A Phase 4, Open-label Study of KRYSTEXXA® (Pegloticase) Co-administered With Methotrexate (MTX) in Patients With Uncontrolled Gout (FORWARD OL) (FORWARD OL)
Primary Purpose
Uncontrolled Gout, Chronic Gout
Status
Active
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Pegloticase and Methotrexate (MTX)
Pegloticase and Methotrexate (MTX)
Sponsored by
About this trial
This is an interventional treatment trial for Uncontrolled Gout focused on measuring Gout, KRYSTEXXA, Pegloticase, Methotrexate, Uncontrolled gout
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 and <80 years of age.
Uncontrolled gout, defined as meeting 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 one tophus
- Recurrent flares defined as 2 or more flares in the past 12 months prior to screening
- Presence of chronic gouty arthritis as evidenced by either clinical signs consistent with chronic synovitis on clinical examination or the presence of typical gouty erosion(s) on hand and/or foot X-rays
- Willing to discontinue any oral urate lowering therapy for at least 7 days prior to MTX dosing at Week -4 and remain off while receiving pegloticase treatments.
- 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/urine pregnancy tests during Screening and Week -4; subjects must agree to use 2 reliable forms of contraception during the trial, one of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started ≥1 full cycle prior to Week -4 (start of MTX) and continue for 4 weeks/30 days after the last dose of pegloticase, or at least one ovulatory cycle after the last dose of MTX (whichever is the longest duration after the last dose of pegloticase or MTX). 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 -4 and continuing and for at least 3 months after the last dose of MTX.
- Able to tolerate MTX 15 mg orally for 4 weeks (Week -4 through Day 1) prior to enrollment.
Exclusion Criteria:
- 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 Day 1 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, or mycophenolate mofetil; prednisone ≥10 mg/day or equivalent dose of other corticosteroid on a chronic basis (3 months or longer) would also meet exclusion criteria.
- History of any transplant surgery requiring maintenance immunosuppressive therapy.
- Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity.
- Known history of hepatitis C virus RNA positivity, unless treated and viral load is negative.
- Known history of Human Immunodeficiency Virus (HIV) positivity.
- Glucose-6-phosphate dehydrogenase deficiency (tested at the Screening Visit centrally or locally).
- Chronic renal impairment defined as estimated glomerular filtration rate (eGFR) <40 mL/min/1.73 m^2 or currently on dialysis.
- Non-compensated congestive heart failure 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), or uncontrolled blood pressure (>160/100 mmHg) prior to enrollment at Day 1.
- 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 pegloticase, another recombinant uricase (rasburicase), or concomitant therapy with a polyethylene glycol-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 -4 or plans to take an investigational drug during the trial.
- Liver transaminase levels (AST or ALT) > 1.25 X upper limit of normal (ULN) or albumin < the lower limit of normal (LLN) at the Screening Visit.
- Chronic liver disease.
- White blood cell count <4000/µl, hematocrit <32 percent, or platelet count <75,000/µl.
- Currently receiving systemic or radiologic treatment for ongoing cancer, excluding non-melanoma skin cancer.
- History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix.
- Diagnosis of osteomyelitis.
- Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
- Unsuitable candidate for the trial, based on the opinion of the Investigator (e.g., cognitive impairment), 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 regimens (i.e., subject must be able to tolerate at least one: colchicine and/or non-steroidal anti-inflammatory drugs and/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.
Sites / Locations
- Orthopedic Physicians Alaska
- Arizona Arthritis & Rheumatology Research, PLLC
- East Bay Rheumatology Medical Group, Inc.
- ProHealth Research Center
- Napa Research Center
- GCP Clinical Research
- The Center for Rheumatology and Bone Research
- Shelby Clinical Research, LLC
- Altoona Center for Clinical Research
- Biopharma Informatic, LLC
- Arthritis Clinic: Western Washington Medical Group
- Arthritis Northwest PLLC
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Pegloticase 16mg cohort
Pegloticase 24/32mg cohort
Arm Description
16 mg IV dose of pegloticase q4 weeks with 15 mg methotrexate (MTX) weekly
24 to 32 mg IV dose of pegloticase q4 weeks with 15 mg MTX weekly
Outcomes
Primary Outcome Measures
Proportion of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6
Responders are defined as participants achieving and maintaining sUA < 6 mg/dL for at least 80% of the time during Month 6. Participants meeting the sUA discontinuation criteria (pre-infusion sUA >6 mg/dL at 2 consecutive scheduled trial visits beginning with the Week 1 Visit) were counted as non-responders.
Time to first sUA ≥6 mg/dL after first achieving sUA <6 mg/dL, from the first pegloticase infusion until Week 24
Secondary Outcome Measures
Pharmacokinetic parameters (e.g., AUC and, Cmax)
Proportion of subjects with pre-infusion sUA <6 mg/dL at each scheduled visit
Area under the sUA concentration vs time curve from Day 1 to Week 24 and Day 1 to Week 48
Proportion of the subjects sustained sUA< 6 mg/dL from Day 1 to Week 24 and Day 1 to Week 48
Proportion of subjects with anti-uricase antibodies and the proportion of subjects with anti-poly (ethylene glycol) antibodies and their titers at each scheduled visit
Full Information
NCT ID
NCT04762498
First Posted
February 12, 2021
Last Updated
October 18, 2023
Sponsor
Horizon Therapeutics Ireland DAC
1. Study Identification
Unique Protocol Identification Number
NCT04762498
Brief Title
A Phase 4, Open-label Study of KRYSTEXXA® (Pegloticase) Co-administered With Methotrexate (MTX) in Patients With Uncontrolled Gout (FORWARD OL)
Acronym
FORWARD OL
Official Title
A Phase 4, Open-Label, Multicenter, Efficacy, Safety, Pharmacokinetics and Pharmacodynamics Trial of Intravenous KRYSTEXXA® (Pegloticase) Administered Every 4 Weeks With Co-Administration of Weekly Doses of Methotrexate in Patients With Uncontrolled Refractory Gout (FORWARD Open-Label [OL] Trial)
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 26, 2021 (Actual)
Primary Completion Date
November 29, 2023 (Anticipated)
Study Completion Date
March 13, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Horizon Therapeutics Ireland DAC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This trial is to assess efficacy, safety, blood levels and bodily effects of up to 2 dose levels of intravenous (IV) pegloticase (KRYSTEXXA) infusions at every 4 week intervals (Q4 Weeks) for up to 6 months (Day 1 to 24 weeks with an optional 24 - 48 weeks treatment duration) when given in combination with weekly oral doses of methotrexate (MTX). The goal is to identify an appropriate dose to be administered every 4 weeks to be used for future clinical trials for patients with chronic gout that does not adequately respond to conventional therapy.
Detailed Description
The primary objective is to choose a dose for further investigation by assessing the effect of up to 2 dose levels of pegloticase administered IV Q4 weeks, co-administered with weekly doses of oral MTX, as measured by the sustained normalization of serum uric acid (sUA) to < 6 mg/dL for at least 80% of the time during Month 6 and the duration of sUA to < 6 mg/dL over 24 week treatment period in adult participants with chronic gout refractory to conventional therapy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Uncontrolled Gout, Chronic Gout
Keywords
Gout, KRYSTEXXA, Pegloticase, Methotrexate, Uncontrolled gout
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Sequential Assignment
Model Description
Screening period up to 35 days, followed by 4-week methotrexate (MTX) tolerability run-in. Treatment consists of pegloticase IV Q4 Wks dose for a total of 6 infusions (24 Weeks) with co-administered weekly oral MTX. Optional extension treatment (24-48 weeks) will be available for 6 more infusions (total of 12). Study will consist of Cohort 1: 16 mg pegloticase, co-administered with weekly doses of oral MTX; and, potential Cohort 2: 24 to 32 mg pegloticase, co-administered with weekly doses of oral MTX and/or potential infusion duration reduction to 60 min.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
40 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Pegloticase 16mg cohort
Arm Type
Experimental
Arm Description
16 mg IV dose of pegloticase q4 weeks with 15 mg methotrexate (MTX) weekly
Arm Title
Pegloticase 24/32mg cohort
Arm Type
Experimental
Arm Description
24 to 32 mg IV dose of pegloticase q4 weeks with 15 mg MTX weekly
Intervention Type
Biological
Intervention Name(s)
Pegloticase and Methotrexate (MTX)
Intervention Description
16 mg IV dose of pegloticase q4 weeks co-administered with 15 mg oral dose methotrexate weekly
Intervention Type
Biological
Intervention Name(s)
Pegloticase and Methotrexate (MTX)
Intervention Description
Potential higher IV dose of pegloticase (between 24-32 mg) q4 weeks co-administered with 15 mg oral dose methotrexate weekly and/or potential reduction of infusion duration
Primary Outcome Measure Information:
Title
Proportion of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6
Description
Responders are defined as participants achieving and maintaining sUA < 6 mg/dL for at least 80% of the time during Month 6. Participants meeting the sUA discontinuation criteria (pre-infusion sUA >6 mg/dL at 2 consecutive scheduled trial visits beginning with the Week 1 Visit) were counted as non-responders.
Time Frame
Month 6 (Weeks 20, 21, 22, 23, and 24)
Title
Time to first sUA ≥6 mg/dL after first achieving sUA <6 mg/dL, from the first pegloticase infusion until Week 24
Time Frame
Day 1 to Week 24
Secondary Outcome Measure Information:
Title
Pharmacokinetic parameters (e.g., AUC and, Cmax)
Time Frame
Baseline to Week 48
Title
Proportion of subjects with pre-infusion sUA <6 mg/dL at each scheduled visit
Time Frame
Baseline to Week 48
Title
Area under the sUA concentration vs time curve from Day 1 to Week 24 and Day 1 to Week 48
Time Frame
Day 1 to Week 24 and Day 1 to Week 48
Title
Proportion of the subjects sustained sUA< 6 mg/dL from Day 1 to Week 24 and Day 1 to Week 48
Time Frame
Day 1 to Week 24 and Day 1 to Week 48
Title
Proportion of subjects with anti-uricase antibodies and the proportion of subjects with anti-poly (ethylene glycol) antibodies and their titers at each scheduled visit
Time Frame
Baseline to Week 48
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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 and <80 years of age.
Uncontrolled gout, defined as meeting 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 one tophus
Recurrent flares defined as 2 or more flares in the past 12 months prior to screening
Presence of chronic gouty arthritis as evidenced by either clinical signs consistent with chronic synovitis on clinical examination or the presence of typical gouty erosion(s) on hand and/or foot X-rays
Willing to discontinue any oral urate lowering therapy for at least 7 days prior to MTX dosing at Week -4 and remain off while receiving pegloticase treatments.
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/urine pregnancy tests during Screening and Week -4; subjects must agree to use 2 reliable forms of contraception during the trial, one of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started ≥1 full cycle prior to Week -4 (start of MTX) and continue for 4 weeks/30 days after the last dose of pegloticase, or at least one ovulatory cycle after the last dose of MTX (whichever is the longest duration after the last dose of pegloticase or MTX). 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 -4 and continuing and for at least 3 months after the last dose of MTX.
Able to tolerate MTX 15 mg orally for 4 weeks (Week -4 through Day 1) prior to enrollment.
Exclusion Criteria:
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 Day 1 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, or mycophenolate mofetil; prednisone ≥10 mg/day or equivalent dose of other corticosteroid on a chronic basis (3 months or longer) would also meet exclusion criteria.
History of any transplant surgery requiring maintenance immunosuppressive therapy.
Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity.
Known history of hepatitis C virus RNA positivity, unless treated and viral load is negative.
Known history of Human Immunodeficiency Virus (HIV) positivity.
Glucose-6-phosphate dehydrogenase deficiency (tested at the Screening Visit centrally or locally).
Chronic renal impairment defined as estimated glomerular filtration rate (eGFR) <40 mL/min/1.73 m^2 or currently on dialysis.
Non-compensated congestive heart failure 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), or uncontrolled blood pressure (>160/100 mmHg) prior to enrollment at Day 1.
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 pegloticase, another recombinant uricase (rasburicase), or concomitant therapy with a polyethylene glycol-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 -4 or plans to take an investigational drug during the trial.
Liver transaminase levels (AST or ALT) > 1.25 X upper limit of normal (ULN) or albumin < the lower limit of normal (LLN) at the Screening Visit.
Chronic liver disease.
White blood cell count <4000/µl, hematocrit <32 percent, or platelet count <75,000/µl.
Currently receiving systemic or radiologic treatment for ongoing cancer, excluding non-melanoma skin cancer.
History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix.
Diagnosis of osteomyelitis.
Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
Unsuitable candidate for the trial, based on the opinion of the Investigator (e.g., cognitive impairment), 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 regimens (i.e., subject must be able to tolerate at least one: colchicine and/or non-steroidal anti-inflammatory drugs and/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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Supra Verma, MD
Organizational Affiliation
Horizon Therapeutics
Official's Role
Study Director
Facility Information:
Facility Name
Orthopedic Physicians Alaska
City
Anchorage
State/Province
Alaska
ZIP/Postal Code
99508
Country
United States
Facility Name
Arizona Arthritis & Rheumatology Research, PLLC
City
Glendale
State/Province
Arizona
ZIP/Postal Code
85306
Country
United States
Facility Name
East Bay Rheumatology Medical Group, Inc.
City
San Leandro
State/Province
California
ZIP/Postal Code
94578
Country
United States
Facility Name
ProHealth Research Center
City
Doral
State/Province
Florida
ZIP/Postal Code
33166
Country
United States
Facility Name
Napa Research Center
City
Pompano Beach
State/Province
Florida
ZIP/Postal Code
33064
Country
United States
Facility Name
GCP Clinical Research
City
Tampa
State/Province
Florida
ZIP/Postal Code
33064
Country
United States
Facility Name
The Center for Rheumatology and Bone Research
City
Wheaton
State/Province
Maryland
ZIP/Postal Code
20902
Country
United States
Facility Name
Shelby Clinical Research, LLC
City
Shelby
State/Province
North Carolina
ZIP/Postal Code
28150
Country
United States
Facility Name
Altoona Center for Clinical Research
City
Duncansville
State/Province
Pennsylvania
ZIP/Postal Code
16635
Country
United States
Facility Name
Biopharma Informatic, LLC
City
Houston
State/Province
Texas
ZIP/Postal Code
77043
Country
United States
Facility Name
Arthritis Clinic: Western Washington Medical Group
City
Bothell
State/Province
Washington
ZIP/Postal Code
98021
Country
United States
Facility Name
Arthritis Northwest PLLC
City
Spokane
State/Province
Washington
ZIP/Postal Code
99204
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
A Phase 4, Open-label Study of KRYSTEXXA® (Pegloticase) Co-administered With Methotrexate (MTX) in Patients With Uncontrolled Gout (FORWARD OL)
We'll reach out to this number within 24 hrs