Adalimumab vs. Conventional Immunosuppression for Uveitis Trial (ADVISE)
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|ClinicalTrials.gov Identifier: NCT03828019|
Recruitment Status : Recruiting
First Posted : February 4, 2019
Last Update Posted : November 21, 2019
|Condition or disease||Intervention/treatment||Phase|
|Uveitis||Biological: Adalimumab (ADA) Drug: Conventional immunosuppression (CON)||Phase 3|
Abstract from protocol: The uveitides are a collection of diseases characterized by intraocular inflammation. Collectively, they are the 5th leading cause of blindness in the US, and the estimated cost of treating them is similar to that of treating diabetic retinopathy. Non-infectious intermediate, posterior, and panuveitides have the highest rates of visual loss and typically are treated with oral corticosteroids and immunosuppression. The Multicenter Uveitis Steroid Treatment (MUST) Trial (a randomized, comparative effectiveness trial, which compared 2 treatment paradigms for these diseases, systemic therapy with corticosteroids and immunosuppression vs. regional therapy [the fluocinolone acetonide implant]), and Follow-up Study demonstrated the superiority of the systemic approach to the regional ocular approach in terms of long-term visual outcomes with essentially no increase in systemic side effects in the systemic group. One key to systemic therapy's success was the use of systemic immunosuppression in 88% of participants, coupled with tapering the prednisone to <7.5 mg/day, a relatively safe dose. Non-alklyating agents are typically the first choice and the most often used are azathioprine, methotrexate, mycophenolate, cyclosporine, and tacrolimus. The alkylating agents, cyclophosphamide and chlorambucil, are used less often because of concerns about potential increased malignancy risk. Data from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study suggest that each of the conventional, non-alkylating agent immunosuppressive drugs is effective in controlling the inflammation while permitting tapering prednisone in ~40-55% of patients; hence combination therapy often is needed. Furthermore, minimizing the daily dose of prednisone is important, as the risk of cardiovascular disease and mortality increase with the cumulative dose of oral corticosteroids. In June 2016, the fully-human, anti-TNF-α monoclonal antibody, adalimumab, was approved by the US Food and Drug Administration (FDA) for the treatment of uveitis. Anti-TNF-α monoclonal antibody therapy has revolutionized the management of the rheumatic diseases largely due to its superior efficacy compared to conventional Disease Modifying Anti-Rheumatic Drugs. Data from VISUAL III, the extension of the two phase 3 trials that led to the FDA approval of adalimumab for the treatment of uveitis, suggest that adalimumab may be superior to conventional immunosuppression, as ~75% of participants had controlled inflammation with prednisone doses <5 mg/day. The ADalimumab Vs. conventional ImmunoSupprEssion for uveitis (ADVISE) Trial is a randomized, comparative effectiveness trial comparing adalimumab to conventional agent immunosuppression for patients with non-infectious, intermediate, posterior, and panuveitides. The primary outcome is the ability to successfully taper prednisone to <7.5 mg/day by 6 months after randomization while maintaining control of the inflammation. Secondary outcomes include prednisone discontinuation by 1 year, visual acuity, and complications of uveitis and its treatment.
