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History of Changes for Study: NCT03336580
A Study of PRX004 in Subjects With Amyloid Transthyretin (ATTR) Amyloidosis
Latest version (submitted August 18, 2020) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 November 3, 2017 None (earliest Version on record)
2 January 3, 2018 Outcome Measures, Study Design, Study Status and Study Identification
3 September 7, 2018 Recruitment Status, Outcome Measures, Study Status, Contacts/Locations, Arms and Interventions, Study Description, Sponsor/Collaborators, Study Identification, Eligibility, Conditions and Oversight
4 October 11, 2018 Contacts/Locations and Study Status
5 December 5, 2018 Contacts/Locations and Study Status
6 December 14, 2018 Arms and Interventions, Outcome Measures, Study Description, Study Status and Eligibility
7 January 29, 2019 Study Status and Contacts/Locations
8 March 12, 2019 Contacts/Locations and Study Status
9 June 4, 2019 Contacts/Locations and Study Status
10 July 10, 2019 Study Status and Contacts/Locations
11 November 10, 2019 Contacts/Locations and Study Status
12 June 4, 2020 Recruitment Status, Contacts/Locations, Study Status and Study Design
13 June 9, 2020 Study Status, Contacts/Locations and Eligibility
14 August 18, 2020 Recruitment Status, Study Status and IPDSharing
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Study NCT03336580
Submitted Date:  November 3, 2017 (v1)

Open or close this module Study Identification
Unique Protocol ID: PRX004-101
Brief Title: A Study of PRX004 in Subjects With Amyloid Transthyretin (ATTR) Amyloidosis
Official Title: A Phase 1, Open-label, Dose Escalation Study of Intravenous PRX004 in Subjects With Amyloid Transthyretin (ATTR) Amyloidosis
Secondary IDs:
Open or close this module Study Status
Record Verification: October 2017
Overall Status: Not yet recruiting
Study Start: March 31, 2018
Primary Completion: August 31, 2019 [Anticipated]
Study Completion: December 31, 2019 [Anticipated]
First Submitted: October 23, 2017
First Submitted that
Met QC Criteria:
November 3, 2017
First Posted: November 8, 2017 [Actual]
Last Update Submitted that
Met QC Criteria:
November 3, 2017
Last Update Posted: November 8, 2017 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Prothena Biosciences Ltd.
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary: A Phase 1, open-label, 3+3 dose escalation component to determine the safety, tolerability, PK, PD, and MTD of IV PRX004 when given as a single agent to up to 36 subjects with hATTR amyloidosis An expansion component in up to 2 anticipated PRX004 RP2D cohorts selected from dose escalation (up to an additional 3 subjects in each expanded cohort for up to 6 evaluable subjects total in each expanded cohort; an evaluable subject is defined as a subject who has completed the first 28 days following the first administration of PRX004 or who discontinued within 28 days due to study drug related toxicity). Subjects with wtATTR amyloidosis may be enrolled as part of the expansion component.
Detailed Description:

This study consists of the following:

A Phase 1, open-label, 3+3 dose escalation component to determine the safety, tolerability, PK, PD, and MTD of intravenous (IV) PRX004 when given as a single agent in up to 36 subjects with hATTR amyloidosis An expansion component in up to 2 anticipated PRX004 RP2D cohorts selected from dose escalation (up to an additional 3 subjects in each expanded cohort for up to 6 evaluable subjects total in each expanded cohort; an evaluable subject is defined as a subject who has completed the first 28 days following the first administration of PRX004 or who discontinued within 28 days due to study drug related toxicity). Subjects with wtATTR amyloidosis may be enrolled as part of the expansion component.

Dose Escalation:

The dose escalation component will follow a standard 3+3 design, in which cohorts of 3 to 6 subjects with hATTR amyloidosis will be enrolled at each dose level to receive IV PRX004 once every 28 days, based on scheduling from Month 1-Day 1 for up to 3 doses. A ±4 day visit window may be allowed for Months 2 and 3 Day 1 visits. Each subject will participate in only 1 dose escalation cohort. The starting dose of PRX004 will be 0.1 mg/kg.

