Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect (TRIPLE)

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Gout	Biological: Pegloticase; Drug: Azathioprine	Phase 2

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	177 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Other
Official Title:	Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect
Actual Study Start Date :	December 2015
Estimated Primary Completion Date :	December 2019
Estimated Study Completion Date :	April 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Pegloticase regimen <120 kg - Main Study; Subjects weighing <120 kg will receive a tolerizing dose of pegloticase 8 mg IV weekly for the first 3 weeks of dosing followed by an 8 mg IV dose every 2 weeks for a total of 10 doses.	Biological: Pegloticase; Pegloticase, IV; Other Name: Krystexxa
Experimental: Pegloticase regimen ≥120kg; Subjects weighing ≥ 120 kg will be sequentially assigned to 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.	Biological: Pegloticase; Pegloticase, IV; Other Name: Krystexxa
Experimental: Pegloticase PK Sub-Study; Subjects weighing <120 kg and ≥120 kg will be assigned to 1 of 2 different loading doses (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 have multiple blood sampled for PK levels over the 17 week dosing period.	Biological: Pegloticase; Pegloticase, IV; Other Name: Krystexxa
Experimental: Pegloticase Imaging Sub-Study; A subset of subjects participating in the Main Study and weighing <120 kg will have dual-energy computed tomography (DECT) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) performed at Screen and at Week 17.	Biological: Pegloticase; Pegloticase, IV; Other Name: Krystexxa
Experimental: Pegloticase FDG-PET-CT Sub-Study; A subset of subjects participating in the Main Study and weighing <120 kg will have fluorodeoxyglucose-positron emission tomography (FDG-PET-CT) to evaluate carotid and aortic (chest) atherosclerosis at Screen and at Week 17.	Biological: Pegloticase; Pegloticase, IV; Other Name: Krystexxa
Experimental: Pegloticase and Azathioprine; Subjects weighing <120 kg will receive azathioprine (AZA) daily for a 2-week run-in period, followed by daily AZA plus pegloticase 8 mg IV every 2 weeks through Week 25 for a total of 13 doses.	Biological: Pegloticase; Pegloticase, IV; Other Name: Krystexxa Drug: Azathioprine; Azathioprine (1.25 mg/kg, followed by 2.5 mg/kg) oral, daily; Other Name: Imuran

Outcome Measures

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Primary Outcome Measures :

1. Normalization of serum uric acid (SUA) in subjects receiving a tolerizing regimen of pegloticase [ Time Frame: Week 17 ]
   Determine response rate; the last 3 consecutive levels of SUA must be <6 mg/dL
2. Normalization of serum uric acid (SUA) in subjects receiving pegloticase and azathioprine (AZA) immunosuppressive therapy [ Time Frame: Week 25 ]
   Determine response rate; the last 3 consecutive levels of SUA must be <6 mg/dL

Secondary Outcome Measures :

1. Change from baseline in SUA to end of Treatment [ Time Frame: Baseline and Week 17 ]
   Change from baseline
2. Change from baseline in SUA to end of Treatment [ Time Frame: Baseline and Week 25 ]
   Change from baseline - AZA arm
3. Proportion of subjects with SUA <5 mg/dL [ Time Frame: Week 17 ]
   Proportion of subjects
4. Proportion of subjects with SUA <5 mg/dL [ Time Frame: Week 25 ]
   Proportion of subjects - AZA arm
5. Proportion of subjects with SUA <2 mg/dL [ Time Frame: Week 17 ]
   Proportion of subjects
6. Proportion of subjects with SUA <2 mg/dL [ Time Frame: Week 25 ]
   Proportion of subjects - AZA arm
7. Infusion reactions (IRs) and anaphylaxis [ Time Frame: Week 17 ]
   Incidence - AZA arm
8. Infusion reactions (IRs) and anaphylaxis [ Time Frame: Week 25 ]
   Incidence
9. Incidence of anti-pegloticase antibodies [ Time Frame: Week 17 ]
   Anti-pegloticase antibodies
10. Incidence of anti-pegloticase antibodies [ Time Frame: Week 25 ]
    Anti-pegloticase antibodies - AZA arm
11. Mean titer of anti-pegloticase antibodies [ Time Frame: Week 17 ]
    Anti-pegloticase antibodies
12. Mean titer of anti-pegloticase antibodies [ Time Frame: Week 25 ]
    Anti-pegloticase antibodies AZA arm
13. Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs [ Time Frame: Week 17 ]
    Incidence
14. Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs [ Time Frame: Week 25 ]
    Incidence - AZA arm

Other Outcome Measures:

1. Relationship in change from baseline in SUA from baseline with rate of infusion reactions [ Time Frame: Baseline to Week 17 ]
   Correlation between change in SUA and infusion reactions
2. Relationship in change from baseline in SUA from baseline with rate of infusion reactions [ Time Frame: Baseline to Week 25 ]
   Correlation between change in SUA and infusion reactions - AZA arm
3. Compare trough pegloticase levels [ Time Frame: Week 17 ]
   Descriptive statistics
4. Compare trough AZA levels [ Time Frame: Week 25 ]
   Descriptive statistics
5. Ability of imaging to monitor treatment response [ Time Frame: 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
6. Evaluate change from baseline carotid and aortic (chest) atherosclerosis [ Time Frame: 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
7. Cmax of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
   PK parameter
8. Tmax of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
   PK parameter
9. AUC of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
   PK parameter
10. Terminal phase half-life of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter
11. CL of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter
12. Vss of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter
13. Accumulation Ratio (AR) of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Maggie Pugh, MS	404-892-7002	mpugh@ind2results.com

Locations

United States, Alabama
University of Alabama at Birminingham	Recruiting
Birmingham, Alabama, United States, 35294
Rheumatology Associates of North Alabama	Recruiting
Huntsville, Alabama, United States, 35801
United States, California
Pacific Arthritis Center Medical Group	Withdrawn
Santa Maria, California, United States, 93454
United States, Maryland
The Center for Rheumatology and Bone Research	Recruiting
Wheaton, Maryland, United States, 20902
United States, Massachusetts
Clinical Pharmacology Study Group	Recruiting
Worcester, Massachusetts, United States, 01609
United States, Michigan
Henry Ford Health System	Recruiting
Detroit, Michigan, United States, 48202
United States, Minnesota
Saint Paul Rheumatology	Recruiting
Eagan, Minnesota, United States, 55121
United States, New York
Montefiore Medical Center	Recruiting
Bronx, New York, United States, 10467
Buffalo Rheumatology and Medicine	Recruiting
Orchard Park, New York, United States, 14127
United States, Ohio
Cleveland Clinic	Recruiting
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
Altoona Center for Clinical Research	Recruiting
Duncansville, Pennsylvania, United States, 16635
United States, South Carolina
ACME Research, LLC	Recruiting
Orangeburg, South Carolina, United States, 29118

Sponsors and Collaborators

Ampel BioSolutions, LLC

IND 2 Results LLC

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Ampel BioSolutions, LLC
ClinicalTrials.gov Identifier:	NCT02598596 History of Changes
Other Study ID Numbers:	AMP-001
First Posted:	November 6, 2015
Last Update Posted:	November 14, 2017
Last Verified:	November 2017

Keywords provided by Ampel BioSolutions, LLC:

Refractory gout; Chronic gout

Additional relevant MeSH terms:

Azathioprine; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antineoplastic Agents	Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents