The safety and effectiveness of open-label extended-release carbamazepine in the treatment of children and adolescents with bipolar I disorder suffering from a manic or mixed episode

Figures & data

Table 1 Subject demographics and disposition – safety population

Demographics
Characteristic	Number
	Children (aged 10–12 years) N=60	Adolescents (aged 13–17 years) N=97
Male	37 (61.7%)	53 (54.6%)
Female	23 (38.3%)	44 (45.4%)
Age in years: mean (SD)	11.3 (0.8)	14.7 (1.3)
Race
White	47 (78.3%)	72 (74.2%)
Black/African American	7 (11.7%)	15 (15.5%)
American Indian/Alaska Native	0 (0.0%)	1 (1.0%)
Other	6 (10.0%)	9 (9.3%)
Bipolar episode
Manic	27 (45.0%)	46 (47.4%)
Mixed	33 (55.0%)	51 (52.6%)
Disposition
Status	Number (%)
	Children (aged 10–12 years)	Adolescents (aged 13–17 years)
Enrolled (n=161)a
Treated (safety population)b	60	97
Completed study	27 (45.0)	39 (40.2)
Terminated early	33 (55.0)	58 (59.8)
Reason for discontinuation
Adverse event(s)	11 (18.3)	15 (15.5)
Lack of efficacy	2 (3.3)	6 (6.2)
Protocol violation	3 (5.0)	2 (2.1)
Lost to follow up	7 (11.7)	9 (9.3)
Withdrew consent	7 (11.7)	16 (16.5)
Need for excluded medications	1 (1.7)	4 (4.1)
Other	2 (3.3)	6 (6.2)

Notes:

a Four enrolled subjects terminated before treatment.

b The safety population was defined as subjects who received at least one dose of study medication.

Abbreviation: SD, standard deviation.

Table 2 Final ERC daily dose and overall total exposure

Final ERC daily dose at exit	Number (%) of subjects
	Children (aged 10–12 years) N=60	Adolescents (aged 13–17 years) N=97
200 mg	4 (6.7)	5 (5.2)
400 mg	10 (16.7)	9 (9.3)
600 mg	11 (18.3)	16 (16.5)
800 mg	10 (16.7)	22 (22.7)
1,000 mg	6 (10.0)	21 (21.6)
1,200 mg	19 (31.7)	24 (24.7)

Notes: N=157. Mean duration of treatment was 109.6 days (47 person-years).

Abbreviation: ERC, extended-release carbamazepine.

Table 3 Results of efficacy measurements

Children (N=58)		Adolescents (N=97)		Total (N=155)
Baseline	End of study*	Baseline	End of study	Baseline	End of study
Young Mania Rating Scale total score, mean (SD)
28.9 (6.7)	14.5 (10.4)	28.4 (5.9)	13.3 (8.7)	28.6 (6.2)	13.8 (9.4)
Young Mania Rating Scale > 50% decrease from baseline, N (%)
	35 (60.3)		53 (54.6)		88 (56.8)
Young Mania Rating Scale > 50% decrease from baseline for 2 consecutive months, N (%)
	21 (47.7)		40 (51.9)		61 (50.4)
Young Mania Rating Scale < 12 at end of study, N (%)
	29 (50.0)		47 (48.5)		76 (49.0)
Children’s Depression Rating Scale – Revised total score, mean (SD)
37.0 (12.0)	27.9 (9.2)	37.5 (11.9)	28.1 (10.5)	37.3 (11.9)	28.0 (10.0)
Clinical Global Impression – Severity, mean (SD)
4.7 (0.6)	3.1 (1.3)	4.6 (0.6)	2.9 (1.3)	4.6 (0.6)	3.0 (1.3)
Clinical Global Impression – Improvement** at end of study, N (%)
	19 (32.8)		36 (37.1)		55 (35.5)

Notes:

* End of study = last measurement for each subject.

** Rated on a seven-point scale from 1 (very much improved) to 7 (very much worse).

Abbreviation: SD, standard deviation.

Figure 1 YMRS total score average by duration of treatment: ITT population.

Abbreviations: ITT, intent to treat; YMRS, Young Mania Rating Scale.

Table 4 Overall summary of adverse events – safety population

	Number (%) of subjects
	Children (N=60)	Adolescents (N=97)	All subjects (N=157)
Treatment-emergent adverse events (TEAEs)
Number of subjects with at least one TEAE	46 (76.7)	85 (87.6)	131 (83.4)
Drug-related TEAE	34 (56.7)	58 (59.8)	92 (58.6)
Severe TEAE	9 (15.0)	11 (11.3)	20 (12.7)
TEAE leading to study termination	11 (18.2)	15 (15.5)	26 (16.6)
Serious TEAE	2 (3.3)	5 (5.2)	7 (4.5)
TEAE leading to death	0	0	0
TEAEs reported by at least 5% of subjects
Abdominal pain upper	7 (11.7)	6 (6.2)	13 (8.3)
Diarrhea	2 (3.3)	6 (6.2)	8 (5.1)
Nausea	6 (10.0)	16 (16.5)	22 (14.0)
Vomiting	7 (11.7)	8 (8.2)	15 (9.6)
Fatigue	5 (8.3)	14 (14.4)	19 (12.1)
Nasopharyngitis	5 (8.3)	5 (5.2)	10 (6.4)
Upper respiratory tract infection	3 (5.0)	6 (6.2)	9 (5.7)
Weight increased	1 (1.7)	9 (9.3)	10 (6.4)
Dizziness	4 (6.7)	17 (17.5)	21 (13.4)
Headache	14 (23.3)	27 (27.8)	41 (26.1)
Somnolence	10 (16.7)	20 (20.6)	30 (19.1)
Rash	5 (8.3)	7 (7.2)	12 (7.6)
Severe TEAEs reported by at least two subjects or incidence > 1%
Thrombocytopenia	1 (1.7)	1 (1.0)	2 (1.3)
Irritability	2 (3.3)	2 (2.1)	4 (2.5)
Headache	2 (3.3)	0	2 (1.3)
Bipolar disorder	1 (1.7)	1 (1.0)	2 (1.3)
Drug-related TEAEs reported by at least 2% of subjects
Abdominal pain upper	3 (5.0)	3 (3.1)	6 (3.8)
Diarrhea	1 (1.7)	3 (3.1)	4 (2.5)
Nausea	3 (5.0)	11 (11.3)	14 (8.9)
Vomiting	1 (1.7)	5 (5.2)	6 (3.8)
Fatigue	5 (8.3)	12 (12.4)	17 (10.8)
Weight increased	0	7 (7.2)	7 (4.5)
Dizziness	2 (3.3)	11 (11.3)	13 (8.3)
Headache	5 (8.3)	12 (12.4)	17 (10.8)
Sedation	2 (3.3)	4 (4.1)	6 (3.8)
Somnolence	10 (16.7)	14 (14.4)	24 (15.3)
Rash	4 (6.7)	4 (4.1)	8 (5.1)
Serious adverse events
Bipolar I disorder	1 (1.7)	2 (2.1)	3 (1.9)
Erythema	1 (1.7)	0	1 (0.64)
Thrombocytopenia	0	1(1.0)	1 (0.64)
Cholecystitis acute	0	1(1.0)	1 (0.64)
Suicidal ideation	0	1(1.0)	1 (0.64)
TEAEs leading to premature study discontinuation in at least two subjects
Nausea	1 (1.7)	2 (2.1)	3 (1.9)
Vomiting	1 (1.7)	2 (2.1)	3 (1.9)
Platelet count decreased	2 (3.3)	0	2 (1.3)
White blood cell count decreased	2 (3.3)	3 (3.1)	5 (3.2)
Dizziness	0	2 (2.1)	2 (1.3)
Bipolar disorder	1 (1.7)	1 (1.0)	2 (1.3)
Petechiae	1 (1.7)	1 (1.0)	2 (1.3)
Rash	2 (3.3)	4 (4.1)	6 (3.8)