A therapeutic trial of blockade of interleukin-6 using the drug Tocilizumab in pulmonary arterial hypertension

• Register: EUCTR
• Last refreshed on: 27 July 2020
• Main ID: EUCTR2015-002799-26-GB
• Date of registration: 21/09/2015
• Prospective Registration: Yes
• Primary sponsor: Papworth Hospital NHS Foundation Trust
• Public title: A therapeutic trial of blockade of interleukin-6 using the drug Tocilizumab in pulmonary arterial hypertension
• Scientific title: TRANSFORM-UK: A Therapeutic Open Label Study of Tocilizumab in the Treatment of Pulmonary Arterial Hypertension - An open label study of Tocilizumab in PAH
• Date of first enrolment: 27/10/2015
• Target sample size: 26
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-002799-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: no; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom

Contacts

• Name: Louise Harlow
• Affiliation: Papworth Hospital NHS Trust

• Name: Louise Harlow
• Affiliation: Papworth Hospital NHS Trust

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion Criteria
Patients eligible for enrolment in the study must meet all of the following criteria:
Demographics
1. Subject must be between 18 and 70 years of age, inclusive, at the Screening visit
2. Subject must weigh >40 kg at the Screening Visit.

PAH Diagnosis and Classification
3. Subjects must have a diagnosis of group 1 PAH due to the following:
a. idiopathic or heritable PAH
b. PAH associated with:
i. connective tissue disease excluding SLE, RA and MCTD (e.g., limited scleroderma, diffuse scleroderma, or overlap syndrome)
ii. drugs or toxins

4. Subject must have a current diagnosis of being in WHO Functional Class II-IV.

5. Subject must meet all of the following haemodynamic criteria by means of a RHC
prior to screening:
i. mPAP of =/> 25 mmHg
ii. PVR =/> 300 dynes/sec/cm5
iii. PCWP or LVEDP of 300 to <500 dyne/sec/cm5, or
PCWP/LVEDP <15 mmHg if PVR =/> 500 dynes/sec/cm5
Subject must meet all of the following pulmonary function tests completed no more than 24 weeks before the Screening visit:

i. Total lung capacity (TLC) =/> 60% of predicted normal and
ii. Forced expiratory volume in one second (FEV1) =/> 60% of predicted normal
Subjects are required to have a documented negative V/Q scan or pulmonary arteriogram confirming the absence of CTEPH prior to screening.

7. Subject must walk a distance of =/>100m at the screening visit.

8. Subject, with or without supplemental oxygen, must have a resting arterial oxygen saturation (SaO2) 85% as measured by pulse oximetry at the Screening Visit.

General

9. Female subject of childbearing potential, if sexually active, must agree to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 4 months following the last dose of Investigational Product. Subjects who have had a Copper T 380A IUD or LNg 20 IUD inserted are not required to use additional methods of contraception.

10. Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study.

11. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved ICF and must sign the form prior to the initiation of any study procedures.

Subject must be on stable on an unchanged PAH therapeutic regime for at least 1 month prior to screening.

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 22
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 4

Exclusion criteria:
PAH Treatments
1. Subject is on a continuous intravenous or subcutaneous infusion.
2. Patients on TNF antagonists or other biological treatments
3. Subject has a known hypersensitivity to the Investigational Products, the metabolites, or formulation excipients.
4. Subject has severe renal impairment (creatinine clearance <30 mL/min) at the
Screening Visit

Medical History/Current Medical Conditions
1. Subject with active infection at time of screening
2. Subjects with known Hepatitis B or Tuberculosis
3. Subject has severe hepatic impairment (Child-Pugh class C with or without cirrhosis) at the Screening Visit.
4. Patient with ALT or AST >5 x upper limit normal
Haematology and bleeding disorders
1. Subject has clinically significant anaemia in the opinion of the investigator, in particular from pyruvate kinase and G6PD deficiencies.
2. Subjects with bleeding disorders or significant active peptic ulceration in the opinion of the investigator.
3. Subject with peripheral blood Platelets <100x10/L
4. Subjects with a neutrophil count <2x109/L

Cardiovascular
5. Subject has had an acute myocardial infarction within the last 90 days prior to screening
NB: Subjects must not have 3 or more of the following left ventricular disease/dysfunction risk factors:
i. Body Mass Index (BMI) = 35
ii. Historical evidence of significant coronary disease established by any one of: history of myocardial infarction
• history of percutaneous intervention
• angiographic evidence of CAD (>50% stenosis in at least one vessel), either by invasive angiography or by CT Angiography
• positive stress test with imaging (either pharmacologic or with exercise)
• previous coronary artery surgery
• chronic stable angina

General Medical Conditions
1. Subject with cardiovascular, liver, renal, haematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the investigational product or severely limit the lifespan of the subject other than the condition being studied.
2. Subject has a history of malignancies within the past 5 years, except for a subject with localized, non-metastatic basal cell carcinoma of the skin, in situ carcinoma of the cervix, or prostate cancer who is not currently or expected, during the study, to undergo radiation therapy, chemotherapy, and/or surgical intervention, or to initiate hormonal treatment.
3. History of diverticulitis, diverticulitis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations


General Criteria
1. Female subject who is pregnant or breastfeeding.
2. Subject has demonstrated noncompliance with previous medical regimens.
3. Subject has a recent (within 1 year) history of abusing alcohol or illicit drugs.
4. Subject has participated in a clinical study involving another investigational drug or device within 4 weeks before the Screening Visit.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary arterial hypertension

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Trade Name: RoActemra
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Tocilizumab
CAS Number: 375823-41-9
Current Sponsor code: n/a
Other descriptive name: n/a
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Safety will be assessed continuously throughout the study and specifically at each study visit. Study visits are monthly with an additional safety visit 30 days from trial completion at 6 months.

Pulmonary vascular resistance will be assessed at baseline and at study end at 6 months.

Secondary Objective: What are the effects of the drug tocilizumab on measures of:
1) Quality of life.
2) Patients exercise capacity.
3) The immune systems response measured by blood sampling.

Main Objective: Can blocking the effects of the protein interleukin-6 with the drug tocilizumab safely reduce blood pressure in the lungs of patients with pulmonary arterial hypertension.

Primary end point(s): Co primary end-points of:

1) Safety as defined by the incidence and severity of adverse events.
2) Pulmonary vascular resistance as measured by right heart catheter in dynes/sec/cm5.

Secondary Outcome(s)

Secondary end point(s): 1) 6 minute walking distance. This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes (the 6MWD). It evaluates the global and integrated responses of all the systems involved during exercise, including the pulmonary and cardiovascular systems, systemic
circulation, peripheral circulation, blood, neuromuscular units, and muscle metabolism.
2) BORG dyspnoea scoring index. This is a questionnaire which measures perceived exertion used in the assessment of breathlessness.
3) N-Terminal pro-B-type Natriuretic Peptide.This peptide is released by the heart and is a surrogate measure of heart function
4) WHO Functional Class assessment/disease specific QOL assessment tools. We will utilise the CAMPHOR questionnaire which is an internationally validated disease specific questionnaire which measures quality of life, activity and symptom domains.
5) Analysis of flow cytometric based peripheral blood leucocyte immunophenotyping. we will subtype leucocyte populations known to be responsive to IL6 to assess the immune system and it's response to therapy.
6) Serum and plasma measurements of circulating cytokines using multiplex cytokine arrays. This is also intended to assess the immune system and it's response to therapy.

Timepoint(s) of evaluation of this end point: Secondary endpoints 1)-4) will be assessed monthly throughout the trial. End-points 5) and 6) will be assessed at baseline and study end at 6 months only.

Ethics review

Status: Approved
Approval date: 24/09/2015
Contact:

Results

• Results available: Yes
• Date Posted: 14/04/2019
• Date Completed: 09/02/2018
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-002799-26/results