Clinical trial NCT02676947: A Therapeutic Open Label Study of Tocilizumab in the Treatment of Pulmonary Arterial Hypertension
Official title: A Therapeutic Open Label Study of Tocilizumab in the Treatment of Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: Papworth Hospital NHS Foundation Trust
Sponsor class: OTHER_GOV
Collaborators: name: Roche Pharma AG
name: National Institute for Health Research, United Kingdom
First posted: 2016-02-09
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Safety - Incidence and severity of adverse events
timeFrame: 6 months
measure: Pulmonary vascular resistance- dynes (cm-5)
timeFrame: Change from baseline pulmonary vascular resistance to end of study at 6 months
Secondary outcomes:
measure: Six minute walk test
timeFrame: Baseline and every month for 6 months
measure: N-Terminal pro-B-type Natriuretic Peptide
timeFrame: Baseline and every month for 6 months
measure: World Health Organisation functional class assessment of patient reported symptoms
timeFrame: Baseline and every month for 6 months
measure: Quality of Life
timeFrame: Baseline and every month for 6 months
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Papworth Hospital NHS Foundation Trust
state: Cambridgeshire
Study officials:
affiliation: Papworth Hospital NHS Foundation Trust
name: Mark Toshner, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Toshner M, Church C, Harbaum L, Rhodes C, Villar Moreschi SS, Liley J, Jones R, Arora A, Batai K, Desai AA, Coghlan JG, Gibbs JSR, Gor D, Graf S, Harlow L, Hernandez-Sanchez J, Howard LS, Humbert M, Karnes J, Kiely DG, Kittles R, Knightbridge E, Lam B, Lutz KA, Nichols WC, Pauciulo MW, Pepke-Zaba J, Suntharalingam J, Soubrier F, Trembath RC, Schwantes-An TL, Wort SJ, Wilkins MR, Gaine S, Morrell NW, Corris PA; Uniphy Clinical Trials Network. Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension. Eur Respir J. 2022 Mar 10;59(3):2002463. doi: 10.1183/13993003.02463-2020. Print 2022 Mar.