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

• Sponsor: Ionis Pharmaceuticals, Inc. (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT04136184
• Collaborator: (none)
• Enrollment: 168
• Locations: 47
• Arms: 2
• Anticipated Duration (Months): 43.5
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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/.

Condition or Disease	Intervention/Treatment	Phase
Hereditary Transthyretin-Mediated Amyloid Polyneuropathy	Drug: Eplontersen; 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 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 168 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: Jan 15, 2020
• Anticipated Primary Completion Date: Apr 1, 2023
• Anticipated Study Completion Date: Sep 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eplontersen Eplontersen by subcutaneous injection once every 4 weeks	Drug: Eplontersen; Eplontersen by subcutaneous injection; Other Names: ION-682884 AKCEA-TTR-LRx IONIS-TTR-LRx
Active Comparator: Inotersen 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; Eplontersen by subcutaneous injection; Other Names: ION-682884 AKCEA-TTR-LRx IONIS-TTR-LRx ; Drug: Inotersen; Inotersen by subcutaneous injection; Other Names: TEGSEDI ISIS 420915

Outcome Measures

Primary Outcome Measures

1. Change from baseline in mNIS+7 at Week 66 [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 [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 [Baseline, Week 66]

4. Percent change from baseline in serum transthyretin (TTR) concentration at Week 35 [Baseline, Week 35]

5. Change from baseline in modified neuropathy impairment score plus 7 (mNIS+7) at Week 35 [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 [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 [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 [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 [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 [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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 82 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic - Arizona	Scottsdale	Arizona	United States	85259
2	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
3	Indiana University School of Medicine - Indianapolis	Indianapolis	Indiana	United States	46202
4	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
5	Johns Hopkins University Neurology Research Office	Baltimore	Maryland	United States	21224
6	Boston University School of Medicine	Boston	Massachusetts	United States	02118
7	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
8	The Neurological Institute of New York	New York	New York	United States	10032-3784
9	University of North Carolina Hospitals - Neurology Clinic	Chapel Hill	North Carolina	United States	27599
10	Oregon Health and Science University	Portland	Oregon	United States	97239
11	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania	United States	19104
12	University of Washington Medical Center	Seattle	Washington	United States	98195
13	Hospital Italiano de Buenos Aires	Ciudad Autónoma De Buenos Aires	Buenos Aires	Argentina	C1199ABB
14	Hospital El Cruce	Florencio Varela	Buenos Aires	Argentina	1888
15	STAT Research	Buenos Aires		Argentina	C1023AAB
16	Instituto Fleni	Buenos Aires		Argentina	C1428 AQK
17	Perron Institute for Neurological and Translational Science	Nedlands	Western Australia	Australia	6009
18	Instituto de Neurologia de Curitiba	Curitiba	Parana	Brazil	81210-310
19	Instituto de Neurologia de Curitiba	Curitiba	Paraná	Brazil	81210-310
20	Universidade Estadual de Campinas	Campinas		Brazil	13083-970
21	Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto	Ribeirão Preto		Brazil	14049-900
22	Hospital Universitário Clementino Fraga Filho	Rio De Janeiro		Brazil	21941-617
23	Associação de Assistência à Criança Deficiente - Unidade Lar Escola	São Paulo		Brazil	04032-060
24	Toronto General Hospital	Toronto	Ontario	Canada	M4C 3E7
25	The Cyprus Institute of Neurology and Genetics	Egkomi		Cyprus	2371
26	Centre Hospitalier Universitaire de Toulouse	Toulouse	Haute-Garonne	France	31059
27	Hôpital Bicêtre	Le Kremlin-Bicêtre	Ile-De-France	France	94270
28	Hôpital de la Timone	Marseille		France	13005
29	Universitätsklinikum Würzburg	Würzburg	Bayern	Germany	97080
30	Universitätsklinikum Heidelberg	Heidelberg		Germany	69120
31	University General Hospital of Heraklion (PAGNI)	Heraklion	Crete	Greece	711 10
32	Azienda Ospedaliera Universitaria Policlinico Gaetano Martino	Messina		Italy	98124
33	Fondazione IRCCS Istituto Neurologico Carlo Besta	Milano		Italy	20133
34	Fondazione IRCCS Policlinico San Matteo	Pavia		Italy	27100
35	Fondazione Policlinico Universitario Agostino Gemelli	Roma		Italy	00168
36	Auckland City Hospital	Grafton	Auckland	New Zealand	1023
37	Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria	Lisbon		Portugal	1649-028
38	Centro Hospitalar Universitário do Porto - Hospital Geral de Santo Antonio	Porto		Portugal	4099-001
39	Hospital Son Llàtzer	Palma De Mallorca	Illes Balears	Spain	07198
40	Hospital Son Llàtzer	Palma	Illes Balears	Spain	07198
41	Hospital Clínico San Carlos	Madrid		Spain	28040
42	Norrlands Universitetssjukhus	Umeå		Sweden	907 37
43	Chang Gung Memorial Hospital - Linkou Branch	Taoyuan City	Guishan District	Taiwan	333
44	China Medical University Hospital	Taichung City	Taichung	Taiwan	40447
45	Taipei Veterans General Hospital	Taipei City	Taipei	Taiwan	11217
46	National Taiwan University Hospital	Taipei		Taiwan	100
47	İstanbul Üniversitesi - Istanbul Tıp Fakültesi	İstanbul		Turkey	34093

Sponsors and Collaborators

• Ionis Pharmaceuticals, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The NEURO-TTRansform Study Website

Publications

None provided.

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04136184
• Other Study ID Numbers: ION-682884-CS3; 2019-001698-10
• First Posted: Oct 23, 2019
• Last Update Posted: Jun 10, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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: Polyneuropathies; Amyloid Neuropathies; Amyloidosis

Study Results

No Results Posted as of Jun 10, 2022