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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03862807

Enrollment

Registered

2019-03-05

Start date

2019-03-27

Completion date

2020-10-20

Last updated

2024-04-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Amyloidosis, Familial, Transthyretin Amyloidosis

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.

Interventions

DRUGPatisiran

Patisiran was administered via IV infusion.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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

Design outcomes

Primary

Measure	Time frame	Description
Average of Month 6 and Month 12 Percentage Reduction From Baseline in Serum Transthyretin (TTR)	Baseline, Months 6 and 12	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

Measure	Time frame	Description
Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Score at Month 12	Baseline, 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	Baseline, 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 Neuropathy Impairment Score (NIS) at Month 12	Baseline, 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 the Modified Body Mass Index (mBMI) at Month 12	Baseline, 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	From baseline to end of study at Month 13	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.
Change From Baseline in the Composite Autonomic Symptom Score (COMPASS-31) at Month 12	Baseline, 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.

Countries

France, Germany, Italy, Portugal, Spain, Sweden, United Kingdom

Participant flow

Recruitment details

Participants with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with disease progression post-orthotopic liver transplant were enrolled at nine sites in France, Germany, Italy, Portugal, Spain, Sweden and the United Kingdom.

Participants by arm

Arm	Count
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.	23
Total	23

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Not Treated Due to Eligibility Criteria Failure	1

Baseline characteristics

Characteristic	Patisiran
Age, Continuous	58.1 years STANDARD_DEVIATION 9.9
Race/Ethnicity, Customized Asian	1 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	23 Participants
Race/Ethnicity, Customized White	22 Participants
Serum Transthyretin (TTR)	192.140 mg/L
Sex: Female, Male Female	10 Participants
Sex: Female, Male Male	13 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 23
other Total, other adverse events	23 / 23
serious Total, serious adverse events	5 / 23

Outcome results

Primary

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.

Time frame: Baseline, Months 6 and 12

Population: Safety Analysis Set: All participants who received any amount of patisiran.

Arm	Measure	Value (MEDIAN)
Patisiran	Average of Month 6 and Month 12 Percentage Reduction From Baseline in Serum Transthyretin (TTR)	91.0 percent reduction

Secondary

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.