Istaroxime for Cardiogenic Shock

(SEISMiC-C Trial)

Not currently recruiting at 17 trial locations

Overseen By Phillip D Simmons, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Windtree Therapeutics

Must be taking: Vasoactive agents, Inotropes

Must not be taking: Digoxin

Disqualifiers: Severe renal impairment, Stroke, Severe valvular lesions, Uncontrolled arrhythmia, others

Compensation: Varies

Number of Visits: Unknown

Duration: 48 hours

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called istaroxime for individuals experiencing cardiogenic shock, a serious heart condition where the heart suddenly can't pump enough blood to meet the body's needs. Istaroxime may improve blood pressure and heart function without some downsides of current treatments. Participants will receive standard heart failure care, and some will also receive istaroxime to assess its impact. Suitable candidates include those struggling with severe heart failure, showing signs like low blood pressure and cold skin, which indicate reduced blood flow. As a Phase 1, Phase 2 trial, this research aims to understand how istaroxime works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking heart failure treatment advancements.

Do I have to stop taking my current medications to join the trial?

The trial does not specify if you need to stop taking all current medications, but you cannot be on digoxin unless it was stopped before signing the consent form and your digoxin level is below 0.5 ng/ml.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that istaroxime might raise blood pressure in patients at risk of cardiogenic shock, a serious condition where the heart suddenly can't pump enough blood. In a small study, patients who took istaroxime had higher systolic blood pressure, the top number in a blood pressure reading, suggesting that the treatment might help the heart work better.

Earlier findings also showed that patients taking lower doses of istaroxime experienced fewer unwanted side effects, indicating that lower doses might be safer. Importantly, no worsening of heart failure was reported in these studies.

The current trial is in its early stages, with researchers primarily focused on assessing the safety of istaroxime in humans. This phase is crucial because it helps determine how well patients handle the treatment before testing its effectiveness in larger groups. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for cardiogenic shock, such as inotropes and vasopressors, work by increasing heart muscle contractions or narrowing blood vessels to boost blood pressure. However, Istaroxime is unique because it targets the heart's calcium cycling, enhancing heart muscle relaxation and contraction without significantly increasing heart rate or oxygen demand. This dual mechanism not only improves heart function but also minimizes the risk of adverse effects commonly associated with traditional treatments. Researchers are excited about Istaroxime because it offers a promising new way to stabilize patients with cardiogenic shock more safely and effectively.

What evidence suggests that istaroxime might be an effective treatment for cardiogenic shock?

Research has shown that istaroxime, which participants in this trial may receive, could help treat cardiogenic shock, a condition where the heart suddenly can't pump enough blood. In earlier studies, istaroxime raised systolic blood pressure, crucial for patients with low blood pressure due to heart issues. The drug also improved heart function without some side effects of other treatments. Istaroxime works in two ways: it helps the heart pump better and increases blood pressure. These effects are especially important for patients with sudden heart failure who need quick and reliable help. ^{1 2 6 7 8}

Who Is on the Research Team?

Steven G Simonson, MD

Principal Investigator

Windtree Therapeutics, Inc.

Are You a Good Fit for This Trial?

This trial is for adults aged 18-85 with SCAI Stage C cardiogenic shock, which includes symptoms like sudden mental changes, cool skin, and low blood pressure needing emergency support. They must have a history of reduced heart function (LVEF ≤ 40%) and be in the ICU within 36 hours before joining.

Inclusion Criteria

Signed informed consent form (ICF)

I am in advanced heart failure and experiencing severe symptoms.

I was admitted to the ICU recently with lung congestion and high heart failure markers.

Exclusion Criteria

Recent participation in another interventional trial

I have had a heart transplant or am listed as top priority for one.

Patient is in SCAI B or SCAI D

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either istaroxime or placebo as an IV infusion for a total duration of 48 hours

48 hours

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Istaroxime

Trial Overview The trial tests istaroxime against a placebo in patients receiving standard care for acute heart failure and cardiogenic shock. Istaroxime aims to raise blood pressure and improve heart function without the downsides of current treatments.

How Is the Trial Designed?

Group I: Istaroxime Experimental Treatment 1 Intervention

Istaroxime delivered as an IV infusion via a syringe pump. Dosage regime is 1.0 µg/kg/min for 6 hours, 0.5 µg/kg/min for 42 hours. Total duration 48 hours.

Group II: Placebo Placebo Group 1 Intervention

Placebo (lactose) delivered as an IV infusion via a syringe pump. Total duration 48 hours.

Who Is Running the Clinical Trial?

Windtree Therapeutics

Lead Sponsor

Trials

17

Recruited

1,500+

Momentum Research, Inc.

