Anti-ST2 in COPD
A randomised placebo-controlled trial of anti-ST2 in COPD (COPD-ST2OP)
University of Leicester
U1111-1210-1335, WHO Universal Trial Number (UTN)
Duration of Study in the UK
1 years, 11 months, 29 days
This is a single-centre, double-blind, placebo- controlled, parallel group, randomised controlled trial to assess the efficacy and safety of anti-ST2 compared to placebo, in patients with moderate to very severe COPD (GOLD II-IV). Anti-ST2 will be administered via subcutaneous injection once every 4 weeks (Week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44) during the 48-week treatment period. The treatment period will be followed by a 12-week follow-up period. After signing the informed consent at the initial visit, patients will enter a screening period which should last for up to 2 weeks unless extension of the screening period is necessary under certain circumstances. Patients who qualify to participate in the study will be randomized into a 48-week treatment period in which they will receive either 490 mg anti-ST2 or a matching placebo. Patients will be evaluated for an additional 12 weeks following completion of the randomized treatment period. An interim analysis is planned when the last patient completes the 48-week treatment period. Treatment groups will remain blinded until the 48-week follow-up period is completed, and trial database is locked. This study will be a single centre RCT, sponsored by the University of Leicester and coordinated by the Leicester NIHR Respiratory BRC and Leicester Clinical Trials (LCTU). [COVID-19 amendment 22/05/2020] • Due to COVID-19 restrictions, the trial assessments annotated with the ^ symbol will not be done at Visit 13 (week\n48) and Visit 14 (week 60). All remaining assessments will be competed as per the protocol remotely via a telephone consultation (i.e. participants will not be required to attend the research clinic. Should the restrictions be lifted, participants can attend the research clinic and complete all procedures.\n• For the safety assessments at Visit 13 and Visit 14, we have considered the risks of this vulnerable patient group being in contact with study staff, either at the research clinic or in their home in terms the possibility of being exposed to COVID-19 versus the risk of not completing the following safety tests:\n- Blood tests: LFTs, Haemoglobin A1C (HbA1C), lipid profiles, BNP\n- Electrocardiogram (ECG)\nThroughout the trial, the number of new blood abnormalities were very few (only seven elevated BNP) all of which were attributed to their known co-morbid cardiovascular disease following investigations as outlined in the protocol. None of these participants were withdrawn from the trial. In those that have had ECGs at visit 13 (37 participants) no new ECG abnormalities have been identified at this visit. We therefore feel that in balance, although the risk of exposure to COVID-19 is low, that it is in the interest of the patients to not have these safety assessments as the likelihood of these identifying clinically important changes in very low. These tests are for research purposes and therefore will not impact the primary outcome.\n• The primary outcome will be analysed on the intention-to-treat (ITT) population, where the ITT population consists\nall randomised participants in the trial (regardless of whether they received trial drug). As of 05/05/2020, all participants currently remaining in the trial have completed at least visit 12. This means all participants randomised to the trial (n=81) will be included in the primary analysis. Therefore we do not see any significant impact on the primary outcome of the trial in light of the Urgent Safety Measures being implemented.\n• Note: pregnancy testing is not applicable to any of the remaining participants.\n• Administrative change to ’COPD Exacerbation frequency’ to match wording in schedule of procedures table. The wording in the table was updated as part of Substantial Amendment 01 which was implemented on 28/05/2019.\n• Clarification of time point of 12 week follow-up. This should be 12 weeks from visit 13 (week 48) rather than 12 weeks from end of treatment (visit 12, week 44). This was an error in the original protocol.
Summmary of Results:
Who carried out the research?
The trial was organised by the Respiratory BRC at Glenfield Hospital and sponsored by the University of Leicester. Leicester Clinical Trials Unit oversaw the trial and data management. The results of the trial were analysed in conjunction with Leicester Clinical Trials Unit. The trial was funded by Genentech, Inc. (San Francisco, California, USA), who also supplied the trial drug and placebo. This trial was reviewed by, and received a favourable ethical opinion from, East Midlands – Leicester South Research Ethics Committee.
What public involvement was there in the study (how many people, what their relevant lived experience was, and what they did)?
Through the National Institute for Health Research Biomedical Research Centre (NIHR BRC), the participant information sheet and trial design has been discussed by our patient involvement team within the BRC Respiratory Theme, and across the wider BRC PPI group. There were two lay members on the Trial Steering Committee (TSC), both with lived experience of chronic obstructive pulmonary disease (COPD). They attended the TSC meetings (every three months during the active recruitment phase, and every six months thereafter) and provided their opinions from a lay perspective.
Where and when did the study take place?
The COPD-ST2OP trial took place at a single site: NIHR BRC Respiratory, Glenfield Hospital. The trial opened on 10th October 2018, with the first participant consented the next day on 11th October 2018. Recruitment took place between 11th October 2018 and 5th July 2019. The last participant received their last dose of the trial drug on 5th May 2020, and the final follow-up visit was completed on 11th August 2020. The trial officially closed on 31st December 2020.
Why was the research needed?
