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Study of Pegloticase (KRYSTEXXA®) Plus Methotrexate in Patients With Uncontrolled Gout (MIRROR OL)

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ClinicalTrials.gov Identifier: NCT03635957
Recruitment Status : Completed
First Posted : August 17, 2018
Results First Posted : November 18, 2020
Last Update Posted : May 19, 2021
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics Ireland DAC )

Brief Summary:
The overall objective of the study is to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of the concomitant use of pegloticase with methotrexate (MTX) to enhance the response rate seen with pegloticase alone in adults with uncontrolled gout.

Condition or disease Intervention/treatment Phase
Gout Biological: Pegloticase Drug: Methotrexate (MTX) Drug: Standard Gout Flare Prophylaxis Drug: Infusion Reaction (IR) Prophylaxis Dietary Supplement: Folic Acid Phase 4

Detailed Description:
The study design will include: 1) up to a 2-week Screening Period (screening should be complete within 2 weeks prior to Week -4), 2) a 4-week MTX Run in Period (Week - 4 through Day 1); 3) a 52-week Pegloticase + IMM (immunomodulator), (Pegloticase + MTX) Period 4) a Safety Follow-up (Phone/Email/Site Visit) and 5) a 3 and 6 month Post Treatment Follow-up.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients With Uncontrolled Gout Receiving KRYSTEXXA® (Pegloticase) (MIRROR Open-Label [OL])
Actual Study Start Date : September 26, 2018
Actual Primary Completion Date : October 23, 2019
Actual Study Completion Date : October 26, 2020

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Gout
MedlinePlus related topics: Gout

Arm Intervention/treatment
Experimental: Pegloticase With Methotrexate (MTX)

Run-In Period: oral MTX at a dose of 15 mg weekly for 4 weeks prior to the first dose of pegloticase.

Pegloticase + Immunomodulator (IMM) Period: pegloticase 8 mg administered intravenously (IV) every 2 weeks from Day 1 through the Week 50 Visit for a total of 26 infusions. MTX 15 mg weekly on the same day each week, within 1 to 3 days prior to each pegloticase infusion and one additional weekly dose after the last infusion.

Biological: Pegloticase
pegloticase administered intravenously (IV)

Drug: Methotrexate (MTX)
oral MTX

Drug: Standard Gout Flare Prophylaxis
It is required that before a subject begins the Pegloticase + IMM Period, he or she has been taking at least one 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 continues 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 patients with no tophi detected on physical exam, or 3) 6 months after achieving target serum urate (sUA < 5 mg/dL) for patients with one or more tophi detected on initial physical exam that have since resolved.

Drug: Infusion Reaction (IR) Prophylaxis
For IR prophylaxis, fexofenadine (60 mg or 180 mg orally based on the Principal Investigator's discretion) will be taken the day before each infusion; fexofenadine (60 mg or 180 mg orally based on the Principal Investigator's discretion) and acetaminophen (1000 mg orally) will be taken the morning of each infusion; and methylprednisolone (125 mg IV) given over the infusion duration 10-30 minutes (recommended) or hydrocortisone (200 mg IV) will be administered immediately prior to each infusion.

Dietary Supplement: Folic Acid
Subjects will also take folic acid 1 mg orally every day beginning at Week -4 (the start of MTX) and continuing until prior to the Week 52 Visit.




Primary Outcome Measures :
  1. Percentage of Serum Uric Acid (sUA < 6 mg/dL) Responders During Month 6 [ Time Frame: Month 6 (Weeks 20, 22, and 24) ]
    Serum uric acid (sUA < 6 mg/dL) responders are defined as participants achieving and maintaining sUA < 6 mg/dL for at least 80% of the time during Month 6 (Weeks 20, 22, and 24). Month 6 includes pre-infusion and post-infusion sUA assessments at Week 20, pre-infusion and post-infusion sUA assessments at Week 22, pre-infusion assessments at Week 24, and unscheduled sUA assessments between Week 20 and Week 24.


Secondary Outcome Measures :
  1. Percentage of Serum Uric Acid (sUA < 6 mg/dL) Responders During Month 3 [ Time Frame: Month 3 (Weeks 10, 12, and 14) ]
    Serum uric acid (sUA < 6 mg/dL) responders are defined as participants achieving and maintaining sUA < 6 mg/dL for at least 80% of the time during Month 3 (Weeks 10, 12, and 14). Month 3 includes pre-infusion and post-infusion sUA assessments at Week 10, pre-infusion and post-infusion sUA assessments at Week 12, pre-infusion assessments at Week 14, and unscheduled assessments between Week 10 and Week 14 pre-infusion.

  2. Percentage of Serum Uric Acid (sUA < 6 mg/dL) Overall Responders [ Time Frame: Month 3 and Month 6 combined (Weeks 10, 12, 14, 20, 22, and 24) ]
    Serum uric acid (sUA < 6 mg/dL) overall responders are defined as participants achieving and maintaining sUA < 6 mg/dL for at least 80% of the time during Month 3 and Month 6 (Weeks 10, 12, 14, 20, 22, and 24) combined. Participants with more than one sUA result in Month 3 and Month 6 are considered responders if a participant's weighted proportion of hours that sUA is < 6 mg/dL is greater than or equal to 80%. Participants with the proportion of hours less than 80% are counted as non-responders. Participants with only one value in Month 3 and Month 6 are considered overall responders if they are considered responders in both Month 3 and Month 6.

  3. Percentage of Serum Uric Acid (sUA < 5 mg/dL) Responders During Month 3 [ Time Frame: Month 3 (Weeks 10, 12, and 14) ]
    Serum uric acid (sUA < 5 mg/dL) responders are defined as participants achieving and maintaining sUA < 5 mg/dL for at least 80% of the time during Month 3. Month 3 includes pre-infusion and post-infusion sUA assessments at Week 10, pre-infusion and post-infusion sUA assessments at Week 12, pre-infusion assessments at Week 14, and unscheduled assessments between Week 10 and Week 14 pre-infusion.

  4. Percentage of Serum Uric Acid (sUA < 5 mg/dL) Responders During Month 6 [ Time Frame: Month 6 (Weeks 20, 22, and 24) ]
    Serum uric acid (sUA < 5 mg/dL) responders are defined as participants achieving and maintaining sUA < 5 mg/dL for at least 80% of the time during Month 6. Month 6 includes pre-infusion and post-infusion sUA assessments at Week 20, pre-infusion and post-infusion sUA assessments at Week 22, pre-infusion assessments at Week 24, and unscheduled sUA assessments between Week 20 and Week 24.

  5. Percentage of Serum Uric Acid (sUA < 5 mg/dL) Overall Responders [ Time Frame: Month 3 and Month 6 combined (Weeks 10, 12, 14, 20, 22, and 24) ]
    Serum uric acid (sUA < 5 mg/dL) overall responders are defined as participants achieving and maintaining sUA < 5 mg/dL for at least 80% of the time during Month 3 and Month 6 (Weeks 10, 12, 14, 20, 22, and 24) combined. Participants with more than one sUA result in Month 3 and Month 6 are considered responders if a participant's weighted proportion of hours that sUA is < 6 mg/dL is greater than or equal to 80%. Participants with the proportion of hours less than 80% are counted as non-responders. Participants with only one value in Month 3 and Month 6 are considered overall responders if they are considered responders in both Month 3 and Month 6.

  6. Mean Change in sUA From Pegloticase Baseline to Weeks 14, 24, 36, 52 [ Time Frame: Baseline (defined as the last measurement taken prior to the first infusion of pegloticase in the pegloticase + IMM period), Pre- and Post-Infusion at Weeks 14, 24, 36 and Week 52 ]
    The mean change from baseline is based on observed values in participants remaining on treatment at given time point. For sUA values less than the lower limit of detection (up to 1.5 mg/dL), 0 is used in the analysis.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 to ≤65 years of age.
  4. 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 the Screening/(methotrexate) MTX Run in Period; participants 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 -4 (start of MTX dosing) and continue for 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.
  5. Men who are not vasectomized must not impregnant their female partner during the study and for at least 3 months after the last dose of MTX.
  6. Hyperuricemia at the Screening, Week -4, or Week -2 Visit of the Screening/MTX Run in Period, as documented by sUA ≥6 mg/dL.
  7. Uncontrolled gout, defined as meeting the following criteria:

    serum uric acid (sUA) ≥6 mg/dL prior to entry into the pegloticase +IMM Period (any laboratory tests during screening up to and including during the MTX Run in Period) and at least 1 of the following: inability to maintain sUA <6 mg/dL on other urate-lowering therapy; intolerable side effects associated with current urate-lowering therapy; functionally limiting tophaceous deposits (including those detected clinically or by dual-energy computed tomography [DECT] imaging)

  8. Able to tolerate MTX 15 mg for 4 weeks during the MTX Run-in Period prior to the first dose of pegloticase.

Exclusion Criteria:

  1. Weight >160 kg (352 pounds).
  2. Any serious acute bacterial infection, unless treated and completely resolved with antibiotics at least 2 weeks prior to the Week -4 Visit of the MTX Run-in Period.
  3. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis.
  4. Current immunocompromised condition, including current or chronic treatment with systemic immunosuppressive agents, including prednisone >10 mg/day or equivalent dose of other corticosteroid.
  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 RNA positivity.
  8. Human immunodeficiency virus (HIV) positivity (tested at the Screening Visit).
  9. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at the Screening Visit).
  10. Severe chronic renal impairment (glomerular filtration rate <25 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) at the end of the Screening/MTX Run-in Period.
  12. Pregnant, planning to become pregnant, breastfeeding, planning to impregnant female partner, or not on an effective form of birth control, as determined by the Investigator.
  13. Prior treatment with pegloticase (KRYSTEXXA®), 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 -4 or plans to take an investigational drug during the study.
  18. Current liver disease, as determined by alanine transaminase or aspartate transaminase levels >3 times upper limit of normal at the Screening Visit.
  19. Currently receiving systemic or radiologic treatment for ongoing cancer, excluding non melanoma skin cancer.
  20. History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix.
  21. Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at screening that is not subsequently controlled by the end of the Screening/MTX Run-in Period.
  22. Diagnosis of osteomyelitis.
  23. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
  24. 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 participant or interfere with the participant's ability to comply with the protocol requirements or complete the study.
  25. Alcohol use in excess of 3 alcoholic beverages per week.
  26. Currently receiving allopurinol and unable to discontinue medication 7 days prior to MTX dosing at Week -4 and unable to discontinue treatment during the duration of the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03635957


Locations
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United States, Alaska
Orthopedic Physicians Alaska
Anchorage, Alaska, United States, 99508
United States, Arizona
Arizona Arthritis & Rheumatology -West Valley
Glendale, Arizona, United States, 85306
Arizona Arthritis & Rheumatology -East Valley
Mesa, Arizona, United States, 85210
United States, Florida
Avail Clinical Research
DeLand, Florida, United States, 32720
United States, Washington
Western Washington Arthritis Clinic
Bothell, Washington, United States, 98021
Arthritis Northwest PLLC
Spokane, Washington, United States, 99204
Sponsors and Collaborators
Horizon Therapeutics Ireland DAC
Investigators
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Study Director: Colleen Canavan, BS Horizon Therapeutics Ireland DAC
  Study Documents (Full-Text)

Documents provided by Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics Ireland DAC ):
Study Protocol  [PDF] April 1, 2020
Statistical Analysis Plan  [PDF] July 10, 2020

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Horizon Therapeutics Ireland DAC
ClinicalTrials.gov Identifier: NCT03635957    
Other Study ID Numbers: HZNP-KRY-201
First Posted: August 17, 2018    Key Record Dates
Results First Posted: November 18, 2020
Last Update Posted: May 19, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics Ireland DAC ):
gout
uncontrolled gout
Additional relevant MeSH terms:
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Gout
Arthritis
Joint Diseases
Musculoskeletal Diseases
Crystal Arthropathies
Rheumatic Diseases
Purine-Pyrimidine Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Folic Acid
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Hematinics
Vitamin B Complex
Vitamins