A Therapeutic Open Label Study of Tocilizumab in the Treatment of Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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An open label study to assess the safety and efficacy of tocilizumab in group 1 pulmonary arterial hypertension patients

Detailed Description
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In Pulmonary Arterial Hypertension (PAH) raised blood pressure in the lungs leads to heart failure and early death. Patients not only have a significantly reduced life expectancy, but their quality of life is severely affected. If left untreated life expectancy is 2-3 years. Current treatments all aim to relax the vessels in the lung and lower the blood pressures, however none target the causes of the disease and currently there is not cure. Despite the availability of treatments the impact on mortality has been modest at best with one third of patients still dying within two years of diagnosis. There remains an urgent need to test new ways of treating PAH. PAH is often associated with auto-immune diseases (when the bodies own system attacks itself rather than fight infection). Targeting components of the immune system involved in the development of disease offer a potential new area of treatment for PAH; an example known to be involved in the progression of PAH is the protein Interleukin-6 (IL-6). Tocilizumab is a drug which blocks the action of Interleukin-6 and blocking Interleukin-6 has been shown to be effective in animal models of PAH. Tocilizumab was demonstrated to be safe and effective in trials in other diseases associated with PAH, such as rheumatoid arthritis. This study is a 6 month open label phase II trial of IV Tocilizumab in 21 patients with group 1 PAH. The aim of the trial is to see if Tocilizumab is safe and whether it reduces the blood pressure in the lungs. Patients will be given Tocilizumab intravenously once a month for six months with close safety monitoring. The trial will be led by Papworth Hospital and a total of 7 UK specialist centres will take part. The trial will assess the safety of the drug and response to treatment by measuring heart function, blood pressure in the lungs, exercise capacity and quality of life measurements.

Official Title
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A Therapeutic Open Label Study of Tocilizumab in the Treatment of Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Group 1 PAH due to: Idiopathic or Heritable PAH, PAH associated with connective tissue disease excluding SLE, RA and mixed CTD, Drug and Toxins WHO functional class II-IV Weight more than 40kg 6 minute walk distance of 100-500 m Haemodynamic criteria measure by RHC Documented negative V/Q scan or pulmonary arteriogram confirming absence of chromic thromboembolic disease Resting oxygen saturations of >85% Lung function confirming absence of significant lung disease Stable on unchanged PAH therapeutic regime for at least 1 month Exclusion Criteria: Subjects on continuous infusions either intravenously or subcutaneously Hypersensitivity to Investigational Product Severe hepatic impairment Severe renal impairment Clinically significant anaemia Blood platelets <100x10 Neutrophil count <2x10/L Left ventricular disease/dysfunction risk factors Myocardial infarction within 90 days prior to screening Female subjects who are pregnant or breastfeeding History of malignancies within past 5 years

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label<br>Intravenous Tocilizumab 8mg/kg monthly (up to a maximum dose 800mg) for 6 months | Drug: Tocilizumab<br> <br> * Other names: RoActemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Incidence and severity of adverse events | Incidence and severity of treatment emergent adverse events | 6 months | 
| Pulmonary vascular resistance- dynes (cm-5) | Invasive haemodynamic assessment by right heart catheter | Change from baseline pulmonary vascular resistance to end of study at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six minute walk test |  | Baseline and every month for 6 months | 
| N-Terminal pro-B-type Natriuretic Peptide | Blood test - marker of cardiac function | Baseline and every month for 6 months | 
| World Health Organisation functional class assessment of patient reported symptoms | Assessment of pulmonary hypertension/heart failure symptoms and patient related daily living function. | Baseline and every month for 6 months | 
| Quality of Life | Disease specific questionnaire | Baseline and every month for 6 months |