Protocolversion1.0

Johns Hopkins Bloomberg SPH

410 N Washington Street, Baltimore, United States, 21231

Elizabeth Sugar, PhD, Johns Hopkins Bloomberg School of Public Health (SPH), +1 410 614 7837, esugar2@jhu.edu

Elizabeth Sugar, PhD, Johns Hopkins Bloomberg School of Public Health (SPH), +1 410 614 7837, esugar2@jhu.edu

No

No

No

Final

09 Sep 2024

Yes

09 Sep 2024

Yes

09 Sep 2024

No

The ADVISE Trial is a randomized, parallel-treatment, comparative effectiveness trial, comparing adalimumab to conventional immunosuppression for the treatment of non-infectious, intermediate, posterior, and panuveitides. Based on the preliminary data we assume that adalimumab will be superior to conventional immunosuppression for successful corticosteroid-sparing with no clinically important increase in uveitis symptoms namely inactive uveitis and prednisone <7.5 mg/day for 2 visits >28 days apart by 6 months of follow-up.

The protocol and consent were approved by the IRB/Ethics of participating centers before beginning recruitment of patients. All participants signed a consent statement and medical record release form as well as HIPAA – complaint privacy practices acknowledgment prior to participation in the study. Surveillance of uveitis and treatment complications is conducted throughout the study; any such complications encountered are managed by the best medical judgment of the treating ophthalmologist. These events are recorded on study data forms and are submitted to the CC. Summaries of these data are reviewed by the DSMC at each meeting. Important, serious, or unusual adverse events require expedited reporting to the CC and are reviewed by the CC Safety Officer, who makes the determination as to whether the event meets the criteria for a safety report and whether expedited review by DSMC Safety Officer is warranted. The CC Safety Officer follows all serious adverse events through resolution. All serious and unexpected events possibly related to uveitis treatment will be reported as safety reports to the NEI project officer, the FDA, the pharmaceutical supplier (where appropriate), and all clinical centers in accordance with FDA regulations. The CC and clinical centers will submit all safety reports as expedited reports to their IRBs. Reports of serious events not deemed to be unexpected will be submitted to the CC IRB, to the IRB of the clinical center in which the event was reported, as well as to any other study center IRBs, which require such reports. Confidentiality of patient data will be maintained in accordance with legal regulations. Protected health information (PHI) not be transmitted to the CO, CC, RC, or to other ADVISE sites. PHI collected for study purposes, possibly including name, social security number, address, and other such personal data will be kept solel

19 Aug 2019

No

Yes

United Kingdom: 12

Australia: 23

United States: 192

227

0

0

0

0

0

0

3

199

25

0

Overall study 12 months (overall period)

Randomised - controlled

Visual acuity and ophthalmic reading center graders were masked as to treatment assignment

Yes

Adalimumab

Humira

Injection

Injection

Adalimumab administeredby subcutaneous injectionat dosage and frequencyspecified below; totalduration of treatment is 12months. Adults (≥ 18 years of age)and adolescents ≥30 kg:80 mg as initial dose; oneweek later by 40 mg then40 mg every two weeks.Adolescents <30 kg: 40 mgas initial dose; one weeklater 20 mg then 20 mgevery 2 weeks. Adalimumab (ADA):Adalimumab is a fully-human monoclonalantibody to tumor necrosisfactor (TNF-α), which isapproved by the U.S. FDAfor the treatment of non-infectious intermediate,posterior, and panuveitidesin adults and children 2years of age and older

Azathioprine:

Imuran

Tablet

Oral use

initially 2mg/kg/day; max dose 200mg/day.

Methotrexate

Tablet, Injection

Oral use, Injection

Methotrexate initially 15mg/wk; max dose25 mg/wk.

Mycophenolate

CellCept

Tablet

Oral use

Mycophenolateinitially 1 gm twice a day(BID); max dose1.5 gmBID

Cyclosporine

Sandimmune, Neoral

Tablet

Oral use

dose 2.5mg/kg BID

Tacrolimus

Prograf

Tablet

Oral use

initially 1 mg BID; max dose 3 mg BID.

Adalimumab (ADA)

Conventional Immunosuppression (CID)

Eyes with uveitis from Arm 1 (ADA)

Eyes with uveitis from participants assigned to ADAL. Each patient can contribute one or both eyes to the analysis set. Randomization was per person.

Eyes with uveitis from Arm 2 (CID)

Eyes with uveitis from participants assigned to ADAL. Each patient can contribute one or both eyes to the analysis set. Randomization was per person.

Adalimumab (ADA)

Conventional Immunosuppression (CID)

Eyes with uveitis from Arm 1 (ADA)

Eyes with uveitis from participants assigned to ADAL. Each patient can contribute one or both eyes to the analysis set. Randomization was per person.

Eyes with uveitis from Arm 2 (CID)

Eyes with uveitis from participants assigned to ADAL. Each patient can contribute one or both eyes to the analysis set. Randomization was per person.

Corticosteroid-sparing success is defined as achieving inactive uveitis for two consecutive visits >= 28 days apart while on <= 7.5 mg/day of corticosteroids. Uveitis status (active vs inactive) is determined by the study ophthalmologist after reviewing the eye exam and imaging. Steroid dose and uveitis activity from visit months 6,8,10 and 12 were included in the analysis. Generalized estimating equations were used to fit logistic regression models to compare the cumulative proportion of corticosteroid sparing between the two treatment groups over time while accounting for correlation between replicate measurements on the same individual with an unstructured covariance matrix. Results were reported at 6 months (primary outcome) and 12 months (secondary outcome).

Primary

At 6 months

Odds ratio ADA / CID Generalized estimating equations were used to fit logistic regression models to compare the cumulative proportion of corticosteroid outcomes (sparing and cessation) between the two treatment groups over time while accounting for correlation between replicate measurements on the same individual with an unstructured covariance matrix

Adalimumab (ADA) v Conventional Immunosuppression (CID)

217

Pre-specified

1.86

2-sided

Corticosteroid discontinuation success is defined as achieving inactive uveitis for two consecutive visits >= 28 days apart after discontinuing corticosteroids. Uveitis status (active vs inactive) is determined by the study ophthalmologist after reviewing the eye exam and imaging. Steroid dose and uveitis activity from visit months 6,8,10 and 12 were included in the analysis. Generalized estimating equations were used to fit logistic regression models to compare the cumulative proportion of corticosteroid discontinuation between the two treatment groups over time while accounting for correlation between replicate measurements on the same individual with an unstructured covariance matrix. Results were reported at 6 months and 12 months.

Secondary

6 months

Greater that 1 indicates ADA was superior in participants achieving cessation of corticosteroid treatment

Adalimumab (ADA) v Conventional Immunosuppression (CID)

217

Pre-specified

1.53

2-sided

on <= 7.5 mg/day of corticosteroids. Uveitis status (active vs inactive) is determined by the study ophthalmologist after reviewing the eye exam and imaging. Steroid dose and uveitis activity from visit months 6,8,10 and 12 were included in the analysis. Generalized estimating equations were used to fit logistic regression models to compare the cumulative proportion of corticosteroid sparing between the two treatment groups over time while accounting for correlation between replicate measurements on the same individual with an unstructured covariance matrix. Results were reported at 6 months (primary outcome) and 12 months (secondary outcome).

Secondary

At 12 months

Odds ratio ADA / CID Generalized estimating equations were used to fit logistic regression models to compare the cumulative proportion of corticosteroid outcomes (sparing and cessation) between the two treatment groups over time while accounting for correlation between replicate measurements on the same individual with an unstructured covariance matrix

Adalimumab (ADA) v Conventional Immunosuppression (CID)

207

Pre-specified

1.89

2-sided

Corticosteroid discontinuation success is defined as achieving inactive uveitis for two consecutive visits >= 28 days apart after discontinuing corticosteroids. Uveitis status (active vs inactive) is determined by the study ophthalmologist after reviewing the eye exam and imaging. Steroid dose and uveitis activity from visit months 6,8,10 and 12 were included in the analysis. Generalized estimating equations were used to fit logistic regression models to compare the cumulative proportion of corticosteroid discontinuation between the two treatment groups over time while accounting for correlation between replicate measurements on the same individual with an unstructured covariance matrix. Results were reported at 6 months and 12 months.

Secondary

12 months

Greater that 1 indicates ADA was superior in participants achieving cessation of corticosteroid treatment

Conventional Immunosuppression (CID) v Adalimumab (ADA)

207

Pre-specified

1.85

2-sided

Mean change in best-corrected visual acuity from baseline to 12 months. Participants' visual acuity was measured by certified examiners with best refractive correction in place. Participants were challenged with reading letters on lines of the standard ETDRS eye chart (5 letters per line). Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until no more meaningful readings could be made and were scored by how many letters could be correctly identified. More letters read is associated with higher visual acuity (85 letters is 20/20 vision). Visual acuity data was collected at baseline and months 1,2,3,4,5,6,8,10, and 12 and estimated at 12 months with a mixed model.

Secondary

12 months

Mixed effects models were used with a linear link. The fixed effects included initial steroid dose and immunosuppression use at baseline. Additional visit indicators (months 1-12) and corresponding treatment by visit interaction terms. An unstructured correlation was used to model repeated measurements by eye . A person-level random intercept was added to account for between-eye correlations.

Eyes with uveitis from Arm 1 (ADA) v Eyes with uveitis from Arm 2 (CID)

386

Pre-specified

0.4

2-sided

Macular edema is defined as central retinal thickness greater than or equal to 300 micrometers as measured by a masked grader's review of OCT images. Greater retinal thickness is associated with poorer vision. Outcome measure is the odds ratio comparing macular edema at 12 months to baseline macular edema. Macular edema was measured at baseline and months 3, 6, and 12. The odds ratio at 12 months was estimated with a mixed model.

Secondary

12 months

Mixed effects models with a log link were used to assess treatment differences . The outcome measure was the odds ratio of having macular edema (OCT central subfield thickness > 300 um) at 12 months compared to baseline (BL). The treatment effect was the ratio of Odds ratios (ADA/CID) at 12 months. Values less than one indicate improvement in macular edema for the ADA treatment group relative to the CID group. Decrease in subfield thickness is good

Eyes with uveitis from Arm 1 (ADA) v Eyes with uveitis from Arm 2 (CID)

386

Pre-specified

0.55

2-sided

Cumulative proportion of participants having elevated levels of aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than twice the upper level of normal by 12 months. Elevated levels of AST and ALT may indicate decline in liver function. Lab values of AST and ALT were measured at baseline and months 1,2,3,4,5,6,8,10, and 12 and the cumulative proportion of participants with elevated lab values by 12 months was estimated by Kaplan Meier methods.

Secondary

12 months

Kaplan Meier techniques and Cox proportional hazards models were used to evaluate this outcome

Adalimumab (ADA) v Conventional Immunosuppression (CID)

221

Pre-specified

0.16

2-sided

Cumulative proportion of uveitis eyes having cataract surgery by 12 months. Whether the patient had cataract surgery in the prior time period was determined at baseline and months 1,2,3,4,5,6,8,10,12 and the cumulative proportion of eyes having cataract surgery by12 months was estimated by Kaplan-Meier methods

Secondary

12 months

Eyes with uveitis from Arm 1 (ADA) v Eyes with uveitis from Arm 2 (CID)

348

Pre-specified

0.21

2-sided

Over 12 months of study.

Non serious events were collected in both systemic and non-systemic forms. Systematic collections was asking participants if they experienced any new occurrence of a specify diagnosis, event, or side effect symptom on the case report form at each clinic visit. Non-systemic data was collected by asking if the patient experienced any other events.

4

All participants in Arm 1 with follow up after baseline visit

All participants in Arm 2 with follow up after baseline visit