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A Study of PRX004 in Subjects With Amyloid Transthyretin (ATTR) Amyloidosis

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ClinicalTrials.gov Identifier: NCT03336580
Recruitment Status : Recruiting
First Posted : November 8, 2017
Last Update Posted : December 7, 2018
Sponsor:
Information provided by (Responsible Party):
Prothena Biosciences Limited

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. Subjects with wtATTR amyloidosis may be enrolled as part of the expansion component.

Condition or disease Intervention/treatment Phase
Amyloidogenic Transthyretin (ATTR) Amyloidosis Drug: PRX004 Phase 1

Detailed Description:

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. 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. 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.

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. 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Dose Escalation Study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-label, Dose Escalation Study of Intravenous PRX004 in Subjects With Amyloid Transthyretin (ATTR) Amyloidosis
Actual Study Start Date : April 5, 2018
Estimated Primary Completion Date : August 31, 2019
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis

Arm Intervention/treatment
Experimental: 3+3 Cohort Study
This is a Phase 1 3+3 design Cohort Study Up to 6 dose levels may be nvestigated with IV infusions every 28 days
Drug: PRX004
Experimental: 3+3 Cohort Study with PRX004




Primary Outcome Measures :
  1. Maximum Tolerated Dose of PRX004 [ Time Frame: 28 days ]
    Maximum Tolerated Dose of PRX004

  2. Number of subjects with treatment-emergent adverse events and clinically significant changes in ECGs, echocardiograms, cardiac telemetry, vital signs, and laboratory evaluations [ Time Frame: 3 months ]
    Number of subjects with treatment-emergent adverse events and clinically significant changes in ECGs, echocardiograms, cardiac telemetry, vital signs, and laboratory evaluations


Secondary Outcome Measures :
  1. Change from baseline in mBMI [ Time Frame: 3 months ]
    Change from baseline in mBMI, defined as subject's weight (kg) / subject's squared height (m) × serum albumin (g/L) at the end of 3 months of treatment

  2. PRX004 pharmacokinetic parameters [ Time Frame: 3 months ]
    Pharmacokinetic parameters as measured by minimum observed concentration (Cmin)

  3. PRX004 pharmacokinetic parameters [ Time Frame: 3 months ]
    Pharmacokinetic parameters as measured by maximum observed concentration (Cmax)

  4. PRX004 pharmacokinetic parameters [ Time Frame: 3 months ]
    Pharmacokinetic parameters as measured by terminal elimination half-life (T1/2)

  5. PRX004 pharmacokinetic parameters [ Time Frame: 3 months ]
    Pharmacokinetic parameters as measured by area under the concentration-time curve from time zero to the last quantifiable concentration time-point (AUClast)

  6. PRX004 pharmacokinetic parameters [ Time Frame: 3 months ]
    Pharmacokinetic parameters as measured by area under the concentration-time curve over the dosing interval (AUCtau)

  7. Immunogenicity indicators [ Time Frame: 3 months ]
    Immunogenicity indicators: Anti-drug antibodies (ADA)

  8. Total TTR in plasma [ Time Frame: 3 months ]
    Total TTR in plasma

  9. Misfolded TTR in plasma [ Time Frame: 3 months ]
    Misfolded TTR in plasma



Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Age ≥18 years
  2. Confirmed diagnosis of ATTR amyloidosis
  3. Known TTR mutation except for subjects in the expansion component
  4. For subjects with wtATTR amyloidosis in the expansion component:

    Molecular definition of the absence of a TTR mutation or immunohistochemical staining of amyloid fibrils

  5. 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)
  6. Karnofsky Performance Status (KPS) score ≥60
  7. 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
  8. 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

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 eficiencies, 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. Hospitalized for heart failure within the 12 weeks prior to the first dose of study drug

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03336580


Contacts
Contact: Wendy Currlin 650-615-2145 wendy.currlin@prothena.com
Contact: Jay Soto 650-615-2131 jay.soto@prothena.com

Locations
United States, California
Stanford Cancer Institute (SCI) Completed
Stanford, California, United States, 94305
United States, Massachusetts
Tufts Medical Center Recruiting
Boston, Massachusetts, United States, 02111
Contact: George Mensing         
Principal Investigator: Raymond Comenzo         
United States, Minnesota
Mayo Clinic Minnesota Recruiting
Rochester, Minnesota, United States, 55905
Principal Investigator: Martha Grogan         
United States, Missouri
Washington University Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Daniel Lenihan         
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Principal Investigator: Mathew Maurer         
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Principal Investigator: Stephen Heitner, MD         
Portugal
Centro Hospitalar do Porto Recruiting
Porto, Portugal
Principal Investigator: Ana Martins Silva         
Sweden
Umeå University Hospital Recruiting
Umeå, Sweden
Principal Investigator: Ole Suhr         
Sponsors and Collaborators
Prothena Biosciences Limited

Responsible Party: Prothena Biosciences Limited
ClinicalTrials.gov Identifier: NCT03336580     History of Changes
Other Study ID Numbers: PRX004-101
2017-003521-15 ( EudraCT Number )
First Posted: November 8, 2017    Key Record Dates
Last Update Posted: December 7, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases