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
- Conditions
- Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
- Interventions
- Registration Number
- NCT04136184
- Lead Sponsor
- Ionis Pharmaceuticals, Inc.
- Brief Summary
The main objective of this study was to evaluate the efficacy of eplontersen as compared with the historical control of the placebo cohort in the NEURO-TTR trial (NCT01737398/2012-001831-30), in subjects with hereditary transthyretin-mediated amyloidosis polyneuropathy (hATTR-PN). For more information, please visit http://www.neuro-ttransform.com/.
- Detailed Description
This study was a multicenter, open-label study in up to 168 participants, who were randomized to receive subcutaneous (SC) injections of either eplontersen once every 4 weeks or inotersen once a week. Participants also received daily supplemental doses of the recommended daily allowance of vitamin A. Participants included in the inotersen reference arm crossed over to eplontersen at Week 37 after completing the Week 35 assessments.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 168
-
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 participant or the participantss 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 Neuropathy Impairment Score (NIS) ≥ 10 and ≤ 130
Key
- Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a participants 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 participant unsuitable for inclusion, or could interfere with the participant 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Inotersen Inotersen Participants received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, participants received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81. Inotersen Eplontersen Participants received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, participants received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81. Eplontersen Eplontersen Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.
- Primary Outcome Measures
Name Time Method Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66 Baseline, Week 66 mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: the NIS composite score (maximum of 244 points) \& the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. Least square (LS) mean \& standard error (SE) were analyzed using Mixed Effects Model with Repeated Measures (MMRM). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 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 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Percent Change From Baseline in Serum TTR Concentration at Week 65 Baseline, Week 65 As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.
Percent Change From Baseline in Serum TTR Concentration at Week 35 Baseline, Week 35 As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.
Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35 Baseline, Week 35 mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: NIS composite score (maximum of 244 points) \& the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
- Secondary Outcome Measures
Name Time Method Change From Baseline in Norfolk QOL-DN at Week 35 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 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66 Baseline, Week 35, Week 66 NSC score is a questionnaire composed of 38 questions divided into 5 domains: muscle weakness, sensory (hypo/loss of sensation), sensory (paresthesia, hyper sensation), autonomic (gastrointestinal \& urinary incontinence), \& autonomic (non-GI/non-urinary incontinence)\]. Answers to questionnaire are yes/no and if yes, then degree of severity is graded as 1 (slight +), 2 (moderate ++) and 3 (severe +++). 0=no symptom. NSC total score is a sum of scores across all 5 domains. Total score= 0-114. Higher scores=more neuropathy symptoms. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Change From Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65 Baseline, Week 65 SF-36 comprises 36 items that yield 8 subscales and 2 summary measures (PCS and Mental component summary \[MCS\]). Multi-item subscales (35 items) includes: physical function=10 items, role physical =4 items, bodily pain=2 items, general health=5 items, vitality=4 items, social functioning=2 items, role emotional =3 items and mental health=5 items. 8 subscales are scored from 0-100. Higher scores indicate better health. 8 subscales are aggregated into a PCS score ranging from 0-100. Higher scores indicate better health. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65 Baseline, Week 65 PND is a 5-stage scoring system. PND score is defined as I=sensory disturbances in limbs without motor impairment; II=difficulty walking without the need of a walking aid; IIIa=one stick or one crutch required for walking; IIIb=two sticks or two crutches needed; IV=wheelchair required or patient confined to bed. For analysis, no impairment is scored as 0, I is scored as 1, II as 2, IIIa as 3, IIIb as 4 and IV as 5. Lower scores indicate greater ambulatory function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Change From Baseline in Modified Body Mass Index (mBMI) at Week 65 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). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Trial Locations
- Locations (45)
Mayo Clinic - Arizona
🇺🇸Scottsdale, Arizona, United States
Mayo Clinic - Jacksonville
🇺🇸Jacksonville, Florida, United States
Indiana University School of Medicine - Indianapolis
🇺🇸Indianapolis, Indiana, United States
Hôpital Bicêtre
🇫🇷Le Kremlin-Bicêtre, Ile-De-France, France
Hôpital de la Timone
🇫🇷Marseille, France
Universitätsklinikum Würzburg
🇩🇪Würzburg, Bayern, Germany
Universitätsklinikum Heidelberg
🇩🇪Heidelberg, Germany
University General Hospital of Heraklion (PAGNI)
🇬🇷Heraklion, Crete, Greece
Azienda Ospedaliera Universitaria Policlinico Gaetano Martino
🇮🇹Messina, Italy
Fondazione IRCCS Istituto Neurologico Carlo Besta
🇮🇹Milano, Italy
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
Fondazione Policlinico Universitario Agostino Gemelli
🇮🇹Roma, Italy
Auckland City Hospital
🇳🇿Grafton, Auckland, New Zealand
Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria
🇵🇹Lisbon, Portugal
Centro Hospitalar Universitário do Porto - Hospital Geral de Santo Antonio
🇵🇹Porto, Portugal
Hospital Son Llàtzer
🇪🇸Palma De Mallorca, Illes Balears, Spain
Hospital Clínico San Carlos
🇪🇸Madrid, Spain
Norrlands Universitetssjukhus
🇸🇪Umeå, Sweden
Chang Gung Memorial Hospital - Linkou Branch
🇨🇳Taoyuan City, Guishan District, Taiwan
China Medical University Hospital
🇨🇳Taichung City, Taichung, Taiwan
Taipei Veterans General Hospital
🇨🇳Taipei City, Taipei, Taiwan
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
İstanbul Üniversitesi - Istanbul Tıp Fakültesi
🇹🇷İstanbul, Turkey
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States
Johns Hopkins University Neurology Research Office
🇺🇸Baltimore, Maryland, United States
Boston University School of Medicine
🇺🇸Boston, Massachusetts, United States
Mayo Clinic - Rochester
🇺🇸Rochester, Minnesota, United States
The Neurological Institute of New York
🇺🇸New York, New York, United States
University of North Carolina Hospitals - Neurology Clinic
🇺🇸Chapel Hill, North Carolina, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Penn Presbyterian Medical Center
🇺🇸Philadelphia, Pennsylvania, United States
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
Hospital Italiano de Buenos Aires
🇦🇷Ciudad Autónoma De Buenos Aires, Buenos Aires, Argentina
Hospital El Cruce
🇦🇷Florencio Varela, Buenos Aires, Argentina
STAT Research
🇦🇷Buenos Aires, Argentina
Instituto Fleni
🇦🇷Buenos Aires, Argentina
Perron Institute for Neurological and Translational Science
🇦🇺Nedlands, Western Australia, Australia
Instituto de Neurologia de Curitiba
🇧🇷Curitiba, Paraná, Brazil
Universidade Estadual de Campinas
🇧🇷Campinas, Brazil
Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto
🇧🇷Ribeirão Preto, Brazil
Hospital Universitário Clementino Fraga Filho
🇧🇷Rio De Janeiro, Brazil
Associação de Assistência à Criança Deficiente - Unidade Lar Escola
🇧🇷São Paulo, Brazil
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
The Cyprus Institute of Neurology and Genetics
🇨🇾Egkomi, Cyprus
Centre Hospitalier Universitaire de Toulouse
🇫🇷Toulouse, Haute-Garonne, France