Midodrine in Heart Failure With Reduced Ejection Fraction With Hypotension

NCT06405555 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: 5784
• Study Type: interventional
• Target: 56
• Locations: 0 countries
• Sites: N/A

Brief Summary

The evidence-based pharmacologic treatments available for patients with heart failure with reduced ejection fraction (HFrEF) has been established over the last few decades of cardiovascular research. These treatments, termed Foundational Guideline-Directed-Medical Therapies (GDMT), prolong patient life, improve patient-reported symptoms, and reduce hospitalizations for heart failure. A direct effect of most medication classes encompassed within GDMT is the reduction in blood pressure due to their mechanisms of action. In addition, as patients with HFrEF become more advanced in their disease, a significant proportion develop hypotension related to pump failure and autonomic dysfunction, amongst other possible mechanisms. As a result, a significant proportion of HFrEF patients are not optimized on GDMT with hypotension as their limiting barrier that would otherwise have served to improve their heart function, heart failure symptoms, and mortality. Currently, there does not exist any evidence-based strategies to address the problem of hypotension in HFrEF patients who are not optimized on GDMT. Midodrine is an alpha-adrenergic agonist (α1-AR) that exerts its effects on peripheral venous and arteriolar vasculature to increase blood pressure. This medication has been used off-label by some clinicians in the hypotensive HFrEF population to increase blood pressure and has been reported to have beneficial effects in improving GDMT utilization as well as increasing left ventricular ejection fraction (LVEF) in published case reports/case series. There does not exist any randomized prospective data on the use of midodrine in the hypotensive HFrEF population. The investigators' objective is to complete the first open-label, randomized control trial of midodrine in the hypotensive HFrEF population to demonstrate feasibility in performing a trial in this patient population and to show efficacy in increasing blood pressure without associated harm. The results of this trial will be used as the foundation and rationale for future studies assessing the impact of midodrine use on GDMT utilization as well as hard cardiovascular outcomes in the hypotensive HFrEF population, including hospitalizations for heart failure and mortality.

Conditions

Heart Failure With Reduced Ejection Fraction; Hypotension; LV Dysfunction

Keywords

Heart Failure; GDMT; Midodrine

Outcome Measures

Primary Outcomes (5)

• Enrollment rate

  Number of participants enrolled per week

  From the date of enrolment of the first study participant, to the date of enrolment of up to 56 patients, assessed up to a maximum of 80 weeks (20 months)

• Percent enrollment

  Number of participants enrolled divided by number screened eligible

  From the date of enrolment of the first study participant, to the date of enrolment of up to 56 patients, assessed up to a maximum of 80 weeks (20 months)

• Randomization proportion

  Number of participants randomized divided by number of participants enrolled

  From the date of enrolment of the first study participant, to the date of enrolment of up to 56 patients, assessed up to a maximum of 80 weeks (20 months)

• Percentage of protocol completion

  Number of participants completing the study protocol divided by the number of participants randomized.

  From the date of enrolment of the first study participant, to the date of enrolment of up to 56 patients, assessed up to a maximum of 80 weeks (20 months)

• Percentage lost to follow-up

  Number of participants lost to follow-up divided by number of participants randomized.

  From the date of enrolment of the first study participant, to the date of enrolment of up to 56 patients, assessed up to a maximum of 80 weeks (20 months)

Secondary Outcomes (23)

• SBP at baseline compared to Day 4 or hospital discharge if earlier

  Measures from time of enrolment (Day -1 or 0) and Day 4, or hospital discharge if earlier

• Proportion of patients achieving sBP > 105 mmHg on Day 4 or hospital discharge if earlier

  Measurement from Day 4 of study protocol, or hospital discharge if earlier

• DBP at baseline compared to Day 4 or hospital discharge if earlier

  Measures from time of enrolment (Day -1 or 0) and Day 4, or hospital discharge if earlier

• NT-proBNP at baseline compared to Day 4 or hospital discharge if earlier.

  Measures from time of enrolment (Day -1, or earlier if available) and Day 4, or hospital discharge if earlier

• Time from randomization to hospital discharge (days).

  From the date of participant randomization to the date of discharge from hospital (to home, rehabilitation or transitional institution, long-term care/nursing home), up to 4 weeks.

Other Outcomes (3)

• Number of serious adverse events after initiation of midodrine.

  At Day 0 (or hospital discharge if earlier) up to 48 hours after last dose of midodrine

• Midodrine intolerance

  At Day 0 to Day 4 (or hospital discharge if earlier).

