Tofacitinib for Diaphragm Injury

Overseen By Cheyenne A Clinical Research Coordinator, B.S, M.S

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stanford University

Must not be taking: Immunosuppressants, Antifungals

Disqualifiers: Pulmonary dysfunction, Neuromuscular disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 2 days

70 Participants Needed

Trial Summary

What is the purpose of 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.

Will I have to stop taking my current medications?

If you are taking any immunosuppressant or antifungal medications, you will need to stop taking them to participate in this trial.

What data supports the effectiveness of the drug tofacitinib for diaphragm injury?

Tofacitinib is known to be effective for treating rheumatoid arthritis, as it is an oral drug that inhibits Janus kinases, which are involved in inflammation. While there is no direct evidence for diaphragm injury, its effectiveness in reducing inflammation in other conditions suggests potential benefits. ^{1 2 3 4 5}

How is the drug tofacitinib unique for treating diaphragm injury?

Tofacitinib is unique because it is an oral drug that selectively inhibits Janus kinases, which are involved in immune and inflammatory processes. This mechanism of action is different from other treatments that may not target these specific pathways, and its oral administration offers a convenient alternative to injectable therapies. ^{3 6 7 8 9}

Research Team

Joseph Shrager, MD

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for patients who are undergoing esophagectomy surgery and do not have neuromuscular diseases, liver or kidney issues, or severe lung problems. They shouldn't be on immunosuppressants or antifungal meds, haven't lost more than 5% of their weight recently, aren't pregnant, and don't have a history of tuberculosis.

Inclusion Criteria

I am scheduled for or have had an esophagectomy.

Exclusion Criteria

I am currently taking immunosuppressant or antifungal medications.

I have a condition that could affect my diaphragm's ability to work.

My liver or kidney function is not normal.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive two days of treatment with either placebo or tofacitinib prior to surgery

2 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

5-6 years

Treatment Details

Interventions

• Placebo to match Tofacitinib
• Tofacitinib

Trial Overview The study tests if Tofacitinib (Xeljanz) can prevent diaphragm muscle weakness caused by mechanical ventilation during surgery compared to a placebo. It's based on previous animal studies showing that blocking certain molecular pathways can prevent this condition.

Participant Groups

Group I: Tofacitinib Experimental Treatment 1 Intervention

Patient will receive two days treatment with tofacitinib prior to the surgery.

Group II: Placebo Placebo Group 1 Intervention

Patient will receive two days treatment with placebo prior to the surgery.

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

A study involving 52 healthy Chinese subjects demonstrated that a generic immediate-release tofacitinib tablet is bioequivalent to the brand-name version, showing no significant differences in key pharmacokinetic measures like maximum plasma concentration and area under the curve.

The study found that food intake did not significantly affect the drug's absorption or elimination, indicating that tofacitinib can be taken with or without food without impacting its efficacy or safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Bioequivalence of 2 Immediate-Release Tofacitinib Tablet Formulations in Chinese Healthy Volunteers Under Fasting and Fed Conditions. Li, X., Liu, L., Deng, Y., et al.[2022]

Tofacitinib at doses of 3 mg or higher taken twice daily showed significant efficacy in treating active rheumatoid arthritis, with ACR20 response rates reaching up to 71.9% by week 12, compared to 22.0% for placebo.

The treatment was generally well-tolerated, with manageable side effects, the most common being urinary tract infections and diarrhea, indicating a favorable safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Fleischmann, R., Cutolo, M., Genovese, MC., et al.[2022]

Tofacitinib aspartate (7.13 mg) demonstrated bioequivalence to the reference formulation tofacitinib citrate (8.08 mg) in a study involving 41 healthy volunteers, indicating similar pharmacokinetic profiles for both formulations.

The study found that both formulations were well-tolerated, with no significant differences in maximum concentration (Cmax) and area under the concentration-time curve (AUClast), suggesting that tofacitinib aspartate can be a viable alternative to the existing formulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects. Shin, W., Yang, AY., Yun, H., et al.[2022]

Transdermal systems of tofacitinib, including a transdermal patch and a microneedle array, demonstrated significant efficacy in reducing arthritis symptoms and inflammatory cytokines in a rat model, outperforming traditional oral administration methods.

Both systems showed good stability over 90 days and effective drug release and permeation, making them promising alternatives for rheumatoid arthritis treatment with improved clinical relevance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and evaluation of tofacitinib transdermal system for the treatment of rheumatoid arthritis in rats. Li, Y., Sun, Y., Wei, S., et al.[2022]

Tofacitinib, an oral JAK inhibitor for rheumatoid arthritis, successfully transitioned from immediate-release (IR) to extended-release (XR) formulation without needing a phase III trial, thanks to a model-informed exposure-response approach.

The study demonstrated that the XR formulation had equivalent total systemic exposure to the IR formulation, supporting its efficacy and leading to regulatory approval by the FDA for once-daily dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Model-Informed Development and Registration of a Once-Daily Regimen of Extended-Release Tofacitinib. Lamba, M., Hutmacher, MM., Furst, DE., et al.[2018]

Tofacitinib is the first JAK inhibitor approved for treating rheumatoid arthritis (RA) and works by selectively inhibiting JAKs, which play a key role in inflammatory processes related to the disease.

In large clinical trials, tofacitinib was found to be effective and generally well tolerated for adult patients with moderately to severely active RA who did not respond adequately to previous treatments, including methotrexate and other DMARDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofacitinib: a review of its use in adult patients with rheumatoid arthritis. Scott, LJ.[2022]

Tofacitinib, an oral Janus kinase inhibitor, was found to be safe and well-tolerated in a study involving 95 healthy participants, with only mild adverse events like nausea and headache reported.

The pharmacokinetics of tofacitinib showed rapid absorption and elimination, indicating that it reaches peak serum concentration quickly and is eliminated from the body efficiently, which is important for its potential therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers. Krishnaswami, S., Boy, M., Chow, V., et al.[2022]

Tofacitinib, an oral JAK inhibitor, demonstrated bioequivalence to Xeljanz® in a phase I trial involving 32 healthy Chinese subjects, with pharmacokinetic parameters such as peak concentration and area under the curve falling within the acceptable range of 80-125%.

The safety profile of tofacitinib was found to be comparable to that of Xeljanz®, supporting its potential for clinical use in treating inflammatory and autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, crossover, phase I clinical study to evaluate bioequivalence and safety of tofacitinib and Xeljanz® in Chinese healthy subjects. Xu, Z., Wang, Y., Liu, Z., et al.[2022]

Tofacitinib (Xeljanz®) is an effective oral treatment for rheumatoid arthritis (RA), showing significant improvements in symptoms and quality of life compared to placebo, as demonstrated in Phase III clinical trials.

While tofacitinib has a generally acceptable safety profile, it can lead to serious adverse effects such as infections and cardiovascular events, necessitating careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European perspective on the management of rheumatoid arthritis: clinical utility of tofacitinib. Kawalec, P., Śladowska, K., Malinowska-Lipień, I., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Bioequivalence of 2 Immediate-Release Tofacitinib Tablet Formulations in Chinese Healthy Volunteers Under Fasting and Fed Conditions. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. [2022]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Development and evaluation of tofacitinib transdermal system for the treatment of rheumatoid arthritis in rats. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Model-Informed Development and Registration of a Once-Daily Regimen of Extended-Release Tofacitinib. [2018]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Tofacitinib: a review of its use in adult patients with rheumatoid arthritis. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

A randomized, crossover, phase I clinical study to evaluate bioequivalence and safety of tofacitinib and Xeljanz® in Chinese healthy subjects. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

European perspective on the management of rheumatoid arthritis: clinical utility of tofacitinib. [2020]