Patisiran in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) Disease Progression Post-Liver Transplant

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of patisiran in participants with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with disease progression after liver transplant.

Official Title
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An Open-label Study to Evaluate Safety, Efficacy and Pharmacokinetics (PK) of Patisiran-LNP in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) With Disease Progression Post-Orthotopic Liver Transplant

Conditions
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Amyloidosis, Familial, Transthyretin Amyloidosis

Intervention / Treatment
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* Drug: Patisiran


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Received liver transplant for treatment of hATTR amyloidosis ≥12 months before study start Has increase in polyneuropathy disability (PND) score after liver transplant Has received stable immunosuppressive regimen with ≤10 mg/day of prednisone for at least 3 months before study start Has Karnofsky Performance Status (KPS) of ≥70% Has vitamin A level greater than or equal to lower limit of normal Exclusion Criteria: Has previously received inotersen or patisiran Has clinically significant liver function test abnormalities Has known portal hypertension with ascites Has estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m^2 Has known leptomeningeal amyloidosis Has infection with hepatitis B, hepatitis C or human immunodeficiency virus (HIV) Has New York Heart Association heart failure classification of >2 Is wheelchair bound or bedridden Has received organ transplants other than liver transplant Will be using another tetramer stabilizer during 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patisiran<br>Participants received patisiran 0.3 milligrams/kilogram (mg/kg) via intravenous (IV) infusion once every 3 weeks (q3w) for 12 months. Dosing was based on actual body weight. For participants weighing 100 kg or more, patisiran was administered at a total dose of 30 mg IV q3w. | Drug: Patisiran<br>* Patisiran was administered via IV infusion.<br>* Other names: ONPATTRO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average of Month 6 and Month 12 Percentage Reduction From Baseline in Serum Transthyretin (TTR) | Serum TTR was assessed using enzyme linked immunosorbent assay (ELISA). The average of the percentage reduction in serum TTR observed at Month 6 and at Month 12 is first calculated for each patient and then the median (95% CI) of these averaged values is summarized for the Safety Analysis Set. | Baseline, Months 6 and 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 12 | The NIS is a composite neurologic impairment score that assesses motor weakness (NIS-W), sensation (NIS-S) and reflexes (NIS-R) by physical exam. The minimum and maximum values are 0 and 244, respectively. A higher score indicates a worse outcome. | Baseline, Month 12 | 
| Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Score at Month 12 | The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome. | Baseline, Month 12 | 
| Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 12 | The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations. The minimum and maximum values are 0 and 48, respectively. A higher score indicates a better outcome. | Baseline, Month 12 | 
| Change From Baseline in the Composite Autonomic Symptom Score (COMPASS-31) at Month 12 | The COMPASS-31 questionnaire is a measure of autonomic neuropathy symptoms. The questions evaluate 6 autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor). The minimum and maximum values are 0 and 100, respectively. A higher score indicates a worse outcome. | Baseline, Month 12 | 
| Change From Baseline in the Modified Body Mass Index (mBMI) at Month 12 | Nutritional status of participants was evaluated using the mBMI, calculated as BMI (kg/m^2) multiplied by albumin (g/L). An increase from baseline in mBMI suggests improvement, and a decrease from baseline suggests worsening. | Baseline, Month 12 | 
| Percentage of Participants With Adverse Events | An AE is any untoward medical occurrence in a participant or clinical investigational patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. | From baseline to end of study at Month 13 |