Efficacy and safety of two fast-absorbing formulations of paracetamol in combination with caffeine for episodic tension-type headache: results from two randomized placebo- and active-controlled trials

Figures & data

Figure 1 (A) Subject disposition, study 1; (B) subject disposition, study 2.

Notes: ^aIn both studies, the safety population consisted of all participants who were randomized and received any study medication. In study 1, the intent-to-treat (ITT) population consisted of participants who received at least one study treatment and had at least one postbaseline efficacy assessment. In study 2, the ITT population consisted of those who had at least one evaluable headache during the treatment phase, received at least one dose of study medication, and had at least one postbaseline pain-intensity assessment.
Abbreviations: ITT, intent to treat; AE, adverse event.

Table 1 Demographics and baseline characteristics, study 1, safety/ITT population

Demographics	Overall (n=66)
Sex, n (%)
Male	22 (33.3)
Female	44 (66.7)
Race, n (%)
White	37 (56.1)
Black/African-American	29 (43.9)
Age, years
Mean (SD)	42 (12.5)
Range	18–63

Characteristics	Paracetamol-sodium bicarbonate-caffeine (n=48)	Ibuprofen (n=51)	Paracetamol (n=49)	Placebo (n=50)
n	47	50	45	45
Baseline pain severity,^a n (%)
Moderate^b	8 (17)	8 (16)	6 (13.3)	10 (22.2)
Severe^b	39 (83)	42 (84)	39 (86.7)	35 (77.8)
Baseline pain intensity,^a mean (SD)
	3.3 (0.75)	3.3 (0.75)	3.3 (0.7)	3.2 (0.79)

Notes:

a Participants rated their baseline headache severity using the eDiary on a 5-point categorical scale (0, no headache; 1, mild headache; 2, moderate headache; 3, moderately severe headache; 4, severe headache);

b moderate group included those with pain rating of 2, severe group those with pain rating of 3 or 4; headaches with ratings of 0 or 1 were not considered qualifying headaches for treatment.

Abbreviations: ITT, intent to treat; SD, standard deviation.

Table 2 Demographics and baseline characteristics for study 2, safety/ITT population

Demographics/characteristics	Overall (n=157)	Paracetamol with Optizorb-caffeine (n=62)	Ibuprofen (n=62)	Placebo (n=33)
Sex, n (%)
Male	44 (28)	16 (25.8)	18 (29)	10 (30.3)
Female	113 (72)	46 (74.2)	44 (71)	23 (69.7)
Race, n (%)
White	139 (88.5)	56 (90.3)	55 (88.7)	28 (84.8)
Black/African-American	14 (8.9)	4 (6.5)	6 (9.7)	4 (12.1)
Asian	2 (1.3)	1 (1.6)	0	1 (3)
Multiple	2 (1.3)	1 (1.6)	1 (1.6)	0
Ethnicity, n (%)
Hispanic/Latino	17 (10.8)	7 (11.3)	8 (12.9)	2 (6.1)
Not Hispanic/Latino	140 (89.2)	55 (88.7)	54 (87.1)	31 (93.9)
Age, years
Mean (SD)	38.9 (12.3)	39.9 (11.4)	38.1 (13.1)	38.5 (12.7)
Range	18–65	18–63	18–65	19–63
Duration of historical headaches (if untreated), n (%)
2–4 hours	2 (1.3)	2 (3.2)	0	0
>4 hours	155 (98.7)	60 (96.8)	62 (100)	33 (100)
Number of historical headaches in 3 months prior to run-in
Mean (SD)	19 (5.9)	20.3 (6.5)	18 (5.7)	18.2 (4.8)
Range	8–42	9–42	9–36	8–30
Number of qualifying treatment-phase headaches, n (%)
1	6 (3.8)	2 (3.2)	4 (6.5)	0
2	13 (8.3)	4 (6.5)	5 (8.1)	4 (12.1)
3	138 (87.9)	56 (90.3)	53 (85.5)	29 (87.9)
Baseline severity of the first qualifying treatment-phase headache,^a n (%)
Moderate	131 (83.4)	51 (82.3)	56 (90.3)	24 (72.7)
Severe	26 (16.6)	11 (17.7)	6 (9.7)	9 (27.3)
Baseline pain severity for all qualifying treatment-phase headaches,^a mean (SD)	2.17 (0.34)	2.16 (0.32)	2.14 (0.31)	2.25 (0.4)

Notes:

a Participants rated their baseline headache severity using the eDiary on a 4-point categorical scale (0, no headache; 1, mild headache; 2, moderate headache; 3, severe headache). Headaches with ratings of 0 or 1 were not considered qualifying headaches for treatment.

Abbreviations: ITT, intent to treat; SD, standard deviation.

Figure 2 Time to perceptible pain relief (primary outcome), Kaplan–Meier curve, study 1, intent-to-treat population.

Notes: Hazard ratios (95% confidence interval) for comparison with placebo were 1.25 (0.83–1.9) for paracetamol–sodium bicarbonate–caffeine, 1.08 (0.72–1.61) for ibuprofen, and 0.95 (0.62–1.45) for paracetamol.

Figure 3 Adjusted mean SPID_0–60, SPID_0–90, SPID_0–120, and SPID_0–240 (secondary outcomes), study 1, ITT population.

Notes: ^aAdjusted means are least squares means from ANCOVA adjusted for baseline pain intensity. Positive values indicate reduction in pain. ^bP<0.05 vs placebo; ^cP<0.05 vs paracetamol.
Abbreviations: SPID, sum of pain-intensity difference (numeric subscript ranges indicate minutes); ITT, intent to treat; ANCOVA, analysis of covariance.

Figure 4 Adjusted mean TOTPAR (secondary outcome), study 1, ITT population.

Notes: ^aAdjusted means are least squares means from ANCOVA adjusted for baseline pain intensity. ^bP<0.05 vs placebo; ^cP<0.05 vs paracetamol.
Abbreviations: TOTPAR, total pain relief (numeric subscript ranges indicate minutes); ITT, intent to treat; ANCOVA, analysis of covariance.

Table 3 Number of subjects with headache resolution and global impression of treatment (secondary efficacy outcomes), study 1, ITT population

Outcomes	Paracetamol-sodium bicarbonate-caffeine (n=48)	Ibuprofen (n=51)	Paracetamol (n=49)	Placebo (n=50)
Number (%) of subjects with headaches resolved (PRS 4 and pain intensity 0)
In 1 hour	15/47 (31.9)^a,^b	7/50 (14)	4/45 (8.9)	7/45 (15.6)
In 2 hours	29/47 (61.7)	30/50 (60)	25/45 (55.6)	24/45 (53.3)
Global impression of treatment response, n (%)
0 (very poor)	1/39 (2.6)	1/44 (2.3)	1/34 (2.9)	2/38 (5.3)
1 (poor)	0/39	1/44 (2.3)	1/34 (2.9)	4/38 (10.5)
2 (neutral)	10/39 (25.6)	5/44 (11.4)	6/34 (17.6)	3/38 (7.9)
3 (good)	16/39 (41)	19/44 (43.2)	15/34 (44.1)	17/38 (44.7)
4 (very good)	12/39 (30.8)	18/44 (40.9)	11/34 (32.4)	12/38 (31.6)

Notes:

a P<0.05 vs paracetamol;

b P<0.05 vs ibuprofen. Numbers of patients shown in the column headings represent the full ITT population; sample sizes for the individual end points varied, due to missing data at some time points for some outcomes.

Abbreviations: ITT, intent to treat; PRS, pain-relief score.

Figure 5 Adjusted mean SPID_0–1, SPID_0–2, SPID_0–3 (secondary outcomes), and SPID_0–4 (primary outcome), study 2, ITT population.

Notes: ^aAdjusted means and confidence limits for treatment differences from ANCOVA model with treatment and pooled site as fixed factors and baseline intensity as covariate. Negative values indicate reduction in pain. Treatment differences shown are for paracetamol with Optizorb–caffeine versus either ibuprofen or placebo such that a negative result favors paracetamol with Optizorb–caffeine.
Abbreviations: SPID, sum of pain-intensity difference (numeric subscript ranges indicate hours); ITT, intent to treat; ANCOVA, analysis of covariance; CI, confidence interval.

Figure 6 Adjusted mean TOTPAR_0–1, TOTPAR_0–2, TOTPAR_0–3, and TOTPAR_0–4 (secondary outcomes), study 2, ITT population.

Notes: ^aAdjusted means and confidence limits for treatment differences from ANCOVA model with treatment and pooled site as fixed factors and baseline intensity as covariate. Treatment differences shown are for paracetamol with Optizorb–caffeine versus either ibuprofen or placebo such that a positive result favors paracetamol with Optizorb–caffeine.
Abbreviations: TOTPAR, total pain relief (numeric subscript ranges indicate hours); ITT, intent to treat; ANCOVA, analysis of covariance; CI, confidence interval.

Figure 7 (A) Time to perceptible pain relief and (B) time to meaningful pain relief (both secondary outcomes), Kaplan–Meier curves, study 2, intent-to-treat population.

Notes: Time to perceptible relief: hazard ratio (95% confidence interval [CI]) for comparison with placebo was 1.12 (0.72–1.73) for paracetamol with Optizorb–caffeine and 0.97 (0.62–1.52) for ibuprofen; hazard ratio (95% CI) for paracetamol with Optizorb–caffeine compared with ibuprofen was 1.17 (0.81–1.67). Time to meaningful relief: hazard ratio (95% CI) for comparison with placebo was 1.11 (0.72–1.73) for paracetamol with Optizorb–caffeine and 1.09 (0.69–1.73) for ibuprofen; hazard ratio (95% CI) for paracetamol with Optizorb–caffeine compared with ibuprofen was 1.03 (0.71–1.48). Circles represent censored data.

