Primary ObjectiveTo evaluate the safety and tolerability of dutogliptin in combination with filgrastim in subjects with STEMI compared with placebo Secondary ObjectivesTo assess preliminary efficacy of dutogliptin in combination with filgrastim in…
ID
Source
Brief title
Condition
- Myocardial disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety Endpoints:
Safety assessments will include reporting of AEs and serious AEs (SAEs),
clinical laboratory tests, ECGs, vital signs, and physical examinations.
Primary Efficacy Endpoints:
Change from baseline to Day 90 (Month 3) in the following cardiac functional
parameters as assessed by central, blinded review of cMRI:
- Left ventricular ejection fraction (LVEF)
- Left ventricular end systolic volume (LVESV; absolute and indexed)
- Left ventricular end diastolic volume (LVEDV; absolute and indexed)
- Infarct size
- Left ventricular mass (absolute and indexed)
- Regional wall motion
Secondary outcome
Secondary Efficacy Endpoints:
- Individual clinical endpoints, including recurrent non-fatal MI, non-fatal
stroke, death due to any cause, cardiovascular (CV) death (death due to acute
MI, chronic heart failure [CHF], stroke, or sudden cardiac death), stent
thrombosis or CHF hospitalization.
- Combined clinical endpoints, including major adverse cardiac events, defined
as non-fatal MI, non-fatal stroke, CV death, stent thrombosis, and CHF
hospitalization
- Time to cardiovascular event, as defined by the time from Randomization to
the first occurrence of recurrent non-fatal MI, non-fatal stroke, death due to
any cause, stent thrombosis, and CHF hospitalization
Exploratory Endpoints:
Change from baseline in plasma biomarkers NT-proBNP and high sensitivity
troponin.
PK/PD Endpoints (in selected centers):
- Plasma dutogliptin concentration profiles (PK)
- Trough dutogliptin concentrations
- Maximum plasma concentration (Cmax)
- Time corresponding to Cmax
- Area under the drug concentration-time curve
- Additional parameters may also be determined (volume of distribution,
clearance and terminal phase half-life)
Plasma DPP4 activity (PD)
- Maximum effect on plasma DPP4 activity (Emax)
- Trough plasma DPP4 activity
Change from baseline in plasma SDF-1* levels.
Background summary
Pre-clinical studies have demonstrated that G-CSF-based stem cell mobilization
in combination with genetic or pharmaceutical CD26/DPP4 inhibition after acute
MI results in improved cardiac homing of stem cells, enhanced heart function,
and increased survival. In mice, combining genetic and pharmacologic inhibition
of DPP4 with G-CSFmediated stem cell mobilization after MI led to (1) decreased
myocardial DPP4 activity,
(2) increased myocardial homing of circulating CXCR-4+ stem cells, (3) reduced
cardiac remodeling, and (4) improved heart function and survival [Zaruba, 2009;
Theiss, 2013; Nix2016].
In a Phase 1 study in healthy volunteers, dutogliptin was administered as
single and multiple daily SC doses ranging from 30 to 120 mg. Inhibition of
plasma DPP4 increased in duration with increasing dose. However, complete
(*80%) inhibition could not be achieved for 24 hour with daily doses up to 120
mg. Sustained inhibition was observed to last for 8*12 hours following a single
60 mg dose, therefore twice daily 60 mg dosing has been selected as the active
dose for this study. Once daily doses up to 120 mg were well tolerated in the
Phase 1 study.
The current study will investigate the safety and efficacy of dutogliptin
administered in combination with filgrastim compared with placebo in subjects
with ST-elevation myocardial infarction (STEMI) who are successfully
revascularized following percutaneous coronary intervention (PCI) and stent
implantation.
Study objective
Primary Objective
To evaluate the safety and tolerability of dutogliptin in combination with
filgrastim in subjects with STEMI compared with placebo
Secondary Objectives
To assess preliminary efficacy of dutogliptin in combination with filgrastim in
subjects with STEMI compared with placebo
To determine the pharmacokinetics (PK) of dutogliptin in a subset of the study
population
To establish the pharmacodynamics (PD) of dutogliptin (plasma
dipeptidylpeptidase-IV (DPP4) activity) in a subset of the study population
Exploratory Objectives
To examine the effects of dutogliptin in combination with filgrastim on:
Change from baseline in plasma stromal cell-derived factor (SDF)-1a levels
Change from baseline in plasma biomarkers N-terminal pro-b-type natriuretic
peptide (NTproBNP) and high sensitivity troponin
Note: This is an international study, which is conducted in the US as well as
Europe. In addition to the objectives that are assessed in Europe as well as
US, PK/PD data are collected in the US only. However, even if PK/PD data are
not assessed in EU, this assessment is part of the study design and hence
described in the protocol. As the study needs to be considered in its entirety,
the information on assessments performed in the US only cannot be excluded when
describing the study for other involved countries.
Study design
Study REC-DUT-002 is a multicenter, randomized, double-blind,
placebo-controlled study to evaluate the safety, tolerability, and preliminary
efficacy of dutogliptin administered in combination with filgrastim in subjects
with STEMI following PCI and stent implantation. 140 evaluable subjects will be
randomized in this study in order to have 110 subjects complete the study.
Intervention
Dutogliptin 60 mg administered by twice daily subcutaneous (SC) injection for
14 days in combination with a fixed standard dose of filgrastim (10 *g/kg)
administered SC daily for 5 days
Study burden and risks
Subjects will be screened for eligibility as soon as possible after hospital
admission for treatment of STEMI. Eligible subjects will have received local
standard of care procedures including PCI and stent implantation (bare metal or
drug-eluting). The allowable time between onset of STEMI symptoms and stent
implantation is >2 and <24 hours.
Eligibility for study randomization will be evaluated in a step-wise manner. It
is recommended that medical history, physical examination, and safety
laboratory screening tests are completed prior to conducting the cardiac
echocardiography (cECHO). Subjects who do not meet all eligibility criteria
will be considered ineligible and will not be randomized.
Eligible subjects will be randomized in a 1:1 ratio to receive twice daily SC
injections of 60 mg dutogliptin for 14 days in combination with 10 *g/kg
filgrastim for 5 days or matching dutogliptin placebo for 14 days in
combination with matching filgrastim placebo for 5 days. Subjects must be
randomized and study treatment initiated within 36 hours after stent
implantation. Study treatment will be administered SC to subjects by the site
hospital staff at the Day 1 visit and while the subject remains hospitalized.
Upon discharge, adequate supplies of investigational medicinal products (IMPs)
to complete all dosing will be issued to the homes care nursing service who
will administer all remaining doses to the subject at home. The homecare
nursing service will be blinded to study allocation.
Safety assessments will be performed on Day 1 (baseline), Day 3 or day of
discharge if before Day 3, Day 15 and Day 90 (Month 3). Safety assessments will
include physical examinations, vital signs, and an assessment of adverse events
(AEs) at each time point.
An independent Data Safety Monitoring Board (DSMB) will review study data
following completion of Day 90 by the initial 30 subjects and evaluate if it is
appropriate to continue the study according to the protocol. The DSMB may
recommend changes in the conduct of the study to the Sponsor to ensure subject
safety. The DSMB will meet and review the study data at least biannually and
make safety recommendations to the Sponsor.
Efficacy assessments will be performed within 72 hours after PCI (baseline) and
on Day 90. Efficacy assessments will include an evaluation of cardiac
functional parameters as determined by cardiac magnetic resonance imaging
(cMRI) and individual and combined clinical endpoints.
Electrocardiograms (ECG), clinical laboratory tests, and exploratory
assessments will be performed at selected time points. Exploratory assessments
will include changes in biomarker concentrations and in selected centers an
evaluation of plasma dutogliptin concentrations (PK) and pharmacodynamics (PD)
changes (DPP4 and SDF-1*).
The patient only will come back to study site for D15 and D90 visit.
There is no guarantee that the patient will benefit from this study and taking
part in this study may or may not cause his health to improve. Information from
this study may help doctors learn more about Dutogliptin and the regenerative
treatment of his condition.
What are the risks?
There are possible risks, disadvantages and inconveniences with any research
study:
risks of tests and procedures (more tests and procedures, study visits could
take more time), blood tests (pain where the needle is inserted, and there is a
small risk of bruising or infection at this location, dizziness, upset stomach,
or fainting), injection site reactions (some rash, pain/tenderness, blistering
or ulcers), ECG risks (skin irritation from the ECG electrode pads, pain when
the pads are removed), MRI Scan (claustrophobie, noisy), side effects of
Filgrastim (mild to moderate bone pain, allergic reactions, affect pregnancy),
side effects of Dutogliptin (headache, stomach discomfort, diarrhoea, passing
wind and frequent bowel movements nausea, dizziness)
This is the first study in which the drug will be delivered by an injection and
to patients following a heart attack and the placement of a stent. There may be
some additional risks of use that are unknown right now. Furthermore the
safety of Dutogliptin during pregnancy and breast feeding are not known as well
as the effects of Dutogliptin and Filgrastim on sperm.
1 Market Street Spear Tower, 36th
San Francisco CA 94105
US
1 Market Street Spear Tower, 36th
San Francisco CA 94105
US
Listed location countries
Age
Inclusion criteria
1. Male or female,age 18 to 85 (having reached 18 and before having reached 86
at the time of ICF signing).
2. Body weight <96 kg (~212 lb).
3. Able to provide written informed consent, including signing and dating the
ICF.
4. Diagnosis of STEMI (defined as new ST-segment elevation at the J point of at
least 2 continuous leads of >2 mm [0.2 mV] in men or >1.5 mm [0.1 mV] in
women in leads V2 and V3 OR >1 mm in any other contiguous precordial leads
or the limb leads [for both men and women]) with PCI (bare metal or
drug-eluting stent) and Thrombolysis in Myocardial Infarction flow grade 2 or 3
occurring up to 24 hours after symptom onset (to time of first balloon
inflation).
5. Left ventricular ejection fraction (LVEF) *45% obtained by cECHO performed
within 36 hours post-stent placement.
6. Receiving standard medical therapy for post-myocardial infarction (MI)
treatment, according to local procedures and Principal Investigator's
discretion.
7. Female subjects of childbearing potential must have a negative serum
pregnancy test at Screening and an additional negative urine pregnancy test
prior to the first dose of IMP unless regulated differently by national
legislation.
8. Sexually active female subjects of childbearing potential (i.e., women
who are not postmenopausal or who have not had a bilateral
oophorectomy, hysterectomy, or tubal ligation) and all male subjects
(who have not been surgically sterilized by vasectomy) must agree to
use effective contraception during treatment and for 4 weeks after the last
dose.
Exclusion criteria
1. Previous MI prior to Screening.
2. Complex peri/post-MI clinical course, including arrhythmias, cardiogenic
shock, pulmonary edema requiring mechanical ventilation, or requirement for
vasopressor medications.
3. Significant pre-existing cardiomyopathy with known LVEF *45% or moderate to
severe mitral or aortic valvular disease.
4. Amyloidosis, hypertrophic obstructive cardiomyopathy, restrictive
cardiomyopathy, or constrictive pericarditis.
5. Existing heart transplant.
6. Ventricular tachycardia or fibrillation not associated with an acute
ischemic episode.
7. Uncontrolled hypertension (systolic >180 mmHg or diastolic >120 mmHg).
8. Treatment with any DPP4 inhibitors (e.g., alogliptin, linagliptin,
vildagliptin, saxagliptin, sitagliptin) or granulocyte-colony stimulating
factor medication (e.g., filgrastim, lenograstim, pegfilgrastim,
lipegfilgrastim) within 4 months prior to Randomization.
9. Contraindication to treatment with filgrastim, including known allergy to
filgrastim or other G-CSF medication.
10. Anemia defined as hemoglobin <9 g/dL prior to Randomization.
11. Thrombocytosis (platelets > 500 k/uL).
12. Known positive serology for hepatitis B, hepatitis C, or human
immunodeficiency virus (HIV), any other indication of liver disease or injury.
13. ALT concentrations >3 times the upper limit of normal (ULN) and
bilirubin (TBL) >2 x ULN, or INR >1.5 prior to Randomization, according to
local laboratory assessments, and/or any indication of liver disease or
injury. If ALT is between >3 and 8 x ULN, and all other admission criteria are
met, the test may be repeated within the time window before Randomization.
14. History of cirrhosis and Child-Pugh score B or C.
15. Current fever greater than 101.4 °F (38.6 °C) or recent systemic infection
within 2 weeks prior to Randomization.
16. Contraindication to cMRI procedure, including prior implantable
cardioverter defibrillator placement, known reaction to gadolinium,
claustrophobia, non-MRI-compatible, cochlear implant, obesity, or presence of
ferromagnetic material including shunts, shrapnel, penile prostheses, or blood
vessel coil.
17. Pregnant, planning to become pregnant, or nursing female subjects.
18. Autoimmune disease requiring immunosuppressive therapy or chronic steroid
treatment >5 mg/day prednisolone or equivalent.
19. Significant renal impairment defined as estimated glomerular filtration
rate <45 mL/min/1.73 m2, using the Chronic Kidney Disease Epidemiology
Collaboration equation.
20. Active neoplasm requiring surgery, chemotherapy, or radiation within the
prior 12 months (subjects with a history of malignancy who have undergone
curative resection or otherwise not requiring treatment for at least 12 months
prior to Screening with no detectable recurrence are allowed).
21. Malignant hematological disease, i.e., chronic myeloid leukemia or
myelodysplastic syndrome.
22. History of cerebrovascular accident or transient ischemic attack in the
past 6 months.
23. History of pneumonia in the last 4 weeks.
24. History of any significant medical or psychiatric disorder that in the
opinion of the investigator would make the subject unsuitable for participation
in the study.
25. Treatment with an investigational drug within 30 days or five
halflives(whichever is longer) or treatment with an investigational biologic
drug within 6 weeks prior to randomization.
26. Participation in another concurrent clinical trial involving a therapeutic
intervention (participation in observational studies and/or registry studies is
permitted).
27. Unable or unwilling to comply with the requirements of the study.
28. Subject and/or an immediate family member is an employee of the
investigational site directly affiliated with this study, the sponsor or the
contract research organization.
29. Considered by the investigator to be unsuitable to participate in the study
for any other reason.
30. Persons who are in an institution as a result of an administrative or
judicial order, or soldiers.
31. History of alcohol or drug abuse.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-000916-75-NL |
| ClinicalTrials.gov | NCT03486080 |
| CCMO | NL65070.068.18 |