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Trial record 1 of 1 for:    NCT04601051
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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 29, 2021
Sponsor:
Information provided by (Responsible Party):
Intellia Therapeutics

Tracking Information
First Submitted Date  ICMJE October 19, 2020
First Posted Date  ICMJE October 23, 2020
Last Update Posted Date December 29, 2021
Actual Study Start Date  ICMJE November 5, 2020
Estimated Primary Completion Date August 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 21, 2021)
  • Number of Participants with Treatment-Emergent Adverse Events [ Time Frame: up to Day 730 ]
  • Number of Participants with Clinically Significant Clinical Laboratory Test Findings [ Time Frame: up to Day 730 ]
  • Number of Participants with Clinically Significant Safety Measurements [ Time Frame: up to Day 730 ]
  • Percent Change from Baseline in Serum TTR (enzyme-linked immunosorbent assay [ELISA]) [ Time Frame: up to Day 730 ]
  • Percent Change from Baseline in Serum Prealbumin [ Time Frame: up to Day 730 ]
  • 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 ]
  • 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 ]
  • Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  • Mean Time of the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  • Mean Terminal Half-Life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  • Mean Apparent Clearance (CL) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  • Mean Volume of Distribution (Vd) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 730 ]
  • 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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: October 19, 2020)
  • Parts 1 and 2: Number of Participants with Treatment-emergent Adverse Events [ Time Frame: up to Day 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: Number of Participants with Clinically Significant Clinical Laboratory Test Findings [ Time Frame: up to Day 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: Number of Participants with Clinically Significant Safety Measurements [ Time Frame: up to Day 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: Percent Change from Baseline in Serum TTR (ELISA) [ Time Frame: Baseline (Predose); Days 7, 14, 28, 56, 112, 168, 252, 365, 545, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: Percent Change from Baseline in Serum Prealbumin [ Time Frame: Baseline (Predose); Days 14 and 28 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: 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 168 ]
    Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
  • Parts 1 and 2: 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 168 ]
    Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
  • Parts 1 and 2: Mean Maximum Concentration (Cmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 168 ]
    Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
  • Parts 1 and 2: Mean Time to the Maximum Concentration (Tmax) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 168 ]
    Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
  • Parts 1 and 2: Mean Terminal Half-life (t½) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 168 ]
    Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
  • Parts 1 and 2: Mean Apparent Oral Clearance (CL/F) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 168 ]
    Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
  • Parts 1 and 2: Mean Apparent Volume of Distribution (Vd/F) for DMG-PEG2k, LP000001, Cas9 mRNA, and sgRNA [ Time Frame: up to Day 168 ]
    Samples will be collected predose, 30 minutes (min), 60 min, and at end of infusion during the infusion period. Post infusion samples will be collected at 15 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 12 h, 24 h (Day 2), and 48 h (Day 4), Day 4, Day 7, Day 14, Day 28, Day 56, Day 112, and Day 168.
  • Part 1 and 2: Change from Baseline in Anti-drug Antibody and Anti-Cas9 Protein Antibody Levels [ Time Frame: Baseline; Days 14, 28, 168, 365, 545, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2021)
  • Polyneuropathy only: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage. [ Time Frame: up to Day 730 ]
  • Polyneuropathy only: Change from Baseline in Polyneuropathy Disability (PND) Score [ Time Frame: up to Day 730 ]
  • Polyneuropathy only: Change from Baseline in Modified Body Mass Index (mBMI) [ Time Frame: up to Day 730 ]
  • Polyneuropathy only: Change from Screening in Neuropathy Impairment Score (NIS) [ Time Frame: up to Day 730 ]
  • Polyneuropathy only: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7) [ Time Frame: up to Day 730 ]
  • Polyneuropathy only: Change from Screening in 10-Meter Walk Test (10-MWT) [ Time Frame: up to Day 730 ]
  • Polyneuropathy only: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) [ Time Frame: up to Day 730 ]
  • Polyneuropathy only: Change from Baseline in EuroQOL (EQ)-5D-5L [ Time Frame: up to Day 730 ]
  • Cardiomyopathy only: Change from Baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) [ Time Frame: up to Day 730 ]
  • Cardiomyopathy only: Change from Baseline in hs Troponin T [ Time Frame: up to Day 730 ]
  • Cardiomyopathy only: Change from Baseline in Magnetic resonance imaging (MRI) [ Time Frame: up to Day 730 ]
  • Cardiomyopathy only: Change from Baseline in Echocardiogram [ Time Frame: up to Day 730 ]
  • Cardiomyopathy only: Change from Baseline in Cardio-pulmonary exercise test [ Time Frame: up to Day 730 ]
  • Cardiomyopathy only: Change from Baseline in 6-Minute Walk Test (6-MWT) [ Time Frame: up to Day 730 ]
  • Cardiomyopathy only: Change from Baseline in New York Heart Association (NYHA) Classification [ Time Frame: up to Day 730 ]
  • Cardiomyopathy only: Change from Baseline in Patient-reported outcomes (KCCQ) [ Time Frame: up to Day 730 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 19, 2020)
  • Parts 1 and 2: Change from Baseline in Familial Amyloid Polyneuropathy (FAP) Stage [ Time Frame: Baseline (Predose); Days 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: Change from Baseline in Polyneuropathy Disability (PND) Score [ Time Frame: Baseline (Predose); Days 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: Change from Baseline in Modified Body Mass Index (mBMI) [ Time Frame: Baseline (Predose); Days 28, 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: Change from Baseline in Serum Neurofilament Light Chain (NfL) Levels [ Time Frame: Baseline (Predose); Days 28, 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: Change from Screening in Neuropathy Impairment Score (NIS) [ Time Frame: Screening; Days 28, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Part 2: Change from Baseline in Modified Neuropathy Impairment Score +7 (mNIS+7) [ Time Frame: Baseline (Predose); Days 365 and 730 (up to 24 months) ]
  • Parts 1 and 2: Change from Screening in 10-Meter Walk Test (10-MWT) [ Time Frame: Screening; Days 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) [ Time Frame: Baseline (Predose); Days 28, 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
  • Parts 1 and 2: Change from Baseline in EuroQOL (EQ)-5D-5L [ Time Frame: Baseline (Predose); Days 168, 365, and 730 for each dose-escalation cohort in Part 1 and in Part 2 (up to 24 months) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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)
Official Title  ICMJE 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)
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)
Detailed Description

For ATTR-PN participants, Part 1 consists of an open-label, single ascending dose which may identify the optimal biologically active dose (OBD) of NTLA-2001, followed by Part 2, if applicable, an open-label, single- dose expansion at the OBD to further characterize activity of NTLA-2001, provide an initial assessment of the effect of NTLA-2001 on clinical measures of neuropathy and neurologic function, and obtain additional safety data at the OBD.

For ATTR-CM participants, Part 1 consists of open-label, single ascending doses which may identify the dose(s) for cohort expansion in Part 2. Part 2, if applicable, will follow as an open-label, single-dose expansion to further characterize activity of NTLA-2001, provide an assessment of the effect of NTLA-2001 on cardiac measures and obtain additional safety data for CM Part 1 dose levels.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy
  • Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy
  • Wild-Type Transthyretin Cardiac Amyloidosis
Intervention  ICMJE Biological: NTLA-2001
A clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system delivered by lipid nanoparticles (LNPs) for intravenous (IV) administration
Study Arms  ICMJE
  • Experimental: Polyneuropathy Part 1: NTLA-2001
    Participants, assigned to one of 4 dose-escalation cohorts, will receive a single dose of NTLA-2001 on Day 1 and will then be followed for up to 24 months.
    Intervention: Biological: NTLA-2001
  • Experimental: Polyneuropathy Part 2: NTLA-2001
    Participants will receive the optimal biologically active dose (OBD) of NTLA-2001 identified in Part 1 as a single dose on Day 1 and will then be followed for up to 24 months.
    Intervention: Biological: NTLA-2001
  • 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 on Day 1 and will then be followed for up to 24 months
    Intervention: Biological: NTLA-2001
  • Experimental: Cardiomyopathy Part 2 (UK only): NTLA-2001
    Participants will receive the dose of NTLA-2001 identified in part 1 as a single dose on Day 1 and will then be followed for up to 24 months
    Intervention: Biological: NTLA-2001
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 21, 2021)
74
Original Estimated Enrollment  ICMJE
 (submitted: October 19, 2020)
38
Estimated Study Completion Date  ICMJE November 2024
Estimated Primary Completion Date August 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Trial Manager at Intellia 833-888-0387 clinicalscience@intelliatx.com
Listed Location Countries  ICMJE New Zealand,   Sweden,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04601051
Other Study ID Numbers  ICMJE ITL-2001-CL-001
2020-002034-32 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Intellia Therapeutics
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Intellia Therapeutics
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Intellia Therapeutics
Verification Date December 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP