The Role of Trimetazidine on Right Ventricle Function in Pulmonary Arterial Hypertension Patients in National Cardiovascular Center Harapan Kita Hospital Indonesia
Phase: PHASE2
Conditions: Precapillary Pulmonary Hypertension
Sponsor: Indonesia University

The Role of Trimetazidine on Right Ventricle Function in 
Pulmonary Arterial Hypertension in National 
Cardiovascular Center Harapan Kita Hospital 
(TRIMETA-PH) 
 
STUDY PROTOCOL AND STATISTICAL ANALYSIS 
NCT: 03273387 
STUDY DATES: SEPTEMBER 10th 2017 
 
 
 
 
 
 
 
 
 
 
 
 
DEPARTMENT OF CARDIOLOGY AND VASCULAR MEDICINE 
FACULTY OF MEDICINE UNIVERSITAS INDONESIA 
NATIONAL CARDIOVASCULAR CENTER HARAPAN KITA HOSPITAL  
 

This study is a single centre, randomized, double-blind, placebo-controlled, proof of 
concept study of trimetazidine effect in RV function of PAH patients. The study protocol 
was approved by the institutional review board in National Cardiovascular Center 
Harapan Kita Hospital Universitas Indonesia (NCCHK-UI). The member of committee 
were involved in the study design, protocol review, and guidance throughout the study 
conduct.  All patients gave written informed consent. 
 
Study Population 
Patients which eligible for the study were recruited from  (NCCHK-UI) PAH outpatient 
clinic. Patients were selected based on following inclusion and exclusion criteria. 
Inclusion criteria including age 18-65 years old, presence of precapillary pulmonary 
hypertension mPAP > 25 mmHg with left ventricle end diastolic pressure (LVEDP) or 
mean left atrial pressure (mLAP) < 15 mmHg, WHO functional class II or III, evidence of 
RV dysfunction with RVEF < 45% according to cardiovascular magnetic resonance 
imaging (CMR),  and stable dose of pulmonary vasodilator therapy in the 4 weeks 
before randomization. 
Exclusion criteria including LVEDP or mLAP > 15 mmHg, WHO functional class IV, 
pregnancy or lactation, severe renal dysfunction with estimated glomerular filtration < 30 
ml/min/1.73 m2 or routine hemodialysis, presenting malignant arrhythmia, left 
ventricular ejection fraction (LVEF) < 50%, claustrophobia, and Parkinson disease.  
 
 
 

Study Protocol 
Patients who met the following inclusion and exclusion criteria will be randomized in 1:1 
ratio  to receive twice-daily 35 mg trimetazidine or twice-daily placebo on top of their 
standard PAH regime for 3 months. Study procedure included cardiac catheterization at 
baseline, physical examination, SF-36 functional capacity questionnaire, and  CMR 
examination at baseline and after 3 month treatment.  Follow-up visits will be recorded 
during annual PAH outpatient visit at months 1,2, and 3. Adherence to study medication 
was encourage throughout study period including phone call reminder and pill counts 
during annual outpatient visit. All adverse event were recorded, including major adverse 
cardiovascular event (MACE) which defined as severe deterioration of health resulting 
in death, risk of death, hospitalization, or disability. 
Participants required right heart catheterization to evaluate the eligibility. Right heart 
and pulmonary artery catheterization was performed from the right femoral vein 
approach. Multipurpose (MP) catheter was used to record mPAP (MP 90cm, Mach1TM, 
Boston Scientific. Left heart catheterization was performed from right femoral artery 
using pigtail 6F catheter to record LVEDP (pigtail6F, Boston Scientific). In the case of 
PAH due to congenital heart disease with left to right shunt, we measured mLAP using 
MP catheter directly from the  appropriate shunt. Pressure recordings were analyzed 
using Siemens Axiom Sensis XP. 
Participants underwent CMR (Phillips Achieva 1.5 Tesla) examination at baseline and 
after 3 months treatment to assess RVEF, LVEF, LV and RV end diastolic volume 
(RVEDV and LVEDV0, RV and LV end systolic volume (RVESV and LVESV), and 
fibrosis using native T1 mapping. General RV and LV structure and function protocol 

were conducted according to SMCR guideline 2013.  Cardiac fibrosis analysis was 
performed using Look Locker imaging protocol. All CMR analysis was done using circle 
CVI42 version 5.9 software (Circle Cardiovascular imaging inc. Canada).  
Functional class was assessed during monthly visit according to WHO.  Their functional 
status was calculated using short form health survey (SF-36) questionnaire which was 
recorded at baseline and after 3 months treatment.  
 
Study Outcomes 
The primary outcome was the differences of RVEF after 3 months therapy of  
trimetazidine or placebo group. Secondary outcomes included the differences of clinical 
outcomes, WHO functional class, functional capacity based on SF-36 questionnaire, 
lactate dehydrogenase and others CMR parameters after 3 months therapy of 
trimetazidine or placebo group. 
 
Statistical Analysis 
The type I error was set two-sided 0.005 with power of 80%. Approximately a minimum 
18 patients with PAH and RV dysfunction will be randomized in 1:1 ratio to trimetazidine 
and placebo group after adjusting to 10% of dropout. A two-sided p value <0.05  was 
considered statistically significant. Baseline demographic, clinical, laboratory,  heart 
catheterization, and CMR parameters were compared between trimetazidine and 
placebo group at baseline. Normal distribution of continuous and categorical data were 
displayed as mean + standard error mean and percentage respectively.  Categorical 
data were analyzed using either fisher exact test if one of the data column less than 5 or 

Chi square test for larger data. Numerical data were analyzed using independent t tests 
between trimetazidine and placebo group. Multivariate analysis of covariance 
(ANCOVA) was performed to determine treatment effect. All analyses were performed 
using SPSS version 23 (SPSS inc, IBM, Armonk, New York). 
TRIMETA-PH Study Protocol