Janus Kinase Inhibition to Prevent Ventilator-induced Diaphragm Dysfunction

ConditionDiaphragm Injury

Trial statusRecruiting

Trial phasePhase 2

Trial typeInterventional

Biological sexAll

Age18+

SponsorStanford University

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Patients undergoing esophagectomy

Disqualifiers

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

Trial design

Design model

Parallel

Treatments tested in this trial

Tofacitinib 10 MG [Xeljanz]
Drug
administered twice daily for two days
Placebo to match Tofacitinib
Drug
administered twice daily for two days

Treatment groups

70 Participants

are divided into 2 treatment groups

Group A: TofacitinibExperimental treatment 1 intervention

Group B: PlaceboPlacebo comparator 1 intervention

Trial outcomes

Primary outcomes

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

Time frame

5-6 years

Secondary outcomes

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

Time frame

4-5 years

Other outcomes

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).

Time frame

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).

Time frame

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..

Time frame

4-6 years