Pegloticase and Methotrexate Co-administered in Participants With Uncontrolled Gout Who Previously Failed Pegloticase Monotherapy

Study Overview
=================
Brief Summary
-----------------
This is a Phase 4, multicenter, open-label trial of pegloticase with methotrexate (MTX) in adult participants with uncontrolled gout who were previously treated with pegloticase without a concomitant immunomodulator and stopped pegloticase due to failure to maintain serum uric acid (sUA) response and/or a clinically mild infusion reaction (IR). Approximately 30 participants will be enrolled. Pegloticase + MTX will be administered for approximately 24 weeks, with an optional extension up to 48 weeks. The trial design will include 5 distinct components: Screening Period, lasting up to 42 days; 6-week MTX Tolerability Assessment Period (hereafter referred to as the MTX Run-in Period); 24-week Pegloticase + MTX Treatment Period, which will include a Week 24/End of Trial/Early Termination Visit (subjects that end MTX and pegloticase treatment prior to the Week 24 will remain on trial for follow up until the Week 24 visit) Optional Pegloticase + MTX Extension Period up to 24 weeks 30-Day Post Treatment Follow -up

Detailed Description
-----------------
All participants who meet eligibility criteria at Screening will begin once-weekly subcutaneous (SC) MTX Run-in period. Participants must be able to tolerate MTX at a minimum dose of 15 mg during the 6-week MTX Run-in Period to be eligible to participate in the Pegloticase + MTX Treatment Period. All participants who meet the inclusion/exclusion criteria and complete the MTX Run-in Period will be considered enrolled participants. During the Pegloticase + MTX Treatment Period, pegloticase 8 mg will be administered IV every 2 weeks and MTX SC weekly. Two sequential cohorts of participants will be enrolled in this trial. Cohort 1 is targeted to enroll 10 participants who previously failed to maintain sUA response with pegloticase monotherapy and stopped pegloticase treatment without a history of pegloticase-related infusion reaction. If the safety assessment during Cohort 1 indicates that the pegloticase infusions are well tolerated, then the trial can begin enrolling Cohort 2 for 20 participants who failed to maintain sUA response with pegloticase monotherapy with or without a history of pegloticase-related clinically mild IRs.

Official Title
-----------------
A Phase 4, Multicenter, Open-label, Efficacy and Safety Trial of Pegloticase and Methotrexate Co-administered in Patients With Uncontrolled Gout Who Have Previously Received Pegloticase Monotherapy But Did Not Maintain a Serum Uric Acid Response

Conditions
-----------------
Uncontrolled Gout

Intervention / Treatment
-----------------
* Biological: Pegloticase
* Drug: Methotrexate (MTX)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Willing and able to give informed consent. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial. Adult men or women ≥18 years of age. Uncontrolled gout, defined by the following criteria: Hyperuricemia during the Screening Period, defined as sUA ≥6 mg/dL, and; Failure to maintain normalization of sUA with xanthine oxidase inhibitors at the maximum medically appropriate dose or with a contraindication to xanthine oxidase inhibitor therapy based on medical record review or subject interview, and; Symptoms of gout, including at least 1 of the following: Presence of at least 1 tophus Recurrent flares, defined as 2 or more flares in the 12 months prior to Screening Presence of chronic gouty arthritis Subject was previously treated with pegloticase without concomitant immunomodulation and stopped pegloticase due to failure to maintain sUA reduction response (had ≥1 sUA >6 mg/dL within 2 weeks post pegloticase infusion) and did not experience an IR (Cohort 1) and/or stopped pegloticase treatment due to pegloticase-related clinically mild IR (Cohort 2). Subject for whom the last pegloticase infusion occurred >6 months prior to Screening. Willing to discontinue any oral urate-lowering therapy for at least 7 days prior to Day 1 and remain off other urate-lowering therapy during the Pegloticase + MTX Treatment Period. Women of childbearing potential (including those with an onset of menopause <2 years prior to Screening, non-therapy-induced amenorrhea for <12 months prior to Screening or not surgically sterile [absence of ovaries and/or uterus]) must have negative serum pregnancy tests during Screening: Subjects must agree to use 2 reliable forms of contraception during the trial, 1 of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started ≥1 full cycle prior to Week -6 (start of MTX) and continue for 30 days after the last dose of pegloticase, or at least 1 ovulatory cycle after the last dose of MTX (whichever is the longer duration after the last dose of pegloticase). Highly effective contraceptive methods (with a failure rate <1% per year), when used consistently and correctly, include implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomized partner. Men who are not vasectomized must agree to use appropriate contraception so as to not impregnate a female partner of reproductive potential during the trial, beginning with the initiation of MTX at Week -6 and continuing for at least 3 months after the last dose of MTX. Able to tolerate MTX at SC doses of at least 15 mg during the MTX Run-in Period, regardless of estimated glomerular filtration rate (eGFR) status. Exclusion Criteria: Known history of medically confirmed prior anaphylactic reaction. Known history of moderate or severe IR (including but not limited to difficulty in breathing, hypotension, generalized urticaria, generalized erythema, angioedema and/or required treatment with IV steroids or epinephrine; or other serious adverse events (SAEs) related to pegloticase or any other pegylated product treatment. Weight >160 kg (352 pounds) at Screening. Any serious acute bacterial infection, unless treated and completely resolved with antibiotics at least 2 weeks prior to the Week 6 Visit. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis. Current or chronic treatment with systemic immunosuppressive agents, such as MTX, azathioprine, cyclosporine, leflunomide, cyclophosphamide or mycophenolate mofetil. Current treatment with prednisone >10 mg/day or equivalent dose of another corticosteroid on a chronic basis (defined as 3 months or longer). Known history of any solid organ transplant surgery requiring maintenance immunosuppressive therapy. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity, unless treated, viral load is negative and no chronic or active infection confirmed by hepatitis B virus serology. Known history of hepatitis C virus RNA positivity, unless treated and viral load is negative. Known history of human immunodeficiency virus positivity. glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at the Screening Visit). Severe chronic renal impairment (eGFR <30 mL/min/1.73 m^2) at the Screening Visit based on 4 variable Modification of Diet in Renal Disease [MDRD] formula or currently on dialysis. Non-compensated congestive heart failure, hospitalization for congestive heart failure or treatment for acute coronary syndrome (myocardial infarction or unstable angina) within 3 months of the Screening Visit, current uncontrolled arrhythmia or current uncontrolled blood pressure (>160/100 mm Hg) prior to Week -6. Pregnant, planning to become pregnant, breastfeeding, planning to impregnate female partner, or not on an effective form of birth control, as determined by the Investigator. Prior treatment with another recombinant uricase (rasburicase) or concomitant therapy with a PEG-conjugated drug. Known allergy to pegylated products or history of anaphylactic reaction to a recombinant protein or porcine product. Contraindication to MTX treatment or MTX treatment considered inappropriate. Known intolerance to MTX. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to MTX administration at Week -6 or plan to take an investigational drug during the trial. Current liver disease, as determined by alanine transaminase (ALT) or aspartate transaminase (AST) >1.25 × upper limit of normal (ULN) or albumin <lower limit of normal at the Screening Visit. Currently receiving systemic or radiologic treatment for ongoing cancer, excluding nonmelanoma skin cancer. History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix. White blood cell count <4.0 × 10^9/L, hematocrit <32% or platelet count <75 × 10^9/L. Diagnosis of osteomyelitis. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome. Unsuitable candidate for the trial (e.g., cognitive impairment), based on the opinion of the Investigator, such that participation might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements or complete the trial. Alcohol use in excess of 3 alcoholic beverages per week. A known intolerance to all protocol standard gout flare prophylaxis regimen (i.e., unable to tolerate any of the following 3 agents: colchicine,nonsteroidal anti-inflammatory drugs (NSAIDs) or low- dose prednisone (≤10 mg/day). Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis. If deemed necessary by the Investigator, a chest x-ray may be performed during Screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pegloticase plus Methotrexate (MTX)<br>Pegloticase (8 mg) intravenous (IV) every two weeks. Methotrexate (15 or 25 mg weekly) SC. | Biological: Pegloticase<br>* Participants will receive pegloticase with MTX for up to 24 weeks during the treatment period. Participants may opt to receive pegloticase with MTX for an additional 24 weeks.<br>Drug: Methotrexate (MTX)<br>* Participants will receive MTX during the run-in period then pegloticase with MTX for up to 24 weeks during the treatment period. Participants may opt to receive pegloticase with MTX for an additional 24 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6 | An sUA responder is defined as a participant achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 6 (Weeks 20, 21, 22, 23 and 24). | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of sUA Responders (sUA < 6 mg/dL) During Month 3 | An sUA responder is defined as a participant achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 3 (Weeks 10 to 14). | Month 3 | 
| Percentage of Participants Who Experienced Any of the Following Events From Day 1 to Week 24: Infusion Reaction (IR) Leading to Discontinuation of Treatment, Anaphylaxis or Meeting Individual Participant sUA Discontinuation Criteria | Individual participant sUA discontinuation criteria are met when the lowest available interim sUA value after the pegloticase infusion at Week 2, 4, 6, 8, 10 or 12 is less than a 50% reduction from the highest sUA value measured between Screening and pre-infusion on Day 1. | Day1 to Week 24 | 
| Mean Change From Baseline in Urate Deposition Volume Measured by Dual Energy Computed Tomography (DECT) to Week 24 | DECT scans measure urate deposition volume. DECT scans at Week 24 were taken for hands, foot/ankle, and knees. | Baseline to Week 24 | 
| Mean Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Weeks 14 and 24 | HAQ-DI is a self-report functional status instrument that is filled out by the participant and measures disability over the past week via 20 questions relating to 8 domains of function: dressing grooming, arising, eating, walking, hygiene, reach, grip, usual activities. For each of the categories, participants reported the amount of difficulty they had in performing 2 or 3 specific subcategory items. The standard disability score is calculated from the 8 categories by dividing the sum of the individual categories by the number of categories answered, yielding a score from 0 (without any difficulty) to 3 (unable to do), with higher values indicating higher disability. | Baseline, Week 14, Week 24 | 
| Mean Change From Baseline in Health Assessment Questionnaire (HAQ) Pain Score at Weeks 14 and 24 | The HAQ pain scale asks participants to record how much pain they have had in the past week on a scale of 0-100 where zero represents no pain and 100 represents severe pain. | Baseline, Week 14, Week 24 | 
| Mean Change From Baseline in HAQ Health Score at Weeks 14 and 24 | The HAQ health scale is a measure of overall health. Participants are asked to rate how well they are doing on a scale of 0 to 100, where zero represents very well and 100 represents very poor health. | Baseline, Week 14, Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Gout