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A Phase III Study of TK-023 in Patients with Mild to Moderate Dementia of the Alzheimer's Type

A Phase III Study of TK-023 in Patients with Mild to Moderate Dementia of the Alzheimer's Type

339

There were no major differences between groups in terms of baseline demographics (gender, age, body weight, duration of illness) and clinical characteristics (MMSE, ADAS-J cog, DAD, ABC dementia scale, use of prior ChEIs, types of prior ChEI therapy) in the PPS, FAS, and safety analysis sets.

Among 508 patients who provided informed consent, 489 patients were administered during the observation period and 340 patients were randomized. Among them 339 patients were administered the investigational drugs [test drug group (TK-023 27.5 mg patch group, hereafter, DP), n = 173; reference therapy group (donepezil hydrochloride tablet group, hereafter, DT), n = 166], of which 303 patients completed the double-blind period (DP, n = 156; DT, n = 147). During the double-blind period, 36 patients discontinued (DP, n = 17; DT, n = 19). Total of 301 patients entered open-label period and 2 patients discontinued before the administration in open-label period started (DP, n = 0; DT, n = 2). Among the patients who entered open-label period [DP, n = 156; the group switched from donepezil hydrochloride tablet to donepezil patch 27.5 mg, hereafter, switched group, n = 145], 24 patients discontinued (DP, n=17; switched group, n=7), and as a result, total of 277 patients completed open-label period.

<Noninferiority study (Double-blind period)> The incidence rates of AEs (adverse events) were 76.9% and 66.9% in DP and DT, respectively. The incidences of SAEs (serious adverse events) were 9.2% and 7.8% in DP and DT, respectively, and decreased appetite (one patient) in DP and nephrotic syndrome (one patient) in DT were considered related to the study drugs. AEs leading to discontinuation were observed in 4.0% in DP and 3.6% in DT. <Extension Study (Open-Label period)> The incidence rates of AEs were 64.7% and 73.8% in DP and switched group, respectively. The incidences of SAEs (serious adverse events) were 10.3% and 6.2% in DP and switched group, respectively, and weight decreased (one patient) in DP and lymphoma (one patient) in switched group were considered related to the study drugs. AEs leading to discontinuation were observed in 3.2% in DP and 1.4% in switched group.

At week 24, mean changes [LS mean (SE)] in the ADAS-J cog from baseline were -0.7 (0.4) in DP and 0.2 (0.4) in DT. The difference in the LS means (95% CI) between the groups was -0.9 (-2.01 to 0.14). The upper bound of the 95% CI was less than the predefined noninferiority margin of 2.15.

In the PPS, mean (SD) changes from baseline in ADAS-Jcog at week 4, 12, 24 were 0.0 (3.9), -0.7 (4.0), and -0.7 (4.3) in DP and 0.5 (4.2), 0.0 (4.5), and 0.2 (4.5) in DT. In the PPS, mean (SD) changes from baseline in DAD at week 4, 12, 24 were -0.2 (9.2), 0.5 (9.9), and -2.2 (12.3) in DP and -0.2 (10.1), 0.0 (10.8), and -3.5 (10.9) in DT. In the PPS, mean (SD) changes from baseline in ABC dementia scale (total scores) at week 4, 12, 24 were 0.5 (6.0), -0.5 (6.7), and -1.5 (7.7) in DP and -0.2 (5.5), -0.2 (6.2), and -1.6 (7.2) in DT. In the FAS, mean (SD) changes from baseline in ADAS-Jcog at week 28, 36, 52 were 0.5 (4.3), 0.8 (5.1), and 1.2 (5.2) in DP and 1.5 (4.5), 1.4 (4.5) and 1.9 (5.4) in switched group. In the FAS, mean (SD) changes from baseline in ABC dementia scale (total scores) were -2.4 (7.8), -2.1 (8.2), and -3.2 (9.4) in DP and -1.8 (7.9), -2.9 (8.8), and -4.7 (9.6) in switched group.

Noninferiority was demonstrated for the donepezil patch (27.5 mg, once per day) when compared to the oral donepezil hydrochloride tablet 5 mg. In open-label period, ADAS-Jcog and ABC dementia scale showed similar time course between DP and switched group.

No

TEIKOKU SEIYAKU Co., LTD.

TOKYO OFFICE 6-6 Nihonbashi-kobunacho, Chuo-ku, Tokyo 103-0024 Japan

rinsho@teiyaku.co.jp

TEIKOKU SEIYAKU Co., LTD.

TOKYO OFFICE 6-6 Nihonbashi-kobunacho, Chuo-ku, Tokyo 103-0024 Japan

+81-3-6264-9123

rinsho@teiyaku.co.jp

completed

Jan. 18, 2019

Interventional

Multicenter, Randomized, Double-Blind, Double-Dummy, Open-Label Study, Parallel-Group, Non-inferiority Study

treatment purpose

3

1. Diagnostic evidence of probable dementia of the Alzheimer's Type consistent with the Diagnostic and Statistical Manual for Mental Disorders-version V (DSM-V) at Screening
2. Hachinski Ischemic Score < 4 at Screening
3. ABC dementia scale < 100 and > 71 at Baseline
4. Mini-Mental State Examination (MMSE) score of 10 to 26 at Baseline
5. ADAS-Jcog score > 15 at Baseline
6. Subjects who have a caregiver

1. Subjects with dementia other than Alzheimer's type
2. Subjects with a cause of Dementia which is supported by any laboratory tests
3. Subjects with an active skin lesion/disorder that may affect adhesion and skin symptom assessment on the application site
4. Subjects with history of photosensitivity
5. Subjects with allergy to component of donepezil hydrochloride (including excipients) or piperidine derivative
6. Subjects with allergy to external preparation

Both

Dementia of the Alzheimer's type

investigational material(s)
Generic name etc : Donepezil
INN of investigational material : Donepezil
Therapeutic category code : 119 Other agents affecting central nervous system
Dosage and Administration for Investigational material : Once daily (27.5 mg)

control material(s)
Generic name etc : Donepezil Hydrochloride
INN of investigational material : Donepezil
Therapeutic category code : 119 Other agents affecting central nervous system
Dosage and Administration for Investigational material : Once daily (3 or 5 mg)

efficacy
confirmatory
ADAS-Jcog score and changes from baseline at 24 weeks of double-blind period

efficacy
1. ADAS-Jcog score and changes from baseline (4-12 weeks)
2. ADL assessment: DAD score and changes from baseline (4-24 weeks)
3. Clinical global impression of change rating: ABC dementia scale and the changes from baseline (4-24 weeks)
4. ADAS-Jcog score, the changes from baseline/24th week (28-52 weeks)
5. Clinical global impression of change rating: ABC dementia scale and the changes from baseline/24th week (28-52 weeks)

Dec. 14, 2018