Individual Study Table Referring to Part of the€¦ · 3. Diagnosis of major depressive disorder by the M.I.N.I. according to the DSM-IV-TR . 4. Female patients of childbearing potential

FK949E ISN 6949-CL-0009 Major Depressive Disorder (MDD) CONFIDENTIAL Name of Sponsor:

Astellas Pharma Inc. Product Name: Not determined

Name of Active Ingredient:

FK949E (quetiapine fumarate)

Individual Study Table

Referring to Part of the

Dossier

Volume: Not determined Page: Not determined

(For National Authority Use Only)

Study Design and Methodology:

Multicenter, open-label design

Planned Sample Size: 150 mg treatment group: A maximum of 12 subjects receiving study drug (8 completing treatment)

300 mg treatment group: A maximum of 12 subjects receiving study drug (8 completing treatment

600 mg treatment group: A maximum of 16 subjects receiving study drug (8 completing treatment)

[Rationale]

The sample size was determined as the number of subjects that was considered sufficient to evaluate the safety and pharmacokinetics of the study drug, and also in consideration of the feasibility of the study. A maximum of 12 subjects receiving study drug (8 completing treatment) were to be assigned to each group in consideration of discontinuation.

Although the 600 mg treatment group had more discontinuations than expected, the analysis of adverse events, their severity, and clinical course found no significant safety concerns. Therefore, the maximum number of subjects receiving the study drug was changed to 16 based on the conclusion that more subjects could be added to ensure there would be 8 subjects completing treatment.

15 Dec 2011 Astellas Page 2 of 37







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Diagnosis and Inclusion/Exclusion Criteria:

Patients with major depressive disorder were eligible for the study if all of the following inclusion criteria applied and none of the exclusion criteria were met.

1. Inclusion criteria

1. Provision of written informed consent.

2. Aged 20 to 64 years, inclusive, at the time of providing written informed consent

3. Diagnosis of major depressive disorder by the M.I.N.I. according to the DSM-IV-TR

4. Female patients of childbearing potential with a negative serum pregnancy test result and who were willing and able to use a reliable method of birth control during the study.

5. Patients who could understand and comply with the requirements of the study, as judged by the investigator/sub-investigator.

2. Exclusion criteria

1. A current or past history of a DSM-IV-TR Axis I disorder other than major depressive disorder within 6 months prior to provision of written informed consent.

2. Diagnosis of a DSM-IV-TR Axis II disorder that was considered to have a major impact on the patient’s current psychiatric status.

3. A history of substance or alcohol abuse or dependence excluding caffeine and nicotine.

4. Patients who were unable to abstain from drugs that induce or inhibit the drug-metabolizing enzyme CYP3A4 from 14 days prior to screening assessment and throughout the study period.

5. Pregnant or lactating women

6. Patients showing evidence or signs of renal or hepatic failure, serious heart disease, cerebrovascular disease, viral hepatitis B or C, or acquired immunodeficiency syndrome (AIDS) (carrier).

7. Patients being treated for hypertension or patients with clinical finding that in the opinion of the investigator/sub-investigator could be negatively affected by the study or that would affect the study results (e.g., hypertension, unstable angina).








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8. Patients with concomitant hypotension or orthostatic hypotension (hypotension is defined as systolic blood pressure of less than 100 mmHg)

9. Conditions that could affect absorption and metabolism of the study medication (e.g., malabsorption syndrome, liver disease).

10. A current diagnosis of malignant tumor unless in remission for at least 5 years (except basal or squamous cell skin carcinoma).

11. A history of transient ischemic attack (TIA).

12. A history of seizure disorder, except for febrile convulsions.

13. Application of electroconvulsive therapy within 90 days prior to the start of study drug administration.

14. Use of a depot antipsychotic injection and inability to be off the drug for a period of twice the dosing interval prior to screening assessment and throughout the study period.

15. Patients could require psychotherapy (other than supportive psychotherapy) during the study period, unless psychotherapy had been ongoing for a minimum of 90 days prior to the start of study drug administration.

16. A score of ≥ 3 on the HAM-D17 Item (suicide) or a suicide attempt within the past 6 months. Patients judged to be at serious suicidal or homicidal risk in the opinion of the investigator/sub-investigator.

17. A current or past history of diabetes mellitus* or glycated hemoglobin (HbA1c) of ≥ 6.5% at screening within 2 months before the start of study drug administration (*refer to the guidelines for monitoring blood glucose levels in patients treated with atypical antipsychotics).

18. Clinically significant deviation from the reference range in clinical laboratory test results, as judged by the investigator/sub-investigator (refer to grade 3 adverse drug reactions according to the “Criteria for Classification of the Grade of Adverse Drug Reactions to Pharmaceutical Products” [Pharmaceutical Affairs Bureau/Safety Division (PAB/SD) Notification No. 80, dated 29 June 1992]).

19. A white blood cell count (WBC) of ≤ 3,000/mm3 at screening assessment.

20. Elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values at screening assessment (grade 2 or higher according to the “Criteria for Classification of the Grade of Adverse Drug Reactions to Pharmaceutical Products” [Pharmaceutical Affairs Bureau/Safety Division (PAB/SD) Notification No. 80, dated








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29 June 1992]).

21. Treatment with adrenaline at the time of providing written informed consent.

22. A known history of hypersensitivity to quetiapine or to any other component in the FK949E tablets at the time of providing written informed consent.

23. Previous use of quetiapine.

24. Involvement in the planning and conduct of the study (applies to Astellas staff, CRO staff concerned, and staff at the study site).

25. Previous randomization in a clinical study of quetiapine.

26. Participation in another clinical study or post-marketing study within 12 weeks prior to the start of study drug administration.

27. Patients who were judged to be inappropriate as subjects of this study by the investigator/sub-investigator.








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Test Drug, Dose, and Mode of Administration

1. Test drug and lot numbers Test drug Lot number

FK949E Tablets 50 mg An oval, pale yellowish-red film-coated tablet, containing

50 mg of quetiapine.

(Manufacturer: AstraZeneca)

FK949E Tablets 150 mg An oval, white film-coated tablet, containing 150 mg of

quetiapine.

(Manufacturer: AstraZeneca) 2. Dosage and mode of administration

[Dose]

1. 150 mg treatment group: 150 mg/day on Day 3 and subsequent days

Days 1 and 2 (50 mg) one FK949E 50 mg Tablet

Days 3 to 9 (150 mg) one FK949E 150 mg Tablet




Days 5 to 11 (300 mg) two FK949E 150 mg Tablets




Days 5 and 6 (300 mg) two FK949E 150 mg Tablets

Days 7 to 13 (600 mg) four FK949E 150 mg Tablets

[Dose regimen and administration period]

The prescribed number of tablets was taken orally once daily in the morning under fasting conditions. Treatment started at around 10:00. Breakfast, if any, was given at around 7:30 and finished within 30 minutes, and the study drug was administered 2 hours or more after breakfast (at around 10:00).

1. 150 mg treatment group: 9 days










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Number of tablets administered

Hospitalization

Treat- ment group

Study drug

Day

1

Day

2

Day

3

Day

4

Day

5

Day

6

Day

7

Day

8

Day

9

Day

10

Day

11

Day

12

Day

13

50 mg tablet

1 1 150 mg treatment group

150 mg tablet

1 1 1 1 1 1 1 - - - -

50 mg tablet


150 mg tablet

1 1 2 2 2 2 2 2 2 - -

50 mg tablet


150 mg tablet

1 1 2 2 4 4 4 4 4 4 4

[Rationale for the dose, dose regimen, and administration period]

The dosage and administration of FK949E approved in the US was 150 mg to 300 mg once daily for patients receiving treatment with existing antidepressants, and the clinical dose in Japan was therefore supposed to be 150 mg to 300 mg. As a result of the evaluation of safety in the 300 mg treatment group in the Japanese phase I study (Study No. 6949-CL-0001), it was considered appropriate to proceed to the study of the 600 mg treatment group. However, the safety of FK949E at 300 mg could not be confirmed adequately because of the medical treatment administered to the subjects in the 600 mg treatment group for an adverse event (orthostatic hypotension) during the 300 mg dose period. It was therefore decided to reconfirm the safety of FK949E administered at 300 mg, which is the maximum dose in phase II and subsequent studies. Prior to treatment at 300 mg, FK949E was to be administered at 150 mg, which was supposed to be a lower clinical dose, and the safety was to be confirmed in a stepwise manner. Furthermore, to ensure adequate safety in phase II and subsequent studies, the safety of FK949E at doses exceeding 300 mg was to be examined. Taking into consideration the differences between individuals, the safety of FK949E at a dose of up to 600 mg was investigated.

The dose escalation schedule (every 2 days) was established based on the results of overseas clinical studies (Study No. D1448C00001 to D1448C00007). In the Japanese phase I study (Study No. 6949-CL-0001), FK949E was studied on an every-2-day stepwise dose-escalation schedule, reaching 300 mg on Day 5, and there were no serious adverse events reported








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during the dose escalation period.

In overseas clinical studies, treatment-related adverse events such as somnolence and sedation have been reported with the use of FK949E due to its pharmacological action, and there is a concern that similar AEs could occur in the planned Japanese clinical studies. In fact, orthostatic hypotension was reported in the phase I study that was conducted in Japan (Study No. 6949-CL-0001). Due to a concern about a possible effect of food-induced elevation of plasma FK949E concentrations on AEs, and giving more consideration to safety, it was decided to administer FK949E under fasting conditions. The fasting state is defined as at least 2 hours after a meal, referring to “at least 1 hour before or 2 hours after a meal” given in the FDA Guidelines, for proper treatment.








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Investigational Period:

Pre-investigational period: No more than 28 days

Administration period: 9 days for the 150 mg treatment group, 11 days for the 300 mgtreatment group, and 13 days for the 600 mg treatment group

Observation period after administration: 7 days

Concomitant Medications and Therapies:

[Concomitant drugs and therapies permitted with restrictions]

1. Antidepressant

Only one of the antidepressants listed below was permitted provided that it had been ongoing since at least 28 days prior to the start of study drug administration. The dose was not to exceed the maximum approved daily dose of the drug, and the dosage and administration had to remain the same as those used from 28 days prior to the start of study drug administration.

Paroxetine hydrochloride hydrate, sertraline hydrochloride, milnacipran hydrochloride, duloxetine hydrochloride

2. Hypnotics

Only one of the hypnotics listed below was permitted for insomnia provided that it had been ongoing since at least 28 days prior to the start of study drug administration. The dose was not to exceed the maximum approved daily dose of the drug.

Triazolam, zolpidem tartrate, zopiclone, brotizolam, rilmazafone hydrochloride, lormetazepam

3. Anticholinergics

Only one of the anticholinergics listed below could be used for the treatment of emergent extrapyramidal symptoms. However, prophylactic use was not allowed.

Trihexyphenidyl hydrochloride, profenamine, biperiden, metixene hydrochloride, piroheptine hydrochloride, and mazaticol hydrochloride hydrate

4. Psychotherapy

Psychotherapy was allowed if it had been ongoing since at least 90 days prior to the start of study drug administration.

5. Non-psychoactive medications








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Non-psychoactive medications were allowed provided that they had been ongoing since at least 28 days prior to the start of study drug administration. The dosage and administration were not to be changed and new non-psychoactive medications were not to be administered during the study period unless the drug was considered unnecessary (e.g., occurrence of adverse events, recovery of symptoms, etc.). Prophylactic use was also not allowed.

[Prohibited concomitant drugs and therapies]

For drugs other than concomitant ones permitted with restrictions, the following drug washout periods were to be observed before screening assessment:

1) Mood stabilizer: More than 5 times the t1/2

2) Antipsychotics: More than 5 times the t1/2

3) Anticholinergic agents: More than 5 times the t1/2

4) Anxiolytics, antidepressants, and hypnotics: More than 5 times the t1/2

5) Psychostimulants: More than 5 times the t1/2

6) P450 (CYP) 3A4 inhibitors and inducers: 14 days

7) MAO inhibitors: 14 days

8) Depot antipsychotic injection: Twice the dosing interval

9) Electroconvulsive therapy: 90 days








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Variables

1. Pharmacokinetics

• Plasma unchanged FK949E concentration (Cmax, tmax, AUC24h, AUCinf, t1/2, CL/F, MRTlast, MRTinf, Ctrough, C8h)

2. Safety:

• Adverse events

• Vital signs (axillary body temperature, supine blood pressure, standing blood pressure, supine pulse rate, standing pulse rate)

• 12-lead ECGs

• Laboratory assessments (hematology tests, blood biochemistry tests, urinalysis)

Statistical Analysis

1. Populations for analysis:

The analysis sets were established as planned below, in principle, based on the data review.

Safety Analysis Set (SAF): The safety analysis set included all subjects who received the study drug.

Pharmacokinetic Analysis Set (PKAS): The pharmacokinetic analysis set included all subjects who received the study drug and in which samples for pharmacokinetic assessment were measured (collected) for at least one time point after administration.

2. Demographics and other baseline characteristics:

The following analyses were performed by treatment group on the SAF and PKAS.

• Summary of the discrete data.

• Calculation of the descriptive statistics for continuous data.








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3. Pharmacokinetics:

On the PKAS, the pharmacokinetic parameters were calculated from the measured plasma unchanged FK949E concentrations, and the descriptive statistics were summarized. Non-compartment model analysis of the time course of the plasma unchanged FK949E concentration by each subject was performed to estimate Cmax, t max, AUC24h, AUCinf, t1/2, CL/F, MRTlast, and MRTinf. Plasma unchanged FK949E concentrations before administration on the day of drug administration or 24 hours post-dose were handled as Ctrough. The actual time course after administration (time elapsed after the last study drug administration) was used for the calculation of the pharmacokinetic parameters. As exploratory analysis, the relationship between dose and exposure (Cmax and AUC24h) in Japanese patients, comparison between the initial and last administration of the final dose (Cmax and AUC24h), and parameters following the final dose at steady state (Ctrough and C8h) were examined.

4. Safety:

The following analyses were performed by treatment group on the SAF.

1. Vital signs (axillary body temperature, blood pressure, pulse rate)

• Descriptive statistics for the measured values of each item were calculated for each time point.

• Descriptive statistics for the difference between the supine and standing values for each item were calculated for each time point.

• For each item, spaghetti plot and graphical representation of mean ± SD of the measured values were created. Graphical representations of the difference between the supine and standing values were created.

2. Laboratory assessments (hematology, blood biochemistry, urinalysis)

• For continuous data, descriptive statistics of the measured values were calculated for each time point.

• For continuous data, spaghetti plots of the measured values were created.

• For discrete data, shift table for the data before administration and at each time point of measurement was created.








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3. Electrocardiogram

• Shift table for 12-lead ECGs on the day preceding the day of study drug administration and at each time point was created.

4. Adverse events

• The number and percentage of subjects with AEs and AEs considered to be drug related were summarized.

• The number and percentage of subjects with AEs and AEs considered to be drug related, as classified by MedDRA System Organ Class (SOC) and Preferred Term (PT), were summarized.

Results:

1. Disposition of subjects and analysis set:

The disposition of subjects in the present study is shown in Figure 1. Written informed consent was obtained from a total of 54 subjects, 16 in the 150 mg treatment group, 17 in the 300 mg treatment group, and 21 in the 600 mg treatment group. In the 150 mg treatment group, 6 subjects were screening failures so that 10 subjects in this group received the study drug. Likewise, 7 subjects in the 300 mg treatment group and 9 subjects in the 600 mg treatment group were screening failures so that 10 and 12 subjects in these groups received the study drug, respectively. After each of the 150 and 300 mg treatment groups was completed, the sponsor’s responsible person, in consultation with the medical consultant and in consideration of the safety data obtained from each group, decided that the study could proceed with higher dose groups.

The most frequently reported reason for screening failures was “Not fulfil inclusion/exclusion criteria” in all groups (5 subjects in the 150 mg treatment group, 4 in the 300 mg treatment group, and 8 in the 600 mg treatment group). Two subjects in the 150 mg treatment group, 1 subject in the 300 mg treatment group, and 4 subjects in the 600 mg treatment group discontinued the study. The reasons for discontinuation were “Withdrawal of consent” in 1 subject in the 600 mg treatment group and “Adverse events” in 6 other subjects (orthostatic hypotension in 4 subjects, dizziness in 1 subject, and influenza in 1 subject).








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150 mg treatment

group

300 mg treatment

group

600 mg treatment

group

Figure 1: Disposition of Subjects

The analysis set is presented in Table 1. All subjects in each group who received the study drug were included in the SAF and PKAS.

Table 1: Number of Subjects in Each Analysis Set Analysis set 150 mg treatment

group 300 mg treatment

group 600 mg treatment

group Total

Subjects who received study drug (n)

10 10 12 32

SAF (n) 10 10 12 32 PKAS (n) 10 10 12 32

2. Demographics and other baseline characteristics:

Table 2 shows the major demographics of the PKAS and SAF of each group. When the demographics were compared among the treatment groups, the 150 mg treatment group had a higher proportion of female subjects (70.0%), and the 300 and 600 mg treatment groups had a lower proportion of female subjects (10.0% and 25.0%, respectively). The mean age was

Screening failures (9)

Subjects who signed informed consent (21)

Subjects who received the

study drug (12)

Discontinued (4)

Subjects who completed

treatment (8)



Subjects who received the

study drug (10)

Discontinued (1)


treatment (9)

Discontinued (2)




treatment (8)

Subjects who received the study

drug (10)








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37.2 years in the 300 mg treatment group and higher than the 150 mg (28.1 years) and 600 mg (31.2 years) treatment groups. There was no marked difference in other parameters.

Table 2: Major Demographics

Variable 150 mg

treatment groupN = 10†

300 mg treatment group

N = 10†


N = 12† Male 3 (30.0%) 9 (90.0%) 9 (75.0%)

Female 7 (70.0%) 1 (10.0%) 3 (25.0%) Sex Total 10 10 12 No 10 (100.0%) 10 (100.0%) 11 (91.7%) Yes 0 (0.0%) 0 (0.0%) 1 (8.3%) Past disease

Total 10 10 12 No 3 (30.0%) 2 (20.0%) 4 (33.3%) Yes 7 (70.0%) 8 (80.0%) 8 (66.7%) Concurrent disease

Total 10 10 12 Age (yrs) (at the time of informed consent)

Mean ± SD Median

Min - Max

28.1 ± 6.19 27.5

21-42

37.2 ± 13.97 34.5

22-58

31.2 ± 9.53 28.0

21-51 Body weight (kg) (day preceding the day of study drug administration)

Mean ± SD Median

Min - Max

64.73 ± 17.03062.35

42.8-102.4

67.11 ± 7.273 67.15

56.4-79.0

67.67 ± 9.870 67.60

50.7-84.2

BMI (kg/m2) (at the time of screening assessment)

Mean ± SD Median

Min - Max

24.45 ± 5.243 23.26

17.5-32.1

24.28 ± 2.667 23.34

21.2-28.6

23.84 ± 3.256 23.71

20.6-32.0

†SAF and PKAS

Number of subjects (%)

3. Study drug exposure:

Of 10 subjects in the 150 mg treatment group, 2 subjects (Subject No. and ) discontinued the study after administration on Day 1. Of 10 subjects in the 300 mg treatment group, 1 subject (Subject No. ) discontinued the study after administration on Day 4. Of 12 subjects in the 600 mg treatment group, 3 subjects discontinued the study after administration on Day 2 (Subject No. ) or Day 7 (Subject No. and

), and 1 subject (Subject No. ) discontinued the study after the completion of study drug administration on Day 13 (last day of study drug administration).








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4. Pharmacokinetics:

Table 3 shows the pharmacokinetic parameters of plasma concentrations of unchanged FK949E in the 150 mg treatment group at each measurement time point (the first day of the 50 mg dose period, the first day of the 150 mg dose period, and the seventh day of the 150 mg dose period). Similarly, Tables 4 and 5 show the pharmacokinetic parameters of plasma concentrations of unchanged FK949E in the 300 and 600 mg treatment groups at each measurement time point, respectively. Figures 2, 3, and 4 show changes in mean plasma unchanged FK949E concentrations at each measurement time point.

In the 150 mg treatment group, the Cmax values of unchanged FK949E (mean ± SD) in plasma were 34.58 ± 15.13 ng/mL on the first day of the 50 mg dose period, 151.16 ± 67.02 ng/mL on the first day of the 150 mg dose period, and 131.20 ± 65.65 ng/mL on the seventh day of the 150 mg dose period; likewise, the AUC24h values were 413.72 ± 112.22 ng·h/mL, 1582.91 ± 633.24 ng·h/mL, and 1513.20 ± 431.43 ng·h/mL, respectively. Both Cmax and AUC24h increased with increasing dose of FK949E. There was no marked change in both Cmax and AUC24h between the first day of the 150 mg dose period and the seventh day of the 150 mg dose period. Mean tmax values were in the range of 6.3 to 7.8 h at each measurement time point.

In the 300 mg treatment group, the Cmax values of unchanged FK949E in plasma were 37.85 ± 19.01 ng/mL on the first day of the 50 mg dose period, 243.82 ± 110.56 ng/mL on the first day of the 300 mg dose period, and 313.81 ± 150.64 ng/mL on the seventh day of the 300 mg dose period; likewise, the AUC24h values were 430.27 ± 204.71 ng·h/mL, 2572.48 ± 1239.30 ng·h/mL, and 3728.42 ± 2158.81 ng·h/mL, respectively. Both Cmax and AUC24h increased with increasing dose of FK949E. Both Cmax and AUC24h on the seventh day of the 300 mg dose period were increased compared with those on the first day of the 300 mg dose period. Mean tmax values were in the range of 4.2 to 7.1 h at each measurement time point.

In the 600 mg treatment group, the Cmax values of unchanged FK949E in plasma were 22.80 ± 9.45 ng/mL on the first day of the 50 mg dose period, 317.65 ± 83.96 ng/mL on the first day of the 600 mg dose period, and 335.50 ± 74.75 ng/mL on the seventh day of the 600 mg dose period; likewise, the AUC24h values were 321.86 ± 132.02 ng·h/mL, 4078.93 ± 981.93 ng·h/mL, and 4180.96 ± 851.87 ng·h/mL, respectively. Both Cmax and AUC24h increased with increasing dose of FK949E. There was no marked change in both Cmax and AUC24h between the first day of the 600 mg dose period and the seventh day of the 600 mg dose period. Mean tmax values were in the range of 5.0 to 10.6 h at each measurement time point.

When changes in mean plasma unchanged FK949E concentrations were compared among the treatment groups, 50 mg of FK949E was administered in all treatment groups on the first day








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of the 50 mg dose period (Figure 2), and despite high interindividual variability, there was no marked difference in the changes in mean plasma unchanged FK949E concentrations. As for changes in mean plasma unchanged FK949E concentrations following the final dose (Figures 3 and 4), 150, 300, and 600 mg of FK949E were administered in 150, 300, and 600 mg treatment groups, respectively, and plasma unchanged FK949E concentrations tended to increase with increasing dose of FK949E. On the seventh day of the final dose period, mean plasma unchanged FK949E concentrations were relatively higher in the 300 mg treatment group than in other treatment groups, and this seems to be because there were subjects with relatively high plasma unchanged FK949E concentrations in the 300 mg treatment group.

Table 3: Pharmacokinetic Parameters of Plasma Concentrations of Unchanged FK949E (Mean ± SD) (150 mg Treatment Group)

Pharmacokinetic parameter

First day of the 50 mg dose period

N=8†


N=8‡

Seventh day of the 150 mg dose period)

N=8†† Cmax

(ng/mL) 34.58 ± 15.13 151.16 ± 67.02 131.20 ± 65.65

tmax (h)

7.8 ± 3.5 6.5 ± 3.6 6.3 ± 3.3

AUC24h (ng·h/mL)

413.72 ± 112.22 1582.91 ± 633.24 1513.20 ± 431.43

AUCinf (ng·h/mL)

443.56 ± 163.03 1533.06 ± 546.10 1766.07 ± 608.33

t1/2 (h)

5.8 ± 0.8 7.9 ± 5.5 8.0 ± 2.5

CL/F (L/h)

125.79 ± 49.37 115.72 ± 65.15 106.55 ± 30.91

MRTlast (h)

10.8 ± 1.7 - -

MRTinf (h)

11.3 ± 1.4 13.3 ± 7.4 13.9 ± 3.5

†N = 4 for AUCinf, t1/2, CL/F, and MRTinf ‡N = 5 for AUCinf, t1/2, and MRTinf ††N = 6 for AUCinf, t1/2, and MRTinf








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N = 10†


N=9‡

Seventh day of the 300 mg dose period

N=9†† Cmax

(ng/mL) 37.85 ± 19.01 243.82 ± 110.56 313.81 ± 150.64

tmax (h)

6.8 ± 3.9 4.2 ± 2.1 7.1 ± 3.2

AUC24h (ng·h/mL)

430.27 ± 204.71 2572.48 ± 1239.30 3728.42 ± 2158.81

AUCinf (ng·h/mL)

431.08 ± 130.25 3119.43 ± 1545.21 4217.97 ± 2340.10

t1/2 (h)

9.5 ± 4.0 7.9 ± 3.2 6.5 ± 2.9

CL/F (L/h)

128.26 ± 51.81 139.45 ± 58.21 116.48 ± 79.38

MRTlast (h)

10.9 ± 2.2 - -

MRTinf (h)

17.1 ± 4.9 12.8 ± 4.0 11.6 ± 3.7









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N = 12†


N=9‡

Seventh day of the 600 mg dose period

N=8†† Cmax

(ng/mL) 22.80 ± 9.45 317.65 ± 83.96 335.50 ± 74.75

tmax (h)

10.6 ± 6.7 5.5 ± 2.2 5.0 ± 1.5

AUC24h (ng·h/mL)

321.86 ± 132.02 4078.93 ± 981.93 4180.96 ± 851.87

AUCinf (ng·h/mL)

503.17 ± 168.87 4839.56 ± 1348.55 5204.65 ± 880.32

t1/2 (h)

6.3 ± 1.4 8.2 ± 2.6 7.9 ± 2.1

CL/F (L/h)

109.55 ± 45.50 154.31 ± 34.33 148.70 ± 29.64

MRTlast (h)

12.0 ± 2.0 - -

MRTinf (h)

12.4 ± 2.5 13.9 ± 3.6 13.8 ± 3.0









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150mg投与群300mg投与群600mg投与群

Figure 2: Changes in Mean Plasma Unchanged FK949E Concentrations (Mean ± SD)

(First Day of the 50 mg Dose Period)


Figure 3: Changes in Mean Plasma Unchanged FK949E Concentrations (Mean ± SD)

(First Day of the Final Dose Period)

treatmtreatmtreatm

ent group ent group ent group

treatmtreatmtreatm

ent group ent group ent group








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Figure 4: Changes in Mean Plasma Unchanged FK949E Concentrations (Mean ± SD) (Seventh Day of the Final Dose Period)

5. Safety:

Adverse events

A summary of adverse events in each treatment group is shown in Table 6. Adverse events and those considered to be drug related were observed in all subjects in each treatment group. There were 59 (150 mg treatment group), 69 (300 mg treatment group), and 99 (600 mg treatment group) adverse events reported, and 54, 59, and 93 adverse events were, respectively, considered to be drug related. The number of adverse events and those considered to be drug related increased with increasing dose of FK949E.

There were no deaths or other serious adverse events in any treatment group. Adverse events resulting in discontinuation of the study occurred in 2 (150 mg treatment group), 1 (300 mg treatment group), and 3 (600 mg treatment group) subjects. They included 1 subject with orthostatic hypotension and 1 with dizziness in the 150 mg treatment group, 1 with influenza in the 300 mg treatment group, and 3 with orthostatic hypotension in the 600 mg treatment group.

treatment group treatmtreatm

ent group ent group








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Table 6: Summary of Adverse Events 150 mg treatment group

N = 10 300 mg treatment group


N = 12

Number of subjects with an

AE†

Number of AEs


AE†

Number of AEs


AE†

Number of AEs

SAF 10 10 12

Adverse events 10

(100.0%) 59

10 (100.0%)

69 12 (100.0%)

99

Adverse events considered to be drug related

10 (100.0%)

54 10

(100.0%)59

12 (100.0%)

93

Death 0 0 0 0 0 0 Serious adverse events 0 0 0 0 0 0 Adverse events resulting in discontinuation

2 (20.0%) 2 1 (10.0%) 1 3 (25.0%) 3

†Number of subjects (incidence)

The incidence of adverse events and incidence of adverse events considered to be drug related in each treatment group are shown in Tables 7 and 8, respectively.

The most commonly observed adverse event was somnolence occurring in 9 subjects (90.0%) in the 150 mg treatment group, 10 (100.0%) in the 300 mg treatment group, and 11 (91.7%) in the 600 mg treatment group. Adverse events with an incidence of 20% or more in all groups were dry mouth, blood prolactin increased, dizziness postural, somnolence, and orthostatic hypotension. Other adverse events with an incidence of 20% or more in any of the groups were palpitations, constipation, diarrhoea, feeling abnormal, back pain, dizziness, nasal congestion, and upper respiratory tract inflammation. No adverse events were severe in severity. As moderate adverse events, tachycardia and hypomania were reported in 2 (16.7%) and 1 (8.3%) subjects in the 600 mg treatment group, respectively; however, other adverse events were all mild in severity. All moderate adverse events were considered to be drug related.

Adverse events considered to be drug related occurred in a similar way. The most commonly observed adverse event considered to be drug related was somnolence occurring in 9 subjects (90.0%) in the 150 mg treatment group, 10 subjects (100.0%) in the 300 mg treatment group, and 11 subjects (91.7%) in the 600 mg treatment group. Adverse events with an incidence of 20% or more in all groups were dry mouth, somnolence, and orthostatic hypotension. Other adverse events with an incidence of 20% or more in any of the groups were palpitations, constipation, diarrhoea, feeling abnormal, blood prolactin increased,








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dizziness, dizziness postural, and nasal congestion.

By date of onset, the incidence of somnolence and orthostatic hypotension generally tended to be high on the day of the first dose (Day 1, 50 mg) and the increased dose (Day 3 in the 150 mg treatment group, Days 3 and 5 in the 300 mg treatment group, and Days 3, 5, and 7 in the 600 mg treatment group) in each group. Similar results were also obtained for adverse events considered to be drug related.

Table 7: Incidence of Adverse Events

System Organ Class/Preferred Term† 150 mg

treatment groupN = 10


N = 10


N = 12 Cardiac disorders 1 (10.0%) 0 (0.0%) 4 (33.3%)

Palpitations 1 (10.0%) 0 (0.0%) 3 (25.0%) Tachycardia 0 (0.0%) 0 (0.0%) 2 (16.7%)

Eye disorders 0 (0.0%) 1 (10.0%) 0 (0.0%) Chromatopsia 0 (0.0%) 1 (10.0%) 0 (0.0%)

Gastrointestinal disorders 7 (70.0%) 8 (80.0%) 7 (58.3%) Abdominal discomfort 0 (0.0%) 0 (0.0%) 2 (16.7%) Abdominal pain 0 (0.0%) 0 (0.0%) 1 (8.3%) Abdominal pain upper 0 (0.0%) 0 (0.0%) 1 (8.3%) Constipation 4 (40.0%) 1 (10.0%) 1 (8.3%) Diarrhoea 2 (20.0%) 4 (40.0%) 1 (8.3%) Dry mouth 6 (60.0%) 7 (70.0%) 6 (50.0%) Lip dry 0 (0.0%) 1 (10.0%) 0 (0.0%) Nausea 0 (0.0%) 1 (10.0%) 2 (16.7%) Paraesthesia oral 1 (10.0%) 0 (0.0%) 0 (0.0%) Oropharyngeal pain 1 (10.0%) 0 (0.0%) 0 (0.0%)

General disorders and administration site conditions

2 (20.0%) 0 (0.0%) 4 (33.3%)

Feeling abnormal 1 (10.0%) 0 (0.0%) 3 (25.0%) Malaise 0 (0.0%) 0 (0.0%) 1 (8.3%) Oedema peripheral 0 (0.0%) 0 (0.0%) 1 (8.3%) Thirst 1 (10.0%) 0 (0.0%) 0 (0.0%)

Infections and infestations 0 (0.0%) 1 (10.0%) 0 (0.0%) Influenza 0 (0.0%) 1 (10.0%) 0 (0.0%)








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Table 7: Incidence of Adverse Events (Continued)

System Organ Class/Preferred Term† 150 mg

treatment groupN = 10


N = 10


N = 12 Injury, poisoning and procedural complications

1 (10.0%) 0 (0.0%) 0 (0.0%)

Fall 1 (10.0%) 0 (0.0%) 0 (0.0%) Investigations 4 (40.0%) 5 (50.0%) 6 (50.0%)

Blood bilirubin increased 0 (0.0%) 1 (10.0%) 1 (8.3%) Blood creatine phosphokinase increased 0 (0.0%) 1 (10.0%) 0 (0.0%) Blood glucose increased 0 (0.0%) 0 (0.0%) 1 (8.3%) Blood prolactin increased 3 (30.0%) 4 (40.0%) 3 (25.0%) Blood triglycerides increased 1 (10.0%) 0 (0.0%) 0 (0.0%) Blood uric acid increased 0 (0.0%) 1 (10.0%) 0 (0.0%) Electrocardiogram QT prolonged 0 (0.0%) 0 (0.0%) 1 (8.3%) Platelet count decreased 0 (0.0%) 0 (0.0%) 1 (8.3%) White blood cell count decreased 0 (0.0%) 0 (0.0%) 1 (8.3%)

Musculoskeletal and connective tissue disorders

1 (10.0%) 2 (20.0%) 1 (8.3%)

Arthralgia 0 (0.0%) 1 (10.0%) 0 (0.0%) Back pain 0 (0.0%) 2 (20.0%) 1 (8.3%) Hip swelling 1 (10.0%) 0 (0.0%) 0 (0.0%)

Nervous system disorders 10 (100.0%) 10 (100.0%) 12 (100.0%) Akathisia 0 (0.0%) 1 (10.0%) 1 (8.3%) Dizziness 2 (20.0%) 0 (0.0%) 1 (8.3%) Dizziness postural 4 (40.0%) 2 (20.0%) 6 (50.0%) Dysgeusia 0 (0.0%) 0 (0.0%) 1 (8.3%) Headache 0 (0.0%) 0 (0.0%) 1 (8.3%) Somnolence 9 (90.0%) 10 (100.0%) 11 (91.7%)

Psychiatric disorders 1 (10.0%) 1 (10.0%) 2 (16.7%) Hypomania 0 (0.0%) 0 (0.0%) 1 (8.3%) Insomnia 0 (0.0%) 1 (10.0%) 1 (8.3%) Nervousness 1 (10.0%) 0 (0.0%) 0 (0.0%)

Respiratory, thoracic and mediastinal disorders

0 (0.0%) 6 (60.0%) 3 (25.0%)

Nasal congestion 0 (0.0%) 5 (50.0%) 1 (8.3%) Upper respiratory tract inflammation 0 (0.0%) 2 (20.0%) 2 (16.7%)

Skin and subcutaneous tissue disorders 0 (0.0%) 0 (0.0%) 1 (8.3%) Dermatitis contact 0 (0.0%) 0 (0.0%) 1 (8.3%)

Vascular disorders 5 (50.0%) 4 (40.0%) 10 (83.3%) Orthostatic hypotension 5 (50.0%) 4 (40.0%) 10 (83.3%)

Number of subjects (incidence) †MedDRA/J ver.12.0 (SOC/PT)








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Table 8: Incidence of Adverse Events Considered to Be Drug Related

System Organ Class/Preferred Term†

150 mg treatment

group N = 10

300 mg treatment

group N = 10

600 mg treatment

group N = 12

Cardiac disorders 1 (10.0%) 0 (0.0%) 4 (33.3%) Palpitations 1 (10.0%) 0 (0.0%) 3 (25.0%) Tachycardia 0 (0.0%) 0 (0.0%) 2 (16.7%)

Eye disorders 0 (0.0%) 1 (10.0%) 0 (0.0%) Chromatopsia 0 (0.0%) 1 (10.0%) 0 (0.0%)

Gastrointestinal disorders 7 (70.0%) 8 (80.0%) 7 (58.3%) Abdominal discomfort 0 (0.0%) 0 (0.0%) 2 (16.7%) Abdominal pain 0 (0.0%) 0 (0.0%) 1 (8.3%) Abdominal pain upper 0 (0.0%) 0 (0.0%) 1 (8.3%) Constipation 4 (40.0%) 1 (10.0%) 1 (8.3%) Diarrhoea 2 (20.0%) 3 (30.0%) 0 (0.0%) Dry mouth 6 (60.0%) 7 (70.0%) 6 (50.0%) Nausea 0 (0.0%) 1 (10.0%) 2 (16.7%) Paraesthesia oral 1 (10.0%) 0 (0.0%) 0 (0.0%) Oropharyngeal pain 1 (10.0%) 0 (0.0%) 0 (0.0%)


2 (20.0%) 0 (0.0%) 4 (33.3%)

Feeling abnormal 1 (10.0%) 0 (0.0%) 3 (25.0%) Malaise 0 (0.0%) 0 (0.0%) 1 (8.3%) Oedema peripheral 0 (0.0%) 0 (0.0%) 1 (8.3%) Thirst 1 (10.0%) 0 (0.0%) 0 (0.0%)

Investigations 3 (30.0%) 5 (50.0%) 5 (41.7%) Blood bilirubin increased 0 (0.0%) 1 (10.0%) 1 (8.3%) Blood glucose increased 0 (0.0%) 0 (0.0%) 1 (8.3%) Blood prolactin increased 3 (30.0%) 4 (40.0%) 2 (16.7%) Blood uric acid increased 0 (0.0%) 1 (10.0%) 0 (0.0%) Electrocardiogram QT prolonged 0 (0.0%) 0 (0.0%) 1 (8.3%) Platelet count decreased 0 (0.0%) 0 (0.0%) 1 (8.3%) White blood cell count decreased 0 (0.0%) 0 (0.0%) 1 (8.3%)

Nervous system disorders 10 (100.0%) 10 (100.0%) 12 (100.0%) Akathisia 0 (0.0%) 1 (10.0%) 1 (8.3%) Dizziness 2 (20.0%) 0 (0.0%) 1 (8.3%) Dizziness postural 4 (40.0%) 1 (10.0%) 6 (50.0%) Dysgeusia 0 (0.0%) 0 (0.0%) 1 (8.3%) Headache 0 (0.0%) 0 (0.0%) 1 (8.3%) Somnolence 9 (90.0%) 10 (100.0%) 11 (91.7%)

Psychiatric disorders 1 (10.0%) 1 (10.0%) 2 (16.7%) Hypomania 0 (0.0%) 0 (0.0%) 1 (8.3%) Insomnia 0 (0.0%) 1 (10.0%) 1 (8.3%) Nervousness 1 (10.0%) 0 (0.0%) 0 (0.0%)








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Table 8: Incidence of Adverse Events Considered to Be Drug Related (Continued)


150 mg treatment

group N = 10

300 mg treatment

group N = 10

600 mg treatment

group N = 12

Respiratory, thoracic and mediastinal disorders

0 (0.0%) 5 (50.0%) 1 (8.3%)

Nasal congestion 0 (0.0%) 5 (50.0%) 1 (8.3%) Vascular disorders 5 (50.0%) 4 (40.0%) 10 (83.3%)

Orthostatic hypotension 5 (50.0%) 4 (40.0%) 10 (83.3%)


Orthostatic hypotension, the most common adverse event in the phase I multiple-dose study (Study No. 6949-CL-0001) conducted before the present study, was further investigated (Tables 9 and 10). As in the phase I study (Study No. 6949-CL-0001), the effects of change of position from supine to standing on blood pressure and pulse rate were examined. While blood pressure and pulse rate were measured in the supine position and 1 minute after standing up in the phase I study (Study No. 6949-CL-0001), they were also measured in the supine position and 1 and 3 minutes after standing up in this study.

Ten, 8, and 18 events of orthostatic hypotension were observed, respectively, in 5 (50.0%) subjects in the 150 mg treatment group, 4 (40.0%) in the 300 mg treatment group, and 10 (83.3%) in the 600 mg treatment group; the incidence was higher in the 600 mg treatment group than in the 150 and 300 mg treatment groups. When orthostatic hypotension-related events such as dizziness postural and palpitations were also included, 16, 10, and 40 events of orthostatic hypotension-related events were reported, respectively, in 7 (70.0%) subjects in the 150 mg treatment group, 4 (40.0%) in the 300 mg treatment group, and 11 (91.7%) in the 600 mg treatment group; the incidence was higher in the 600 mg treatment group than in the 150 and 300 mg treatment groups. However, there were no orthostatic hypotension-related events that the investigator or sub-investigator considered to be uncontrollable or unpredictable events, and all of them were controllable or predictable. Among subjects with orthostatic hypotension, a decrease in standing systolic blood pressure (< 80 mmHg) also occurred in some subjects, but it was considered mild in all such subjects because systolic blood pressure returned to normal immediately after subjects with subjective symptoms lay quietly in the supine position.








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Table 9: Summary of Orthostatic Hypotension-Related Events 150 mg treatment group



N = 12 Number of

subjects with an AE†

Number of AEs

Number of subjects

with an AE†

Number of AEs

Number of subjects

with an AE†

Number of AEs

Orthostatic hypotension 5 (50.0%) 10 4 (40.0%) 8 10 (83.3%) 18 Presence or absence of orthostatic hypotension-related events

7 (70.0%) 16 4 (40.0%) 10 11 (91.7%) 40

Presence or absence of uncontrollable or unpredictable orthostatic hypotension-related events

0 0 0 0 0 0

†Number of subjects (incidence)

Table 10: Incidence of Symptoms of Orthostatic Hypotension-Related Events


150 mg treatment

group N = 10

300 mg treatment

group N = 10

600 mg treatment

group N = 12

Cardiac disorders 0 (0.0%) 0 (0.0%) 4 (33.3%) Palpitations 0 (0.0%) 0 (0.0%) 3 (25.0%) Tachycardia 0 (0.0%) 0 (0.0%) 2 (16.7%)


1 (10.0%) 0 (0.0%) 3 (25.0%)

Feeling abnormal 1 (10.0%) 0 (0.0%) 2 (16.7%) Oedema peripheral 0 (0.0%) 0 (0.0%) 1 (8.3%)

Nervous system disorders 4 (40.0%) 1 (10.0%) 5 (41.7%) Dizziness 1 (10.0%) 0 (0.0%) 1 (8.3%) Dizziness postural 3 (30.0%) 1 (10.0%) 5 (41.7%)

Vascular disorders 5 (50.0%) 4 (40.0%) 10 (83.3%) Orthostatic hypotension 5 (50.0%) 4 (40.0%) 10 (83.3%)


Clinical laboratory evaluations

In hematology and blood biochemistry, the mean values of total bilirubin (high, 600 mg treatment group), LDH (low, 300 and 600 mg treatment groups), and HDL cholesterol (low, 300 mg treatment group) after study drug administration were each outside the normal reference range. However, total bilirubin (600 mg treatment group) was also high at baseline and did not change greatly after study drug administration. The mean values of LDH and HDL cholesterol were slightly lower than the normal reference range, and they were found to be within the normal reference range at the post-study visit. In urinalysis, none of the test results, except those from 1 subject in the 600 mg treatment group who tested positive for urine protein (+) at the post-study visit, was found to be outside the normal








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reference range.

Adverse events related to clinical laboratory tests observed in more than 1 subject were blood prolactin increased (3 subjects in the 150 mg treatment group, 4 subjects in the 300 mg treatment group, and 3 subjects in the 600 mg treatment group) and blood bilirubin increased (1 subject in the 300 mg treatment group and 1 subject in the 600 mg treatment group). Other adverse events related to clinical laboratory tests included blood creatine phosphokinase increased, blood glucose increased, blood triglycerides increased, blood uric acid increased, platelet count decreased, and white blood cell count decreased, all of which occurred in 1 subject each. All adverse events related to clinical laboratory tests were mild in severity.

Vital signs

The mean values of systolic and diastolic blood pressure showed a tendency to decrease after administration on each day, and as the systolic and diastolic blood pressure decreased, the mean pulse rate tended to increase. The differences between the supine and standing (1 minute later) values of blood pressure (1 minute after standing up minus supine) are presented in Figures 5, 6, and 7. Similar results were also obtained for the differences between the supine and standing (3 minutes later) values of blood pressure (3 minutes after standing up minus supine).

Blood pressure and pulse rate were measured before administration and at 1 and 8 hours post-dose on each day of the investigational period to follow the time course of these parameters. Overall, the differences between the standing and supine values of blood pressure and pulse rate were the largest at 8 hours post-dose, and tended to resolve before administration on the following day. In the 150 mg treatment group, the differences between the standing and supine values of blood pressure and pulse rate were comparable on or after the day when the dose was increased to the maximum (Day 3). However, the differences tended to be slightly large on or after the day when the dose was increased to the maximum (Day 5) in the 300 mg treatment group, and the differences were marked on or after the day when the dose was increased to the maximum (Day 7) in the 600 mg treatment group.

Mean axillary body temperature ranged from 36.26 to 36.61°C in the 150 mg treatment group, from 36.37 to 36.69°C in the 300 mg treatment group, and from 36.13 to 36.56°C in the 600 mg treatment group, indicating no notable changes.








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Figure 5: Changes in the Difference between Systolic and Diastolic Blood Pressure (1 Minute after Standing Up − Supine) (Mean ± SD) (150 mg Treatment Group) Time points of measurement: 1 h: 1 hour post-dose; 8 h: 8 hours post-dose; no description: before administration; FU: post-study visit

収縮期血圧（立位－臥位）投与群=150mg投与群

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Figure6: Changes in the Difference between Systolic and Diastolic Blood Pressure (1 Minute after Standing Up − Supine) (Mean ± SD) (300 mg Treatment Group) Time points of measurement: 1 h: 1 hour post-dose; 8 h: 8 hours post-dose; no description: before administration; FU: post-study visit



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Figure 7: Changes in the Difference between Systolic and Diastolic Blood Pressure (1 Minute after Standing Up − Supine) (Mean ± SD) (600 mg Treatment Group) Time points of measurement: 1 h: 1 hour post-dose; 8 h: 8 hours post-dose; no description: before administration; FU: post-study visit



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Electrocardiograms

The ECG was “abnormal - clinically significant” in 1 subject ( ) in the 600 mg treatment group on Day 14. This abnormal finding was considered an adverse event (electrocardiogram QT prolonged) but recovery to “normal” was confirmed at the post-study visit. There were no other remarkable ECG abnormalities.








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Conclusions:

In order to evaluate the safety and pharmacokinetics of multiple oral doses of FK949E (extended-release formulation of quetiapine) of 150 mg/day, 300 mg/day and 600 mg/day in the morning under fasting conditions, the multicenter, open-label clinical study was conducted in patients with major depressive disorder using oral administration of FK949E, beginning with the initial dose of 50 mg followed by dose escalation of up to 150 mg, 300 mg or 600 mg.

The planned sample size was set at a maximum of 12 subjects (8 completing treatment) in each group, and 10 subjects received the study drug in the 150 and 300 mg treatment groups. Since more cases of discontinuation occurred in the 600 mg treatment group than expected, the maximum number of subjects receiving study drug was changed to 16 and the study drug was administered to 12 subjects. All subjects receiving study drug were included in the SAF and PKAS.

Prior to the present study, the phase I oral multiple-dose study (Study No. 6949-CL-0001, Japan) was conducted in non-elderly adult patients with major depressive disorder. An initial oral dose of FK949E 50 mg was administered repeatedly after breakfast and the dose was gradually escalated up to 300 mg or 600 mg. However, because of the medical treatment administered to the subjects in the 600 mg treatment group for an adverse event (orthostatic hypotension) during the 300 mg dose period, precise evaluation of safety during the 300 mg and 600 mg dose periods became impossible. Further studies were therefore considered necessary. In the present study, it was thus decided that FK949E was to be administered at 150 mg, which was supposed to be a lower clinical dose, and the safety was to be confirmed at 300 and 600 mg in a stepwise manner, and that the study design was to be changed for orthostatic hypotension (e.g., addition of the exclusion criteria and detailed variables) in order to reevaluate the safety of FK949E. Based on the results of the food effect study, the dosage regimen was also changed to administration under fasting conditions.

For pharmacokinetics, when FK949E Tablets were administered, at an initial dose of 50 mg, in a dose-escalation manner and the final dose (150, 300, or 600 mg) was given repeatedly for 7 days in each group, both Cmax and AUC24h of unchanged FK949E in plasma on the last day of the final dose (Day 7) increased with increasing dose of FK949E. Mean tmax values on the last day of the final dose (Day 7) were 6.3 h in the 150 mg treatment group, 7.1 h in the 300 mg treatment group, and 5.0 h in the 600 mg treatment group. The present study examined steady state at each dose and accumulation following multiple-dose administration in an exploratory manner. The steady state was examined using Ctrough as an indicator, and it appeared to be achieved immediately after the start of multiple-dose administration. When the accumulation following multiple-dose administration was investigated using Cmax








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and AUC24h as indicators, it was considered that comparable steady state concentrations were obtained on the first day and last day (seventh day) of the multiple dose.

As for safety, adverse events and those considered to be drug related were observed in all subjects in the 150, 300, and 600 mg treatment groups. There were 59 (150 mg treatment group), 69 (300 mg treatment group), and 99 (600 mg treatment group) adverse events reported, and 54, 59, and 93 adverse events were, respectively, considered to be drug related. The number of adverse events and those considered to be drug related increased with increasing dose of FK949E. Adverse events resulting in discontinuation of the study occurred in 2 (150 mg treatment group), 1 (300 mg treatment group), and 3 (600 mg treatment group) subjects. No deaths or other serious adverse events occurred in any treatment group.

The most commonly observed adverse event was somnolence occurring in 9 subjects (90.0%) in the 150 mg treatment group, 10 subjects (100.0%) in the 300 mg treatment group, and 11 subjects (91.7%) in the 600 mg treatment group. Adverse events with an incidence of 20% or more in all groups were dry mouth, blood prolactin increased, dizziness postural, somnolence, and orthostatic hypotension. No adverse events were severe in severity. As moderate adverse events, tachycardia and hypomania were reported in 2 (16.7%) and 1 (8.3%) subjects in the 600 mg treatment group, respectively; however, other adverse events were all mild in severity. Ten, 8, and 18 events of orthostatic hypotension were observed, respectively, in 5 (50.0%) subjects in the 150 mg treatment group, 4 subjects (40.0%) in the 300 mg treatment group, and 10 subjects (83.3%) in the 600 mg treatment group; the incidence was higher in the 600 mg treatment group than in the 150 and 300 mg treatment groups. There were no orthostatic hypotension-related events that the investigator or sub-investigator considered to be uncontrollable or unpredictable events, and all of them were controllable or predictable. Among subjects with orthostatic hypotension, a decrease in standing systolic blood pressure (< 80 mmHg) also occurred in some subjects, but it was considered mild in all such subjects because systolic blood pressure returned to normal immediately after subjects with subjective symptoms lay quietly in the supine position. Orthostatic hypotension is a characteristic vital change that has been reported in overseas clinical studies or observed with the existing formulation of quetiapine, and it also occurred in the present study. For the date of onset of an adverse event, the incidence of somnolence and orthostatic hypotension generally tended to be high on the day of the first dose (Day 1, 50 mg) and the increased dose in each group.

On clinical laboratory evaluations of hematology and blood biochemistry, the mean values of total bilirubin (high, 600 mg treatment group), LDH (low, 300 and 600 mg treatment groups), and HDL cholesterol (low, 300 mg treatment group) after study drug administration were each outside the normal reference range, and none of these findings seemed to be clinically


FK949E ISN 6949-CL-0009 Major Depressive Disorder (MDD) CONFIDENTIAL


Name of Sponsor:






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significant. In urinalysis, none of the test results, except those from 1 subject in the 600 mg treatment group who tested positive for urine protein (+) at the post-study visit, was found to be outside the normal reference range. All adverse events related to clinical laboratory tests were mild in severity. The mean values of systolic and diastolic blood pressure showed a tendency to decrease after administration on each day, and as the systolic and diastolic blood pressure decreased, the mean pulse rate tended to increase.

With respect to safety in the present study, adverse events such as dry mouth, blood prolactin increased, dizziness postural, somnolence, orthostatic hypotension, palpitations, constipation, diarrhoea, feeling abnormal, back pain, dizziness, nasal congestion, and upper respiratory tract inflammation occurred relatively frequently, but they had been reported in the phase I oral multiple-dose study (Study No. 6949-CL-0001) and overseas clinical studies or observed with the existing formulation of quetiapine. In addition, there were no orthostatic hypotension-related events that the investigator or sub-investigator considered to be uncontrollable or unpredictable events, and all of them were controllable or predictable. All orthostatic hypotension-related events were mild, and blood pressure returned to normal immediately after subjects with subjective symptoms lay quietly in the supine position. Based on these results, FK949E appeared to be well-tolerated because all adverse events frequently reported with FK949E (150, 300, and 600 mg) had previously been observed and acceptable. However, safety measures may be required (e.g., occurrence of orthostatic hypotension) in future clinical studies. Attention should be paid to treatment with 600 mg of FK949E because the incidence of orthostatic hypotension and orthostatic hypotension-related events was higher in the 600 mg treatment group than in the 150 and 300 mg treatment groups.

Date of Document: 15 December 2011

FK949E ISN 6949-CL-0009 Major Depressive Disorder (MDD) CONFIDENTIAL

30 Mar 2012 Astellas Page 2 of 2

1. BACKGROUND The purpose of this amendment is to make corrections to the clinical study report synopsis of Phase I Study of FK949E - Phase I Oral Multiple-dose Study in Patients with Major Depressive Disorder -. After completion of this clinical study report synopsis on 15 December 2011, errors were found in analysis of number of orthostatic hypotension-related events. Therefore, the corrections of errors are made, including errors in text.

2. CONTENTS OF AMENDMENT Changed parts are indicated by underline in the folloing table. Data interpretation in the clinical study report synopsis was not changed in relation to this amendment.

Item Was Is Amended To Rationale 5. Safety: When orthostatic

hypotension-related events such as dizziness postural and palpitations were also included, 16, 10

When orthostatic hypotension-related events such as dizziness postural and palpitations were also included, , and 40

events of orthostatic hypotension-related events were reported, respectively, in 7 (70.0%) subjects in the 150 mg treatment group, 4 (40.0%) in the 300 mg treatment group, and 11 (91.7%) in the 600 mg treatment group; the incidence was higher in the 600 mg treatment group than in the 150 and 300 mg treatment groups.

15

Reanalysis of number of orthostatic hypotension- related events

, 9, and 40 events of orthostatic hypotension-related events were reported, respectively, in 7 (70.0%) subjects in the 150 mg treatment group, 4 (40.0%) in the 300 mg treatment group, and 11 (91.7%) in the 600 mg treatment group; the incidence was higher in the 600 mg treatment group than in the 150 and 300 mg treatment groups.

Table 9: Summary of Orthostatic Hypotension- Related Events

Presence or absence of orthostatic hypotension-related events Number of AEs in 150 mg treatment group: Number of AEs in 300 mg treatment group:

16

Presence or absence of orthostatic hypotension-related events

10

Number of AEs in 150 mg treatment group: Number of AEs in 300 mg treatment group: 9

15

Reanalysis of number of orthostatic hypotension- related events

Conclusions: All orthostatic hypotension-related events were mild, and blood pressure returned to normal immediately after subjects with subjective symptoms lay quietly in the supine position.

All events of orthostatic hypotension

Correction of errors in text were mild, and blood

pressure returned to normal immediately after subjects with subjective symptoms lay quietly in the supine position.

Documents

Individual Study Table Referring to Part of the€¦ · 3. Diagnosis of major depressive disorder by the M.I.N.I. according to the DSM-IV-TR . 4. Female patients of childbearing potential