Effect of Tofacitinib on Coagulation and Platelet Function, and Its Role in Thromboembolic Events

Study Overview
=================
Brief Summary
-----------------
Post-authorization, prospective and unicenter clinical trial, in which patients with UC will be included. The treatment with anti-TNFα (infliximab, adalimumab or golimumab) or JAK-inhibitors (tofacitinib) will be initiated by clinical practice and the choice will be made at the discretion of the investigator at the center where the patients will be recruited (Hospital Universitario de La Princesa). In the case of the group of patients treated with tofacitinib, the selection will be made following the action protocol implemented in our center, in which this drug is usually reserved for those cases refractory to anti-TNFα and/or vedolizumab. There will be no random assignment of treatment. The drugs will be used in the approved indications and conditions of use.

Detailed Description
-----------------
BACKGROUND Ulcerative colitis (UC) is a chronic pathology that causes inflammation of the colonic mucosa (1, 2). The most common symptoms include bloody diarrhea, abdominal pain, and urgent bowel movements, which has a great impact on the quality of life (3). The chronic course of this disease is characterized by alternating periods of relapse and remission (4). The prevalence of UC is relatively high, with a rate of 505 cases per 100,000 population in Europe and 249 cases per 100,000 population in North America (5). In terms of incidence, it is increasing rapidly due to industrialization and westernization of lifestyles (6). The EpiCOM study recorded an overall incidence of 8.2 cases/100,000 person-years of UC (7). In Spain, a recent multicenter study coordinated from our center, which includes 17 Autonomous Communities of the country, confirmed that the current incidence of UC is higher than previously described, with rates of 8 new cases per 100,000 person-years, approximately (8,9). The complexity, the social burden and the costs of treatment make this disease very relevant for health systems. Specifically, in Europe, the annual direct cost is estimated at 9,000 euros per patient (regardless of severity) and 10,000 euros for those cases with moderate to severe UC. The total economic burden of UC has been estimated at 8-15 billion dollars in the US and 12-29 billion euros in Europe (10). All of this underscores the strategic importance of UC to society, including patients and health systems. The goal of drug treatment is to control inflammation to prevent the development of progressive intestinal damage and the onset of complications, so patients can achieve an optimal quality of life. Biological drugs are effective in maintaining clinical remission (11-13). However, approximately half of the patients treated do not reach remission with biological treatment (14-16). The reason for this reduced effectiveness is because therapies are administered based on empirical approaches due to the lack of prognostic biomarkers, adapting them according to the clinical evolution and complications of each case (17). A novel treatment for these refractory cases is tofacitinib (Xeljanz®), a synthetic small molecule inhibitor of JAK kinases, which has been shown to be effective in treating UC (18). Tofacitinib has been recently approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). It is indicated for the treatment of rheumatoid arthritis and active psoriatic arthritis, as well as in the treatment of adult patients with moderate to severe UC who have had an insufficient response, a loss of response or have been intolerant to conventional treatment or biological therapy. The recommended dose for UC is 10 mg twice daily for induction for 8 weeks, followed by 5 mg twice daily for maintenance (19). A relevant aspect to consider of this drug is its oral administration, unlike biological therapies, which are prescribed intravenously or subcutaneously. Despite these advantages, it has been observed that some patients treated with tofacitinib have a higher incidence of severe thromboembolic events, including dose dependent pulmonary embolism and deep vein thrombosis. Recent data from a randomized, post-authorization safety trial (A3921133) in patients with rheumatoid arthritis over 50 years of age and at least one cardiovascular risk factor, treated with tofacitinib 10 mg twice daily, have shown an increased risk of pulmonary embolism and overall mortality. The increased risk of pulmonary embolism was 5 times higher compared to patients treated with anti-TNFα. The incidence rates of pulmonary embolism for tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, and anti- TNFα were 0.54 (95% CI, 0.32-0.87), 0.27 (0.12-0.52), and 0.09 (0.02-0.26) per 100 patient-years treated, respectively. Furthermore, mortality due to any cause in the tofacitinib 10 mg every 12-hour group was 2 times higher than the mortality of the groups treated with tofacitinib 5 mg twice daily and anti-TNFα. The incidence rates of deep vein thrombosis for tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, and anti-TNFα were 0.38 (0.20-0.67), 0.30 (0.14-0.55), and 0.18 (0.07-0.39) per 100 patient-years, respectively (20). These results support the current recommendation for cautious use of tofacitinib in patients with high thromboembolic risk. As a result of the serious consequences associated with pulmonary embolism and the uncertainty about the underlying mechanism, the Advisory Committee for Risk Assessment in Pharmacovigilance decided to evaluate the impact of these findings on the benefit-risk balance of tofacitinib in all authorized indications, as well as the dose of administration. Both FDA and EMA have recently issued new warnings recommending against prescribing tofacitinib 10 mg twice daily for maintenance treatment in patients with UC who have one or more of the following known risk factors for venous thromboembolism (advanced age, obesity, diabetes, hypertension smoking, medical history of deep vein thrombosis and pulmonary embolism, immobilization of myocardial infarction in the previous three months, heart failure, use of combined hormonal contraceptives or hormone replacement therapy, inherited clotting disorders, neoplasia), unless appropriate alternative treatment is not available (21,22). In addition, the recommendations established by AEMPS to health professionals include monitoring all patients undergoing treatment with tofacitinib for signs and symptoms suggestive of pulmonary embolism, instructing them to request medical assistance immediately if they experience such symptoms (23). Regarding thromboembolic risk specifically in UC patients treated with tofacitinib, the results of a recent post-hoc analysis showed that during tofacitinib treatment one patient had venous thromboembolism [incidence rate, patients with events/100 patient-years: 0.04; (0.00-0.23)] and four had pulmonary embolism [0.16 (0.04- 0.41)] at a dose of 10 mg predominantly, with risk factors for venous thromboembolism (24). Although data concerning UC patients are still limited, the results of the above-mentioned clinical trial in rheumatoid arthritis are relevant for any therapeutic indication. Other drugs that inhibit the JAK-STAT pathway, such as baricitinib, ruxolitinib, and upadacitinib, have also been associated with an increased incidence of venous thromboembolism. However, the mechanism leading to these events is not known (25). Therefore, a possible class effect of JAK inhibitors in the development of these events cannot be ruled out. Moreover, other JAK inhibitors (pefacitinib, filgotinib and pacritinib) are currently being studied in phase 3 clinical trials in rheumatoid arthritis, atopic dermatitis, Crohn's disease and myelofibrosis (26-28). Because safety data on these new drugs are very limited, both regulatory agencies and clinical researchers have shown great concern about their thromboembolic risk. Therefore, it is clear that new studies are required to evaluate the safety of these new drugs. This is an utmost need is order to offer these drugs to patients under the safest circumstances. In summary, the pathophysiological mechanism that leads to an increased thromboembolic event in patients treated with tofacitinib or other JAK inhibitors is not currently known. Therefore, despite being effective and rapid drugs, their use has been restricted, since it is not known what would be the effective preventive antiplatelet or anticoagulation treatment, for example, to avoid thromboembolic events in these patients. This not only affects tofacitinib but may also involve the other JAK inhibitor drugs that will be approved for inflammatory bowel disease (or for other diseases) in the future. In this line, our project has an ambitious objective: to characterize in-depth this adverse event by studying the alterations in haemostasis. To that aim, the effect of tofacitinib on the general haemostatic profile (i.e., coagulation, platelet aggregation and activation) will be studied in vivo in patients with UC in the short and long term (baseline, 3 and 12 month follow-up). Finally, it is highly probable that from the results obtained in the present project significant advances will be achieved in the knowledge of the molecular mechanisms involved in the appearance of venous thromboembolism caused by exposure to tofacitinib. Therefore, this will allow, in clinical practice, to adopt effective pharmacological measures and facilitate prevention strategies to reduce the onset of these complications. Furthermore, it is expected that the results obtained can be extrapolated to other JAK inhibitor drugs of the same family, due to the possible class effect.

Official Title
-----------------
Effect of Tofacitinib on Coagulation and Platelet Function, and Its Role in Thromboembolic Events

Conditions
-----------------
Ulcerative Colitis, Thromboembolism

Intervention / Treatment
-----------------
* Drug: Tofacitinib
* Drug: Infliximab Adalimumab y Golimumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: EX VIVO STUDY IN PATIENTS WITH UC PATIENTS WITH UC: Over 18 years old. Diagnosis of UC according to the criteria of the European Crohn's and Colitis Organisation (ECCO). Previous treatments are allowed, provided they have remained stable for the past 3 months. In the case of patients with active UC, they should have endoscopic activity within 1 month of starting the treatment (Mayo endoscopic sub-index of ≥ 2). Women of childbearing age using contraceptive methods with an error rate <1% per year. Examples of contraceptive methods whose error rate is <1% per year are: Intrauterine device (IUD). Bilateral tubal occlusion. Couple with vasectomy. Sexual abstinence. INDIVIDUALS WITHOUT UC: Over 18 years old. Subjects not diagnosed with UC, or other inflammatory allergic, malignant or autoimmune diseases. Women of childbearing age using contraceptive methods with an error rate <1% per year. Examples of contraceptive methods whose error rate is <1% per year are: Intrauterine device (IUD). Bilateral tubal occlusion. Couple with vasectomy. Sexual abstinence. IN VIVO STUDY IN PATIENTS WITH UC PATIENTS WITH UC: Over 18 years old. Diagnosis of UC according to the criteria of the European Crohn's and Colitis Organisation (ECCO). Have indication of treatment with anti-TNFα (infliximab, adalimumab or golimumab) o tofacitinib. Be the first received JAK-inhibitor or anti-TNFα with a given mechanism of action. Have endoscopic activity of UC within 1 month of starting the treatment (Mayo endoscopic sub-index of ≥ 2). Previous treatments (including corticosteroids and immunosuppressants) are allowed provided that they have been stable for the last 3 months before beginning treatment with JAK-inhibitor or anti-TNFα and that they are maintained at a stable dose for the duration of the study Women of childbearing age using contraceptive methods with an error rate <1% per year. Examples of contraceptive methods whose error rate is <1% per year are: Intrauterine device (IUD). Bilateral tubal occlusion. Couple with vasectomy. Sexual abstinence. INDIVIDUALS WITHOUT UC: Over 18 years old. Subjects not diagnosed with UC, or other inflammatory, allergic, malignant or autoimmune diseases. Women of childbearing age using contraceptive methods with an error rate <1% per year. Examples of contraceptive methods whose error rate is <1% per year are: Intrauterine device (IUD). Bilateral tubal occlusion. Couple with vasectomy. Sexual abstinence. Exclusion Criteria: EX VIVO STUDY IN PATIENTS WITH UC PATIENTS WITH UC: Under 18 years old. Immune-mediated disease, neoplasm or active infection. Pregnancy or lactation. Alcohol or drug abuse. Ostomy. Abdominal surgery in the last 6 months. Colectomy. Active infection with hepatitis B, C or HIV virus. Medical history of thromboembolic events. Treatment with anticoagulants, antiplatelets or other drugs that alter the coagulation. Use of combined hormonal contraceptives or hormone replacement therapy. Hereditary coagulation disorders. Refusal to give consent for participation in the study. INDIVIDUALS WITHOUT UC: Under 18 years of age. Advanced chronic disease or any other pathology that prevents the monitoring of the protocol of this study. Pregnancy or lactation. Alcohol or drug abuse. Ostomy. Abdominal surgery in the last 6 months. Colectomy. Active infection with hepatitis B, C or HIV virus. Medical history of thromboembolic events. Treatment with anticoagulants, antiplatelets or other drugs that alter the coagulation. Use of combined hormonal contraceptives or hormone replacement therapy. Hereditary coagulation disorders. Refusal to give consent for participation in the study. IN VIVO STUDY IN PATIENTS WITH UC PATIENTS WITH UC: Under 18 years old. Immune-mediated disease. Neoplasm or active infection. Pregnancy or lactation. Alcohol or drug abuse. Ostomy. Colectomy. Active infection with hepatitis B, C or HIV virus. Indication of anti-TNFα or JAK-inhibitors treatment for a cause other than UC. Have previously received a drug with the same mechanism of action (anti-TNFα or JAK-inhibitors) Medical history of thromboembolic events. Treatment with anticoagulants, antiplatelets or other drugs that alter the coagulation. Use of combined hormonal contraceptives or hormone replacement therapy. Hereditary coagulation disorders. Refusal to give consent for participation in the study. INDIVIDUALS WITHOUT UC: Under 18 years of age. Advanced chronic disease or any other pathology that prevents the monitoring of the protocol of this study. Pregnancy or lactation. Alcohol or drug abuse. Active infection with hepatitis B, C or HIV virus. Finding of macroscopic alterations during the colonoscopy or finding of relevant inflammatory alterations in the biopsies obtained during the colonoscopy. Treatment with immunomodulators, immunosuppressants, corticosteroids or other drugs that alter the immune system. Medical history of thromboembolic events. Treatment with anticoagulants, antiplatelets or other drugs that alter the coagulation. Use of combined hormonal contraceptives or hormone replacement therapy. Hereditary coagulation disorders. Refusal to give consent for participation in the study. Abdominal surgery in the last 6 months.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ulcerative colitis patients treated with tofacitinib<br>Tofacitinib 5 mg/day oral per clinical practice | Drug: Tofacitinib<br>* Tofacitinib 5 MG/day per clinical practice<br>|
| Active Comparator: Ulcerative colitis patients treated with an anti-TNFα drug<br>Infliximab (Infusion 5mg/kg milligram(s)/Kilogram-Intravenous use) per clinical practice, or adalimumab (Subcutaneus 40 mg milligram(s)-subcutaneus) per clinical practice, or golimumab (subcutaneus 50 mg milligram(s)-subcutaneus) per clinical practice | Drug: Infliximab Adalimumab y Golimumab<br>* Infliximab (Infusion 5mg/kg milligram(s)/Kilogram-Intravenous use) per clinical practice or adalimumab (Subcutaneus 40 mg milligram(s)-subcutaneus) per clinical practice or or golimumab (subcutaneus 50 mg milligram(s)-subcutaneus) per clinical practice.<br>|
| No Intervention: healthy controls<br> | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| platelet activation | Platelet activation status will be assessed ex vivo in platelet-rich plasma (PRP) samples from UC patients (active and quiescent) and healthy controls incubated in the absence or presence of drug (tofacitinib or anti-TNFα). Regarding the in vivo study, platelet activation will be analyzed in samples from patients with active UC before and after initiating treatment with tofacitinib or anti-TNFα. It will be mesured by rate of platelet agregation | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endoscopic activity | It will be evaluated by the Mayo endoscopic sub-score; endoscopic activity will be considered as ≥ 2. | 1 year | 
| Endoscopic response | It will be defined as a decrease of ≥ 1 point in the Mayo endoscopic sub-score 3 months after starting treatment. | 1 year | 
| Endoscopic remission | It will be defined as an endoscopic subscore ≤1, 3 months after starting treatment. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ulcerative colitis, Tromboembolism, Coagulation, Platelet Function, Tofacitinib, JAK inhibitors, anti-TNF, Infliximab, Adalimumab, Golimumab