NEURO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of eplontersen 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/.

Detailed Description
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This is a multicenter, open-label study in up to 140 participants, who will be randomized to receive subcutaneous (SC) injections of either eplontersen 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 eplontersen at Week 37 after completing the Week 35 assessments.

Official Title
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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

Conditions
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Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Intervention / Treatment
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* Drug: Eplontersen
* Drug: Inotersen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 to 82 years at the time of informed consent Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent 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 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: 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 Karnofsky performance status ≤ 50 Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes Prior liver transplant or anticipated liver transplant within 1-yr of Screening New York Heart Association (NYHA) functional classification of ≥ 3 Acute coronary syndrome within 6 months of screening or major surgery within 3 months of Screening Other types of amyloidosis 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 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 Previous treatment with Tegsedi™ (Inotersen) or Onpattro™ (patisiran), or other oligonucleotide or RNA therapeutic (including siRNA)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 82 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eplontersen<br>Eplontersen by subcutaneous injection once every 4 weeks. | Drug: Eplontersen<br>* Eplontersen by subcutaneous injection<br>* Other names: IONIS-TTR-LRx;|
| Active Comparator: Inotersen<br>Inotersen by subcutaneous injection once weekly through week 34. Participants will then convert to Eplontersen administered subcutaneously once every 4 weeks until the end of study. | Drug: Eplontersen<br>* Eplontersen by subcutaneous injection<br>* Other names: IONIS-TTR-LRx;Drug: Inotersen<br>* Inotersen by subcutaneous injection<br>* Other names: ISIS 420915;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in mNIS+7 at 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. | Baseline, Week 66 | 
| Change from baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at 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. | Baseline, Week 66 | 
| Percent change from baseline in serum TTR concentration at Week 66 |  | Baseline, Week 66 | 
| Percent change from baseline in serum transthyretin (TTR) concentration at Week 35 |  | Baseline, Week 35 | 
| Change from baseline in modified neuropathy impairment score plus 7 (mNIS+7) at 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. | Baseline, Week 35 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Norfolk QOL-DN at 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. | Baseline, Week 35 | 
| Change from baseline in Neuropathy Symptom and Change (NSC) score at Weeks 35 and 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). | Baseline, Week 35, Week 66 | 
| Change from baseline in the Physical Component Summary (PCS) score of the 36-Item Short Form Survey (SF-36) at 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. | Baseline, Week 65 | 
| Change from baseline in Polyneuropathy Disability (PND) score at 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. | Baseline, Week 65 | 
| Change from baseline in modified body mass index (mBMI) at 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). | Baseline, Week 65 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polyneuropathy, Amyloidosis, ATTR, TTR