Clinical trial NCT00610051: ALP-1 Continuous Intravenous Infusion to Maintain Clinical Stability in Advanced Heart Failure
Official title: Phase 3 Study of Alprostadil Continuous Intravenous Infusion to Maintain Clinical Stability in Severe Heart Failure Patients
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Heart Failure
Keywords: severe heart failure
Lead sponsor: Biopeutics Co., Ltd
Sponsor class: INDUSTRY
First posted: 2008-02-07
Enrollment: 1500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This multicenter, double-blind, placebo-controlled, randomized, parallel-group trial will study up to approximately 700 patients with advanced HFrEF who are not expected to receive heart transplant or LVAD placement for 6 months after enrollment. Eligible patients will be randomized (1:1) to receive either alprostadil 250 μg/day, regardless of body weight, or placebo (normal saline) given in a continuous infusion. Study drug administration will continue until study closure so long as clinically tolerated and the mortality endpoint has not been achieved; patients are to be followed for survival regardless of whether or not they remain on study drug. The difference in mortality rates between the two groups will be compared after approximately 350 deaths, LVAD placements, or heart transplantations have occurred. The study will include an embedded pilot evaluation of secondary nonfatal clinical endpoints and AESIs/ tolerability for purposes of possible protocol modification.
Primary purpose: TREATMENT

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 6 months of study drug therapy (Double-Blind Treatment Phase).

Detailed description: This multicenter, double-blind, placebo-controlled, randomized, parallel-group trial will study up to approximately 700 patients with advanced HFrEF who are not expected to receive heart transplant or LVAD placement for 6 months after enrollment. Eligible patients will be randomized (1:1) to receive either alprostadil 250 μg/day, regardless of body weight, or placebo (normal saline) given in a continuous infusion. The treatments are further described in the section on Dose/Route/Regimen. Study drug administration will continue until study closure so long as clinically tolerated and the mortality endpoint has not been achieved; patients are to be followed for survival regardless of whether or not they remain on study drug. The difference in mortality rates between the two groups will be compared after approximately 350 deaths, LVAD placements, or heart transplantations have occurred. The study will include an embedded pilot evaluation of secondary nonfatal clinical endpoints and AESIs/ tolerability for purposes of possible protocol modification. Specifically, selected data for the first 70 patients entered (i.e., randomized) will be evaluated in an unblinded manner after the 6-month assessment of the last surviving patient (of the first 70 randomized patients) to discern the effects on (1) patient global assessment, KCCQ, and worsening heart failure events; (2) the occurrence of hypotension, joint/bone pain, diarrhea and headache; and (3) difficulties with protocol implementation. The interim assessment and possible revision of the primary endpoint are discussed further below in the roles of the independent review committees and in the Study Power and Planned Sample Size section.

The screening activities will be performed on stable patients on an outpatient basis or on recently hospitalized patients (inpatient) who are otherwise ready for discharge after clinical stabilization and stabilization of dose of diuretics. Selected patients need to be on all appropriate doses of recommended HF therapy as judged by the Investigator. Screening should not exceed 14 days. The following independent committees will be established and operate under charters outlining operational procedures and responsibilities, briefing desccribed as follows:

* A Steering Committee (SC), involved in initial protocol development, will review selected data from the embedded pilot phase; all-cause mortality data will not be shared. Following the placement of the central catheter in the first 70 patients, a determination will be made whether or not the subsequent entered patients need to be hospitalized for the first 24 hours; this assessment will be on the basis of blinded data accrued until discharge and the initial study nurse home visit. Once the last of the first 70 patients achieves the 6-month milestone, unblinded data, other than mortality, will be reviewed. If the analysis indicates that there is little unblinding based on tolerability (i.e., AESIs) and there is a reasonable expectation of clinical benefit on one or more of the secondary endpoints, the SC may designate one as primary or design and implement a "hierarchical composite" of the nonfatal and fatal events as the primary endpoint to be applied to all patients randomized into the trial AFTER the 70th randomized patient. If this were to occur, all-cause mortality would become a key secondary endpoint, to be analyzed for non-inferiority based on all randomized patients inclusive of the first 70 patients.
* A Data Safety Monitoring Board (DSMB) will review unblinded mortality and safety data at regular intervals throughout the study. The role of the DSMB will primarily be to advise the Sponsor on whether or not the study should continue.

Eligibility criteria: 1. Patients older than 18 years of age, of any gender/sex and race/ethnicity
2. Patients with a diagnosis of advanced HFrEF as evidenced by (all must apply):

   1. Left ventricular ejection fraction (LVEF) ≤30% by any acceptable method at the time of screening or documented within the previous 3 months
   2. Nt-proBNP \>3000pg/mL or BNP \>600pg/mL at screening
   3. 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
   4. Renal dysfunction reflected by a glomerular filtration rate (GFR) \<60 mL/min approximated by the Modification of Diet in Renal Disease formula.
   5. A clinical summary scoreof KCCQ of \<50
   6. Patients on all appropriate recommended HF therapy.
3. Patient should not be receiving continuous or planned intermittent intravenous infusions with a positive inotropic or vasodilator drug in a non-hospitalized setting
4. Patients should not be considered as candidates for heart transplantation or LVAD for at least 6 months from randomization according to the opinion of the treating physician.
5. 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.

   Note: 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.
6. Patients must be willing and able to give written informed consent, including local data privacy consents, as required

Primary outcomes:
measure: Time to all-cause mortality (defined as death, heart transplant, or LVAD placement)
timeFrame: 6 months infusion
Secondary outcomes:
measure: To assess the effect of continuous long-term alprostadil infusion compared to placebo on secondary efficacy endpoints over 6 months ALP-1-infusion over 52 weeks compared to placebo in patients with advanced HFrEF
timeFrame: 6 months
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical university Vienna
Study officials:
affiliation: Medical university Vienna, Department of Cardiology
name: Martin Huelsmann, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University Vienna, department of Cardiology
name: Noemi Pavo, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: