Primary* To evaluate the ability of elamipretide compared to placebo to improve cardiac function measured by a reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) up to Day 8 ((or at discharge if earlier) in patients hospitalized with…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in NT-proBNP between Baseline and Day 8/Early Discharge
Secondary outcome
* To evaluate the effect of elamipretide on changes between baseline and both
Day 3 and Day8/Earlier Discharge on:
o renal function (eGFR as per MDRD)
o body weight
o body weight per mg of furosemide administered
* Clinical status (e.g patients and physician global assessment and treatment
failures) at Day 3 and Day 8
* The average daily dose of diuretic (furosemide * adjusted for thiazide dose
if administered) between baseline and Day 3 and Day 8/Early Discharge
* The safety and tolerability of elamipretide
* The plasma pharmacokinetics (PK) of elamipretide, its metabolites, and
furosemide following a single dose and multiple doses of elamipretide in a
selected number of patients
Pharmacokinetics
The following plasma PK parameters will be determined for elamipretide
(MTP-131), its metabolites (M1 and M2), and furosemide where possible and
appropriate:
* Day 1: Cmax, Tmax, AUC(0-last), AUC(0-inf), AUC%extrap, t*, Cl, Vd, MRT
* Day 7: Cmin,ss, Cmax,ss, Tmax, AUC(0-tau),ss, AUC(0-last), AUC(0-inf),
AUC%extrap, t*, Vd
* Additional Parameters:
- Cmax, Cmin on Days 2 - 6
- P/T fluctuation (%) under steady state conditions, accumulation ratio for
Cmax and AUC(0-tau)
Background summary
Elamipretide acts upon mitochondrial cardiolipin and is believed to improve the
function of the mitochondrial respiratory chain, reduce free-radical production
and increase adenosine triphosphate (ATP) production. It is organ *agnostic*
and thus could improve function in the kidney, liver, blood vessels, skeletal
muscle and brain as well as the heart. Its multi-organ potential beneficial
actions on function and metabolism observed in vitro and in animal models make
it a promising candidate for targeting the complex interplay of factors that
ultimately result in the syndrome of clinical heart failure. In a small study
of patients with chronic heart failure, a single four-hour infusion of
elamipretide acutely reduced both end-diastolic and end-systolic volumes
determined by echocardiography. In an animal model of renal insufficiency,
elamipretide improved renal blood flow, glomerular filtration rate and
attenuated the extent of tubular injury and fibrosis. It represents an
important opportunity to address a critical and
unmet clinical need.
Study objective
Primary
* To evaluate the ability of elamipretide compared to placebo to improve
cardiac function measured by a reduction in N-terminal pro-brain natriuretic
peptide (NT-proBNP) up to Day 8 ((or at discharge if earlier) in patients
hospitalized with congestion due to heart failure
Secondary
* To evaluate the effect of elamipretide on changes between baseline and both
Day 3 and Day 8/Early Discharge on:
o renal function (eGFR as per MDRD)
o body weight
o body weight per mg of furosemide administered
* Clinical status (e.g. patients and physician global assessment and treatment
failures) at Day 3 and Day 8
* The average daily dose of diuretic (furosemide * adjusted for thiazide dose
if administered) between baseline and Day 3 and Day 8/Early Discharge
* The safety and tolerability of elamipretide
* The plasma pharmacokinetics (PK) of elamipretide, its metabolites, and
furosemide following a single dose and multiple doses of elamipretide in a
selected number of patients
Study design
A prospective, randomized, double-blind, parallel-group, placebo-controlled,
multiple dose study comparing placebo and elamipretide given intravenously
daily for up to 7 days to patients requiring an intravenous infusion of
furosemide for the treatment of congestion complicating heart failure.
Patients will be consented, have baseline investigations, be initiated (or
continued) on an intravenous infusion of furosemide at 10mg/hour and
subsequently randomized to either elamipretide or placebo within 72 hours
(ideally between 12 and 36 hours) of hospital presentation. Patients will
continue the intravenous infusion of furosemide ideally for at least 48 hours,
however the dose can be modified if dictated by the clinical situation.
Patients who clinically improve sufficiently for discharge prior to Day 8, in
the opinion of the Investigator, may receive less than 7 days of treatment.
Please note that patients being discharged earlier than Day 8 should receive
the last dose of treatment on the day of discharge.
Safety will be assessed starting at randomization up to Day 40. There will be
two Safety Visits after discharge, one at Day 21 and one at Day 40.
Efficacy will be evaluated by assessing changes in NT-proBNP, body weight, body
weight/mg furosemide, total dose of diuretics, eGFR, and patient reported
outcomes. Safety will be evaluated by assessing adverse events and serious
adverse events, vital signs, ECGs, and laboratory evaluations. At selected
sites, samples for plasma PK analysis of elamipretide, its metabolites, and
furosemide will be collected. An independent Data and Safety Monitoring Board
(DSMB) will assess subject safety during the trial.
Intervention
All patients will receive the following interventions:
- ECG
- Blood draws for safety (chemistry and hematology)
- Blood draws for pharmacokinetic parameters at selected sites
- Echocardiography at selected sites
- Daily IV infusion of IP or placebo for 7 days
- IV infusion of furosemide for 48 hours followed by tablets upon investigator
decision
Study burden and risks
4.2.1. Potential Benefits
In animal models of heart failure, elamipretide has shown promising effects on
several potential therapeutic targets for heart failure. In canine studies of
severe, well-established heart failure both a single infusion and 3 months of
daily elamipretide injections improved left ventricular
(LV) ejection fraction, LV end diastolic pressure, and rate of rise of LV
pressure (dP/dtmax), without changes in heart rate or mean aortic pressure. In
murine models of heart failure, elamipretide ameliorated cardiac hypertrophy
and enlargement, systolic and diastolic dysfunction, and myocardial fibrosis.
The effects of elamipretide on cardiac function assessed by echocardiography
were assessed in a Phase 1 trial (SPIHF-101) evaluating single ascending
intravenous (IV) doses in 24 patients with moderate chronic heart failure
receiving concomitant standard of care pharmacological therapy for chronic
heart failure. An independent blinded core lab analysis by Duke Clinical
Research Institute suggested that the highest dose of elamipretide (0.25
mg/kg/hr administered intravenously over 4 hours) improved mean LV end systolic
volume (absolute change from baseline -11.1 mL versus 1.5 mL for placebo; mean
difference = -12.6 mL; p=.0157) and mean LV end diastolic volume (absolute
change from baseline -17.9 mL versus 2.9 mL for placebo; mean difference =
-20.8 mL; p=.002) at the end of the infusion. These changes occurred in the
absence of any heart rate or blood pressure change. These findings, after a
single dose of elamipretide, suggest beneficial effects that require further
investigation with repeat dosing.
There are currently two additional ongoing studies with elamipretide in
subjects with heart failure. These trials are investigating the effects of 28
days of subcutaneous (SC) therapy of elamipretide. The SPIHF-201 study is
investigating the effects of 4 mg and 40 mg of elamipretide on left ventricular
function in approximately 45 subjects with stable heart failure with reduced
ejection fraction (HFrEF). The SPIHF-203 study is investigating the effects of
40 mg of elamipretide on left ventricular function in approximately 45 subjects
with stable heart failure with preserved ejection fraction (HFpEF).
4.2.2. Potential Risks
4.2.2.1. Safety findings * Nonclinical studies
Toxicology studies in rats and dogs showed that elamipretide has an acceptable
profile that permits clinical investigations in humans for the proposed
duration of the study.
In rats and dogs, no safety issues relevant to either IV infusion or SC
administration at therapeutic doses were identified during the non-clinical
evaluation of elamipretide. Elamipretide did not cause end-organ toxicity at
any dose tested in either rats or dogs. Systemic toxicity at high doses was
manifested primarily by acute and transient clinical signs, which may have been
mediated by histaminergic-like reactions. Effects were associated with maximum
elamipretide plasma concentration (Cmax) and were rapidly reversible as plasma
concentrations of elamipretide and histamine decreased. Dose administration was
not associated with any adverse effects on cardiovascular, respiratory or
central nervous system function; off-target non-adverse effects were limited to
transient decrease of blood pressure and increase in heart rate, which is
thought to be consistent with histaminergic-like reactions. In all studies, the
severity of the effects was proportional to Cmax for elamipretide; thus, the
safety margin is estimated based on Cmax, and not area under the
plasma-concentration-time curve (AUC). The plasma elamipretide threshold
concentration for clinically-relevant adverse effects appears to be ~20,000
ng/mL in both rats and dogs, which is more than 10-fold higher than the maximum
anticipated human exposures. Local injection site reactions evident upon SC
administration varied with species, dose and dose concentration. In rats, it
was determined that 40 mg/day and 40 mg/mL, respectively, were well tolerated.
Elamipretide did not show genotoxicity in the full battery of tests and caused
no significant haemolysis or inhibition of receptor binding. Elamipretide was
not associated with adverse effects on fertility or embryo-fetal development.
No formal immunotoxicity studies have been performed. As a tetrapeptide the
immunogenic potential of the drug is expected to be low.
4.2.2.2. Human safety
The safety profile of 7 daily IV doses of elamipretide has not yet been
evaluated in heart failure patients.
In 7 completed single-dose IV trials in healthy subjects, the most commonly
reported treatment emergent adverse events (TEAEs) in subjects dosed with
elamipretide were headache, nausea, and hyponatremia. Across the 3 trials
evaluating single IV doses of elamipretide in cardio-renal
patient populations (i.e., chronic heart failure, acute kidney injury, and
acute coronary syndrome), single IV doses of elamipretide were generally safe
and well tolerated with no notable differences between the elamipretide and
placebo treatment groups in the frequency or severity of adverse events.
Both single-dose SC administration and multiple-dose SC administration for
seven days were well tolerated in healthy adult subjects at doses up to 40 mg.
No deaths or drug-related serious adverse events (SAEs) occurred, and no
subjects withdrew from the study for drug-related reasons. The most commonly
reported TEAE in the elamipretide treatment group was mild injection site
pruritus, reported with similar frequency after single and multiple doses.
Patients with chronic heart failure: Single elamipretide doses up to 1 mg/kg
administered IV over 4 hours were safe and well-tolerated in 24 patients with
stable chronic heart failure in a Phase 1 trial. No SAEs or deaths were
recorded. A total of four TEAEs were reported in three elamipretide-treated
subjects: worsening renal failure, dyspnea, tachycardia, and low haemoglobin.
These events were assessed by the investigator to be of mild or moderate
severity and unrelated to study drug.
Patients with first-time anterior ST-segment elevated myocardial infarction
(STEMI) undergoing primary PCI for a proximal or mid left anterior descending
(LAD) artery occlusion: 297 subjects received elamipretide or placebo (1:1
randomization) infused at a rate of 0.05 mg/kg/h for 1
hour. Study drug was administered for *15 minutes, but < 60 minutes prior to
PCI and for 1 hour following reperfusion. Elamipretide was safe and well
tolerated. There were no significant differences in arrhythmias, deaths, SAEs,
TEAEs or in the incidence of hyponatremia between
the elamipretide patients and the controls. There were 3 deaths (1 stroke on
day 18, 1 shock due to coronary artery dissection during angioplasty and 1
sudden death on day 7) in the elamipretide-treated patients and 1 death
(multi-organ failure on day 13) in the placebo-treated patients within the
first 30 days after STEMI.
There have been no pregnancies, exposures during lactation, overdoses, abuses
or misuses, or medication errors reported thus far in the elamipretide clinical
program.
4.2.3. Conclusions
In summary, based on the clinical and non-clinical study data, acceptable
safety risks are expected for the proposed current study. Hence the
benefit:risk ratio of this study is considered favourable.
Grove Street 275
Newton MA02466
US
Grove Street 275
Newton MA02466
US
Listed location countries
Age
Inclusion criteria
1. Willing and able to provide signed informed consent form (ICF) prior to participation in any study-related procedures
2. Aged *18 years
3. A history of chronic heart failure for at least 1 month
4. Treated with *40 mg/day of furosemide or bumetanide *1 mg/day or torasemide *10 mg/day for at least 1 month
5. In-hospital observation/admission and treatment for *72 hours and primary cause for admission is heart failure with persistent congestion in the opinion of the Investigator (i.e. at least +2 pitting oedema and/or an estimated 8 kg gain in weight over baseline over the past 4 weeks) requiring intravenous loop diuretic therapy
6. Able to be weighed
7. Sufficiently severe oedema to justify treatment by an intravenous infusion of furosemide of 10 mg/hour for at least 48 hours
Note: dose should be modified if dictated by the clinical situation and should be adjusted to the patient*s needs
8. Systolic blood pressure >/<=90 mmHg and considered to be haemodynamically stable, in the opinion of the Investigator
9. History of left ventricular ejection fraction (LVEF) *40% confirmed in the last 18 months
10. NT-proBNP >1500 pg/ml or BNP >500 pg/ml
11. An eGFR of >/<=30 mL/min/1.73 m2 using the MDRD study equation:
eGFR (mL/min/1.73 m2) <= 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African American)
12. Women of childbearing potential must agree to use 1 of the following methods of birth control from the date they sign the ICF until two months after the last dose of study drug:
a. Abstinence, when it is in line with the preferred and usual lifestyle of the subject. Subject agrees to use an acceptable method of contraception should they become sexually active
b. Maintenance of a relationship with a male partner who has been surgically sterilized by vasectomy (the vasectomy procedure must have been conducted at least 60 days prior to the Screening Visit or confirmed via sperm analysis)
c. Barrier method (e.g., condom or occlusive cap) with spermicidal foam/gel/film/cream AND either hormonal contraception (oral, implanted, or injectable) or an intrauterine device or system
Note: Non-childbearing potential is defined as surgical sterilization (e.g., bilateral oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as permanent cessation of menstruation for at least 12 consecutive months prior to the Screening Visit)
13. Willing to adhere to the study requirements for the length of the trial
Exclusion criteria
1. Completely bedridden for >2 weeks prior to admission. Patients should at least have been able to go the toilet and back and to get out of bed for meals at some time during this period
2. Known intolerance of furosemide
3. Acute coronary syndrome, stroke, or transient ischemic attack (TIA), coronary or peripheral revascularization procedures, valve procedures, OR any major surgical procedure within the previous 6 weeks
4. Invasive cardiac investigation and/or treatment (i.e. coronary angiography, percutaneous coronary intervention [PCI] or surgery) or other surgical procedure planned in the next 4 weeks
5. Use of intravenous radiographic contrast agent within 72 hours prior to screening or planned use during the study
6. Severe, in the investigators opinion, uncorrected valve disease or congenital heart disease as the cause for cardiac decompensation
7. Acute mechanical cause of decompensated heart failure such as papillary muscle rupture
8. Obstructive or infiltrative cardiomyopathy (e.g. amyloid, sarcoid, etc), suspected acute myocarditis, or heart failure related to an untreated metabolic condition (e.g. haemochromatosis)
9. Second or third degree heart block unless the subject has a ventricular pacemaker
10. Atrial fibrillation/flutter with sustained ventricular response of >130 bpm
11. Placement of a ventricular resynchronization device within the previous 6 weeks
12. Treatment or planned treatment with intravenous inotropic agents other than digoxin at any time on this admission
13. Receipt of intravenous vasodilator therapy * 6 hours prior to randomization
14. The presence of any mechanical assist device or listed for or a history of a heart transplant
15. Suspected systemic infection or pneumonia and/or the need for antibiotic treatment between admission and time of consent. Patients given antibiotics without clear justification can be included as long as it is appropriate to discontinue the antibiotics
16. Severe respiratory disease or anticipated need for mechanical respiratory support (i.e. mechanical ventilation)
17. Anuric in the previous 24 hours
18. Haemoglobin <9 g/dL at screening or planned blood transfusions in the next 30 days
19. Serum potassium >5.5 mEq/L
20. Marked proteinuria suggestive of nephrotic syndrome
21. Estimated GFR (eGFR) as per MDRD equation <30 ml/min
22. Serum albumin of < 2.8 g/dL
23. Liver enzymes (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) elevation >5 times the upper limit of normal (ULN)
24. Total bilirubin >2.0 times ULN in the absence of Gilbert*s Syndrome
25. Known active hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV) infection, or diagnosis of immunodeficiency
26. Known active drug or alcohol abuse within 1 year of the Screening Visit at the discretion of the Investigator (i.e. 15 or more drinks for men per week or 8 or more for women).
27. Currently receiving treatment with chemotherapeutic agents or immunosuppressant agents or having received prior radiation therapy to the chest
28. Current or planned ultrafiltration, paracentesis, haemofiltration or dialysis
29. Currently receiving treatment with any intravenous steroid or > 5 mg of oral prednisone (or equivalent)
30. Recipient of stem cell or gene therapy or current therapeutic investigational devices
31. Participation in another clinical trial with an investigative product within 3 months prior to the Screening Visit
32. Any significant acute or chronic medical or psychiatric illness or social situation that, in the judgment of the Investigator, could compromise a subject*s safety, limit subject*s ability to complete the study and follow-up period, and/or compromise the objectives of the study
33. Women who are pregnant, planning to become pregnant, or lactating
34. Currently receiving treatment with therapeutic doses of any of the novel or direct oral anticoagulants (vitamin K antagonist are permitted)
35. Currently receiving treatment with sacubitril (Entresto*)
Note: This is because, currently, there is a lack of interaction data available
36. Hypersensitivity to elamipretide or any of its excipients
Design
Recruitment
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 | EUCTR2016-000126-19-NL |
| CCMO | NL57646.042.16 |