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The study will evaluate the effect of trimetazidine versus placebo in addition to standard pulmonary arterial hypertension regime on right ventricular function in pulmonary arterial hypertension patients.
Right ventricular dysfunction is the worst mortality predictor in pulmonary arterial hypertension (PAH). Recent study has described that approximately 25% of PAH patients will developed into right ventricular failure despite therapeutic reduction of pulmonary vascular resistance. Subsequently, several studies have shown that fatty acid accumulation in right ventricle was inversely correlated with right ventricular function in PAH patients. Several PAH animal studies have revealed that metabolic glucose oxidation impairment through increased aerobic glycolysis, mitochondrial dysfunction, and lipotoxicity play significant role in right ventricular failure. Moreover, several pulmonary hypertension animal studies have demonstrated the benefit of partial fatty acid inhibitor such as trimetazidine on right ventricle function. It was hypothesize that trimetazidine improved right ventricular function through indirect effect of increased glucose oxidation by blocking the Randle cycle. Therefore, we hypothesize that trimetazidine can improve right ventricular function in pulmonary arterial hypertension patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sugar pill | Placebo Comparator | The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy. |
|
| trimetazidine | Experimental | The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Trimetazidine | Drug | The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Right Ventricular Ejection Fraction (RVEF %) After 3 Months Intervention | Right ventricular ejection fraction (RVEF %) assessed by Cardiac MRI at 3 months intervention minus with RVEF at baseline. | Baseline and 3 months after intervention |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Cardiac Fibrosis After 3 Months Intervention | Native T1 mapping (ms) assessed by Cardiac MRI at 3 months intervention minus with Native T1 at baseline. | Baseline and 3 months after intervention |
| Changes in Functional Capacity After 3 Month Intervention |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hary Sakti Muliawan, MD,PhD | Department Cardiology and Vascular Medicine Universitas Indonesia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Cardiovascular Center Harapan Kita Hospital | Jakarta | 11420 | Indonesia |
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A total of 35 Patients were enrolled between September 2017 and November 2018 at NCCHK PAH outpatient clinic. A total of 26 patients were consent to underwent the trial and randomly assigned to receive trimetazidine or placebo with ratio 1:1.
Subjects were recruited from NCCHK PH outpatient clinic from September 2017 until November 2018
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| ID | Title | Description |
|---|---|---|
| FG000 | Sugar Pill | The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy. Placebo oral capsule: The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy. |
| FG001 | Trimetazidine | The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. Trimetazidine: The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sugar Pill | The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy. Placebo oral capsule: The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy. |
| BG001 | Trimetazidine |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Changes in Right Ventricular Ejection Fraction (RVEF %) After 3 Months Intervention | Right ventricular ejection fraction (RVEF %) assessed by Cardiac MRI at 3 months intervention minus with RVEF at baseline. | A total 13 patients were assigned to each group equally. There were 6 patients who were not able to complete the study. A total of 2 patients from both group died due to RV failure. One patients from trimetazidine group withdrawn due to atypical angina and one patients from placebo group withdrawn due to claustrophobia. | Posted | Mean | Standard Error | percentage of ejected blood | Baseline and 3 months after intervention |
|
three months for each intervention.
safety population included all participants who received at least one dose of intervention.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sugar Pill | The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy. Placebo oral capsule: The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiovascular mortality | Cardiac disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| paresthesia | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| dr. Bambang WIdyantoro, FIHA, PhD | Department of Cardiology and Vascular Medicine, Universitas Indonesia | +628128164299 | bambang_ui@yahoo.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 10, 2017 | Sep 11, 2019 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Sep 10, 2017 | Sep 11, 2019 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D014292 | Trimetazidine |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D002241 | Carbohydrates |
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| Placebo oral capsule | Drug | The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy. |
|
|
Functional capacity assessed by SF-36 score after 3 month intervention minus with functional capacity at baseline. SF-36 functional capacity score scale 0 to 100 with better functional capacity along with higher score. |
| Baseline and 3 months after intervention |
The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. Trimetazidine: The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Percentage of gender differences in our PAH patients. | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| onset of diagnosis to study | The number of days since first diagnosed with PAH until intervention. The longer the onset of diagnosis to study intervention suggest longer the patients suffered from PAH which may or may not correlated with PAH severity | Mean | Standard Deviation | days |
|
| SF-36 Functional Capacity | SF-36 functional capacity score is an questionnaire instrument which evaluate quality of life including functional capacity. The SF-36 functional capacity score scale from 0-100 with better functional capacity along with higher scale. | Mean | Standard Deviation | units on a scale |
|
| WHO Functional Class | Percentage of participant with WHO functional class II or III on each group. WHO functional class II defines as PAH patients with slight limitation of physical activity. They are comfortable at rest. Ordinary activity causes dyspnea, fatigue, chest pain, or syncope. WHO functional class III defines as PAH patients with marked limitation of physical activity. They are comfortable with rest. Less than ordinary activities causes dyspnea, fatigue, chest pain or syncope. | Count of Participants | Participants |
|
| Glomerular Filtration Rate | Mean | Standard Deviation | ml/min/1.73 m^2 |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| Phosphodiesterase-5 inhibitor | Percentage of participant with Phosphodiesterase-5 inhibitor treatment. | Count of Participants | Participants |
|
| Prostacyclin analogue (beraprost) | Percentage of participants with oral prostacyclin analogue (beraprost) treatment | Count of Participants | Participants |
|
| beta blocker | Percentage of participant with beta blocker treatment. | Count of Participants | Participants |
|
| ACE-inhibitor | Percentage of participant with ACE-Inhibitor treatment. | Count of Participants | Participants |
|
| Angiotensin receptor II blocker | Percentage of participant with Angiotensin receptor II blocker treatment. | Count of Participants | Participants |
|
| Warfarin | Percentage of participant with warfarin treatment. | Count of Participants | Participants |
|
| spironolactone | Percentage of participant with spironolactone treatment. | Count of Participants | Participants |
|
| furosemide | Percentage of participant with furosemide treatment. | Count of Participants | Participants |
|
| digoxin | Percentage of participant with digoxin treatment. | Count of Participants | Participants |
|
| mean Right atrial pressure | Mean | Standard Deviation | mmHg |
|
| mean pulmonary arterial pressure | Mean | Standard Deviation | mmHg |
|
| LV end diastolic pressure | Mean | Standard Deviation | mmHg |
|
| RV end diastolic volume | Mean | Standard Deviation | ml |
|
| RV end systolic volume | Mean | Standard Deviation | ml |
|
| RV ejection fraction | Mean | Standard Deviation | % |
|
| LV end diastolic volume | Mean | Standard Deviation | ml |
|
| LV end systolic volume | Mean | Standard Deviation | ml |
|
| LV ejection fraction | Mean | Standard Deviation | % |
|
| Native T1 anteroseptal | Native T1 is measuring the T1 tissue using CMR with MOLLI technique at 1.5 T which normal value ranged between 900 to 1100ms. Native T1 is increased in edema, inflammation, cellular edema, myocyte necrosis, and fibrosis. | Mean | Standard Deviation | ms |
|
| Native T1 septal | Mean | Standard Deviation | ms |
|
| Native T1 inferoseptal | Mean | Standard Deviation | ms |
|
| Native T1 Lateral | Mean | Standard Deviation | ms |
|
| OG001 | Trimetazidine | The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. Trimetazidine: The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. |
|
|
|
| Secondary | Changes in Cardiac Fibrosis After 3 Months Intervention | Native T1 mapping (ms) assessed by Cardiac MRI at 3 months intervention minus with Native T1 at baseline. | Posted | Mean | Standard Error | ms | Baseline and 3 months after intervention |
|
|
|
|
| Secondary | Changes in Functional Capacity After 3 Month Intervention | Functional capacity assessed by SF-36 score after 3 month intervention minus with functional capacity at baseline. SF-36 functional capacity score scale 0 to 100 with better functional capacity along with higher score. | Posted | Mean | Standard Error | score on a scale | Baseline and 3 months after intervention |
|
|
|
|
| 2 |
| 13 |
| 2 |
| 13 |
| 1 |
| 13 |
| EG001 | Trimetazidine | The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. Trimetazidine: The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. | 2 | 13 | 2 | 13 | 2 | 13 |
| nausea | Gastrointestinal disorders | Systematic Assessment |
|
| musculoskeletal angina | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
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| Native T1 Inferoseptal |
|
| Native T1 Lateral |
|