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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called Tofacitinib to determine if it can prevent diaphragm injuries in individuals undergoing esophagus surgery. Researchers aim to discover whether this drug can prevent diaphragm damage that sometimes occurs during surgery, which can lead to breathing difficulties afterward. In the trial, some participants will receive Tofacitinib, while others will receive a placebo (a harmless pill resembling the real drug). Individuals undergoing esophagectomy surgery without severe lung problems or certain other health issues may be suitable for this trial. As a Phase 2 trial, this research focuses on assessing how well Tofacitinib works in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tofacitinib has been studied to assess its safety and effectiveness. In one study with Japanese patients, researchers compared different doses of tofacitinib to a placebo (a pill with no active medicine). The results indicated that tofacitinib was generally well-tolerated, though some side effects were reported. Another study found a higher risk of serious heart problems and cancer when used for arthritis and ulcerative colitis.

Tofacitinib is already approved for other conditions, providing a basic understanding of its safety. However, because this trial is in an earlier phase, researchers are closely monitoring its safety. Participants should consider these findings and discuss any concerns with the trial team. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for diaphragm injury, which often involves surgical repair or supportive therapies, Tofacitinib offers a unique approach by targeting specific inflammatory pathways. Tofacitinib is a JAK inhibitor, which means it works by interfering with the Janus kinase pathways involved in the body's inflammatory response. This mechanism not only helps reduce inflammation but could also speed up recovery by being administered just two days before surgery, potentially improving surgical outcomes. Researchers are excited about Tofacitinib because it could offer a more targeted and efficient treatment option compared to traditional methods.

What evidence suggests that Tofacitinib might be an effective treatment for diaphragm injury?

Research has shown that Tofacitinib, a medication for rheumatoid arthritis, might prevent diaphragm injury by blocking certain pathways in the body. In studies with arthritis patients, Tofacitinib improved symptoms more than a placebo, indicating its effectiveness in reducing inflammation, which is crucial for preventing muscle damage. In this trial, some participants will receive Tofacitinib, while others will receive a placebo. The researchers aim to determine if Tofacitinib can also prevent diaphragm injury, as this condition shares some causes with other inflammatory issues. Although direct data on diaphragm injury is limited, the drug's mechanism suggests its potential in this area is worth exploring. ^{1 4 6 7 8}

Who Is on the Research Team?

Joseph Shrager, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 (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]

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 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]

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 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]

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, 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8671221/

Rationale and Design of a Mechanistic Clinical Trial of JAK ... The primary hypothesis tested is that JAK inhibition with Tofacitinib will prevent VIDD (defined as reduction maximal isometric force of ...

2. arthritis-research.biomedcentral.com arthritis-research.biomedcentral.com/articles/10.1186/s13075-023-03154-z

Efficacy and safety of tofacitinib in patients with rheumatoid ... At month 3, efficacy was generally improved with tofacitinib (both doses) vs placebo in each population. Generally, efficacy outcomes with ...

3. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000PharmR.pdf

203214Orig1s000 - accessdata.fda.gov Tofacitinib produced external, skeletal and visceral malformations in rabbits and external and skeletal malformations in rats. The NOAEL for ...

4. xeljanz.com xeljanz.com/ra/clinical-trials

Clinical Trials | XELJANZ® (tofacitinib) For RA | Safety Info At 6 months, XELJANZ patients experienced less joint damage progression than methotrexate patients. Common side effects of XELJANZ in rheumatoid arthritis ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9114845/

Efficacy of tofacitinib in patients with rheumatoid arthritis ... Tofacitinib showed greater efficacy improvements versus placebo in each BMI category. Differences in efficacy outcomes (adjusted and unadjusted) ...

6. fda.gov fda.gov/safety/medical-product-safety-information/xeljanz-xeljanz-xr-tofacitinib-drug-safety-communication-initial-safety-trial-results-find-increased

Xeljanz, Xeljanz XR (tofacitinib): Drug Safety Communication Preliminary results from a safety clinical trial show an increased risk of serious heart-related problems and cancer with the arthritis and ulcerative colitis ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/21584942/

Phase II study of tofacitinib (CP-690550) combined with ... Objective: To compare the efficacy, safety, and tolerability of 4 doses of oral tofacitinib (CP-690,550) with placebo in Japanese patients with active ...

8. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/04/NCT03281304/Prot_001.pdf

A PHASE 3B/4, MULTI-CENTER, DOUBLE- ... The tofacitinib 10 mg BID group also had statistically significantly higher proportions of subjects with the secondary endpoints of clinical ...