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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03994731
Recruitment Status : Completed
First Posted : June 21, 2019
Results First Posted : May 16, 2022
Last Update Posted : May 16, 2022
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics Ireland DAC )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Gout
Interventions Biological: Pegloticase
Drug: methotrexate
Drug: placebo
Dietary Supplement: folic acid
Drug: gout flare prophylaxis regimen
Drug: fexofenadine
Drug: acetaminophen
Drug: methylprednisolone
Enrollment 152
Recruitment Details This record presents results data as of 14 October 2021 (database lock date).
Pre-assignment Details This study included a 2-week MTX Tolerability Assessment Period consisting of 2 weeks oral MTX. 159 participants received MTX in this period. The 7 participants who were unable to tolerate MTX in this period or who met other exclusion criteria were not randomized and were classified as screen failures per protocol section 9.4.6.3.2.2. 152 randomized participants were considered enrolled in this trial.
Arm/Group Title Pegloticase + MTX Pegloticase + Placebo
Hide Arm/Group Description Participants were randomized to receive blinded oral MTX 15 mg weekly during the Run-in Period. During the Pegloticase + Immunomodulator (IMM) Period, in addition to oral MTX 15 mg, participants received intravenous (IV) pegloticase 8 mg every 2 weeks (Q2W) for a total of 26 infusions from Day 1 through the Week 50 Visit. Participants were randomized to receive blinded oral placebo weekly during the Run-in Period. During the Pegloticase + IMM Period, in addition to oral placebo for MTX, participants received IV pegloticase 8 mg Q2W for a total of 26 infusions from Day 1 through the Week 50 Visit.
Period Title: Run-in Period (From Week -4 to Day 1)
Started [1] 100 52
Took at Least 1 Dose of MTX or Placebo 98 51
Completed 96 49
Not Completed 4 3
[1]
Randomized
Period Title: Pegloticase + IMM Period
Started 96 49
Discontinued Study Treatment Early 38 33
Completed 76 34
Not Completed 20 15
Reason Not Completed
Death             2             0
Lost to Follow-up             3             6
Withdrawal by Subject             15             9
Arm/Group Title Pegloticase + MTX Pegloticase + Placebo Total
Hide Arm/Group Description Participants were randomized to receive blinded oral MTX 15 mg weekly during the Run-in Period. During the Pegloticase + IMM Period, in addition to oral MTX 15 mg, participants received IV pegloticase 8 mg Q2W for a total of 26 infusions from Day 1 through the Week 50 Visit. Participants were randomized to receive blinded oral placebo weekly during the Run-in Period. During the Pegloticase + IMM Period, in addition to oral placebo for MTX, participants received IV pegloticase 8 mg Q2W for a total of 26 infusions from Day 1 through the Week 50 Visit. Total of all reporting groups
Overall Number of Baseline Participants 100 52 152
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 100 participants 52 participants 152 participants
55.6  (12.74) 53.0  (12.12) 54.7  (12.56)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 100 participants 52 participants 152 participants
Female
9
   9.0%
8
  15.4%
17
  11.2%
Male
91
  91.0%
44
  84.6%
135
  88.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 100 participants 52 participants 152 participants
Hispanic or Latino
19
  19.0%
9
  17.3%
28
  18.4%
Not Hispanic or Latino
81
  81.0%
42
  80.8%
123
  80.9%
Unknown or Not Reported
0
   0.0%
1
   1.9%
1
   0.7%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 100 participants 52 participants 152 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
8
   8.0%
6
  11.5%
14
   9.2%
Black or African American
16
  16.0%
6
  11.5%
22
  14.5%
Native Hawaiian or Other Pacific Islander
4
   4.0%
1
   1.9%
5
   3.3%
White
69
  69.0%
36
  69.2%
105
  69.1%
Other, Not Specified
3
   3.0%
2
   3.8%
5
   3.3%
Missing
0
   0.0%
1
   1.9%
1
   0.7%
1.Primary Outcome
Title Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6
Hide Description 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 with < 2 sUA observations and those meeting the stopping rule (pre-infusion sUA > 6 mg/dL at 2 consecutive scheduled trial visits beginning with the Week 2 Visit stopped) were counted as non-responders.
Time Frame Month 6 (Weeks 20, 21, 22, 23 and 24)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) Population: all randomized participants.
Arm/Group Title Pegloticase + MTX Pegloticase + Placebo
Hide Arm/Group Description:
Participants were randomized to receive blinded oral MTX 15 mg weekly during the Run-in Period. During the Pegloticase + IMM Period, in addition to oral MTX 15 mg, participants received IV pegloticase 8 mg Q2W for a total of 26 infusions from Day 1 through the Week 50 Visit.
Participants were randomized to receive blinded oral placebo weekly during the Run-in Period. During the Pegloticase + IMM Period, in addition to oral placebo for MTX, participants received IV pegloticase 8 mg Q2W for a total of 26 infusions from Day 1 through the Week 50 Visit.
Overall Number of Participants Analyzed 100 52
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
71.0
(61.1 to 79.6)
38.5
(25.3 to 53.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pegloticase + MTX, Pegloticase + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments The 2-sided p-value was calculated assuming the test statistic was distributed as a standard normal random variable.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Stratified difference in proportions
Estimated Value 32.31
Confidence Interval (2-Sided) 95%
16.3 to 48.3
Parameter Dispersion
Type: Standard Error of the Mean
Value: 8.157
Estimation Comments Stratified difference (Pegloticase+MTX - Pegloticase+Placebo) is a weighted average of the difference within each stratum. Estimates from the 2 strata (tophi presence at baseline: yes, no) were combined with Cochran-Mantel-Haenszel (CMH) weights.
2.Secondary Outcome
Title Percentage of sUA (sUA < 6 mg/dL) Responders During Month 12
Hide Description 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, 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 with < 2 observations and those meeting the stopping rule (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.
Time Frame Month 12 (Weeks 48, 50 and 52)
Outcome Measure Data Not Reported
3.Secondary Outcome
Title Percentage of Participants With Complete Resolution of ≥ 1 Tophi at Week 52
Hide Description 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.
Time Frame Baseline, Week 52
Outcome Measure Data Not Reported
4.Secondary Outcome
Title Mean Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52
Hide Description 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.
Time Frame Baseline, Week 52
Outcome Measure Data Not Reported
5.Secondary Outcome
Title Mean Change From Baseline HAQ Pain Score at Week 52
Hide Description 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 postbaseline values.
Time Frame Baseline, Week 52
Outcome Measure Data Not Reported
6.Secondary Outcome
Title Mean Change From Baseline in HAQ Health Score at Week 52
Hide Description 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 postbaseline values.
Time Frame Baseline, Week 52
Outcome Measure Data Not Reported
Time Frame All Cause Mortality: from signing of informed consent up to Week 52 + 30 days after last pegloticase infusion (±3 days), as of 14 October 2021 (database lock date). Adverse events (AEs) in MTX Tolerability Assessment Period: from first dose of open-label MTX until Week -4. Run-in Period: from first dose of blinded MTX or Placebo (Week -4) to Day 1 (predose). Pegloticase+IMM Period: Day 1 to Week 52 + 30 days after last pegloticase infusion (±3 days), as of 14 October 2021 (database lock date).
Adverse Event Reporting Description Other (not including serious) AE table: The total number affected represents number of participants with an event that occurred in 5% or more participants in either treatment group during a given period.
 
Arm/Group Title MTX: Methotrexate Tolerability Assessment Period MTX: Run-In Period Placebo: Run-In Period Pegloticase + MTX: Pegloticase + IMM Period Pegloticase + Placebo: Pegloticase + IMM Period
Hide Arm/Group Description Participants received open-label oral MTX 15 mg for 2 weeks. 7 participants who were unable to tolerate MTX in this period or who met other exclusion criteria were not randomized and were classified as screen failures per protocol section 9.4.6.3.2.2. Participants were randomized to receive blinded oral MTX 15 mg weekly during the Run-in Period. Participants were randomized to receive blinded oral placebo weekly during the Run-in Period. Participants were randomized to receive blinded oral MTX 15 mg weekly during the Run-in Period. During the Pegloticase + IMM Period, in addition to oral MTX 15 mg, participants received IV pegloticase 8 mg Q2W for a total of 26 infusions from Day 1 through the Week 50 Visit. Participants were randomized to receive blinded oral placebo weekly during the Run-in Period. During the Pegloticase + IMM Period, in addition to oral placebo for MTX, participants received IV pegloticase 8 mg Q2W for a total of 26 infusions from Day 1 through the Week 50 Visit.
All-Cause Mortality
MTX: Methotrexate Tolerability Assessment Period MTX: Run-In Period Placebo: Run-In Period Pegloticase + MTX: Pegloticase + IMM Period Pegloticase + Placebo: Pegloticase + IMM Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/159 (0.00%)   0/98 (0.00%)   0/51 (0.00%)   2/96 (2.08%)   0/49 (0.00%) 
Hide Serious Adverse Events
MTX: Methotrexate Tolerability Assessment Period MTX: Run-In Period Placebo: Run-In Period Pegloticase + MTX: Pegloticase + IMM Period Pegloticase + Placebo: Pegloticase + IMM Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/159 (0.00%)   1/98 (1.02%)   0/51 (0.00%)   13/96 (13.54%)   5/49 (10.20%) 
Blood and lymphatic system disorders           
Leukocytosis  1  0/159 (0.00%)  1/98 (1.02%)  0/51 (0.00%)  0/96 (0.00%)  0/49 (0.00%) 
Cardiac disorders           
Cardiac Arrest  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
Mitral Valve Incompetence  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
Gastrointestinal disorders           
Small Intestinal Obstruction  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
General disorders           
Non-Cardiac Chest Pain  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  0/96 (0.00%)  1/49 (2.04%) 
Immune system disorders           
Anaphylactic Reaction  1 [1]  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
Infections and infestations           
Abscess Soft Tissue  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  0/96 (0.00%)  1/49 (2.04%) 
Covid-19  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  2/96 (2.08%)  0/49 (0.00%) 
Osteomyelitis  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
Injury, poisoning and procedural complications           
Gun Shot Wound  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
Infusion Related Reaction  1 [1]  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  2/49 (4.08%) 
Rib Fracture  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
Subdural Haematoma  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  0/96 (0.00%)  1/49 (2.04%) 
Investigations           
Blood Bilirubin Increased  1  0/159 (0.00%)  1/98 (1.02%)  0/51 (0.00%)  0/96 (0.00%)  0/49 (0.00%) 
Metabolism and nutrition disorders           
Failure To Thrive  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  0/96 (0.00%)  1/49 (2.04%) 
Musculoskeletal and connective tissue disorders           
Polymyalgia Rheumatica  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
Renal and urinary disorders           
Acute Kidney Injury  1  0/159 (0.00%)  1/98 (1.02%)  0/51 (0.00%)  0/96 (0.00%)  0/49 (0.00%) 
Nephrolithiasis  1  0/159 (0.00%)  1/98 (1.02%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
Respiratory, thoracic and mediastinal disorders           
Pneumothorax  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
Pulmonary Embolism  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  1/96 (1.04%)  0/49 (0.00%) 
1
Term from vocabulary, MedDRA version 23.1
Indicates events were collected by systematic assessment
[1]
Based on events adjudicated by external committee.
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
MTX: Methotrexate Tolerability Assessment Period MTX: Run-In Period Placebo: Run-In Period Pegloticase + MTX: Pegloticase + IMM Period Pegloticase + Placebo: Pegloticase + IMM Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   45/159 (28.30%)   28/98 (28.57%)   10/51 (19.61%)   71/96 (73.96%)   42/49 (85.71%) 
Gastrointestinal disorders           
Nausea  1  4/159 (2.52%)  3/98 (3.06%)  2/51 (3.92%)  5/96 (5.21%)  6/49 (12.24%) 
Vomiting  1  1/159 (0.63%)  0/98 (0.00%)  1/51 (1.96%)  0/96 (0.00%)  4/49 (8.16%) 
General disorders           
Fatigue  1  2/159 (1.26%)  1/98 (1.02%)  0/51 (0.00%)  5/96 (5.21%)  2/49 (4.08%) 
Infections and infestations           
COVID-19  1  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  7/96 (7.29%)  3/49 (6.12%) 
Injury, poisoning and procedural complications           
Infusion related reaction  1 [1]  0/159 (0.00%)  0/98 (0.00%)  0/51 (0.00%)  2/96 (2.08%)  13/49 (26.53%) 
Metabolism and nutrition disorders           
Gout  1  45/159 (28.30%)  28/98 (28.57%)  10/51 (19.61%)  64/96 (66.67%)  35/49 (71.43%) 
Musculoskeletal and connective tissue disorders           
Arthralgia  1  0/159 (0.00%)  2/98 (2.04%)  1/51 (1.96%)  13/96 (13.54%)  5/49 (10.20%) 
Pain in extremity  1  1/159 (0.63%)  2/98 (2.04%)  0/51 (0.00%)  1/96 (1.04%)  3/49 (6.12%) 
Vascular disorders           
Hypertension  1  0/159 (0.00%)  0/98 (0.00%)  1/51 (1.96%)  1/96 (1.04%)  3/49 (6.12%) 
1
Term from vocabulary, MedDRA version 23.1
Indicates events were collected by systematic assessment
[1]
Based on events adjudicated by external committee.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Horizon requests that any investigator/institution that plans on presenting/publishing results provide written notification of their request 60 days prior to their presentation/publication. Horizon requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if Horizon needs to secure patent or proprietary protection.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Supra Verma, MD
Organization: Horizon Therapeutics USA, Inc.
Phone: 866-479-6742
EMail: clinicaltrials@horizontherapeutics.com
Layout table for additonal information
Responsible Party: Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics Ireland DAC )
ClinicalTrials.gov Identifier: NCT03994731    
Other Study ID Numbers: HZNP-KRY-202
First Submitted: June 19, 2019
First Posted: June 21, 2019
Results First Submitted: March 4, 2022
Results First Posted: May 16, 2022
Last Update Posted: May 16, 2022