Uncontrolled Gout, Chronic Gout
Conditions
Keywords
Gout, KRYSTEXXA, Pegloticase, Methotrexate, Uncontrolled gout
Brief summary
This trial is to assess efficacy, safety, blood levels and bodily effects of up to 2 dose levels of intravenous (IV) pegloticase (KRYSTEXXA) infusions at every 4 week intervals (Q4 Weeks) for up to 6 months (Day 1 to 24 weeks with an optional 24 - 48 weeks treatment duration) when given in combination with weekly oral doses of methotrexate (MTX). The goal is to identify an appropriate dose to be administered every 4 weeks to be used for future clinical trials for patients with chronic gout that does not adequately respond to conventional therapy.
Detailed description
The primary objective is to choose a dose for further investigation by assessing the effect of up to 2 dose levels of pegloticase administered IV Q4 weeks, co-administered with weekly doses of oral MTX, as measured by the sustained normalization of serum uric acid (sUA) to \< 6 mg/dL for at least 80% of the time during Month 6 and the duration of sUA to \< 6 mg/dL over 24 week treatment period in adult participants with chronic gout refractory to conventional therapy. Acquired from Horizon in 2024.
Interventions
BIOLOGICALPegloticase
IV dose of pegloticase q4 weeks co-administered with weekly oral methotrexate
DRUGMethotrexate (MTX)
15 mg oral dose methotrexate administered weekly
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Screening period up to 35 days, followed by 4-week methotrexate (MTX) tolerability run-in. Treatment consists of pegloticase IV Q4 Wks dose for a total of 6 infusions (24 Weeks) with co-administered weekly oral MTX. Optional extension treatment (24-48 weeks) will be available for 6 more infusions (total of 12). Study will consist of Cohort 1: 16 mg pegloticase, co-administered with weekly doses of oral MTX; and, potential Cohort 2: 24 to 32 mg pegloticase, co-administered with weekly doses of oral MTX and/or potential infusion duration reduction to 60 min.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
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 trial. 3. Adult men or women ≥18 and \<80 years of age. 4. Uncontrolled gout, defined as meeting the following criteria: * Hyperuricemia during the screening period defined as sUA ≥6 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 as evidenced by either clinical signs consistent with chronic synovitis on clinical examination or the presence of typical gouty erosion(s) on hand and/or foot X-rays 5. Willing to discontinue any oral urate lowering therapy for at least 7 days prior to MTX dosing at Week -4 and remain off while receiving pegloticase treatments. 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 -4; subjects must agree to use 2 reliable forms of contraception during the trial, 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) and continue for 4 weeks/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. 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 trial, beginning with the initiation of MTX at Week -4 and continuing and for at least 3 months after the last dose of MTX. 8. Able to tolerate MTX 15 mg orally for 4 weeks (Week -4 through Day 1) prior to enrollment.
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 Day 1 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 Participants Who Were 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. Participants meeting the sUA discontinuation criteria (pre-infusion sUA \>6 mg/dL at 2 consecutive scheduled trial visits beginning with the Week 1 Visit) were counted as non-responders. |
| Time to First sUA ≥6 mg/dL After First Achieving sUA <6 mg/dL, From the First Pegloticase Infusion Until Week 24 | Day 1 to Week 24 | The number of participants who had pre-Infusion sUA ≥ 6 mg/dL post-day 1 pegloticase infusion were included in this analysis. The date of the first pre-infusion sUA ≥ 6 mg/dL was the event date. Participants who did not have the event were censored at the date of the last collected pre-infusion sample with non-missing sUA result. Participants who never achieved sUA \< 6 mg/dL were excluded from the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration (Cmax) of Pegloticase | Post infusion on Day 1, at Weeks 1, 2, 3 and pre-dose at Week 4 | Noncompartmental Pharmacokinetic (PK) parameters of pegloticase were estimated using concentration data after the first dose (including Week 4 predose concentration data) using Phoenix WinNonlin® software. The linear/log trapezoidal rule was used in conjunction with the appropriate noncompartmental model, with input values for dose level, dosing time, serum concentration, and corresponding real-time values, based on drug dosing times whenever possible. Below limit of quantification (BLQ) values prior to the first quantifiable concentration were set to 0; BLQ values at all other time points were set to half the lower limit of quantification (LLOQ) (0.025 µg/mL). |
| Area Under the Concentration- Time Curve From Time 0 to Week 4 Predose of Pegloticase | Post infusion on Day 1, at Weeks 1, 2, 3 and pre-dose at Week 4 | Noncompartmental PK parameters of pegloticase were estimated using concentration data after the first dose (including Week 4 predose concentration data) using Phoenix WinNonlin® software. The linear/log trapezoidal rule was used in conjunction with the appropriate noncompartmental model, with input values for dose level, dosing time, serum concentration, and corresponding real-time values, based on drug dosing times whenever possible. BLQ values prior to the first quantifiable concentration were set to 0; BLQ values at all other time points were set to half LLOQ (0.025 µg/mL). |
| Trough Serum Concentration (Ctrough) of Pegloticase at Week 24 Pre-dose | Week 24 Pre-dose | Blood samples were collected for measurement of serum concentrations of pegloticase. The median concentration of pegloticase taken at Week 24 pre-dose was reported as the Ctrough concentration at Week 24. |
| Percentage of Participants With Pre-infusion sUA <6 mg/dL at Each Scheduled Visit | Pre-infusion on Day 1, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40 and 44 | The percentage of participants with pre-infusion sUA \<6 mg/dL at each scheduled infusion visit, regardless of treatment status, was presented. |
| Area Under the sUA Concentration vs Time Curve From Day 1 to Week 24 and Day 1 to Week 48 | Day 1 to Week 24 and Day 1 to Week 48 | The AUC from Day 1 to Week 24 and from Day 1 to Week 48 was calculated as time-adjusted AUC derived using the trapezoidal rule divided by the number of total days in the given period. The AUC from Day 1 to Week 48 was only calculated for participants who continued in the optional treatment period from Week 24 to Week 48. |
| Percentage of Time Participants Sustained sUA < 6 mg/dL From Day 1 to Week 24 or Day 1 to Week 48 | Day 1 to Week 24 and Day 1 to Week 48 | The percentage of time that participants sustained sUA \< 6 mg/dL was derived using linear interpolation across all observed data points between Day 1 and the end of each analysis period. The percentage of time during a given period is the time that sUA \< 6 mg/dL divided by the total time from the first to the last scheduled visit in the given period. |
| Percentage of Participants With Anti-uricase Antibodies at Each Scheduled Visit | Day 1 (Baseline) and Weeks 2, 4, 8, 16, 24, 36 and 48 | Pegloticase immunogenicity was assessed by incidence of anti-poly (Ethylene Glycol) (PEG) and anti-uricase immunoglobulin G (IgG) antibodies. The percentage of participants who were treatment-emergent anti-drug antibody (ADA) positive is presented below. Participants were considered treatment-emergent ADA positive if they were ADA negative at the data collection timepoint of Day 1 (Baseline) and ADA positive at one of the specified post-dose timepoints. |
| Percentage of Participants With Anti-PEG Antibodies at Each Scheduled Visit | Day 1 (Baseline) and Weeks 2, 4, 8, 16, 24, 36 and 48 | Pegloticase immunogenicity was assessed by incidence of anti-PEG and anti-uricase IgG antibodies. The percentage of participants who were treatment-emergent ADA positive is presented below. Participants were considered treatment-emergent ADA positive if they were ADA negative at the data collection timepoint of Day 1 (Baseline) and ADA positive at one of the specified post-dose timepoints. |
Countries
United States
Contacts
STUDY_DIRECTORMD
Amgen
STUDY_DIRECTORSupra Verma, MD
Horizon Therapeutics
Participant flow
Recruitment details
A total of 54 participants were enrolled into this trial in the United States between March 2021 and December 2023.
Pre-assignment details
This trial included a screening period of up to 5 weeks, a methotrexate (MTX) run-in period of 4 weeks, a pegloticase + MTX treatment period from Day 1 to Week 24, and an optional extension period from Week 24 to Week 48. A safety follow-up visit occurred 4 weeks after the last pegloticase infusion or MTX dose.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 54.2 years STANDARD_DEVIATION 9.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 45 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 1 / 25 | 0 / 26 |
| other Total, other adverse events | 21 / 54 | 19 / 25 | 21 / 26 |
| serious Total, serious adverse events | 0 / 54 | 3 / 25 | 0 / 26 |
Outcome results
None listed