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

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

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.

Study Overview

• Status: Completed
• Conditions: Amyloidosis, Familial; Transthyretin Amyloidosis
• Intervention / Treatment: Drug: Patisiran

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Créteil, France
    • Clinical Trial Site
  • Le Kremlin-Bicêtre, France
    • Clinical Trial Site
• Germany
  • Münster, Germany
    • Clinical Trial Site
• Italy
  • Messina, Italy
    • Clinical Trial Site
• Portugal
  • Porto, Portugal
    • Clinical Trial Site
• Spain
  • Barcelona, Spain
    • Clinical Trial Site
  • Huelva, Spain
    • Clinical Trial Site
• Sweden
  • Umeå, Sweden
    • Clinical Trial Site
• United Kingdom
  • London, United Kingdom
    • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patisiran; 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; Patisiran was administered via IV infusion.; Other Names: ONPATTRO; ALN-TTR02

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Medical Director, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• Schmidt HH, Wixner J, Plante-Bordeneuve V, Munoz-Beamud F, Llado L, Gillmore JD, Mazzeo A, Li X, Arum S, Jay PY, Adams D; Patisiran Post-LT Study Group. Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation. Am J Transplant. 2022 Jun;22(6):1646-1657. doi: 10.1111/ajt.17009. Epub 2022 Mar 26.
• Seibert K, Wlodarski R, Sarswat N, Appelbaum D, Issa NP, Soliven B, Rezania K. Progressive Multiple Mononeuropathy in a Patient With Familial Transthyretin Amyloidosis After Liver Transplantation. J Clin Neuromuscul Dis. 2022 Mar 1;23(3):143-147. doi: 10.1097/CND.0000000000000368.

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2019
• Primary Completion (Actual): October 6, 2020
• Study Completion (Actual): October 20, 2020

Study Registration Dates

• First Submitted: February 28, 2019
• First Submitted That Met QC Criteria: March 1, 2019
• First Posted (Actual): March 5, 2019

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease Attributes; Genetic Diseases, Inborn; Proteostasis Deficiencies; Metabolism, Inborn Errors; Disease Progression; Amyloidosis; Amyloidosis, Familial
• Other Study ID Numbers: ALN-TTR02-008; 2018-003519-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU.

Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes