Pulmonary Hypertension (Idiopathic, Familial or Anorexigen-associated)Phase 1NCT01083524
Dichloroacetate (DCA) for the Treatment of Pulmonary Arterial Hypertension
A Phase 1 study testing Dichloroacetate Sodium in people with Pulmonary Hypertension (Idiopathic, Familial or Anorexigen-associated), run by University of Alberta at 2 sites in 2 countries.
Trial summary
Hypothesis: The small molecule and metabolic modulator Dichloroacetate (DCA) is safe, tolerated as a potential therapy in patients with moderate or severe Pulmonary Arterial Hypertension (PAH). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pulmonary Hypertension (Idiopathic, Familial or Anorexigen-associated)
- What is being tested?
- Dichloroacetate Sodium
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 2 sitesin 2 countries
- Study dates
- Mar 2010to Sep 2013
- Phase
- 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
- Males or females 18 years or older
- Willing and able to complete informed consent form.
- Documented diagnosis of PAH:
- idiopathic, associated with anorexigens or familial;
- mean pulmonary arterial pressure >25 mm Hg, pulmonary capillary wedge pressure =/< 15 mm Hg and pulmonary vascular resistance >240 dynes/sec/cm5 (measured by catheter).
- Receiving stable doses for at least 2 months of one or more medications that are approved for treatment of PAH (endothelin receptor antagonists or phosphodiesterase type 5 inhibitors). Note: Anticoagulant therapy can be adjusted according to target INR and diuretic dose can be adjusted as required.
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- Modified World Health Organization(WHO) classification III-IV; stable for at least 8 weeks prior to enrollment.
- 6MWD, as performed at screening or within three months (12 weeks) prior to screening, of ≥ 150 meters.
- Expected survival of > 6 months.
- ALT or AST levels < 3 times the upper limit of normal
- Sexually active subjects must use an acceptable method of contraception while participating in the study, consisting of:
- Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner of female subject
- Oral contraceptives (either combined or progestogen only) with double-barrier method of contraception consisting of spermicide with either condom or diaphragm. Women of child-bearing potential using an oral contraceptive in combination with a double-barrier method of contraception are required to continue to use this form of contraception for 6 weeks following discontinuation of study medication
- Double-barrier method of contraception consisting of spermicide with either condom or diaphragm
- IUD with documented failure rate of less than 1% per year
- Females of childbearing potential must have negative pregnancy test at screening and be willing to have additional pregnancy tests during the study.
Who cannot join
- Previous treatment with any formulation of DCA.
- Known allergy or hypersensitivity to any excipient of DCA.
- Clinically significant biochemical abnormality.
- Clinical evidence of pre-existing neuropathy.
- Use of investigational product or device within 30 days prior to dosing, or known requirement for any investigational agent prior to completion of all scheduled study assessments.
- Known to be positive for human immunodeficiency virus (HIV).
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- Additional medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities, including bleeding disorders, arrhythmia, organ transplant, organ failure, current neoplasm, poorly controlled diabetes mellitus, and serious neurological disorders.
- Blood results (performed within 14 days from study registration) as outlined below:
- Absolute neutrophil count (ANC)<1500 cells/mm3.
- Platelets<100,000 cells/mm3.
- Hemoglobin <10 g/dl. (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10 g/dl is acceptable.)
- S-Urea > 25 mg/dl
- Creatinine clearance ≤ 30 ml
- Bilirubin > 2.0 mg/dl
- ALT >3 x normal range
- AST >3 x normal range
- Pregnant or lactating at screening, or planning to become pregnant (self or partner) at any time during study.
- Contraindication to magnetic resonance imaging.
- Unable to provide informed consent.
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
About this study
Official title: A Phase I, Open-Label, Two Centre Study to Evaluate Dichloroacetate(DCA) in Advanced Pulmonary Arterial Hypertension.
Hypothesis: The small molecule and metabolic modulator Dichloroacetate (DCA) is safe, tolerated as a potential therapy in patients with moderate or severe Pulmonary Arterial Hypertension (PAH).
This is a Phase I, two centre study in subjects with PAH WHO functional class III-IV whose symptoms have been clinically stable on their prescribed medical treatment (which includes endothelin and/or phosphodiesterase type 5 inhibitors) for 8 weeks prior to enrollment. Such patients will be given either DCA 3.0 mg/kg BID (group I), 6.25 mg/kg BID (group II) or 12.5 mg/kg BID (group III) as an additional treatment for 16 weeks. The design is open-label with the subjects acting as their own controls.
Read more
Primary endpoint is the safety and tolerability of DCA. Secondary end points include: a) functional capacity including a change in the 6 minute walk form baseline, b) change in pulmonary vascular resistance (measured by right heart catheterization), c) right ventricular volumes and mass (measured by MRI), d) NT-proBNP levels changed from baseline, e) change in FDG-glucose uptake in the lung and right ventricle (measured by PET) and f) change in quality of life indices.
15 evaluable patients in each site are expected to be included.
Read the detailed description
The vascular remodeling in PAH is a state of apoptosis-resistance. As in cancer, a switch from the anti-apoptotic glycolytic metabolism towards the pro-apoptotic oxidative phosphorylation metabolism, has been shown to cause regression of vascular remodeling and PAH in several animal models. This has been achieved with the small molecular DCA, an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase kinase.
DCA has been used in humans for over 30 years, mostly in the treatment of inherited mitochondrial disorders and is also currently being evaluated as a potential therapy in cancer.
This is a first-in-humans, Phase I, two centre study (University of Alberta and Imperial College) in subjects with advanced PAH, whose symptoms have been clinically stable on their prescribed medical treatment for 8 weeks prior to enrollment. These treatments include standard (eg diuretics, warfarin) or specific PAH therapies (eg endothelin or phosphodiesterase type 5 inhibitors). From the known metabolism of the drugs involved, no pharmacokinetic interaction is anticipated. In line with most safety and efficacy studies, the design is open-label with the subjects acting as their own controls.
Patients with PAH who have been stable on their current therapy for the preceding 2 months will be given either DCA 3.0 mg/kg BID (group I), 6.25 mg/kg BID (group II) or 12.5 mg/kg BID (group III) as an additional treatment for 16 weeks. Following the baseline visit, the patients will be followed every week for the first month, and then at weeks 6, 8 10, 12 and 16. In weeks 1, 3, 6 and 10, the patients' status will be assessed by telephone interview.
At all the other visits: medical history and physical examination will be performed. With the exception of week 2 (unless clinically indicated), this will be combined with routine hematology and biochemistry and an assessment of functional capacity (6 minute walk test). Serum lactate and NT-pro-BNP levels will be measured and PDH activity assay will be performed. Urine will be obtained for DCA metabolite studies.
At baseline and 16 weeks: A cardiac catheterization to assess change in pulmonary hemodynamics; a routine cardiac MR (RV mass/volumes, MR angiography); FDG-PET to examine for an effect on regional lung or RV glucose uptake.
If tolerated well, the subjects will continue with their medication and return for follow-up assessments at Weeks 20, 24 and 28. At each follow-up visit, a physical examination will be performed and functional capacity will be assessed (6 minute walk test). At the Week 28 visit a routine cardiac MR will also be performed. Enrollment will continue until 30 evaluable subjects (15 in each site) are included.
- Being tested
- Dichloroacetate Sodium
- Keywords
- Pulmonary arterial hypertension, Pulmonary hypertension, Dichloroacetate, Dichloroacetate Sodium, DCA
- Medical subject headings
- Hypertension, Pulmonary, Pulmonary Arterial Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dichloroacetate SodiumDrug
Also called DCA
3 mg po bid for 28 weeks
Dichloroacetate SodiumDrug
Also called DCA
6.25 mg po bid
Dichloroacetate SodiumDrug
Also called DCA
12.5 mg po bid
| Study group | Role | What they receive |
|---|---|---|
| Group 1 | Experimental | Dichloroacetate Sodium 3.0 mg/kg, BID Receives: Drug: Dichloroacetate Sodium |
| Group 2 | Experimental | Dichloroacetate Sodium 6.25 mg/kg, BID Receives: Drug: Dichloroacetate Sodium |
| Group 3 | Experimental | Dichloroacetate Sodium 12.5 mg po bid Receives: Drug: Dichloroacetate Sodium |
What is being measured
The primary outcome is the main question the study is designed to answer.
Assessment of safety and tolerability of DCA in patients with pulmonary arterial hypertension.
Measured: December 2010
Secondary outcomes (3)
The change in pulmonary vascular resistance from baseline at 16 weeks, measured by cardiac catheterization;
Measured: December 2010
Functional capacity: change from baseline in Functional Class and 6 min walk
Measured: December 2010
Changes in Right Ventricular size/function (measured by MRI), biomarkers (NT-proBNP), lung/RV metabolism (measured by FDG-PET)
Measured: December 2010
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Mar 2010 (estimated)
- Study startMar 2010
- Primary completionSep 2013
- Study completionSep 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Pulmonary Hypertension (Idiopathic, Familial or Anorexigen-associated)Studies of the same condition, open and under way.
- More trials run by University of AlbertaThe 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
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alberta
- Sponsor type
- University, hospital or other
- Collaborators
- Imperial College London
- Responsible party
- Sponsor
- Investigators
- Evangelos D. Michelakis, MD, Principal investigator, University of AlbertaMartin R Wilkins, MD, Principal investigator, Imperial College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01083524
- Sponsor's protocol ID
- DCA 20001
- Status last verified
- May 2014
- First submitted
- 8 Mar 2010
- Last updated
- 3 Jun 2014
- Results posted
- No
- Data monitoring committee
- Yes
Publications
McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 2004 Oct 15;95(8):830-40. doi: 10.1161/01.RES.0000145360.16770.9f. Epub 2004 Sep 16.
PubMed 15375007
Study at a glance
From the registry record, last updated by the sponsor on 3 Jun 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Open-Label, Two Centre Study to Evaluate Dichloroacetate(DCA) in Advanced Pulmonary Arterial Hypertension.
- ClinicalTrials.gov ID
- NCT01083524
- Acronym / sponsor ID
- DCA 20001
- Keywords
- Pulmonary arterial hypertension, Pulmonary hypertension, Dichloroacetate, Dichloroacetate Sodium, DCA
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- University of AlbertaUniversity, hospital or other
- Collaborators
- Imperial College London
- Study start
- Mar 2010
- Primary completion
- Sep 2013 (actual)
- Study completion
- Sep 2013 (actual)
- First posted
- 9 Mar 2010 (estimated)
- 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.
Hypothesis: The small molecule and metabolic modulator Dichloroacetate (DCA) is safe, tolerated as a potential therapy in patients with moderate or severe Pulmonary Arterial Hypertension (PAH).
This is a Phase I, two centre study in subjects with PAH WHO functional class III-IV whose symptoms have been clinically stable on their prescribed medical treatment (which includes endothelin and/or phosphodiesterase type 5 inhibitors) for 8 weeks prior to enrollment. Such patients will be given either DCA 3.0 mg/kg BID (group I), 6.25 mg/kg BID (group II) or 12.5 mg/kg BID (group III) as an additional treatment for 16 weeks. The design is open-label with the subjects acting as their own controls.
Primary endpoint is the safety and tolerability of DCA. Secondary end points include: a) functional capacity including a change in the 6 minute walk form baseline, b) change in pulmonary vascular resistance (measured by right heart catheterization), c) right ventricular volumes and mass (measured by MRI), d) NT-proBNP levels changed from baseline, e) change in FDG-glucose uptake in the lung and right ventricle (measured by PET) and f) change in quality of life indices.
15 evaluable patients in each site are expected to be included.
Detailed description
The vascular remodeling in PAH is a state of apoptosis-resistance. As in cancer, a switch from the anti-apoptotic glycolytic metabolism towards the pro-apoptotic oxidative phosphorylation metabolism, has been shown to cause regression of vascular remodeling and PAH in several animal models. This has been achieved with the small molecular DCA, an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase kinase.
DCA has been used in humans for over 30 years, mostly in the treatment of inherited mitochondrial disorders and is also currently being evaluated as a potential therapy in cancer.
This is a first-in-humans, Phase I, two centre study (University of Alberta and Imperial College) in subjects with advanced PAH, whose symptoms have been clinically stable on their prescribed medical treatment for 8 weeks prior to enrollment. These treatments include standard (eg diuretics, warfarin) or specific PAH therapies (eg endothelin or phosphodiesterase type 5 inhibitors). From the known metabolism of the drugs involved, no pharmacokinetic interaction is anticipated. In line with most safety and efficacy studies, the design is open-label with the subjects acting as their own controls.
Patients with PAH who have been stable on their current therapy for the preceding 2 months will be given either DCA 3.0 mg/kg BID (group I), 6.25 mg/kg BID (group II) or 12.5 mg/kg BID (group III) as an additional treatment for 16 weeks. Following the baseline visit, the patients will be followed every week for the first month, and then at weeks 6, 8 10, 12 and 16. In weeks 1, 3, 6 and 10, the patients' status will be assessed by telephone interview.
At all the other visits: medical history and physical examination will be performed. With the exception of week 2 (unless clinically indicated), this will be combined with routine hematology and biochemistry and an assessment of functional capacity (6 minute walk test). Serum lactate and NT-pro-BNP levels will be measured and PDH activity assay will be performed. Urine will be obtained for DCA metabolite studies.
At baseline and 16 weeks: A cardiac catheterization to assess change in pulmonary hemodynamics; a routine cardiac MR (RV mass/volumes, MR angiography); FDG-PET to examine for an effect on regional lung or RV glucose uptake.
If tolerated well, the subjects will continue with their medication and return for follow-up assessments at Weeks 20, 24 and 28. At each follow-up visit, a physical examination will be performed and functional capacity will be assessed (6 minute walk test). At the Week 28 visit a routine cardiac MR will also be performed. Enrollment will continue until 30 evaluable subjects (15 in each site) are included.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Group 1 | Experimental | Drug: Dichloroacetate SodiumDichloroacetate Sodium 3.0 mg/kg, BID |
| Group 2 | Experimental | Drug: Dichloroacetate SodiumDichloroacetate Sodium 6.25 mg/kg, BID |
| Group 3 | Experimental | Drug: Dichloroacetate SodiumDichloroacetate Sodium 12.5 mg po bid |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Males or females 18 years or older
- Willing and able to complete informed consent form.
- Documented diagnosis of PAH:
- Receiving stable doses for at least 2 months of one or more medications that are approved for treatment of PAH (endothelin receptor antagonists or phosphodiesterase type 5 inhibitors). Note: Anticoagulant therapy can be adjusted according to target INR and diuretic dose can be adjusted as required.
- Modified World Health Organization(WHO) classification III-IV; stable for at least 8 weeks prior to enrollment.
Key exclusion criteria (19 listed)
- Previous treatment with any formulation of DCA.
- Known allergy or hypersensitivity to any excipient of DCA.
- Clinically significant biochemical abnormality.
- Clinical evidence of pre-existing neuropathy.
- Use of investigational product or device within 30 days prior to dosing, or known requirement for any investigational agent prior to completion of all scheduled study assessments.
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 |
|---|---|---|
| Dichloroacetate SodiumAlso: DCA3 mg po bid for 28 weeks | Drug | Group 1 |
| Dichloroacetate SodiumAlso: DCA6.25 mg po bid | Drug | Group 2 |
| Dichloroacetate SodiumAlso: DCA12.5 mg po bid | Drug | Group 3 |
Primary outcome
Assessment of safety and tolerability of DCA in patients with pulmonary arterial hypertension.
Time frame: December 2010
3 secondary outcomes
The change in pulmonary vascular resistance from baseline at 16 weeks, measured by cardiac catheterization;
Time frame: December 2010
Functional capacity: change from baseline in Functional Class and 6 min walk
Time frame: December 2010
Changes in Right Ventricular size/function (measured by MRI), biomarkers (NT-proBNP), lung/RV metabolism (measured by FDG-PET)
Time frame: December 2010
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 3 Jun 2014.
- Results publication: PubMed 15375007McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 2004 Oct 15;95(8):830-40. doi: 10.1161/01.RES.0000145360.16770.9f. Epub 2004 Sep 16.
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.
Evangelos D. Michelakis, MD principal investigator
University of Alberta
Martin R Wilkins, MD principal investigator
Imperial College London
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Dichloroacetate Sodium in people with Pulmonary Hypertension (Idiopathic, Familial or Anorexigen-associated), run by University of Alberta at 2 sites in 2 countries.
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 16 inclusion and 19 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 3 Jun 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Canada, United Kingdom. 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 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.
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?
Assessment of safety and tolerability of DCA in patients with pulmonary arterial hypertension. (time frame: December 2010). 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 NCT01083524, which also lists 1 linked publication.
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 3 Jun 2014.