Each cohort must include at least 2 of 3 (or 4 of 6) subjects with evidence of ATTR amyloidosis cardiac involvement and at least 1 subject with ATTR amyloidosis peripheral neuropathy involvement although it is recognized that subjects may have evidence of both manifestations. A single subject will be dosed at the initial PRX004 dose level of 0.1 mg/kg and observed for 7 days for tolerance to the dose before enrollment of an additional 2 subjects at the starting dose of 0.1 mg/kg may be considered. The first 3 subjects will be dosed at the initial PRX004 dose of 0.1 mg/kg and must complete the first 28 days following the first administration of PRX004 before dose escalation in subsequent cohorts of subjects may occur.

Each subsequent dose escalation cohort will follow the same dosing strategy; one subject will be enrolled at the new dose level and will be treated and observed for the first 7 days following treatment for tolerance to the dose before an additional 2 subjects may be treated at that dose level. Dose escalation in subsequent cohorts will occur after the third evaluable subject has completed the first 28 days following the first administration of PRX004. Up to 6 dose levels of PRX004 may be investigated (0.1, 0.3, 1, 3, 10, and 30 mg/kg) if tolerable. In addition, intermediate dose levels may be investigated. In the event the starting dose is not tolerated, the dose escalation will be halted and the study stopped.

Each subject will receive a maximum of 3 infusions of PRX004. Dosing beyond 3 infusions may be added in a subsequent protocol amendment after the availability of 6 month nonclinical toxicology study results.

Subjects who discontinue study drug before the third infusion should have an Early Termination from Study (ETS) Visit 30 (±5 days) after their final administration of study drug.

Open or close this module Conditions
Conditions: Amyloid Transthyretin (ATTR) Amyloidosis
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Other
Study Phase: Phase 1
Interventional Study Model: Single Group Assignment
Dose Escalation Study
Number of Arms: 1
Masking: None (Open Label)
Allocation: N/A
Enrollment: 36 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: 3+3 Cohort Study
This is a Phase 1 3+3 design Cohort Study
Drug: PRX004
PRX004 is supplied as a sterile, lyophilized dosage form in 20 mL vials, each containing 250 mg of product.
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Maximum tolerated dose (MTD) of PRX004 in subjects with hATTR amyloidosis
[ Time Frame: 18 months ]

To determine the maximum tolerated dose (MTD) of PRX004 in subjects with hATTR amyloidosis
Secondary Outcome Measures:
1. Safety, of the anticipated RP2D(s) of PRX004 in subjects with hATTR or wtATTR amyloidosis
[ Time Frame: 18 months ]

To identify the safety of the anticipated Recommended Phase 2 Dose of PRX004 in subjects with hATTR or wtATTR amyloidosis as assessed by the CTCAE Criteria for Adverse Events (CTCAE) Grade 1-5
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  1. Age ≥18 years
  2. Ability to understand and willingness to sign an informed consent form (ICF) prior to initiation of any study procedures
  3. Diagnosis of amyloidosis determined by polarizing light microscopy of green birefringent material in Congo Red-stained tissue specimens; and confirmed diagnosis of ATTR amyloidosis by immunohistochemistry, mass spectrometry, or ONLY in the case of subjects with predominant cardiac involvement, 99m technitium-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scans and/or technetium pyrophosphate (PYP) SPECT cardiac imaging. If scintigraphy is used for diagnosis then the grade must be 2 or greater, indicative of ATTR-CM (Gillmore 2016)
  4. Known TTR mutation except for subjects in the expansion component
  5. For subjects with wtATTR amyloidosis in the expansion component: Molecular definition of the absence of a TTR mutation or immunohistochemical staining of amyloid fibrils with anti TTR antibody and negative genetic testing for a TTR mutation
  6. For subjects enrolled at European sites: Subjects with peripheral neuropathy and receiving concomitant tafamidis may enroll in the study (providing the dose of tafamidis has been stable for the last 6 months). For subjects enrolled at any site: Subjects receiving concomitant diflunisal (any geography and either phenotype) may enroll in the study (providing the dose of diflunisal has been stable for the last 6 months)
  7. Karnofsky Performance Status (KPS) score ≥60
  8. Adequate organ function, including all of the following:
    1. Adequate bone marrow reserve, defined as the following: absolute neutrophil count ≥1.0 × 109/L; platelet count ≥100 × 109/L; hemoglobin ≥10 g/dL
    2. Hepatic: total bilirubin ≤2 × upper limit of normal (ULN), transaminases (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT]) ≤3 × ULN; alkaline phosphatase ≤5 × ULN
    3. Renal: estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2
  9. If currently receiving a diuretic, must have been on a stable dose for at least 4 weeks prior to the first dose of study drug
  10. Systolic blood pressure ≥90 mmHg and ≤180 mmHg
  11. Subjects with cardiomyopathy must have an NT-proBNP ≥650 pg/mL and ≤5000 pg/mL (i.e., ≥76.9 pmol/L and ≤591 pmol/L) or evidence of septal wall thickening >1.2 cm on echocardiogram
  12. Subjects with peripheral neuropathy predominant disease must have a biopsy unless data are available from a previous one
  13. Women of childbearing potential (WOCBP) must have 2 negative pregnancy tests during Screening, the second within 24 hours prior to the first administration of study drug and must agree to use highly effective physician approved contraception (Appendix 1) from Screening to 90 days following the last study drug administration
  14. Male subjects must be surgically sterile or must agree to use highly effective physician approved contraception (Appendix 1) from Screening to 90 days following the last study drug administration

Exclusion Criteria:

  1. Amyloid light chain or other non-ATTR amyloidosis
  2. For subjects with peripheral neuropathy: any past history of or present abuse of alcohol, diabetes, B12 or folate deficiencies, autoimmune diseases, hereditary disorders other than TTR (e.g. Charcot Marie-Tooth), uncontrolled hypothyroidism or other etiologies for the peripheral neuropathy
  3. Received prior liver transplant
  4. Planned liver transplant
  5. mBMI ≤600 kg/m2 × g/L
  6. New York Heart Association (NYHA) Stage 3 or 4
  7. LVEF ≤45%
  8. Uncontrolled symptomatic orthostatic hypotension
  9. Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the first dose of study drug
  10. Any history of clinically significant sinus pauses on ECG
  11. Sinus pauses >3 seconds in the day or sinus pauses >5 seconds at night during the 48 hour pre-dose cardiac monitoring (i.e., prior to first dose of study drug)
  12. Arrhythmia requiring treatment diagnosed during the 48-hour pre-dose cardiac monitoring (i.e., prior to first dose of study drug). Note: subject could be reconsidered for entry into the study if appropriate treatment is obtained
  13. Hospitalized for heart failure within the 12 weeks prior to the first dose of study drug
  14. Uncontrolled infection, or active malignancy with the exception of the following:
    • Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
    • Low risk prostate cancer with Gleason score <7 and prostate specific antigen <10 mg/mL
    • Any other cancer from which the subject has been disease-free for ≥2 years
  15. Clinically significant pleural effusion per Investigator (e.g., presence of pleural effusion ≥30% in either hemithorax)
  16. History of Grade ≥3 hypersensitivity-associated AEs or hypersensitivities to other mAbs or the excipients found in the PRX004 formulation
  17. Known HIV infection or known hepatitis B or C virus carrier
  18. Women who are pregnant or breastfeeding
  19. Treatment with an investigational agent within 30 days or 5 half-lives (whichever is longer) of Month 1-Day 1
  20. Any condition which could interfere with, or the treatment for which might interfere with, the conduct of the study or which would, in the opinion of the Investigator unacceptably increase the subject's risk by participating in the study
Open or close this module Contacts/Locations
Central Contact Person: Dimple Jashnani
Telephone: 650-837-8550
Email: dimple.jashnani@prothena.com
Central Contact Backup: Laura Maher
Telephone: +353 1 236 2500
Email: laura.maher@prothena.com
Locations:
Open or close this module IPDSharing
Plan to Share IPD: Undecided
Open or close this module References
Links:
Available IPD/Information:

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