CBS DeficiencyPhase 1/2NCT04015557
Effect of Acetaminophen and N-Acetylcysteine on Liver Metabolism on Homocystinuria
A Phase 1/2 study testing Acetaminophen and N-acetylcysteine in people with CBS Deficiency, run by Hospital de Clinicas de Porto Alegre at 1 site in Brazil.
Trial summary
In homocystinuria due to cystathionine beta synthase (CBS) deficiency or classical homocystinuria, decreased blood cysteine levels are observed. Cysteine is essential for the synthesis of molecules such as glutathione and taurine. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- CBS Deficiency
- What is being tested?
- Acetaminophen and N-acetylcysteine
- 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 siteBrazil
- Study dates
- 11 Feb 2022to 1 Dec 2022
- Phase
- Phase 1/2
- 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 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Age over 18 years
- For patients: molecular diagnosis of homocystinuria due to cystathionine beta synthase (CBS) deficiency
Who cannot join
- Gastric, hepatic or kidney disease
- Smoking
- Illicit drug users;
- Acetaminophen or N-acetylcysteine hypersensitivity.
- Controls: use of vitamins supplements
Trial locations and contacts
1 site in 1 country.
Brazil1 site
Hospital de Clínicas de Porto Alegre
Porto Alegre, Rio Grande do Sul, 90035-007
About this study
Official title: Functional Consequences and Therapeutic Intervention in Hampered Production of Cysteine, Glutathione and Taurine in Classical Homocystinuria
In homocystinuria due to cystathionine beta synthase (CBS) deficiency or classical homocystinuria, decreased blood cysteine levels are observed. Cysteine is essential for the synthesis of molecules such as glutathione and taurine. Main functions of glutathione are to detoxify drugs and to scavenge reactive oxygen species. N-acetylcysteine is a commercially available drug chemically similar to cysteine. In CBS deficient animal models, N-acetylcysteine supplementation improves cysteine and liver glutathione concentrations. N-acetylcysteine also acts directly as a scavenger of free radicals. In CBS deficiency, increased oxidative damage has been described and possibly contributes to the clinical manifestations of CBS deficiency. Acetaminophen (Paracetamol) is a common painkiller and its overdose (>4 g/day) is a major cause of acute liver failure. Glutathione is required for Acetaminophen detoxification, and the preferred treatment for an overdose is the administration of N-acetylcysteine.
The aim of this study is to demonstrate that CBS deficiency patients have glutathione depletion and to investigate if Acetaminophen can induce subclinical liver damage and if N-acetylcysteine supplementation could prevent the toxic-effects of acetaminophen.
The investigators' hypothesis is that CBS deficiency patients have an inadequate supply of cysteine for the glutathione synthesis, which impairs antioxidants defenses and increases risk of intoxication of drugs that require glutathione, such as Acetaminophen. This potential increased liver toxicity induced by drugs or other xenobiotics that are detoxified by the glutathione pathway has not been explored in CBS deficiency patients. The experiments should provide answers about the functional role of cysteine and glutathione depletion in CBS deficiency and if N-acetylcysteine might have a place as an adjunct therapy for CBS deficiency.
Read the detailed description
STUDY PROCEDURES
A phase I-II clinical cross-over, not blinded, trial will be conducted. Adult patients with homocystinuria and paired-sex and age- healthy controls will be enrolled. Individuals with hepatic, renal or gastric disease; smokers, illicit drugs users or those who are hypersensitive to any of the components of the drugs tested (acetaminophen and N-acetylcysteine ) will be excluded.
Patients will be submitted to two procedures:
Step 1: In this stage, individuals will receive a single standard dose of Acetaminophen (1.5g) orally and blood samples will be drawn at time 0, 2, 4, 6 and 8 hours after the administration.
Step 2: In this stage, individuals will receive again a normal dose of acetaminophen (1.5g) orally and one hour later a single dose of oral N-acetylcysteine (70 mg per kilogram of body weight)(. Blood samples will be drawn at the same points.
In plasma we will measure methionine, homocysteine, cysteine and glutathione by LC-MS/MS. Taurine will also be determined by Biochrom 30 Amino Acid Analyser. Pyroglutamate will be determined as a marker for glutathione depletion.
As markers of oxidative stress we will assay thiobarbituric acid-reactive substances, protein carbonyl content, thiol content, DNA damage 2',7'-dichlorofluorescein fluorescence assay, and activities of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase . Liver function parameters aspartate transaminase (AST) and alanine transaminase (ALT) activities will also be determined.
All measurements will be performed at all 5 points of blood collection and in the two stages of the trial.
- Conditions
- CBS Deficiency
- Being tested
- Acetaminophen, N-acetylcysteine
- Keywords
- Homocystinuria, Glutathione, Acetaminophen, N-acetylcysteine, Cysteine, Homocysteine
- Medical subject headings
- Homocystinuria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AcetaminophenDrug
Also called paracetamol
Adult patients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive a single dose of Acetaminophen (1.5g) orally. Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose to measure liver enzymes and markers of oxidative stress.
N-acetylcysteineDrug
Also called NAC
Patients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive again a normal dose of acetaminophen (1.5g) orally and one hour later oral N-acetylcysteine (70 mg per kilogram of body weight). Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose to measure liver enzymes and markers of oxidative stress.
| Study group | Role | What they receive |
|---|---|---|
| Acetaminophen | Experimental | Adult patients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive a single dose of Acetaminophen (1.5g) orally. Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose. Receives: Drug: Acetaminophen |
| Acetaminophen + N-acetylcysteine | Experimental | Patients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive again a normal dose of acetaminophen (1.5g) orally and one hour later oral N-acetylcysteine (70 mg per kilogram of body weight). Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose. Receives: Drug: Acetaminophen; Drug: N-acetylcysteine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in aspartate transaminase (AST) in 4 hours
A difference >30% between pre and pos Acetaminophen administration will be considered clinically significant.
Measured: 4 hours
Change in aspartate transaminase (AST) in 6 hours
A difference >30% between pre and pos Acetaminophen administration will be considered clinically significant.
Measured: 6 hours
Change in alanine transaminase (ALT) in 4 hours
A difference >30% between pre and pos Acetaminophen administration will be considered clinically significant.
Measured: 4 hours
Change in alanine transaminase (ALT) in 6 hours
A difference >30% between pre and pos Acetaminophen administration will be considered clinically significant.
Measured: 6 hours
Secondary outcomes (8)
Change in sulfhydryl levels in 2 hours
A difference >30% between pre and pos measurements will be considered clinically significant.
Measured: 2 hours
Change in sulfhydryl levels in 4 hours
A difference >30% between pre and pos measurements will be considered clinically significant.
Measured: 4 hours
Change in sulfhydryl levels in 6 hours
A difference >30% between pre and pos measurements will be considered clinically significant.
Measured: 6 hours
Change in sulfhydryl levels in 8 hours
A difference >30% between pre and pos measurements will be considered clinically significant.
Measured: 8 hours
Change in plasma GST activity in 2 hours
A difference >30% between pre and pos measurements will be considered clinically significant.
Measured: 2 hours
Change in plasma GST activity in 4 hours
A difference >30% between pre and pos measurements will be considered clinically significant.
Measured: 4 hours
Change in plasma GST activity in 6 hours
A difference >30% between pre and pos measurements will be considered clinically significant.
Measured: 6 hours
Change in plasma GST activity in 8 hours
A difference >30% between pre and pos measurements will be considered clinically significant.
Measured: 8 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jul 2019
- Study start11 Feb 2022 (estimated)
- Primary completion30 Jun 2022 (estimated)
- Study completion1 Dec 2022 (estimated)
Why it stopped: Study was interrupted due to COVID-19 pandemic
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for CBS DeficiencyStudies of the same condition, open and under way.
- More trials run by Hospital de Clinicas de Porto AlegreThe 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
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital de Clinicas de Porto Alegre
- Sponsor type
- University, hospital or other
- Collaborators
- Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil
- Responsible party
- Sponsor
- Investigators
- Ida VD Schwartz, PhD, Principal investigator, Professor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04015557
- Sponsor's protocol ID
- 20180677
- Other IDs
- 34863.494.21707.15062018
- Status last verified
- Jun 2021
- First submitted
- 28 May 2019
- Last updated
- 30 Jun 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 30 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Functional Consequences and Therapeutic Intervention in Hampered Production of Cysteine, Glutathione and Taurine in Classical Homocystinuria
- ClinicalTrials.gov ID
- NCT04015557
- Acronym / sponsor ID
- 20180677
- Conditions
- CBS Deficiency
- Keywords
- Homocystinuria, Glutathione, Acetaminophen, N-acetylcysteine, Cysteine, Homocysteine
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: Study was interrupted due to COVID-19 pandemic
- Enrolment
- 10 participants (estimated)
- Lead sponsor
- Hospital de Clinicas de Porto AlegreUniversity, hospital or other
- Collaborators
- Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil
- Study start
- 11 Feb 2022 (estimated)
- Primary completion
- 30 Jun 2022 (estimated)
- Study completion
- 1 Dec 2022 (estimated)
- First posted
- 11 Jul 2019 (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.
In homocystinuria due to cystathionine beta synthase (CBS) deficiency or classical homocystinuria, decreased blood cysteine levels are observed. Cysteine is essential for the synthesis of molecules such as glutathione and taurine. Main functions of glutathione are to detoxify drugs and to scavenge reactive oxygen species. N-acetylcysteine is a commercially available drug chemically similar to cysteine. In CBS deficient animal models, N-acetylcysteine supplementation improves cysteine and liver glutathione concentrations. N-acetylcysteine also acts directly as a scavenger of free radicals. In CBS deficiency, increased oxidative damage has been described and possibly contributes to the clinical manifestations of CBS deficiency. Acetaminophen (Paracetamol) is a common painkiller and its overdose (>4 g/day) is a major cause of acute liver failure. Glutathione is required for Acetaminophen detoxification, and the preferred treatment for an overdose is the administration of N-acetylcysteine.
The aim of this study is to demonstrate that CBS deficiency patients have glutathione depletion and to investigate if Acetaminophen can induce subclinical liver damage and if N-acetylcysteine supplementation could prevent the toxic-effects of acetaminophen.
The investigators' hypothesis is that CBS deficiency patients have an inadequate supply of cysteine for the glutathione synthesis, which impairs antioxidants defenses and increases risk of intoxication of drugs that require glutathione, such as Acetaminophen. This potential increased liver toxicity induced by drugs or other xenobiotics that are detoxified by the glutathione pathway has not been explored in CBS deficiency patients. The experiments should provide answers about the functional role of cysteine and glutathione depletion in CBS deficiency and if N-acetylcysteine might have a place as an adjunct therapy for CBS deficiency.
Detailed description
STUDY PROCEDURES
A phase I-II clinical cross-over, not blinded, trial will be conducted. Adult patients with homocystinuria and paired-sex and age- healthy controls will be enrolled. Individuals with hepatic, renal or gastric disease; smokers, illicit drugs users or those who are hypersensitive to any of the components of the drugs tested (acetaminophen and N-acetylcysteine ) will be excluded.
Patients will be submitted to two procedures:
Step 1: In this stage, individuals will receive a single standard dose of Acetaminophen (1.5g) orally and blood samples will be drawn at time 0, 2, 4, 6 and 8 hours after the administration.
Step 2: In this stage, individuals will receive again a normal dose of acetaminophen (1.5g) orally and one hour later a single dose of oral N-acetylcysteine (70 mg per kilogram of body weight)(. Blood samples will be drawn at the same points.
In plasma we will measure methionine, homocysteine, cysteine and glutathione by LC-MS/MS. Taurine will also be determined by Biochrom 30 Amino Acid Analyser. Pyroglutamate will be determined as a marker for glutathione depletion.
As markers of oxidative stress we will assay thiobarbituric acid-reactive substances, protein carbonyl content, thiol content, DNA damage 2',7'-dichlorofluorescein fluorescence assay, and activities of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase . Liver function parameters aspartate transaminase (AST) and alanine transaminase (ALT) activities will also be determined.
All measurements will be performed at all 5 points of blood collection and in the two stages of the trial.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Acetaminophen | Experimental | Drug: AcetaminophenAdult patients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive a single dose of Acetaminophen (1.5g) orally. Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose. |
| Acetaminophen + N-acetylcysteine | Experimental | Drug: Acetaminophen, Drug: N-acetylcysteinePatients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive again a normal dose of acetaminophen (1.5g) orally and one hour later oral N-acetylcysteine (70 mg per kilogram of body weight). Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Age over 18 years
- For patients: molecular diagnosis of homocystinuria due to cystathionine beta synthase (CBS) deficiency
Key exclusion criteria (5 listed)
- Gastric, hepatic or kidney disease
- Smoking
- Illicit drug users;
- Acetaminophen or N-acetylcysteine hypersensitivity.
- Controls: use of vitamins supplements
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 |
|---|---|---|
| AcetaminophenAlso: paracetamolAdult patients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive a single dose of Acetaminophen (1.5g) orally. Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose to measure liver enzymes and markers of oxidative stress. | Drug | Acetaminophen, Acetaminophen + N-acetylcysteine |
| N-acetylcysteineAlso: NACPatients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive again a normal dose of acetaminophen (1.5g) orally and one hour later oral N-acetylcysteine (70 mg per kilogram of body weight). Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose to measure liver enzymes and markers of oxidative stress. | Drug | Acetaminophen + N-acetylcysteine |
Primary outcome
Change in aspartate transaminase (AST) in 4 hours
Time frame: 4 hours
A difference >30% between pre and pos Acetaminophen administration will be considered clinically significant.
Change in aspartate transaminase (AST) in 6 hours
Time frame: 6 hours
A difference >30% between pre and pos Acetaminophen administration will be considered clinically significant.
Change in alanine transaminase (ALT) in 4 hours
Time frame: 4 hours
A difference >30% between pre and pos Acetaminophen administration will be considered clinically significant.
Change in alanine transaminase (ALT) in 6 hours
Time frame: 6 hours
A difference >30% between pre and pos Acetaminophen administration will be considered clinically significant.
8 secondary outcomes
Change in sulfhydryl levels in 2 hours
Time frame: 2 hours
Change in sulfhydryl levels in 4 hours
Time frame: 4 hours
Change in sulfhydryl levels in 6 hours
Time frame: 6 hours
Change in sulfhydryl levels in 8 hours
Time frame: 8 hours
Change in plasma GST activity in 2 hours
Time frame: 2 hours
Change in plasma GST activity in 4 hours
Time frame: 4 hours
Change in plasma GST activity in 6 hours
Time frame: 6 hours
Change in plasma GST activity in 8 hours
Time frame: 8 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jun 2021.
- Individual participant dataSharing planned: No
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Pegtibatinase as a Treatment for Patients With Classical Homocystinuria (HCU) (Also Known as the COMPOSE Study)
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Enrolling by invitationPhase 3
A Long-term Extension Study to Assess the Long-term Safety and Efficacy of Pegtibatinase Treatment in Participants ≥5 to ≤65 Years of Age With Classical Homocystinuria (HCU) (ENSEMBLE)
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RecruitingObservational study
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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.
Ida VD Schwartz, PhD principal investigator
Professor
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Acetaminophen and N-acetylcysteine in people with CBS Deficiency, run by Hospital de Clinicas de Porto Alegre at 1 site in Brazil.
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: paused, as of the sponsor's last update on 30 Jun 2021. 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 Brazil. 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
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 aspartate transaminase (AST) in 4 hours (time frame: 4 hours). The study lists 4 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 30 Jun 2021.