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

Hereditary Transthyretin-Mediated Amyloid Polyneuropathy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04136184
• Other study ID #: ION-682884-CS3
• Secondary ID: 2019-001698-10
• Status: Completed
• Phase: Phase 3
• Start date: January 15, 2020
• Est. completion date: July 12, 2023

Study information

• Verified date: March 2024
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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/.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 168
• Est. completion date: July 12, 2023
• Est. primary completion date: April 11, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 82 Years

Eligibility

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)

Related Conditions & MeSH terms

• Amyloid Neuropathies
• Amyloidosis
• Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
• Polyneuropathies

Intervention

Drug:
• Eplontersen
Eplontersen by subcutaneous injection
• Inotersen
Inotersen by subcutaneous injection

Locations

Country	Name	City	State
Argentina	Instituto Fleni	Buenos Aires
Argentina	STAT Research	Buenos Aires
Argentina	Hospital Italiano de Buenos Aires	Ciudad Autónoma De Buenos Aires	Buenos Aires
Argentina	Hospital El Cruce	Florencio Varela	Buenos Aires
Australia	Perron Institute for Neurological and Translational Science	Nedlands	Western Australia
Brazil	Universidade Estadual de Campinas	Campinas
Brazil	Instituto de Neurologia de Curitiba	Curitiba	Parana
Brazil	Instituto de Neurologia de Curitiba	Curitiba	Paraná
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
Canada	Toronto General Hospital	Toronto	Ontario
Cyprus	The Cyprus Institute of Neurology and Genetics	Egkomi
France	Hôpital Bicêtre	Le Kremlin-Bicêtre	Ile-De-France
France	Hôpital de la Timone	Marseille
France	Centre Hospitalier Universitaire de Toulouse	Toulouse	Haute-Garonne
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Würzburg	Würzburg	Bayern
Greece	University General Hospital of Heraklion (PAGNI)	Heraklion	Crete
Italy	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
New Zealand	Auckland City Hospital	Grafton	Auckland
Portugal	Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria	Lisbon
Portugal	Centro Hospitalar Universitário do Porto - Hospital Geral de Santo Antonio	Porto
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Son Llàtzer	Palma	Illes Balears
Spain	Hospital Son Llàtzer	Palma De Mallorca	Illes Balears
Sweden	Norrlands Universitetssjukhus	Umeå
Taiwan	China Medical University Hospital	Taichung City	Taichung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei City	Taipei
Taiwan	Chang Gung Memorial Hospital - Linkou Branch	Taoyuan City	Guishan District
Turkey	Istanbul Üniversitesi - Istanbul Tip Fakültesi	Istanbul
United States	Johns Hopkins University Neurology Research Office	Baltimore	Maryland
United States	Boston University School of Medicine	Boston	Massachusetts
United States	University of North Carolina Hospitals - Neurology Clinic	Chapel Hill	North Carolina
United States	Indiana University School of Medicine - Indianapolis	Indianapolis	Indiana
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	The Neurological Institute of New York	New York	New York
United States	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Mayo Clinic - Arizona	Scottsdale	Arizona
United States	University of Washington Medical Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Cyprus,  France,  Germany,  Greece,  Italy,  New Zealand,  Portugal,  Spain,  Sweden,  Taiwan,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Percent change from baseline in serum TTR concentration at Week 66		Baseline, Week 66
Primary	Percent change from baseline in serum transthyretin (TTR) concentration at Week 35		Baseline, Week 35
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   The NEURO-TTRansform Study Website