Amyloidosis, Familial Amyloid Polyneuropathy, FAP, Transthyretin, TTR
Conditions
Keywords
FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis
Brief summary
This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.
Detailed description
Familial Amyloid Polyneuropathy (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. IONIS-TTR Rx is an antisense drug that is designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein will result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression. This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.
Interventions
DRUGInotersen
Inotersen SC
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Satisfactory completion of dosing & efficacy assessments in ISIS 420915-CS2
Exclusion criteria
* Any new condition or worsening of existing condition that could make the patient unsuitable for participation, or interfere with the patient participating in and/or completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug | From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks) | An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence that at any dose that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported. |
| Percentage of Participants With Change From Baseline in Vital Signs | From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks) | Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported. |
| Percentage of Participants With Change From Baseline in Weight | From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks) | As prespecified in the protocol, percentage of participants with change from baseline in weight is reported in 2 categories, decrease of ≥7% from Baseline and increase of ≥7% from Baseline. |
| Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values | From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks) | Clinical laboratory tests included the analysis of chemistry, haematology, and urinalysis. Any value outside the normal range will be flagged for the attention of the investigator who will assess whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. Normal range of creatinine clearance is 110 to 150 mL/min in males and 100 to 130 mL/min in females. Normal urine protein to creatinine (P/C) ratio= \<0.2. Normal range for Alanine Aminotransferase (ALT) is 4 to 36 units per liter (U/L). Platelets normal range=140×10\^9/L to 400×10\^9/L. |
| Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) | From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks) | Normal QTcF at Baseline is defined as ≤450 milliseconds (ms) for males or ≤470 ms for females. Percentage of participants with QT interval outside of normal range are reported. |
| Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders | From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks) | A concomitant therapy was any non-protocol-specified drug or substance (including over-the counter medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the final post-treatment visit for treating nervous and cardiovascular system disorders. |
| Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes | From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks) | — |
| Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5 | The Reflexes Score involves testing 5 reflexes to stimuli. The score range of this component is 0 to 20 points. Higher scores indicate worsening. MMRM was used for the analysis. |
| Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5 | The Sensory Score is based on testing an index finger and a big toe each to 4 stimuli. The score of this component ranges from 0 to 32 points. Higher scores indicate impairment. MMRM was used for the analysis. |
| Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of Years 4 and 5) | 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. A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis. |
| Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the Week 52 of Year 4 | 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 quality of life (QoL). A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis. |
| Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | BMI=weight (kg)/\[height (m)\^2\]. The mBMI is the BMI multiplied by the serum albumin (g/L). |
| Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156 | Baseline, Weeks 78 and 156 | BMI=weight (kg)/\[height (m)\^2\]. |
| Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | 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 worsening disease. A positive change from Baseline indicates worsening of polyneuropathy impairments. Mixed Effects Model with Repeated Measures (MMRM) was used for the analysis. |
| Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set | Baseline, Weeks 78 and 156 | GLS by ECHO is a measure of cardiac systolic function. |
| Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup | Weeks 78 and 156 | GLS by ECHO is a measure of cardiac systolic function. |
| Change From Baseline in Transthyretin (TTR) Level | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | Transthyretin protein concentration in serum was measured. |
| Change From Baseline in Retinol Binding Protein 4 (RBP4) Level | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156, and at the end of each subsequent treatment year (Week 52 of Years 4 and 5) | RBP4 protein concentration in serum was measured. |
| Ctrough: Trough Plasma Concentration of ISIS 420915 | Pre-dose on Days 1, 43, 85, 120, 176, 267, 358, 449, 540, 631, 722, 813, 904, 995, 1086, 1268; Days 1359 and 1450 of Year 4; Days 1632, 1723 and 1814 of Year 5 | — |
| Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year) | PND score is defined as I = sensory disturbances in limbs without motor impairment; II = difficulty walking without the need of a walking aid; III = one stick or one crutch required for walking; IV = two sticks or two crutches needed. V = wheelchair required or patient confined to bed. The change from Baseline values have been categorized as: improved, not changed, worsened, and unknown. Percentage of participants with changes from Baseline are presented category-wise in this outcome measure. Only categories with at least one participant with event are reported. |
| Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | Heart rate to deep breathing is a quantitative autonomic test using the CASE IV instrument that measures a participant's change in heart rate after deep breathing. The score of this component ranges from 0 to 3.72 points. Higher scores indicate impairment. MMRM was used for the analysis. |
| Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | The nerve conduction tests are quantitative tests that measure the conduction attributes of preselected nerves. The score range of this component is 0 to 18.6 points. Higher scores indicate impairment. MMRM was used for the analysis. |
| Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | The Heat-Pain Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pain sensory thresholds in response to heat. The maximum score of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis. |
| Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | The Touch-Pressure Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pressure sensory thresholds in response to touch. The score range of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis. |
| Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5 | 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. A positive change from Baseline indicates worsening. MMRM was used for the analysis. |
| Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5 | Cranial Nerve assessment involves testing 3rd and 6th nerves and facial, palate, and tongue weakness. The score range for this component is 0 to 40 points. Higher scores indicate worsening. MMRM was used for the analysis. |
| Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5 | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5 | Muscle weakness involves testing 19 movements of muscles. The score range of this component is 0 to 152 points. Higher scores indicate worsening. MMRM was used for the analysis. |
Countries
Argentina, Brazil, France, Germany, Italy, Portugal, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 135 participants, out of which 50 participants had received placebo, and 85 participants had received inotersen in the previous study ISIS 420915-CS2 (NCT01737398 - CS2 Study). Participants were enrolled into this study to receive inotersen. This study consisted of a 260-week Treatment Period, and a 3-month Post-treatment Evaluation Period. The data is reported as per the previous treatment received in CS2 study.
Participants by arm
| Arm | Count |
|---|---|
| Previous Placebo-Inotersen 300 mg Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 were included in this group. | 50 |
| Previous Inotersen-Inotersen 300 mg Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group. | 85 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event or Serious Adverse Event (SAE) | 5 | 14 |
| Overall Study | Disease Progression | 1 | 0 |
| Overall Study | Investigator Judgment | 1 | 4 |
| Overall Study | Liver Transplant | 1 | 0 |
| Overall Study | Participants Started Treatment With Commercially Available/Post-study Inotersen | 27 | 39 |
| Overall Study | Voluntary Withdrawal | 6 | 19 |
Baseline characteristics
| Characteristic | Previous Inotersen-Inotersen 300 mg | Total | Previous Placebo-Inotersen 300 mg |
|---|---|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 11.86 | 60.4 years STANDARD_DEVIATION 12.9 | 60.5 years STANDARD_DEVIATION 14.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 18 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 73 Participants | 117 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Percentage of Participants Abnormal Electroretinogram Results at Baseline | 18.4 percentage of participants | 29.6 percentage of participants | 51.3 percentage of participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Black | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 3 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 81 Participants | 125 Participants | 44 Participants |
| Race/Ethnicity, Customized Race White & Grayish-Brown | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 26 Participants | 41 Participants | 15 Participants |
| Sex: Female, Male Male | 59 Participants | 94 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 50 | 15 / 85 |
| other Total, other adverse events | 50 / 50 | 80 / 85 |
| serious Total, serious adverse events | 18 / 50 | 46 / 85 |
Outcome results
Primary
Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders
A concomitant therapy was any non-protocol-specified drug or substance (including over-the counter medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the final post-treatment visit for treating nervous and cardiovascular system disorders.
Time frame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders | Nervous System Disorders | 88.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders | Cardiovascular System Disorders | 68.0 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders | Nervous System Disorders | 81.2 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders | Cardiovascular System Disorders | 75.3 percentage of participants |
Primary
Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography | Participants With Change From Baseline at Week 78 | 25.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography | Participants With Change From Baseline at Week 156 | 31.3 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography | Participants With Change From Baseline at Week 78 | 12.7 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography | Participants With Change From Baseline at Week 156 | 9.1 percentage of participants |
Primary
Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes
Time frame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes | 0.0 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes | 2.4 percentage of participants |
Primary
Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG)
Normal QTcF at Baseline is defined as ≤450 milliseconds (ms) for males or ≤470 ms for females. Percentage of participants with QT interval outside of normal range are reported.
Time frame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) | QTcF >480 ms | 20.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) | QTcF >500 ms | 12.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) | QTcF >450 ms | 44.0 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) | QTcF >450 ms | 43.5 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) | QTcF >480 ms | 23.5 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) | QTcF >500 ms | 16.5 percentage of participants |
Primary
Percentage of Participants With Change From Baseline in Vital Signs
Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported.
Time frame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Systolic Blood Pressure: <90 millimeters of mercury (mmHg) | 12.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Systolic Blood Pressure: >140 mmHg | 32.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Systolic Blood Pressure: >160 mmHg | 8.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Diastolic Blood Pressure: <50 mmHg | 6.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Diastolic Blood Pressure: >90 mmHg | 30.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Diastolic Blood Pressure: >100 mmHg | 10.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Heart Rate: <60 beats per minute (bpm) | 30.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Heart Rate: >100 bpm | 16.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Temperature (°C): <36.0°C | 46.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Respiratory Rate (breaths/minute): >20 breaths/minute | 24.0 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Heart Rate: >100 bpm | 9.4 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Systolic Blood Pressure: <90 millimeters of mercury (mmHg) | 18.8 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Diastolic Blood Pressure: >100 mmHg | 7.1 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Systolic Blood Pressure: >140 mmHg | 41.2 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Respiratory Rate (breaths/minute): >20 breaths/minute | 21.2 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Systolic Blood Pressure: >160 mmHg | 20.0 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Heart Rate: <60 beats per minute (bpm) | 38.8 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Diastolic Blood Pressure: <50 mmHg | 9.4 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Temperature (°C): <36.0°C | 55.3 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Vital Signs | Diastolic Blood Pressure: >90 mmHg | 28.2 percentage of participants |
Primary
Percentage of Participants With Change From Baseline in Weight
As prespecified in the protocol, percentage of participants with change from baseline in weight is reported in 2 categories, decrease of ≥7% from Baseline and increase of ≥7% from Baseline.
Time frame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3. Overall number analyzed are the number of participants available for analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Weight | Weight (kg): Decrease of ≥7% From Baseline | 30.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Weight | Weight (kg): Increase of ≥7% From Baseline | 24.0 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Weight | Weight (kg): Decrease of ≥7% From Baseline | 47.1 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in Weight | Weight (kg): Increase of ≥7% From Baseline | 11.8 percentage of participants |
Primary
Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values
Clinical laboratory tests included the analysis of chemistry, haematology, and urinalysis. Any value outside the normal range will be flagged for the attention of the investigator who will assess whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. Normal range of creatinine clearance is 110 to 150 mL/min in males and 100 to 130 mL/min in females. Normal urine protein to creatinine (P/C) ratio= \<0.2. Normal range for Alanine Aminotransferase (ALT) is 4 to 36 units per liter (U/L). Platelets normal range=140×10\^9/L to 400×10\^9/L.
Time frame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3. Number analyzed is the number of participants with data available for analysis for the given category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values | Confirmed Value of Platelets <75 × 10^9/L | 12.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values | Confirmed Urine P/C Ratio >5 × Upper Limit of Normal (ULN) | 8.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values | Confirmed Creatinine Clearance by CKD-EPI <30 ml/min/1.73m^2 | 4.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values | Confirmed Alanine Aminotransferase (ALT) ≥3 x ULN | 4.0 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values | Confirmed Creatinine Clearance by CKD-EPI <30 ml/min/1.73m^2 | 4.7 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values | Confirmed Value of Platelets <75 × 10^9/L | 12.9 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values | Confirmed Alanine Aminotransferase (ALT) ≥3 x ULN | 4.7 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values | Confirmed Urine P/C Ratio >5 × Upper Limit of Normal (ULN) | 10.6 percentage of participants |
Primary
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence that at any dose that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported.
Time frame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Population: SS included all enrolled participants who received at least 1 injection of inotersen in CS3.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug | TEAEs | 100 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug | TEAEs Related to Study Drug | 82.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug | Serious TEAEs | 36.0 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug | TEAEs | 96.5 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug | Serious TEAEs | 54.1 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug | TEAEs Related to Study Drug | 69.4 percentage of participants |
Secondary
Change From Baseline in Retinol Binding Protein 4 (RBP4) Level
RBP4 protein concentration in serum was measured.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156, and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in Retinol Binding Protein 4 (RBP4) Level | Change From Baseline at Week 52 of Year 4 | -28307.1 micrograms per liter (µg/L) | Standard Deviation 9539.75 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in Retinol Binding Protein 4 (RBP4) Level | Change From Baseline at Week 156 | -21489.4 micrograms per liter (µg/L) | Standard Deviation 10670.52 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in Retinol Binding Protein 4 (RBP4) Level | Change From Baseline at Week 78 | -21073.1 micrograms per liter (µg/L) | Standard Deviation 11038.53 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in Retinol Binding Protein 4 (RBP4) Level | Change From Baseline at Week 52 of Year 5 | -24444.0 micrograms per liter (µg/L) | — |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in Retinol Binding Protein 4 (RBP4) Level | Change From Baseline at Week 156 | -22372.3 micrograms per liter (µg/L) | Standard Deviation 10372.05 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in Retinol Binding Protein 4 (RBP4) Level | Change From Baseline at Week 78 | -19365.9 micrograms per liter (µg/L) | Standard Deviation 10511.83 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in Retinol Binding Protein 4 (RBP4) Level | Change From Baseline at Week 52 of Year 4 | -24893.7 micrograms per liter (µg/L) | Standard Deviation 5559.01 |
Secondary
Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156
BMI=weight (kg)/\[height (m)\^2\].
Time frame: Baseline, Weeks 78 and 156
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156 | Change From Baseline at Week 78 | -0.16 kg/m^2 | Standard Deviation 2.617 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156 | Change From Baseline at Week 156 | -0.34 kg/m^2 | Standard Deviation 1.908 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156 | Change From Baseline at Week 78 | -0.44 kg/m^2 | Standard Deviation 1.427 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156 | Change From Baseline at Week 156 | -0.66 kg/m^2 | Standard Deviation 2.22 |
Secondary
Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156
Heart rate to deep breathing is a quantitative autonomic test using the CASE IV instrument that measures a participant's change in heart rate after deep breathing. The score of this component ranges from 0 to 3.72 points. Higher scores indicate impairment. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 0.23 score on a scale | Standard Deviation 0.977 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 0.44 score on a scale | Standard Deviation 1.099 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 0.11 score on a scale | Standard Deviation 0.761 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 0.30 score on a scale | Standard Deviation 0.504 |
Comparison: Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Week 78p-value: 0.63895% CI: [-0.32, 0.2]MMRM
Comparison: Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Week 156p-value: 0.96595% CI: [-0.3, 0.29]MMRM
Secondary
Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156
The Heat-Pain Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pain sensory thresholds in response to heat. The maximum score of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 2.60 score on a scale | Standard Deviation 8.44 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 2.90 score on a scale | Standard Deviation 9.224 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 2.45 score on a scale | Standard Deviation 7.557 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 3.40 score on a scale | Standard Deviation 8.774 |
Comparison: Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Week 78p-value: 0.82195% CI: [-2.67, 3.36]MMRM
Comparison: Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Week 156p-value: 0.29395% CI: [-6.21, 1.9]MMRM
Secondary
Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156
The nerve conduction tests are quantitative tests that measure the conduction attributes of preselected nerves. The score range of this component is 0 to 18.6 points. Higher scores indicate impairment. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 1.86 score on a scale | Standard Deviation 2.313 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 2.05 score on a scale | Standard Deviation 2.351 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 0.57 score on a scale | Standard Deviation 1.361 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 0.77 score on a scale | Standard Deviation 1.724 |
Comparison: Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Week 78p-value: <0.00195% CI: [-1.68, -0.5]MMRM
Comparison: Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Week 156p-value: 0.06795% CI: [-1.38, 0.05]MMRM
Secondary
Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156
The Touch-Pressure Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pressure sensory thresholds in response to touch. The score range of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 1.00 score on a scale | Standard Deviation 6.886 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 1.95 score on a scale | Standard Deviation 6.866 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156 | Change From Baseline at Week 78 | -3.05 score on a scale | Standard Deviation 8.878 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156 | Change From Baseline at Week 156 | -2.34 score on a scale | Standard Deviation 8.306 |
Comparison: Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Week 78p-value: 0.04795% CI: [-5.53, -0.03]MMRM
Comparison: Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Week 156p-value: 0.04195% CI: [-6, -0.13]MMRM
Secondary
Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156
BMI=weight (kg)/\[height (m)\^2\]. The mBMI is the BMI multiplied by the serum albumin (g/L).
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156 | Change From Baseline at Week 78 | -166.27 kg/m^2*g/L | Standard Deviation 159.644 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156 | Change From Baseline at Week 156 | -191.68 kg/m^2*g/L | Standard Deviation 130.37 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156 | Change From Baseline at Week 78 | -161.52 kg/m^2*g/L | Standard Deviation 134.779 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156 | Change From Baseline at Week 156 | -172.52 kg/m^2*g/L | Standard Deviation 131.602 |
Secondary
Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156
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 worsening disease. A positive change from Baseline indicates worsening of polyneuropathy impairments. Mixed Effects Model with Repeated Measures (MMRM) was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Population: Full Analysis Set (FAS) included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk quality of life-diabetic neuropathy (QoL-DN) questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 33.11 score on a scale | Standard Deviation 28.915 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 37.34 score on a scale | Standard Deviation 29.03 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 10.11 score on a scale | Standard Deviation 18.204 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 17.21 score on a scale | Standard Deviation 27.307 |
Comparison: Change From Baseline in the mNIS+7 Composite Score at Week 78p-value: <0.00195% CI: [-26.12, -9.56]MMRM
Comparison: Change From Baseline in the mNIS+7 Composite Score at Week 156p-value: <0.00195% CI: [-31.27, -8.95]MMRM
Secondary
Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5
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. A positive change from Baseline indicates worsening. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses.Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 4 | 35.78 score on a scale | Standard Deviation 21.071 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 4 | 18.32 score on a scale | Standard Deviation 20.97 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 5 | 17.75 score on a scale | — |
Comparison: Change From Baseline in the NIS Composite Score at Week 52 of Year 4p-value: <0.00195% CI: [-26.92, -8.03]MMRM
Secondary
Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5
Cranial Nerve assessment involves testing 3rd and 6th nerves and facial, palate, and tongue weakness. The score range for this component is 0 to 40 points. Higher scores indicate worsening. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 4 | 0.0 score on a scale | Standard Deviation 0 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 4 | 0.0 score on a scale | Standard Deviation 0 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 5 | 0.0 score on a scale | — |
Comparison: Change from Baseline in the NIS Component: Cranial Nerves Score Score at Week 52 of Year 4p-value: 0.94195% CI: [-0.19, 0.17]MMRM
Secondary
Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5
Muscle weakness involves testing 19 movements of muscles. The score range of this component is 0 to 152 points. Higher scores indicate worsening. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 4 | 23.67 score on a scale | Standard Deviation 16.712 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 4 | 14.71 score on a scale | Standard Deviation 19.479 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 5 | 13.75 score on a scale | — |
Comparison: Change from Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4p-value: 0.01195% CI: [-16.97, -2.16]MMRM
Secondary
Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5
The Reflexes Score involves testing 5 reflexes to stimuli. The score range of this component is 0 to 20 points. Higher scores indicate worsening. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 4 | 4.17 score on a scale | Standard Deviation 3.553 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 4 | 2.32 score on a scale | Standard Deviation 1.957 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 5 | 4.00 score on a scale | — |
Comparison: Change from Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4p-value: 0.35695% CI: [-3.28, 1.18]MMRM
Secondary
Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5
The Sensory Score is based on testing an index finger and a big toe each to 4 stimuli. The score of this component ranges from 0 to 32 points. Higher scores indicate impairment. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 4 | 7.94 score on a scale | Standard Deviation 5.288 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 4 | 1.29 score on a scale | Standard Deviation 3.662 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5 | Change From Baseline at Week 52 of Year 5 | 0.00 score on a scale | — |
Comparison: Change from Baseline in the NIS Component: Sensory Score at Week 52 of Years 4p-value: <0.00195% CI: [-8.58, -2.19]MMRM
Secondary
Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score
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 quality of life (QoL). A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the Week 52 of Year 4
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Overall number analyzed are the number of participants available for analyses. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score | Change From Baseline at Week 78 | 11.21 score on a scale | Standard Deviation 11.026 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score | Change From Baseline at Week 156 | 12.60 score on a scale | Standard Deviation 10.784 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score | Change From Baseline at Week 52 of Year 4 | 9.50 score on a scale | Standard Deviation 9.192 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score | Change From Baseline at Week 78 | 3.61 score on a scale | Standard Deviation 11.5 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score | Change From Baseline at Week 156 | -0.55 score on a scale | Standard Deviation 8.042 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score | Change From Baseline at Week 52 of Year 4 | 3.50 score on a scale | Standard Deviation 7.047 |
Comparison: Change From Baseline in the Norfolk QOL-DN Change From CS2 Baseline in the Norfolk QOL-DN Questionnaire Total Score at Week 78p-value: 0.09795% CI: [-13.75, 1.15]MMRM
Comparison: Change from Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score at Week 156p-value: 0.08195% CI: [-18.88, 1.11]MMRM
Comparison: Change From Baseline in the Norfolk QOL-DN Physical Functioning/Large Fiber Neuropathy Domain Score at Week 52 of Year 4p-value: 0.17195% CI: [-28.89, 5.16]MMRM
Secondary
Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156
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. A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 | Change From Baseline at Week 52 of Year 4 | 6.22 score on a scale | Standard Deviation 18.6 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 14.94 score on a scale | Standard Deviation 28.944 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 15.22 score on a scale | Standard Deviation 24.024 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 | Change From Baseline at Week 52 of Year 5 | -1.00 score on a scale | — |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 | Change From Baseline at Week 156 | 5.98 score on a scale | Standard Deviation 22.891 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 | Change From Baseline at Week 78 | 3.76 score on a scale | Standard Deviation 20.832 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156 | Change From Baseline at Week 52 of Year 4 | 2.36 score on a scale | Standard Deviation 25.12 |
Comparison: Change From Baseline in the Norfolk QOL-DN Questionnaire Total Score at Week 78p-value: 0.02695% CI: [-17.48, -1.14]MMRM
Comparison: Change From Baseline in the Norfolk QOL-DN Questionnaire Total Score at Week 156p-value: 0.10795% CI: [-16.41, 1.62]MMRM
Comparison: Change From Baseline in the Norfolk QOL-DN Questionnaire Total Score at Week 52 of Year 4p-value: 0.66995% CI: [-15.22, 9.77]MMRM
Secondary
Change From Baseline in Transthyretin (TTR) Level
Transthyretin protein concentration in serum was measured.
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Change From Baseline in Transthyretin (TTR) Level | Change From Baseline at Week 156 | -0.1498 g/L | Standard Deviation 0.06366 |
| Previous Placebo-Inotersen 300 mg | Change From Baseline in Transthyretin (TTR) Level | Change From Baseline at Week 78 | -0.1581 g/L | Standard Deviation 0.05887 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in Transthyretin (TTR) Level | Change From Baseline at Week 156 | -0.1692 g/L | Standard Deviation 0.06025 |
| Previous Inotersen-Inotersen 300 mg | Change From Baseline in Transthyretin (TTR) Level | Change From Baseline at Week 78 | -0.1555 g/L | Standard Deviation 0.06751 |
Secondary
Ctrough: Trough Plasma Concentration of ISIS 420915
Time frame: Pre-dose on Days 1, 43, 85, 120, 176, 267, 358, 449, 540, 631, 722, 813, 904, 995, 1086, 1268; Days 1359 and 1450 of Year 4; Days 1632, 1723 and 1814 of Year 5
Population: CS3 Pharmacokinetic (PK) Set included all enrolled participants who received at least 1 dose of inotersen in CS3 and who had at least 1 evaluable PK sample collected and analyzed with reportable result in CS3. Number analyzed is the number of participants with data available for analyses at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1723 of Year 5 | 113 nanograms per milliliter (ng/ml) | — |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 43 | 22.9 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 97.6 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 85 | 28.6 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 43.6 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 120 | 31.5 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 43.7 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 722 | 97.6 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 245 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 813 | 98.0 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 354 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 904 | 91.4 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 230 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 995 | 147 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 809 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1086 | 131 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 340 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1268 of Year 4 | 167 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 258 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 176 | 38.0 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 52.9 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 267 | 47.3 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 83.4 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 358 | 56.2 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 102 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 449 | 71.1 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 158 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 540 | 78.7 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 163 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 631 | 83.8 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 211 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1359 of Year 4 | 432 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 307 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1450 of Year 4 | 55.0 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 61.1 |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1632 of Year 5 | 37.4 nanograms per milliliter (ng/ml) | — |
| Previous Placebo-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1 | NA nanograms per milliliter (ng/ml) | — |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1632 of Year 5 | 75.3 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 26.9 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1 | 34.1 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 247 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 176 | 80.0 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 104 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 43 | 74.0 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 123 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 631 | 141 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 187 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 85 | 83.0 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 138 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 267 | 98.2 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 183 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 120 | 81.9 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 142 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1268 of Year 4 | 102 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 202 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 722 | 101 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 127 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 358 | 110 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 130 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 813 | 150 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 273 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1450 of Year 4 | 83.0 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 111 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 904 | 116 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 148 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 449 | 130 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 218 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 995 | 134 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 246 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1359 of Year 4 | 157 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 233 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1086 | 101 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 159 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 540 | 111 nanograms per milliliter (ng/ml) | Geometric Coefficient of Variation 219 |
| Previous Inotersen-Inotersen 300 mg | Ctrough: Trough Plasma Concentration of ISIS 420915 | Day 1814 of Year 5 | 62.1 nanograms per milliliter (ng/ml) | — |
Secondary
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score
PND score is defined as I = sensory disturbances in limbs without motor impairment; II = difficulty walking without the need of a walking aid; III = one stick or one crutch required for walking; IV = two sticks or two crutches needed. V = wheelchair required or patient confined to bed. The change from Baseline values have been categorized as: improved, not changed, worsened, and unknown. Percentage of participants with changes from Baseline are presented category-wise in this outcome measure. Only categories with at least one participant with event are reported.
Time frame: Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year)
Population: FAS included all enrolled participants who received at least 1 injection of inotersen in this study (CS3) and who had at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score collected after CS3 Study Day 1. Number analyzed is the number of participants with data available for analysis at the given time point for the specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 78: Improved | 5.6 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 52 of Year 4: Not Changed | 33.3 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 52 of Year 4: Worsened | 55.6 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 78: Not Changed | 69.4 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 78: Worsened | 25.0 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 156: Improved | 4.8 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 156: Not Changed | 52.4 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 156: Worsened | 42.9 percentage of participants |
| Previous Placebo-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 52 of Year 4: Improved | 11.1 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 78: Not Changed | 62.0 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 156: Worsened | 36.6 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 78: Improved | 11.3 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 52 of Year 4: Improved | 14.3 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 78: Worsened | 26.8 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 52 of Year 4: Not Changed | 42.9 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 156: Not Changed | 56.1 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 52 of Year 4: Worsened | 42.9 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 52 of Year 5: Not Changed | 100 percentage of participants |
| Previous Inotersen-Inotersen 300 mg | Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score | Change From Baseline at Week 156: Improved | 7.3 percentage of participants |
Secondary
Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set
GLS by ECHO is a measure of cardiac systolic function.
Time frame: Baseline, Weeks 78 and 156
Population: The Cardiomyopathy-echocardiogram (CM-ECHO) Set included the subset of the 420915-CS2 Randomized Set that had a diagnosis of transthyretin (TTR) cardiomyopathy at study entry of the parent study, but were not in the ECHO Subgroup in the parent study, plus participants who qualified to participate in the ECHO Subgroup (whether consented or not). Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set | Change From Baseline at Week 78 | 0.38 percent change | Standard Deviation 3.178 |
| Previous Placebo-Inotersen 300 mg | Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set | Change From Baseline at Week 156 | 1.46 percent change | Standard Deviation 5.313 |
| Previous Inotersen-Inotersen 300 mg | Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set | Change From Baseline at Week 78 | -0.74 percent change | Standard Deviation 3.12 |
| Previous Inotersen-Inotersen 300 mg | Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set | Change From Baseline at Week 156 | 0.07 percent change | Standard Deviation 4.318 |
Secondary
Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup
GLS by ECHO is a measure of cardiac systolic function.
Time frame: Weeks 78 and 156
Population: The Cardiomyopathy-echocardiogram (CM-ECHO) Set included the subset of the 420915-CS2 Randomized Set that had a diagnosis of transthyretin (TTR) cardiomyopathy at study entry of the parent study, but were not in the ECHO Subgroup in the parent study, plus participants who qualified to participate in the ECHO Subgroup (whether consented or not). Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Previous Placebo-Inotersen 300 mg | Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup | Percent Change From Baseline at Week 78 | -6.93 percent change | Standard Deviation 20.232 |
| Previous Placebo-Inotersen 300 mg | Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup | Percent Change From Baseline at Week 156 | -2.79 percent change | Standard Deviation 24.58 |
| Previous Inotersen-Inotersen 300 mg | Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup | Percent Change From Baseline at Week 78 | 8.99 percent change | Standard Deviation 26.201 |
| Previous Inotersen-Inotersen 300 mg | Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup | Percent Change From Baseline at Week 156 | 11.46 percent change | Standard Deviation 29.383 |