Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect

Gout Clinical Trial

— TRIPLE  

Official title:

Tolerization Reduces Intolerance to Pegloticase and Prolongs the Urate Lowering Effect

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02598596
• Other study ID #: AMP-001
• Status: Completed
• Phase: Phase 2
• Start date: December 2015
• Est. completion date: April 27, 2020

Study information

• Verified date: October 2021
• Source: Ampel BioSolutions, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 132
• Est. completion date: April 27, 2020
• Est. primary completion date: April 13, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Gout

Intervention

Biological:
• Pegloticase
Pegloticase, IV

Drug:
• Azathioprine
Azathioprine (1.25 mg/kg, followed by 2.5 mg/kg) oral, daily

Locations

Country	Name	City	State
United States	University of Alabama at Birminingham	Birmingham	Alabama
United States	Montefiore Medical Center	Bronx	New York
United States	Cleveland Clinic	Cleveland	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	Saint Paul Rheumatology	Eagan	Minnesota
United States	Rheumatology Associates of North Alabama	Huntsville	Alabama
United States	ACME Research, LLC	Orangeburg	South Carolina
United States	Buffalo Rheumatology and Medicine	Orchard Park	New York
United States	The Center for Rheumatology and Bone Research	Wheaton	Maryland
United States	Clinical Pharmacology Study Group	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Ampel BioSolutions, LLC	IND 2 Results LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Relationship in change from baseline in SUA from baseline with rate of infusion reactions	Correlation between change in SUA and infusion reactions	Baseline to Week 17
Other	Relationship in change from baseline in SUA from baseline with rate of infusion reactions	Correlation between change in SUA and infusion reactions - AZA arm	Baseline to Week 25
Other	Compare trough pegloticase levels	Descriptive statistics	Week 17
Other	Compare trough AZA levels	Descriptive statistics	Week 25
Other	Ability of imaging to monitor treatment response	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	Baseline and Week 17
Other	Evaluate change from baseline carotid and aortic (chest) atherosclerosis	Change from baseline as measured by fluorodeoxyglucose-positron emission tomography (FDG-PET-CT), in a subset of subjects weighing < 120 kg	Baseline and Week 17
Other	Cmax of pegloticase in subjects weighing = 120 kg and < 120 kg	PK parameter	Up to Week 17
Other	Tmax of pegloticase in subjects weighing = 120 kg and < 120 kg	PK parameter	Up to Week 17
Other	AUC of pegloticase in subjects weighing = 120 kg and < 120 kg	PK parameter	Up to Week 17
Other	Terminal phase half-life of pegloticase in subjects weighing = 120 kg and < 120 kg	PK parameter	Up to Week 17
Other	CL of pegloticase in subjects weighing = 120 kg and < 120 kg	PK parameter	Up to Week 17
Other	Vss of pegloticase in subjects weighing = 120 kg and < 120 kg	PK parameter	Up to Week 17
Other	Accumulation Ratio (AR) of pegloticase in subjects weighing = 120 kg and < 120 kg	PK parameter	Up to Week 17
Primary	Normalization of serum uric acid (SUA) in subjects receiving a tolerizing regimen of pegloticase	Determine response rate; the last 3 consecutive levels of SUA must be <6 mg/dL	Week 17
Primary	Normalization of serum uric acid (SUA) in subjects receiving pegloticase and azathioprine (AZA) immunosuppressive therapy	Determine response rate; the last 3 consecutive levels of SUA must be <6 mg/dL	Week 25
Secondary	Change from baseline in SUA to end of Treatment	Change from baseline	Baseline and Week 17
Secondary	Change from baseline in SUA to end of Treatment	Change from baseline - AZA arm	Baseline and Week 25
Secondary	Proportion of subjects with SUA <5 mg/dL	Proportion of subjects	Week 17
Secondary	Proportion of subjects with SUA <5 mg/dL	Proportion of subjects - AZA arm	Week 25
Secondary	Proportion of subjects with SUA <2 mg/dL	Proportion of subjects	Week 17
Secondary	Proportion of subjects with SUA <2 mg/dL	Proportion of subjects - AZA arm	Week 25
Secondary	Infusion reactions (IRs) and anaphylaxis	Incidence - AZA arm	Week 17
Secondary	Infusion reactions (IRs) and anaphylaxis	Incidence	Week 25
Secondary	Incidence of anti-pegloticase antibodies	Anti-pegloticase antibodies	Week 17
Secondary	Incidence of anti-pegloticase antibodies	Anti-pegloticase antibodies - AZA arm	Week 25
Secondary	Mean titer of anti-pegloticase antibodies	Anti-pegloticase antibodies	Week 17
Secondary	Mean titer of anti-pegloticase antibodies	Anti-pegloticase antibodies AZA arm	Week 25
Secondary	Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs	Incidence	Week 17
Secondary	Incidence of gout flares, adverse events (AEs), serious AEs (SAEs), and early terminations due to AEs	Incidence - AZA arm	Week 25