Study of KRYSTEXXA® (Pegloticase) Plus Methotrexate in Participants With Uncontrolled Gout

Gout Clinical Trial

— MIRROR RCT  

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients With Uncontrolled Gout Receiving KRYSTEXXA® (Pegloticase) (MIRROR Randomized Controlled Trial [RCT])

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03994731
• Other study ID #: HZNP-KRY-202
• Status: Completed
• Phase: Phase 4
• Start date: June 13, 2019
• Est. completion date: April 11, 2022

Study information

• Verified date: February 2023
• Source: Horizon Pharma Ireland, Ltd., Dublin Ireland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the potential for pegloticase with methotrexate (MTX) to increase the response rate seen with pegloticase alone, and to characterize the safety, tolerability and pharmacokinetics (PK) of the concomitant use of pegloticase with MTX, by comparing pegloticase co-administered with MTX to pegloticase co-administered with placebo for MTX in adults with uncontrolled gout.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 152
• Est. completion date: April 11, 2022
• Est. primary completion date: March 17, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Willing and able to give informed consent.

2. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the study.

3. Adult men or women =18 years of age.

4. Uncontrolled gout, defined as meeting the following criteria:

• Hyperuricemia during the screening period defined as sUA =7 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

5. Willing to discontinue any oral urate lowering therapy for at least 7 days prior to MTX dosing at Week -6 and remain off when receiving pegloticase infusions.

6. 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 -6; subjects must agree to use 2 reliable forms of contraception during the study, one 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 one ovulatory cycle after the last dose of MTX or placebo for MTX (whichever is the longest duration after the last dose of pegloticase or MTX or placebo for 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.

7. Men who are not vasectomized must agree to use appropriate contraception so as to not impregnate a female partner of reproductive potential during the study, beginning with the initiation of MTX at Week -6 and continuing and for at least 3 months after the last dose of MTX or placebo for MTX.

8. Able to tolerate MTX 15 mg orally for 2 weeks (Week -6 through Week -4) prior to randomization.

Exclusion Criteria:

1. Weight >160 kg (352 pounds) at Screening.

2. Any serious acute bacterial infection, unless treated and completely resolved with antibiotics at least 2 weeks prior to the Week -6 Visit.

3. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis.

4. 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.

5. History of any transplant surgery requiring maintenance immunosuppressive therapy.

6. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity.

7. Known history of hepatitis C virus ribonucleic acid (RNA) positivity.

8. Known history of Human Immunodeficiency Virus (HIV) positivity.

9. Glucose-6-phosphate dehydrogenase deficiency (tested at the Screening Visit).

10. Chronic renal impairment defined as estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m^2 or currently on dialysis.

11. 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 Randomization at Week -4.

12. 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.

13. Prior treatment with pegloticase, another recombinant uricase (rasburicase), or concomitant therapy with a polyethylene glycol-conjugated drug.

14. Known allergy to pegylated products or history of anaphylactic reaction to a recombinant protein or porcine product.

15. Contraindication to MTX treatment or MTX treatment considered inappropriate.

16. Known intolerance to MTX.

17. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to MTX administration at Week -6 or plans to take an investigational drug during the study.

18. Liver transaminase levels (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) > upper limit of normal (ULN) or albumin < the lower limit of normal (LLN) at the Screening Visit).

19. Chronic liver disease.

20. White blood cell count < 4,000/µL, hematocrit < 32 percent, or platelet count < 75,000/µL.

21. Currently receiving systemic or radiologic treatment for ongoing cancer.

22. History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix.

23. Diagnosis of osteomyelitis.

24. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

25. Unsuitable candidate for the study, 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 study.

26. Alcohol use in excess of 3 alcoholic beverages per week.

27. 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).

28. Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis. If deemed necessary by the Investigator, a chest X-ray may be performed during Screening.

Related Conditions & MeSH terms

• Gout

Intervention

Biological:
• Pegloticase
IV pegloticase 8 mg Q2W

Drug:
• methotrexate
Oral MTX 15 mg weekly
• placebo
Oral placebo for MTX

Dietary Supplement:
• folic acid
Folic acid 1 mg orally every day beginning at Week -6 until prior to the Week 52 Visit.

Drug:
• gout flare prophylaxis regimen
Prior to beginning the Pegloticase + IMM Period, participants must have been taking at least 1 protocol-standard gout flare prophylaxis regimen (i.e. colchicine and/or nonsteroidal anti-inflammatory drugs and/or low-dose prednisone = 10 mg/day) for = 1 week before the first dose of pegloticase and to continue flare prophylaxis per American College of Rheumatology guidelines [Khanna D et al. 2012] for the greater of 1) 6 months, 2) 3 months after achieving target serum urate (sUA < 6 mg/dL) for participants with no tophi detected on physical exam, or 3) 6 months after achieving target serum urate (sUA < 5 mg/dL) for participants with one or more tophi detected on initial physical exam that then resolved.
• fexofenadine
For IR prophylaxis, fexofenadine (180 mg orally) taken the day before each infusion and on the morning of each infusion.
• acetaminophen
For IR prophylaxis, acetaminophen (1000 mg orally) taken the morning of each infusion.
• methylprednisolone
For IR prophylaxis, methylprednisolone (125 mg IV) given over an infusion duration between 10 - 30 minutes, immediately prior to each infusion.

Locations

Country	Name	City	State
United States	Orthopedic Physicians Alaska	Anchorage	Alaska
United States	University of Colorado Division of Rheumatology	Aurora	Colorado
United States	Long Island Arthritis & Osteoporosis Care	Babylon	New York
United States	University of Alabama	Birmingham	Alabama
United States	Western Washington Arthritis Clinic	Bothell	Washington
United States	NorthEast Rheumatology	Concord	North Carolina
United States	NorthEast Rheumatology/Atrium Health	Concord	North Carolina
United States	Premier Clinical/STAT Research	Dayton	Ohio
United States	Avail Clinical Research	DeLand	Florida
United States	Denver Arthritis Clinic	Denver	Colorado
United States	Prohealth Research Center	Doral	Florida
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	TriWest Research Associates	El Cajon	California
United States	Arizona Arthritis and Rheumatology Research, PLLC - Flagstaff	Flagstaff	Arizona
United States	Arizona Arthritis and Rheumatology Research, PLLC-West	Glendale	Arizona
United States	Rheumatic Disease Center	Glendale	Wisconsin
United States	Infusion Associates	Grand Rapids	Michigan
United States	Benefis Hospital	Great Falls	Montana
United States	Medication Management, LLC	Greensboro	North Carolina
United States	Piedmont Arthritis Clinic	Greenville	South Carolina
United States	Advanced Investigative Medicine, Inc.	Hawthorne	California
United States	ClinEdge PMG Research of Hickory, LLC	Hickory	North Carolina
United States	Diagnostic and Interventional Nephrology Of Houston	Houston	Texas
United States	Research Consultants - Astoria	Houston	Texas
United States	Research Consultants - Frostwood	Houston	Texas
United States	West Tennessee Research Institute	Jackson	Tennessee
United States	Physician Research Collaboration, LLC	Lincoln	Nebraska
United States	Applied Research Center of Arkansas, Inc	Little Rock	Arkansas
United States	Axis Clinical Trials	Los Angeles	California
United States	Ramesh C. Gupta, M.D.	Memphis	Tennessee
United States	St. Luke's Clinic - Rheumatology	Meridian	Idaho
United States	Arizona Arthritis and Rheumatology Research, PLLC-East	Mesa	Arizona
United States	Paramount Medical Research & Consulting, LLC	Middleburg Heights	Ohio
United States	Buffalo Rheumatology and Medicine	Orchard Park	New York
United States	Omega Research Maitland	Orlando	Florida
United States	MD Medical Research	Oxon Hill	Maryland
United States	Clinical Research Source Inc.	Perrysburg	Ohio
United States	DMI Research	Pinellas Park	Florida
United States	Napa Research Center	Pompano Beach	Florida
United States	ACRC Studies	Poway	California
United States	ClinEdge Sierra Rheumatology, Inc.	Roseville	California
United States	Clinical Research Institute of Michigan, LLC	Saint Clair Shores	Michigan
United States	ClinEdge PMG Research of Salisbury, LLC	Salisbury	North Carolina
United States	East Bay Rheumatology Medical Group, Inc.	San Leandro	California
United States	Arthritis Clinic of Central Texas	San Marcos	Texas
United States	Santa Fe Rheumatology	Santa Fe	New Mexico
United States	Providence St. John's Health Clinic	Santa Monica	California
United States	Shelby Clinical Research, LLC	Shelby	North Carolina
United States	Arthritis Northwest	Spokane	Washington
United States	Premier Clinical/STAT Research - Springboro	Springboro	Ohio
United States	Articularis Healthcare Group	Summerville	South Carolina
United States	GCP Clinical Research	Tampa	Florida
United States	Medvin Clinical Research	Tujunga	California
United States	San Fernando Valley Health Institute	Van Nuys	California
United States	Ventura Clinical Trials	Ventura	California
United States	Arthritis & Osteoporosis Clinic - Waco	Waco	Texas
United States	Clear Lake Specialties	Webster	Texas
United States	The Center for Rheumatology and Bone Research	Wheaton	Maryland
United States	PMG Research of Wilmington, LLC	Wilmington	North Carolina
United States	Florida Medical Clinic, LLC	Zephyrhills	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Horizon Therapeutics Ireland DAC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage 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. Month 6 includes pre- and post-infusion sUA assessments at Weeks 20 and 22, non-infusion sUA at Weeks 21 and 23, pre-infusion sUA at Week 24 and any unscheduled sUA between Week 20 and Week 24. A participant must have had = 2 sUA observations from different visits in order to be eligible as a responder. Participants meeting the stopping rule (those with a pre-infusion sUA >6 mg/dL at 2 consecutive scheduled trial visits beginning with the Week 2 Visit stopped pegloticase dosing) were counted as non-responders.	Month 6 (Weeks 20, 21, 22, 23 and 24)
Secondary	Percentage of sUA (sUA < 6 mg/dL) Responders During Month 12	Responders are defined as participants achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 12 (Weeks 48, 50 and 52). Month 12 includes pre- and post-infusion sUA Weeks 48 and 50, pre-infusion sUA at Week 52, and any unscheduled sUA assessments done at unscheduled visits between Week 48 and 52. A participant must have had = 2 sUA observations from different visits in order to be eligible as a responder. Participants meeting the stopping rule (those with a pre-infusion sUA >6 mg/dL at 2 consecutive scheduled trial visits beginning with the Week 2 Visit stopped pegloticase dosing) were counted as non-responders.	Month 12 (Weeks 48, 50 and 52)
Secondary	Percentage of Participants With Complete Resolution of = 1 Tophi at Week 52	Percentage of participants with complete resolution of = 1 tophi (using digital photography) at Week 52 in participants with tophi at baseline. Participants with resolution of = 1 tophi at a visit are participants with resolution of = 1 tophi at the visit (i.e. have complete response), and no progressive disease for any other tophi.	Baseline, Week 52
Secondary	Mean Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52	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, and usual activities. The HAQ-DI ranges from 0 to 3 with higher values indicating higher disability. A change from baseline value of 0 is imputed at the first post-baseline visit for any participants without post-baseline values.	Baseline, Week 52
Secondary	Mean Change From Baseline HAQ Pain Score at Week 52	The HAQ-Pain score rates the participant's pain over the past week from 0 to 100 with 0 = no pain and 100 = severe pain. A change from baseline value of 0 is imputed at the first post-baseline visit for any participants without post-baseline values.	Baseline, Week 52
Secondary	Mean Change From Baseline in HAQ Health Score at Week 52	The HAQ health scale is a self-reported measure of overall health. Participants are asked to rate how they are doing, considering all the ways arthritis affects them, on a scale of 0 to 100, where 0 represents very well and 100 represents very poor. A change from baseline value of 0 is imputed at the first post-baseline visit for any participants without post-baseline values.	Baseline, Week 52