Tofacitinib for Diaphragm Injury
Recruiting in Palo Alto (17 mi)
Overseen byJoseph Shrager, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Stanford University
Must not be taking: Immunosuppressants, Antifungals
Disqualifiers: Pulmonary dysfunction, Neuromuscular disease, others
Prior Safety Data
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.12345
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.36789
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.
See 4 more
Trial 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 (Drug)
- Tofacitinib (Janus Kinase (JAK) Inhibitor)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Placebo Group
Group I: TofacitinibExperimental Treatment1 Intervention
Patient will receive two days treatment with tofacitinib prior to the surgery.
Group II: PlaceboPlacebo Group1 Intervention
Patient will receive two days treatment with placebo prior to the surgery.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Stanford University Medical CenterStanford, CA
Loading ...
Who Is Running the Clinical Trial?
Stanford UniversityLead Sponsor
National Institutes of Health (NIH)Collaborator
National Heart, Lung, and Blood Institute (NHLBI)Collaborator
References
Pharmacokinetics and Bioequivalence of 2 Immediate-Release Tofacitinib Tablet Formulations in Chinese Healthy Volunteers Under Fasting and Fed Conditions. [2022]The purpose of this study was to evaluate the bioequivalence of a generic immediate-release tofacitinib tablet versus a brand-named immediate-release tofacitinib tablet under fasting and fed conditions, and the food effect on pharmacokinetic profiles of the both formulations. This randomized, open-label, 2-period, crossover, bioequivalence study included 52 healthy Chinese subjects (fasting cohort: n = 26; fed cohort: n = 26). The subjects were assigned to receive a single 5-mg dose of generic or brand-named tofacitinib. Blood samples were collected at predosing and up to 14 hours after dosing. Tofacitinib concentrations in plasma were analyzed by high-performance liquid chromatography-tandem mass spectrometry. Safety was monitored. There were no significant differences in maximum plasma concentration, area under the plasma concentration-time curve from time zero to time t (AUC0-t ), AUC from time zero to infinity (AUC0-∞ ), and terminal elimination half-life between the test and reference formulations (all P > .05); high-fat food had no significant effect on AUC0-t , AUC0-∞, or terminal elimination half-life of immediate-release tofacitinib tablets (all P > .05). The 90% confidence intervals of the test/reference ratios of log-transformed maximum plasma concentration, AUC0-t , and AUC0-∞ were within the range of 80% to 125% under both fasting and fed conditions. No serious adverse events were reported. The 2 formulations of immediate-release tofacitinib tablets are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese volunteers. Food had no clinically relevant effects on drug exposure of tofacitinib.
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]To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs.
Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects. [2022]Tofacitinib is an oral disease-modifying anti-rheumatic drug to selectively inhibit Janus kinases. Tofacitinib is a representative small molecule inhibitor that is used to treat many diseases including rheumatoid arthritis and various autoimmune conditions. Unlike biological agents, tofacitinib has several advantages, including the ability to be administered orally and a short half-life. This study aimed to evaluate the bioequivalence of the pharmacokinetics (PK) between tofacitinib aspartate 7.13 mg (test formulation) and tofacitinib citrate 8.08 mg (reference formulation; Xeljanz®) in healthy subjects. A randomized, open-label, single-dose, 2-sequence, 2-period, 2-treatment crossover trial was conducted in 41 healthy volunteers. A total of 5 mg of tofacitinib as the test or the reference formulation was administered, and serial blood samples were collected up to 14 hours after dosing for PK analyses. The plasma concentration of tofacitinib was determined by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental analysis was used to estimate the PK parameters. A total of 35 subjects completed the study and the study drug was well-tolerated. The mean maximum concentration (Cmax) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) for the test formulation were 52.67 ng/mL and 133.86 ng∙h/mL, respectively, and 50.61 ng/mL and 133.49 h∙ng/mL for the reference formulation, respectively. The geometric mean ratios (90% confidence intervals) of the Cmax and AUClast between the 2 formulations were 1.041 (0.944-1.148) and 1.003 (0.968-1.039), respectively. Tofacitinib aspartate exhibited bioequivalent PK profiles to those of the reference formulation.
Development and evaluation of tofacitinib transdermal system for the treatment of rheumatoid arthritis in rats. [2022]Tofacitinib tablet is approved for the treatment of rheumatoid arthritis (RA). However, tofacitinib (Tfc) faces extensive first-pass metabolism following oral administration.
Model-Informed Development and Registration of a Once-Daily Regimen of Extended-Release Tofacitinib. [2018]Extended-release (XR) formulations enable less frequent dosing vs. conventional (e.g., immediate release (IR)) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model-informed, exposure-response (E-R) approach to translate controlled trial data from one formulation to another without a phase III trial, using a tofacitinib case study. Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). E-R analyses were conducted using validated clinical endpoints from phase II dose-response and nonclinical dose fractionation studies of the IR formulation. Consistent with the delay in clinical response dynamics relative to PK, average concentration was established as the relevant PK parameter for tofacitinib efficacy and supported pharmacodynamic similarity. These evaluations, alongside demonstrated equivalence in total systemic exposure between IR and XR formulations, provided the basis for the regulatory approval of tofacitinib XR once daily by the US Food and Drug Administration.
Tofacitinib: a review of its use in adult patients with rheumatoid arthritis. [2022]Tofacitinib (Xeljanz(®)) is the first approved drug in a new class of disease modifying antirheumatic drugs (DMARDs), the Janus kinase (JAK) inhibitors. JAKs have a pivotal role in triggering cytokine-induced signal transduction pathways that influence normal and pathological cellular processes of haematopoiesis and immune cell function, including pathogenic mechanisms involved in rheumatoid arthritis (RA). Selective inhibition of JAKs by tofacitinib potentially modulates inflammatory processes and provides a novel approach for the treatment of RA. Oral tofacitinib is indicated for the treatment of adult patients with active RA who have had an inadequate response to methotrexate and/or other DMARDs. In several large well designed trials, tofacitinib, in combination with methotrexate or other nonbiological DMARDs or as monotherapy, was an effective and generally well tolerated DMARD for the treatment of adult patients with moderately to severely active RA who had had an inadequate response to previous DMARDs, including tumour necrosis factor-α inhibitors. Direct head-to-head trials and/or further clinical experience (including long-term safety data), along with robust pharmacoeconomic studies, are required to more definitively position tofacitinib relative to other currently available DMARDs. In the meantime, tofacitinib (alone or in combination with nonbiological DMARDs) is an emerging option for the treatment of DMARD-experienced adult patients with moderately to severely active RA who have had an inadequate response to or are intolerant of methotrexate or other DMARDs.
Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers. [2022]Tofacitinib is an oral Janus kinase inhibitor. This randomized, double-blind, parallel-group, placebo-controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7-9 subjects were randomized to tofacitinib and 3-5 subjects to placebo. Ninety-five males and females (age range 19-45) completed the study. Forty-nine treatment-emergent all-causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax ] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax ] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞ ]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single-dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs.
A randomized, crossover, phase I clinical study to evaluate bioequivalence and safety of tofacitinib and Xeljanz® in Chinese healthy subjects. [2022]Tofacitinib is an oral Janus kinase (JAK) inhibitor that has been marketed and approved in the USA for the clinical treatment of rheumatoid arthritis, psoriasis and other inflammatory and autoimmune diseases. A phase I clinical trial was conducted to compare the bioequivalence and safety of tofacitinib (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.) and Xeljanz® (Pfizer Inc.) in healthy Chinese subjects, providing basis for the clinical application of tofacitinib.
European perspective on the management of rheumatoid arthritis: clinical utility of tofacitinib. [2020]Xeljanz® (tofacitinib) is an oral small-molecule inhibitor that reversibly inhibits Janus-activated kinase (JAK)-dependent cytokine signaling, thus reducing inflammation. As a result of these mechanisms, effects on the immune system such as a moderate decrease in the total lymphocyte count, a dose-dependent decrease in natural killer (NK) cell count, and an increase in B-cell count have been observed. Therefore, tofacitinib provides an innovative approach to modulating the immune and inflammatory responses in patients with rheumatoid arthritis (RA), which is especially important in individuals who do not respond to tumor necrosis factor inhibitors or show a loss of response over time. The aim of this article was to review studies on the pharmacology, mode of action, pharmacokinetics, efficacy, and safety of tofacitinib in patients with RA. Tofacitinib has been shown to reduce symptoms of RA and improve the quality of life in the analyzed groups of patients. Moreover, it showed high efficacy and an acceptable safety profile in Phase III randomized clinical trials on RA and was the first JAK inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the RA therapy, thus providing a useful alternative treatment strategy. Randomized controlled studies revealed a significant benefit over placebo in efficacy outcomes (American College of Rheumatology [ACR] 20 and ACR50 response rates); accordingly, clinically meaningful improvements in patient-related outcomes compared with placebo have been reported. The safety profile seems acceptable, although some severe adverse effects have been observed, including serious infections, opportunistic infections (including tuberculosis and herpes zoster), malignancies, and cardiovascular events, which require strict monitoring irrespective of the duration of tofacitinib administration. As an oral drug, tofacitinib offers an alternative to subcutaneous or intravenous biologic drugs and should be recognized as a more convenient way of drug administration.