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CompletedNCT03273387TRIMETA-PHUpdated Oct 3, 2019Results posted

The Role of Trimetazidine on Right Ventricle Function in Pulmonary Arterial Hypertension

A Phase 2/3 interventional study of Trimetazidine and Placebo oral capsule in Precapillary Pulmonary Hypertension, sponsored by Indonesia University. Completed at 1 site in Indonesia. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2019-10-03.

Sponsored by Indonesia University · Phase 2/3, Interventional, and Treatment

Phase
Phase 2/3
Study type
Interventional
Enrollment
26
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Precapillary Pulmonary Hypertension
03

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Pre-capillary Pulmonary Hypertension patients assessed by right heart catheterization
  • Signed informed consent

Exclusion criteria

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
04

Study design

Phase
Phase 2 / Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
26 participants (actual)

Study arms

  • 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

  • Experimental
    trimetazidine

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

    Drug: Trimetazidine

Interventions

  • DrugTrimetazidine

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

    Also known as: Trizedon MR

  • DrugPlacebo oral capsule

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

    Also known as: sugar pill

05

What researchers measure

Primary outcomes

  1. 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

Secondary outcomes

  1. 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

  2. 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

06

Results

Posted Oct 3, 2019

Participant flow

Subjects were recruited from NCCHK PH outpatient clinic from September 2017 until November 2018

Participant flow — Overall Study
MilestoneSugar PillTrimetazidine
Started1313
Completed1010
Not completed33
Withdrew: Death22
Withdrew: Withdrawal by subject11

Outcome measures

PrimaryChanges 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
Reported as:
Mean · percentage of ejected blood
Changes in Right Ventricular Ejection Fraction (RVEF %) After 3 Months Intervention
percentage of ejected bloodSugar PillTrimetazidine
Changes in Right Ventricular Ejection Fraction (RVEF %) After 3 Months Intervention-2.8 ± 1.63.9 ± 1.5
Statistical analysis
  • Sugar Pill vs Trimetazidine · t-test, 2 sided · p = 0.008 (95% Confidence interval 1.97 - 11.3 statistical significant if p\<0.05)t=2.988 df=18
SecondaryChanges 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
Reported as:
Mean · ms
Changes in Cardiac Fibrosis After 3 Months Intervention
msSugar PillTrimetazidine
Native T1 anteroseptal138 ± 555190 ± 538
Native T1 Septal292 ± 677371 ± 670
Native T1 Inferoseptal294 ± 618-123 ± 645
Native T1 Lateral287 ± 744-194 ± 487
Statistical analysis
  • Sugar Pill vs Trimetazidine · two-way ANOVA · p = 0.33 (statistical significant if p \<0.05)DF=3
SecondaryChanges 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
Reported as:
Mean · score on a scale
Changes in Functional Capacity After 3 Month Intervention
score on a scaleSugar PillTrimetazidine
Changes in Functional Capacity After 3 Month Intervention-17.73 ± 3.7211.5 ± 5.27
Statistical analysis
  • Sugar Pill vs Trimetazidine · t-test, 2 sided · p = 0.0002 (95% Confidence interval 15.92 to 42.53 statistical significant if p \<0.05)t=4.598 df=19

Adverse events

Collected over three months for each intervention.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Sugar Pill2/13 (15.4%)2/13 (15.4%)1/13 (7.7%)
Trimetazidine2/13 (15.4%)2/13 (15.4%)2/13 (15.4%)
Most frequent serious events
Most frequent serious events
EventSugar PillTrimetazidine
Cardiovascular mortalityCardiac disorders2/132/13
Most frequent other events
Most frequent other events
EventSugar PillTrimetazidine
paresthesiaNervous system disorders1/130/13
nauseaGastrointestinal disorders0/131/13
musculoskeletal anginaMusculoskeletal and connective tissue disorders0/131/13

Baseline characteristics

Age, Continuous
Age, Continuous(years)Sugar PillTrimetazidineTotal
Mean47 ± 3.848 ± 1.548 ± 8.9
Sex: Female, Male
Sex: Female, Male(Participants)Sugar PillTrimetazidineTotal
Female111223
Male213
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Sugar PillTrimetazidineTotal
Asian131326
onset of diagnosis to study
onset of diagnosis to study(days)Sugar PillTrimetazidineTotal
Mean1170 ± 387926 ± 2141048 ± 1093
SF-36 Functional Capacity
SF-36 Functional Capacity(units on a scale)Sugar PillTrimetazidineTotal
Mean61.15 ± 4.7746.54 ± 5.4453.84 ± 19.56
WHO Functional Class
WHO Functional Class(Participants)Sugar PillTrimetazidineTotal
WHO functional class II9413
WHO functional class III4913
Glomerular Filtration Rate
Glomerular Filtration Rate(ml/min/1.73 m^2)Sugar PillTrimetazidineTotal
Mean96.6 ± 7.9110.7 ± 3.9106 ± 15.6
Body Mass Index
Body Mass Index(kg/m^2)Sugar PillTrimetazidineTotal
Mean23.3 ± 3.821 ± 0.822.1 ± 8.6

22 further baseline measures are reported on the registry.

07

Study locations

1 site
  • National Cardiovascular Center Harapan Kita Hospital
    Jakarta, 11420, Indonesia
08

References and documents

Study documents

  • Protocol and statistical analysis plan · Sep 10, 2017
  • Informed consent form · Sep 10, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT03273387
Lead sponsor
Indonesia University
Responsible party
Hary Sakti Muliawan, MD, PhD (MD,PhD, Indonesia University) — Principal investigator
First posted
Sep 6, 2017
Start date
Sep 10, 2017
Primary completion
Nov 1, 2018
Completion
Dec 14, 2018
Results posted
Oct 3, 2019
Last update
Oct 3, 2019

Study contacts

Hary Sakti Muliawan, MD,PhD
principal investigator · Department Cardiology and Vascular Medicine Universitas Indonesia

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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