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

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ClinicalTrials.gov Identifier: NCT02598596
Recruitment Status : Active, not recruiting
First Posted : November 6, 2015
Last Update Posted : July 8, 2020
Sponsor:
Collaborator:
IND 2 Results LLC
Information provided by (Responsible Party):
Ampel BioSolutions, LLC

Tracking Information
First Submitted Date  ICMJE October 30, 2015
First Posted Date  ICMJE November 6, 2015
Last Update Posted Date July 8, 2020
Actual Study Start Date  ICMJE December 2015
Actual Primary Completion Date April 13, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 6, 2017)
  • 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
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: November 4, 2015)
Determination of responder rate for refractory gout patients receiving a tolerizing dose regimen of pegloticase [ Time Frame: Baseline to 17 weeks ]
The primary objective of this study is to determine the response rate as measured by the normalization of SUA (<6 mg/dL) at the last 3 SUAs time points (Weeks 13, 15, and 17) in patients who receive a tolerizing dose regimen of pegloticase.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 7, 2017)
  • Change from baseline in SUA to end of Treatment [ Time Frame: Baseline and Week 17 ]
    Change from baseline
  • Change from baseline in SUA to end of Treatment [ Time Frame: Baseline and Week 25 ]
    Change from baseline - AZA arm
  • Proportion of subjects with SUA <5 mg/dL [ Time Frame: Week 17 ]
    Proportion of subjects
  • Proportion of subjects with SUA <5 mg/dL [ Time Frame: Week 25 ]
    Proportion of subjects - AZA arm
  • Proportion of subjects with SUA <2 mg/dL [ Time Frame: Week 17 ]
    Proportion of subjects
  • Proportion of subjects with SUA <2 mg/dL [ Time Frame: Week 25 ]
    Proportion of subjects - AZA arm
  • Infusion reactions (IRs) and anaphylaxis [ Time Frame: Week 17 ]
    Incidence - AZA arm
  • Infusion reactions (IRs) and anaphylaxis [ Time Frame: Week 25 ]
    Incidence
  • Incidence of anti-pegloticase antibodies [ Time Frame: Week 17 ]
    Anti-pegloticase antibodies
  • Incidence of anti-pegloticase antibodies [ Time Frame: Week 25 ]
    Anti-pegloticase antibodies - AZA arm
  • Mean titer of anti-pegloticase antibodies [ Time Frame: Week 17 ]
    Anti-pegloticase antibodies
  • Mean titer of anti-pegloticase antibodies [ Time Frame: Week 25 ]
    Anti-pegloticase antibodies AZA arm
  • Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs [ Time Frame: Week 17 ]
    Incidence
  • Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs [ Time Frame: Week 25 ]
    Incidence - AZA arm
Original Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2015)
  • Change in Serum Uric Acid from Baseline to Week 17 (Efficacy) [ Time Frame: Baseline to 17 weeks ]
    • To determine the change in serum uric acid (SUA) from baseline (defined as Screening visit) to Week 17
  • Proportion of patients with SUA <5 mg/dL at Week 17(Efficacy) [ Time Frame: Baseline to 17 weeks ]
    • To determine the proportion of patients with SUA <5 mg/dL at Week 17
  • Proportion of patients with SUA <2 mg/dL at Week 17(Efficacy) [ Time Frame: Baseline to 17 weeks ]
    • To determine the proportion of patients with SUA <2 mg/dL at Week 17
  • Incidence of infusion reactions (IRs) and anaphylaxis (Safety) [ Time Frame: Baseline to 17 weeks ]
    • To assess the incidence of infusion reactions (IRs) and anaphylaxis
  • Incidence and mean titer of anti-pegloticase antibodies (Safety) [ Time Frame: Baseline to 17 weeks ]
    • To assess the incidence and mean titer of anti-pegloticase antibodies
  • Describe adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs (Safety) [ Time Frame: Baseline to 17 weeks ]
    • To describe adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs
Current Other Pre-specified Outcome Measures
 (submitted: November 7, 2017)
  • 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
  • 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
  • Compare trough pegloticase levels [ Time Frame: Week 17 ]
    Descriptive statistics
  • Compare trough AZA levels [ Time Frame: Week 25 ]
    Descriptive statistics
  • 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
  • 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
  • Cmax of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter
  • Tmax of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter
  • AUC of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter
  • Terminal phase half-life of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter
  • CL of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter
  • Vss of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter
  • Accumulation Ratio (AR) of pegloticase in subjects weighing ≥ 120 kg and < 120 kg [ Time Frame: Up to Week 17 ]
    PK parameter
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect
Official Title  ICMJE Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Gout
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.
    Intervention: Biological: Pegloticase
  • 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.
    Intervention: Biological: Pegloticase
  • 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.
    Intervention: Biological: Pegloticase
  • 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.
    Intervention: Biological: Pegloticase
  • 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.
    Intervention: Biological: Pegloticase
  • 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.
    Interventions:
    • Biological: Pegloticase
    • Drug: Azathioprine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 7, 2020)
132
Original Estimated Enrollment  ICMJE
 (submitted: November 4, 2015)
20
Estimated Study Completion Date  ICMJE September 2020
Actual Primary Completion Date April 13, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02598596
Other Study ID Numbers  ICMJE AMP-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ampel BioSolutions, LLC
Study Sponsor  ICMJE Ampel BioSolutions, LLC
Collaborators  ICMJE IND 2 Results LLC
Investigators  ICMJE Not Provided
PRS Account Ampel BioSolutions, LLC
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP