A tolerability burden index in schizophrenia: incorporating patient perspective in clinical trial adverse event reporting

Figures & data

Table 1. Mean treatment burden scores (unadjusted and adjusted).

Score	Bifeprunox 30 mg (n = 148)	Bifeprunox 40 mg (n = 148)	Risperidone 6 mg (n = 154)	Placebo (n = 149)
Unadjusted
Mean	2.91	2.96	3.05	2.01
Median (range)	2.00 (0–24.00)	2.00 (0–14.00)	2.00 (0–18.00)	1.00 (0–12.00)
Adjusted by patient-experienced impact
Mean	1.85	1.92	2.01	1.31
Median (range)	1.12 (0–15.09)	1.20 (0–9.29)	1.50 (0–11.75)	0.90 (0–7.73)
Adjusted by severity
Mean	4.04	4.26	4.16	2.99
Median (range)	2.00 (0–41.00)	3.00 (0–22.00)	3.00 (0–33.00)	2.00 (0–21.00)
Adjusted by severity-adjusted duration
Mean	8.43	8.74	8.98	6.16
Median (range)	6.02 (0–45.44)	6.11 (0–40.64)	6.61 (0–40.36)	3.67 (0–30.59)
Adjusted by patient-experienced impact and severity-adjusted duration
Mean	7.64	8.40	8.14	6.15
Median (range)	4.30 (0–45.63)	5.42 (0–40.27)	6.34 (0–48.90)	4.10 (0–49.43)

Figure 1. Frequency of treatment-emergent adverse events. (a) Bifeprunox 30 mg (n = 148); (b) bifeprunox 40 mg (n = 148); (c) risperidone 6 mg (n = 154); (d) placebo (n = 149).

Table 2. Burden score adjusted by AE severity.

AEs,	Bifeprunox 30 mg		Bifeprunox 40 mg		Risperidone 6 mg		Placebo
n and severity^a	AEs, n	Burden^b	AEs, n	Burden^b	AEs, n	Burden^b	AEs, n	Burden^b
1 AE
Mild	22	22	17	17	20	20	10	10
Moderate	6	12	8	16	1	2	9	18
Severe	3	9	3	9	3	9	3	9
2 AEs
Mild	17	17	27	27	26	26	28	28
Moderate	12	24	14	28	15	30	20	40
Severe	1	3	5	15	3	9	2	6
10 AEs
Mild	39	39	21	21	25	25	7	7
Moderate	1	2	9	18	5	10	11	22
Severe	0	–	0	–	0	–	2	6
> 20 AEs
Mild	8	8	0	–	0	−	0	−
Moderate	15	30	0	–	0	−	0	−
Severe	1	3	0	–	0	−	0	−
Total burden		598		631		641		445
Mean burden score		4.04		4.26		4.16		2.99

Representative data are presented for patients experiencing 1, 2, 10, or > 20 AEs (e.g., of the 31 patients who received bifeprunox 30 mg and experienced only one AE, 22 experienced a mild AE, six experienced a moderate AE, and three experienced a severe AE).

AE: treatment-emergent adverse event.

^aAE severity was scored as mild = 1, moderate = 2, and severe = 3.

^bBurden scores were calculated by multiplying the AEs for each severity ranking by the score assigned to that ranking and adding the values to determine the total burden.

Table 3. Burden scores based on AE-related treatment discontinuation.

Discontinued Due to AE?	Burden score	Sum	Mean ± SD	Median	Range	Ratio^a
No (n = 526)	Unadjusted	1331	2.53 ± 2.97	2	0–18	1.66
	Adjusted by patient-experienced impact	857.85	1.63 ± 1.93	1.03	0–11.75	1.98
	Adjusted by severity	1796	3.41 ± 4.21	2	0–33	2.08
	Adjusted by severity-adjusted duration	3921.37	7.46 ± 8.49	4.14	0–45.45	1.69
	Adjusted by patient-experienced impact and severity-adjusted duration	3447.63	6.55 ± 7.92	3.71	0–48.90	2.29
Yes (n = 73)	Unadjusted	306	4.19 ± 3.77	3	0–24
	Adjusted by patient-experienced impact	235.3	3.22 ± 2.56	2.43	0–15.88
	Adjusted by severity	519	7.11 ± 6.03	5	0–41
	Adjusted by severity-adjusted duration	921.33	12.62 ± 9.50	9.52	0–39.62
	Adjusted by patient-experienced impact and severity-adjusted duration	1095.21	15.00 ± 10.26	11.07	0–49.93

SD: standard deviation; AE: treatment-emergent adverse event.

^aThe ratio reflects the mean tolerability index score for patients who discontinued because of an AE divided by mean tolerability burden index score for patients who did not. A higher ratio indicates a higher discriminatory property of the methods used to calculate the burden score.

Table 4. Validation of burden scores: discontinuations due to AEs.

	Discontinued due to AEs?
	No (n = 526)	Yes (n = 73)	Odds ratio (95% CI)^c	P value
Burden score, mean ± SD^a
Unadjusted	2.53 ± 2.97	4.19 ± 3.77	1.15 (1.07–1.22)	<0.0001
Adjusted by severity	3.41 ± 4.21	7.11 ± 6.03	1.14 (1.09–1.19)	<0.0001
Adjusted by patient-experienced impact^b	1.63 ± 1.93	3.22 ± 2.56	1.33 (1.20–1.47)	<0.0001
Treatment, n (%)				0.7328
Bifeprunox 30 mg	132 (25.10)	16 (21.92)	0.70 (0.35–1.39)	0.5692
Bifeprunox 40 mg	131 (24.90)	17 (23.29)	0.75 (0.38–1.48)	0.7860
Risperidone 6 mg	136 (25.86)	18 (24.66)	0.76 (0.39–1.49)	0.8525
Placebo	127 (24.14)	22 (30.14)	1

SD: standard deviation; AE: treatment-emergent adverse event.

^aData are presented for 1-unit increments.

^bA weight of 1 was applied for AEs leading to discontinuation.

^cOdds ratios were calculated using a logistic regression.

Figure 2. Cumulative distribution of tolerability index scores by study arm.