Precapillary Pulmonary Hypertension
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGTrimetazidine
The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy.
DRUGPlacebo oral capsule
The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy.
Sponsors
Indonesia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Pre-capillary Pulmonary Hypertension patients assessed by right heart catheterization * Signed informed consent
Exclusion criteria
* Patient belonging to post-capillary, Isolated post-capillary, or combined post -capillary and pre-capillary pulmonary hypertension according to 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. * Moderate to severe chronic pulmonary obstructive disease * Right Ventricular Ejection Fraction \> 45% assessed by cardiac magnetic resonance. * Documented left ventricular dysfunction with left ventricular ejection fraction \< 50% assessed by cardiac magnetic resonance. * Severe renal impairment (Serum creatinine \> 2.5 mg/dL, eGFR \< 30ml/min/1.73 m\^2, or routine dialysis treatment). * Malignant arrhythmia such as total atrioventricular block or ventricular fibrillation or unstable ventricular tachycardia. * Patients who are receiving or have been receiving any investigational drugs within 1 month before the baseline visit * Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements * Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements * Females who are lactating or pregnant or those who plan to become pregnant during the study * Known Parkinson disease * Known hypersensitivity to any of the drug formulation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Right Ventricular Ejection Fraction (RVEF %) After 3 Months Intervention | Baseline and 3 months after intervention | Right ventricular ejection fraction (RVEF %) assessed by Cardiac MRI at 3 months intervention minus with RVEF at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Cardiac Fibrosis After 3 Months Intervention | Baseline and 3 months after intervention | Native T1 mapping (ms) assessed by Cardiac MRI at 3 months intervention minus with Native T1 at baseline. |
| Changes in Functional Capacity After 3 Month Intervention | Baseline and 3 months after 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. |
Countries
Indonesia
Participant flow
Recruitment details
Subjects were recruited from NCCHK PH outpatient clinic from September 2017 until November 2018
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 13 |
| 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. | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Sugar Pill | Total | Trimetazidine |
|---|---|---|---|
| ACE-inhibitor | 4 Participants | 9 Participants | 5 Participants |
| Age, Continuous | 47 years STANDARD_DEVIATION 3.8 | 48 years STANDARD_DEVIATION 8.9 | 48 years STANDARD_DEVIATION 1.5 |
| Angiotensin receptor II blocker | 4 Participants | 5 Participants | 1 Participants |
| beta blocker | 5 Participants | 13 Participants | 8 Participants |
| Body Mass Index | 23.3 kg/m^2 STANDARD_DEVIATION 3.8 | 22.1 kg/m^2 STANDARD_DEVIATION 8.6 | 21 kg/m^2 STANDARD_DEVIATION 0.8 |
| digoxin | 1 Participants | 3 Participants | 2 Participants |
| furosemide | 11 Participants | 19 Participants | 8 Participants |
| Glomerular Filtration Rate | 96.6 ml/min/1.73 m^2 STANDARD_DEVIATION 7.9 | 106 ml/min/1.73 m^2 STANDARD_DEVIATION 15.6 | 110.7 ml/min/1.73 m^2 STANDARD_DEVIATION 3.9 |
| LV ejection fraction | 64 % STANDARD_DEVIATION 2.6 | 62 % STANDARD_DEVIATION 7.5 | 59 % STANDARD_DEVIATION 2.4 |
| LV end diastolic pressure | 7.2 mmHg STANDARD_DEVIATION 1.2 | 7.4 mmHg STANDARD_DEVIATION 3.1 | 7.8 mmHg STANDARD_DEVIATION 0.8 |
| LV end diastolic volume | 79 ml STANDARD_DEVIATION 6.3 | 81 ml STANDARD_DEVIATION 18 | 83 ml STANDARD_DEVIATION 5.3 |
| LV end systolic volume | 29 ml STANDARD_DEVIATION 2.8 | 31 ml STANDARD_DEVIATION 9.7 | 33 ml STANDARD_DEVIATION 3.3 |
| mean pulmonary arterial pressure | 62 mmHg STANDARD_DEVIATION 5.9 | 60 mmHg STANDARD_DEVIATION 11.2 | 59 mmHg STANDARD_DEVIATION 3.6 |
| mean Right atrial pressure | 5.9 mmHg STANDARD_DEVIATION 1.4 | 5.9 mmHg STANDARD_DEVIATION 3.9 | 6 mmHg STANDARD_DEVIATION 1.2 |
| Native T1 anteroseptal | 993 ms STANDARD_DEVIATION 612 | 1164 ms STANDARD_DEVIATION 555 | 1354 ms STANDARD_DEVIATION 441 |
| Native T1 inferoseptal | 930 ms STANDARD_DEVIATION 418 | 1187 ms STANDARD_DEVIATION 637 | 1474 ms STANDARD_DEVIATION 736 |
| Native T1 Lateral | 1090 ms STANDARD_DEVIATION 470 | 1216 ms STANDARD_DEVIATION 478 | 1357 ms STANDARD_DEVIATION 473 |
| Native T1 septal | 1108 ms STANDARD_DEVIATION 512 | 1109 ms STANDARD_DEVIATION 454 | 1110 ms STANDARD_DEVIATION 411 |
| onset of diagnosis to study | 1170 days STANDARD_DEVIATION 387 | 1048 days STANDARD_DEVIATION 1093 | 926 days STANDARD_DEVIATION 214 |
| Phosphodiesterase-5 inhibitor | 12 Participants | 24 Participants | 12 Participants |
| Prostacyclin analogue (beraprost) | 8 Participants | 13 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian | 13 Participants | 26 Participants | 13 Participants |
| RV ejection fraction | 24.5 % STANDARD_DEVIATION 2.8 | 22.4 % STANDARD_DEVIATION 10 | 21.1 % STANDARD_DEVIATION 4.4 |
| RV end diastolic volume | 258 ml STANDARD_DEVIATION 28 | 259 ml STANDARD_DEVIATION 83 | 260 ml STANDARD_DEVIATION 31 |
| RV end systolic volume | 193 ml STANDARD_DEVIATION 20 | 197 ml STANDARD_DEVIATION 67 | 206 ml STANDARD_DEVIATION 25 |
| Sex: Female, Male Female | 11 Participants | 23 Participants | 12 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 1 Participants |
| SF-36 Functional Capacity | 61.15 units on a scale STANDARD_DEVIATION 4.77 | 53.84 units on a scale STANDARD_DEVIATION 19.56 | 46.54 units on a scale STANDARD_DEVIATION 5.44 |
| spironolactone | 9 Participants | 19 Participants | 10 Participants |
| Warfarin | 4 Participants | 10 Participants | 6 Participants |
| WHO Functional Class WHO functional class II | 9 Participants | 13 Participants | 4 Participants |
| WHO Functional Class WHO functional class III | 4 Participants | 13 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 13 | 2 / 13 |
| other Total, other adverse events | 1 / 13 | 2 / 13 |
| serious Total, serious adverse events | 2 / 13 | 2 / 13 |
Outcome results
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.
Time frame: Baseline and 3 months after intervention
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill | Changes in Right Ventricular Ejection Fraction (RVEF %) After 3 Months Intervention | -2.8 percentage of ejected blood | Standard Error 1.6 |
| Trimetazidine | Changes in Right Ventricular Ejection Fraction (RVEF %) After 3 Months Intervention | 3.9 percentage of ejected blood | Standard Error 1.5 |
p-value: 0.008t-test, 2 sided
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.
Time frame: Baseline and 3 months after intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sugar Pill | Changes in Cardiac Fibrosis After 3 Months Intervention | Native T1 anteroseptal | 138 ms | Standard Error 555 |
| Sugar Pill | Changes in Cardiac Fibrosis After 3 Months Intervention | Native T1 Septal | 292 ms | Standard Error 677 |
| Sugar Pill | Changes in Cardiac Fibrosis After 3 Months Intervention | Native T1 Inferoseptal | 294 ms | Standard Error 618 |
| Sugar Pill | Changes in Cardiac Fibrosis After 3 Months Intervention | Native T1 Lateral | 287 ms | Standard Error 744 |
| Trimetazidine | Changes in Cardiac Fibrosis After 3 Months Intervention | Native T1 Lateral | -194 ms | Standard Error 487 |
| Trimetazidine | Changes in Cardiac Fibrosis After 3 Months Intervention | Native T1 anteroseptal | 190 ms | Standard Error 538 |
| Trimetazidine | Changes in Cardiac Fibrosis After 3 Months Intervention | Native T1 Inferoseptal | -123 ms | Standard Error 645 |
| Trimetazidine | Changes in Cardiac Fibrosis After 3 Months Intervention | Native T1 Septal | 371 ms | Standard Error 670 |
p-value: 0.33two-way ANOVA
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.
Time frame: Baseline and 3 months after intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill | Changes in Functional Capacity After 3 Month Intervention | -17.73 score on a scale | Standard Error 3.72 |
| Trimetazidine | Changes in Functional Capacity After 3 Month Intervention | 11.5 score on a scale | Standard Error 5.27 |
p-value: 0.0002t-test, 2 sided