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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 : March 13, 2019
Sponsor:
Information provided by (Responsible Party):
Prothena Biosciences Limited

Brief Summary:
A Phase 1, open-label study of intravenous (IV) PRX004 as a single agent in subjects with hereditary amyloid transthyretin (hATTR) amyloidosis. The study will consist of 3 phases and will enroll up to a total of 36 subjects. A 3+3 dose escalation component to determine the safety, tolerability, PK, PD, and MTD. An expansion component in anticipated PRX004 RP2D cohorts selected from the Dose Escalation Phase. An extended dosing component for eligible subjects from the Dose Escalation or Expansion phases.

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

Detailed Description:

This Phase 1, open-label consists of 3 phases. The Dose Escalation Phase is a 3+3 dose escalation component to determine the safety, tolerability, PK, PD, and MTD of IV PRX004 when given as a single agent in up to 36 evaluable subjects with hATTR amyloidosis. The Expansion Phase is an expansion component in anticipated PRX004 RP2D cohorts selected from the Dose Escalation Phase (this may occur in addition to cohorts in which additional subjects were added due to the observation of a dose-limiting [DLT] in the Escalation Phase). The Long-term Extension (LTE) Phase is an extended dosing component for eligible subjects from the Dose Escalation or Expansion phases.

The Dose Escalation Phase 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.

Dose escalation will occur after the third evaluable subject in a cohort 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 the event the starting dose of 0.1 mg/kg is not tolerated, the dose escalationwill be halted and the study stopped.

Each subject will receive a maximum of 3 infusions of PRX004 in the Dose Escalation Phase. Subjects who complete the Month 3-Day 22 Visit in the Dose Escalation or Expansion phases may be eligible to receive up to 15 additional PRX004 infusions in the LTE Phase.

Each subject will receive a maximum of 3 infusions of PRX004 in the Dose Escalation Phase. Subjects who complete the Month 3-Day 22 Visit in the Dose Escalation or Expansion phases may be eligible to receive up to 15 additional PRX004 infusions in the LTE Phase.

Subjects who completed the EOS Visit in the Dose Escalation Phase prior to implementation of Protocol Amendment 2 may re-enter the study in the LTE Phase if they meet specific inclusion/exclusion criteria.


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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 : November 30, 2021
Estimated Study Completion Date : November 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis

Arm Intervention/treatment
Experimental: PRX004

Dose escalation in up to 6 dose levels

Expansion of previously studied cohort(s) from Dose Escalation

Extended dosing at RP2D

Drug: PRX004

PRX004 (0.1, 0.3, 1, 3, 10, and 30 mg/kg) IV every 28 days

PRX004 IV every 28 days at RP2D(s)

PRX004 IV every 28 days at RP2D(s)





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. PRX004 pharmacokinetic parameters - Cmin [ Time Frame: 3 months ]
    Minimum observed concentration (Cmin) of PRX004 in plasma

  2. PRX004 pharmacokinetic parameters -Cmax [ Time Frame: 3 months ]
    Maximum observed concentration (Cmax) of PRX004 in plasma

  3. PRX004 pharmacokinetic parameters - T1/2 [ Time Frame: 3 months ]
    Terminal elimination half-life (T1/2) of PRX004 in plasma

  4. PRX004 pharmacokinetic parameters -AUClast [ Time Frame: 3 months ]
    Area under the concentration-time curve from time zero to the last quantifiable concentration time-point (AUClast) of PRX004 in plasma

  5. PRX004 pharmacokinetic parameters -AUCtau [ Time Frame: 3 months ]
    Area under the concentration-time curve over the dosing interval (AUCtau) of PRX004 in plasma

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



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
  4. Subjects receiving concomitant tafamidis or diflunisal may enroll in the study (providing the dose has been stable for the last 6 months)
  5. Karnofsky Performance Status (KPS) score ≥60
  6. 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
  7. 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
  8. Must have a biopsy unless data are available from a previous one. The biopsy may be taken from any tissue or organ affected by ATTR amyloidosis (eg, abdominal fat pad, salivary gland), at the Investigator's discretion. Nerve biopsies are not required.
  9. Polyneuropathy Disability (PND) Score ≤IIIB
  10. Neuropathy Impairment Score (NIS) ≥5 and ≤130

Exclusion Criteria:

  1. Amyloid light chain or other non-ATTR amyloidosis
  2. 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) Functional Class III-IV
  7. LVEF ≤45%
  8. Uncontrolled symptomatic orthostatic hypotension
  9. Myocardial infarction, unstable or uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the first dose of study drug
  10. Uncontrolled infection, or active malignancy with the exception of the following:

    • Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer

  11. Hospitalized for heart failure within the 12 weeks prior to the first dose of study drug
  12. Treatment with patisiran or inotersen within 30 days or 5 half-lives whichever is longer) prior to Month 1-Day 1

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
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Contact: Wendy Currlin 650-615-2145 wendy.currlin@prothena.com
Contact: Radhika Tripuraneni, MD 650-615-2106 radhika.tripuraneni@prothena.com

Locations
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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: Jaime Chisholm         
Principal Investigator: Raymond Comenzo         
United States, Minnesota
Mayo Clinic Minnesota Recruiting
Rochester, Minnesota, United States, 55905
Contact: Diane Schmidt         
Principal Investigator: Martha Grogan         
United States, Missouri
Washington University Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Daniel Lenihan         
United States, New York
Icahn School of Medicine at Mount Sinai Not yet recruiting
New York, New York, United States, 10029
Contact: Garnette Mason         
Principal Investigator: Peter Gorevic, MD         
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Stephen Helmke         
Principal Investigator: Mathew Maurer         
United States, Ohio
Cleveland Clinic Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Lauren Ives         
Principal Investigator: Mazan Hanna, MD         
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Chafic Karam, MD         
Principal Investigator: Chafic Karam, MD         
United States, Pennsylvania
Penn Presbyterian Medical Center Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Patricia DiVito         
Principal Investigator: Brian Drachman, MD         
Portugal
Centro Hospitalar do Porto Recruiting
Porto, Portugal
Contact: Marta Novais         
Principal Investigator: Ana Martins Silva         
Spain
Hospital Universitario Puerta de Hierro - Majadahonda Not yet recruiting
Majadahonda, Madrid, Spain, 28222
Contact: Ariadna Gonzalez Segovia         
Principal Investigator: Pablo García Pavia, MD         
Hospital Clinico San Carlos Not yet recruiting
Madrid, Spain, 28040
Contact: Marta Palacios         
Principal Investigator: Lucia Galan, MD         
Sweden
Umeå University Hospital Recruiting
Umeå, Sweden
Contact: Agnetha Lidgren         
Principal Investigator: Ole Suhr         
Sponsors and Collaborators
Prothena Biosciences Limited

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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: March 13, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Additional relevant MeSH terms:
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Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases