Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT02502747 |
| Other study ID # |
RIGENERA 2.0 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
January 2020 |
| Est. completion date |
December 2021 |
Study information
| Verified date |
March 2022 |
| Source |
Catholic University of the Sacred Heart |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Study Objectives: To determine whether, in patients with large acute myocardial infarction
undergoing primary or rescue angioplasty, the administration of subcutaneous Lenograstim
[recombinant human Granulocyte-Colony Stimulating Factor (rhu G-CSF), Myelostim 34,
Italfarmaco] associated with Myocardial Contrast Echocardiography and the intravenous
infusion of sulphur hexafluoride (Sonovue, Bracco) determines an improvement:
- in regional and global contractile function, myocardial perfusion and infarct size
assessed by cardiovascular magnetic resonance.
- Echocardiographic parameters of LV function
- in the serum profile of inflammatory and mobilizing cytokines and of biomarkers of
myocardial damage and wall stress
Description:
1. INTRODUCTION 1.1. BACKGROUND AND RATIONALE OF THE STUDY The long term prognosis of
patients suffering from acute myocardial infarction (AMI) has progressively improved
since the introduction of reperfusion therapies and in particular primary angioplasty
[1]. In the setting of ST-elevation myocardial infarction (STEMI), the immediate
reopening of acutely occluded coronary arteries via primary angioplasty is the treatment
of choice to salvage ischemic myocardium. However, the sudden re-initiation of blood
flow can lead to a local acute inflammatory response with further endothelial and
myocardial damage. This phenomenon, described as 'reperfusion injury', may explain why,
despite optimum myocardial reperfusion, the short-term mortality after AMI approaches 7%
[1] and the incidence of heart failure approaches 15-20% [2][3]. Despite the use of full
conventional treatment, including ACE inhibitors, beta-blockers, aldosterone inhibitors
and diuretics, in the context of randomised controlled trials yearly mortality rates of
patients with post-infarction heart failure are still in the range of 10-13% and
rehospitalisation for worsening of heart failure occurs at a yearly rate of 6-8 % [4].
Registry data indicate a more dismal outcome in real world clinical experience. A major
reason for the high morbidity and mortality is that the heart has an inadequate
regenerative response to the myocardial necrosis sustained following AMI; cell death
from the ischemic damage can lead to progressive ventricular dilation and dysfunction
through the processes of adverse left ventricular remodelling. However, the discovery of
tissue resident cardiac stem cells in the mammalian heart [5] has challenged the long
held belief that the heart is a terminally-differentiated organ and opens up the
possibility of using bone marrow derived stem cells to repair the heart. Indeed, recent
experimental studies documented that bone marrow-derived cell (BMC) injection into the
infarcted heart stimulates the formation of newly formed cardiac myocytes, although the
origin of these myocytes is still a matter of debate[6]. Numerous pre-clinical studies
provided high degree of evidence that bone marrow derived cells do contribute to cardiac
repair after acute myocardial injury, limit infarct expansion and improve cardiac
function most likely via a paracrine mechanism of action. Pre-clinical evidence is
corroborated by several small to intermediate size clinical trials demonstrating
beneficial effects of bone marrow derived cells on top of the state-of-the-art
reperfusion treatment [7]. For this reason, European Community has recently funded
within FP-7 "The effect of intracoronary reinfusion of bone marrow derived mononuclear
cells (BM-MNC) on all cause-mortality in acute myocardial infarction (BAMI)" project
aimed to definitively demonstrate the efficacy of BM-MNC in patients with myocardial
infarction.
Considering that recovery of post-infarction LV function is favourably correlated to
bone marrow derived stem cell mobilization induced by endogenous Granulocyte-Colony
Stimulating Factor (G-CSF) [8-9], therapeutic stem cell mobilization was proposed as an
alternative method to ameliorate post-infarction LV function. Several basic studies have
supported this notion suggesting that stem cell mobilization might improve LV function
by increasing stem cell homing in the damaged myocardium in addition to a favourable
direct effect of G-CSF on LV myocardium [10-12].
On these bases several studies have evaluated the effect of G-CSF on LV function in
patients with myocardial result with mixed results [13]. In general, G-CSF was proven
safe but the effect appeared modest. However, in patients with large myocardial
infarction the effect was significant and clinically relevant approaching a 5% increase
in LVEF. In particular in the Rigenera Trial conducted at the Catholic University of the
Sacred Heart of Rome 41 patients with large anterior wall AMI at high risk of
unfavorable remodeling were randomized 1:2 to Lenograstim (rhu G-CSF, Myelostim 34,
Italfarmaco) (10 μg/kg/day for 5 days) or to conventional therapy. After a median
follow-up of 5 months patients treated with Lenograstim exhibited improvement of 5% in
LVEF, in the absence of LV dilation. In contrast, patients treated conventionally
exhibited significant LV dilation in the absence of an improvement in LVEF [14]. In the
present study, a subgroup of 8 patients randomized to Lenograstim received also the
administration of a second-generation ultrasound contrast agent containing sulphur
hexafluoride (SonoVue®, Bracco, Milan, Italy) administered intravenously (5 ml at 1
ml/min) for myocardial opacification to collect diagnostic images by Myocardial Contrast
Echocardiography. Interestingly, a post hoc analysis, revealed that only patients
receiving Sonovue® showed a significant benefit on LV function [unpublished data]. This
could be due to an increased homing effect of mobilized bone marrow derived stem cells
due to the myocardial destruction of contrast medium-microbubbles by 3.5 MHz ultrasounds
produced by the Echo machine. As this regard, two basic studies demonstrated that the
highly focused ultrasound-mediated stimulation of microbubbles increased the migration
of stem cells across the myocardial endothelium into the post-ischemic myocardium in
vivo [15-16]. Moreover, long term (10 years) follow up data of the RIGENERA trial have
been recently collected, confirming the safety of the procedure and a significant
improvement of the quality of life assessed by NYHA functional class, Seattle Heart
Failure Model, Minnesota Living with Heart Failure Questionnaire (p<0.005) when
compairing patients treated with G-CSF versus standard therapy. Data regarding efficacy,
in terms of LVEF, end-diastolic volume and end-systolic volume are currently under
analysis.
On the basis of the previous results, The Recupero dall'Infarto miocardico con G-CSF E
Nuovi Esempi di Rigenerazione Avanzata (RIGENERA 2.0) trial will specifically test the
efficacy of the combined effect of subcutaneous Granulocyte - Colony Stimulating Factor
and sulphur hexafluoride on post-infarction left ventricular function.
1.2 BENEFIT-RISK ASSESSMENT In every clinical trial, anticipated benefits need to be
weighed against the study associated risks. In previous investigations where G-CSF has
been used, no G-CSF associated adverse reactions were reported. Only the MAGIC trial was
prematurely stopped due to possible safety concerns in treated patients in terms of an
unexpectedly high restenosis rate in stented vessels [17]. However, only three patients
in the G-CSF group received angiographic follow-up, thus no clear conclusion about the
incidence of restenosis should have reasonably be drawn from this study. In all other
studies using G-CSF adverse events were comparable between patients and controls [13].
Nevertheless G-CSF is largely used in oncology for treatment of febrile neutropenia and
in hematology for this indication and for mobilization of stem cells for
transplantation. As this regard G-CSF is considered reasonably safe without any
association with a documented increase in malignancies [18].
SonoVue has been shown to be safe and well tolerated with minimal risk to patients. In
clinical trials, the overall incidence of adverse events was relatively low (10.7%
overall, 5.2% investigational product-related) in subjects receiving SonoVue. The most
frequently reported adverse events were headache (2.1%), nausea (0.9%), chest pain
(0.8%), and chest discomfort (0.5%). All other adverse events occurred at a frequency of
<0.5%. Most adverse events were mild and resolved spontaneously within a short time
without sequelae. Serious adverse events occurred in 0.43% of patients and only 0.08% of
events were considered to be of some relationship to the administration of SonoVue
(probable, possible, or unlikely). No product- related deaths were reported within
MAH-sponsored trials.
The anticipated benefits of RIGENERA 2.0 trial for study participants are expected
better LV function, a parameter that is well-known to influence long-term outcome.
Nevertheless, chiefs of the different Units involved in the present study will form a
Data Monitoring Committee that will stop the study in case of an observed increase in
the rate of adverse events.
2. STUDY OBJECTIVES 2.1. PRIMARY OBJECTIVE Primary efficacy endpoint
• Left ventricular ejection fraction (LVEF) at 6 months assessed by Cardiac Magnetic
Resonance and centrally reviewed
Secondary efficacy endpoints:
- Left ventricular end-diastolic volume (LVEDV) assessed by Cardiac Magnetic
Resonance at 6 months at 6 months and centrally reviewed
- Left ventricular end-systolic volume (LVEDV) assessed by Cardiac Magnetic Resonance
at 6 months and centrally reviewed
- Left ventricular ejection fraction (LVEF) assessed by 2D Echocardiography at 6
months and centrally reviewed
- Left ventricular end-diastolic volume (LVEDV) assessed by 2D Echocardiography at 6
months and centrally reviewed
- Left ventricular end-systolic volume (LVEDV) assessed by 2D Echocardiography at 6
months and centrally reviewed
- Incidence of clinical major adverse events (death, myocardial infarction, sustained
cardiac arrhythmias, cardiogenic shock, stroke and rehospitalization due to heart
failure at 1 year).
Safety endpoints:
• Incidence of new neoplastic and hematological diseases
3. OVERALL DESIGN AND PLAN OF THE STUDY 3.1. OVERVIEW OF STUDY FLOW The RIGENERA 2.0 trial
is a phase II placebo-controlled, randomized, open label, with Blinded Evaluation of
end-points. One hundred and twenty STEMI patients are planned to be enrolled in 4
Italian centers (Rome - Catholic University of the Sacred Heart, Ferrara, Pisa and
Padua). Patients with an acute ST-elevation myocardial infarction as defined by the
universal definition of AMI undergoing acute revascularization (i.e. either acute PCI
within 24 hours of symptom onset or thrombolysis within 12 hours followed by acute PCI
within 24 hours of symptom onset) will be screened at investigational sites. Patients
who had acute PCI at institutions different from the investigational sites (recruiting
centers) can also be included: interested patients may be referred for screening to any
of the participating study sites within 3 to 4 days. Informed consent and assessment of
eligibility of patients with respect to in- and exclusion criteria will be done at the
recruiting centers. If all other eligibility criteria are met, echocardiography will be
performed 3 to 6 days after the acute PCI and ejection fraction will be quantified. In
case of LVEF≤45% the patient will be 1:1 electronically randomized to G-CSF and MCE or
placebo and MCE according to site. Patients will be randomized to receive either
subcutaneous Granulocyte - Colony Stimulating Factor (group 1) or Placebo (group 2) both
added on top of optimal standard of care and Myocardial Contrast Echocardiography with
intravenous infusion of sulphur hexafluoride.
Lenograstim (rhu G-CSF, Myelostim 34, Italfarmaco) (5 µg/kg twice daily for 5 days,
subcutaneously) or placebo (saline solution twice daily for 5 days, subcutaneously) will be
administered at least 5 days after admission.
Both in patients treated with Lenograstim (rhu G-CSF, Myelostim 34, Italfarmaco) and in
patients treated with placebo, immediately before the first dose of Lenograstim (rhu G-CSF,
Myelostim 34, Italfarmaco) or placebo and in the morning of the last day of treatment in
which the peak of BMSC mobilization is expected, an echocardiogram using an echocardiographic
contrast agent (Sonovue, Bracco) will be performed. In the days of administration of the drug
or placebo, ECG, blood pressure, blood count and coagulation analyses will be monitored.
In the case of muscle and bone pain or severe headache patients will be treated with
paracetamol.
In the case of leukocytosis (> 40000/mcl) dose of G-CSF in 24 hours will be halved and in the
case of leukocytosis (> 70000/mcl) completely stopped.
After hospital discharge, all study patients will return to the clinical centre for a follow
up visit after 30 days. Six months after randomization all the patients will undergo
outpatient Cardiac Magnetic Resonance and Conventional Echocardiography. At the same time,
all patients will undergo Myocardial Contrast Echocardiography. At 1 year all patients will
attend a final site visit at the clinical centers collecting any clinical event. However, all
clinical endpoints will be reported as occurring throughout the follow up. Clinical Major
adverse cardio-cerebrovascular events (death, myocardial infarction, stroke and
re-hospitalization due to heart failure) at 1 year will be adjudicated by a clinical event
committee blinded to the patient treatment allocation. This will ensure a consistent and
unbiased adjudication of events across all investigational sites.
3.2. STUDY POPULATION 3.2.1. Number of patients A total of approximately 120 male and female
patients are planned to be enrolled in the RIGENERA 2.0 trial. Enrolment will involve 4
Italian centres (Roma, Pisa, Ferrara, Padua). Recruiting centres will keep a log of all
patients proposed to be included.
3.2.2. Inclusion criteria
1. Signed and dated informed consent
2. Men and women of any ethnic origin aged ≥ 18 years
3. Patients with acute ST-elevation myocardial infarction as defined by the universal
definition of AMI.
4. Successful acute reperfusion therapy (residual stenosis visually <50% and TIMI flow ≥2)
within 24 hours of symptom onset or thrombolysis within 12 hours of symptom onset
followed by successful percutaneous coronary intervention (PCI) within 24 hours after
thrombolysis
5. Left ventricular ejection fraction ≤ 45% with significant regional wall motion
abnormality assessed by quantitative echocardiography 3 to 6 days after reperfusion
therapy
3.3.3. Exclusion criteria
1. Participation in another clinical trial within 30 days prior to randomization
2. Pregnant or nursing women or women in childbearing age not able to esclude the
possibility of a pregnancy
3. Mental condition rendering the patient unable to understand the nature, scope and
possible consequences of the study or to follow the protocol
4. Necessity to revascularize additional vessels, outside the target coronary artery after
investigational therapy/placebo administration (additional revascularizations after
primary PCI and before investigational therapy/placebo administration are allowed)
5. Persistent cardiogenic shock
6. Known hematologic and neoplastic diseases
7. Severe impaired renal function, i.e. eGFR<30 ml/min
8. Persistent fever or diarrhoea not responsive to treatment within 4 weeks prior screening
or severe infection
9. Uncontrolled hypertension (systolic >180 mmHg and diastolic >120 mmHg)
10. Life expectancy of less than 2 years from any non-cardiac cause or neoplastic disease
4. STUDY CONDUCT 4.1. SCHEDULE OF PROCEDURES The schedule of study assessment is listed in
Table 1. Screening Days -6 to - 3 Randomization Treatment Day 0 to 5 Recovery Day 5 to 10 1
month 4-6 Months Informed Consent X Demographics X Medical History X Killip Class X X X NYHA
Class X X X Physical Examination X X X Vital Signs (BP and HR) X X X ECG X X X Safety
Laboratory X X (daily) X X X Concomitant Medications X X X Adverse Event / Endpoint
Collection X X X X Echocardiography+ X X Magnetic Resonance X X Recommended but optional
Bloods (see below) X X X Urine Pregnancy test(where applicable) X X X Investigational therapy
X X
♦Recommended but optional Bloods Screening:
Hematology: Red blood count, white blood count Biochemistry and enzymes: serum urea, serum
uric acid, glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvate transaminase (GPT),
lactate dehydrogenase (LDH), total cholesterol, low density lipoprotein cholesterol (LDL),
high density lipoprotein cholesterol (HDL), triglycerides, glycosylated hemoglobin (HbA1c)
Electrolytes: sodium, potassium Cardiac marker: Creatine kinase (CK), Creatine kinase
muscle-brain (CK-MB), (high sensitive) troponin T or I Coagulation: International Normalised
Ratio (INR) Hematology: hemoglobin, hematocrit, red blood count, white blood count, platelets
Biochemistry and enzymes: serum urea, serum uric acid, GOT, GPT, LDH, total cholesterol,
LDL-cholesterol., HDL-cholesterol, triglycerides, HbA1C Electrolytes: sodium, potassium
Cardiac marker: CK, CK-MB, (high sensitive) troponin T or I Coagulation: INR
4.2. PATIENT SCREENING AND RANDOMISATION Patients will be recruited based on the existing
medical information from the pool of AMI patients at the clinical centres. Patients who had
the primary PCI performed at clinical centres that are different from the recruiting centre
can also be included: interested patients may be referred for screening to any of the
participating study sites within 3 to 4 days. Informed consent and assessment of eligibility
of patients with respect to inclusion and exclusion criteria will be done at the recruiting
centre. Written informed consent must be obtained from patients prior to any study specific
procedures. After consenting, patients undergo the procedures listed for the screening visit.
After ensuring that a patient meets all other eligibility criteria, the investigator will
perform the echocardiography and an electronic record of the echocardiography will be kept
and transferred to the central Echocardiography Core Laboratory for following analyses. After
local quantification of left ventricular ejection fraction, randomisation will be allowed for
all patients with LVEF ≤ 45%. At randomization a patient number that will be used as the key
identifier for the entire study period, will be supplied. Patients will be randomised to
investigational therapy or placebo in a 1:1 ratio. Patients with a LVEF > 45% will not be
randomised, but will be classified as screening failures. Patients randomised but not treated
will be replaced. Patients who discontinue the study after treatment, will not be replaced.
4.3. DESCRIPTION OF STUDY ASSESSMENTS 4.3.1. Medical history / demographics A complete
medical history will be obtained from each patient at the screening visit. Demographics,
including gender, age and ethnic origin, and the smoking status will be recorded.
4.3.2. Killip Class
Patients will be ranked according to the Killip Class status. Definitions of the grading
system are as follows:
Class I: Absence of rales over the lung fields and absence of S3. No heart failure. No
clinical signs of decompensation.
Class II: Rales over 50% or less of the lung fields or the presence of an S3. Heart failure.
Diagnostic criteria include rales, S3 gallop and venous hypertension.
Class III: Rales over more than 50% of the lung fields. Severe heart failure. Frank pulmonary
edema.
Class IV: Cardiogenic shock. Hypotension (a systolic blood pressure of less than 90 mmHg for
at least 30 minutes or the need for supportive measures to maintain a systolic blood pressure
of greater than or equal to 90 mmHg), end-organ hypoperfusion (cool extremities or a urine
output of less than 30 ml/h, and a heart rate of greater than or equal to 60 beats per
minute). The hemodynamic criteria are a cardiac index of no more than 2.2 l/min per square
meter of body-surface area and a pulmonary capillary wedge pressure of at least 15 mmHg.
Signs include hypotension (systolic pressure < 90 mm Hg) and evidence of peripheral
vasoconstriction such as oliguria, cyanosis and diaphoresis. Heart failure, often with
pulmonary oedema, has also been present in the majority of these patients.
4.3.3. Physical examination All patients will undergo standard or abbreviated physical
examinations. The standard examination is based on the following body systems: body
temperature, HEENT (head, eyes, ears, nose, throat), respiratory system, cardiovascular
system, abdomen, extremities, neurological system. The abbreviated physical examination
consists of body temperature, respiratory system, cardiovascular system, and lymph nodes. The
body weight will be determined at each physical examination. The body height will be obtained
at screening only.
4.3.4. Vital signs Blood pressure and heart rate at rest will be determined using a standard
method.
4.3.5. Electrocardiography A 12 lead electrocardiogram (ECG) will be recorded. ECGs will be
recorded while the patient is resting in supine position. Abnormal findings in ECG recordings
will be documented and the clinical relevance will be judged. A de-identified copy of the
baseline ECG will be digitally stored.
4.3.6. Clinical laboratory Blood sampling and sample analysis will be performed at the
clinical centre. The local investigator is responsible for proper judgment of abnormal blood
test results, and is responsible for appropriate patient care following clinically
significant pathological results. Please refer to section 6.4.5 to determine whether an
abnormal laboratory value may constitute an adverse event.
The following analysis will be obtained at screening, daily during the five days of treatment
(from day 0 to day 5) and at 5, 30 and 180 days:
Screening:
Hematology: Hemoglobin, hematocrit, Red blood count, white blood count, platelets
Biochemistry: Serum creatinine, serum urea, serum uric acid, glutamic-oxaloacetic
transaminase (GOT), glutamic-pyruvate transaminase (GPT), lactate dehydrogenase (LDH), total
cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol
(HDL), triglycerides, glycosylated hemoglobin(HbA1c), Creatine kinase (CK), Creatine kinase
muscle-brain(CK-MB), high sensitive troponin T hs-TnT, Vascular Endothelial Growth Factor
(VEGF), Insulin Growth Factor 1 (IGF-1), hepatocyte Growth Factor (HGF), Stromal Derived
Factor 1 alpha (SDF-1 alpha) Urine: Pregnancy test for woman of childbearing potential
Coagulation: Prothrombin Time (PT), International Normalised Ratio (INR), activated partial
thromboplastin time (aPTT) 4.3.7. Concomitant medications All patients participating in the
trial should receive treatment according to evidence based guidelines. Concomitant
medications will be recorded throughout the study.
4.3.8. Standard Echocardiography A resting echocardiogram at enrollment and at 4-6 months
will be recorded and digitally stored. See details in 5.3.1 Only if the patient qualifies
with LVEF ≤ 45% in the local reading, the patients will be randomised
4.3.9. Investigational therapy/placebo Lenograstim (rhu G-CSF, Myelostim 34, Italfarmaco) (5
µg/kg twice daily for 5 days, subcutaneously) or placebo (saline solution twice daily for 5
days, subcutaneously) will be administered at least 5 days after admission.
Both in patients treated with Lenograstim (rhu G-CSF, Myelostim 34, Italfarmaco) and in
patients treated with placebo, immediately before the first dose of Lenograstim (rhu G-CSF,
Myelostim 34, Italfarmaco) or placebo and in the morning of the last day of treatment in
which the peak of BMSC mobilization is expected, an echocardiogram using an echocardiographic
contrast agent (Sonovue, Bracco) will be performed in the days of administration of the drug
or placebo, ECG, blood pressure, blood count and coagulation analyses will be monitored.
In the case of muscle and bone pain or severe headache patients will be treated with
paracetamol.
In the case of leukocytosis (> 40000/mcl) dose of G-CSF in 24 hours will be halved and in the
case of leukocytosis (> 70000/mcl) completely stopped.
Patients will be safely discharged on the basis of laboratory data.
4.4. DURATION OF THE STUDY 4.4.1. Study duration for study patients Each enrolled patient
will remain in the study throughout the entire study duration, with a minimum follow-up of 1
year for each patient. A study patient's participation may be terminated early for reasonable
cause, such as the investigator's medical decision. At any time, the patient has the right to
withdraw consent without a negative impact on her/his medical treatment. However, the
investigators are encouraged to ask for the patient's permission for further follow-up
telephone contacts from those whose decision for discontinuation was based on the need for
further outpatient visits.
4.4.2. Duration of the whole study Patients will be enrolled during a recruitment phase of
approximately 2 years. Since minimum study duration for one patient is one year, the overall
study duration is approximately 3 years. The Data Monitoring Committee may terminate the
study earlier based on safety concerns at any time, or based on the interim efficacy
analysis. Competent authorities/ethics committees retain the right for premature termination
of the study according to applicable regulations. At an individual study centre, the study
may be terminated early if the work performed is not compliant with Good Clinical Practice
(GCP).
