Extension Study Assessing Long Term Safety and Efficacy of IONIS-TTR Rx in Familial Amyloid Polyneuropathy (FAP)

Study Overview
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Brief Summary
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This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.

Detailed Description
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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.

Official Title
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An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (FAP)

Conditions
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FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis

Intervention / Treatment
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* Drug: Inotersen


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Previous Placebo-Inotersen 300 mg<br>Participants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group. | Drug: Inotersen<br>* Inotersen SC<br>* Other names: ISIS 420915;|
| Experimental: Previous Inotersen-Inotersen 300 mg<br>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. | Drug: Inotersen<br>* Inotersen SC<br>* Other names: ISIS 420915;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 Vital Signs | Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported. | 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 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. | 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 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. | 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 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. | From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks) | 
| 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. | 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 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | 
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | 
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | 
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | 
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | 
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5 | 
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5 | 
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5 | 
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5 | 
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5 | 
| 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. | 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) | 
| 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. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the Week 52 of Year 4 | 
| 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). | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | 
| Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156 | BMI=weight (kg)/[height (m)^2]. | Baseline, Weeks 78 and 156 | 
| 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. | Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year) | 
| 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. | Baseline, Weeks 78 and 156 | 
| Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup | GLS by ECHO is a measure of cardiac systolic function. | Weeks 78 and 156 | 
| Change From Baseline in Transthyretin (TTR) Level | Transthyretin protein concentration in serum was measured. | Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 | 
| Change From Baseline in Retinol Binding Protein 4 (RBP4) Level | RBP4 protein concentration in serum was measured. | 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) | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis