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Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions FAP
Familial Amyloid Polyneuropathy
TTR
Transthyretin
Amyloidosis
Interventions Drug: Inotersen
Drug: Placebo
Enrollment 173
Recruitment Details  
Pre-assignment Details 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
Hide 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 [1] 112 60
Safety Set 112 60
Completed 87 52
Not Completed 26 8
Reason Not Completed
Adverse event or SAE             16             1
Stopping rule met             2             1
Voluntary withdrawal             2             3
Ineligibility             1             0
Liver transplant             1             0
Disease progression             2             3
Sponsor's decision             2             0
[1]
One participant in the inotersen group was ineligible, but was randomized in error.
Arm/Group Title Inotersen Placebo Total
Hide 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 Number of Baseline Participants 112 60 172
Hide Baseline Analysis Population Description
Safety Set: Participants who were randomized and received at least 1 dose of study drug (inotersen or placebo). The Safety Set is the population used for the analyses of all safety measures.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 112 participants 60 participants 172 participants
59.0  (12.53) 59.5  (14.05) 59.2  (13.04)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 112 participants 60 participants 172 participants
Female
35
  31.3%
19
  31.7%
54
  31.4%
Male
77
  68.8%
41
  68.3%
118
  68.6%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 112 participants 60 participants 172 participants
Hispanic or Latino
17
  15.2%
7
  11.7%
24
  14.0%
Not Hispanic or Latino
95
  84.8%
53
  88.3%
148
  86.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 112 participants 60 participants 172 participants
Asian
1
   0.9%
3
   5.0%
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
   0.0%
1
   1.7%
1
   0.6%
Other
3
   2.7%
2
   3.3%
5
   2.9%
Participants diagnosed with hATTR-CM  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 112 participants 60 participants 172 participants
Yes
45
  40.2%
22
  36.7%
67
  39.0%
No
67
  59.8%
38
  63.3%
105
  61.0%
1.Primary Outcome
Title Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 85 52
Mean (Standard Deviation)
Unit of Measure: Scores on a Scale
4.16  (15.672) 23.89  (24.190)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inotersen, Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00000004
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -19.73
Confidence Interval (2-Sided) 95%
-26.43 to -13.03
Estimation Comments [Not Specified]
2.Primary Outcome
Title Change From Baseline In The Norfolk Quality Of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 84 52
Mean (Standard Deviation)
Unit of Measure: Scores on a Scale
-0.08  (18.967) 10.77  (21.134)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inotersen, Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -11.68
Confidence Interval (2-Sided) 95%
-18.29 to -5.06
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 55 33
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 29 19
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description The mBMI is the BMI multiplied by the serum albumin g/L
Time Frame Baseline and Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 82 49
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description [Not Specified]
Time Frame Baseline and Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 82 49
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 85 52
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 85 52
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 85 52
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description GLS by ECHO is a measure of cardiac systolic function
Time Frame Baseline and Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 50 25
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description GLS by ECHO is a measure of cardiac systolic function
Time Frame Baseline and Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 30 16
Mean (Standard Deviation)
Unit of Measure: Percent Change
0.25  (3.163) 1.05  (2.745)
12.Secondary Outcome
Title Change From Baseline in Transthyretin (TTR) Level at Week 65
Hide Description [Not Specified]
Time Frame Baseline and Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 84 51
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description [Not Specified]
Time Frame Baseline and Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 83 51
Mean (Standard Deviation)
Unit of Measure: ug/L
-21725.9  (9884.04) -1768.7  (8027.78)
14.Secondary Outcome
Title Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65
Hide Description [Not Specified]
Time Frame Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 5 3
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description [Not Specified]
Time Frame Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 5 3
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description [Not Specified]
Time Frame Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 5 3
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description [Not Specified]
Time Frame Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 4 3
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description [Not Specified]
Time Frame Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 5 3
Mean (Standard Deviation)
Unit of Measure: 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
Hide Description [Not Specified]
Time Frame Week 65
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 4 3
Mean (Standard Deviation)
Unit of Measure: L/hr
3.33  (1.21) 5.46  (5.13)
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
Hide 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 (%) Affected / at Risk (%)
Total   5/112 (4.46%)   0/60 (0.00%) 
Hide Serious Adverse Events
Inotersen Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   36/112 (32.14%)   13/60 (21.67%) 
Blood and lymphatic system disorders     
Thrombocytopenia † 1  2/112 (1.79%)  0/60 (0.00%) 
Cardiac disorders     
Cardiac failure congestive † 1  4/112 (3.57%)  2/60 (3.33%) 
Cardiac failure † 1  2/112 (1.79%)  1/60 (1.67%) 
Cardiac failure acute † 1  2/112 (1.79%)  0/60 (0.00%) 
Sinus arrest † 1  2/112 (1.79%)  0/60 (0.00%) 
Atrioventricular block † 1  1/112 (0.89%)  0/60 (0.00%) 
Bradyarrhythmia † 1  1/112 (0.89%)  0/60 (0.00%) 
Pericardial effusion † 1  1/112 (0.89%)  0/60 (0.00%) 
Sinus bradycardia † 1  1/112 (0.89%)  0/60 (0.00%) 
Bradycardia † 1  1/112 (0.89%)  0/60 (0.00%) 
Gastrointestinal disorders     
Abdominal pain † 1  1/112 (0.89%)  0/60 (0.00%) 
Constipation † 1  1/112 (0.89%)  0/60 (0.00%) 
Gastrointestinal haemorrhage † 1  1/112 (0.89%)  0/60 (0.00%) 
Gastrointestinal hypomotility † 1  1/112 (0.89%)  0/60 (0.00%) 
Haemorrhoids † 1  1/112 (0.89%)  0/60 (0.00%) 
Intestinal perforation † 1  1/112 (0.89%)  0/60 (0.00%) 
Mesenteric arterial occlusion † 1  1/112 (0.89%)  0/60 (0.00%) 
Umbilical hernia † 1  1/112 (0.89%)  0/60 (0.00%) 
Vomiting † 1  1/112 (0.89%)  1/60 (1.67%) 
General disorders     
