Gout
Conditions
Keywords
Refractory gout, Chronic gout
Brief summary
The purpose of this study is to evaluate the effect of a high zone tolerizing regimen of pegloticase on clinical outcome, as defined by an serum uric acid level \<6 mg/dL, in patients with chronic, refractory gout.
Detailed description
This is an exploratory open-label, multicenter study to evaluate the effectiveness of a 16-week high zone tolerance regimen of pegloticase on response to therapy (serum uric acid \<6 mg/dL) with this drug in adult hyperuricemic patients with gout refractory to conventional therapy. Eligible subjects will receive 1 of 3 different loading doses (8, 12, and 16 mg) on Study Day 1, and then receive 8 mg on Week 2 and 3, followed by 8 mg every 2 weeks through Week 17 for a total of 10 doses. Subjects will be monitored for efficacy and safety endpoints through Week 17. Subjects will also have blood drawn for pegloticase levels prior to each dose on Weeks 2, 3, 5, 7, 9, 11, 13,15, and 17. Following Study Week 17, subjects will have an option to continue dosing for an additional 8 weeks. A subset of subjects will participate in additional pharmacokinetic (PK) assessments. The study duration, per enrolled patient, will be approximately 26 weeks including a 2-week screening period, a 16-week treatment period (end of treatment \[EOT\] visit Week 17), and an optional 8-week dosing extension.
Interventions
BIOLOGICALPegloticase
Pegloticase, IV
DRUGAzathioprine
Azathioprine (1.25 mg/kg, followed by 2.5 mg/kg) oral, daily
Sponsors
IND 2 Results LLC
Ampel BioSolutions, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult (age ≥18 years) men and women of non-childbearing potential, with chronic gout refractory to conventional therapy, defined as patients who have failed to normalize SUA and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose, or for whom these drugs are contraindicated. 2. Hyperuricemic - Screening visit SUA must be \>6 mg/dL 3. On gout flare prophylactic regimen for 7 days prior to the first dose. 4. Willing and able to give informed consent and adhere to visit/protocol schedules (informed consent must be given before the first study procedure is performed)
Exclusion criteria
1. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (confirmed at Screening visit) 2. Non-compensated congestive heart failure, uncontrolled arrhythmia, treatment for acute coronary syndrome (ACS) (myocardial infarction or unstable angina) or hospitalization for congestive heart failure within 3 months of screening or uncontrolled blood pressure (\>160/100 mm Hg) at baseline (Screening and pre-dose at Week 1 visit ) 3. Women of childbearing potential defined as: * Pre- or perimenopausal (\<24 months of natural \[spontaneous\] amenorrhea). * \<6 weeks after surgical bilateral oophorectomy with or without hysterectomy. 4. Prior treatment with pegloticase or another recombinant uricase 5. Prior treatment or concomitant therapy with a polyethylene glycol (PEG) conjugated drug 6. Known allergy to PEG products or history of anaphylactic reaction to a recombinant protein or porcine product 7. Concurrent treatment with urate lowering agents (ULAs), such as allopurinol and febuxostat. Patients treated with these medications must discontinue treatment 7 days prior to the first dose of study drug 8. Recipient of an investigational drug within 4 weeks prior to study drug administration or plans to take an investigational agent during the study 9. Current liver disease as determined by alanine transaminase (ALT) or aspartate transaminase (AST) levels \>3 times upper limit of normal (ULN) 10. History of malignancy within 5 years other than basal cell skin cancer or carcinoma in situ of the cervix 11. Has any other medical or psychological condition which, in the opinion of the Investigator, might create undue risk to the patient or interfere with the patient's ability to comply with the protocol requirements, or to complete the study 12. Solid organ transplant recipients 13. Uncontrolled hyperglycemia with a plasma glucose value \>240 mg/dL at screening 14. Currently on dialysis Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Normalization of serum uric acid (SUA) in subjects receiving a tolerizing regimen of pegloticase | Week 17 | Determine response rate; the last 3 consecutive levels of SUA must be \<6 mg/dL |
| Normalization of serum uric acid (SUA) in subjects receiving pegloticase and azathioprine (AZA) immunosuppressive therapy | Week 25 | Determine response rate; the last 3 consecutive levels of SUA must be \<6 mg/dL |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of subjects with SUA <2 mg/dL | Week 17 | Proportion of subjects |
| Infusion reactions (IRs) and anaphylaxis | Week 17 | Incidence - AZA arm |
| Change from baseline in SUA to end of Treatment | Baseline and Week 17 | Change from baseline |
| Mean titer of anti-pegloticase antibodies | Week 17 | Anti-pegloticase antibodies |
| Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs | Week 17 | Incidence |
| Incidence of anti-pegloticase antibodies | Week 17 | Anti-pegloticase antibodies |
| Proportion of subjects with SUA <5 mg/dL | Week 17 | Proportion of subjects |
Other
| Measure | Time frame | Description |
|---|---|---|
| CL of pegloticase in subjects weighing ≥ 120 kg and < 120 kg | Up to Week 17 | PK parameter |
| Relationship in change from baseline in SUA from baseline with rate of infusion reactions | Baseline to Week 17 | Correlation between change in SUA and infusion reactions |
| Accumulation Ratio (AR) of pegloticase in subjects weighing ≥ 120 kg and < 120 kg | Up to Week 17 | PK parameter |
| Vss of pegloticase in subjects weighing ≥ 120 kg and < 120 kg | Up to Week 17 | PK parameter |
| Compare trough pegloticase levels | Week 17 | Descriptive statistics |
| Compare trough AZA levels | Week 25 | Descriptive statistics |
| Ability of imaging to monitor treatment response | Baseline and Week 17 | To compare the ability of dual-energy computed tomography (DECT) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to monitor treatment response, in a subset of subjects weighing \< 120 kg |
| Evaluate change from baseline carotid and aortic (chest) atherosclerosis | Baseline and Week 17 | Change from baseline as measured by fluorodeoxyglucose-positron emission tomography (FDG-PET-CT), in a subset of subjects weighing \< 120 kg |
| Cmax of pegloticase in subjects weighing ≥ 120 kg and < 120 kg | Up to Week 17 | PK parameter |
| Tmax of pegloticase in subjects weighing ≥ 120 kg and < 120 kg | Up to Week 17 | PK parameter |
| AUC of pegloticase in subjects weighing ≥ 120 kg and < 120 kg | Up to Week 17 | PK parameter |
| Terminal phase half-life of pegloticase in subjects weighing ≥ 120 kg and < 120 kg | Up to Week 17 | PK parameter |
Countries
United States
Outcome results
None listed