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NEURO-TTRansform: A Study to Evaluate the Efficacy and Safety of AKCEA-TTR-LRx in Participants With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

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ClinicalTrials.gov Identifier: NCT04136184
Recruitment Status : Recruiting
First Posted : October 23, 2019
Last Update Posted : September 22, 2020
Sponsor:
Collaborator:
Akcea Therapeutics
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Brief Summary:
To evaluate the efficacy and safety of AKCEA-TTR-LRx after administration for 65 weeks to patients with hereditary transthyretin-mediated amyloid polyneuropathy (hATTR-PN), as compared to the NEURO-TTR trial (NCT01737398). For more information, please visit http://www.neuro-ttransform.com/.

Condition or disease Intervention/treatment Phase
Hereditary Transthyretin-Mediated Amyloid Polyneuropathy Drug: AKCEA-TTR-LRx Drug: Inotersen Phase 3

Detailed Description:
This is a multicenter, open-label study in up to 140 participants, who will be randomized to receive subcutaneous (SC) injections of either AKCEA-TTR-LRx once every 4 weeks or inotersen once a week. Participants will also receive daily supplemental doses of the recommended daily allowance of vitamin A. Participants included in the inotersen reference arm will be crossed over to AKCEA-TTR-LRx at Week 37 after completing the Week 35 assessments.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3 Global, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of ION-682884 in Patients With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
Actual Study Start Date : January 15, 2020
Estimated Primary Completion Date : January 2024
Estimated Study Completion Date : January 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis

Arm Intervention/treatment
Experimental: AKCEA-TTR-LRx
AKCEA-TTR-LRx by subcutaneous injection once every 4 weeks
Drug: AKCEA-TTR-LRx
AKCEA-TTR-LRx by subcutaneous injection
Other Name: ION-682884

Active Comparator: Inotersen
Inotersen by subcutaneous injection once weekly through week 34. Participants will then convert to AKCEA-TTR-LRx administered subcutaneously once every 4 weeks until the end of study
Drug: AKCEA-TTR-LRx
AKCEA-TTR-LRx by subcutaneous injection
Other Name: ION-682884

Drug: Inotersen
Inotersen by subcutaneous injection
Other Names:
  • TEGSEDI
  • ISIS 420915




Primary Outcome Measures :
  1. Change from baseline in mNIS+7 at Week 66 [ Time Frame: Baseline, Week 66 ]
    The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 composite score has a range of -22.32 to 346.32, and a higher score indicates lower function.

  2. Change from baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 [ Time Frame: Baseline, Week 66 ]
    The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 136, and a higher score indicates poorer quality of life.

  3. Percent change from baseline in serum TTR concentration at Week 66 [ Time Frame: Baseline, Week 66 ]
  4. Percent change from baseline in serum transthyretin (TTR) concentration at Week 35 [ Time Frame: Baseline, Week 35 ]
  5. Change from baseline in modified neuropathy impairment score plus 7 (mNIS+7) at Week 35 [ Time Frame: Baseline, Week 35 ]
    The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 Composite Score has a range of -22.32 to 346.32, and a higher score indicates lower function.


Secondary Outcome Measures :
  1. Change from baseline in Norfolk QOL-DN at Week 35 [ Time Frame: Baseline, Week 35 ]
    The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 136, and a higher score indicates poorer quality of life.

  2. Change from baseline in Neuropathy Symptom and Change (NSC) score at Weeks 35 and 66 [ Time Frame: Baseline, Week 35, Week 66 ]
    NSC score is a questionnaire composed of 38 questions that assess the presence and severity of these neuropathy symptoms (including weakness, loss of temperature and pain sensation, and manifestations associated with autonomic nervous system dysfunction).

  3. Change from baseline in the Physical Component Summary (PCS) score of the 36-Item Short Form Survey (SF-36) at Week 65 [ Time Frame: Baseline, Week 65 ]
    The SF-36 is composed of 8 multi-item scales (35 items) assessing physical function (10 items), role limitations due to physical health problems (4 items), bodily pain (2 items), general health (5 items), vitality (4 items), social functioning (2 items), role limitations due to emotional problems (3 items) and emotional well-being (5 items). Each of the 8 scales is scored from 0 to 100 with higher scores indicating better health. The 8 scales can be aggregated into a PCS score, which is also scaled from 0 to 100 with higher scores indicating better health.

  4. Change from baseline in Polyneuropathy Disability (PND) score at Week 65 [ Time Frame: Baseline, Week 65 ]
    The PND is a 6-stage scoring system: Stage 0: no impairment; Stage 1: sensory disturbances but preserved walking capabilities; Stage 2: impaired walking capacity, but ability to walk without a stick or crutches; Stage 3A/B: walking with help of 1 or 2 sticks or crutches; Stage 4: confined to wheel chair or bedridden.

  5. Change from baseline in modified body mass index (mBMI) at Week 65 [ Time Frame: Baseline, Week 65 ]
    mBMI is defined as body mass index in kilograms per square meter (kg/m^2) multiplied by serum albumin in grams per liter (g/L)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 82 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 18 to 82 years at the time of informed consent
  2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent
  3. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method
  4. Diagnosis of hereditary transthyretin-mediated polyneuropathy as defined by meeting all 3 of the following:

    • Stage 1 or Stage 2 Familial Amyloid Polyneuropathy (FAP) or Coutinho Stage
    • Documented genetic mutation in the TTR gene
    • Symptoms and signs consistent with neuropathy associated with transthyretin amyloidosis, including NIS ≥ 10 and ≤ 130

Exclusion Criteria:

  1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to abnormal safety labs
  2. Karnofsky performance status ≤ 50
  3. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes
  4. Prior liver transplant or anticipated liver transplant within 1-yr of Screening
  5. New York Heart Association (NYHA) functional classification of ≥ 3
  6. Acute coronary syndrome within 6 months of screening or major surgery within 3 months of Screening
  7. Other types of amyloidosis
  8. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study
  9. Current treatment with any approved drug for hereditary TTR amyloidosis such as Vyndaqel® / Vyndamax™ (tafamidis), Tegsedi™ (inotersen), Onpattro™ (patisiran), off-label use of diflunisal or doxycycline, and tauroursodeoxycholic acid (TUDCA). If previously treated with Vyndaqel® / Vyndamax™, diflunisal or doxycycline, and TUDCA, must have discontinued treatment for at least 2 weeks prior to Study Day 1
  10. Previous treatment with Tegsedi™ (Inotersen) or Onpattro™ (patisiran), or other oligonucleotide or RNA therapeutic (including siRNA)

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): NCT04136184


Contacts
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Contact: Ionis Pharmaceuticals 800-679-4747 patients@ionisph.com

Locations
Show Show 17 study locations
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
Akcea Therapeutics
Additional Information:
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Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04136184    
Other Study ID Numbers: ION-682884-CS3
2019-001698-10 ( EudraCT Number )
First Posted: October 23, 2019    Key Record Dates
Last Update Posted: September 22, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Ionis Pharmaceuticals, Inc.:
Polyneuropathy
Amyloidosis
ATTR
TTR
Additional relevant MeSH terms:
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Polyneuropathies
Amyloid Neuropathies
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases