Article Text

Extended report
ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis
1. Pierre Quartier1,2,3,4,
2. Amandine Baptiste5,
3. Véronique Despert6,
4. Emma Allain-Launay7,
5. Isabelle Koné-Paut8,
6. Alexandre Belot4,9,
7. Laurent Kodjikian10,
8. Dominique Monnet3,11,
9. Michel Weber12,
10. Caroline Elie5,
11. Bahram Bodaghi13
12. On behalf of the ADJUVITE Study Group
1. 1 Pediatric Immunology-Hematology and Rheumatology Unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hopitaux de Paris, Paris, France
2. 2 Imagine Institute, Paris, France
3. 3 Paris Descartes University, Paris, France
4. 4 Pediatric Rheumatology and Systemic Auto-immune Diseases, RAISE National Reference Centre, Rennes, France
5. 5 Clinical Research Unit/CIC Paris Descartes, Necker-Enfants Malades-Cochin University Hospital, Paris, France
6. 6 Pediatric Department, Rennes University Hospital, Rennes, France
7. 7 Pediatric Department, University Hospital of Nantes, Nantes, France
8. 8 Pediatric Rheumatology Department, Kremlin-Bicêtre, Assistance Publique-Hopitaux de Paris, University of Paris-Sud, Orsay, France
9. 9 Pediatric Nephrology, Rheumatology, Dermatology, University of Lyon, INSERM U1111, Lyon, France
10. 10 Ophthalmology, Croix-Rousse University Hospital, Lyon, France
11. 11 UMR-CNRS 52, University Hospital Cochin, Assistance Publique-Hopitaux de Paris, Nantes, France
12. 12 Department of Ophthalmology, University Hospital Hotel Dieu, Nantes, France
13. 13 Department of Ophthalmology, University Hospital Pitie-Salpetriere, Paris, France
1. Correspondence to Professor Pierre Quartier, Pediatric Immunology-Hematology and Rheumatology Unit, Necker-Enfants Malades University hospital, Assistance Publique-Hopitaux de Paris, Paris 75015, France; pierre.quartier{at}nck.aphp.fr

## Abstract

Objectives To assess the efficacy and safety of adalimumab on uveitis in patients with early onset, chronic, juvenile idiopathic arthritis (JIA)-associated or idiopathic anterior uveitis and an inadequate response to topical steroids and methotrexate (MTX).

Methods Patients aged 4 years or more with ocular inflammation quantified by laser flare photometry (LFP) ≥30 photon units/ms were double-blindly randomised (1:1) to 2 groups, one treated with placebo and one with adalimumab subcutaneously at a dose of 24 mg/m2 in patients aged <13 years, 40 mg in the others, every other week. The primary outcome was response at month 2 (M2) defined as a 30% reduction of inflammation on LFP in the assessable eye with more severe baseline inflammation and no worsening on slit lamp examination. From M2 to M12, all patients received adalimumab.

Results At M2, among 31 patients included in intention-to-treat analysis, there were 9/16 responders on adalimumab and 3/15 on placebo (P=0.038, Χ2 test; relative risk=2.81, 95% CI 0.94 to 8.45; risk difference: 36.3%, 95% CI 2.1 to 60.6); there was no significant difference using the Standardised Uveitis Nomenclature classification criteria of improvement. Thirty patients continued the trial after M2 and received adalimumab (open-label phase), 29 reached M12. There were seven serious adverse events none related to study treatment.

Conclusions This trial is in favour of using adalimumab in patients with early onset, chronic anterior uveitis, which is in most cases associated with JIA, in case of inadequate response to topical therapy and MTX. LFP could be a valuable tool to assess early treatment efficacy.

Trial registration number NCT01385826.

