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

Quan Dong Nguyen, Pauline T. Merrill, Glenn J. Jaffe, Andrew D. Dick, Shree Kumar Kurup, John Sheppard, Ariel Schlaen, Carlos Pavesio, Luca Cimino, Joachim Van Calster, Anne A. Camez, Nisha V. Kwatra, Alexandra P. Song, Martina Kron, Samir Tari, Antoine P. Brézin

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

Background Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. Methods We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10–35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01124838. Findings Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77–357) in the placebo group and 245 days (119–564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39–0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group). Interpretation Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis. Funding AbbVie.

Original languageEnglish (US)
Pages (from-to)1183-1192
Number of pages10
JournalThe Lancet
Volume388
Issue number10050
DOIs
StatePublished - Sep 17 2016

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Uveitis
Adrenal Cortex Hormones
Placebos
Treatment Failure
Adalimumab
Prednisone
Safety
Visual Acuity
Oral Tuberculosis
Nasopharyngitis
Population
Inflammation
Oral Candidiasis
Retinal Vessels
Latin America
Opportunistic Infections
Arthralgia
Immunologic Factors
Anterior Chamber
Israel

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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. / Nguyen, Quan Dong; Merrill, Pauline T.; Jaffe, Glenn J.; Dick, Andrew D.; Kurup, Shree Kumar; Sheppard, John; Schlaen, Ariel; Pavesio, Carlos; Cimino, Luca; Van Calster, Joachim; Camez, Anne A.; Kwatra, Nisha V.; Song, Alexandra P.; Kron, Martina; Tari, Samir; Brézin, Antoine P.

In: The Lancet, Vol. 388, No. 10050, 17.09.2016, p. 1183-1192.

Research output: Contribution to journalArticle

Nguyen, QD, Merrill, PT, Jaffe, GJ, Dick, AD, Kurup, SK, Sheppard, J, Schlaen, A, Pavesio, C, Cimino, L, Van Calster, J, Camez, AA, Kwatra, NV, Song, AP, Kron, M, Tari, S & Brézin, AP 2016, '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', The Lancet, vol. 388, no. 10050, pp. 1183-1192. https://doi.org/10.1016/S0140-6736(16)31339-3
Nguyen, Quan Dong ; Merrill, Pauline T. ; Jaffe, Glenn J. ; Dick, Andrew D. ; Kurup, Shree Kumar ; Sheppard, John ; Schlaen, Ariel ; Pavesio, Carlos ; Cimino, Luca ; Van Calster, Joachim ; Camez, Anne A. ; Kwatra, Nisha V. ; Song, Alexandra P. ; Kron, Martina ; Tari, Samir ; Brézin, Antoine P. / 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. In: The Lancet. 2016 ; Vol. 388, No. 10050. pp. 1183-1192.
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abstract = "Background Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. Methods We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10–35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01124838. Findings Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77–357) in the placebo group and 245 days (119–564) in the adalimumab group. Treatment failure occurred in 61 (55{\%}) of 111 patients in the placebo group compared with 45 (39{\%}) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95{\%} CI 0·39–0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1{\%}) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11{\%}] patients in the placebo group and 27 [23{\%}] patients in the adalimumab group), nasopharyngitis (16 [17{\%}] and eight [16{\%}] patients, respectively), and headache (17 [15{\%}] patients in each group). Interpretation Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis. Funding AbbVie.",
author = "Nguyen, {Quan Dong} and Merrill, {Pauline T.} and Jaffe, {Glenn J.} and Dick, {Andrew D.} and Kurup, {Shree Kumar} and John Sheppard and Ariel Schlaen and Carlos Pavesio and Luca Cimino and {Van Calster}, Joachim and Camez, {Anne A.} and Kwatra, {Nisha V.} and Song, {Alexandra P.} and Martina Kron and Samir Tari and Br{\'e}zin, {Antoine P.}",
year = "2016",
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day = "17",
doi = "10.1016/S0140-6736(16)31339-3",
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TY - JOUR

T1 - Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II)

T2 - a multicentre, double-masked, randomised, placebo-controlled phase 3 trial

AU - Nguyen, Quan Dong

AU - Merrill, Pauline T.

AU - Jaffe, Glenn J.

AU - Dick, Andrew D.

AU - Kurup, Shree Kumar

AU - Sheppard, John

AU - Schlaen, Ariel

AU - Pavesio, Carlos

AU - Cimino, Luca

AU - Van Calster, Joachim

AU - Camez, Anne A.

AU - Kwatra, Nisha V.

AU - Song, Alexandra P.

AU - Kron, Martina

AU - Tari, Samir

AU - Brézin, Antoine P.

PY - 2016/9/17

Y1 - 2016/9/17

N2 - Background Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. Methods We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10–35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01124838. Findings Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77–357) in the placebo group and 245 days (119–564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39–0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group). Interpretation Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis. Funding AbbVie.

AB - Background Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. Methods We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10–35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01124838. Findings Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77–357) in the placebo group and 245 days (119–564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39–0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group). Interpretation Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis. Funding AbbVie.

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