ADVISE is being conducted under IND 132532. Adalimumab was FDA approved for the treatment of non-infectious intermediate, posterior, and panuveitides in adult patients in 2016 and in pediatric patients 2 years of age and older in 2018. In 2016, prior to the approval for pediatric patients, the FDA determined that use of adalimumab for the treatment of non-infectious intermediate, posterior, and panuveitides in adolescent patients in the ADVISE Trial does not increase risk for these patients as the drug is approved for treatment of pediatric patients for other indications. Although conventional immunosuppressive drugs are the standard approach and in widespread use, these drugs are not FDA approved for treatment of non-infectious intermediate, posterior, and panuveitides, and therefore an IND has been issued for this trial.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||222 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Randomized treatment assignment with allocation ratio: 1:1 and two stratification variables: (1) number of immunosuppressive drug patient is on at time of enrollment (zero vs. one); (2) Initial dose of prednisone patient will be on in trial (<30 mg/day vs. ≥30 mg/day). The unit of randomization is the patient,|
|Masking:||None (Open Label)|
|Masking Description:||Unmasked treatment administration and outcome assessments (participants, study ophthalmologists, visual function examiners, and study coordinators are all unmasked). Masked assessment of baseline, 1-month, 3-month, and 6-month photographic images and OCT by the Reading Center (graders masked).|
|Official Title:||Adalimumab vs. Conventional Immunosuppression for Uveitis Trial|
|Actual Study Start Date :||August 19, 2019|
|Estimated Primary Completion Date :||August 30, 2022|
|Estimated Study Completion Date :||February 28, 2023|
Active Comparator: Adalimumab (ADA)
Adalimumab administered by subcutaneous injection at dosage and frequency specified below; total duration of treatment is 12 months.
Adults (≥ 18 years of age) and adolescents ≥30 kg: 80 mg as initial dose; one week later by 40 mg then 40 mg every two weeks. Adolescents <30 kg: 40 mg as initial dose; one week later 20 mg then 20 mg every 2 weeks.
Biological: Adalimumab (ADA)
Adalimumab is a fully-human monoclonal antibody to TNF-α, which is approved by the U.S. FDA for the treatment of non-infectious intermediate, posterior, and panuveitides in adults and children 2 years of age and older.
Other Name: Adalimumab, Humira
Active Comparator: Conventional immunosuppression (CON)
Conventional immunosuppressive agent selected by study ophthalmologist at dose and frequency specified below;12 month treatment duration.
Azathioprine: initially 2 mg/kg/day; max dose 200 mg/day. Methotrexate initially 15mg/wk; max dose 25 mg/wk. Mycophenolate initially 1 gm BID; max dose1.5 gm BID. Cyclosporine (Sandimmune - dose 2.5 mg/kg BID and Neoral dose 2 mg/kg BID. Tacrolimus initially 1 mg BID; max dose 3 mg BID.
Drug: Conventional immunosuppression (CON)
The study ophthalmologist will select amongst the permissible drugs (methotrexate, mycophenolate mofetil or azathioprine for antimetabolites; cyclosporine or tacrolimus for calcineurin inhibitors) taking into account the side effect profile of each drug with respect to subject's clinical situation.
- Corticosteroid-sparing treatment success within the first 6 months after randomization [ Time Frame: 6 months ]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.
- Corticosteroid-sparing treatment success within the first 12 months after randomization [ Time Frame: 12 months ]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.
- Prednisone discontinuation success [ Time Frame: 12 months ]Prednisone 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.
- Prednisone exposure [ Time Frame: 12 months ]E.g., cumulative prednisone dose and/or mean prednisone dose
- Best corrected visual acuity [ Time Frame: 12 months ]Best corrected visual acuity measured after a standardized refraction using logarithmic visual acuity charts
- Infections [ Time Frame: 12 months ]Incidence of infections over 12 months of follow-up
- Systemic adverse events [ Time Frame: 12 months ]Systemic adverse events over 12 months of follow-up
- Macular edema [ Time Frame: 12 months ]Macular edema over 12 months of follow-up
- Health utility [ Time Frame: 12 months ]Health utility will be measured using the EQ-5D
- Generic health-related quality of life [ Time Frame: 12 months ]Generic health-related quality of life will be measured using the SF-36
- Vision-related quality of life [ Time Frame: 12 months ]Vision-related quality of life will be measured using the NEI-VFQ-25
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03828019
|Contact: Janet T Holbrook, PhD MPHemail@example.com|
|Contact: Elizabeth A Sugar, PhDfirstname.lastname@example.org|
|Study Chair:||Douglas A Jabs, MD MBA||CCTand Evidence Synthesis, JHU, Bloomberg School of Public Health|