• Adverse Drug Reactions (ADR) reported after initiating midodrine

  At Day 0 (or hospital discharge if earlier) up to 48 hours after last dose of midodrine

Study Arms (2)

Midodrine treatment

EXPERIMENTAL

Patients randomized to receive midodrine for up to 5 days in hospital at escalating doses starting at 2.5 mg po TID x 1 day, 5.0 mg po TID x 1 day, 7.5 mg po TID x 1 day, 10 mg po TID x 2 days. Patients may be discharged from hospital prior to completion of the full 5 day protocol. All patients in the midodrine treatment arm will receive otherwise usual standard of care treatments.

Drug: Midodrine Oral Tablet

Control

NO INTERVENTION

Patients randomized to the control arm will receive usual standard of care treatments without addition of midodrine.

Interventions

Midodrine Oral Tablet DRUG

Exposure to up to 5 days of midodrine (or until hospital discharge) in hospital at escalating doses with the following protocol: 2.5 mg po TID x 1 day, 5.0 mg po TID x 1 day, 7.5 mg po TID x 1 day, 10 mg po TID x 2 days.

Also known as: Midodrine hydrochloride

Midodrine treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults \>= 18 years of age.
• LVEF \<= 40 % within the last 3 months as determined by any one of: Transthoracic echocardiogram, transesophageal echocardiogram, cardiac magnetic resonance imaging, MUGA scan, angiogram with left ventriculogram.
• AHA/ACC Stage B or C Heart Failure
• Hospitalized patients in the ward setting OR in the cardiac intensive care unit (who are \>= 48 hours after their last dose of vasopressor or inotrope).
• Seated upright or supine SBP \<= 100 mmHg on two or more consecutive BP measurements separated by at least 8 hours

You may not qualify if:

• Patient OR substitute decision-maker (SDM) unwilling or unable to provide informed consent
• Documented allergy or intolerance to midodrine
• Treatment for active infection (either documented infection or empiric treatment) with antimicrobials at the time of recruitment.
• Current use OR any use within the last 48 hours of an intravenous inotrope or vasopressor medication OR the need for IV inotrope or vasoproessor use to treat hypotension
• Patient within 72 hours of an acute coronary syndrome.
• Heart transplant recipient.
• Presence of temporary or durable mechanical circulatory support device.
• Severe valvular disease expected to be intervened upon during the incident hospitalization.
• Hyperkalemia \>= 5.5 mmol/L.
• Baseline eGFR (as calculated by the CKD-EPI method) \<= 20 mL/min/1.73 m2 as measured within the last 3 months.
• A treatable cause for hypotension, including but not limited to: hypovolemia (eg. Bleeding, overdiuresis, poor oral intake), obstructive shock, sepsis, adrenal insufficiency.
• Clinical diagnosis of ongoing cardiogenic shock, or diagnosed as defined in SHOCK trial: sBP \<= 90 mmHg with evidence of end-organ hypoperfusion (cool extremities, urine output \< 30 mL/hr, HR \> 60 bpm, or elevated lactate \>=3.5 mmol/L), invasive hemodynamic measurements (if available) of CI \<= 2.2 L/min/m2 and a pulmonary capillary wedge pressure (PCWP) of \>=15 mmHg.
• Pregnant patient.
• Anticipated patient discharge in less than two days from enrolment (ie. less than 6 anticipated doses of midodrine, if randomized to treatment/intervention arm).
• Acute brain pathology (including, but not limited to intracranial hemorrhage or hematoma) in which most-responsible clinician deems it unsafe to augment blood pressure.

Sponsors & Collaborators

• Ottawa Heart Institute Research Corporation: lead

MeSH Terms

Conditions

Hypotension; Ventricular Dysfunction, Left; Heart Failure

Interventions

Midodrine

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Ventricular Dysfunction; Heart Diseases

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines

Study Officials

• :Lisa M Mielniczuk, MD

  Ottawa Heart Institute Research Corporation

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lisa M Mielniczuk, MD

CONTACT

6136967274; lmielniczuk@ottawaheart.ca

Shihab Sarwar, MD

CONTACT

ssarwar@ottawaheart.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: The study is open label and neither the study participant, research team, or members within the circle of care of the patient will be blinded to the randomization/treatment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants are randomized in a 1:1 fashion to either the treatment arm (midodrine + standard of care) or control (no-midodrine, standard of care).

Study Record Dates

• First Submitted: April 25, 2024
• First Posted: May 8, 2024
• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028
• Last Updated: April 30, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share