Adalimumab in Active and Inactive, Non-Infectious Uveitis: Global Results from the VISUAL I and VISUAL II Trials

Figures & data

TABLE 1. Criteria for treatment failure for VISUAL I and VISUAL II clinical trials.

Treatment Failure Parameters*	VISUAL I		VISUAL II
	Week 6	All other visits after week 6	At or after week 2
Inflammatory, chorioretinal and/or inflammatory retinal vascular lesions	New active, inflammatory lesions relative to baseline	New active, inflammatory lesions relative to baseline	New active, inflammatory lesions relative to baseline
Anterior chamber cell grade (SUN criteria)	Inability to achieve ≤0.5+	2-step increase relative to best state achieved^†	2-step increase relative to baseline^†
Vitreous haze grade (NEI/SUN criteria)	Inability to achieve ≤0.5+	2-step increase relative to best state achieved^†	2-step increase relative to baseline^†
Visual acuity (ETDRS)	Worsening of BCVA by ≥15 letters relative to best state achieved	Worsening of BCVA by ≥15 letters relative to best state achieved	Worsening of BCVA by ≥15 letters relative to baseline

BCVA = best corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; NEI = National Eye Institute; SUN = Standardization of Uveitis Nomenclature.

*Treatment failure defined as ≥1 of the 4 criteria in ≥1 eye.

^†A 2-step increase was represented by a change of grade 0 to grade 2+; or grade 0.5+ to grade 3+.

TABLE 2. Primary endpoint and ranked secondary endpoints for VISUAL I and VISUAL II trials.

A) Primary Endpoint

Time to treatment failure

B) Ranked Secondary Endpoints*

1 Change in AC cell grade in each eye

2 Change in VH grade in each eye

3 Change in BCVA (logMAR) in each eye

AC = anterior chamber; BCVA = best corrected visual acuity; VH = vitreous haze.

*Data reflect change from best state achieved prior to week 6 to the final/early termination visit for VISUAL I and change from baseline to final/early termination visit for VISUAL II.

TABLE 3. Participants’ demographics and baseline characteristics (intent-to-treat population).

	VISUAL I, Integrated		VISUAL I, Japan Substudy		VISUAL II, Integrated		VISUAL II, Japan Substudy
	Placebo (n = 115)	Adalimumab (n = 118)	Placebo (n = 8)	Adalimumab (n = 8)	Placebo (n = 127)	Adalimumab (n = 131)	Placebo (n = 16)	Adalimumab (n = 16)
Sex, n (%)
Female	70 (61)	65 (55)	5 (63)	6 (75)	82 (65)	75 (57)	10 (63)	9 (56)
Race, n (%)
White	86 (75)	88 (75)	0	0	93 (73)	96 (73)	0	0
Asian	10 (9)	12 (10)	8 (100)	8 (100)	19 (15)	19 (15)	16 (100)	16 (100)
Age, years
Mean ± SD	43.0 ± 14.5	43.5 ± 15.5	47.9 ± 18.6	53.9 ± 9.9	43.0 ± 14.1	43.2 ± 12.7	48.1 ± 13.9	45.5 ± 11.2
Type of uveitis, n (%)
Intermediate	23 (20)	25 (21)	0	1 (13)	30 (24)	17 (13)	0	0
Posterior	37 (32)	38 (32)	0	2 (25)	35 (28)	41 (31)	1 (6)	2 (13)
Panuveitis	55 (48)	55 (47)	8 (100)	5 (63)	61 (48)	71 (54)	15 (94)	14 (88)
Intermediate/Posterior	0	0	0	0	1 (.8)	2 (1.5)	0	0
Diagnosis, n (%)
Idiopathic	49 (43)	39 (33)	4 (50)	3 (38)	44 (35)	33 (25)	4 (25)	4 (25)
Birdshot chorioretinopathy	20 (17)	24 (20)	0	0	15 (12)	15 (11)	0	0
Multifocal choroiditis & panuveitis	3 (3)	8 (7)	0	0	2 (2)	5 (4)	0	0
Vogt Koyanagi Harada disease	14 (12)	12 (10)	0	1 (13)	29 (23)	34 (26)	4 (25)	8 (50)
Sarcoidosis	12 (10)	12 (10)	4 (50)	2 (25)	20 (16)	22 (17)	6 (38)	4 (25)
Behçet’s disease	4 (3)	14 (12)	0	2 (25)	7 (5)	10 (8)	1 (6)	0
Other	13 (11)	9 (8)	0	0	10 (8)	12 (9)	1 (6)	0
Affected eye, n (%)
Left	5 (4.3)	6 (5.1)	0	1 (12.5)	3 (2.4)	3 (2.3)	0	1 (6.3)
Right	4 (3.5)	7 (5.9)	1 (12.5)	0	5 (3.9)	2 (1.5)	1 (6.3)	1 (6.3)
Both	106 (92.2)	105 (89.0)	7 (87.5)	7 (87.5)	119 (93.7)	126 (96.2)	15 (93.8)	14 (87.5)
Duration of uveitis, months
Mean ± SD	51.4 ± 71.9	41.3 ± 53.7	57.0 ± 72.5	57.3 ± 83.8	59.7 ± 65.2	58.4 ± 61.8	37.5 ± 39.4	50.0 ± 37.
No. of flares in past 12 months, n (%)
0–1	20 (17.4)	20 (16.9)	1 (12.5)	2 (25.0)	51 (40.2)	57 (43.5)	5 (31.3)	9 (56.3)
2	50 (43.5)	59 (50.0)	4 (50.0)	5 (62.5)	45 (35.4)	46 (35.1)	5 (31.3)	3 (18.8)
≥ 3	45 (39.1)	39 (33.1)	3 (37.5)	1 (12.5)	31 (24.4)	28 (21.4)	6 (37.5)	4 (25.0)
Concomitant immunomodulators at baseline, n (%)
Mycophenolate mofetil	14 (12.2)	11 (9.3)	0	0	17 (13.4)	17 (13.0)	0	0
Cyclosporine	3 (2.6)	11 (9.3)	0	1 (12.5)	12 (9.4)	15 (11.5)	1 (6.3)	0
Methotrexate	14 (12.2)	9 (7.6)	2 (25.0)	0	14 (11.0)	21 (16.0)	0	2 (12.5)
Azathioprine	4 (3.5)	4 (3.4)	0	0	11 (8.7)	3 (2.3)	0	0
Tacrolimus	0	0	0	0	0	0	0	0

FIGURE 1. Participant disposition. VISUAL I (A) and VISUAL II (B). GCP = Good Clinical Practice.

*Includes participants who experienced treatment failure, reached 80 weeks of treatment without treatment failure, or had to terminate the study because the planned number of treatment failures was reached.^†Some participants had multiple reasons for discontinuation; total counts for reasons for discontinuation exceed the total number of discontinuations.

FIGURE 1. (Continued).

TABLE 4. Primary endpoint for main study, integrated study, and Japan substudy for VISUAL I and VISUAL II trials.

	Treatment (N)	Comparison Adalimumab to Placebo
		Hazard Ratio*	95% CI	p-value^†
VISUAL I
Main study (ex-Japan)^Citation13	Placebo (n = 107)	0.50	0.36–0.70	<0.001
	Adalimumab (n = 110)
Integrated study	Placebo (n = 115)	0.56^‡	0.40–0.76	<0.001
	Adalimumab (n = 118)
Japan substudy	Placebo (n = 8)	1.20	0.41–3.54	NC
	Adalimumab (n = 8)
Japan substudy (excluding the outlier participant)	Placebo (n = 7)	0.73	0.22–2.40	NC
	Adalimumab (n = 8)
VISUAL II
Main study (ex-Japan)^Citation14	Placebo (n = 111)	0.57	0.39–0.84	0.004
	Adalimumab (n = 115)
Integrated study	Placebo (n = 127)	0.52^‡	0.37–0.74	<0.001
	Adalimumab (n = 131)
Japan substudy	Placebo (n = 16)	0.45	0.20–1.03	NC
	Adalimumab (n = 16)

NC = not calculated.

