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

Primary Purpose

Amyloidosis, Familial, Transthyretin Amyloidosis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Patisiran
Sponsored by
Alnylam Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyloidosis, Familial

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Patisiran

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.

Full Information

First Posted
February 28, 2019
Last Updated
November 22, 2021
Sponsor
Alnylam Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT03862807
Brief Title
Patisiran in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) Disease Progression Post-Liver Transplant
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Completed
Study Start Date
March 27, 2019 (Actual)
Primary Completion Date
October 6, 2020 (Actual)
Study Completion Date
October 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alnylam Pharmaceuticals

4. Oversight

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

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyloidosis, Familial, Transthyretin Amyloidosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Patisiran
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Patisiran
Other Intervention Name(s)
ALN-TTR02, ONPATTRO
Intervention Description
Patisiran was administered via IV infusion.
Primary Outcome Measure Information:
Title
Average of Month 6 and Month 12 Percentage Reduction From Baseline in Serum Transthyretin (TTR)
Description
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.
Time Frame
Baseline, Months 6 and 12
Secondary Outcome Measure Information:
Title
Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 12
Description
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.
Time Frame
Baseline, Month 12
Title
Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Score at Month 12
Description
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.
Time Frame
Baseline, Month 12
Title
Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 12
Description
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.
Time Frame
Baseline, Month 12
Title
Change From Baseline in the Composite Autonomic Symptom Score (COMPASS-31) at Month 12
Description
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.
Time Frame
Baseline, Month 12
Title
Change From Baseline in the Modified Body Mass Index (mBMI) at Month 12
Description
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.
Time Frame
Baseline, Month 12
Title
Percentage of Participants With Adverse Events
Description
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.
Time Frame
From baseline to end of study at Month 13

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Alnylam Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Trial Site
City
Créteil
Country
France
Facility Name
Clinical Trial Site
City
Le Kremlin-Bicêtre
Country
France
Facility Name
Clinical Trial Site
City
Münster
Country
Germany
Facility Name
Clinical Trial Site
City
Messina
Country
Italy
Facility Name
Clinical Trial Site
City
Porto
Country
Portugal
Facility Name
Clinical Trial Site
City
Barcelona
Country
Spain
Facility Name
Clinical Trial Site
City
Huelva
Country
Spain
Facility Name
Clinical Trial Site
City
Umeå
Country
Sweden
Facility Name
Clinical Trial Site
City
London
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35213769
Citation
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.
Results Reference
derived
PubMed Identifier
35188911
Citation
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.
Results Reference
derived

Learn more about this trial

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

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