Pyruvate Dehydrogenase Complex DeficiencyPhase 2TIGEM2-PDHNCT03734263
Use of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.
A Phase 2 study testing sodium phenylbutyrate in people with Pyruvate Dehydrogenase Complex Deficiency, run by Fondazione Telethon at 1 site in Italy.
Trial summary
In this study phenylbutyrate is used for patients with pyruvate dehydrogenase complex deficiency. The aim of the study is to investigate the safety and efficacy of therapy. Read more about this study
- Who is it for?
- Ages 3 months to 18 years
- Conditions the study is for
- Pyruvate Dehydrogenase Complex Deficiency
- What is being tested?
- sodium phenylbutyrate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 1 siteItaly
- Study dates
- 1 Oct 2018to 30 Dec 2020
- Phase
- Phase 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 3 months to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Subject must be older than 3 months old and younger than 18 years old.
- Clinical diagnosis of PDC deficiency confirmed by DNA testing showing a missense mutation in the PDHA1 gene.
- Lactate concentration ≥ 2.5 mmol/l or ≥ 2 mmol/l, respectively in venous or arterial blood samples.
- Provision of signed and dated informed consent form by the parents/legal guardians of the patient
- Negative pregnancy test for women of childbearing potential, and agree to use effective form of contraception until 6 weeks post treatment.
Who cannot join
- Frameshift or nonsense mutations of the PDHA1 gene.
- Defects affecting any gene encoding PDC subunits other than PDHA1
- Secondary forms of lactic acidosis (e.g. impaired oxygenation or circulation).
- Tracheostomy or requirement for artificial ventilation.
- Hyperlactatemia or organic acidosis associated with other metabolic disorders (e.g. biotinidase deficiency, primary disorders of gluconeogenesis, organic acidurias, primary defects of fatty acids oxidation)
- Evidence of hepatic insufficiency, renal insufficiency, edema with sodium retention, cardiac arrhythmia, congenital heart defects, hypertension, blood dyscrasia, symptomatic pancreatitis, or inflammatory bowel disease.
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- Any clinical condition or medications known to significantly affect renal clearance.
- Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful completion of the study.
- Known allergic reactions to components of the study agent.
- Treatment with another investigational drug or other intervention (including DCA) or participation in a clinical study with an investigational drug within 6 months prior to enrolment.
- Pregnancy or lactation.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Pilot Clinical Trial to Investigate the Safety and Efficacy of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.
In this study phenylbutyrate is used for patients with pyruvate dehydrogenase complex deficiency. The aim of the study is to investigate the safety and efficacy of therapy.
Read the detailed description
The Investigator will evaluate the safety and efficacy of a 4-weeks treatment with sodium phenylbutyrate in patients with pyruvate dehydrogenase complex deficiency. Efficacy will be evaluated based on biochemical endpoints (blood lactate and pyruvate).
- Being tested
- sodium phenylbutyrate
- Medical subject headings
- Pyruvate Dehydrogenase Complex Deficiency Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
sodium phenylbutyrateDrug
Enrolled subjects will receive a four-week period of treatment with sodium phenylbutyrate (oral use)
| Study group | Role | What they receive |
|---|---|---|
| open label | Experimental | sodium phenylbutyrate Receives: Drug: sodium phenylbutyrate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Efficacy: blood lactate (mmol/L)
blood lactate (mmol/L)
Measured: two weeks after starting therapy
Efficacy: blood lactate (mmol/L)
blood lactate (mmol/L)
Measured: four weeks after starting therapy
Secondary outcomes (6)
Efficacy: blood pyruvate (mmol/L)
blood pyruvate (mmol/L)
Measured: two weeks after starting therapy
Efficacy:urinary lactate (mmol/mol crea)
urinary lactate (mmol/mol crea)
Measured: two weeks after starting therapy
Efficacy: blood pyruvate (mmol/L)
blood pyruvate (mmol/L)
Measured: four weeks after starting therapy
Efficacy: urinary lactate (mmol/mol crea)
urinary lactate (mmol/mol crea)
Measured: four weeks after starting therapy
Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Measured: two weeks after starting therapy
Safety and tolerability: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Measured: four weeks after starting therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Nov 2018
- Study start1 Oct 2018
- Primary completion30 Jul 2019
- Study completion30 Dec 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Pyruvate Dehydrogenase Complex DeficiencyStudies of the same condition, open and under way.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- An open-label, uncontrolled, multicentric clinical trial will be performed on pediatric patients with PDC deficiency. Enrolled subjects will receive a four-week period of treatment with NaPB; primary and secondary endpoints will be evaluated at defined time points. Before NaPB treatment, all patients will undergo a four-week period of observation during which the same parameters will be analyzed at different time points, with the aim of evaluating basal conditions in the absence of treatment.
- Masking
- None (open label)
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fondazione Telethon
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Nicola Brunetti-Pierri, Fondazione Telethon
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03734263
- Sponsor's protocol ID
- TIGEM2-PDH
- Acronym
- TIGEM2-PDH
- Status last verified
- Oct 2021
- First submitted
- 25 Oct 2018
- Last updated
- 13 Oct 2021
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 2013 Mar 6;5(175):175ra31. doi: 10.1126/scitranslmed.3004986.
PubMed 23467562Ferriero R, Brunetti-Pierri N. Phenylbutyrate increases activity of pyruvate dehydrogenase complex. Oncotarget. 2013 Jun;4(6):804-5. doi: 10.18632/oncotarget.1000. No abstract available.
PubMed 23868807Ferriero R, Boutron A, Brivet M, Kerr D, Morava E, Rodenburg RJ, Bonafe L, Baumgartner MR, Anikster Y, Braverman NE, Brunetti-Pierri N. Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects. Ann Clin Transl Neurol. 2014 Jul;1(7):462-70. doi: 10.1002/acn3.73. Epub 2014 Jun 19.
PubMed 25356417Ferriero R, Iannuzzi C, Manco G, Brunetti-Pierri N. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis. 2015 Sep;38(5):895-904. doi: 10.1007/s10545-014-9808-2. Epub 2015 Jan 20.
PubMed 25601413
Study at a glance
From the registry record, last updated by the sponsor on 13 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Clinical Trial to Investigate the Safety and Efficacy of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.
- ClinicalTrials.gov ID
- NCT03734263
- Acronym / sponsor ID
- TIGEM2-PDH / TIGEM2-PDH
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1 participants (actual)
- Lead sponsor
- Fondazione TelethonUniversity, hospital or other
- Study start
- 1 Oct 2018 (actual)
- Primary completion
- 30 Jul 2019 (actual)
- Study completion
- 30 Dec 2020 (actual)
- First posted
- 7 Nov 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.
In this study phenylbutyrate is used for patients with pyruvate dehydrogenase complex deficiency. The aim of the study is to investigate the safety and efficacy of therapy.
Detailed description
The Investigator will evaluate the safety and efficacy of a 4-weeks treatment with sodium phenylbutyrate in patients with pyruvate dehydrogenase complex deficiency. Efficacy will be evaluated based on biochemical endpoints (blood lactate and pyruvate).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- An open-label, uncontrolled, multicentric clinical trial will be performed on pediatric patients with PDC deficiency. Enrolled subjects will receive a four-week period of treatment with NaPB; primary and secondary endpoints will be evaluated at defined time points. Before NaPB treatment, all patients will undergo a four-week period of observation during which the same parameters will be analyzed at different time points, with the aim of evaluating basal conditions in the absence of treatment.
| Arm | Type | Receives |
|---|---|---|
| open label | Experimental | Drug: sodium phenylbutyratesodium phenylbutyrate |
Who may qualify
- Ages
- 3 months to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- Subject must be older than 3 months old and younger than 18 years old.
- Clinical diagnosis of PDC deficiency confirmed by DNA testing showing a missense mutation in the PDHA1 gene.
- Lactate concentration ≥ 2.5 mmol/l or ≥ 2 mmol/l, respectively in venous or arterial blood samples.
- Provision of signed and dated informed consent form by the parents/legal guardians of the patient
- Negative pregnancy test for women of childbearing potential, and agree to use effective form of contraception until 6 weeks post treatment.
Key exclusion criteria (11 listed)
- Frameshift or nonsense mutations of the PDHA1 gene.
- Defects affecting any gene encoding PDC subunits other than PDHA1
- Secondary forms of lactic acidosis (e.g. impaired oxygenation or circulation).
- Tracheostomy or requirement for artificial ventilation.
- Hyperlactatemia or organic acidosis associated with other metabolic disorders (e.g. biotinidase deficiency, primary disorders of gluconeogenesis, organic acidurias, primary defects of fatty acids oxidation)
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 |
|---|---|---|
| sodium phenylbutyrateEnrolled subjects will receive a four-week period of treatment with sodium phenylbutyrate (oral use) | Drug | open label |
Primary outcome
Efficacy: blood lactate (mmol/L)
Time frame: two weeks after starting therapy
blood lactate (mmol/L)
Efficacy: blood lactate (mmol/L)
Time frame: four weeks after starting therapy
blood lactate (mmol/L)
6 secondary outcomes
Efficacy: blood pyruvate (mmol/L)
Time frame: two weeks after starting therapy
Efficacy:urinary lactate (mmol/mol crea)
Time frame: two weeks after starting therapy
Efficacy: blood pyruvate (mmol/L)
Time frame: four weeks after starting therapy
Efficacy: urinary lactate (mmol/mol crea)
Time frame: four weeks after starting therapy
Safety and tolerability:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: two weeks after starting therapy
Safety and tolerability: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: four weeks after starting therapy
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 13 Oct 2021.
- Background: PubMed 23467562Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 2013 Mar 6;5(175):175ra31. doi: 10.1126/scitranslmed.3004986.
- Background: PubMed 23868807Ferriero R, Brunetti-Pierri N. Phenylbutyrate increases activity of pyruvate dehydrogenase complex. Oncotarget. 2013 Jun;4(6):804-5. doi: 10.18632/oncotarget.1000. No abstract available.
- Background: PubMed 25356417Ferriero R, Boutron A, Brivet M, Kerr D, Morava E, Rodenburg RJ, Bonafe L, Baumgartner MR, Anikster Y, Braverman NE, Brunetti-Pierri N. Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects. Ann Clin Transl Neurol. 2014 Jul;1(7):462-70. doi: 10.1002/acn3.73. Epub 2014 Jun 19.
- Background: PubMed 25601413Ferriero R, Iannuzzi C, Manco G, Brunetti-Pierri N. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis. 2015 Sep;38(5):895-904. doi: 10.1007/s10545-014-9808-2. Epub 2015 Jan 20.
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing sodium phenylbutyrate in people with Pyruvate Dehydrogenase Complex Deficiency, run by Fondazione Telethon at 1 site in Italy.
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 5 inclusion and 11 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 13 Oct 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 Italy. 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?
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?
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?
Efficacy: blood lactate (mmol/L) (time frame: two weeks after starting therapy). 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?
On the ClinicalTrials.gov record for NCT03734263, which also lists 4 linked publications.
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 13 Oct 2021.