Chest pain † 1  1/112 (0.89%)  0/60 (0.00%) 
Infections and infestations     
Pneumonia † 1  2/112 (1.79%)  2/60 (3.33%) 
Bronchitis † 1  2/112 (1.79%)  0/60 (0.00%) 
Gastroenteritis † 1  1/112 (0.89%)  1/60 (1.67%) 
Urinary tract infection † 1  1/112 (0.89%)  1/60 (1.67%) 
Clostridium difficile infection † 1  1/112 (0.89%)  0/60 (0.00%) 
Encephalitis † 1  1/112 (0.89%)  0/60 (0.00%) 
Herpes zoster † 1  1/112 (0.89%)  0/60 (0.00%) 
Peritonitis † 1  1/112 (0.89%)  0/60 (0.00%) 
Pyelonephritis acute † 1  1/112 (0.89%)  0/60 (0.00%) 
Staphylococcal infection † 1  1/112 (0.89%)  0/60 (0.00%) 
Wound infection † 1  1/112 (0.89%)  0/60 (0.00%) 
Cellulitis † 1  0/112 (0.00%)  1/60 (1.67%) 
Injury, poisoning and procedural complications     
Gastrointestinal stoma complication † 1  1/112 (0.89%)  0/60 (0.00%) 
Ankle fracture † 1  0/112 (0.00%)  2/60 (3.33%) 
Hip fracture † 1  0/112 (0.00%)  1/60 (1.67%) 
Pelvic fracture † 1  0/112 (0.00%)  1/60 (1.67%) 
Metabolism and nutrition disorders     
Dehydration † 1  3/112 (2.68%)  0/60 (0.00%) 
Cachexia † 1  2/112 (1.79%)  0/60 (0.00%) 
Hyponatraemia † 1  1/112 (0.89%)  0/60 (0.00%) 
Nervous system disorders     
Dementia † 1  1/112 (0.89%)  0/60 (0.00%) 
Embolic stroke † 1  1/112 (0.89%)  0/60 (0.00%) 
Haemorrhage intracranial † 1  1/112 (0.89%)  0/60 (0.00%) 
Myelopathy † 1  1/112 (0.89%)  0/60 (0.00%) 
Myoclonus † 1  1/112 (0.89%)  0/60 (0.00%) 
Neuritis † 1  1/112 (0.89%)  0/60 (0.00%) 
Seizure † 1  1/112 (0.89%)  0/60 (0.00%) 
Syncope † 1  1/112 (0.89%)  0/60 (0.00%) 
Neuralgia † 1  0/112 (0.00%)  1/60 (1.67%) 
Psychiatric disorders     
Confusional state † 1  2/112 (1.79%)  0/60 (0.00%) 
Renal and urinary disorders     
Acute kidney injury † 1  2/112 (1.79%)  0/60 (0.00%) 
Glomerulonephritis † 1  2/112 (1.79%)  0/60 (0.00%) 
Renal failure † 1  1/112 (0.89%)  0/60 (0.00%) 
Renal impairment † 1  1/112 (0.89%)  0/60 (0.00%) 
Tubulointerstitial nephritis † 1  1/112 (0.89%)  0/60 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Pleural effusion † 1  1/112 (0.89%)  0/60 (0.00%) 
Pulmonary embolism † 1  1/112 (0.89%)  0/60 (0.00%) 
Pulmonary oedema † 1  1/112 (0.89%)  0/60 (0.00%) 
Vascular disorders     
Orthostatic hypotension † 1  2/112 (1.79%)  0/60 (0.00%) 
Deep vein thrombosis † 1  1/112 (0.89%)  1/60 (1.67%) 
Angiopathy † 1  0/112 (0.00%)  1/60 (1.67%) 
1
Term from vocabulary, MedDRA (19.1)
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Inotersen Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   110/112 (98.21%)   60/60 (100.00%) 
Blood and lymphatic system disorders     
Anaemia † 1  15/112 (13.39%)  2/60 (3.33%) 
Thrombocytopenia † 1  14/112 (12.50%)  1/60 (1.67%) 
Cardiac disorders     
Atrial fibrillation † 1  6/112 (5.36%)  1/60 (1.67%) 
Eye disorders     
Conjunctival haemorrhage † 1  2/112 (1.79%)  3/60 (5.00%) 
Blepharitis † 1  2/112 (1.79%)  4/60 (6.67%) 
Gastrointestinal disorders     
Abdominal pain † 1  6/112 (5.36%)  4/60 (6.67%) 
Diarrhoea † 1  27/112 (24.11%)  12/60 (20.00%) 
Dry mouth † 1  6/112 (5.36%)  1/60 (1.67%) 
Dysphagia † 1  2/112 (1.79%)  3/60 (5.00%) 
Constipation † 1  15/112 (13.39%)  6/60 (10.00%) 
Nausea † 1  35/112 (31.25%)  7/60 (11.67%) 
Vomiting † 1  17/112 (15.18%)  2/60 (3.33%) 
General disorders     
Asthenia † 1  14/112 (12.50%)  8/60 (13.33%) 
Chills † 1  20/112 (17.86%)  2/60 (3.33%) 
Fatigue † 1  28/112 (25.00%)  12/60 (20.00%) 
Gait disturbance † 1  6/112 (5.36%)  5/60 (8.33%) 
Injection site bruising † 1  8/112 (7.14%)  2/60 (3.33%) 
Injection site erythema † 1  35/112 (31.25%)  0/60 (0.00%) 
Injection site pain † 1  23/112 (20.54%)  4/60 (6.67%) 
