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The European Union Clinical Trials Register allows you to search for protocol and results information on:
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    The EU Clinical Trials Register currently displays   42771   clinical trials with a EudraCT protocol, of which   7044   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


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    Summary
    EudraCT Number:2015-002799-26
    Sponsor's Protocol Code Number:
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-09-21
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-002799-26
    A.3Full title of the trial
    TRANSFORM-UK: A Therapeutic Open Label Study of Tocilizumab in the Treatment of Pulmonary Arterial Hypertension
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A therapeutic trial of blockade of interleukin-6 using the drug Tocilizumab in pulmonary arterial hypertension
    A.3.2Name or abbreviated title of the trial where available
    An open label study of Tocilizumab in PAH
    A.4.1Sponsor's protocol code number
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPapworth Hospital NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPapworth Hospital NHS Trust
    B.5.2Functional name of contact pointLouise Harlow
    B.5.3 Address:
    B.5.3.1Street AddressPapworth Hospital
    B.5.3.2Town/ cityPapworth-Everard
    B.5.3.3Post codeCB233RE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number014808430541
    B.5.6E-maillouise.harlow@papworth.nhs.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name RoActemra
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTocilizumab
    D.3.9.1CAS number 375823-41-9
    D.3.9.2Current sponsor coden/a
    D.3.9.3Other descriptive namen/a
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pulmonary arterial hypertension
    E.1.1.1Medical condition in easily understood language
    High blood pressure in the lungs
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 </= 12 mmHg if PVR =/> 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 22
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state26
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 26
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Roche have committed to indefinite off label use Tocilizumab in participants who demonstrate a treatment response as defined by an improvement in PVR of greater than 20% and as adjudged by the local investigator. This will allow us to collect longer-term safety data.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-10-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-02-09
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