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Dichloroacetate (DCA) for the Treatment of Pulmonary Arterial Hypertension

Primary Purpose

Pulmonary Hypertension (Idiopathic, Familial or Anorexigen-associated)

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Dichloroacetate Sodium

About this trial

This is an interventional treatment trial for Pulmonary Hypertension (Idiopathic, Familial or Anorexigen-associated) focused on measuring Pulmonary arterial hypertension, Pulmonary hypertension, Dichloroacetate, Dichloroacetate Sodium, DCA

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.
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:
1. Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner of female subject
2. 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
3. Double-barrier method of contraception consisting of spermicide with either condom or diaphragm
4. 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.

Exclusion Criteria:

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).
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.

Sites / Locations

University of Alberta Hospital
Imperial College

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Group 1

Group 2

Group 3

Arm Description

Dichloroacetate Sodium 3.0 mg/kg, BID

Dichloroacetate Sodium 6.25 mg/kg, BID

Dichloroacetate Sodium 12.5 mg po bid

Outcomes

Primary Outcome Measures

Assessment of safety and tolerability of DCA in patients with pulmonary arterial hypertension.

Secondary Outcome Measures

The change in pulmonary vascular resistance from baseline at 16 weeks, measured by cardiac catheterization;

Functional capacity: change from baseline in Functional Class and 6 min walk

Changes in Right Ventricular size/function (measured by MRI), biomarkers (NT-proBNP), lung/RV metabolism (measured by FDG-PET)

Full Information

NCT ID

NCT01083524

First Posted

March 8, 2010

Last Updated

May 30, 2014

Sponsor

University of Alberta

Collaborators

Imperial College London

1. Study Identification

Unique Protocol Identification Number

NCT01083524

Brief Title

Dichloroacetate (DCA) for the Treatment of Pulmonary Arterial Hypertension

Official Title

A Phase I, Open-Label, Two Centre Study to Evaluate Dichloroacetate(DCA) in Advanced Pulmonary Arterial Hypertension.

Study Type

Interventional

2. Study Status

Record Verification Date

May 2014

Overall Recruitment Status

Completed

Study Start Date

March 2010 (undefined)

Primary Completion Date

September 2013 (Actual)

Study Completion Date

September 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Alberta

Collaborators

Imperial College London

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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). 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Hypertension (Idiopathic, Familial or Anorexigen-associated)

Keywords

Pulmonary arterial hypertension, Pulmonary hypertension, Dichloroacetate, Dichloroacetate Sodium, DCA

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group 1

Arm Type

Experimental

Arm Description

Dichloroacetate Sodium 3.0 mg/kg, BID

Arm Title

Group 2

Arm Type

Experimental

Arm Description

Dichloroacetate Sodium 6.25 mg/kg, BID

Arm Title

Group 3

Arm Type

Experimental

Arm Description

Dichloroacetate Sodium 12.5 mg po bid

Intervention Type

Drug

Intervention Name(s)

Dichloroacetate Sodium

Other Intervention Name(s)

DCA

Intervention Description

3 mg po bid for 28 weeks

Intervention Type

Drug

Intervention Name(s)

Dichloroacetate Sodium

Other Intervention Name(s)

DCA

Intervention Description

6.25 mg po bid

Intervention Type

Drug

Intervention Name(s)

Dichloroacetate Sodium

Other Intervention Name(s)

DCA

Intervention Description

12.5 mg po bid

Primary Outcome Measure Information:

Title

Assessment of safety and tolerability of DCA in patients with pulmonary arterial hypertension.

Time Frame

December 2010

Secondary Outcome Measure Information:

Title

The change in pulmonary vascular resistance from baseline at 16 weeks, measured by cardiac catheterization;

Time Frame

December 2010

Title

Functional capacity: change from baseline in Functional Class and 6 min walk

Time Frame

December 2010

Title

Changes in Right Ventricular size/function (measured by MRI), biomarkers (NT-proBNP), lung/RV metabolism (measured by FDG-PET)

Time Frame

December 2010

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. 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. Exclusion Criteria: 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). 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Evangelos D. Michelakis, MD

Organizational Affiliation

University of Alberta

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Martin R Wilkins, MD

Organizational Affiliation

Imperial College London

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Alberta Hospital

City

Edmonton

State/Province

Alberta

ZIP/Postal Code

T6G 2B7

Country

Canada

Facility Name

Imperial College

City

London

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

15375007

Citation

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.

Results Reference

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Dichloroacetate (DCA) for the Treatment of Pulmonary Arterial Hypertension

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