• Anti-tnf
• Juvenile Idiopathic Arthritis
• Treatment
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## Introduction

More than 20% of children with early onset (usually before 6 years), rheumatoid factor negative polyarticular or oligoarticular juvenile idiopathic arthritis (JIA), and some children without arthritis, most of them with non-specific antinuclear antibodies develop chronic, remitting, anterior uveitis.1 Most of them require long-lasting local steroid treatment or even oral and pulsed intravenous steroids. Severe complications develop in many cases due to long-lasting ocular inflammation and steroid treatment.2–7 Treatment with methotrexate (MTX) has been reported with an improvement of uveitis and a reduction of the number of flares8–11; however, many patients do not respond adequately.12 Adalimumab is an antitumour necrosis factor-α (anti-TNF-α) antibody that demonstrated its efficacy on arthritis, alone or in association with MTX, in children with JIA and a polyarticular course in the absence of active uveitis.13 In patients with JIA-associated uveitis and an inadequate response to MTX and topical steroids, several uncontrolled studies are in favour of using adalimumab.14–25 In such patients, the randomised placebo-controlled SYCAMORE trial recently demonstrated that adding adalimumab to MTX was effective in preventing treatment failure.26 The assessment of ocular inflammation was based on grading the cellularity of the anterior chamber of the eye by slit lamp (SL), using definitions of improvement or worsening according to the Standardised Uveitis Nomenclature (SUN) classification.27 Treatment failure was defined by a set of criteria that included presence on two consecutive assessments of high-grade uveitis activity at 3 months or later, uveitis worsening, new-onset or worsening of uveitis complication. Patients were followed until treatment failure or for 18 months. Treatment failure was observed in 16 out of 60 patients on adalimumab versus 18 out of 30 on placebo, which was highly significant.

Grading uveitis activity by SL may lack sensitivity to document improvement, particularly in patients with chronic active uveitis but low cell counts. Laser flare photometry (LFP), which measures the anterior chamber protein flare in an objective and sensitive manner, has previously shown its reliability to assess the degree of ocular inflammation, the prognosis of uveitis and the effect of treatments.28–33

Although neither the SUN criteria nor LFP has been validated in paediatric uveitis, experts are in favour of using the SUN criteria as an important outcome measure and consider LFP as a tool for clinical trials.33 34 Based on preliminary experience of ophthalmologists, we designed a double-blind randomised trial, which objective was to assess adalimumab efficacy versus placebo on uveitis over a period of 2 months by using LFP in addition to SL examination in patients with early onset, chronic anterior uveitis and an inadequate response to topical steroids and MTX.

## Methods

### Study design and participants

This was a double-blind, 1:1 randomised, placebo-controlled multicentre phase III trial that aimed at assessing the efficacy of 2 months of adalimumab treatment, with then an open-label period where all patients were followed up under adalimumab for an extra 10 months.

The trial involved nine French tertiary care centres for paediatric rheumatology and seven associated ophthalmologic centres experienced in using LFP in children.

An independent data and safety monitoring board was appointed for this trial. The study is registered at ClinicalTrials.gov under number NCT01385826.

Eligibility criteria are listed in online supplementary table S1. Patients aged at least 4 years had chronic, active anterior uveitis (defined by an inflammation of at least 30 ph/ms quantified with LFP) associated with JIA or idiopathic, and an inadequate response to well-conducted topical steroid therapy and MTX at a dose of 0.3–0.6 mg/kg (without exceeding 25 mg) once a week for at least 3 months.

### Supplementary file 1

Major exclusion criteria were: systemic-onset, rheumatoid factor positive or enthesitis-related JIA, previous treatment with anti-TNF monoclonal antibody, any contraindication to administration of immunosuppressive therapy, complications requiring surgery.

### Treatment and procedures

An initial screening visit aimed to assess patient eligibility and present the study to the patient and its parents. After signing the informed consent form, patient was examined by an investigator ophthalmologist and a rheumatologist or paediatrician experienced in paediatric rheumatology, then biologic tests and other investigations required to confirm eligibility were performed (see online supplementary table S2). Inclusion visit could occurred from 2 days to 1 month later. When inclusion was confirmed, patients were randomly assigned (1:1) to receive either adalimumab or placebo. Patients on MTX were maintained on stable dose. The random assignment sequence stratified on age (<13 or ≥13 years) and using blocks of size four was computer-generated at Paris Descartes Clinical Research Unit. Patient received placebo or adalimumab at a dose of 24 mg/m2 in patients aged <13 years, 40 mg in patients aged ≥13 years, every other week subcutaneous injections. Blinded injections were realised in consultation at day (D)0, D14, month (M)1 visit and at home at D42.

The double-blind phase lasted from D0 until M2, except in the case of dropout from the trial. From visit M2, all patients who continued the trial received adalimumab treatment during 10 months (open-labelled phase). Visits were held at M3, M4, M6, M9 and M12.

At each visit, there was an assessment by two investigators, first an ophthalmologist, then a paediatrician or a rheumatologist, to check the absence of contraindication to maintain the patient in the trial and to assess treatment tolerance. These two assessors were blinded to each other following D0 visit and the first injection of study treatment. Particular attention was demanded for patients who presented a significant worsening of ophthalmological condition or any other condition that justified rescue therapy.

Online supplementary table S2 details the clinical assessment performed by the ophthalmologist and an investigator paediatrician or rheumatologist, the assessment of JIA response or flare using the JIA American College of Rheumatology (ACR) core-set criteria35 36 and the laboratory tests.

#### Primary and secondary outcomes

The primary outcome was response to treatment at the end of double-blind period (M2), defined as a reduction of at least 30% of ocular inflammation quantified by LFP without worsening of cell counts or protein flare on SL examination according to SUN criteria, in the assessable eye with more severe baseline inflammation. The method of analysis by LFP is described in online supplementary table S3.

Secondary outcomes included assessment of treatment efficacy on ocular inflammation quantified by SL examination and LFP at each visit (using 30%, 50% and 70% threshold to define response), modifications of the dose of topical and/or systemic steroid therapy between M2 and M12, JIA response or flare using the paediatric ACR core-set criteria, assessment of treatment safety at M2 and until M12, with adverse events (AE) reported according to the MedDRA dictionary and a peculiar attention to any AE of special interest, such as neoplasia, opportunist infection or occurrence of a new inflammatory disease.

At each visit, both the eye of the primary outcome and the fellow eye were evaluated.

### Statistical analysis

Our study was designed to detect a response rate to treatment 40 percentage points upper in adalimumab group at the end of double-blind period (ie, equal to 50%), assuming a response of 10% under placebo. With a two-sided alpha risk equal to 5% and 80% power, 19 patients randomised per group were required. A total enrolment of 40 patients was thus planned.

All statistical analyses were undertaken using R V.2.11.1 software, and in accordance with the statistical analysis plan prespecified before the lock of the database. Statistical tests were two-sided and P values <0.05 were considered statistically significant. Baseline characteristics of the two groups were described as median (range) for quantitative variables and frequencies (%) for qualitative variables.

Our intention-to-treat (ITT) population consisted in all randomised participants who received at least one injection of trial medication. A per-protocol population was also defined, including all randomised patients without violation of eligibility criteria, who properly had their planned injections until the end of double-blind period and whose primary outcome is evaluable.

Primary outcome was compared between groups using Χ2 test. Primary analysis was done on the ITT population, with patients who prematurely ended double-blind period or non-assessable patients considered as non-responders. No other imputation method of missing data was considered due to the small sample size. Treatment effect size was presented as a relative risk and 95% CI using a log-binomial regression model. To investigate the consistency of results, an analysis on per-protocol population was also performed.

Secondary outcomes and safety data related to the double-blind period were compared between groups using Χ 2 test (or Fisher’s exact test when it was appropriate) and Student’s t-test (or Wilcoxon test for non-normally distributed variables). No formal adjustment was made to any P values to allow for the large number of secondary end points analysed, and thus P values for secondary analyses need to be interpreted conservatively. Secondary outcomes and safety data related to the open-label period were not compared but only described globally and according to previous allocated group in all patients from their first administration of open-label treatment.

## Results

From June 2011 to August 2014, 32 patients were randomised in five centres. Enrolment was slower than anticipated and we could not extend the trial duration to reach the number of patients expected.

All but one patient received at least one study treatment injection; the latter withdrew from study before the first administration and was thus excluded from ITT population. Two other patients were included with baseline LFP value inferior to 30 ph/ms, hence not respecting one of the inclusion criteria, both in the adalimumab arm; they were excluded from per-protocol population (figure 1). Patients baseline characteristics are shown in table 1. Some differences between both group can be noticed such as the proportion of patients with bilateral uveitis, cataract or on MTX treatment at baseline.

Figure 1

Patients flow chart. D, day; JIA, juvenile idiopathic arthritis; LFP, laser flare photometry ; M, month.

Table 1

Patients characteristics at study treatment onset

### Double-blind period (D0-M2)

Five patients prematurely ended double-blind period, one in the adalimumab arm, four in the placebo arm (Figure 1). Four of these five patients had a premature M2 visit but continued the open-label phase of trial under adalimumab afterwards. One patient from the placebo arm, with a past history of ocular hypertonia definitively ended the trial at D14 for marked hypertonia that was documented as a serious AE (SAE).

For primary outcome analysis, as shown in table 2, there were in ITT 9/16 responders (56%) in the adalimumab arm and 3/15 (20%) in the placebo arm (P=0.038, Χ2 test; relative risk (RR)=2.81 (95% CI 0.94 to 8.45)). As two non-responders from adalimumab arm had violation of inclusion criteria (baseline LFP value <30 ph/ms), in per-protocol population, there were 9/14 responders (64%) on adalimumab and 3/15 responders (20%) on placebo (P=0.015, Χ 2 test; RR=3.21 (95% CI 1.09 to 9.51)).

Table 2

Responses at month 2 (end of double-blind period)

Changes in topical steroid therapy in the eye evaluated for the primary outcome was documented in four patients from screening to M2. In two responders on placebo, the number of eye drops was increased from 1 to 3 and 5 drops, respectively at or before screening visit. In a non-responder patient on adalimumab, the number of drops had been decreased from 3 to 2 after screening visit. Finally, in one non-responder patient on placebo the number of eye drops had been decreased from 3 to 2 in both eyes between D14 and M1.

Among M2 responders, two patients were responders from D14 (one patient on adalimumab, one on placebo) and six from M1 (five on adalimumab, one patient on placebo). Fifty per cent improvement on LFP from baseline was documented at M1 in two patients on adalimumab, at M2 in four patients on adalimumab and two on placebo; 70% improvement was documented at M2 in three patients on adalimumab.

Worsening in SL cellular as defined by the SUN occurred in one patient from placebo group (who was non-responder according to LFP measurements) at M2. There was no significant difference between both arms regarding the proportion of patients who disclosed improvement according to the SUN criteria from D0 to M2 in SL cellular or protein grading (table 2).

A JIA flare (ACR 70 criteria) was observed in one patient under placebo at D14; there was no significant change in this patient regarding ophthalmologic assessment.

### Open-label phase (M2-M12)

Among 30 patients who entered the open-label phase of trial after M2 visit, one discontinued 5.8 months later due to a flare of both uveitis and arthritis; the other 29 patients reached M12 under adalimumab.

Figure 2A,B show at each visit and for each patient the changes of anterior chamber flare measured by LFP. Among 45 eyes with LFP >10 ph/ms at M2, 36 were assessable at M12 and 17 had improved by 30% or more compared with M2. Online supplementary table S4 indicates the main changes regarding outcome measures and steroid therapy at M3 in patients who had been on adalimumab since D0 and at M12.

A JIA flare (ACR 70 criteria) was observed at M12 in one patient.

### Safety

In addition to the SAE that occurred during the double-blind phase, six SAEs occurred during the open-labelled phase, all in patients who were initially randomised to placebo. No SAE was related to study treatment and their outcome was favourable in all cases. Regarding non-SAEs, there were equally distributed between both groups during the double-blind phase and no event of special interest was reported (table 3 and supplementary table S5).

Table 3

## Discussion

In patients with early onset idiopathic or JIA-associated chronic uveitis and an inadequate response to topical steroids and MTX, 2 months of treatment with adalimumab was effective in reducing ocular inflammation compared with placebo, as assessed by 30% improvement or more of anterior chamber inflammation on LFP and improvement or stable appearance on SL examination. Over 12 months, all patients but two continued adalimumab, which was well tolerated and associated with persistent uveitis improvement in most cases.

The result of the primary end point should be interpreted with caution given the small size of this study. This is also reflected by the wide CI RR which contains 1. However, this CI is narrower when recalculated with a more appropriate method for small samples (Koopman asymptotic score),37 38 RR=2.81 (1.05–8.50).

Combining LFP to SL examination, we were able to document early improvement on adalimumab. This would not have been feasible using only SL examination based on SUN criteria in our population of patients who had in most cases low or relatively low cell counts, as can be expected nowadays for patients carefully followed by their ophthalmologist. On the other hand, only few ophthalmologists were equipped with LFP and experienced using it in children when we started the trial, which limited both the number of participating centres and the number of patients we were able to enrol, hence reducing the power to detect a difference between groups. Proposing a 30% decrease of anterior chamber flare to define significant LFP improvement was based on the experience of expert ophthalmologists and ended up being a reasonable target, even if more patients on placebo than expected reached it. Interestingly, the observation that patients with very high LFP could be quick responders but that some patients with relatively mild inflammation on LFP at study entry needed more than 2 months to reach 30% improvement suggests that a longer period could be required to document significant improvement in such patients.

The proportion of M2 responders may have been influenced in favour of the placebo arm by a marked increase in the number of drops at or before screening visit in the eye of the primary outcome in two patients from the placebo group who responded from D14. Although clinically justified from an ophthalmologic point of view, such significant modifications of local therapy most likely negatively affected the trial results.

The latest follow-up data are encouraging as 29 out of 31 patients were still on adalimumab and most had no more inflammation or less inflammation than at study entry. In addition, most patients on oral steroids had stopped or decreased this treatment. Also, most of patients had stopped local treatment or decreased the number of drops between M2 and M12. This is particularly important as persistent, long-lasting inflammation and local steroids therapy are associated with a high risk of complications in young adults.2–7

Safety data were reassuring as there was no SAE or AE of special interest that were related to adalimumab therapy, most SAEs being linked to the underlying disease and to complications that had developed before trial onset, particularly ocular hypertonia. Therefore, starting adalimumab at an earlier stage might be worth considering in the future. However, this was a small series with a relatively short follow-up and the risk of AEs including severe infections, although relatively low, has been well documented in children as in adults on anti-TNF-α treatment.39

Our results confirm several observational series of patients, who showed that anti-TNF-α antibodies, could be associated with a reduction of inflammation and of the number of uveitis flare.14–25 While the SYCAMORE trial aimed to demonstrate that adalimumab could prevent treatment failure, and indeed demonstrated in a double-blind randomised fashion in a large number of patients that adalimumab was superior to placebo in either reducing inflammation or avoid uveitis worsening within 3 months and well tolerated over 12 months,26 ADJUVITE aimed to demonstrate early uveitis improvement on adalimumab. In addition to conforming the results of SYCAMORE on several common outcome measures, ADJUVITE showed that LFP assessment, which detects inflammation even in patients with low-grade inflammation and sometimes no cells on SL examination as shown by response to maximised therapy,33 enables an earlier documentation of improvement on adalimumab therapy. This could help to decide after a few months (2 months in the patients with high LFP values at treatment onset, possibly more in the other patients), if adalimumab therapy should be continued or other treatments discussed.

In conclusion, this trial is in favour of using adalimumab in patients with early onset, chronic anterior uveitis, which is in most cases associated with JIA, in case of inadequate response to topical therapy and MTX. It also suggests that LFP could be a valuable tool to assess early treatment efficacy.

