Short-term Effects of TOLCAPONE on Transthyretin Stability in Subjects With Leptomeningeal TTR Amyloidosis (ATTR)

Transthyretin Amyloidosis Clinical Trial

Official title:

An Open-Label, Investigator Study to Evaluate the Short-term (4 Weeks) Effects of TOLCAPONE on Transthyretin Stability in Subjects With Leptomeningeal TTR Amyloidosis (ATTR) With and Without CNS Manifestations

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03591757
• Other study ID #: H-37757
• Status: Completed
• Phase: Early Phase 1
• Start date: October 30, 2018
• Est. completion date: April 26, 2019

Study information

• Verified date: June 2019
• Source: Boston University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether Tolcapone crosses from the blood stream into the fluid around the brain and stabilizes the protein that makes leptomeningeal amyloid. Tolcapone is a commercially available generic drug that treats Parkinson's disease.

The Investigator plans to evaluate Tolcapone as a treatment for ATTR (Transthyretin Amyloidosis), a rare genetic disease often causing death within 5-15 years after diagnosis. ATTR is characterized by deposition of misfolded protein known as amyloid, in one or more organ systems (including the peripheral and autonomic nervous systems, the heart, the brain and the eyes). The age at which symptoms begin to develop varies widely ranging between 20 to 70 years old. ATTR is progressive, and some variants can have a fatal outcome within a few years of presentation. Treatment options include supportive and symptomatic care that may slow or stop progressive decline in functional state but do not alter the pathological process. Liver transplant can be performed in selected patients but is limited by organ supply, requires lifelong immunosuppression, and may be complicated by progressive heart and nerve amyloid deposition. Importantly, liver transplant does not alter the natural course of central nervous system amyloid disease. To date, no treatment for ATTR penetrates the CNS.

At present there is no FDA approved treatment for ATTR amyloidosis in the US. In Europe, Tafamidis has been approved for treatment of stage 1 ATTR-polyneuropathy since 2012. Tafamidis and Tolcapone bind to the thyroxine binding site of TTR (with different drug-transthyretin interactions) and in so doing stabilizes the tetrameric form of TTR, preventing dissociation and amyloid fibril formation The preclinical and clinical data from a variety of experimental systems support the therapeutic activity of TOLCAPONE in TTR mediated disease.

Description:

This study is designed as a clinical proof-of-concept evaluating whether TOLCAPONE is capable of stabilizing tetrameric TTR (Transthyretin) in the plasma and CSF of symptomatic or asymptomatic patients with leptomeningeal ATTR. Additionally the study will determine the plasma and CSF concentrations of TOLCAPONE needed to induce maximal stabilization of TTR across different TTR variants (TTR mutations).

The study will be carried out in two different populations of subjects, defined by the TTR variant expressed:

• Mutant TTR (up to 10 subjects): symptomatic leptomeningeal TTR patient with any documented leptomeningeal mutations in the TTR gene.

• Mutant TTR (remaining subjects up to 10): asymptomatic leptomeningeal TTR patient with any documented leptomeningeal mutation in the TTR gene.

TTR tetramers stability in plasma and CSF samples will be determined by urea-induced denaturation methodology.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: April 26, 2019
• Est. primary completion date: April 26, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Genotyping of variant TTR

• Documented CNS manifestation or expression of variant TTR with leptomeningeal potential

Exclusion Criteria:

• Patients who are unable to provide informed consent

• Contraindication for Tolcapone

• An ALT or AST measurement > 2 times the ULN (Upper Limit of Normal)

• Estimated glomerular filtration rate (eGFR) = 25 ml/min/1.72M2

• Treatment with a known TTR tetramer protein stabilizer within the last 2 weeks

Related Conditions & MeSH terms

• Amyloid Neuropathies, Familial
• Amyloidosis
• Amyloidosis, Leptomeningeal, Transthyretin-Related
• Transthyretin Amyloidosis

Intervention

Drug:
• Tolcapone
Tolcapone will be administered at 300 mg/day (100mg TID) orally to participants for 14 days and then 600 mg/day (200 mg TID) orally to participants for 14 days (approximately 5 hours apart). Participants will initiate 200mg TID after blood collection on Day 14.

Locations

Country	Name	City	State
United States	Amyloidosis Center, Boston Medical Center	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Boston University	Corino Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in plasma TTR stabilization	TTR stabilization will be measured in plasma samples from each participant before the first dose of study drug and 2 hours after the last 100 mg study drug dose.	pre-treatment (Day 0) and Day 28
Primary	Change in CSF TTR stabilization	TTR stabilization will be measured in CSF samples obtained from each participant before the first dose of study drug and 2 hours after the last 200 mg dose.	pre-treatment (Day 0) and Day 28
Secondary	Changes in plasma TTR stabilization	TTR stabilization will be measured in plasma samples from each participant before the first dose of study drug and 2 hours after the day 14 study drug dose.	pre-treatment (Day 0) and Day 14
Secondary	Changes in plasma TTR stabilization	TTR stabilization will be measured in plasma samples from each participant 2 hours after the day 14 study drug dose.and 2 hours after the 28 day study dose	Day 14 and Day 28
Secondary	Tolcapone Concentration in CSF	Tolcapone concentration will be measured in CSF at Day 14 prior to starting 200mg TID dosing.	Day 14
Secondary	Tolcapone Concentration in CSF	Tolcapone concentration will be measured in CSF at Day 28 2 hours after dose	Day 28
Secondary	Tolcapone Concentration in Serum	Tolcapone concentration will be measured in serum at Day 14 prior to initiating 200 mg TID dosing	Day 14
Secondary	Tolcapone Concentration in Serum	Tolcapone concentration will be measured in serum at Day 28 2 hours after last dose	Day 28