Table 4 Number of subjects with complete relief, global impression of treatment, and use of rescue medication (secondary efficacy outcomes), study 2, ITT population

Outcomes	Paracetamol with Optizorb-caffeine (n=62)	Ibuprofen (n=62)	Placebo (n=33)
Subjects with complete relief in 1 hour (PRS 4), n (%)	18 (29)	17 (27.4)	6 (18.2)
Subjects with complete relief in 2 hours (“yes” response to “Do you have complete relief?”), n (%) Global impression of response to treatment	38 (61.3) n=62	41 (66.1) n=62	20 (60.6) n=33
LS mean	2.85	2.78	2.63
Treatment difference^a (95% CI)
Treatment vs placebo	0.22 (−0.13 to 0.57)	0.15 (−0.2 to 0.5)	—
Treatment vs ibuprofen	0.07 (−0.22 to 0.35)	—	—
Rescue medication
Subjects taking rescue medication, n (%)	2 (3.2)	4 (6.5)	4 (12.1)
Mean (SD) time to rescue medication use, minutes	239 (6.9)	235.1 (24.1)	235.6 (12.6)

Note:

a Difference between the first-named treatment group and the second-named treatment group such that a positive result favors the first treatment.

Abbreviations: ITT, intent to treat; PRS, pain-relief score; LS, least squares; CI, confidence interval; SD, standard deviation.

Table 5 TEAEs in study 1, safety population

TEAEs	Paracetamol-sodium bicarbonate-caffeine (n=47)	Ibuprofen, (n=50)	Paracetamol (n=45)	Placebo (n=45)
Subjects with ≥1 TEAE, n (%)	2 (4.3)	4 (8)	0	3 (6.7)
Number of TEAEs	2	4	0	3
TEAEs occurring in ≥2% of any treatment arm, n (%)
Abdominal pain, upper	0	1 (2)	0	0
Asthma	1 (2.1)	0	0	0
Dry mouth	0	0	0	1 (2.2)
Dyspepsia	0	1 (2)	0	0
Oral pain	0	1 (2)	0	0
Pharyngitis, streptococcal	0	1 (2)	0	0
Plantar fasciitis	0	0	0	1 (2.2)
Rhinitis	0	0	0	1 (2.2)
Upper respiratory tract infection	1 (2.1)	0	0	0

Abbreviation: TEAEs, treatment-emergent adverse events.

Table 6 TEAEs in study 2, safety population

TEAEs	Paracetamol with Optizorb-caffeine (n=62)	Ibuprofen (n=50)	Placebo (n=45)
Subjects with ≥1 TEAE, n (%)	4 (6.5)	3 (4.8)	1 (3)
Number of TEAEs	6	5	1
TEAEs occurring in ≥1% of any treatment arm, n (%)
Depression	0	1 (1.6)	0
Dyspepsia	1 (1.6)	0	0
Feeling jittery	1 (1.6)	0	0
Hypothyroidism	1 (1.6)	0	0
Insomnia	0	1 (1.6)	0
Nasopharyngitis	1 (1.6)	0	0
Oropharyngeal pain	0	1 (1.6)	0
Paranasal sinus discomfort	0	1 (1.6)	0
Sinus congestion	0	1 (1.6)	0
Upper respiratory tract infection	0	0	1 (3)
Viral upper respiratory tract infection	1 (1.6)	0	0

Abbreviation: TEAEs, treatment-emergent adverse events.

Table S1 Additional secondary efficacy outcomes from study 1, ITT population

Outcomes	Paracetamol-sodium bicarbonate-caffeine (n=48)	Ibuprofen (n=51)	Paracetamol (n=49)	Placebo (n=50)
PID, LS mean
15 minutes	0.33	0.15	0.17	0.16
30 minutes	0.93	0.64	0.67	0.74
45 minutes	1.58^Table Footnotea	1.4	1.33	1.13
60 minutes	2.02^Table Footnotea,Table Footnoteb	1.83	1.62	1.63
90 minutes	2.34	2.33	2.22	2.1
120 minutes	2.5	2.75^Table Footnotea	2.35	2.29
240 minutes	2.75	2.78	2.62	2.64
PRS, LS mean
15 minutes	0.17	0.1	0.26	0.08
30 minutes	1.02	0.81	0.68	0.77
45 minutes	1.83^Table Footnoteb	1.6	1.41	1.59
60 minutes	2.51^Table Footnotea,Table Footnoteb	2.13	1.73	1.92
90 minutes	2.97	2.95	2.7	2.63
120 minutes	3.24	3.46	3.01	2.97
240 minutes	3.55	3.69	3.21	3.47

Notes: LS means are from the analysis-of-covariance model adjusted for baseline pain intensity. Patient numbers shown in the column headings represent the full ITT population; sample sizes for the individual end points varied, due to missing data at some time points for some outcomes.

a P<0.05 vs placebo;

b P<0.05 vs paracetamol.

Abbreviations: ITT, intent to treat; PID, pain-intensity difference; LS, least squares; PRS, pain-relief score.