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Trial record 1 of 2 for:    NTLA-2001 | Amyloidosis
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Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2001 in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (ATTRv-PN) and Patients With Transthyretin Amyloidosis-Related Cardiomyopathy (ATTR-CM)

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ClinicalTrials.gov Identifier: NCT04601051
Recruitment Status : Recruiting
First Posted : October 23, 2020
Last Update Posted : December 2, 2022
Sponsor:
Information provided by (Responsible Party):
Intellia Therapeutics

Study Description
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Brief Summary:
This study will be conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NTLA-2001 in participants with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and participants with hereditary transthyretin amyloidosis with cardiomyopathy (ATTRv-CM) or wild type cardiomyopathy (ATTRwt-CM)

Condition or disease Intervention/treatment Phase
Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy Wild-Type Transthyretin Cardiac Amyloidosis Biological: NTLA-2001 Phase 1

Detailed Description:

For ATTRv-PN participants, Part 1 consists of an open-label, single-ascending dose study, which identifies the dose for evaluation in the cohort expansion of Part 2. Part 2 will follow as an open-label, dose expansion study to further characterize the activity of NTLA-2001, provide an initial assessment of the effect of NTLA-2001 on clinical measures of neuropathy and neurological function, and obtain additional safety data.

For ATTR-CM participants, Part 1 consists of an open-label, single-ascending dose study, which identifies the dose for evaluation in the cohort expansion of Part 2. Part 2 will follow as an open-label, dose expansion study to further characterize the activity of NTLA-2001, provide an initial assessment of the effect of NTLA-2001 on cardiac measures, and obtain additional safety data.

All participants who are dosed with NTLA-2001 will be offered to participate in a long-term safety monitoring follow-up study via a separate protocol.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Two-Part (Open-label, Single Ascending Dose (Part 1) and Open-label, Single Dose Expansion (Part 2)) Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2001 in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (ATTRv-PN) and Patients With Transthyretin Amyloidosis-Related Cardiomyopathy (ATTR-CM)
Actual Study Start Date : November 5, 2020
Estimated Primary Completion Date : March 2025
Estimated Study Completion Date : March 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Polyneuropathy Part 1: NTLA-2001
Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001.
 Biological: NTLA-2001
A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
Experimental: Polyneuropathy Part 2: NTLA-2001
Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.
 Biological: NTLA-2001
A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
Experimental: Cardiomyopathy Part 1 (UK only): NTLA-2001
Participants, assigned to one of 2 dose-escalation cohorts, will receive a single dose of NTLA-2001.
 Biological: NTLA-2001
A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
Experimental: Cardiomyopathy Part 2 (UK only): NTLA-2001
Participants, assigned to the dose-expansion cohort, will receive a single dose of NTLA-2001.
 Biological: NTLA-2001
A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants with Treatment-Emergent Adverse Events [ Time Frame: up to Day 730 ]
  2. Number of Participants with Clinically Significant Clinical Laboratory Test Findings [ Time Frame: up to Day 730 ]
  3. Number of Participants with Clinically Significant Safety Measurements [ Time Frame: up to Day 730 ]
  4. Percent Change from Baseline in Serum TTR (enzyme-linked immunosorbent assay [ELISA]) [ Time Frame: up to Day 730 ]
  5. Percent Change from Baseline in Serum Prealbumin [ Time Frame: up to Day 730 ]
  6. Mean Area Under the Plasma Concentration-Time Curve from Time Zero to the Time of the Last Measurable Concentration (AUClast) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  7. Mean Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUCinf) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  8. Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  9. Mean Time of the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  10. Mean Terminal Half-Life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  11. Mean Apparent Clearance (CL) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  12. Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  13. Change from Baseline in Anti-Drug Antibody to NTLA-2001 and Anti-Cas9 Protein Antibody to Transgene Product Levels [ Time Frame: up to Day 730 ]

Secondary Outcome Measures :
  1. Polyneuropathy only: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage. [ Time Frame: up to Day 730 ]
  2. Polyneuropathy only: Change from Baseline in Polyneuropathy Disability (PND) Score [ Time Frame: up to Day 730 ]
  3. Polyneuropathy only: Change from Baseline in Modified Body Mass Index (mBMI) [ Time Frame: up to Day 730 ]
  4. Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS) [ Time Frame: up to Day 730 ]
  5. Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7) [ Time Frame: up to Day 730 ]
  6. Polyneuropathy only: Change from Screening in 10-Meter Walk Test (10-MWT) [ Time Frame: up to Day 730 ]
  7. Polyneuropathy only: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) [ Time Frame: up to Day 730 ]
  8. Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L [ Time Frame: up to Day 730 ]
  9. Cardiomyopathy only: Change from Baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) [ Time Frame: up to Day 730 ]
  10. Cardiomyopathy only: Change from Baseline in hs Troponin T [ Time Frame: up to Day 730 ]
  11. Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI) [ Time Frame: up to Day 730 ]
  12. Cardiomyopathy only: Change from Baseline in Echocardiogram [ Time Frame: up to Day 730 ]
  13. Cardiomyopathy only: Change from Baseline in Cardio-pulmonary exercise test [ Time Frame: up to Day 730 ]
  14. Cardiomyopathy only: Change from Baseline in 6-Minute Walk Test (6-MWT) [ Time Frame: up to Day 730 ]
  15. Cardiomyopathy only: Change from Baseline in New York Heart Association (NYHA) Classification [ Time Frame: up to Day 730 ]
  16. Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ) [ Time Frame: up to Day 730 ]

Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Polyneuropathy Inclusion Criteria:

  • Male and/or female participants 18 to 80 years of age inclusive, at the time of signing the informed consent
  • Diagnosis of polyneuropathy (PN) due to transthyretin (TTR) amyloidosis (ATTR)
  • Must have a body weight of at least 45 kilograms (kg) at Screening visit
  • Lack of access to approved treatments for ATTR and/or progression of hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) despite use of approved treatment for ATTRv-PN

Polyneuropathy Exclusion Criteria:

  • Amyloidosis attributable to non-TTR protein, e.g., amyloid light-chain (AL) amyloidosis
  • Known leptomeningeal transthyretin amyloidosis

  • Use of any of the following TTR-directed therapy for ATTR within certain timeframe:

    1. Patisiran
    2. Inotersen
    3. Vutrisiran
    4. Tafamidis
    5. Diflunisal
    6. Doxycycline and/or tauroursodeoxycholic acid
    7. Any other investigational agent for the treatment of ATTRv-PN:
  • Other protocol defined Inclusion/Exclusion criteria may apply

Cardiomyopathy Inclusion Criteria (UK only):

  • Male and/or female participants 18 to 90 years of age inclusive, at the time of signing the informed consent
  • Diagnosis of transthyretin (ATTR) amyloidosis with cardiomyopathy, classified as hereditary ATTR amyloidosis with cardiomyopathy (ATTRv-CM) or wild type cardiomyopathy (ATTRwt-CM).
  • Must have a body weight of at least 45 kilograms (kg) at Screening visit
  • New York Heart Association (NYHA) Class I-III heart failure
  • At least 1 prior hospitalization for heart failure and/or clinical evidence of heart failure.
  • Able to complete ≥150 meters on the 6-minute walk test (6-MWT) during the Screening period.

Cardiomyopathy Exclusion Criteria (UK only):

  • Amyloidosis attributable to non-TTR protein, e.g., amyloid light-chain (AL) amyloidosis
  • Known leptomeningeal transthyretin amyloidosis

  • Use of any of the following TTR-directed therapy for ATTR within certain timeframes:

    1. Patisiran
    2. Inotersen
    3. Vutrisiran
    4. Tafamidis
    5. Diflunisal
    6. Doxycycline and/or tauroursodeoxycholic acid
    7. Investigational TTR stabilizer (e.g., AG-10)
  • Participants with heart failure that in the opinion of the investigator is caused by ischemic heart disease, hypertension, or uncorrected valvular disease and not primarily due to transthyretin amyloid cardiomyopathy.
  • Participants with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker is indicated but will not be placed. Pacemaker or defibrillator placement, initiation of or change in anti-arrhythmic medication within 28 days prior to study drug administration.
  • Other protocol defined Inclusion/Exclusion criteria may apply
Contacts and Locations
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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): NCT04601051


Contacts
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Contact: Trial Manager at Intellia 833-888-0387 clinicalscience@intelliatx.com

Locations
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France
Clinical Trial Site Recruiting
Paris, France
New Zealand
Clinical Trial Site Recruiting
Auckland, New Zealand
Sweden
Clinical Trial Site Recruiting
Umea, Sweden
United Kingdom
Clinical Trial Site Recruiting
London, United Kingdom
Sponsors and Collaborators
Intellia Therapeutics
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Intellia Therapeutics
ClinicalTrials.gov Identifier: NCT04601051    
Other Study ID Numbers: ITL-2001-CL-001
2020-002034-32 ( EudraCT Number )
First Posted: October 23, 2020    Key Record Dates
Last Update Posted: December 2, 2022
Last Verified: November 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Intellia Therapeutics:
NTLA-2001
Amyloidosis
Familial Amyloid Polyneuropathy
Pharmacokinetics
Pharmacodynamics
Neurologic Function
Clustered Regularly Interspaced Short Palindromic Repeats
 CRISPR
Polyneuropathy
ATTR
Transthyretin
TTR
FAP
Cardiomyopathy
Additional relevant MeSH terms:
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Amyloid Neuropathies, Familial
Amyloid Neuropathies
Amyloidosis
Amyloidosis, Familial
Polyneuropathies
Cardiomyopathies
Heart Diseases
Cardiovascular Diseases
Proteostasis Deficiencies
 Metabolic Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Metabolism, Inborn Errors