Clinical trial NCT02598596: Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect
Official title: Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Gout
Keywords: Refractory gout
Chronic gout
Lead sponsor: Ampel BioSolutions, LLC
Sponsor class: INDUSTRY
Collaborators: name: IND 2 Results LLC
First posted: 2015-11-06
Enrollment: 132
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.

Eligibility criteria: 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 Exclusion Criteria for Imaging Sub-study Only
15. Contraindication to receiving a gadolinium-based contrast agent (GBCA) or \> 2 previous lifetime exposures to a GBCA
16. Implanted pacemaker, certain older intracranial aneurysm clips, cochlear implants, certain prosthetic devices, implanted drug infusion pumps, neurostimulators, bone-growth stimulators, certain intrauterine contraceptive devices, or any other type of iron-based metal implants.
17. Any internal metallic objects such as bullets or shrapnel, as well as most surgical clips, pins, plates, screws, metal sutures, or wire mesh.

    Additional Exclusion Criteria for FDG-PET-CT Sub-study Only
18. Contraindication to FDG

    Additional Exclusion Criteria for Pegloticase and AZA Therapy Arm Only
19. Any active serious bacterial infection (2 weeks prior to screening) requiring antibiotic treatment
20. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia, chronic bronchiectasis
21. Current immunocompromised condition, including current or chronic treatment with systemic immunosuppressive agents (e.g., prednisone or equivalent dose \>510 mg/day)
22. At risk for tuberculosis. Specifically, subjects with: a) current clinical, radiographic, or laboratory evidence of active or latent tuberculosis; b) a history of active tuberculosis within the last 31 years even if it was treated; c) a history of active tuberculosis \>31 years ago unless there is documentation that the prior anti-tuberculosis treatment was appropriate in duration and type
23. Known history of hepatitis B surface antigen-positivity or hepatitis B DNA positivity
24. Known history of hepatitis C RNA-positivity
25. Known history of human immunodeficiency virus positivity
26. Severe chronic renal impairment (glomerular filtration rate \<25 mL/min/1.73 m2)
27. AZA treatment is contraindicated or considered inappropriate
28. Subject has a homozygous or heterozygous thiopurine methyltransferase (TPMT) variant genotype
29. Diagnosis of osteomyelitis
30. Known hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome
31. Concurrent use of a xanthine oxidase inhibitor

Primary outcomes:
measure: Normalization of serum uric acid (SUA) in subjects receiving a tolerizing regimen of pegloticase
timeFrame: Week 17
measure: Normalization of serum uric acid (SUA) in subjects receiving pegloticase and azathioprine (AZA) immunosuppressive therapy
timeFrame: Week 25
Secondary outcomes:
measure: Change from baseline in SUA to end of Treatment
timeFrame: Baseline and Week 17
measure: Change from baseline in SUA to end of Treatment
timeFrame: Baseline and Week 25
measure: Proportion of subjects with SUA <5 mg/dL
timeFrame: Week 17
measure: Proportion of subjects with SUA <5 mg/dL
timeFrame: Week 25
measure: Proportion of subjects with SUA <2 mg/dL
timeFrame: Week 17
measure: Proportion of subjects with SUA <2 mg/dL
timeFrame: Week 25
measure: Infusion reactions (IRs) and anaphylaxis
timeFrame: Week 17
measure: Infusion reactions (IRs) and anaphylaxis
timeFrame: Week 25
measure: Incidence of anti-pegloticase antibodies
timeFrame: Week 17
measure: Incidence of anti-pegloticase antibodies
timeFrame: Week 25
measure: Mean titer of anti-pegloticase antibodies
timeFrame: Week 17
measure: Mean titer of anti-pegloticase antibodies
timeFrame: Week 25
measure: Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs
timeFrame: Week 17
measure: Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs
timeFrame: Week 25
Other outcomes:
measure: Relationship in change from baseline in SUA from baseline with rate of infusion reactions
timeFrame: Baseline to Week 17
measure: Relationship in change from baseline in SUA from baseline with rate of infusion reactions
timeFrame: Baseline to Week 25
measure: Compare trough pegloticase levels
timeFrame: Week 17
measure: Compare trough AZA levels
timeFrame: Week 25
measure: Ability of imaging to monitor treatment response
timeFrame: Baseline and Week 17
measure: Evaluate change from baseline carotid and aortic (chest) atherosclerosis
timeFrame: Baseline and Week 17
measure: Cmax of pegloticase in subjects weighing ≥ 120 kg and < 120 kg
timeFrame: Up to Week 17
measure: Tmax of pegloticase in subjects weighing ≥ 120 kg and < 120 kg
timeFrame: Up to Week 17
measure: AUC of pegloticase in subjects weighing ≥ 120 kg and < 120 kg
timeFrame: Up to Week 17
measure: Terminal phase half-life of pegloticase in subjects weighing ≥ 120 kg and < 120 kg
timeFrame: Up to Week 17
measure: CL of pegloticase in subjects weighing ≥ 120 kg and < 120 kg
timeFrame: Up to Week 17
measure: Vss of pegloticase in subjects weighing ≥ 120 kg and < 120 kg
timeFrame: Up to Week 17
measure: Accumulation Ratio (AR) of pegloticase in subjects weighing ≥ 120 kg and < 120 kg
timeFrame: Up to Week 17
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birminingham
state: Alabama
city: Huntsville
country: United States
facility: Rheumatology Associates of North Alabama
state: Alabama
city: Wheaton
country: United States
facility: The Center for Rheumatology and Bone Research
state: Maryland
city: Worcester
country: United States
facility: Clinical Pharmacology Study Group
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Eagan
country: United States
facility: Saint Paul Rheumatology
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Orchard Park
country: United States
facility: Buffalo Rheumatology and Medicine
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Orangeburg
country: United States
facility: ACME Research, LLC
state: South Carolina
Study officials:
References: