| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| heart failure caused by heart attacks |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077980 |
| E.1.2 | Term | Chronic systolic heart failure |
| E.1.2 | System Organ Class | 100000004849 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Trial 1: (1) Primary: (1) to assess the effect of shockwave energy and pulse number on the cardiac-to-peripheral blood gradients of high-throughput cytokine panel (minimum SDF1, MCP1, VEGF, substance P) and (2) patients’ safety and tolerability to treatments.
Trial (2): Primary: 1) to assess whether there is a change in EF as assessed using Cardiac MRI from baseline to end of trial period compared to controls.
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|
| E.2.2 | Secondary objectives of the trial |
| Trial 1: Secondary: (1) composite cardiac events [MACEs]: death and mode of death, rehospitalisation for worsening heart failure, recurrent myocardial infarction, sustained ventricular tachycardia, revascularization, and stroke, (2) to assess whether there is any change in cardiac imaging parameters (eg. EF, global and segmental strain parameters, MRI mapping of tissue characteristics, scar, perfusion) of baseline compared to end of 16-weeks period and at end of second cycle, (3) change the CD immunophenotypes of the marrow progenitors before and after shockwave treatments, (4) to assess whether the addition of DPP-IV inhibitor to shockwave treatment will release more marrow progenitors, (5) to assess whether the addition of PTH to DPP-IV inhibitor will release more marrow progenitors than DPP-IV inhibitor to shockwave treatment alone (6) the influence of infarct transmurality (segmental phenotype on production of secretomes, (7) assess cardiopulmonary exercise parameters: VO2max and V |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a) Age: 25-70 years old
b) Gender: male or female
c) Evidence of coronary artery disease with ejection fraction of <40%
d) Patient no longer benefit from standard revascularisation procedure
e) Agree to implantable venous catheter line insertion
f) Agree to take DPP4 inhibitor
g) Agree to peripheral mobilisation using PTH of stem cells
h) Agree to shockwave treatment
i) Must be available throughout the study period
j) Must able to give consent
k) Any other inclusion criteria that the investigators deem suitable that
not apparent during the drafting of the protocol |
|
| E.4 | Principal exclusion criteria |
a)Females of childbearing potential and males must be willing to use an
effective method of contraception (hormonal or barrier method of birth
control; abstinence) from the time consent is signed until 6 weeks after
treatment discontinuation. Double contraception is advised.
b)Females of childbearing potential must have a negative pregnancy test
within 7 days prior to being registered for trial treatment. NOTE:
Subjects are considered not of child bearing potential if they are
surgically sterile (i.e. they have undergone a hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
c) Females must not be breastfeeding.
d) Have contraindications to trial treatment or incompatible concurrent
treatments (as listed in SmPc).
e) Recent involvement in other research.
f) Allergies to excipients of IMP
g) Cardiac thrombus
h) Have contraindications for MRI
i) Malignancy
j) Severe COPD
k) Unstable coronary artery disease
l) Unstable cardiac arrhythmia
m) Severe renal impairment
n) Severe liver failure
o) Severe valvular disease
p) Autoimmune disease
p) Alcohol abuse
q) Drugs abuse
r) Smoking
s) Unwilling to use contraception during study period
t) Life expectancy less than a year
u) Active participation in other clinical trial
v) Any other criteria that the investigators deem not suitable that not apparent the drafting of the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary outcomes
• Trial 1: (1) The abundance of blood cytokines/proteins (minimum of SDF1, VEGF, MCP1 & substance P) in the cardiac venous blood and peripheral blood, and their difference (gradients), taken before and after shockwave treatments will be taken for analysis in a continuous form.
• Trial 1: Safety and tolerability to treatments will be assessed by examining the frequency and severity of adverse events (AEs). It will be taken for analysis in a categorical form.
Trial (2): The change in EF at baseline, end of cycle 1 and end of cycle 2. It will be taken for analysis in a continuous form. If, after Trial 1, index GLS validated and found superior for assessment of global systolic function and satisfy the statistical power requirement, it may be used instead of EF and EF will be a secondary outcome.
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Trial 1: The concentration of cytokines over time will be plotted on a graph. The optimum times for SDF1, VEGF, MCP1 & substance P release are not yet known.
Trial 2: At baseline, week 16 and week 32. |
|
| E.5.2 | Secondary end point(s) |
Trial (1):
- Any major cardiac events (MACEs): events death and mode of death, rehospitalisation for worsening heart failure, recurrent myocardial infarction, ventricular tachycardia, revascularization, and stroke. It will be taken for analysis in categorical form.
- any change in cardiac imaging parameters (eg. EF, regional strain, strain rate, global longitudinal strain, MRI mapping of tissue characteristics, scar, perfusion) of baseline compared to end of 16-week and 32-week. It will be taken for analysis in a continuous form.
- Rise in other proteins (secretomes): It will be taken for analysis in a continuous form.
- Rise in the CD immunophenotypes of the marrow progenitors before and after shockwave treatments. It will be taken for analysis in a continuous form.
- Rise in marrow progenitors after the addition of DPP-IV inhibitor to shockwave treatment will release more. It will be taken for analysis in a continuous form.
- Rise in marrow progenitors after the addition of PTH to DPPIV inhibitor than DPP-IV inhibitor to shockwave treatment alone. It will be taken for analysis in a continuous form.
- the influence of infarct transmurality (segmental phenotype) on production of SDF1-a. It will be taken for analysis in a continuous form.
- Assess cardiopulmonary exercise parameters: VO2max and VE/VCO2 slope. It will be taken for analysis in a continuous form.
- Improvement in NT-ProBNP. It will be taken for analysis as a continuous form.
Trial 2:
- Safety and tolerability to treatments will be assessed by examining the frequency and severity of adverse events (AEs). It will be taken for analysis in a categorical form.
- Any major cardiac events (MACEs): events death and mode of death, rehospitalization for worsening heart failure, recurrent myocardial infarction, ventricular tachycardia, revascularization, and stroke. It will be taken for analysis in categorical form.
- Any change in other cardiac imaging parameters (regional strain, strain rate, global longitudinal strain, scar, perfusion). It will be taken for analysis in a continuous form.
-Change in cardiopulmonary exercise parameters from baseline to end of 32 week period compared to control. It will be
taken for analysis in a continuous form.
- Change in symptoms and quality of life from baseline to end of 32 week period compared to controls. It will be taken for
analysis in a categorical form.
- Improvement in NT-ProBNP. It will be taken for analysis as a continuous form.
- The abundance of blood cytokines/proteins in the cardiac venous blood and peripheral blood, and their difference, marrow
progenitors, as described in Trial 1, will be taken before and after shockwave treatments will be taken for analysis in a continuous form.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-At baseline, week 16 and week 32 for CMR, CPET, MLHFQ for both trial 1 and cohort B in trial 2
-At baseline and end of week 32 for CMR, detail echo, CPET and MLHFQ for cohort A in trial 1
-At baseline and every 4 weeks until end of 32 weeks later for detail echocardiogram for both trial 1 and 2 (cohort B)
-For AE & MACEs anytime during the 32 week period of study for both trial 1 and 2
-At baseline, week 16 and week 32 for CMR, detail echo and CPX in cohort A of trial 2.
-Proteins concentration over time plot. The optimum time for protein release is not yet known.
-Seattle Angina Questionnaire at least 4 weekly for all. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| We will consider the trial complete when all patients have completed their visits, all laboratory analyses have been performed, the data entered into a database and checked (i.e. database lock) and research papers published. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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