Inhibition of Sterile Inflammation by Digoxin

To investigate the effect of digoxin on pyruvate kinase isoform 2 (PKM2) binding to pro-inflammatory loci and innate immune inflammatory responses in the peripheral blood in healthy subjects.

Study Overview

• Status: Completed
• Conditions: Inflammatory Response
• Intervention / Treatment: Other: Placebo; Drug: Digoxin; Drug: Digoxin

Detailed Description

To investigate the effect of orally administered digoxin on innate immune inflammatory responses in the peripheral blood of healthy subjects. We hypothesize the reduction in innate immune inflammatory responses will be expected in the peripheral blood with the effect of oral digoxin.

To investigation how human peripheral blood immune cells change their inflammatory responses after exposure to digoxin in vitro.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale Centre of Clinical Investigation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria

1. Age >18 y ≤ 70 years
2. subjects with normal serum creatinine, normal EKG and currently not taking any medication.

Exclusion criteria

1. Autoimmune liver disease (ANA > 1/320)
2. Chronic viral hepatitis
3. Hepatocellular carcinoma
4. Complete portal vein thrombosis
5. Extrahepatic terminal disease
6. Pregnancy
7. Treatment with prednisolone or pentoxifyllin for more than 3 days prior to inclusion/start date
8. Active alcohol abuse (>50 g/day for men and >40 g/day for women) in the last 3 months
9. AST > ALT and total bilirubin > 3 mg/dl in the past 3 months
10. Liver biopsy and/or clinical picture consistent with alcoholic hepatitis
11. Lack of signed informed consent.
12. Known hypersensitivity to digoxin or other forms of digitalis, ventricular fibrillation.
13. Any significant medical conditions, any electrolyte abnormalities, over the counter medications, natural products and prescription drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; oral placebo	Other: Placebo; Oral placebo
Active Comparator: Digoxin 3 mcg/Kg/day; Patients receiving oral digoxin 3 mcg/Kg/day	Drug: Digoxin; Participants will receive 3 mcg/Kg/day doses of oral digoxin; Drug: Digoxin; Participants will receive 0.15 mcg/Kg/day doses of oral digoxin
Active Comparator: Digoxin 0.15 mcg; Patients receiving oral digoxin 0.15 mcg/Kg/day	Drug: Digoxin; Participants will receive 3 mcg/Kg/day doses of oral digoxin; Drug: Digoxin; Participants will receive 0.15 mcg/Kg/day doses of oral digoxin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lower Levels of Spontaneous Reactive Oxygen Species (ROS) Production	Investigators will be take neutrophils (PMN's) from the blood and seeing if the patients on digoxin have lower levels of spontaneous reactive oxygen species (ROS) production. This will be determined as a greater than 25% reduction in ROS compared to individuals not taking digoxin. The serum digoxin levels are just being done per usual guidelines to make sure that supratherapeutic levels of digoxin are not reached.	after starting digoxin
Lower Levels of Spontaneous Reactive Oxygen Species (ROS) Production	Investigators will take neutrophils (PMN's) from the blood and seeing if the patients on digoxin have lower levels of spontaneous reactive oxygen species (ROS) production. This will be determined as a greater than 25% reduction in ROS compared to individuals not taking digoxin. The serum digoxin levels are just being done per usual guidelines to make sure that supratherapeutic levels of digoxin are not reached.	1 week after starting digoxin
Lower Levels of Spontaneous Reactive Oxygen Species (ROS) Production	Investigators will take neutrophils (PMN's) from the blood and seeing if the patients on digoxin have lower levels of spontaneous reactive oxygen species (ROS) production. This will be determined as a greater than 25% reduction in ROS compared to individuals not taking digoxin. The serum digoxin levels are just being done per usual guidelines to make sure that supratherapeutic levels of digoxin are not reached.	2 weeks after starting digoxin
Lower Levels of Spontaneous Reactive Oxygen Species (ROS) Production	Investigators will take neutrophils (PMN's) from the blood and seeing if the patients on digoxin have lower levels of spontaneous reactive oxygen species (ROS) production. This will be determined as a greater than 25% reduction in ROS compared to individuals not taking digoxin. The serum digoxin levels are just being done per usual guidelines to make sure that supratherapeutic levels of digoxin are not reached.	3 weeks after starting digoxin

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigation of How Human Peripheral Blood Immune Cells Change Their Inflammatory Responses After Exposure to Digoxin in Vitro	Blood (25ml) will be obtained from healthy blood donors at one time. Human peripheral monocytes will be isolated using Polymorphprep™ density sedimentation according to the manufacturer's instructions. Data presented here are the mean concentrations.	6 weeks

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: Wajahat Mehal, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Actual): May 5, 2023
• Study Completion (Actual): May 5, 2023

Study Registration Dates

• First Submitted: June 6, 2018
• First Submitted That Met QC Criteria: June 6, 2018
• First Posted (Actual): June 18, 2018

Study Record Updates

• Last Update Posted (Actual): July 12, 2024
• Last Update Submitted That Met QC Criteria: July 10, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Digoxin
• Other Study ID Numbers: 2000025289; 1U01AA026962-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes