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

• 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: Horizon Therapeutics Ireland DAC
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		Pegloticase + MTX	Pegloticase + Placebo	Total
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
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%

Outcome Measures

1. Primary Outcome

Title	Percentage 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. 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)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) Population: all randomized participants.

Arm/Group Title	Pegloticase + MTX	Pegloticase + Placebo
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)

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
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
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
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
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
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

Adverse Events

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
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%)
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.
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.

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Supra Verma, MD
• Organization: Horizon Therapeutics USA, Inc.
• Phone: 866-479-6742
• EMail: clinicaltrials@horizontherapeutics.com

• 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