Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
Conditions
Keywords
Polyneuropathy, Amyloidosis, ATTR, TTR
Brief summary
The main objective of this study was to evaluate the efficacy of eplontersen as compared with the historical control of the placebo cohort in the NEURO-TTR trial (NCT01737398/2012-001831-30), in subjects with hereditary transthyretin-mediated amyloidosis polyneuropathy (hATTR-PN). For more information, please visit http://www.neuro-ttransform.com/.
Detailed description
This study was a multicenter, open-label study in up to 168 participants, who were randomized to receive subcutaneous (SC) injections of either eplontersen once every 4 weeks or inotersen once a week. Participants also received daily supplemental doses of the recommended daily allowance of vitamin A. Participants included in the inotersen reference arm crossed over to eplontersen at Week 37 after completing the Week 35 assessments.
Interventions
DRUGInotersen
Inotersen by subcutaneous injection
DRUGEplontersen
Eplontersen by subcutaneous injection
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 82 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Aged 18 to 82 years at the time of informed consent 2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent 3. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the participant or the participantss non-pregnant female partner must be using a highly effective contraceptive method 4. Diagnosis of hereditary transthyretin-mediated polyneuropathy as defined by meeting all 3 of the following: * Stage 1 or Stage 2 Familial Amyloid Polyneuropathy (FAP) or Coutinho Stage * Documented genetic mutation in the TTR gene * Symptoms and signs consistent with neuropathy associated with transthyretin amyloidosis, including Neuropathy Impairment Score (NIS) ≥ 10 and ≤ 130 Key
Exclusion criteria
1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a participants unsuitable for inclusion, including but not limited to abnormal safety labs 2. Karnofsky performance status ≤ 50 3. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes 4. Prior liver transplant or anticipated liver transplant within 1-yr of Screening 5. New York Heart Association (NYHA) functional classification of ≥ 3 6. Acute coronary syndrome within 6 months of screening or major surgery within 3 months of Screening 7. Other types of amyloidosis 8. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the Study 9. Current treatment with any approved drug for hereditary TTR amyloidosis such as Vyndaqel® / Vyndamax™ (tafamidis), Tegsedi™ (inotersen), Onpattro™ (patisiran), off-label use of diflunisal or doxycycline, and tauroursodeoxycholic acid (TUDCA). If previously treated with Vyndaqel® / Vyndamax™, diflunisal or doxycycline, and TUDCA, must have discontinued treatment for at least 2 weeks prior to Study Day 1 10. Previous treatment with Tegsedi™ (Inotersen) or Onpattro™ (patisiran), or other oligonucleotide or RNA therapeutic (including siRNA)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35 | Baseline, Week 35 | mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: NIS composite score (maximum of 244 points) & the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. |
| Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66 | Baseline, Week 66 | mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: the NIS composite score (maximum of 244 points) & the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. Least square (LS) mean & standard error (SE) were analyzed using Mixed Effects Model with Repeated Measures (MMRM). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. |
| Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 | Baseline, Week 66 | The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. |
| Percent Change From Baseline in Serum TTR Concentration at Week 65 | Baseline, Week 65 | As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis. |
| Percent Change From Baseline in Serum TTR Concentration at Week 35 | Baseline, Week 35 | As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified Body Mass Index (mBMI) at Week 65 | Baseline, Week 65 | mBMI is defined as body mass index in kilograms per square meter (kg/m\^2) multiplied by serum albumin in grams per liter (g/L). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. |
| Change From Baseline in Norfolk QOL-DN at Week 35 | Baseline, Week 35 | 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 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. |
| Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66 | Baseline, Week 35, Week 66 | NSC score is a questionnaire composed of 38 questions divided into 5 domains: muscle weakness, sensory (hypo/loss of sensation), sensory (paresthesia, hyper sensation), autonomic (gastrointestinal & urinary incontinence), & autonomic (non-GI/non-urinary incontinence)\]. Answers to questionnaire are yes/no and if yes, then degree of severity is graded as 1 (slight +), 2 (moderate ++) and 3 (severe +++). 0=no symptom. NSC total score is a sum of scores across all 5 domains. Total score= 0-114. Higher scores=more neuropathy symptoms. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. |
| Change From Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65 | Baseline, Week 65 | SF-36 comprises 36 items that yield 8 subscales and 2 summary measures (PCS and Mental component summary \[MCS\]). Multi-item subscales (35 items) includes: physical function=10 items, role physical =4 items, bodily pain=2 items, general health=5 items, vitality=4 items, social functioning=2 items, role emotional =3 items and mental health=5 items. 8 subscales are scored from 0-100. Higher scores indicate better health. 8 subscales are aggregated into a PCS score ranging from 0-100. Higher scores indicate better health. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. |
| Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65 | Baseline, Week 65 | PND is a 5-stage scoring system. PND score is defined as I=sensory disturbances in limbs without motor impairment; II=difficulty walking without the need of a walking aid; IIIa=one stick or one crutch required for walking; IIIb=two sticks or two crutches needed; IV=wheelchair required or patient confined to bed. For analysis, no impairment is scored as 0, I is scored as 1, II as 2, IIIa as 3, IIIb as 4 and IV as 5. Lower scores indicate greater ambulatory function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. |
Countries
Argentina, Australia, Brazil, Canada, Cyprus, France, Germany, Greece, Italy, New Zealand, Portugal, Spain, Sweden, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
Participants took part in the study at 46 investigative sites in 15 countries (Argentina, Australia, Brazil, Canada, Cyprus, France, Germany, Italy, New Zealand, Portugal, Spain, Sweden, Taiwan, Turkey, and the United States) from 11 December 2019 to 12 July 2023.
Pre-assignment details
Participants with a diagnosis of hereditary transthyretin-mediated amyloid Polyneuropathy (hATTR-PN) were randomized in a 6:1 ratio to receive eplontersen (ION-682884) or inotersen respectively. As pre-specified in the protocol, the placebo-cohort group from ISIS 420915-CS2 (NEURO-TTR) study (NCT01737398-3), which was used as an external control for efficacy analysis in this study.
Participants by arm
| Arm | Count |
|---|---|
| Inotersen Participants received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, participants received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81. | 24 |
| Eplontersen Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81. | 144 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Voluntary Withdrawal (including enrolled OLE) | 23 | 119 |
Baseline characteristics
| Characteristic | Inotersen | Total | Eplontersen |
|---|---|---|---|
| Age, Continuous | 51.1 years STANDARD_DEVIATION 14.38 | 52.8 years STANDARD_DEVIATION 14.88 | 53.0 years STANDARD_DEVIATION 15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 27 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 138 Participants | 120 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Modified Neuropathy Impairment Score Plus 7 (mNIS+7) Composite Score | 65.06 scores on a scale STANDARD_DEVIATION 33.515 | 78.97 scores on a scale STANDARD_DEVIATION 42.43 | 81.28 scores on a scale STANDARD_DEVIATION 43.401 |
| Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Total Score | 40.05 scores on a scale STANDARD_DEVIATION 21.488 | 43.49 scores on a scale STANDARD_DEVIATION 25.87 | 44.09 scores on a scale STANDARD_DEVIATION 26.59 |
| Race/Ethnicity, Customized Asian | 2 Participants | 24 Participants | 22 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 5 Participants | 5 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 19 Participants | 131 Participants | 112 Participants |
| Serum Transthyretin (TTR) Concentration | 0.22 grams per litre (g/L) STANDARD_DEVIATION 0.069 | 0.23 grams per litre (g/L) STANDARD_DEVIATION 0.074 | 0.23 grams per litre (g/L) STANDARD_DEVIATION 0.075 |
| Sex: Female, Male Female | 8 Participants | 52 Participants | 44 Participants |
| Sex: Female, Male Male | 16 Participants | 116 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 144 | 0 / 24 | 0 / 20 |
| other Total, other adverse events | 131 / 144 | 24 / 24 | 18 / 20 |
| serious Total, serious adverse events | 27 / 144 | 3 / 24 | 3 / 20 |
Outcome results
Primary
Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35
mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: NIS composite score (maximum of 244 points) & the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Time frame: Baseline, Week 35
Population: FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen \& had a baseline \& 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug \& had a baseline \& 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Eplontersen | Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35 | 0.6795 scores on a scale | Standard Error 1.9073 |
| External Placebo | Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35 | 10.0337 scores on a scale | Standard Error 1.8544 |
p-value: 0.0001220395% CI: [-13.8691, -4.8394]MMRM
Primary
Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66
mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: the NIS composite score (maximum of 244 points) & the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. Least square (LS) mean & standard error (SE) were analyzed using Mixed Effects Model with Repeated Measures (MMRM). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Time frame: Baseline, Week 66
Population: FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen \& had a baseline \& 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug \& had a baseline \& 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Eplontersen | Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66 | 0.2964 scores on a scale | Standard Error 2.4123 |
| External Placebo | Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66 | 25.0557 scores on a scale | Standard Error 2.3874 |
p-value: 1e-895% CI: [-30.9552, -18.5635]MMRM
Primary
Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Time frame: Baseline, Week 66
Population: FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen \& had a baseline \& 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug \& had a baseline \& 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Eplontersen | Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 | -5.4964 scores on a scale | Standard Error 2.2976 |
| External Placebo | Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 | 14.2388 scores on a scale | Standard Error 2.3488 |
p-value: 1e-895% CI: [-25.6301, -13.8403]MMRM
Primary
Percent Change From Baseline in Serum TTR Concentration at Week 35
As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.
Time frame: Baseline, Week 35
Population: FAS was defined as all randomized participants who received at least 1 injection of ION-682884/inotersen and had a baseline \& at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized participants who received at least 1 injection of study drug and had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Eplontersen | Percent Change From Baseline in Serum TTR Concentration at Week 35 | -81.14 percentage | Standard Error 1.674 |
| External Placebo | Percent Change From Baseline in Serum TTR Concentration at Week 35 | -14.49 percentage | Standard Error 1.966 |
p-value: 1e-895% CI: [-71.59, -61.71]MMRM
Primary
Percent Change From Baseline in Serum TTR Concentration at Week 65
As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.
Time frame: Baseline, Week 65
Population: FAS was defined as all randomized participants who received at least 1 injection of ION-682884/inotersen and had a baseline \& at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized participants who received at least 1 injection of study drug and had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Eplontersen | Percent Change From Baseline in Serum TTR Concentration at Week 65 | -81.65 percentage | Standard Error 1.605 |
| External Placebo | Percent Change From Baseline in Serum TTR Concentration at Week 65 | -11.24 percentage | Standard Error 1.91 |
p-value: 1e-895% CI: [-75.17, -65.66]MMRM
Secondary
Change From Baseline in Modified Body Mass Index (mBMI) at Week 65
mBMI is defined as body mass index in kilograms per square meter (kg/m\^2) multiplied by serum albumin in grams per liter (g/L). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Time frame: Baseline, Week 65
Population: FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen \& had a baseline \& 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug \& had a baseline \& 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Eplontersen | Change From Baseline in Modified Body Mass Index (mBMI) at Week 65 | -8.0655 kilogram(kg)/metre(m)^2*gram(g)/litre(L) | Standard Error 10.3786 |
| External Placebo | Change From Baseline in Modified Body Mass Index (mBMI) at Week 65 | -90.7645 kilogram(kg)/metre(m)^2*gram(g)/litre(L) | Standard Error 10.9465 |
p-value: 2e-795% CI: [54.6431, 110.7551]MMRM
Secondary
Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66
NSC score is a questionnaire composed of 38 questions divided into 5 domains: muscle weakness, sensory (hypo/loss of sensation), sensory (paresthesia, hyper sensation), autonomic (gastrointestinal & urinary incontinence), & autonomic (non-GI/non-urinary incontinence)\]. Answers to questionnaire are yes/no and if yes, then degree of severity is graded as 1 (slight +), 2 (moderate ++) and 3 (severe +++). 0=no symptom. NSC total score is a sum of scores across all 5 domains. Total score= 0-114. Higher scores=more neuropathy symptoms. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Time frame: Baseline, Week 35, Week 66
Population: FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen \& had a baseline \& 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug \& had a baseline \& 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Eplontersen | Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66 | At Week 66 | -0.03 scores on a scale | Standard Error 0.955 |
| Eplontersen | Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66 | At Week 35 | 0.79 scores on a scale | Standard Error 0.867 |
| External Placebo | Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66 | At Week 66 | 8.18 scores on a scale | Standard Error 0.962 |
| External Placebo | Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66 | At Week 35 | 4.73 scores on a scale | Standard Error 0.87 |
Comparison: Week 35p-value: 0.0005244795% CI: [-6.08, -1.8]MMRM
Comparison: Week 66p-value: 1e-895% CI: [-10.65, -5.76]MMRM
Secondary
Change From Baseline in Norfolk QOL-DN at Week 35
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 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Time frame: Baseline, Week 35
Population: FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen \& had a baseline \& 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug \& had a baseline \& 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Eplontersen | Change From Baseline in Norfolk QOL-DN at Week 35 | -3.6306 scores on a scale | Standard Error 2.0678 |
| External Placebo | Change From Baseline in Norfolk QOL-DN at Week 35 | 8.1896 scores on a scale | Standard Error 2.073 |
p-value: 0.0000187395% CI: [-16.8927, -6.7477]MMRM
Secondary
Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65
PND is a 5-stage scoring system. PND score is defined as I=sensory disturbances in limbs without motor impairment; II=difficulty walking without the need of a walking aid; IIIa=one stick or one crutch required for walking; IIIb=two sticks or two crutches needed; IV=wheelchair required or patient confined to bed. For analysis, no impairment is scored as 0, I is scored as 1, II as 2, IIIa as 3, IIIb as 4 and IV as 5. Lower scores indicate greater ambulatory function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Time frame: Baseline, Week 65
Population: FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen \& had a baseline \& 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug \& had a baseline \& 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Eplontersen | Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65 | 0.1 scores on a scale | Standard Error 0.07 |
| External Placebo | Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65 | 0.3 scores on a scale | Standard Error 0.07 |
p-value: 0.0240789795% CI: [-0.4, 0]MMRM
Secondary
Change From Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65
SF-36 comprises 36 items that yield 8 subscales and 2 summary measures (PCS and Mental component summary \[MCS\]). Multi-item subscales (35 items) includes: physical function=10 items, role physical =4 items, bodily pain=2 items, general health=5 items, vitality=4 items, social functioning=2 items, role emotional =3 items and mental health=5 items. 8 subscales are scored from 0-100. Higher scores indicate better health. 8 subscales are aggregated into a PCS score ranging from 0-100. Higher scores indicate better health. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.
Time frame: Baseline, Week 65
Population: FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen \& had a baseline \& 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug \& had a baseline \& 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Eplontersen | Change From Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65 | 0.851 scores on a scale | Standard Error 0.7913 |
| External Placebo | Change From Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65 | -4.455 scores on a scale | Standard Error 0.8338 |
p-value: 0.0000055895% CI: [3.195, 7.416]MMRM