Industry Sponsor

Trials

8

Recruited

8,300+

Published Research Related to This Trial

Compound 14 is a potent thromboxane A2 receptor antagonist with an IC50 value of 22 nM, effectively preventing platelet aggregation induced by arachidonic acid and U-46619, indicating its potential as a therapeutic agent in preventing blood clots.

In addition to inhibiting platelet aggregation, compound 14 also relaxed blood vessels and airways in animal models, demonstrating its efficacy in both vascular and respiratory contexts, with IC50 values of 20.4 nM and 5.47 nM, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor. Dogné, JM., Wouters, J., Rolin, S., et al.[2019]

In a study of 15 patients with reentrant supraventricular tachycardia (SVT), dexmedetomidine successfully terminated 96% of SVT episodes within a median time of 30 seconds, suggesting it has strong antiarrhythmic properties.

Compared to adenosine, which had a 63% success rate and caused more side effects like bradycardia and hypotension, dexmedetomidine showed a more favorable safety profile with fewer adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexmedetomidine: therapeutic use for the termination of reentrant supraventricular tachycardia. Chrysostomou, C., Morell, VO., Wearden, P., et al.[2013]

In a study involving anesthetized open-chest dogs, the thromboxane A2 receptor antagonist SQ 29,548 significantly reduced ST-segment elevation during pacing-induced ischemia, indicating its potential efficacy in alleviating ischemic conditions.

The reduction in ST-elevation was observed without affecting arterial blood pressure or heart rate, suggesting that SQ 29,548's mechanism of action is specifically related to its blockade of TXA2 receptors rather than systemic cardiovascular effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of the thromboxane A2 receptor antagonist SQ 29,548 on the severity of pacing-induced ischemia. Grover, GJ., Schumacher, WA.[2019]

S18886, a thromboxane A2 receptor antagonist, significantly reduced atherogenesis in diabetic apoE(-/-) mice, preventing a more than fourfold increase in aortic lesion area caused by diabetes, without affecting blood sugar or cholesterol levels.

The drug improved endothelial function and reduced inflammation markers, suggesting it works by counteracting the negative effects of diabetes on blood vessel health, making it a promising candidate for preventing cardiovascular events in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The thromboxane A2 receptor antagonist S18886 prevents enhanced atherogenesis caused by diabetes mellitus. Zuccollo, A., Shi, C., Mastroianni, R., et al.[2014]

In a study involving 35 dogs with induced coronary thrombosis, simultaneous inhibition of TxA2 synthase and blockade of TxA2/PGH2 receptors (using R 68070) significantly enhanced thrombolysis and prevented reocclusion after treatment with tissue plasminogen activator (t-PA), compared to other treatments.

Dogs treated with R 68070 experienced a much shorter time to thrombolysis (11 minutes) and had no instances of reocclusion, while control and other treatment groups showed significant reocclusion rates, highlighting the efficacy of this combined approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endogenous prostaglandin endoperoxides and prostacyclin modulate the thrombolytic activity of tissue plasminogen activator. Effects of simultaneous inhibition of thromboxane A2 synthase and blockade of thromboxane A2/prostaglandin H2 receptors in a canine model of coronary thrombosis. Golino, P., Rosolowsky, M., Yao, SK., et al.[2018]

In a study of 25 patients with coronary artery disease, the thromboxane synthetase inhibitor dazoxiben significantly reduced ischemic responses during stress tests, indicating its potential efficacy in improving blood flow by inhibiting TxA2 while preserving PGI2 production.

In contrast, acetylsalicylic acid (ASA) did not show a significant effect on ischemia despite reducing TxB2 levels, suggesting that while both drugs lower TxA2, dazoxiben may be more effective in managing ischemic conditions due to its selective action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a selective thromboxane synthetase inhibitor, dazoxiben, and of acetylsalicylic acid on myocardial ischemia in patients with coronary artery disease. Thaulow, E., Dale, J., Myhre, E.[2019]

Fetal supraventricular tachycardia (SVT) is a common condition that can lead to serious complications like non-immune fetal hydrops if not treated early, with echocardiography being the preferred diagnostic method.

In a case study of a fetus diagnosed with SVT at 26 weeks, initial treatment with digoxin was effective, but persistent episodes required the addition of another antiarrhythmic medication, leading the parents to opt for premature delivery at 32 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fetal supraventricular tachycardia, treating the baby by targeting the mother. Husain, A., Hubail, Z., Al Banna, R.[2021]

In a study of 8 infants with refractory supraventricular tachycardia (SVT), flecainide was effective in terminating the arrhythmia in all patients after they failed to respond to first-line treatments like digoxin and propranolol.

