ALP-1 Continuous Intravenous Infusion to Maintain Clinical Stability in Advanced Heart Failure
Study Details
Study Description
Brief Summary
This is a global multicenter, doubleblind, placebo-controlled, randomized, parallel-group study that compares ALP-1 given in a continuous infusion and placebo in patients with advanced HF. The difference between the two groups for the primary endpoint will be compared after 52 weeks of study drug therapy (Double-Blind Treatment Phase).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Detailed Description
The screening activities may be performed on stable patients on an outpatient basis or on unstable patients who are already hospitalized (inpatient). Elective patients need to be on maximum tolerated dosage of recommended HF therapy. For patients who are not receiving target dosages adequate reasons for inability to follow the titration schema should be present and documented according to pre-defined criteria. The selection of HF therapy and dose adjustment will be as appropriate to country of origin. Screening should not exceed 14 days. Patients who fulfill all of the inclusion and none of the exclusion criteria will enter the blinded Run-in Phase for tolerability. If ambulatory, patients will be admitted to the cardiac care ward. A central line for chronic infusion therapy will be placed, and the blinded continuous infusion will be started. ALP-1 or placebo (0.9% sodium chloride) will be administered for 24 hours followed by the matching substance for another 24 hours. Close monitoring of vital signs, laboratory tests, and adverse events (AEs) will be performed, and an education program will be undertaken. Successful completion of the Blinded Run-in Phase means stable patients with systolic blood pressure predominantly >95 mmHg in all in-hospital measurements performed without the following patient reported treatment-related side effects: headache, joint or bone pain, or diarrhea.
Eligible patients will be re-randomized 1:1 into the Double-Blind Treatment Phase to receive the 52-week long-term continuous intravenous infusion of either ALP1 (at a starting dose that is consistent to 500 µg/48 hours) or matching placebo. Patients are to remain in the hospital for another 24 hours. If after 24 hours the infusion is tolerated and the patient is adequately trained, the patient will be discharged. Patients will be evaluated for safety and efficacy on an outpatient basis: weekly visits for the first 4 weeks and then every 4 weeks until the final visit at Week 52. The initial dose at discharge will be 500 µg/48 hours for every patient. Physicians are encouraged to perform an up-titration of the study drug within 4 weeks as described in Dose/Route/Regimen. At each visit, patients will be evaluated for safety by recording all AEs, including those judged catheter-related. Additionally, a trained nurse will visit the patient at home after discharge to evaluate the patient's ability to correctly use the pump and prepare and deliver the study drug solution. The frequency of visits depends on the ability of the patient and his/her relatives to handle the pump by their own. Usually, visits will be weekly in the first month. Once the nurse is convinced that the patient and his/her relative/caregiver can correctly perform these activities, phone contact will occur monthly between clinic visits. If necessary, the nurse should also add unscheduled home visits, which should also be documented. Throughout the study, patients should be maintained on and also if needed/possibly adjusted to optimal medical therapy in accordance with national guidelines for HF, which are mostly based on the European Guidelines for Heart Failure and the American Guidelines for Heart Failure. These include therapy with angiotensin converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin II receptor/neprilysin inhibitors (ARNIs), beta-blocking agents, mineralocorticoid receptor antagonists (MRAs), ivabradine, sodium glucose co-transporter 2 inhibitors (SGLT2i), and diuretics, as well as device therapy, i.e., cardiac resynchronization [CRT] and automated implantable cardioverter defibrillator [AICD] therapy, as appropriate. Current therapy, including type of medication and daily dosage will equally be documented at the study visits.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: trial arm 12 months central continuous infusion with Alp_1 by infusion pump. |
Drug: Alprostadil
central venous access continuous delivery with 500mcg/48 hours in active arm
|
| Placebo Comparator: Placebo arm 12 months central infusion with NS by infusion pump with exact infusion rat as trial arm. |
Drug: Alprostadil
central venous access continuous delivery with 500mcg/48 hours in active arm
|
Outcome Measures
Primary Outcome Measures
- time to all-cause death [12 months infusion]
To access the effect of continue long term ALP-1infusion at a maximally tolerated dose of up to 1500mcg/48 hr. in patinets with advanced heart failure with reduced ejection fraction(HrEF) compare to placebo.
Secondary Outcome Measures
- All-cause hospitalisation through 12 months ALP-1-infusion over 52 weeks compared to placebo in patients with advanced HFrEF [12 months]
determine efficacy ALP-1 compare to placebo, any changes of KCCQ, NTproBNP or BNP from baseline to 3 months.
Eligibility Criteria
Criteria
-
Patients older than 18 years of age, of any gender/sex and race/ethnicity
-
Patients with a diagnosis of advanced HFrEF as evidenced by (all must apply):
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Left ventricular ejection fraction (LVEF) ≤30% by any acceptable method at the time of screening or documented within the previous 3 months
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Nt-proBNP >3000pg/mL or BNP >600pg/mL at screening
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New York Heart Association (NYHA) functional class IIIb or IV, i.e., chronic dyspnea or fatigue at rest or with minimal exertion at the time of screening or within the previous 3 months
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Renal dysfunction reflected by a glomerular filtration rate (GFR) <45 mL/min approximated by the Modification of Diet in Renal Disease formula.
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A clinical summary scoreof KCCQ of <50
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Patients on individually maximum tolerated dosage of recommended HF therapy. If not on optimal therapyrelevant to local guideline targets, previous attempts within the previous 3 months to optimze therapy which was poorly tolerated should be documented.
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Patients should NOT be considered as candidates for heart transplantation or LVAD for the duration of the study at inclusion according to the opinion of treating physicians.
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Women of childbearing potential (i.e., who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months) must commit either to abstain continuously from heterosexual sexual contact or to use at least one "highly effective" method of birth control (e.g., intrauterine device [IUD], hormonal contraception, tubal ligation, or partner's vasectomy) or two "effective" methods (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to screening and throughout study participation
- As alprostadil is not genotoxic and female sexual partners of male study participants are not likely to have substantial exposure via semen, there are no contraception requirements for men.
- Patients must be willing and able to give written informed consent, including local data privacy consents, as required.
Exclusion Criteria
Patients meeting any of the following criteria will be considered ineligible for enrollment into the study:
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Patients with most advanced disease or other treatment options:
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Systolic blood pressure less than 95 mmHg under euvolemic or hypervolemic conditions
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End-stage HF cardiac cachexia with current Body Mass Index (BMI) <18.5 kg/m 2 or weight loss of >10% of body mass within the last 6 months
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Patients with other special medical conditions:
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Presenting with unstable angina, valvular heart diseases other than mitral regurgitation, pulmonary edema, or acute gastric or duodenal ulcers
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History of type I myocardial infarction or stroke within 3 months of screening
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Any concomitant illness or other finding that, in the opinion of the Investigator, would confound the interpretation of the study results or place the patient at unacceptable risk if the patient were to participate in the study
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Patients or their relatives/caregivers who are determined by the training nurse not to be capable of correctly using the pump delivery system and handling the study drug
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Female patients who are pregnant or nursing
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Patients with a known hypersensitivity to alprostadil or any component of the formulation of study drug (denatured ethanol)
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Patients with prior participation in a study of systemically administered alprostadil
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Patients participating in another research study within 30 days prior to screening (i.e., the day the informed consent is signed) or anticipated to enroll in such during this study
-
Patients for whom informed consent cannot be obtained
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Medical university Vienna | Vienna | Austria |
Sponsors and Collaborators
- Biopeutics Co., Ltd
Investigators
- Principal Investigator: Martin Huelsmann, MD, Medical university Vienna, Department of Cardiology
- Principal Investigator: Noemi Pavo, MD PhD, Medical University Vienna, department of Cardiology
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 3-T02-07-0105