Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy

• Sponsor: Ionis Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01737398
• Collaborator: (none)
• Enrollment: 173
• Locations: 24
• Arms: 2
• Actual Duration (Months): 55.8
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
FAP; Familial Amyloid Polyneuropathy; TTR; Transthyretin; Amyloidosis	Drug: Inotersen; Drug: Placebo	Phase 2/Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 173 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Mar 15, 2013
• Actual Primary Completion Date: Mar 3, 2017
• Actual Study Completion Date: Nov 7, 2017

Arms and Interventions

Arm	Intervention/Treatment
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	Drug: Inotersen; Other Names: TEGSEDI IONIS-TTR Rx ISIS 420915
Active Comparator: Placebo Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66 [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.

2. Change From Baseline In The Norfolk Quality Of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 [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.

Secondary Outcome Measures

1. Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66 [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.

2. Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66 [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.

3. Change From Baseline In Modified Body Mass Index (mBMI) at Week 65 [Baseline and Week 65]

   The mBMI is the BMI multiplied by the serum albumin g/L

4. Change From Baseline In Body Mass Index (BMI) at Week 65 [Baseline and Week 65]

5. Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66 [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.

6. Change From Baseline in Modified +7 at Week 66 [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.

7. Change From Baseline in NIS+7 at Week 66 [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.

8. Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set [Baseline and Week 65]

   GLS by ECHO is a measure of cardiac systolic function

9. Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup [Baseline and Week 65]

   GLS by ECHO is a measure of cardiac systolic function

10. Change From Baseline in Transthyretin (TTR) Level at Week 65 [Baseline and Week 65]

11. Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65 [Baseline and Week 65]

12. Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65 [Week 65]

13. Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65 [Week 65]

14. Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65 [Week 65]

15. Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65 [Week 65]

16. Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65 [Week 65]

17. Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65 [Week 65]

Eligibility Criteria

Criteria

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Irvine	Orange	California	United States	92868
2	Indiana University School of Medicine	Indianapolis	Indiana	United States	46202
3	Johns Hopkins University Bayview Medical Center	Baltimore	Maryland	United States	21205
4	Boston University School of Medicine - Amyloid Treatment & Research Program	Boston	Massachusetts	United States	02118
5	Mayo Clinic	Rochester	Minnesota	United States	55905
6	Mount Sinai Medical Center	New York	New York	United States	10029
7	Columbia University Medical Center - The Neurological Institute	New York	New York	United States	10032
8	Oregon Health & Science University	Portland	Oregon	United States	97239
9	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania	United States	19104
10	FLENI	Buenos Aires		Argentina
11	Federal University of Rio de Janeiro - University Hospital	Rio de Janeiro		Brazil	CEP 21941913
12	AACD	Sao Paulo		Brazil
13	UNIFESP	Sao Paulo		Brazil
14	CHU Henri Mondor - Department of Neurology	Creteil		France	94000
15	CHU Bicetre Aphp French Referral Center for FAP/Cornamyl Network	Le Kremlin Bicetre		France	94275
16	UKM; Universitätsklinikum Münster, Klinik für Transplantationsmedizin	Munster		Germany	48149
17	Universita Degli Studi Di Messina - Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino"	Messina	Sicily	Italy	98124
18	Centro per lo Studio e la Cura delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico San Matteo	Pavia		Italy	27100
19	Auckland City Hospital	Auckland		New Zealand
20	CHLN - Hospital de Santa Maria	Lisbon		Portugal	1649-035
21	CHP-HGSA, Unidade Clinica de Paramiloidose	Porto		Portugal	4099-001
22	Hospital Universitari Vall D' Hebron	Barcelona		Spain	08035
23	Hospital Clínic	Barcelona		Spain	08036
24	University College London - National Amyloidosis Centre	London		United Kingdom	NW3 2PF

Sponsors and Collaborators

• Ionis Pharmaceuticals, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 13, 2016
• Statistical Analysis Plan - Apr 21, 2017

More Information

Publications

None provided.

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01737398
• Other Study ID Numbers: ISIS 420915-CS2
• First Posted: Nov 29, 2012
• Last Update Posted: Jul 17, 2019
• Last Verified: Jul 1, 2019

• 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
• Keywords provided by Ionis Pharmaceuticals, Inc.: FAP; Familial Amyloid Polyneuropathy; TTR; Transthyretin; Amyloidosis
• Additional relevant MeSH terms: Polyneuropathies; Amyloid Neuropathies; Amyloid Neuropathies, Familial; Amyloidosis

Study Results

Participant Flow

Pre-assignment Detail	Participants randomized: 113 inotersen and 60 placebo; received study treatment: 112 inotersen and 60 placebo. This study consisted of a 65-week Treatment Period, 1-week End of Treatment (EOT) Period, and a 6-month Post-treatment Evaluation Period.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 subcutaneous (SC) doses of 300 milligrams (mg) inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Period Title: Overall Study
STARTED	113	60
Received at Least 1 Dose of Study Drug	112	60
Safety Set	112	60
COMPLETED	87	52
NOT COMPLETED	26	8

Baseline Characteristics

Arm/Group Title	Inotersen	Placebo	Total
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.	Total of all reporting groups
Overall Participants	112	60	172
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.0 (12.53)	59.5 (14.05)	59.2 (13.04)
Sex: Female, Male (Count of Participants)
Female	35 31.3%	19 31.7%	54 31.4%
Male	77 68.8%	41 68.3%	118 68.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	17 15.2%	7 11.7%	24 14%
Not Hispanic or Latino	95 84.8%	53 88.3%	148 86%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 0.9%	3 5%	4 2.3%
Black	3 2.7%	1 1.7%	4 2.3%
White	105 93.8%	53 88.3%	158 91.9%
White & Grayish-Brown	0 0%	1 1.7%	1 0.6%
Other	3 2.7%	2 3.3%	5 2.9%
Participants diagnosed with hATTR-CM (Count of Participants)
Yes	45 40.2%	22 36.7%	67 39%
No	67 59.8%	38 63.3%	105 61%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66
Description	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.
Time Frame	Baseline and Week 66

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	85	52
Mean (Standard Deviation) [Scores on a Scale]	4.16 (15.672)	23.89 (24.190)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inotersen, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00000004
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-19.73
	Confidence Interval	(2-Sided) 95%; -26.43 to -13.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline In The Norfolk Quality Of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
Description	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.
Time Frame	Baseline and Week 66

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	84	52
Mean (Standard Deviation) [Scores on a Scale]	-0.08 (18.967)	10.77 (21.134)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inotersen, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-11.68
	Confidence Interval	(2-Sided) 95%; -18.29 to -5.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66
Description	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.
Time Frame	Baseline and Week 66

Outcome Measure Data

Analysis Population Description

This endpoint only measured participants with Stage 1 hATTR-PN in Full Analysis Set. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	55	33
Mean (Standard Deviation) [Scores on a Scale]	-1.40 (4.763)	1.18 (5.270)

4. Secondary Outcome

Title	Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66
Description	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.
Time Frame	Baseline and Week 66

Outcome Measure Data

Analysis Population Description

This endpoints only measured participants who had Stage 2 hATTR-PN in Full Analysis Set. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	29	19
Mean (Standard Deviation) [Scores on a Scale]	1.05 (11.924)	8.74 (9.689)

5. Secondary Outcome

Title	Change From Baseline In Modified Body Mass Index (mBMI) at Week 65
Description	The mBMI is the BMI multiplied by the serum albumin g/L
Time Frame	Baseline and Week 65

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	82	49
Mean (Standard Deviation) [kg/m^2*g/L]	-73.32 (96.311)	-85.21 (91.259)

6. Secondary Outcome

Title	Change From Baseline In Body Mass Index (BMI) at Week 65
Time Frame	Baseline and Week 65

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	82	49
Mean (Standard Deviation) [kg/m^2]	-0.24 (1.521)	-0.87 (1.202)

7. Secondary Outcome

Title	Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66
Description	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.
Time Frame	Baseline and Week 66

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	85	52
Mean (Standard Deviation) [Scores on a Scale]	4.47 (10.329)	17.29 (16.986)

8. Secondary Outcome

Title	Change From Baseline in Modified +7 at Week 66
Description	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.
Time Frame	Baseline and Week 66

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	85	52
Mean (Standard Deviation) [Scores on a Scale]	-0.31 (11.134)	6.60 (12.770)

9. Secondary Outcome

Title	Change From Baseline in NIS+7 at Week 66
Description	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.
Time Frame	Baseline and Week 66

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	85	52
Mean (Standard Deviation) [Scores on a Scale]	5.10 (10.709)	19.00 (16.824)

10. Secondary Outcome

Title	Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set
Description	GLS by ECHO is a measure of cardiac systolic function
Time Frame	Baseline and Week 65

Outcome Measure Data

Analysis Population Description

The CM-ECHO Set includes the subset of the Randomized Set who had a diagnosis of TTR cardiomyopathy at study entry but are not in the ECHO subgroup, plus participants who qualified to participate in the ECHO subgroup (whether consented or not). Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	50	25
Mean (Standard Deviation) [Percent Change]	0.69 (3.134)	0.46 (2.702)

11. Secondary Outcome

Title	Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup
Description	GLS by ECHO is a measure of cardiac systolic function
Time Frame	Baseline and Week 65

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	30	16
Mean (Standard Deviation) [Percent Change]	0.25 (3.163)	1.05 (2.745)

12. Secondary Outcome

Title	Change From Baseline in Transthyretin (TTR) Level at Week 65
Time Frame	Baseline and Week 65

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	84	51
Mean (Standard Deviation) [g/L]	-0.1570 (0.0619)	-0.0146 (0.0402)

13. Secondary Outcome

Title	Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65
Time Frame	Baseline and Week 65

Outcome Measure Data

Analysis Population Description

The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data.

Arm/Group Title	Inotersen	Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.	Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
Measure Participants	83	51
Mean (Standard Deviation) [ug/L]	-21725.9 (9884.04)	-1768.7 (8027.78)

14. Secondary Outcome

Title	Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65
Time Frame	Week 65

Outcome Measure Data

Analysis Population Description

The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result.

Arm/Group Title	Inotersen 300 mg IM Negative	Inotersen 300 mg IM Positive
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a negative immunogenicity (IM) status.	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a positive IM status.
Measure Participants	5	3
Mean (Standard Deviation) [ug/mL]	6.76 (1.88)	11.1 (4.80)

15. Secondary Outcome

Title	Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65
Time Frame	Week 65

Outcome Measure Data

Analysis Population Description

The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result.

Arm/Group Title	Inotersen 300 mg IM Negative	Inotersen 300 mg IM Positive
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a negative IM status.	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a positive IM status.
Measure Participants	5	3
Mean (Standard Deviation) [hours]	4.14 (1.88)	3.48 (0.68)

16. Secondary Outcome

Title	Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65
Time Frame	Week 65

Outcome Measure Data

Analysis Population Description

The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result.

Arm/Group Title	Inotersen 300 mg IM Negative	Inotersen 300 mg IM Positive
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a negative IM status.	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a positive IM status.
Measure Participants	5	3
Mean (Standard Deviation) [ug*hr/mL]	93.1 (30.7)	92.4 (77.3)

17. Secondary Outcome

Title	Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65
Time Frame	Week 65

Outcome Measure Data

Analysis Population Description

The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result.

Arm/Group Title	Inotersen 300 mg IM Negative	Inotersen 300 mg IM Positive
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a negative IM status.	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a positive IM status.
Measure Participants	4	3
Mean (Standard Deviation) [ug*hr/mL]	98.9 (33.5)	103.0 (88.2)

18. Secondary Outcome

Title	Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65
Time Frame	Week 65

Outcome Measure Data

Analysis Population Description

The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result.

Arm/Group Title	Inotersen 300 mg IM Negative	Inotersen 300 mg IM Positive
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a negative IM status.	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a positive IM status.
Measure Participants	5	3
Mean (Standard Deviation) [L/hr]	3.57 (1.32)	6.14 (5.92)

19. Secondary Outcome

Title	Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65
Time Frame	Week 65

Outcome Measure Data

Analysis Population Description

The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result.

Arm/Group Title	Inotersen 300 mg IM Negative	Inotersen 300 mg IM Positive
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a negative IM status.	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks, and had a positive IM status.
Measure Participants	4	3
Mean (Standard Deviation) [L/hr]	3.33 (1.21)	5.46 (5.13)

Adverse Events

Time Frame	Week 1 to Week 91
Adverse Event Reporting Description	Adverse events that first occurred or worsened after the first dose of study drug (inotersen or placebo), including serious adverse events, were summarized for each treatment group. Analysis is based on data collected while study treatment was administered and during follow-up until the day of the participant's last contact date within the study. For each treatment, a participant is counted only once within each preferred term.
Arm/Group Title	Inotersen		Placebo
Arm/Group Description	Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks.		Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
All Cause Mortality
	Inotersen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/112 (4.5%)		0/60 (0%)
Serious Adverse Events
	Inotersen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/112 (32.1%)		13/60 (21.7%)
Blood and lymphatic system disorders
Thrombocytopenia	2/112 (1.8%)		0/60 (0%)
Cardiac disorders
Cardiac failure congestive	4/112 (3.6%)		2/60 (3.3%)
Cardiac failure	2/112 (1.8%)		1/60 (1.7%)
Cardiac failure acute	2/112 (1.8%)		0/60 (0%)
Sinus arrest	2/112 (1.8%)		0/60 (0%)
Atrioventricular block	1/112 (0.9%)		0/60 (0%)
Bradyarrhythmia	1/112 (0.9%)		0/60 (0%)
Pericardial effusion	1/112 (0.9%)		0/60 (0%)
Sinus bradycardia	1/112 (0.9%)		0/60 (0%)
Bradycardia	1/112 (0.9%)		0/60 (0%)
Gastrointestinal disorders
Abdominal pain	1/112 (0.9%)		0/60 (0%)
Constipation	1/112 (0.9%)		0/60 (0%)
Gastrointestinal haemorrhage	1/112 (0.9%)		0/60 (0%)
Gastrointestinal hypomotility	1/112 (0.9%)		0/60 (0%)
Haemorrhoids	1/112 (0.9%)		0/60 (0%)
Intestinal perforation	1/112 (0.9%)		0/60 (0%)
Mesenteric arterial occlusion	1/112 (0.9%)		0/60 (0%)
Umbilical hernia	1/112 (0.9%)		0/60 (0%)
Vomiting	1/112 (0.9%)		1/60 (1.7%)
General disorders
Chest pain	1/112 (0.9%)		0/60 (0%)
Infections and infestations
Pneumonia	2/112 (1.8%)		2/60 (3.3%)
Bronchitis	2/112 (1.8%)		0/60 (0%)
Gastroenteritis	1/112 (0.9%)		1/60 (1.7%)
Urinary tract infection	1/112 (0.9%)		1/60 (1.7%)
Clostridium difficile infection	1/112 (0.9%)		0/60 (0%)
Encephalitis	1/112 (0.9%)		0/60 (0%)
Herpes zoster	1/112 (0.9%)		0/60 (0%)
Peritonitis	1/112 (0.9%)		0/60 (0%)
Pyelonephritis acute	1/112 (0.9%)		0/60 (0%)
Staphylococcal infection	1/112 (0.9%)		0/60 (0%)
Wound infection	1/112 (0.9%)		0/60 (0%)
Cellulitis	0/112 (0%)		1/60 (1.7%)
Injury, poisoning and procedural complications
Gastrointestinal stoma complication	1/112 (0.9%)		0/60 (0%)
Ankle fracture	0/112 (0%)		2/60 (3.3%)
Hip fracture	0/112 (0%)		1/60 (1.7%)
Pelvic fracture	0/112 (0%)		1/60 (1.7%)
Metabolism and nutrition disorders
Dehydration	3/112 (2.7%)		0/60 (0%)
Cachexia	2/112 (1.8%)		0/60 (0%)
Hyponatraemia	1/112 (0.9%)		0/60 (0%)
Nervous system disorders
Dementia	1/112 (0.9%)		0/60 (0%)
Embolic stroke	1/112 (0.9%)		0/60 (0%)
Haemorrhage intracranial	1/112 (0.9%)		0/60 (0%)
Myelopathy	1/112 (0.9%)		0/60 (0%)
Myoclonus	1/112 (0.9%)		0/60 (0%)
Neuritis	1/112 (0.9%)		0/60 (0%)
Seizure	1/112 (0.9%)		0/60 (0%)
Syncope	1/112 (0.9%)		0/60 (0%)
Neuralgia	0/112 (0%)		1/60 (1.7%)
Psychiatric disorders
Confusional state	2/112 (1.8%)		0/60 (0%)
Renal and urinary disorders
Acute kidney injury	2/112 (1.8%)		0/60 (0%)
Glomerulonephritis	2/112 (1.8%)		0/60 (0%)
Renal failure	1/112 (0.9%)		0/60 (0%)
Renal impairment	1/112 (0.9%)		0/60 (0%)
Tubulointerstitial nephritis	1/112 (0.9%)		0/60 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/112 (0.9%)		0/60 (0%)
Pulmonary embolism	1/112 (0.9%)		0/60 (0%)
Pulmonary oedema	1/112 (0.9%)		0/60 (0%)
Vascular disorders
Orthostatic hypotension	2/112 (1.8%)		0/60 (0%)
Deep vein thrombosis	1/112 (0.9%)		1/60 (1.7%)
Angiopathy	0/112 (0%)		1/60 (1.7%)
Other (Not Including Serious) Adverse Events
	Inotersen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	110/112 (98.2%)		60/60 (100%)
Blood and lymphatic system disorders
Anaemia	15/112 (13.4%)		2/60 (3.3%)
Thrombocytopenia	14/112 (12.5%)		1/60 (1.7%)
Cardiac disorders
Atrial fibrillation	6/112 (5.4%)		1/60 (1.7%)
Eye disorders
Conjunctival haemorrhage	2/112 (1.8%)		3/60 (5%)
Blepharitis	2/112 (1.8%)		4/60 (6.7%)
Gastrointestinal disorders
Abdominal pain	6/112 (5.4%)		4/60 (6.7%)
Diarrhoea	27/112 (24.1%)		12/60 (20%)
Dry mouth	6/112 (5.4%)		1/60 (1.7%)
Dysphagia	2/112 (1.8%)		3/60 (5%)
Constipation	15/112 (13.4%)		6/60 (10%)
Nausea	35/112 (31.3%)		7/60 (11.7%)
Vomiting	17/112 (15.2%)		2/60 (3.3%)
General disorders
Asthenia	14/112 (12.5%)		8/60 (13.3%)
Chills	20/112 (17.9%)		2/60 (3.3%)
Fatigue	28/112 (25%)		12/60 (20%)
Gait disturbance	6/112 (5.4%)		5/60 (8.3%)
Injection site bruising	8/112 (7.1%)		2/60 (3.3%)
Injection site erythema	35/112 (31.3%)		0/60 (0%)
Injection site pain	23/112 (20.5%)		4/60 (6.7%)
Injection site pruritus	13/112 (11.6%)		0/60 (0%)
Injection site reaction	6/112 (5.4%)		0/60 (0%)
Injection site swelling	6/112 (5.4%)		0/60 (0%)
Influenza like illness	9/112 (8%)		2/60 (3.3%)
Oedema	1/112 (0.9%)		3/60 (5%)
Oedema peripheral	21/112 (18.8%)		6/60 (10%)
Pain	2/112 (1.8%)		5/60 (8.3%)
Pyrexia	22/112 (19.6%)		5/60 (8.3%)
Peripheral swelling	7/112 (6.3%)		0/60 (0%)
Immune system disorders
Seasonal allergy	1/112 (0.9%)		4/60 (6.7%)
Infections and infestations
Urinary tract infection	21/112 (18.8%)		11/60 (18.3%)
Nasopharyngitis	9/112 (8%)		6/60 (10%)
Upper respiratory tract infection	7/112 (6.3%)		3/60 (5%)
Influenza	4/112 (3.6%)		3/60 (5%)
Rhinitis	0/112 (0%)		4/60 (6.7%)
Injury, poisoning and procedural complications
Fall	19/112 (17%)		13/60 (21.7%)
Contusion	9/112 (8%)		1/60 (1.7%)
Thermal burn	6/112 (5.4%)		6/60 (10%)
Ligament sprain	1/112 (0.9%)		3/60 (5%)
Investigations
Glomerular filtration rate decreased	6/112 (5.4%)		2/60 (3.3%)
Platelet count decreased	12/112 (10.7%)		0/60 (0%)
Weight decreased	4/112 (3.6%)		5/60 (8.3%)
Metabolism and nutrition disorders
Decreased appetite	11/112 (9.8%)		0/60 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	13/112 (11.6%)		5/60 (8.3%)
Back pain	10/112 (8.9%)		5/60 (8.3%)
Muscle spasms	11/112 (9.8%)		4/60 (6.7%)
Musculoskeletal pain	6/112 (5.4%)		1/60 (1.7%)
Muscular weakness	11/112 (9.8%)		6/60 (10%)
Myalgia	17/112 (15.2%)		6/60 (10%)
Pain in extremity	10/112 (8.9%)		8/60 (13.3%)
Nervous system disorders
Headache	26/112 (23.2%)		7/60 (11.7%)
Paraesthesia	11/112 (9.8%)		2/60 (3.3%)
Dizziness	14/112 (12.5%)		7/60 (11.7%)
Syncope	9/112 (8%)		2/60 (3.3%)
Hypoaesthesia	10/112 (8.9%)		6/60 (10%)
Presyncope	6/112 (5.4%)		0/60 (0%)
Neuralgia	3/112 (2.7%)		8/60 (13.3%)
Neuropathy peripheral	2/112 (1.8%)		4/60 (6.7%)
Psychiatric disorders
Depression	7/112 (6.3%)		4/60 (6.7%)
Insomnia	6/112 (5.4%)		3/60 (5%)
Anxiety	1/112 (0.9%)		4/60 (6.7%)
Renal and urinary disorders
Proteinuria	7/112 (6.3%)		2/60 (3.3%)
Haematuria	5/112 (4.5%)		5/60 (8.3%)
Dysuria	2/112 (1.8%)		4/60 (6.7%)
Urinary retention	2/112 (1.8%)		3/60 (5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	10/112 (8.9%)		2/60 (3.3%)
Cough	10/112 (8.9%)		8/60 (13.3%)
Oropharyngeal pain	6/112 (5.4%)		2/60 (3.3%)
Dyspnoea exertional	2/112 (1.8%)		3/60 (5%)
Skin and subcutaneous tissue disorders
Ecchymosis	5/112 (4.5%)		4/60 (6.7%)
Vascular disorders
Hypotension	6/112 (5.4%)		2/60 (3.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.