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TRIMETA-PH: The Role of Trimetazidine on Right Ventricle Function in Pulmonary Arterial Hypertension

Sponsor
Indonesia University (Other)
Overall Status
Completed
CT.gov ID
NCT03273387
Collaborator
(none)
26
Enrollment
1
Location
2
Arms
15.1
Actual Duration (Months)
1.7
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
26 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
The Role of Trimetazidine on Right Ventricle Function in Pulmonary Arterial Hypertension Patients in National Cardiovascular Center Harapan Kita Hospital Indonesia
Actual Study Start Date :
Sep 10, 2017
Actual Primary Completion Date :
Nov 1, 2018
Actual Study Completion Date :
Dec 14, 2018

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Sugar pill

The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy.

Drug: Placebo oral capsule
The participant will received placebo oral capsule bid for 3 months on top of their regular PAH specific therapy.
Other Names:
  • sugar pill

    		•
    Experimental: trimetazidine

    The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy.

    Drug: Trimetazidine
    The participant will received trimetazidine 35 mg bid for 3 months on top of their regular PAH specific therapy.
    Other Names:
  • Trizedon MR

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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 Outcome Measures

    1. 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.

    2. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 National Cardiovascular Center Harapan Kita Hospital Jakarta Indonesia 11420

    Sponsors and Collaborators

    • Indonesia University

    Investigators

    • Principal Investigator: Hary Sakti Muliawan, MD,PhD, Department Cardiology and Vascular Medicine Universitas Indonesia

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Hary Sakti Muliawan, MD, PhD, MD,PhD, Indonesia University
    ClinicalTrials.gov Identifier:
    NCT03273387
    Other Study ID Numbers:
    • LB.02.01/VII/172/KEP.009/2017
    First Posted:
    Sep 6, 2017
    Last Update Posted:
    Oct 3, 2019
    Last Verified:
    Sep 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Hypertension, Pulmonary
    Pulmonary Arterial Hypertension
    Hypertension
    Trimetazidine

    Study Results

    Participant Flow

    Recruitment Details Subjects were recruited from NCCHK PH outpatient clinic from September 2017 until November 2018
    Pre-assignment Detail 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.
    Arm/Group Title Sugar Pill Trimetazidine
    Arm/Group Description 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. 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.
    Period Title: Overall Study
    STARTED 13 13
    COMPLETED 10 10
    NOT COMPLETED 3 3

    Baseline Characteristics

    Arm/Group Title Sugar Pill Trimetazidine Total
    Arm/Group Description 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. 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. Total of all reporting groups
    Overall Participants 13 13 26
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    47
    (3.8)
    48
    (1.5)
    48
    (8.9)
    Sex: Female, Male (Count of Participants)
    Female
    11
    84.6%
    12
    92.3%
    23
    88.5%
    Male
    2
    15.4%
    1
    7.7%
    3
    11.5%
    Race/Ethnicity, Customized (Count of Participants)
    Asian
    13
    100%
    13
    100%
    26
    100%
    onset of diagnosis to study (days) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [days]
    1170
    (387)
    926
    (214)
    1048
    (1093)
    SF-36 Functional Capacity (units on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [units on a scale]
    61.15
    (4.77)
    46.54
    (5.44)
    53.84
    (19.56)
    WHO Functional Class (Count of Participants)
    WHO functional class II
    9
    69.2%
    4
    30.8%
    13
    50%
    WHO functional class III
    4
    30.8%
    9
    69.2%
    13
    50%
    Glomerular Filtration Rate (ml/min/1.73 m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ml/min/1.73 m^2]
    96.6
    (7.9)
    110.7
    (3.9)
    106
    (15.6)
    Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m^2]
    23.3
    (3.8)
    21
    (0.8)
    22.1
    (8.6)
    Phosphodiesterase-5 inhibitor (Count of Participants)
    Count of Participants [Participants]
    12
    92.3%
    12
    92.3%
    24
    92.3%
    Prostacyclin analogue (beraprost) (Count of Participants)
    Count of Participants [Participants]
    8
    61.5%
    5
    38.5%
    13
    50%
    beta blocker (Count of Participants)
    Count of Participants [Participants]
    5
    38.5%
    8
    61.5%
    13
    50%
    ACE-inhibitor (Count of Participants)
    Count of Participants [Participants]
    4
    30.8%
    5
    38.5%
    9
    34.6%
    Angiotensin receptor II blocker (Count of Participants)
    Count of Participants [Participants]
    4
    30.8%
    1
    7.7%
    5
    19.2%
    Warfarin (Count of Participants)
    Count of Participants [Participants]
    4
    30.8%
    6
    46.2%
    10
    38.5%
    spironolactone (Count of Participants)
    Count of Participants [Participants]
    9
    69.2%
    10
    76.9%
    19
    73.1%
    furosemide (Count of Participants)
    Count of Participants [Participants]
    11
    84.6%
    8
    61.5%
    19
    73.1%
    digoxin (Count of Participants)
    Count of Participants [Participants]
    1
    7.7%
    2
    15.4%
    3
    11.5%
    mean Right atrial pressure (mmHg) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mmHg]
    5.9
    (1.4)
    6
    (1.2)
    5.9
    (3.9)
    mean pulmonary arterial pressure (mmHg) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mmHg]
    62
    (5.9)
    59
    (3.6)
    60
    (11.2)
    LV end diastolic pressure (mmHg) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mmHg]
    7.2
    (1.2)
    7.8
    (0.8)
    7.4
    (3.1)
    RV end diastolic volume (ml) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ml]
    258
    (28)
    260
    (31)
    259
    (83)
    RV end systolic volume (ml) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ml]
    193
    (20)
    206
    (25)
    197
    (67)
    RV ejection fraction (%) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [%]
    24.5
    (2.8)
    21.1
    (4.4)
    22.4
    (10)
    LV end diastolic volume (ml) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ml]
    79
    (6.3)
    83
    (5.3)
    81
    (18)
    LV end systolic volume (ml) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ml]
    29
    (2.8)
    33
    (3.3)
    31
    (9.7)
    LV ejection fraction (%) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [%]
    64
    (2.6)
    59
    (2.4)
    62
    (7.5)
    Native T1 anteroseptal (ms) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ms]
    993
    (612)
    1354
    (441)
    1164
    (555)
    Native T1 septal (ms) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ms]
    1108
    (512)
    1110
    (411)
    1109
    (454)
    Native T1 inferoseptal (ms) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ms]
    930
    (418)
    1474
    (736)
    1187
    (637)
    Native T1 Lateral (ms) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ms]
    1090
    (470)
    1357
    (473)
    1216
    (478)

    Outcome Measures

    1. Primary Outcome
    Title Changes in Right Ventricular Ejection Fraction (RVEF %) After 3 Months Intervention
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Sugar Pill Trimetazidine
    Arm/Group Description 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. 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.
    Measure Participants 10 10
    Mean (Standard Error) [percentage of ejected blood]
    -2.8
    (1.6)
    3.9
    (1.5)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Sugar Pill, Trimetazidine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.008
    Comments 95% Confidence interval 1.97 - 11.3 statistical significant if p<0.05
    Method t-test, 2 sided
    Comments t=2.988 df=18
    2. Secondary Outcome
    Title Changes in Cardiac Fibrosis After 3 Months Intervention
    Description 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sugar Pill Trimetazidine
    Arm/Group Description 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. 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.
    Measure Participants 10 10
    Native T1 anteroseptal
    138
    (555)
    190
    (538)
    Native T1 Septal
    292
    (677)
    371
    (670)
    Native T1 Inferoseptal
    294
    (618)
    -123
    (645)
    Native T1 Lateral
    287
    (744)
    -194
    (487)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Sugar Pill, Trimetazidine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.33
    Comments statistical significant if p <0.05
    Method two-way ANOVA
    Comments DF=3
    3. Secondary Outcome
    Title Changes in Functional Capacity After 3 Month Intervention
    Description 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sugar Pill Trimetazidine
    Arm/Group Description 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. 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.
    Measure Participants 10 10
    Mean (Standard Error) [score on a scale]
    -17.73
    (3.72)
    11.5
    (5.27)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Sugar Pill, Trimetazidine
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments 95% Confidence interval 15.92 to 42.53 statistical significant if p <0.05
    Method t-test, 2 sided
    Comments t=4.598 df=19

    Adverse Events

    Time Frame three months for each intervention.
    Adverse Event Reporting Description safety population included all participants who received at least one dose of intervention.
    Arm/Group Title Sugar Pill Trimetazidine
    Arm/Group Description 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. 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.
    All Cause Mortality
    Sugar Pill Trimetazidine
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/13 (15.4%) 2/13 (15.4%)
    Serious Adverse Events
    Sugar Pill Trimetazidine
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/13 (15.4%) 2/13 (15.4%)
    Cardiac disorders
    Cardiovascular mortality 2/13 (15.4%) 2 2/13 (15.4%) 2
    Other (Not Including Serious) Adverse Events
    Sugar Pill Trimetazidine
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/13 (7.7%) 2/13 (15.4%)
    Gastrointestinal disorders
    nausea 0/13 (0%) 0 1/13 (7.7%) 1
    Musculoskeletal and connective tissue disorders
    musculoskeletal angina 0/13 (0%) 0 1/13 (7.7%) 1
    Nervous system disorders
    paresthesia 1/13 (7.7%) 1 0/13 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title dr. Bambang WIdyantoro, FIHA, PhD
    Organization Department of Cardiology and Vascular Medicine, Universitas Indonesia
    Phone +628128164299
    Email bambang_ui@yahoo.com
    Responsible Party:
    Hary Sakti Muliawan, MD, PhD, MD,PhD, Indonesia University
    ClinicalTrials.gov Identifier:
    NCT03273387
    Other Study ID Numbers:
    • LB.02.01/VII/172/KEP.009/2017
    First Posted:
    Sep 6, 2017
    Last Update Posted:
    Oct 3, 2019
    Last Verified:
    Sep 1, 2019