Gout
Conditions
Keywords
gout, uncontrolled gout
Brief 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.
Detailed description
Study acquired from Horizon in 2024.
Interventions
BIOLOGICALPegloticase
IV pegloticase 8 mg Q2W
DRUGmethotrexate
Oral MTX 15 mg weekly
DRUGplacebo
Oral placebo for MTX
DIETARY_SUPPLEMENTfolic acid
Folic acid 1 mg orally every day beginning at Week -6 until prior to the Week 52 Visit.
DRUGgout 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.
DRUGfexofenadine
For IR prophylaxis, fexofenadine (180 mg orally) taken the day before each infusion and on the morning of each infusion.
DRUGacetaminophen
For IR prophylaxis, acetaminophen (1000 mg orally) taken the morning of each infusion.
DRUGmethylprednisolone
For IR prophylaxis, methylprednisolone (125 mg IV) given over an infusion duration between 10 - 30 minutes, immediately prior to each infusion.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6 | Month 6 (Weeks 20, 21, 22, 23 and 24) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of sUA (sUA < 6 mg/dL) Responders During Month 12 | Month 12 (Weeks 48, 50 and 52) | 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. |
| Percentage of Participants With Complete Resolution of ≥ 1 Tophi at Week 52 | Baseline, 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. |
| Mean Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 | Baseline, 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. |
| Mean Change From Baseline HAQ Pain Score at Week 52 | Baseline, 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. |
| Mean Change From Baseline in HAQ Health Score at Week 52 | Baseline, 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. |
Countries
United States
Participant flow
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, were classified as screen failures, and were not considered enrolled per protocol section 9.4.6.3.2.2. 152 randomized participants were considered enrolled in this trial.
Participants by arm
| Arm | Count |
|---|---|
| Pegloticase + MTX 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.
Per protocol, participants were also required to take folic acid, 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), and a regimen of fexofenadine, acetaminophen, and methylprednisolone for IR prophylaxis. | 100 |
| Pegloticase + Placebo 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 placebo for MTX, participants received IV pegloticase 8 mg Q2W for a total of 26 infusions from Day 1 through the Week 50 Visit.
Per protocol, participants were also required to take folic acid, 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), and a regimen of fexofenadine, acetaminophen, and methylprednisolone for IR prophylaxis. | 52 |
| Total | 152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Pegloticase + IMM Period | Death | 2 | 0 |
| Pegloticase + IMM Period | Lost to Follow-up | 3 | 6 |
| Pegloticase + IMM Period | Withdrawal by Subject | 15 | 9 |
Baseline characteristics
| Characteristic | Pegloticase + Placebo | Total | Pegloticase + MTX |
|---|---|---|---|
| Age, Continuous | 53.0 years STANDARD_DEVIATION 12.12 | 54.7 years STANDARD_DEVIATION 12.56 | 55.6 years STANDARD_DEVIATION 12.74 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 28 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 42 Participants | 123 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 14 Participants | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants | 22 Participants | 16 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 2 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 36 Participants | 105 Participants | 69 Participants |
| Sex: Female, Male Female | 8 Participants | 17 Participants | 9 Participants |
| Sex: Female, Male Male | 44 Participants | 135 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 159 | 0 / 98 | 0 / 51 | 2 / 96 | 0 / 49 |
| other Total, other adverse events | 45 / 159 | 28 / 98 | 10 / 51 | 71 / 96 | 42 / 49 |
| serious Total, serious adverse events | 0 / 159 | 1 / 98 | 0 / 51 | 13 / 96 | 5 / 49 |
Outcome results
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.
Time frame: Month 6 (Weeks 20, 21, 22, 23 and 24)
Population: Intent-to-treat (ITT) Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegloticase + MTX | Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6 | 71.0 percentage of participants |
| Pegloticase + Placebo | Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6 | 38.5 percentage of participants |
p-value: <0.000195% CI: [16.3, 48.3]Cochran-Mantel-Haenszel
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.
Time frame: Baseline, Week 52
Population: ITT Population: all randomized participants. Participants with an assessment at Week 52.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pegloticase + MTX | Mean Change From Baseline HAQ Pain Score at Week 52 | -31.02 score on a scale | Standard Error 2.208 |
| Pegloticase + Placebo | Mean Change From Baseline HAQ Pain Score at Week 52 | -22.59 score on a scale | Standard Error 3.23 |
p-value: 0.027295% CI: [-15.88, -0.97]MMRM ANCOVA
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.
Time frame: Baseline, Week 52
Population: ITT Population: all randomized participants. Participants with an assessment at Week 52.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pegloticase + MTX | Mean Change From Baseline in HAQ Health Score at Week 52 | -28.85 score on a scale | Standard Error 2.531 |
| Pegloticase + Placebo | Mean Change From Baseline in HAQ Health Score at Week 52 | -18.69 score on a scale | Standard Error 3.722 |
p-value: 0.022295% CI: [-18.84, -1.48]MMRM ANCOVA
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.
Time frame: Baseline, Week 52
Population: ITT Population: all randomized participants. Participants with an assessment at Week 52.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pegloticase + MTX | Mean Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 | -0.35 score on a scale | Standard Error 0.049 |
| Pegloticase + Placebo | Mean Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 | -0.31 score on a scale | Standard Error 0.071 |
p-value: 0.628795% CI: [-0.21, 0.13]MMRM ANCOVA
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.
Time frame: Baseline, Week 52
Population: ITT Population: all randomized participants with ≥ 1 tophi at baseline. Modified non-responder imputation was done for participants with missing tophi evaluation data at Week 52.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegloticase + MTX | Percentage of Participants With Complete Resolution of ≥ 1 Tophi at Week 52 | 53.8 percentage of participants |
| Pegloticase + Placebo | Percentage of Participants With Complete Resolution of ≥ 1 Tophi at Week 52 | 31.0 percentage of participants |
p-value: 0.048295% CI: [1.2, 44.4]Chi-squared
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.
Time frame: Month 12 (Weeks 48, 50 and 52)
Population: ITT Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegloticase + MTX | Percentage of sUA (sUA < 6 mg/dL) Responders During Month 12 | 60.0 percentage of participants |
| Pegloticase + Placebo | Percentage of sUA (sUA < 6 mg/dL) Responders During Month 12 | 30.8 percentage of participants |
p-value: 0.000395% CI: [13.2, 44.9]Cochran-Mantel-Haenszel