Injection site pruritus † 1  13/112 (11.61%)  0/60 (0.00%) 
Injection site reaction † 1  6/112 (5.36%)  0/60 (0.00%) 
Injection site swelling † 1  6/112 (5.36%)  0/60 (0.00%) 
Influenza like illness † 1  9/112 (8.04%)  2/60 (3.33%) 
Oedema † 1  1/112 (0.89%)  3/60 (5.00%) 
Oedema peripheral † 1  21/112 (18.75%)  6/60 (10.00%) 
Pain † 1  2/112 (1.79%)  5/60 (8.33%) 
Pyrexia † 1  22/112 (19.64%)  5/60 (8.33%) 
Peripheral swelling † 1  7/112 (6.25%)  0/60 (0.00%) 
Immune system disorders     
Seasonal allergy † 1  1/112 (0.89%)  4/60 (6.67%) 
Infections and infestations     
Urinary tract infection † 1  21/112 (18.75%)  11/60 (18.33%) 
Nasopharyngitis † 1  9/112 (8.04%)  6/60 (10.00%) 
Upper respiratory tract infection † 1  7/112 (6.25%)  3/60 (5.00%) 
Influenza † 1  4/112 (3.57%)  3/60 (5.00%) 
Rhinitis † 1  0/112 (0.00%)  4/60 (6.67%) 
Injury, poisoning and procedural complications     
Fall † 1  19/112 (16.96%)  13/60 (21.67%) 
Contusion † 1  9/112 (8.04%)  1/60 (1.67%) 
Thermal burn † 1  6/112 (5.36%)  6/60 (10.00%) 
Ligament sprain † 1  1/112 (0.89%)  3/60 (5.00%) 
Investigations     
Glomerular filtration rate decreased † 1  6/112 (5.36%)  2/60 (3.33%) 
Platelet count decreased † 1  12/112 (10.71%)  0/60 (0.00%) 
Weight decreased † 1  4/112 (3.57%)  5/60 (8.33%) 
Metabolism and nutrition disorders     
Decreased appetite † 1  11/112 (9.82%)  0/60 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia † 1  13/112 (11.61%)  5/60 (8.33%) 
Back pain † 1  10/112 (8.93%)  5/60 (8.33%) 
Muscle spasms † 1  11/112 (9.82%)  4/60 (6.67%) 
Musculoskeletal pain † 1  6/112 (5.36%)  1/60 (1.67%) 
Muscular weakness † 1  11/112 (9.82%)  6/60 (10.00%) 
Myalgia † 1  17/112 (15.18%)  6/60 (10.00%) 
Pain in extremity † 1  10/112 (8.93%)  8/60 (13.33%) 
Nervous system disorders     
Headache † 1  26/112 (23.21%)  7/60 (11.67%) 
Paraesthesia † 1  11/112 (9.82%)  2/60 (3.33%) 
Dizziness † 1  14/112 (12.50%)  7/60 (11.67%) 
Syncope † 1  9/112 (8.04%)  2/60 (3.33%) 
Hypoaesthesia † 1  10/112 (8.93%)  6/60 (10.00%) 
Presyncope † 1  6/112 (5.36%)  0/60 (0.00%) 
Neuralgia † 1  3/112 (2.68%)  8/60 (13.33%) 
Neuropathy peripheral † 1  2/112 (1.79%)  4/60 (6.67%) 
Psychiatric disorders     
Depression † 1  7/112 (6.25%)  4/60 (6.67%) 
Insomnia † 1  6/112 (5.36%)  3/60 (5.00%) 
Anxiety † 1  1/112 (0.89%)  4/60 (6.67%) 
Renal and urinary disorders     
Proteinuria † 1  7/112 (6.25%)  2/60 (3.33%) 
Haematuria † 1  5/112 (4.46%)  5/60 (8.33%) 
Dysuria † 1  2/112 (1.79%)  4/60 (6.67%) 
Urinary retention † 1  2/112 (1.79%)  3/60 (5.00%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnoea † 1  10/112 (8.93%)  2/60 (3.33%) 
Cough † 1  10/112 (8.93%)  8/60 (13.33%) 
Oropharyngeal pain † 1  6/112 (5.36%)  2/60 (3.33%) 
Dyspnoea exertional † 1  2/112 (1.79%)  3/60 (5.00%) 
Skin and subcutaneous tissue disorders     
Ecchymosis † 1  5/112 (4.46%)  4/60 (6.67%) 
Vascular disorders     
Hypotension † 1  6/112 (5.36%)  2/60 (3.33%) 
1
Term from vocabulary, MedDRA (19.1)
†
Indicates events were collected by systematic assessment
[Not Specified]
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Ionis Pharmaceuticals, Inc.
Organization: Ionis Pharmaceuticals, Inc.
Phone: 800-679-4747
EMail: patients@ionisph.com
Publications of Results:
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.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01737398    
Other Study ID Numbers: ISIS 420915-CS2
First Submitted: November 27, 2012
First Posted: November 29, 2012
Results First Submitted: November 2, 2018
Results First Posted: January 23, 2019
Last Update Posted: July 17, 2019