Spectrum of Peripheral and Autonomic Neuropathies in Patients With aTTRwt Amyloidosis and Response to Patisiran Therapy

To evaluate the efficacy and safety of patisiran in patients with wtATTR amyloidosis and symptomatic polyneuropathy by evaluating the effect on neurologic impairment and quality of life.

Study Overview

• Status: Completed
• Conditions: Polyneuropathies; Transthyretin Amyloidosis; Wild-Type Transthyretin-Related (ATTR)Amyloidosis; Wild-Type Transthyretin Cardiac Amyloidosis; Wild Type ATTR Amyloidosis
• Intervention / Treatment: Drug: patisiran

Detailed Description

The study will consist of a baseline screening period and a 24-month treatment period. Eligible patient will receive patisiran administered as an IV infusion once every 21 days for a 24-month period. During the 24-month treatment period study patients will undergo assessments for efficacy and/or safety as outlined in the schedule of assessments with key efficacy assessments being performed prior to the first dose and proceeding as outlined in the schedule of assessments.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78759
      • Austin Neuromuscler Center/National Neuromuscular Research Institute

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Male or female >18
2. Diagnosis of symptomatic polyneuropathy
3. wtATTR based on cardiac biopsy or Tc99m PYP
4. Negative hATTR sequencing
5. 0 to 0.5 gram/dl serum monoclonal protein.
6. No history of other secondary causes of neuropathy.
7. Have adequate complete blood counts and liver function tests
8. Have negative serology for hepatitis B virus (HBV) and hepatitis C virus (HCV)

Exclusion Criteria:

1. Other Causes of neuropathy as determined by the principle investigator.
2. Has known human immunodeficiency virus (HIV) infection;
3. Primary AL.

4. NYHA Class IV at the Screening visit. 5. Has any of the following laboratory parameter assessments at screening:

   1. Aspartate transaminase (AST) or alanine transaminase (ALT) levels ˃2.0 × the upper limit of normal (ULN).
   2. Total bilirubin ˃ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert's syndrome are eligible if total bilirubin <2 × ULN.

   3. International normalized ratio (INR) ˃1.5 (unless patient is on anticoagulant therapy, in which case excluded if INR ˃3.5).

      6. Has eGFR < 30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] formula). 7. Is currently taking diflunisal; if previously on this agent, must have at least a 6-month wash-out prior to dosing (Day 1).

      8. Is currently taking doxycycline, or tauroursodeoxycholic acid; if previously on any of these agents must have completed a 30-day wash-out prior to dosing (Day 1).

      9. Received prior TTR-lowering treatment or participated in a gene therapy trial for amyloidosis. 10. Current or future participation in another investigational device or drug study, Scheduled to occur during this study, or has received an investigational agent or device within 30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing (Day 1). In the case of investigational TTR stabilizer drugs, washout for 6 months prior to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at baseline (per inclusion Criterion 4).

      11. Requires treatment with calcium channel blockers (eg, verapamil, diltiazem) or digitalis.

      12. Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to valvular heart disease, or cardiomyopathy due to ischemic heart disease.

      13. Has non-amyloid disease affecting exercise testing (eg, severe chronic obstructive pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation).

      14. Had acute coronary syndrome or unstable angina within the past 3 months. 15. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.

      16. Has persistent elevation of systolic (˃180 mmHg) and diastolic (˃100 mmHg) blood pressure that is considered uncontrolled by physician.

17-Has untreated hypo- or hyperthyroidism. 18-Prior or planned heart, liver, or other organ transplant. 19. Had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.

20. Has other medical conditions or comorbidities which, in the opinion of the Investigator would interfere with study compliance or data interpretation. 21. Female Is not willing to comply with the contraceptive requirements during the study period.

22. History of illicit drug abuse within the past 5 years that in the opinion of the Investigator would interfere with compliance with study procedures or follow-up visits.

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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

Other: open label; single open arm label

Drug: patisiran; Patients will receive 0.3 mg/kg patisiran once every 21 days administered as an IV infusion over 70 minutes (approximately 1 mL/minute for the first 15 minutes followed by approximately 3 mL/minute for the remainder of the infusion) by a controlled infusion device. All patients in this study will be premedicated prior to dosing with patisiran. Study drug supplied for this study must not be used for any purpose other than the present study and must not be administered to any person not enrolled in the study. The first dose of study drug (week 1) will be administered under the supervision of site personnel. After the first dose of patisiran, patients should return to the site for patisiran dosing once every 21 days or receive the patisiran infusions at a local infusion center by a healthcare professional trained on the Protocol, administration of premedication, and patisiran infusion. Patient must receive a dose of interventional drug within the dosing window (±3 days).; Other Names: ONPATTRO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Neurological Impairment Score	to assess the severity of functional impairment of motor and sensory nerves.NIS is a measure of motor strength, comprised of cranial nerve and both upper and lower limb motor assessments. The minimum and maximum values are 0 and 192, respectively. A higher score indicates a worse outcome.	baseline to 24 months
Norfolk QOL-DN	Change in Norfolk Quality of Life Questionnaire (Norfolk QOL-DN).The change from baseline in Norfolk QoL-DN at 24 months. The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure 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 to 24 months
COMPASS 31score	Composite Autonomic Symptom Score (COMPASS) 31a self-assessment instrument for patient reported autonomic symptoms such as dizziness, constipation, diarrhea, nausea/vomiting, and incontinence. The minimum and maximum values are 0 and 100, respectively. A higher score indicates a worse outcome	baseline to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PND Polyneuropathy disability (PND) Score	To compare and identify changes. Stage 0: no impairment Stage I: sensory disturbances but preserved walking capability Stage II: impaired walking capability but ability to walk without a stick or crutches Stage III a: walking only with the help of one stick or crutch Stage III b: walking with the help of two sticks or crutches. V: confined to wheelchair or bedridden A higher score indicates a worse outcome.	baseline to 24 months
Karnofsky, performance status score	Karnofsky performance score is 11 level score which ranges between 0 (death) to 100 (no evidence of disease). Higher score means higher ability to perform daily tasks.	baseline to 24 months
EuroQOL	EuroQOL,- A measurement tool that assesses generic quality of life in mobility, self-care, usual activities, pain/discomfort, anxiety/depression The minimum and maximum values are 0 and 100, respectively. A higher score indicates a worse outcome.	baseline to 24 months
EMG -Electromyography	(EMG) is a diagnostic test that measures how the muscles and nerves work to evaluate peripheral Neuropathies pattern and progression	baseline to 24 months
Tilt Table Test	Evaluate and compare the response of blood pressure and heart rate changes in posture and position.	24 months
Optional exploratory nerve and muscle biopsy	to identify amyloid deposits in skeletal muscle and peripheral nerve	during screening visit ( 28 day window)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac MRI	to identify cardiac abnormalities or changes and comparison	start of study, and study end at 2 years
Echo with strain	to identify cardiac abnormalities or changes and comparison	start of study, and study end at 2 years
PYP - mTc99-PYP	for cardiac amyloidosis imaging. - to identify cardiac function changes and comparison	start of study, and study end at 2 years
NT Pro BNP blood draw	serum biomarker to evaluate heart failure severity, ( pg/ml)	start of study, and study end at 2 years
NFL blood draw	Serum Neurofilament Light Chain level in patients with evolving disease, ( pg/mL)	at start, month 1,2,3,6 and every 6 months after until study end at two years

Collaborators and Investigators

• Sponsor: Austin Neuromuscular Center
• Collaborators: Alnylam Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 3, 2022
• Primary Completion (Actual): April 1, 2026
• Study Completion (Actual): April 13, 2026

Study Registration Dates

• First Submitted: August 11, 2021
• First Submitted That Met QC Criteria: August 20, 2021
• First Posted (Actual): August 27, 2021

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Peripheral Nervous System Diseases; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Proteostasis Deficiencies; Amyloid Neuropathies; Amyloidosis, Familial; Amyloidosis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Polyneuropathies; Amyloid Neuropathies, Familial; Amyloidosis, Hereditary, Transthyretin-Related; patisiran
• Other Study ID Numbers: 001 amendment 02

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