Open-label Study of Rituximab (RTX) Pretreatment Followed by Standard of Care (SOC) Methotrexate-Pegloticase (MTXPEG) to Treat Poorly Controlled Tophaceous Gout in Individuals With Prior Loss of Response to Pegloticase.
Overview
- Phase
- Phase 1
- Intervention
- Rituximab
- Conditions
- Tophaceous Gout
- Sponsor
- University of California, Los Angeles
- Enrollment
- 2
- Locations
- 1
- Primary Endpoint
- Neutralizing antibody titers (assays provided by Horizon labs) will be measured at Screening (Visit 0), prior to first Pegloticase infusion (Visit 3, Week 0), Visit 9, Week 12 and Visit 16, Week 26.
- Status
- Completed
- Last Updated
- 5 months ago
Overview
Brief Summary
This safety and feasibility, open-label study of up to 9 subjects will examine a group of subjects with poorly controlled tophaceous gout (intolerant to or ineffective oral urate lowering agents and loss of prior Pegloticase response) pre-treated with Rituximab to recapture response to Methotrexate-Pegloticase.
Detailed Description
Rituximab 1000 mg will be administered at week -6 and week -4 via intravenous infusion over the duration of 5 hours prior to Methotrexate-Pegloticase Standard-of-Care treatment. Per FDA approved dosing in the package insert, Rituximab infusion with concentration of 10 mg/mL will begin at 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour or total dose of 1000 mg. All subjects will be treated with Methotrexate-Pegloticase Standard-of-Care with FDA-approved dosing of Pegloticase 8 mg IV infusion every 2 weeks, co-administered with methotrexate 15 mg orally once weekly (started 4 weeks prior to Pegloticase initiation). Standard-of-Care includes Pegloticase infusion every 2 weeks as long as clinically indicated (e.g., persistent tophus), concluding treatment when all tophaceous gout lesions resolve or up to 12-months, safety stop point, or subject withdrawal from the study. Subjects will be on study for up to 24 months. Screening visit: up to 28-days. Treatment visit: 1. Rituximab Pre-Treatment: up to 6-weeks + 1 week prior to Pegloticase treatment. (Pre-treatment of Rituximab will occur at -6 and -4 weeks.) 2. Methotrexate Treatment (Standard-of-Care): up to 6 weeks + 1 week prior to Pegloticase treatment. (Administered four weeks prior to Pegloticase and weekly during Pegloticase treatment). 3. Methotrexate-Pegloticase Study Treatment (Standard-of-Care): up to 12 months of Standard-of-Care. (Methotrexate is administered weekly and Pegloticase is coadministered every two weeks). Follow-up phone visits: up to 30 and 60 days after last dose of Methotrexate-Pegloticase + 7 days. Total subject participation duration is up to 24 months. Total study duration for recruitment, enrollment, and study completion of all subjects is up to 5 years.
Investigators
John D. Fitzgerald, MD, PhD
Clin Prof, Clinical Chief
University of California, Los Angeles
Eligibility Criteria
Inclusion Criteria
- •Eligible subjects must meet/provide all the following criteria:
- •Must be able to provide written informed consent.
- •Male or female ≥ 18 years of age at Baseline Visit.
- •Meets the American College of Rheumatology Classification Criteria for Gout.
- •Poorly controlled tophaceous gout, defined as meeting the following criteria:
- •Hyperuricemia during the screening period defined as serum urate ≥ 6 mg/dL.
- •Failure to maintain normalization of serum urate 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:
- •i. Presence of at least one tophus. ii. Recurrent flares defined as 2 or more flares in the past 12 months prior to screening.
- •Prior discontinued use of Pegloticase due to failure (rising SU \> 6 mg/dL or history of moderate to severe infusion reaction).
Exclusion Criteria
- •Subjects will be ineligible for trial participation if they meet any of the following criteria:
- •Glucose-6-phosphate dehydrogenase deficiency (documented or tested at the Screening Visit).
- •Chronic renal impairment defined as estimated glomerular filtration rate (epidermal growth factor receptor) \< 30 mL/min/1.73 m2 or currently on dialysis.
- •Non-compensated congestive heart failure (stage C) or hospitalization for congestive heart failure within 3 months of the Screening Visit, uncontrolled arrhythmia.
- •Treatment for acute coronary syndrome (myocardial infarction or unstable angina).
- •Uncontrolled blood pressure (\>160/100 mmHg) prior to Rituximab infusion (week -6, week -4).
- •On treatment for current non-skin cell cancer.
- •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.
- •Anaphylaxis or other prior severe infusion reaction to Pegloticase that the study allergy-immunologist deems treatment with Pegloticase to be unsafe to rechallenge.
Arms & Interventions
Rituximab
Rituximab 1000 mg will be administered at week -6 and week -4 via intravenous infusion over the duration of 5 hours prior to the Pegloticase (Standard-of-Care) treatment.
Intervention: Rituximab
Outcomes
Primary Outcomes
Neutralizing antibody titers (assays provided by Horizon labs) will be measured at Screening (Visit 0), prior to first Pegloticase infusion (Visit 3, Week 0), Visit 9, Week 12 and Visit 16, Week 26.
Time Frame: 2 years
Mean change between baseline and the specified follow up measurements will be analyzed using general linear modelling with adjustment to control for within person correlation of repeated measurements.
The study will be measured by the frequency and grade of adverse event (AEs) (solicited and unsolicited), serious adverse experience (SAEs), adverse event of special interest (AESI1s), medically attended adverse events (MAAEs).
Time Frame: 2 years
Simple descriptive statistics will be used to summarize toxicities in terms of type, severity and minimum or maximum values for laboratory measures, time of onset, duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects. Safety Analyses will be performed on Safety Analysis Set. After the first Pegloticase infusion, any subsequent pre-Pegloticase infusion lab result of serum urate \> 6 mg/dL will terminate the study.