REduCing Immunogenicity to PegloticasE (RECIPE) Study

Study Overview
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Brief Summary
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Pegloticase treatment for chronic refractory gout is limited by immunogenicity. The investigators propose the REduCing Immunogenicity to PegloticasE (RECIPE) trial to begin to investigate the question of whether a short course of immune modulating therapy with mycophenolate mofetil can significantly and safely attenuate immunogenicity to pegloticase and ensure patients afflicted with chronic refractory gout have better treatment outcomes and improved quality of life.

Detailed Description
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Pegloticase is highly efficacious therapy for chronic refractory gout patients (n = > 400K in the US alone). It decreases serum urate (sUA) levels to often undetectable levels and reduces tophi burden. However, its long-term real world effectiveness is severely limited due to its immunogenicity caused by anti-pegloticase antibody formation. REducing Immunogenicity to PEgloticase (RECIPE) is a Phase II, double-blind, placebo controlled, proof-of-concept trial in 32 subjects initiating pegloticase for treatment of chronic refractory gout. RECIPE will investigate the preliminary efficacy and safety of using immune modulating therapy with mycophenolate mofetil (MMF) to prevent immunogenicity conferred by pegloticase. Subjects will be randomized 3:1 to receive MMF vs. placebo in addition to everyone receiving pegloticase. The co-primary aims of the RECIPE trial are to 1) determine if a 12 week course of immune modulating therapy with daily MMF can safely and significantly attenuate immunogenicity to pegloticase as determined by the proportion of participants achieving and maintaining an sUA less than or equal to 6 mg/dL through 12 weeks, compared to concurrent controls, and 2) to assess the incidence and types of adverse events and infusion reaction. After 12 weeks of co-administration, all participants will continue on pegloticase for an additional 12 weeks without combination MMF immune modulating therapy to evaluate the longer term benefits (durability) and safety of this approach. The secondary aims are to: 1) Determine the 6 month durability of immune modulation after discontinuation of the short course of MMF by: a) assessing the absolute change in sUA from baseline to Week 24, and Week 12 to Week 24 and b) determining the proportion of participants with sUA ≤ 6 mg/dL through 24 weeks, and Week 12 to Week 24; 2) Identify and characterize the pegloticase immune response by immunoglobulin isotypes (IgG and IgM), specificities, and antibody titer; and 3) Examine patient reported outcomes (PROs) using the NIH supported Patient Reported Outcomes Measurement Information System (PROMIS) and Gout Impact Scale (GIS) instruments. The University of Alabama at Birmingham (UAB) and the University of Michigan (UM), two large academic gout and immunology research centers, which in aggregate see nearly 10,000 gout patients annually, will serve as the two lead study sites and are very well-positioned to address the clinical and immunologic questions posed.

Official Title
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REduCing Immunogenicity to PegloticasE (RECIPE) Study

Conditions
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Gout Chronic

Intervention / Treatment
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* Drug: Pegloticase 8 MG/ML [Krystexxa]
* Drug: MMF
* Drug: Placebo
* Drug: Pegloticase 8 MG/ML [Krystexxa]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women > 18 years of age Diagnosed with chronic refractory gout* Defined as: Persons whose signs and symptoms are inadequately controlled with urate lowering therapy (e.g. xanthine oxidase inhibitors or uricosuric agents) at a medically appropriate dose or for whom these drugs are contraindicated. Exclusion Criteria: Any serious acute bacterial infection (2 weeks prior to Visit 1), unless treated and completely resolved with antibiotics Severe chronic or recurrent bacterial infections (such as recurrent pneumonia, chronic bronchiectasis) Current immunocompromised condition, including current or chronic treatment with immunosuppressive agents Subjects at risk for tuberculosis. Specifically, subjects with: i) current clinical, radiographic or laboratory evidence of active or latent TB; ii) a history of active TB within the last 3 years even if it was treated; iii) a history of active TB greater than 3 years ago unless there is documentation that the prior anti-TB treatment was appropriate in duration and type Known Hepatitis B surface antigen-positive or Hepatitis B DNA positive subjects Known Hepatitis C RNA-positive subjects Human Immunodeficiency Virus (HIV) infection G6PD deficiency (tested at Screening Visit 1) Severe chronic renal impairment (glomerular filtration rate [GFR] <25 mL/min/1.73 m2) or currently on dialysis Subjects having any transplant surgery requiring maintenance immunosuppressive therapy Non-compensated congestive heart failure, uncontrolled arrhythmia, treatment for acute coronary syndrome (myocardial infarction or unstable angina), or hospitalization for congestive heart failure within 3 months of screening or uncontrolled blood pressure (>160/100 mm Hg) at baseline (Screening Visit 1 and Week 0/Baseline visits) Participants who are pregnant, planning to become pregnant, breastfeeding, or not on an effective form of birth control (defined in Study Protocol section 7.1) Prior treatment with pegloticase, another recombinant uricase, or concomitant therapy with a polyethylene glycol (PEG)-conjugated drug Known allergy to pegylated products or history of anaphylactic reaction to a recombinant protein or porcine product Subjects in whom MMF treatment is contraindicated or considered inappropriate Recipient of an investigational drug within 4 weeks prior to study drug administration or plans to take an investigational agent during the study Current liver disease as determined by alanine transaminase ALT or aspartate transaminase (AST) levels >3 times upper limit of normal Currently receiving treatment for ongoing cancer, excluding non-melanoma skin cancer History of malignancy within 5 years other than skin cancer or in situ carcinoma of cervix Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at screening Diagnosed osteomyelitis Individuals with hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) deficiency such as Lesch-Nyhan and Kelley-Seegmiller syndrome Not good candidate for the study based on opinion of the Investigator (e.g., cognitive impairment) that might create undue risk to the participant or interfere with the participant's ability to comply with the protocol requirements, or to complete the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase II, double blind, placebo controlled multisite proof-of-concept trial in subjects initiating pegloticase for treatment of chronic gout
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pegloticase + MMF<br>Participants randomized to this arm will receive pegloticase + mycophenolate mofetil. | Drug: Pegloticase 8 MG/ML [Krystexxa]<br>* Participants randomized to the pegloticase + MMF arm will start two week run-in on 1) mycophenolate mofetil at 500 mg/BID or the first week, titrating dose up to 1000mg/BID for the second week of run-in prior to the first infusion; and 2) Pegloticase 8 mg IV every two weeks following 2 week run-in period, Mycophenolate mofetil therapy will continue for 12 weeks at the highest tolerated dose. After the 12-week combination mycophenolate mofetil and pegloticase study period, participants will continue open label pegloticase therapy for an additional three months.<br>* Other names: Krystexxa;Drug: MMF<br>* Participants randomized to the pegloticase + MMF arm will start two week run-in on 1) mycophenolate mofetil at 500 mg/BID or the first week, titrating dose up to 1000mg/BID for the second week of run-in prior to the first infusion; and 2) Pegloticase 8 mg IV every two weeks following 2 week run-in period, Mycophenolate mofetil therapy will continue for 12 weeks at the highest tolerated dose. After the 12-week combination mycophenolate mofetil and pegloticase study period, participants will continue open label pegloticase therapy for an additional three months.<br>* Other names: Cell Cept;|
| Placebo Comparator: pegloticase + placebo<br>Participants randomized to this arm will receive pegloticase + placebo | Drug: Placebo<br>* Participants randomized to the pegloticase + placebo arm will start two week run-in on 1) placebo at 500 mg/BID or the first week, titrating dose up to 1000mg/BID for the second week of run-in prior to the first infusion; and 2) Pegloticase 8 mg IV every two weeks following 2 week run-in period. After the 12-week combination placebo and pegloticase study period, participants will continue open label pegloticase therapy for an additional three months.<br>Drug: Pegloticase 8 MG/ML [Krystexxa]<br>* Participants randomized to the pegloticase + placebo arm will start two week run-in on 1) placebo at 500 mg/BID or the first week, titrating dose up to 1000mg/BID for the second week of run-in prior to the first infusion; and 2) Pegloticase 8 mg IV every two weeks following 2 week run-in period. After the 12-week combination placebo and pegloticase study period, participants will continue open label pegloticase therapy for an additional three months.<br>* Other names: Krystexxa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Achieving and Maintaining an sUA ≤ to 6 Milligram Per Deciliter (mg/dL) Through 12 Weeks | Proportion of participants achieving and maintaining an sUA ≤ to 6 mg/dL through 12 weeks, compared to concurrent controls. | 12 weeks |