Clinical trial NCT03273387
Conditions: Precapillary Pulmonary Hypertension
Sponsor: Indonesia University
Start date: 2017-09-10; Completion date: 2018-12-14
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy. arm 2: The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy.
Interventions: intervention 1: Trimetazidine intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy. intervention 2: The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy.

Protocol documents:
Prot_SAP_000.pdf: 
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 
 
 
 

ICF_001.pdf: 
 
 
The Role of Trimetazidine on Right Ventricle Function in Pulmonary Arterial 
Hypertension in National Cardiovascular Center Harapan Kita Hospital 
(TRIMETA-PH) 
 
INDONESIA VERSION OF INFORMED CONSENT  
AND ENGLISH VERSION OF CASE REPORT FORM  
NCT 03273387 
STUDY DATES: SEPTEMBER 10th 2017 
 
 
 
 
 
Patient Code: …………………………………………….. 


 
 
DEPARTMENT OF CARDIOLOGY AND VASCULAR MEDICINE 
FACULTY OF MEDICINE UNIVERSITAS INDONESIA 
NATIONAL CARDIOVASCULAR CENTER HARAPAN KITA HOSPIT 
INFORMED CONSENT FORM 
 
Saya, dr. Hary Sakti Muliawan, PhD dengan dosen pembimbing dr. Bambang Widyantro, SpJP, PhD dan dr. Rarsari Soerarso, SpJP dari 
Departemen Kardiologi dan Kedokteran Vaskular, Pusat Jantung Nasional Harapan Kita, akan melakukan penelitian yang berjudul “Efek 
Trimetazidine Terhadap Fungsi Ventrikel Kanan Pada Pasien Hipertensi Pulmonal Prekapiler”. Penelitian ini bertujuan untuk mengetahui 
efek obat trimetazidine di atas obat hipertensi paru standar yang sudah diberikan terhadap fungsi jantung kanan pasien hipertensi paru. Studi 
terbaru menunjukan bahwa trimetazidine dapat memperbaiki fungsi jantung kanan pada hewan coba hipertensi paru. Namun, saat ini belum 
diketahui efek trimetazidine pada fungsi jantung kanan pasien hipertensi paru. Tim peneliti mengajak bapak/ibu untuk ikut serta dalam penelitian 
ini. Penelitian ini membutuhkan sekitar 50 subyek penelitian, dengan jangka keikutsertaan  masing-masing subjek selama 90 hari.  
A. Kesukarelaan untuk ikut penelitian 
Bapak/Ibu bebas memilih keikutsertaan dalam penelitian ini tanpa ada paksaan.  Kami memberikan kebebasan kepada bapak/ibu untuk 
memutuskan untuk mundur dari penelitian ini sewaktu-waktu.   
 
 
 


 
 
B. Prosedur Penelitian 
Apabila bapak/ibu bersedia berpartisipasi dalam penelitian ini, bapak/ibu diminta menandatangani lembar persetujuan ini.  
Prosedur selanjutnya adalah:  
1. Bapak/Ibu akan diwawancarai oleh dokter untuk menanyakan: Data pribadi (Nama, usia, pendidikan, pekerjaan, tempat tinggal, nomor 
kontak dan jaminan kesehatan) riwayat penyakit (lama diagnosis), riwayat penggunaan obat (lama pengobatan), riwayat alergi, riwayat 
penyakit jantung di keluarga, dilakukan pemeriksaan fisik dan tanda vital. 
2. Melengkapi pemeriksaan standar diagnosis hipertensi paru berupa kateterisasi jantung kanan. 
3. Apabila hasil kateterisasi jantung kanan bapak/ibu sesuai dengan hipertensi paru prekapiler, maka selanjutnya bapak/ibu akan menjalani 
pemeriksaan Magnetic Resonance Imaging (MRI) jantung dan pemeriksaan serum darah untuk menilai fungsi jantung kanan sebelum 
intervensi.  
4. Apabila hasil kateterisasi jantung kanan bapak/ibu tidak masuk dalam kriteria hipertensi paru prekapiler, maka bapak/ibu tidak dapat 
melanjutkan keikutsertaan dalam penelitian ini. 
5. Setelah itu bapak/ibu akan dibagi menjadi 2 kelompok yang dipilih secara acak dan tersamar dari pasien maupun peneliti. Berdasarkan 
jenis kelompok yang tersamar tersebut, ibu/bapak akan menerima tablet trimetazidine atau tablet salut gula selama 90 hari di atas obat 
hipertensi paru yang sudah rutin diminum sebelumnya. Pemberian obat akan disertai lembaran aturan pakai, serta makanan/minuman/obat 
yang sebaiknya dihindari selama konsumsi obat intervensi.  
6. Bapak/ibu akan diminta untuk kontrol setiap bulan untuk evaluasi kondisi klinis serta ada tidaknya efek samping yang mungkin timbul. 
7. Pada hari ke-90, pasca pemberian obat, bapak/ibu akan kembali menjalani pemeriksaan MRI jantung dan serum darah untuk menilai 
fungsi jantung kanan. 
8. Semua tindakan dan pemeriksaan akan dilakukan di di RSPJNHK.  


 
 
 
C. Kewajiban subyek penelitian 
Sebagai subyek penelitian, bapak/ibu berkewajiban mengikuti aturan atau petunjuk penelitian seperti yang tertulis di atas. Bila ada yang belum 
jelas, bapak/ibu bisa bertanya lebih lanjut kepada peneliti. 
D. Risiko dan Efek Samping dan Penanganannya  
Obat yang akan diberikan adalah obat lama yang sebelumnya direkomendasikan pada pasien penyakit jantung koroner stabil untuk mengurangi 
gejala nyeri dada. Namun penelitian terbaru menunjukan bahwa obat ini memiliki efek menguntungkan pada hipertensi paru.  Efek samping yang 
sering dijumpai antara lain pusing, mual, nyeri perut, dan  gatal-gatal di kulit dengan insidensi bervariasi antara 1%-10%. Selain itu, obat ini juga 
dapat menimbulkan gangguan saraf seperti tremor dan mudah terjatuh dengan angka kejadian yang belum diketahui. Apabila ditemukan gangguan 
saraf tersebut, maka pemberian obat akan dihentikan.   
E. Manfaat  
Keuntungan langsung yang bapak/ibu dapatkan adalah bapak/ibu mendapatkan pemeriksaan  kateterisasi jantung kanan (mengetahui tekanan 
hipertensi paru), pemeriksaan serum darah  dan MRI jantung kanan secara gratis.  
F. Kerahasiaan  
Semua informasi yang berkaitan dengan identitas bapak/ibu akan dirahasiakan dan hanya akan diketahui oleh peneliti dan staf penelitian. Hasil 
penelitian akan dipublikasikan tanpa identitas bapak/ibu.  
G. Pembiayaan 


 
 
Semua biaya yang terkait penelitian akan ditanggung oleh peneliti.  
Sebagai informasi tambahan bapak/ibu diberi kesempatan untuk menanyakan semua hal yang belum jelas sehubungan dengan penelitian ini. Bila 
sewaktu-waktu membutuhkan penjelasan lebih lanjut, bapak/ibu dapat menghubungi dr. Hary Sakti Muliawan, PhD pada no. HP 081311666626, 
dengan Alamat: Pusat Jantung Nasional Harapan Kita,  Jl. Letjen. S. Parman Kav. 87, Slipi, Jakarta 11420, Indonesia. Nomor telepon: 021-
5684085.  
PERSETUJUAN KEIKUTSERTAAN DALAM PENELITIAN 
 
 
Saya telah mendapat penjelasan mengenai penelitian yang berjudul “Efek Trimetazidine Terhadap Fungsi Ventrikel Kanan Pasien Hipertensi 
Pulmonal Prekapiler” oleh dr. Hary Sakti Muliawan, PhD dan tim peneliti, dan mendapat jawaban setiap pertanyaan dengan jelas. Setelah 
mengetahui manfaatnya, memahami hak dan kewajiban sebagai subyek penelitian, dengan ini secara sukarela menyatakan ikut serta/berpartisipasi 
dalam penelitian tersebut. 
 
    Jakarta,……….…...… 
       Tanda tangan tim Penelitian      
 
        Tanda Tangan Subjek Penelitian  
 
(Nama jelas :.................................)  
 
        (Nama jelas :............................. 


 
 
CASE REPORT FORM 
 
I 
DEMOGRAPHY 
I.1 
Patient Initial 
  
  
  
Physician Initial 
  
  
  
I.2 
Patient Code 
  
  
  
I.3 
Medical Record 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I.4 
Date of Birth 
Day 
  
  
Month   
  
Year   
  
I.5 
First visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I.6 
Age  
  
Year 
  
 Month 
  
 Day 
I.7 
Address 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
I.8 
Phone Number 
  
  
  
  
  
  
  
  
  
  
I.9 
Gender 
  
Male 
  
Female 
I.10 
Job 
  
  
  
  
  
  
  
  
  
  
I.11 
Education 
  
No 
  
Junior HS 
  
University 


 
 
  
Elementary 
  
Senior HS 
I.12 
Funding 
  
Private 
  
National Insurance 
  
Insurance 
 
 
II 
Clinical outcomes 
II.1 
History 
Symptoms 
Dyspnea d'effort 
  
Paroxysmal nocturnal dyspnea 
  
Orthopnea 
  
Dyspepsia 
  
Leg edema 
  
Chest pain 
  
Palpitation 
  
Syncope 
  
Symptoms duration 
  
  
  
  
  
Past disease 
  
  
  
  
  
Family history of PAH 
  
yes 
  
No 
Other 
  
  


 
 
II.2 
Physical examination 
BW 
  Height 
  
BMI 
  
Cardiac 
S2 accentuation 
  
RV heaving 
  
Murmur 
  
Other 
  
Respiratory 
rales 
  
Abdomen 
ascites 
  
hepatomegaly 
  
Extremity 
Pitting edema 
  
clubbing finger 
  
II.3 
Examination 
II.3.1 
EKG 
yes 
  
No 
  
Date 
  
  
  
Results  
Rhythm 
  
Axis 
  
P pulmonal 
  
RVH 
  
RBBB 
  
ST-T changes 
  


 
 
II.3.2 
Blood examination 
yes 
  
No 
  
Date 
  
  
  
Lactate dehydrogenase 
  
II.3.3 
Right Heart Cath 
yes 
  
No 
  
Date 
  
  
  
mPAP 
  
  
PARi 
  
  
PCWP 
  
  
 
PVR 
  
 
 
 
 
 
 
  
 
 
 
 
LA Pressure/LVEDP 
  
  
II.4 
Therapy 
PAH specific therapy 
PDE-5 inhibitor 
yes 
  
no 
  
Starting date 
  
  
  
Last dose 
  
  
  


 
 
beraprost 
yes 
  
no 
  
starting date 
  
  
  
last dose 
  
  
  
iloprost 
yes 
  
no 
  
starting date 
  
  
  
last dose 
  
  
  
endothelin-1 antagonist 
yes 
  
no 
  
starting date 
  
  
  
last dose 
  
  
  
Anticoagulant 
yes 
  
no 
  
Simarc 
yes 
  
no 
  
starting date 
  
  
  
last dose 
  
  
  
NOAC 
yes 
  
no 
  
starting date 
  
  
  
last dose 
  
  
  
Beta blocker 
yes 
  
no 
  
starting date 
  
  
  
last dose 
  
  
  
 


 
 
 
ACE-inhibitor 
yes 
  
no 
  
starting date 
  
  
  
last dose 
  
  
  
ARB 
yes 
  
no 
  
starting date 
  
  
  
last dose 
  
  
  
Others 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
III. 
Pre Therapy CMR 
Date 
  
  
  
Right Ventricle 
REDV 
  
  
  
RESV 
  
  
  
RVEF 
  
  
  
LGE 
  
  
  


 
 
Native T1 
  
  
  
LEDV 
  
  
  
LESV 
  
  
  
LVEF 
  
  
  
 
IV. 
Intervention  
Grup A 
  
Grup B 
  
1st  month visit 
Date 
  
  
  
Adverse event 
  
  
  
  
  
  
  
  
  
  
  
  
2nd month visit 
Date 
  
  
  


 
 
Adverse event 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
3rd Month visit 
Date 
  
  
  
Adverse event 
  
  
  
  
  
  
  
  
  
  
  
  
V. 
Post therapy intervention 
V.I 
 
Blood serum 
yes 
  
no 
  
 
 
 
 
 
 
 
 
Date 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
Kadar 
Satuan 
 
 
 
 
Creatinine serum 
 
 
 
 
 
 
Lactate dehydrogenase 
  
 
 
 
 


 
 
 
V.II 
CMR 
 
Date  
  
  
  
Right Ventricle 
REDV 
  
  
  
RESV 
  
  
  
RVEF 
  
  
  
LGE 
  
  
  
Native T1 
  
  
  
LEDV 
  
  
  
LESV 
  
  
  
LVEF