A Therapeutic Open Label Study of Tocilizumab in the Treatment of Pulmonary Arterial Hypertension (TRANSFORM-UK)

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

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Tocilizumab

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB23 3RE
      • Papworth Hospital NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open Label; Intravenous Tocilizumab 8mg/kg monthly (up to a maximum dose 800mg) for 6 months	Drug: Tocilizumab; Other Names: RoActemra

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Papworth Hospital NHS Foundation Trust
• Collaborators: Roche Pharma AG; National Institute for Health Research, United Kingdom
• Investigators: Principal Investigator: Mark Toshner, MD, Papworth Hospital NHS Foundation Trust

Publications and helpful links

General Publications

• 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. Erratum In: Eur Respir J. 2022 Jul 7;60(1):

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Actual): February 18, 2018
• Study Completion (Actual): February 18, 2018

Study Registration Dates

• First Submitted: December 21, 2015
• First Submitted That Met QC Criteria: February 8, 2016
• First Posted (Estimate): February 9, 2016

Study Record Updates

• Last Update Posted (Actual): April 19, 2018
• Last Update Submitted That Met QC Criteria: April 17, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: PO2060

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO