Transthyretin AmyloidosisEarly Phase 1NCT03591757
Short-term Effects of TOLCAPONE on Transthyretin Stability in Subjects With Leptomeningeal TTR Amyloidosis (ATTR)
A Early Phase 1 study testing Tolcapone in people with Transthyretin Amyloidosis and Amyloidosis, Leptomeningeal, Transthyretin-Related, run by Boston University at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Transthyretin Amyloidosis, Amyloidosis, Leptomeningeal, Transthyretin-Related
- What is being tested?
- Tolcapone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- 30 Oct 2018to 26 Apr 2019
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Genotyping of variant TTR
- Documented CNS manifestation or expression of variant TTR with leptomeningeal potential
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Amyloidosis Center, Boston Medical Center
Boston, Massachusetts, 02118
About this study
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
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.
Read the detailed 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.
- Being tested
- Tolcapone
- Keywords
- Tolcapone, Transthyretin (TTR), Mutant TTR, Plasma TTR, CSF TTR, Tetramer stability, Leptomeningeal, Amyloidosis
- Medical subject headings
- Amyloidosis, Hereditary, Transthyretin-Related, Amyloidosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TolcaponeDrug
Also called Tasmar
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Tolcapone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: pre-treatment (Day 0) and Day 28
Secondary outcomes (6)
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.
Measured: pre-treatment (Day 0) and Day 14
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
Measured: Day 14 and Day 28
Tolcapone Concentration in CSF
Tolcapone concentration will be measured in CSF at Day 14 prior to starting 200mg TID dosing.
Measured: Day 14
Tolcapone Concentration in CSF
Tolcapone concentration will be measured in CSF at Day 28 2 hours after dose
Measured: Day 28
Tolcapone Concentration in Serum
Tolcapone concentration will be measured in serum at Day 14 prior to initiating 200 mg TID dosing
Measured: Day 14
Tolcapone Concentration in Serum
Tolcapone concentration will be measured in serum at Day 28 2 hours after last dose
Measured: Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jul 2018
- Study start30 Oct 2018
- Primary completion26 Apr 2019
- Study completion26 Apr 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Transthyretin AmyloidosisStudies of the same condition, open and under way.
- More trials run by Boston UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Patients with hATTR mutations conferring leptomeningeal amyloidosis.
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Boston University
- Sponsor type
- University, hospital or other
- Collaborators
- Corino Therapeutics, Inc.
- Responsible party
- Principal investigator, John L. Berk, Boston University
- Investigators
- John L Berk, MD, Principal investigator, The Amyloidosis Center, BUSM
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03591757
- Sponsor's protocol ID
- H-37757
- Status last verified
- Jun 2019
- First submitted
- 9 Jul 2018
- Last updated
- 14 Jun 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Jun 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03591757
- Acronym / sponsor ID
- H-37757
- Keywords
- Tolcapone, Transthyretin (TTR), Mutant TTR, Plasma TTR, CSF TTR, Tetramer stability, Leptomeningeal, Amyloidosis
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Boston UniversityUniversity, hospital or other
- Collaborators
- Corino Therapeutics, Inc.
- Study start
- 30 Oct 2018 (actual)
- Primary completion
- 26 Apr 2019 (actual)
- Study completion
- 26 Apr 2019 (actual)
- First posted
- 19 Jul 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Patients with hATTR mutations conferring leptomeningeal amyloidosis.
| Arm | Type | Receives |
|---|---|---|
| Tolcapone | Experimental | Drug: TolcaponeTolcapone 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Genotyping of variant TTR
- Documented CNS manifestation or expression of variant TTR with leptomeningeal potential
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TolcaponeAlso: TasmarTolcapone 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. | Drug | Tolcapone |
Primary outcome
Change in plasma TTR stabilization
Time frame: pre-treatment (Day 0) and Day 28
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.
Change in CSF TTR stabilization
Time frame: pre-treatment (Day 0) and Day 28
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.
6 secondary outcomes
Changes in plasma TTR stabilization
Time frame: pre-treatment (Day 0) and Day 14
Changes in plasma TTR stabilization
Time frame: Day 14 and Day 28
Tolcapone Concentration in CSF
Time frame: Day 14
Tolcapone Concentration in CSF
Time frame: Day 28
Tolcapone Concentration in Serum
Time frame: Day 14
Tolcapone Concentration in Serum
Time frame: Day 28
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jun 2019.
- Individual participant dataSharing planned: No
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MAGNITUDE: A Phase 3 Study of NTLA-2001 in Participants With Transthyretin Amyloidosis With Cardiomyopathy (ATTR-CM)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John L Berk, MD principal investigator
The Amyloidosis Center, BUSM
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Tolcapone in people with Transthyretin Amyloidosis and Amyloidosis, Leptomeningeal, Transthyretin-Related, run by Boston University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in plasma TTR stabilization (time frame: pre-treatment (Day 0) and Day 28). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jun 2019.