Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy

• ClinicalTrials.gov Identifier: NCT01737398
• Recruitment Status: Completed
• First Posted: November 29, 2012
• Results First Posted: January 23, 2019
• Last Update Posted: July 17, 2019
• Sponsor: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

Tracking Information

• First Submitted Date: November 27, 2012
• First Posted Date: November 29, 2012
• Results First Submitted Date: November 2, 2018
• Results First Posted Date: January 23, 2019
• Last Update Posted Date: July 17, 2019
• Actual Study Start Date: March 15, 2013
• Actual Primary Completion Date: March 3, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 2, 2019)

• Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66 [ Time Frame: Baseline and 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 mNIS+7 composite score indicates lower function.
• Change From Baseline In The Norfolk Quality Of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 [ Time Frame: Baseline and 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 Norfolk QoL-DN score indicates poorer QoL.

• Original Primary Outcome Measures (submitted: November 27, 2012): Efficacy of ISIS TTR Rx as measured by change from baseline in the modified Neuropathy Impairment Score +7 [ Time Frame: 65 weeks ]

Current Secondary Outcome Measures (submitted: January 2, 2019)

• Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66 [ Time Frame: Baseline and Week 66 ]
  The Norfolk QoL-DN symptoms score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN symptoms domain score has a range of 0-32, and a higher Norfolk QoL-DN score indicates poorer QoL.
• Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66 [ Time Frame: Baseline and Week 66 ]
  The Norfolk QoL-DN physical functioning/large fiber neuropathy domain score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN physical function/large fiber neuropathy domain score has a range of -4 to 56, and a higher Norfolk QoL-DN domain score indicates poorer QoL.
• Change From Baseline In Modified Body Mass Index (mBMI) at Week 65 [ Time Frame: Baseline and Week 65 ]
  The mBMI is the BMI multiplied by the serum albumin g/L
• Change From Baseline In Body Mass Index (BMI) at Week 65 [ Time Frame: Baseline and Week 65 ]
• Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66 [ Time Frame: Baseline and Week 66 ]
  The NIS score is a measure of neurologic impairment. The NIS Score has a range of 0 to 244 and a higher NIS score indicates lower function.
• Change From Baseline in Modified +7 at Week 66 [ Time Frame: Baseline and Week 66 ]
  The Modified +7 score is a version of the NIS score that is a measure of neurologic impairment. The Modified +7 Score has a range of -22.32 to 102.32 and a higher NIS score indicates lower function.
• Change From Baseline in NIS+7 at Week 66 [ Time Frame: Baseline and Week 66 ]
  The NIS+7 score is a version of the NIS score that is a measure of neurologic impairment. The NIS+7 Score has a range of -26.04 to 270.04 and a higher NIS score indicates lower function.
• Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set [ Time Frame: Baseline and Week 65 ]
  GLS by ECHO is a measure of cardiac systolic function
• Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup [ Time Frame: Baseline and Week 65 ]
  GLS by ECHO is a measure of cardiac systolic function
• Change From Baseline in Transthyretin (TTR) Level at Week 65 [ Time Frame: Baseline and Week 65 ]
• Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65 [ Time Frame: Baseline and Week 65 ]
• Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
• Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
• Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
• Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
• Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
• Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65 [ Time Frame: Week 65 ]

Original Secondary Outcome Measures (submitted: November 27, 2012)

• Efficacy of ISIS TTR Rx based on the change from baseline in the following measures: [ Time Frame: 65 weeks ]
  • Norfolk Quality of Life Diabetic Neuropathy questionnaire
  • Modified Body Mass Index and Body Mass Index
  • Individual components of the mNIS+7
  • NIS+7
  • NIS
• Pharmacodynamic effect of ISIS TTR Rx based on the change from baseline in transthyretin and retinol binding protein 4 [ Time Frame: 65 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy
• Official Title: A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (NEURO-TTR Study)
• Brief Summary: The purpose of this study is to evaluate the efficacy and safety of inotersen given for 65 weeks in participants with Familial Amyloid Polyneuropathy (FAP).

Detailed Description

FAP is a rare, hereditary disease caused by mutations in the transthyretin (TTR) protein. TTR is made by the liver and secreted into the blood. TTR mutations cause it to misfold and deposit in multiple organs causing FAP.

Inotersen (also known as ISIS 420915) is an antisense drug that was designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein would result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression.

The purpose of this study is to determine if inotersen can slow or stop the nerve damage caused by TTR deposits. This study will enroll late Stage 1 and early Stage 2 FAP participants. Participants will receive either inotersen or placebo for 65 weeks.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• FAP
• Familial Amyloid Polyneuropathy
• TTR
• Transthyretin
• Amyloidosis

Intervention

• Drug: Inotersen
  Other Names:

  • TEGSEDI
  • IONIS-TTR Rx
  • ISIS 420915
• Drug: Placebo

Study Arms

• Active Comparator: Inotersen
  300 mg inotersen administered subcutaneously (SC) 3 times on alternate days in the first week and then once-weekly for 64 weeks
  Intervention: Drug: Inotersen
• Active Comparator: Placebo
  Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks
  Intervention: Drug: Placebo

Publications *

• Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Plante-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH 3rd, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceicao I, Schmidt HH, Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM, Solomon SD, Monia BP, Hughes SG, Kwoh TJ, McEvoy BW, Jung SW, Baker BF, Ackermann EJ, Gertz MA, Coelho T. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):22-31. doi: 10.1056/NEJMoa1716793.
• Karam C, Brown D, Yang M, Done N, Zhu JJ, Greatsinger A, Bozas A, Vera-Llonch M, Signorovitch J. Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial. Muscle Nerve. 2022 Oct;66(4):438-446. doi: 10.1002/mus.27675. Epub 2022 Aug 4.
• Karam C, Brown D, Yang M, Done N, Dieye I, Bozas A, Vera Llonch M, Signorovitch J. Factors associated with increased health-related quality-of-life benefits in hereditary transthyretin amyloidosis polyneuropathy patients treated with inotersen. Muscle Nerve. 2022 Sep;66(3):319-328. doi: 10.1002/mus.27668. Epub 2022 Jul 15.
• Yarlas A, Lovley A, McCausland K, Brown D, Vera-Llonch M, Conceicao I, Karam C, Khella S, Obici L, Waddington-Cruz M. Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR. Neurol Ther. 2021 Dec;10(2):865-886. doi: 10.1007/s40120-021-00268-x. Epub 2021 Aug 5.
• Yarlas A, Lovley A, Brown D, Kosinski M, Vera-Llonch M. Responder analysis for neuropathic impairment and quality-of-life assessment in patients with hereditary transthyretin amyloidosis with polyneuropathy in the NEURO-TTR study. J Neurol. 2022 Jan;269(1):323-335. doi: 10.1007/s00415-021-10635-1. Epub 2021 Jun 14.
• Yu RZ, Wang Y, Norris DA, Kim TW, Narayanan P, Geary RS, Monia BP, Henry SP. Immunogenicity Assessment of Inotersen, a 2'-O-(2-Methoxyethyl) Antisense Oligonucleotide in Animals and Humans: Effect on Pharmacokinetics, Pharmacodynamics, and Safety. Nucleic Acid Ther. 2020 Oct;30(5):265-275. doi: 10.1089/nat.2020.0867. Epub 2020 Aug 19.
• Dyck PJB, Kincaid JC, Wiesman JF, Polydefkis M, Litchy WJ, Mauermann ML, Ackermann EJ, Guthrie S, Pollock M, Jung SW, Baker BF, Dyck PJ. mNIS+7 and lower limb function in inotersen treatment of hereditary transthyretin-mediated amyloidosis. Muscle Nerve. 2020 Oct;62(4):502-508. doi: 10.1002/mus.27022. Epub 2020 Aug 13.
• Dyck PJB, Coelho T, Waddington Cruz M, Brannagan TH 3rd, Khella S, Karam C, Berk JL, Polydefkis MJ, Kincaid JC, Wiesman JF, Litchy WJ, Mauermann ML, Ackermann EJ, Baker BF, Jung SW, Guthrie S, Pollock M, Dyck PJ. Neuropathy symptom and change: Inotersen treatment of hereditary transthyretin amyloidosis. Muscle Nerve. 2020 Oct;62(4):509-515. doi: 10.1002/mus.27023. Epub 2020 Aug 7.
• Coelho T, Yarlas A, Waddington-Cruz M, White MK, Sikora Kessler A, Lovley A, Pollock M, Guthrie S, Ackermann EJ, Hughes SG, Karam C, Khella S, Gertz M, Merlini G, Obici L, Schmidt HH, Polydefkis M, Dyck PJB, Brannagan Iii TH, Conceicao I, Benson MD, Berk JL. Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis. J Neurol. 2020 Apr;267(4):1070-1079. doi: 10.1007/s00415-019-09671-9. Epub 2019 Dec 18.
• Pinto MV, Dyck PJB, Gove LE, McCauley BM, Ackermann EJ, Hughes SG, Waddington-Cruz M, Dyck PJ. Kind and distribution of cutaneous sensation loss in hereditary transthyretin amyloidosis with polyneuropathy. J Neurol Sci. 2018 Nov 15;394:78-83. doi: 10.1016/j.jns.2018.08.031. Epub 2018 Aug 30.
• Waddington-Cruz M, Ackermann EJ, Polydefkis M, Heitner SB, Dyck PJ, Barroso FA, Wang AK, Berk JL, Dyck PJB, Monia BP, Hughes SG, Tai L, Jesse Kwoh T, Jung SW, Coelho T, Benson MD, Gertz MA. Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial. Amyloid. 2018 Sep;25(3):180-188. doi: 10.1080/13506129.2018.1503593. Epub 2018 Aug 31.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 2, 2019): 173
• Original Estimated Enrollment (submitted: November 27, 2012): 195
• Actual Study Completion Date: November 7, 2017
• Actual Primary Completion Date: March 3, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Stage 1 and Stage 2 FAP participants with the following:

  1. NIS score within protocol criteria
  2. Documented transthyretin variant by genotyping
  3. Documented amyloid deposit by biopsy
• Females of child-bearing potential must use appropriate contraception and be non-pregnant and non-lactating. Males engaging in relations of child-bearing potential are to use appropriate contraception

Exclusion Criteria:

• Low Retinol level at screen
• Karnofsky performance status ≤50
• Poor Renal function
• Known type 1 or type 2 diabetes mellitus
• Other causes of sensorimotor or autonomic neuropathy (for example, autoimmune disease)
• If previously treated with Vyndaqel®, will need to have discontinued treatment for 2 weeks prior to Study Day 1. If previously treated with Diflunisal, will need to have discontinued treatment for 3 days prior to Study Day 1
• Previous treatment with any oligonucleotide or siRNA within 12 months of screening
• Prior liver transplant or anticipated liver transplant within 1 year of screening
• New York Heart Association (NYHA) functional classification of ≥3
• Acute Coronary Syndrome or major surgery within 3 months of screening
• Known Primary or Leptomeningeal Amyloidosis
• Anticipated survival less than 2 years
• Any other conditions in the opinion of the investigator which interfere with the participant participating in or completing the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 82 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Brazil, France, Germany, Italy, New Zealand, Portugal, Spain, United Kingdom, United States
• Removed Location Countries: Bulgaria

Administrative Information

• NCT Number: NCT01737398
• Other Study ID Numbers: ISIS 420915-CS2
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Ionis Pharmaceuticals, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Ionis Pharmaceuticals, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Ionis Pharmaceuticals, Inc.
• Verification Date: July 2019