	21.4±4.7	22.0
24 weeks	32	21.9±3.8	22.0		29	19.5±6.0	22.0
Changes 24 weeks	32	−0.3±2.8	0.5	0.622	29	−1.9±3.5	−2.0	0.006	0.044
Insomnia subpopulation
Baseline	6	24.0±3.7	25.0		5	20.6±3.1	20.0
24 weeks	6	25.5±3.6	26.0		5	17.8±2.9	17.0
Changes 24 weeks	6	1.5±2.9	2.5	0.375	5	−2.8±2.9	−3.0	0.250	0.017

Notes:

* P-value indicates significant within the two study groups (paired t-test).

** P-value indicates significant for changes from baseline between the two study groups, with adjustment for baseline assessments (ANCOVA model).

*** P-value indicates significant for changes from baseline between the two study groups (median test).

+ P-value indicates significant within the two study groups (sign-rank test).

+++ P-value indicates significant for changes from baseline between the two study groups, with adjustment for baseline assessment, sex, and age (ANCOVA model).

Abbreviations: AD, Alzheimer’s disease; ADAS-Cog, AD Assessment Scale–Cognition; ANCOVA, analysis of covariance; FAS, full analysis set; IADL, Instrumental Activities of Daily Living; MMSE, Mini–Mental State Examination; PRM, prolonged-release melatonin; SD, standard deviation.

Figure 3 Cognitive assessments.

Notes: (A) The change in median ADAS-Cog between baseline and 24 weeks, by treatment FAS and insomnia subpopulation (PSQI ≥6 at baseline). P-value indicates significant for changes from baseline between the two study groups (median test). (B) The change in mean MMSE (± SEM) between baseline and 24 weeks of treatment in the FAS and in the insomnia subpopulation (PSQI ≥6 at baseline). P-value indicates significant for changes from baseline between the two study groups, with adjustment for baseline assessment (ANCOVA model). (C) The change in mean IADL (± SEM) between baseline and 24 weeks, by treatment in the FAS and insomnia subpopulation (PSQI ≥6 at baseline). P-value indicates significant for changes from baseline between the two study groups, with adjustment for baseline assessment (ANCOVA model). (D) Global treatment effect of PRM on mean IADL (± SEM) change from baseline, over the 24-week period (MMRM), in the FAS.
Abbreviations: AD, Alzheimer’s disease; ADAS-Cog, AD Assessment Scale–Cognition; ANCOVA, analysis of covariance; FAS, full analysis set; IADL, Instrumental Activities of Daily Living; MMRM, mixed-effects model for repeated measures; MMSE, Mini–Mental State Examination; PRM, prolonged-release melatonin; PSQI, Pittsburgh Sleep Quality Index; SEM, standard error of the mean.

Table 2 Effects of PRM and placebo on PSQI global score and items, by treatment and period – FAS population

PSQI item	Period	PRM				Placebo
		N	Mean	SD	P-valuea	N	Mean	SD	P-valuea	P-valueb
PSQI global	Baseline	31	4.61	3.25		29	4.03	3.55
	Changes 12 wks	31	−1.52	3.38	0.018*	29	−0.21	2.69	0.682	0.131
	Changes 24 wks	29	−1.62	2.74	0.004*	27	−0.74	2.52	0.139	0.351
Component 1	Baseline	31	0.77	0.76		29	0.55	0.63
	Change 12 wks	31	−0.26	0.73	0.058	29	0.03	0.50	0.712	0.193
	Change 24 wks	29	−0.14	0.79	0.355	25	0.04	0.54	0.714	0.841
Component 2	Baseline	31	1.16	1.16		29	0.97	1.12
	Change 12 wks	31	−0.48	1.06	0.016*	29	−0.14	0.83	0.380	0.229
	Change 24 wks	29	−0.34	1.37	0.186	27	−0.30	0.91	0.103	0.656
Component 3	Baseline	29	0.38	0.68		29	0.45	0.83
	Change 12 wks	29	−0.31	0.71	0.026*	26	−0.04	0.87	0.824	0.072
	Change 24 wks	27	−0.30	0.72	0.043*	25	−0.28	0.61	0.032*	0.443
Component 4	Baseline	29	0.86	1.06		29	0.59	1.12
	Change 12 wks	28	−0.46	1.45	0.102	26	0.00	1.17	1.000	0.373
	Change 24 wks	27	−0.67	1.11	0.004*	24	0.00	0.72	1.000	0.017*
Component 5	Baseline	31	0.94	0.44		29	0.97	0.42
	Change 12 wks	31	−0.10	0.47	0.264	29	0.00	0.53	1.000	0.357
	Change 24 wks	29	−0.21	0.56	0.056	27	−0.15	0.46	0.103	0.546
Component 6	Baseline	31	0.00	0.00		29	0.07	0.37
	Change 12 wks	31	0.00	0.00	NA	29	−0.07	0.37	0.326	NA
	Change 24 wks	29	0.00	0.00	NA	27	−0.04	0.44	0.663	0.295
Component 7	Baseline	31	0.58	0.92		29	0.45	0.74
	Change 12 wks	31	−0.16	0.78	0.258	29	0.10	0.90	0.541	0.300
	Change 24 wks	29	−0.10	0.67	0.415	27	0.04	0.76	0.802	0.753
Question 2 (SL, minutes)	Baseline	31	27.39	24.6		29	19.66	17.1
	Change 12 wks	31	−8.32	21.8	0.042*	28	−1.32	9.90	0.486	0.348
	Change 24 wks	29	−9.28	25.3	0.059	26	0.69	45.7	0.939	0.619
Question 4 (TST, hours)	Baseline	29	7.91	1.80		29	8.69	2.40
	Change 12 wks	29	0.58	1.38	0.032*	26	−0.28	1.87	0.454	0.221
	Change 24 wks	27	0.73	1.21	0.004*	25	0.06	1.28	0.811	0.109

Notes:

a P-value comparison within the two study groups (paired t-test)

b P-value comparison of changes from baseline between the two study groups (baseline adjusted ANCOVA model).

* P≤0.05.

Abbreviations: ANCOVA, analysis of covariance; FAS, full analysis set; PRM, prolonged-release melatonin; PSQI, Pittsburgh Sleep Quality Index; SD, standard deviation; wks, weeks; SL, sleep latency; TST, total sleep time; NA, not applicable.

Table 3 Effects of PRM and placebo on PSQI global score and items, by treatment and period – insomnia comorbidity subpopulation

PSQI item	Period	PRM				Placebo				P-valueb
		N	Mean	SD	P-valuea	N	Mean	SD	P-valuea
PSQI global	Baseline	7	9.86	1.68		6	10.00	1.79
	Changes 12 wks	7	−5.29	3.45	0.063	6	−2.83	2.56	0.063	0.194
	Changes 24 wks	6	−5.50	2.88	0.031*	5	−3.80	1.30	0.063	0.303
Component 1	Baseline	7	1.57	0.79		6	1.33	0.52
	Change 12 wks	7	−0.57	0.79	0.250	6	−0.33	0.52	0.500	0.775
	Change 24 wks	6	−0.83	0.41	0.063	5	−0.40	0.55	0.500	0.211
Component 2	Baseline	7	2.71	0.49		6	2.67	0.82
	Change 12 wks	7	−1.43	1.13	0.063	6	−0.67	0.82	0.250	0.223
	Change 24 wks	6	−1.50	1.22	0.125	5	−1.40	0.55	0.063	0.906
Component 3	Baseline	7	1.43	0.53		6	1.67	0.82
	Change 12 wks	7	−1.29	0.76	0.031*	6	−0.67	1.21	0.375	0.162
	Change 24 wks	6	−1.33	0.82	0.063	5	−1.20	0.84	0.125	0.693
Component 4	Baseline	7	2.43	0.53		6	2.67	0.52
	Change 12 wks	7	−2.00	1.41	0.031*	6	−1.00	1.67	0.375	0.099
	Change 24 wks	6	−2.00	1.55	0.063	5	−0.60	1.34	0.500	0.040*
Component 5	Baseline	7	1.14	0.38		6	1.17	0.41
	Change 12 wks	7	0.14	0.38	1.00	6	−0.17	0.41	1.00	0.145
	Change 24 wks	6	0.00	0.63	1.00	5	−0.20	0.45	1.00	0.596
Component 6	Baseline	7	0.00	0.00		6	0.00	0.00
	Change 12 wks	7	0.00	0.00	NA	6	0.00	0.00	NA	NA
	Change 24 wks	6	0.00	0.00	NA	5	0.00	0.00	NA	NA
Component 7	Baseline	7	0.57	1.13		6	0.50	0.84
	Change 12 wks	7	−0.14	1.35	1.00	6	0.00	1.10	1.00	0.865
	Change 24 wks	6	0.17	0.41	1.00	5	0.00	0.71	1.00	0.650
Question 2 (SL, minutes)	Baseline	7	55.71	32.9		6	47.50	11.7
	Change 12 wks	7	−29.3	31.5	0.031*	6	−10.3	9.52	0.125	0.186
	Change 24 wks	6	−35.0	37.4	0.063	5	−35.6	8.76	0.063	0.404
Question 4 (TST, hours)	Baseline	7	5.64	0.63		6	5.42	1.32
	Change 12 wks	7	2.14	1.18	0.031*	6	0.75	1.57	0.500	0.108
	Change 24 wks	6	1.63	1.28	0.063	5	1.20	0.67	0.063	0.462

Notes:

a P-value comparison within the two study groups (paired t-test)

b P-value comparison of changes from baseline between the two study groups (baseline adjusted ANCOVA model).

* P≤0.05.

Abbreviations: ANCOVA, analysis of covariance; PRM, prolonged-release melatonin; PSQI, Pittsburgh Sleep Quality Index; SD, standard deviation; SL, sleep latency; TST, total sleep time; wks, weeks; NA, not applicable.

Figure 4 Sleep assessments.

Notes: (A) The improvement from baseline (absolute value) in mean sleep efficiency over time (sleep efficiency PSQI component 4) – FAS. (B) The improvement from baseline (absolute value) in mean sleep efficiency (sleep efficiency PSQI component 4) in the insomnia subpopulation (PSQI ≥6 at baseline). P-value indicates significant changes from baseline between the two study groups, with adjustment for baseline assessment (ANCOVA model).
Abbreviations: ANCOVA, analysis of covariance; C4, component 4; FAS, full analysis set; PRM, prolonged-release melatonin; PSQI, Pittsburgh Sleep Quality Index.

Table S1 Baseline characteristics of the study population

Parameter	PRM	Placebo
	N=39	N=34
Mean age (years) ± SD (N)	73.5±8.6	77.3±6.6
Age range (years)	52.0–85.0	57.0–85.0
Sex males, N (%)	23 (59.0)	14 (41.2)
Sex females, N (%)	16 (41.0)	20 (58.8)
Height (cm) ± SD	163.2±18.9	163.7±10.3
Weight (kg) ± SD	75.7±14.3	70.3±14.7
Body mass index (kg/m^2) ± SD	27.5±4.5	25.7±4.1
Medical history
CNS (including psychiatric) N (%)	38 (97.4)	33 (97.1)
Cardiovascular N (%)	31 (79.5)	28 (82.4)
Hypertension N (%)	20 (51.2)	17 (50)
Ischemic heart disease N (%)	4 (10.2)	3 (8.8)
Endocrine/metabolic N (%)	20 (51.3)	18 (52.9)
Type 2 diabetes N (%)	5 (12.8)	6 (17.6)
Musculoskeletal N (%)	28 (71.8)	22 (64.7)
AD severity and medications
Mild (MMSE >20) N (%)	23 (67.6)	17 (54.8)
Moderate (MMSE 15–20) N (%)	11 (32.4)	14 (45.2)
Patients taking memantine, N (%)	10 (29.4)	16 (51.6)
Lifestyle habits
Patients consuming alcohol, N (%)	21 (53.8)	11 (32.4)
Patients consuming caffeine, N (%)	35 (89.7)	26 (76.5)
Patients consuming cigarettes, N (%)	5 (12.8)	2 (5.9)
Sleep habits
Number of awakenings/night ± SD (%)	1.8±1.5 (39)	1.7±1.4 (31)
Total sleep hours/night ± SD (%)	7.7±2.0 (39)	7.8±2.2 (34)
PSQI ≥6 N (%)	7 (22.6)	6 (20.7)
PSQI <6 N (%)	24 (77.4)	23 (79.3)

Abbreviations: AD, Alzheimer’s disease; CNS, central nervous system; MMSE, Mini–Mental State Examination; PRM, prolonged-release melatonin; PSQI, Pittsburgh Sleep Quality Index; SD, standard deviation.

Table S2 The change in sleep quality measured from sleep diary parameters, between baseline and 12 weeks of treatment (FAS)

	PRM				Placebo
	N	Mean ± SD	Median	P*	N	Mean ± SD	Median	P*	P**
Baseline	34	2.94±0.75	3		30	2.99±0.87	3
12 weeks	29	3.25±0.66	3		27	2.88±1.06	3
Changes 12 weeks	30	0.34±0.63	0	0.007	26	−0.14±1.12	0	0.535	0.065

Notes:

* P-value indicates significant within the two study groups (paired t-test).

** P-value indicates significant for changes from baseline between the two study groups, with adjustment for baseline assessments (ANCOVA model).

Abbreviations: ANCOVA, analysis of covariance; FAS, full analysis set; PRM, prolonged-release melatonin; SD, standard deviation.

Table S3 Number (%) of patients who had an adverse event (AE), in the safety population

	PRM		Placebo
	N	(%)	N	(%)
Subjects treated	39	(100.0)	34	(100.0)
Subjects reporting AEs	32	(82.1)	23	(67.6)
Number of AEs	86		70
Subjects reporting drug-related AEs	8	(20.5)	2	(5.9)
Number of drug-related AEs	12		2
Subjects reporting SAEs	2	(5.1)	5	(14.7)
Number of SAEs	3		9
Subjects reporting drug-related SAEs	0	(0)	0	(0)

Notes: Percentage based on number of patients in the safety population for each treatment group.

Abbreviations: AE, adverse event; PRM, prolonged-release melatonin; SAE, serious adverse event

Table S4 Overall adverse events and most frequent events, by system organ class and preferred term, in >5% of patients (two patients) in any cohort, and drug-related AEs

System organ class/preferred term	PRM N=39		Control N=34
	N	(%)	N	(%)
All AEs	32	(82.1)	23	(67.6)
Angina pectoris	2	(5.1)	–	–
Abdominal discomfort	2	(5.1)	1	(2.9)
Diarrhea	4	(10.3)	2	(5.9)
Nausea	–	–	2	(5.9)
Vomiting	2	(5.1)	1	(2.9)
Fatigue	3	(7.7)	1	(2.9)
Blood creatinine increased	–	–	2	(5.9)
Blood glucose increased	2	(5.1)	1	(2.9)
Decreased appetite	2	(5.1)	–	–
Back pain	2	(5.1)	1	(2.9)
Abnormal dreams	2	(5.1)	–	–
Agitation	2	(5.1)	2	(5.9)
Cognitive disorder	1	(2.6)	2	(5.9)
Insomnia	2	(5.1)	1	(2.9)
Urinary tract infection	1	(2.6)	6	(17.6)
Cough	2	(5.1)	–	–
Nasopharyngitis	2	(5.1)	1	(2.9)
Upper respiratory tract infection	2	(5.1)	3	(8.8)
Drug-related AEs	8	(20.5)	2	(5.9)
Fatigue	2	(5.1)	1	(2.9)
Fall	1	(2.6)	–	–
Thyroid neoplasm	1	(2.6)	–	–
Abnormal dreams	2	(5.1)	–	–
Burning feet syndrome	1	(2.6)	–	–
Headache	–	–	1	(2.9)
Somnolence	1	(2.6)	–	–
Delusion	1	(2.6)	–	–
Restlessness	1	(2.6)	–	–

Note: Percentage based on number of patients in the safety population for each treatment group.

Abbreviations: AE, adverse event; PRM, prolonged-release melatonin; SAE, serious adverse event.