Flecainide was well-tolerated with no reported side effects, and it provided long-term control of SVT, with recurrences manageable through dose adjustments over a mean follow-up of 24.75 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral flecainide is effective in management of refractory tachycardia in infants. Kohli, V.[2021]

In a study involving dogs with induced myocardial ischemia/reperfusion injury, the thromboxane A receptor antagonist KT2-962 significantly reduced the incidence of ventricular fibrillation and myocardial infarct size by approximately 40%, while daltroban did not show these benefits.

The protective effects of KT2-962 are likely due to its ability to scavenge free radicals, as demonstrated by in-vitro assays, rather than its action as a TXA receptor blocker, indicating a unique mechanism of action compared to daltroban.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of cardioprotective efficacy of two thromboxane A2 receptor antagonists. Ge, ZD., Auchampach, JA., Piper, GM., et al.[2019]

Tecadenoson effectively converted paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm in 86.5% of patients, with most conversions occurring rapidly after the first dose, demonstrating its efficacy in managing this condition.

Unlike traditional adenosine, tecadenoson did not cause hypotension or bronchoconstriction, making it a safer alternative for patients, as it selectively targets the A1 adenosine receptor without the unwanted side effects associated with non-selective adenosine receptor activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Termination of paroxysmal supraventricular tachycardia by tecadenoson (CVT-510), a novel A1-adenosine receptor agonist. Prystowsky, EN., Niazi, I., Curtis, AB., et al.[2022]

Nonpharmacologic treatments for paroxysmal supraventricular tachycardia (PSVT), such as carotid sinus massage and the Valsalva maneuver, effectively increase vagal tone and can help manage PSVT episodes.

For hemodynamically unstable patients, synchronized electrical countershock is the preferred treatment, while hemodynamically stable patients may be treated with intravenous procainamide or digitalis if they do not respond to the first-line medication, verapamil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of paroxysmal supraventricular tachycardia. Ornato, JP.[2004]

The study identified four different agents derived from small structural changes in 7-oxabicyclo[2.2.1]heptyl acids that interact with TXA2 and PG pathways, highlighting their potential roles in modifying these actions.

SQ 30,077 was found to bind reversibly and with high affinity to human platelet membranes, and its binding is influenced by known TXA2 receptor agonists and antagonists, suggesting its potential as a therapeutic target in platelet function modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

7-Oxabicycloheptane analogs: modulators of the arachidonate cascade. Harris, DN., Hedberg, A., Phillips, MB., et al.[2014]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05975021

NCT05975021 | A Safety and Efficacy Trial of Istaroxime for ... The current trial aims to assess the effect of istaroxime in patients with SCAI Stage C Cardiogenic Shock (CS). These patients look unwell, frequently with ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9786901/

Efficacy of the New Inotropic Agent Istaroxime in Acute Heart ... The clinical effects of istaroxime appear to be favorable for patients with AHF with low or borderline SBP, for which inotropes have been ...

3. clinicaltrialvanguard.com clinicaltrialvanguard.com/news/windtree-therapeutics-presents-late-breaking-istaroxime-data-at-heart-failure-conference/

Windtree Therapeutics Presents Late-Breaking Istaroxime ... The continued development of istaroxime holds potential to reshape the treatment landscape for cardiogenic shock and improve patient outcomes.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S107191642300115X

Safety and Efficacy of Istaroxime 1.0 and 1.5 µg/kg/min for ... Istaroxime was shown, in a small study, to increase systolic blood pressure (SBP) in patients with pre-cardiogenic shock (CS) due to acute heart failure (AHF).

5. cardiacwire.com cardiacwire.com/windtrees-istaroxime-scores-in-cardiogenic-shock-trial/

Windtree's Istaroxime Scores in Cardiogenic Shock Trial Windtree Therapeutics' istaroxime appears to have scored in its latest Phase 2b trial, showing that the steroidal drug significantly improves systolic blood ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39375885/

Safety and efficacy of up to 60 h of iv istaroxime in pre- ... The SEISMiC study is designed to examine the safety and efficacy (haemodynamic effect) of istaroxime administrated in pre-CS patients.

7. researchgate.net researchgate.net/publication/362199236_Safety_and_Efficacy_of_Istaroxime_for_Patients_with_Acute-Heart-Failure-Related_Pre-cardiogenic_Shock_-_A_Multicenter_Randomized_Double-Blind_Placebo-Controlled_Parallel_Group_Study_SEISMiC

Safety and Efficacy of Istaroxime for Patients with Acute‐ ... In a post-hoc analysis, patients receiving ≤1.0 μg/kg/min versus 1.5 μg/kg/min had similar increase in BP, but a trend towards less adverse ...

8. onlinejcf.com onlinejcf.com/article/S1071-9164(23)00115-X/abstract

Safety and Efficacy of Istaroxime 1.0 and 1.5 µg/kg/min for ... Ista-1 had no worsening HF events, and DAOH to day 30 were significantly increased. Effects on echocardiographic measures were similar, although decreases in ...