Janus Kinase Inhibition to Prevent Ventilator-induced Diaphragm Dysfunction

A Clinical Trial of JAK Inhibition to Prevent Ventilator-induced Diaphragm Dysfunction

We intend, with this study, to prove that blocking the molecular mechanisms whose blockade prevents VIDD in animals, will indeed prevent the development of VIDD in humans as well. We believe that this evidence will serve as the required basis for proceeding with large, ICU-based clinical trial(s) of a drug to prevent VIDD.

Study Overview

• Status: Recruiting
• Conditions: Diaphragm Injury
• Intervention / Treatment: Drug: Placebo to match Tofacitinib; Drug: Tofacitinib 10 MG [Xeljanz]

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Cheyenne A Clinical Research Coordinator, B.S, M.S; Phone Number: 3107201689; Email: csadeghi@stanford.edu

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford University Medical Center
      • Contact: Study Team; Phone Number: 650-721-6561; Email: csadeghi@stanford.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients undergoing esophagectomy

Exclusion Criteria:

• Patients with more than mild pulmonary dysfunction
• Patients with any neuromuscular disease that might compromise diaphragm function
• Patients with abnormal liver or kidney function
• Patients taking any immunosuppressant medication (including prednisone) or antifungal medications
• History of tuberculosis
• Weight loss of >5% of body weight over previous 6 months
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tofacitinib; Patient will receive two days treatment with tofacitinib prior to the surgery.	Drug: Tofacitinib 10 MG [Xeljanz]; administered twice daily for two days; Other Names: XELJANZ
Placebo Comparator: Placebo; Patient will receive two days treatment with placebo prior to the surgery.	Drug: Placebo to match Tofacitinib; administered twice daily for two days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevention of ventilator-induced diaphragm dysfunction by JAK inhibition	Change in the force deficit that develops between the first and second muscle biopsies in the drug-treated vs. placebo groups	5-6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increase in muscle strength due to JAK inhibition	Difference in force generated by muscle biopsies taken at time point 1 (pre-mechanical ventilation) from the drug-treated vs placebo groups	4-5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory: Determine mechanisms of changes in muscle strength and ventilator-induced diaphragm dysfunction by JAK inhibition.	Compare differences in muscle between the drug-treated and placebo groups in mitochondrial function and oxidative stress (ATP levels, citrate synthase activity, succinate dehydrogenase activity, mitochondrial respiration rate, activity of mitochondial enzymatic compexes).	4-6 years
Exploratory: Determine mechanisms of changes in muscle strength and ventilator-induced diaphragm dysfunction by JAK inhibition.	Compare differences in muscle between the drug-treated and placebo groups in proteolytic pathways (quantitative PCR for atrogein, MuRF1, and FoxO gene expression, western blot analysis for protein levels of these and protein polyubiquitination, proteasomal activity, qPCR and western blots for expression of LC3).	4-6 years
Exploratory: Determine mechanisms of changes in muscle strength and ventilator-induced diaphragm dysfunction by JAK inhibition.	Compare differences in muscle between the drug-treated and placebo groups in transcriptomic gene profiling, and metabolomic profiling..	4-6 years

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Joseph Shrager, MD, Stanford University

Publications and helpful links

General Publications

• Shrager JB, Wang Y, Lee M, Nesbit S, Trope W, Konsker H, Fatodu E, Berry MS, Poulstides G, Norton J, Burdon T, Backhus L, Cooke R, Tang H. Rationale and design of a mechanistic clinical trial of JAK inhibition to prevent ventilator-induced diaphragm dysfunction. Respir Med. 2021 Nov-Dec;189:106620. doi: 10.1016/j.rmed.2021.106620. Epub 2021 Sep 21.
• Shrager JB, Randle R, Lee M, Ahmed SS, Trope W, Lui N, Poultsides G, Liou D, Visser B, Norton JA, Nesbit SM, He H, Kapula N, Wallen B, Fatodu E, Sadeghi CA, Konsker HB, Elliott I, Guenthart B, Backhus L, Cooke R, Berry M, Tang H. JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle. Life Sci Alliance. 2024 Aug 9;7(11):e202402885. doi: 10.26508/lsa.202402885. Print 2024 Nov.

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2019
• Primary Completion (Estimated): November 30, 2025
• Study Completion (Estimated): November 30, 2026

Study Registration Dates

• First Submitted: September 20, 2018
• First Submitted That Met QC Criteria: September 20, 2018
• First Posted (Actual): September 24, 2018

Study Record Updates

• Last Update Posted (Actual): November 25, 2024
• Last Update Submitted That Met QC Criteria: November 21, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Ventilator-induced Diaphragm Dysfunction
• Additional Relevant MeSH Terms: Janus Kinase Inhibitors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tofacitinib
• Other Study ID Numbers: IRB-47826; 3R01AG069858-02W1 (U.S. NIH Grant/Contract: NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No plan to share IPD.

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.: No