Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy

Amyloidosis Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01737398
• Other study ID #: ISIS 420915-CS2
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: March 15, 2013
• Est. completion date: November 7, 2017

Study information

• Verified date: July 2019
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 173
• Est. completion date: November 7, 2017
• Est. primary completion date: March 3, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 82 Years

Eligibility

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

Related Conditions & MeSH terms

• Amyloid Neuropathies
• Amyloid Neuropathies, Familial
• Amyloidosis
• Familial Amyloid Polyneuropathy
• FAP
• Polyneuropathies
• Transthyretin
• TTR

Intervention

Drug:
• Inotersen

• Placebo

Locations

Country	Name	City	State
Argentina	FLENI	Buenos Aires
Brazil	Federal University of Rio de Janeiro - University Hospital	Rio de Janeiro
Brazil	AACD	Sao Paulo
Brazil	UNIFESP	Sao Paulo
France	CHU Henri Mondor - Department of Neurology	Creteil
France	CHU Bicetre Aphp French Referral Center for FAP/Cornamyl Network	Le Kremlin Bicetre
Germany	UKM; Universitätsklinikum Münster, Klinik für Transplantationsmedizin	Munster
Italy	Universita Degli Studi Di Messina - Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino"	Messina	Sicily
Italy	Centro per lo Studio e la Cura delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico San Matteo	Pavia
New Zealand	Auckland City Hospital	Auckland
Portugal	CHLN - Hospital de Santa Maria	Lisbon
Portugal	CHP-HGSA, Unidade Clinica de Paramiloidose	Porto
Spain	Hospital Clínic	Barcelona
Spain	Hospital Universitari Vall D' Hebron	Barcelona
United Kingdom	University College London - National Amyloidosis Centre	London
United States	Johns Hopkins University Bayview Medical Center	Baltimore	Maryland
United States	Boston University School of Medicine - Amyloid Treatment & Research Program	Boston	Massachusetts
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	Columbia University Medical Center - The Neurological Institute	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	University of California, Irvine	Orange	California
United States	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  France,  Germany,  Italy,  New Zealand,  Portugal,  Spain,  United Kingdom, 

References & Publications (1)

Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Planté-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH 3rd, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceição I, Schmidt HH, Vita G, Campistol J — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score 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 mNIS+7 composite score indicates lower function.	Baseline and 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 Norfolk QoL-DN score indicates poorer QoL.	Baseline and Week 66
Secondary	Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at 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.	Baseline and Week 66
Secondary	Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at 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.	Baseline and Week 66
Secondary	Change From Baseline In Modified Body Mass Index (mBMI) at Week 65	The mBMI is the BMI multiplied by the serum albumin g/L	Baseline and Week 65
Secondary	Change From Baseline In Body Mass Index (BMI) at Week 65		Baseline and Week 65
Secondary	Change From Baseline in Neuropathy Impairment Score (NIS) at 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.	Baseline and Week 66
Secondary	Change From Baseline in Modified +7 at 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.	Baseline and Week 66
Secondary	Change From Baseline in NIS+7 at 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.	Baseline and Week 66
Secondary	Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set	GLS by ECHO is a measure of cardiac systolic function	Baseline and Week 65
Secondary	Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup	GLS by ECHO is a measure of cardiac systolic function	Baseline and Week 65
Secondary	Change From Baseline in Transthyretin (TTR) Level at Week 65		Baseline and Week 65
Secondary	Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65		Baseline and Week 65
Secondary	Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65		Week 65
Secondary	Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65		Week 65
Secondary	Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65		Week 65
Secondary	Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65		Week 65
Secondary	Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65		Week 65
Secondary	Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65		Week 65