Clinical validation of a fast-acting acetaminophen: a randomized, active and placebo controlled dental pain study

Figures & data

Table 1. Fixed sequence testing with fallback method: order of tests, assigned alpha values, and success.

	Pre-assigned α-value	α-value available if previous test positive	α-value available if previous test(s) negative	Success
1. TCPR, FA-acetaminophen vs placebo	0.049	–	–	Yes
2. TMPR, FA-acetaminophen vs placebo	0.000	0.049	0.000	Yes
3. TCPR, FA-acetaminophen vs ES-acetaminophen	0.000	0.049	0.000	Yes
4. TCPR, FA-acetaminophen vs LG-ibuprofen	0.000	0.049	0.000	Yes
5. TMPR, FA-acetaminophen vs ES-acetaminophen	0.000	0.049	0.000	No, p = 0.671
6. % subjects with confirmed perceptible pain relief from 30 min to successively earlier minutes in one-minute increments FA-acetaminophen vs placebo	0.001	0.05	0.001	p < 0.001 starting from 14 min

Table 2. Baseline and demographic characteristics of randomized subjects.

	FA-acetaminophen	ES-acetaminophen	LG-ibuprofen	Placebo	Total
N	249	232	124	59	664
Mean Age (years)	19.0	18.9	19.2	18.3	18.9
Weight (lb) Mean ± SD	145.7 ± 25.82	150.6 ± 24.68	148.7 ± 23.07	149.6 ± 24.17	148.3 ± 24.82
Race, n (%) White	229 (92.0%)	215 (92.7%)	108 (87.1%)	55 (93.2%)	607 (91.4%)
Sex: male, n (%)	110 (44.2%)	108 (46.6%)	59 (47.6%)	25 (42.4%)	302 (45.5%)
Number of teeth extracted, n (%)
3 (%)	12 (4.8%)	15 (6.5%)	8 (6.5%)	5 (8.5%)	40 (6.0%)
4 (%)	231 (92.8%)	213 (91.8%)	114 (91.9%)	53 (89.8%)	611 (92.0%)
>4	6 (2.4%)	4 (1.7%)	2 (1.6%)	1 (1.7%)	13 (2.0%)
Baseline pain score Mean ± SD	7.7 ± 1.30	7.8 ± 1.23	7.7 ± 1.20	7.7 ± 1.30	7.8 ± 1.26

Figure 1. Kaplan-Meier estimates of the cumulative percentage of subjects with confirmed perceptible pain relief. Intent-to-treat subjects.

Table 3. Summary of primary and secondary efficacy endpoints. Intent-to-treat subjects.

	FA-acetaminophen	ES-acetaminophen	LG-ibuprofen	Placebo
N	249	232	124	59
Primary endpoint
TCPR, median time^a, min (95% CI)	15.7 (15.2, 18.8)	20.2 (17.1, 22.3)	23.2 (21.8, 25.0)	NE (NE, NE)
p value^b vs placebo	<0.001	<0.001	<0.001
p value^c vs FA-acetaminophen		0.035	<0.001
Secondary endpoints
TMPR, median time^a, min (95% CI)	46.1 (40.4, 55.2)	44.2 (41.8, 51.6)	43.9 (41.8, 48.1)	NE (NE, NE)
p value^b vs placebo	<0.001	<0.001	<0.001
p value^c vs FA-acetaminophen		0.671	0.487
Percentage of subjects with confirmed perceptible pain relief, n (%)
Earliest time that was significant vs placebo at p < 0.001^d	14 min 79 (31.7%)			14 min 5 (8.5%)

Abbreviations. NE, not estimable; TCPR, time to confirmed perceptible pain relief; TMPR, time to meaningful pain relief.

^a Median survival time estimated by Kaplan-Meier method.

^b p value from Wilcoxon test comparing the survival curves.

^c p value is from the comparison of median survival times using the bootstrap re-sampling method.

^d p value is from the logistic regression analysis with treatment as a factor.

Figure 2. Kaplan-Meier estimates of the cumulative percentage of subjects with meaningful pain relief. Intent-to-treat subjects.

Table 4. Summary of tertiary efficacy endpoints and mean cumulative percentage of subjects rescuing during the 4 h study period. Intent-to-treat subjects.

	FA-acetaminophen	ES-acetaminophen	LG-ibuprofen	Placebo
N	249	232	124	59
% Subjects with confirmed perceptible pain relief
15 min, n (%)	103 (41.4)	69 (29.7)	23 (18.5)	6 (10.2)
p value^a vs placebo	<0.001	0.004	0.153
p value^a vs FA-acetaminophen		0.008	<0.001
20 min, n (%)	145 (58.2)	114 (49.1)	42 (33.9)	8 (13.6)
p value^a vs placebo	<0.001	<0.001	0.005
p value^a vs FA-acetaminophen		0.046	<0.001
25 min, n (%)	173 (69.5)	145 (62.5)	73 (58.9)	11 (18.6)
p value^a vs placebo	<0.001	<0.001	<0.001
p value^a vs FA-acetaminophen		0.107	0.042
Percentage of subjects with meaningful pain relief
35 min, n (%)	84 (33.7)	70 (30.2)	*	*
p value^a vs FA-acetaminophen		0.403
40 min, n (%)	105 (42.2)	92 (39.7)	*	*
p value^a vs FA-acetaminophen		0.575
45 min, n (%)	122 (49.0)	118 (50.9)	*	*
p value^a vs FA-acetaminophen		0.683
SPID 0–4
Least square mean (SE)	15.74 (0.556)	16.07 (0.578)	19.72 (0.787)	2.79 (1.140)
p value^b vs placebo	<0.001	<0.001	<0.001
p value^b vs FA-acetaminophen		0.684	<0.001
TOTPAR 0–4
Least square mean (SE)	21.68 (0.687)	22.02 (0.714)	26.59 (0.972)	6.25 (1.408)
p value^b vs placebo	<0.001	<0.001	<0.001
p value^b vs FA-acetaminophen		0.732	<0.001
Median time to rescue^c, min	NE	NE	NE	88.0
Cumulative percentage of subjects who used rescue medication by 4 h, (%)	18.07	16.81	5.65	71.19
p value^d vs placebo	<0.001	<0.001	<0.001
p value^d vs FA-acetaminophen		0.626	0.001
Subject global evaluation (Scale: 0–4)
Least square mean (SE)	2.4 (0.07)	2.5 (0.07)	3.0 (0.10)	0.6 (0.14)
p value^b vs placebo	<0.001	<0.001	<0.001
p value^b vs FA-acetaminophen		0.121	<0.001
Rating = good, very good, or excellent (%)	79.9%	83.6%	91.9%	15.3%

* Not a predefined statistical test.

^a p values based on logistic regression analysis with treatment as a factor.

^b p values based on ANOVA model with terms of treatment and baseline categorical pain score.

^c Median is estimated using Kaplan-Meier method.

^d p values are from Wilcoxon test comparing the survival curves.

^e Global Evaluation: 0 = poor; 1 = fair; 2 = good; 3 = very good; 4 = excellent.

Abbreviations. NE, not estimable; SE, standard error.

Figure 3. Pain intensity difference (PID) score at each time point (a) and pain relief (PAR) score at each time point (b). Intent-to-treat subjects. Data presented as least square mean (LSMean) + standard error (SE).

Figure 4. Kaplan-Meier estimates of the cumulative percentage of subjects using rescue medication. Intent-to-treat subjects.