Figure 2

Values of the anterior chamber flare measured by laser flare photometry (ph/ms) visit after visit in each patient; (A) patients of the adalimumab group and (B) patients of the placebo group. In blue, eye of the primary outcome and in dotted green the fellow eye. The dotted vertical line indicates the M2 visit (primary end point visit) and the dotted horizontal line indicates for each patient the threshold of 30% improvement compared with baseline (day 0) visit for the eye of the primary outcome.

## Acknowledgments

The authors would like to thank the members of the independent data safety monitoring committee: Rolando Cimaz, Yan Guex-Crosier and Michael Hofer, the members of the Assistance Publique Hôpitaux de Paris Clinical Research Development Department and Agence générale des équipements et produits de santé: Christine Lanau, Aurelie Guimfack, Blandine Lehman, Florence Capelle, Kamyl Baghli, colleagues and member of the clinical trial units: Isabelle Marie, Alexandre Vallon, Behrouz Kassai, Marie Desgranges, Agnès Mogenet, Mame Diagne, Solimda Sotou-Bere, Laurence Lecomte, Christelle Turuban, Elodie Henry, Sophie Pfister, Neila Iken, Celine Hauw, Ngoc-Phoi Duong, Jean-Marc Treluyer.

## References

View Abstract

## Footnotes

• Handling editor Tore K Kvien

• Contributors All authors were involved in drafting the article or revising it critically for important intellectual content and approved the final manuscript to be submitted and agreed to be accountable for all aspects of the work. Conception and design of the study: PQ, BB. Acquisition of data: PQ, VD, EAL, IK-P, AB, LK, DM, MW, BB and the ADJUVITE Study Group. Analysis and interpretation of data: PQ, AB, CE and BB.

• Funding Assistance Publique-Hôpitaux de Paris Clinical Research and Development Department (PHRC 2009 01-48).

• Competing interests PQ has received speakers’s fees (<US$10 000) from AbbVie, Novartis, Pfizer, Roche and SOBI, grants from AbbVie, Pfizer and Novartis, payment for lecture (<US$10 000) from Novartis, personal fees for consultancy (<US$10 000) from AbbVie, Novartis, Novimmune and Sanofi, invitation to congress from AbbVie, BMS, Novartis, Pfizer, Roche and SOBI and has participated as an investigator to clinical trials from AbbVie, BMS, Novartis, Pfizer, Roche and Sanofi. IK-P has received speakers fees (<US$10 000) from AbbVie, Chugai, LFB, Novartis, Pfizer and SOBI, grants from Roche and SOBI, payment for lectures (<US$10 000) from Novartis and SOBI, personal fees for consultancy (<US$10 000) from AbbVie, LFB, Novartis, Novimmune, Pfizer and SOBI, invitation to congress from Novartis and Pfizer and has participated as an investigator to clinical trials from AbbVie, BMS, Novartis, Pfizer, Roche. AB has received invitation to congress from Novartis. LK has received personal fess for consultancy (<US$10 000) from AbbVie, Alcon, Allergan , Bayer, Horus, Novartis, Roche and Théa. DM has received speakers fees (<US$10 000) from AbbVie. MW has participated as an investigator to a clinical trial from AbbVie. BB has received grants from Bayer and Novartis, and personal fees for consultancy (<US\$10 000) from AbbVie, Allergan and Santen.

• Patient consent Obtained.

• Ethics approval The protocol was approved by the ethics committee ’Comité pour la protection des Personnes Ile de France IV' and by the French agency for security of health products (AFSSAPS) in 2010.

• Provenance and peer review Not commissioned; externally peer reviewed.

• Collaborators The ADJUVITE Study Group: Brigitte Bader-Meunier, Christelle Bonifas-Rodier, Antoine Brezin, Chloé Couret, Emmanuelle Delair, Marie Desgranges, Agnès Duquesne, Perrine Dusser, Christine Fardeau, Marine Fouillet-Desjonqueres, Caroline Galeotti, Olivier Lebreton, Phuc LeHoang, Candice Meyzer, Richard Mouy, Sylvaine Poignant, Linda Rossi-Semerano, Michaela Semeraro, Soizic Tiriau, Carine H Wouters.

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