*Cox proportional hazards model with treatment as factor.

^†Two-sided p-value from log rank test.

^‡Cox proportional hazards model with treatment and Japanese race as factors.

TABLE 5. Summary of ranked secondary efficacy variables*.

	Difference (Mean)	95% CI	p-value
VISUAL I
1. Change in AC cell grade
Integrated study	–0.25	–0.46, –0.04	0.019^†
Japan substudy	0.22	–0.17, 0.61	NC
Japan substudy (excluding the outlier participant)	0.20	–0.22, 0.62	NC
2. Change in VH grade
Integrated study	–0.28	–0.43, –0.12	< 0.001^†
Japan substudy	–0.41	–1.15, 0.34	NC
Japan substudy (excluding the outlier participant)	–0.58	–1.28, 0.12	NC
3. Change in logMAR BCVA
Integrated study	–0.06	–0.10, –0.02	0.008^†
Japan substudy	0.04	–0.22, 0.31	NC
Japan substudy (excluding the outlier participant)	–0.03	–0.26, 0.21	NC
VISUAL II
1. Change in AC cell grade
Integrated study	–0.15	–0.36, 0.06	0.164^†
Japan substudy	–0.22	–0.90, 0.46	NC
2. Change in VH grade
Integrated study	–0.17	–0.31, −0.03	0.016^†
Japan substudy	–0.45	–0.98, 0.07	NC
3. Change in logMAR BCVA
Integrated study	–0.04	–0.09, 0.00	0.044^†
Japan substudy	–0.08	–0.20, 0.04	NC

AC = anterior chamber; BCVA = best corrected visual acuity; NC = not calculated; VH = vitreous haze.

*Data reflect change from best state achieved prior to week 6 to the final/early termination visit for VISUAL I and change from baseline to final/early termination visit for VISUAL II.

^†From analysis of variance with treatment and Japan vs ex-Japan as factors adjusted for clustered observations.

TABLE 6. Summary of adverse events (safety population).

	VISUAL I		VISUAL II
AEs, Events (Events per 100 PY)	Placebo (n = 120, PYs = 47.4)	Adalimumab (n = 119, PYs = 64.4)	Placebo (n = 130, PYs = 74.4)	Adalimumab (n = 131, PYs = 102.9)
Any AE	455 (960)	685 (1063)	658 (884)	879 (854)
Serious AE	6 (12.7)	19 (29.5)	11 (14.8)	14 (13.6)
AE leading to discontinuation	5 (10.6)	13 (20.2)	7 (9.4)	12 (11.7)
Serious infections	3 (6.3)	5 (7.8)	2 (2.7)	3 (2.9)
Malignancy	0	2 (3.1)*	0	2 (1.9)^†
AE leading to death	0	1 (1.6)^‡	0	2 (1.9)^§
Any active TB	0	1 (1.6)	0	0
Any latent TB	0	1 (1.6)	1 (1.3)	3 (2.9)
Any demyelinating disease	0	1 (1.6)	0	0
Injection site reactions	7 (14.8)	28 (43.5)	16 (21.5)	37 (36.0)

ADA = adalimumab; AE = adverse event; PY = participant-year;  TB = tuberculosis.

*One event each of carcinoid tumor of the gastrointestinal tract (day 244; resolved on day 251; ADA treatment was not interrupted) and glioblastoma multiforme (day 242; ADA was discontinued due to this event; last ADA dose, day 248).

^†One event each of non-serious squamous cell carcinoma of skin (day 210; resolved on day 215; ADA treatment was not interrupted) and lung adenocarcinoma Stage IV (day 274; 14 days after last ADA dose; ADA treatment was not interrupted).

^‡One death due to end-stage chronic renal disease (37 days after baseline).

^§One death due to 2 fatal AEs of aortic dissection and cardiac tamponade (18 days after last ADA dose), not related to ADA treatment.

Jaffe GJ, Dick AD, Brezin AP, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016;375:932–943. doi:10.1056/NEJMoa1509852.

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Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016;388:1183–1192. doi:10.1016/S0140-6736(16)31339-3.

 Web of Science ®Google Scholar