Clinical Trial Results:
TRANSFORM-UK: A Therapeutic Open Label Study of Tocilizumab in the Treatment of Pulmonary Arterial Hypertension
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Summary
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EudraCT number |
2015-002799-26 |
Trial protocol |
GB |
Global end of trial date |
09 Feb 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Apr 2019
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First version publication date |
14 Apr 2019
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Other versions |
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Summary report(s) |
Final Report |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
PO2060
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02676947 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Royal Papworth Hospital NHS Trust
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Sponsor organisation address |
Papworth Everard, Cambridge, United Kingdom, CB233RE
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Public contact |
Emily Knightbridge, Royal Papworth Hospital NHS Trust, 44 01223 639694 , e.knightbridge@nhs.net
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Scientific contact |
Emily Knightbridge, Royal Papworth Hospital NHS Trust, 44 01223 639694 , e.knightbridge@nhs.net
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
17 Sep 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Feb 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Feb 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main 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.
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Protection of trial subjects |
Strict withdrawal criteria were put in place to protect all subjects, they were as follows: • Development of an Adverse Event (AE) where continuation of the subject’s participation in the study is thought by the Investigator to be inappropriate.
• Subject meets liver stopping criteria.
• Subject begins treatment with a prohibited concomitant therapy.
• Subject adjudged by investigator to have a clinically significant neutropaenia or thrombocytopaenia.
Reference ranges for the above laboratory tests were detailed in the protocol.
Monthly blood tests and urine pregnancy tests on women of childbearing potential were performed as a drug safety measure at all clinic visits. These were performed at the subjects local laboratory to ensure timely reporting.
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Background therapy |
Tocilizumab is an IL-6 receptor antagonist established as safe, well tolerated and effective, primarily in rheumatoid arthritis, and has shown promise in scleroderma. In uncommon cases, where the underlying cause of PAH is an established inflammatory process such as SLE, mixed connective tissue disease and Castleman’s disease, there have been case reports of regression of PAH with tocilizumab. We therefore propose a phase II open-label proof of concept study of tocilizumab in group I PAH. | ||
Evidence for comparator |
n/a as the study was open label and all patients received study drug. | ||
Actual start date of recruitment |
01 Oct 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 29
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Worldwide total number of subjects |
29
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EEA total number of subjects |
29
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
20
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From 65 to 84 years |
9
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects will be identified using data collected during their routine outpatient appointments. Recruitment began on the 23rd December 2015 and Papworth Hospital was the first site to be opened. The first patient was screened on the 6th of January 2016. The final patient was recruited on the 7th April 2017. | ||||||||||||||||||
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Pre-assignment
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Screening details |
The screening visit will include the following: Obtain Informed Consent • Medical History • Demographics • Urine pregnancy test (if applicable) • Physical Exam and WHO class assessment • Vital signs • Pulmonary Function tests • Six minute walk test • Borg assessment pre and post 6MWT • PH medication • Routine Bloods | ||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
29 | ||||||||||||||||||
Number of subjects completed |
29 | ||||||||||||||||||
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Period 1
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Period 1 title |
Treatment period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
Blinding implementation details |
n/a open label.
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Arms
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Arm title
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Tocilizumab | ||||||||||||||||||
Arm description |
Study drug - open label | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Tocilizumab
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Investigational medicinal product code |
Ro4877533-000
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Other name |
RoActemra, Actemra, MRA, Atlizumab
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
8mg/kg of Tocilizumab
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Baseline characteristics reporting groups
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Reporting group title |
Treatment period
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Reporting group description |
In this multi-centre open label single-arm study, patients were recruited across 8 centres in the UK. Twenty-nine patients (M/F 10/19; mean age 54.9) were recruited in total between January 2016 to April 2017. Fifteen patients had idiopathic PAH, ten connective tissue disease associated PAH (CTD-PAH), and four heritable/ BMPR2 associated PAH. Six patients were withdrawn prior to drug administration; one chest infection, one exacerbation of co-morbid disease, four at baseline RHC. Twenty-three patients received study drug. Drug was discontinued in 4 patients due to serious adverse events. There were no deaths in the trial. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Tocilizumab
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Reporting group description |
Study drug - open label | ||
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End point title |
Pulmonary vascular resistance measured using invasive haemodynamic assessment by right heart catheter [1] | ||||||||
End point description |
Pulmonary Vascular resistance as measured by invasive haemodynamic assessment via fluid-filled right heart catheter using cardiac output measured by thermodilution technique. This endpoint is looking for a reduction in Pulmonary Vascular resistance at the end of study right heart catheter.
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End point type |
Primary
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End point timeframe |
The subject had a right heart catheter at baseline (unless they had had one in the last 30 days prior to baseline as this one could be used) and one at the end of study visit.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: I have uploaded a summary chart with the analysis that has been completed in it. It was not analysed in such a way that we had any of the values that were required in the statistical analysis field. |
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Attachments |
Summary- PVR |
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| Notes [2] - only completed for those subjects who had a RHC pre and post treatment |
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| No statistical analyses for this end point | |||||||||
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End point title |
Safety as defined by the incidence and severity of adverse events [3] | ||||||
End point description |
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End point type |
Primary
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End point timeframe |
Safety as defined by the incidence and severity of adverse events. adjudged respectively on the occurrence of adverse events and serious adverse events as classified by use of
the Medical Dictionary for Regulatory Activities.
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: I have uploaded a summary chart with the analysis that has been completed in it. It was not analysed in such a way that we had any of the values that were required in the statistical analysis field. Descriptive statistics were used only for this endpoint. |
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Attachments |
Summary |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were reported from the moment the subject had signed the informed consent form to the safety follow up 4 months post end of study.
For serious adverse events they were required to be reported in 24 hours of knowledge of the event.
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Adverse event reporting additional description |
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
Some of the SAEs and SUSARS are broken down into event for MedDRA coding and to ensure everything is captured. So while there were 7 SAEs/SUSARs there are 10 events.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
All subjects who recieved at least one dose of study drug
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Reporting group description |
All subjects who recieved at least one dose of study drug. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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02 Nov 2015 |
Amendment done due to the MHRA requesting some changes to the protocol summarised below:
extending the use of contraceptive methods to at least 3 months post last dose of study drug
adding in an exclusion criteria of active severe infection
safety follow up moved from 30 days to 4 months post end of study
Telephone follow up added at 30 days post end of study visit
Temperature added to vital signs
CRP added to safety blood tests
clarification of study drug continuation
and general formatting |
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12 Jul 2016 |
Addition of trial Website
Trial Poster for sites to display to aid recruitment
Addition of a new site -Royal United Hospitals Bath
Updated patient information sheet: change of working about possible overnight stays. From you will be asked to you may be asked/ may be required. |
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31 Oct 2016 |
Update to the protocol:
• Increase recruitment from 21 to 26
• Removal of 6MWD upper limit
• 30 day RHC can be used at baseline
• Clarification of process for abnormal blood results (platelets, neutrophils and LFTs) in line with the Summary of Product Characteristics (SPC)
• Removal of Ophthalmic exclusion
• Addition of Diverticulitis exclusion
• Extension of termination visit from within 7 days to 14 days
Addition of a Principle investigator from the Bath site
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The final publication is being worked on currently and once published will be disseminated to all trial participants who expressed an interest via their consent form and all participating sites. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/28956500 |
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