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

NCT03591757 | Completed Early Phase 1 FDA Drug

• 1 other identifier: H-37757
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Transthyretin Amyloidosis; Amyloidosis, Leptomeningeal, Transthyretin-Related

Keywords

Tolcapone; Transthyretin (TTR); Mutant TTR; Plasma TTR; CSF TTR; Tetramer stability; Leptomeningeal; Amyloidosis

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (6)

• Changes in plasma TTR stabilization

  pre-treatment (Day 0) and Day 14

• Changes in plasma TTR stabilization

  Day 14 and Day 28

• Tolcapone Concentration in CSF

  Day 14

• Tolcapone Concentration in CSF

  Day 28

• Tolcapone Concentration in Serum

  Day 14

Study Arms (1)

Tolcapone

EXPERIMENTAL

Tolcapone will be administered to assess the short-term (4 weeks) effects on plasma and CSF TTR tetramer stability in subjects with TTR CNS Amyloidosis. Tolcapone is currently licensed for the treatment of Parkinson's disease in combination with levodopa/carbidopa. It is an immediate release product and is currently used at either 100 mg or 200 mg three times a day during waking hours. During this trial, participants will be taking 100mg for 14 days, and then 200mg for 14 days.

Drug: Tolcapone

Interventions

Tolcapone DRUG

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.

Also known as: Tasmar

Tolcapone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Boston University: lead
• Corino Therapeutics, Inc.: collaborator

Study Sites (1)

Amyloidosis Center, Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

MeSH Terms

Conditions

Amyloidosis, Hereditary, Transthyretin-Related; Amyloidosis

Interventions

Tolcapone

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Benzophenones; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Nitrophenols; Phenols; Ketones; Nitro Compounds

Study Officials

• John L Berk, MD

  The Amyloidosis Center, BUSM

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor,Dept of Medicine, Amyloidosis Center

Model Details: Patients with hATTR mutations conferring leptomeningeal amyloidosis.

Study Record Dates

• First Submitted: July 9, 2018
• First Posted: July 19, 2018
• Study Start: October 30, 2018
• Primary Completion: April 26, 2019
• Study Completion: April 26, 2019
• Last Updated: June 14, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)