Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis

Table 1 Summary of published phase 3 tofacitinib studies

Study	Duration	Participants	Demographics	Intervention	Primary outcome
ORAL solo	6 mo	Active RA patients with inadequate response to at least one DMARD (biologic or nonbiologic) receiving stable doses of antimalarial	n = 611 Age: 49.7-52.4 yr Female: 85.2%-88.2% Duration of RA: 7.7-8.6 Baseline HAQ-DI: 1.50-1.53 Baseline DAS-28: 6.65-6.71	Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; placebo for 3 mo then Tofacitinib 5 mg bid; placebo for 3 mo then Tofacitinib 10 mg bid	ACR20 response at month 3; DAS 28-4 ESR < 2.6 at month 3; HAQ-DI at month 3 (change from baseline)
ORAL step	6 mo	Moderate to severe RA patients with inadequate response to TNF alpha inhibitors	n = 399 Age: 54.4-55.4 yr Female: 80.3%-86.36% Duration of RA: 11.3-13.0 yr Baseline HAQ-DI: 1.5-1.6 Baseline DAS-28: 6.4-6.5	Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; placebo for 3 mo then Tofacitinib 5 mg bid; placebo for 3 mo then Tofacitinib 10 mg bid	ACR20 response at month 3; DAS 28-4 ESR < 2.6 at month 3; HAQ-DI at month 3 (change from baseline)
ORAL standard	12 mo	Active RA patients receiving stable doses of methotrexate	n = 717 Age: 51.9-55.5 yr Female: 75.0%-85.3% Duration of RA: 6.9-9.0 yr Baseline HAQ-DI: 1.4-1.5 Baseline DAS-28: 6.3-6.6	Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; adalimumab 40 mg SC every 2 wk; placebo for 6 mo then Tofacitinib 5 mg bid; placebo for 6 mo then Tofacitinib 10 mg bid	ACR20 response at month 6; DAS 28-4 ESR < 2.6 at month 6; HAQ-DI at month 3 (change from baseline)
ORAL sync	12 mo	Active RA patients with inadequate response to one or more DMARD	n = 792 Age: 50.8-53.3 yr Female: 75.0%-83.8% Duration of RA: 8.1-10.2 yr Baseline HAQ-DI: 1.24-1.45 Baseline DAS-28: 6.14-6.44	Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; Placebo	ACR20 response at month 6; DAS 28-4 ESR < 2.6 at month 6; HAQ-DI at month 3 (change from baseline)
ORAL scan	24 mo	Active RA patients receiving background methotrexate	n = 797 Age: 52.0-53.7 yr Female: 80.2%-91.1% Duration of RA: 8.8-9.5 yr Baseline HAQ-DI: 1.23-1.41 Baseline DAS-28: 6.25-6.34	Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; placebo for 3 mo then Tofacitinib 5 mg bid; placebo for 3 mo then Tofacitinib 10 mg bid	ACR20 response at month 6; DAS 28-4 ESR < 2.6 at month 6; HAQ-DI at month 3 (change from baseline); SHS at month 6 (change from baseline)
ORAL start	24 mo	Methotrexate naïve patients with active RA	n = 952 Baseline TSS: 16.51-20.30	Tofacitinib 5 mg bid; Tofacitinib 10 mg bid; methotrexate 10 mg per week with 5 mg increments every 4 wk to 20 mg per week	Modified Total Sharp Score at month 6; ACR70 response at month 6

DMARD: Disease-modifying antirheumatic drug; TSS: Total sharp score; TNF: Tumor necrosis factor; SHS: Sharp/van der Heijde Score; HAQ-DI: Health Assessment Questionnaire Disability Index; DAS: Disease activity score.

Table 2 Results summary for primary outcomes of phase 3 published trials

Primary outcomes	ORAL solo			ORAL step			ORAL standard			ORAL sync			ORAL scan
	Placebo(n = 122)	Tofacitinib 5 mg bid(n = 243)	Tofacitinib 10 mg bid(n = 245)	Placebo(n = 132)	Tofacitinib 5 mg bid(n = 133)	Tofacitinib 10 mg bid(n = 134)	Placebo(n = 108)	Tofacitinib 5 mg bid(n = 204)	Tofacitinib 10 mg bid(n = 201)	Placebo(n = 159)	Tofacitinib5 mgbid(n = 315)	Tofacitinib 10 mgbid(n = 318)	Placebo(n = 160)	Tofacitinib5 mgbid(n = 321)	Tofacitinib 10 mgbid(n = 316)
ACR20 response (%)	26.7	59.8d	65.7d	24.4	41.7b	48.1d	28.3	51.5d	52.6d	30.8	52.1d	56.6d	25.3	51.5d	61.8d
Change from baselineHAQ-DI (LSM change)	-0.19	-0.50d	-0.57d	-0.18	-0.43d	-0.46d	-0.24	-0.55a	-0.61a	-0.16	-0.44d	-0.53d	-0.15	0.402	-0.54d
DAS-28-4(ESR) less than2.6 (%)	4.4	5.61	8.71	1.7	6.7a	8.8a	1.1	6.2a	12.5a	2.6	8.5b	12.5d	1.6	7.22	16.0d

^bP < 0.01;

^aP < 0.05;

^dP < 0.001 vs placebo trials.

¹Not significant;

²Significance not declared for this co-primary endpoint. ORAL: Oral rheumatoid arthritis triaLs; HAQ-DI: Health assessment questionnaire disability index; DAS: Disease activity score.

Table 3 Summary of safety and tolerability data for tofacitinib from phase 3 clinical trials (month 0-3) n (%)

	ORAL solo			ORAL step			ORAL standard				ORAL sync			ORAL scan
	Placebo(n = 122)	Tofacitinib5 mg bid(n = 243)	Tofacitinib10 mg bid(n = 245)	Placebo(n = 132)	Tofacitinib5 mg bid(n = 133)	Tofacitinib10 mg bid(n = 134)	Placebo(n = 108)	Tofacitinib5 mg bid(n = 204)	Tofacitinib10 mg bid(n = 201)	Adalimumab 40 mg once Q2W(n = 204)	Placebo(n = 159)	Tofacitinib5 mg bid(n = 315)	Tofacitinib10 mg bid(n = 318)	Placebo(n = 160)	Tofacitinib5 mg bid(n = 321)	Tofacitinib10 mg bid(n = 316)
Patients with AE,	67 (54.9)	124 (51)	139 (56.7)	75 (56.8)	71 (53.4)	76 (56.7)	51 (47.2)	106 (52)	94 (46.8)	105 (51.5)	97 (61)	166 (52.7)	173 (54.4)	73 (45.6)	157 (48.9)	171 (54.1)
Patients with SAE	6 (4.9)	1 (0.4)	5 (2)	6 (4.5)	2 (1.5)	2 (1.5)	2 (1.9)	12 (5.9)	10 (5)	5 (2.5)	6 (3.8)	9 (2.9)	8 (2.5)	5 (3.1)	12 (3.7)	10 (3.2)
Discontinuation due to AE	5 (4.1)	2 (0.8)	6 (2.4)	7 (5.3)	8 (6)	6 (4.5)	3 (2.8)	14 (6.9)	10 (5)	10 (4.9)	2 (1.3)	13 (4.1)	13 (4.1)	5 (3.1)	15 (4.7)	14 (4.4)

AE: Adverse events; SAE: Serious adverse events; Q2W: Every 2 wk; Oral Rheumatoid Arthritis triaLs (ORAL) Start was not included in the 3-month evaluation since data reported were for all events 0-12 mo.

Table 4 Summary of safety and tolerability data for tofacitinib from phase 3 clinical trials (final safety analysis) n (%)

	1ORAL solo				1ORAL step				2ORAL standard					2ORAL sync				2ORAL scan				4ORAL start
	Tofacit-inib 5 mg bid (after Placebo)(n = 61)	Tofacit-inib 10 mg bid (after Placebo)(n =61)	Tofacit-inib 5 mg bid(n = 243)	Tofaci-tinib 10 mg bid(n = 245)	Tofacit-inib 5 mg bid (after Placebo)(n = 66)	Tofacit-inib 10 mg bid (after Placebo)(n = 66)	Tofacit-inib 5 mg bid(n = 133)	Tofacit-inib 10 mg bid(n = 134)	Tofacit-inib 5 mg bid (after Placebo )(n = 56)	Tofacitinib 10 mg bid (after Placebo)(n = 52)	Tofacit-inib 5 mg bid(n = 204)	Tofacit-inib 10 mg bid(n = 201)	Adalim-umab 40 mg once Q2W(n = 204)	Tofacit-inib 5 mg bid (after Placebo)(n = 79)	Tofacit-inib 10mg bid (after Placebo)(n = 80)	Tofacit-inib 5 mg bid(n = 315)	Tofacit-inib 10 mg bid(n = 318)	Tofacit-inib 5 mg bid (after Placebo)(n = 81)	Tofacit-inib 10 mg bid (after Placebo)(n = 79)	Tofacit-inib 5 mg bid(n = 321)	Tofacit-inib 10 mg bid(n = 316)	Tofacit-inib 5 mg bid(n = 371)	Tofacit-inib 10 mg bid(n =395)	MTX(n = 186)
Patients with AE	22 (36.1)	24 (39.3)	97 (39.9)	101 (41.2)	24 (36.4)	28 (42.4)	57 (42.9)	58 (43.3)	18 (32.1)	21 (40.4)	89 (43.6)	84 (41.8)	83 (40.7)	34 (43)	29 (36.3)	104 (33)	135 (42.5)	34 (42)	35 (44.3)	166 (51.7)	174 (55.1)	(70.1)5	(74.4)5	(69.9)5
Patients with SAE	1 (1.6)	0	5 (2.1)	6 (2.4)	3 (4.5)	2 (3)	5 (3.8)	6 (4.5)	1 (1.8)	4 (7.7)	10 (4.9)	6 (3)	7 (3.4)	2 (2.5)	0	7 (2.2)	9 (2.8)	1 (1.2)	4 (5.1)	13 (4)	9 (2.8)	(6.5)5	(6.1)5	(7.0)5
Discon- tinuation due to AE	0	0	1 (0.4)	3 (1.2)	1 (1.5)	2 (3)	4 (3)	7 (5.2)	0	2 (3.8)	6 (2.9)	3 (1.5)	4 (2)	0	1 (1.3)	1 (0.3)	9 (2.8)	2 (2.5)	2 (2.5)	9 (2.8)	7 (2.2)	13 (3.5)	17 (4.3)	11 (5.9)
Deaths	0	0	0	1 (0.4)	0	1 (1.5)	0	0	0	0	1 (0.5)	0	1 (0.5)	0	0	2 (0.6)	2 (0.6)	1 (1.2)	0	2 (0.6)	1 (0.3)	See note	See note	0
Patients with serious infection events	1 (1.6)	0	1 (0.4)	3 (1.2)	1 (1.5)	0	2 (1.5)	2 (1.5)	2 (3.6)	0	7 (3.4)	8 (4)	3 (1.5)	0	0	2 (0.6)	7 (2.2)	1 (1.2)	2 (2.5)	11 (3.4)	5 (1.6)	(31.8)6	(38.7)6	(27.4)6
Pulm- onary Tube- rculosis	0	0	0	0	0	0	0	0	0	0	0	2 (1)	0	0	0	0	2 (0.6)	0	0	0	0	0	0	0
3Oppor- tunistic infections	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1 (0.3)	1 (0.3)	0	0	3 (0.9)	4 (1.3)	8 (2.2)	11 (2.8)	3 (1.6)
Malign- ancies	0	0	0	0	0	0	0	0	NR	NR	NR	NR	NR	NR	NR	NR	NR	0	0	5 (1.6)	4 (1.3)	NR	NR	NR

AE: Adverse events; SAE: Serious adverse events; Q2W: Every 2 wk; NR: Not reported. ¹3-6 mo data point; ²6-12 mo data point;

³Excludes pulmonary tuberculosis; ⁴0-12 mo data point;

⁵data reported as total number of events;

⁶All infections and infestations; serious infection events, pulmonary tuberculosis, opportunistic infections, and malignancies reported for all trial data.