COPD is a significant cause of morbidity and mortality worldwide and it is associated with acute exacerbations (sudden worsening of COPD symptoms) which can lead to hospitalisation. This trial compared Anti-ST2, an experimental and currently unlicensed drug, with a placebo (a substance containing no active medication) to treat COPD with the aim of reducing the number of exacerbations of the disease. In order to understand the underlying mechanism(s) of COPD exacerbation, we collected and analysed samples of blood, sputum, breath, urine and undertake measurements of lung function (breathing tests) and a CT scan of the chest.
What were the main questions asked?
The main aims of the trial were:
1. To evaluate whether anti-ST2 reduced COPD exacerbation frequency, and improved symptoms and lung function over 48 weeks.
2. To explore effects of anti-ST2 on inflammation measured in airway samples, blood and breath samples.
3. To assess the safety and tolerability of subcutaneous (injection under the skin) doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD.
Who participated in the study?
81 participants were randomised, 41 to Anti-ST2 and 39 to placebo. 51 were male and 30 were female. The average age was 70 years. In terms of ethnicity, 80 participants were white and 1 participant was Indian. This was representative of the COPD population in the UK. 14 participants withdrew from the trial, meaning 67 out of 81 completed the trial.
What treatments or interventions did the participants take/receive?
Participants were randomised to either treatment with the trial drug (Anti-ST2) or the placebo. Participants had underwent 12 dosing visits in total, spread out over 44 weeks (approximately 1 year), with 2 final follow-up visits at 48 and 60 weeks (15 visits in total).
What medical problems (adverse reactions) did the participants have?
There were a total of 222 adverse events (AEs) reported in 62 participants. A total of 28 participants in the placebo arm and 34 participants in the Anti-ST2 arm reported at least one AE. The most commonly reported AEs were headache followed by urinary tract infection and viral upper respiratory tract infection. The safety profile of Anti-ST2 was similar to that of the Placebo.
What were the results of the study?
Although the trial did not show any significant difference between the drug (anti-ST2) and placebo in reduction the frequency of COPD flare-up (exacerbation), in a sub-group of patients with low blood eosinophil counts (a marker of response to steroids inhalers and tablets) the drug (anti-ST2) reduced the frequency of exacerbations compared to placebo. These findings are currently being evaluated in a trial with a larger number of participants.
How has this study helped patients and researchers?
During the trial, irrespective of randomised treatment, participants received close monitoring of their condition to ensure that they were receiving the optimal medical treatment. Any COPD exacerbations were investigated and followed up by the trial team. Any abnormal findings arising from the trial procedures, that were considered to be clinically significant, were managed either by the research team or reported to the participants’ GP for further investigation.
The results of this trial have helped researchers to look into mechanisms of exacerbations in COPD in more detail, and design other studies that may help with developing strategies and treatments that will reduce frequency of COPD exacerbations in the future. The trial also generated sufficient scientific data to enable some of the researchers to complete higher degrees (e.g. PhD).
Details of any further research planned
There is currently a larger trial of anti-ST2 recruiting in the USA, which will begin recruiting in the UK in due course (https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbRehJ-2Fi4xyo44sEgJVCl5BcbW9wgc64X2JjNxW-2BqMpAModsNXV1AjYEaOyhEF7-2BSvQ-3D-3DGV1Z_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YLA0tNWz3uTl2f8YD3yga5gt-2Fe6f8pNgrkbW4F6bfpCuQTlAyOswu-2FL1sQV9cONi3HlFuh-2BFKfzDF72JqZ1iQCjKqJSunfGfFcMlUBulodLAixu1ux8wj4dIH2spyhHIR18e-2BqGu-2BizW5rUwUvjPmA94E6rZIrI44uCqfPFreNz8A-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7Cd07b1421b43142b30d3208d9c70c2a87%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637759677334196981%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=9pzDfsB6hkeTiWA9%2FgFMNOODFX1BUg%2BGc8Gu%2BAJDHEg%3D&reserved=0 The trial aims to recruit 930 participants and the expected completion date is August 2024.
Where can I learn more about this study?
You can learn more about COPD-ST2OP by accessing the trial record on clinicaltrials.gov (https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbRehJ-2Fi4xyo44sEgJVCl5BcbW9wgc64X2JjNxW-2BqMpAMTE7yUHoIt2dNtF3tn-2FJXfg-3D-3D8G1p_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YLA0tNWz3uTl2f8YD3yga5gDMMdmIiVmeRBGIGz2sH5AhvlIfh1JgOtwXIMOMhDHFtQDwMHMAaRk2hKDNLOhA4ViQ0gLUnHyNcd2o5poXwBjONXpy-2FAaY-2FRo-2F8M1LhAXiXzRRYhUlcm15Sbr46enZONcs4vZPYXk0SzwvRUn3W4Mw-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7Cd07b1421b43142b30d3208d9c70c2a87%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637759677334196981%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=JJ7meEQRywDLcU%2Br8XI8M9a1ljj1r69iKUwuRT7DBGA%3D&reserved=0 which is a web-based resource that provides patients, their family members, health care professionals, researchers, and the public with easy access to information on publicly and privately supported clinical studies on a wide range of diseases and conditions.
Thank you to trial participants
We would like to take this opportunity to thank all the trial participants for their support and participation in the COPD-ST2OP trial. Their involvement has been crucial to the trial’s success, and the results have given us important information that will help us to develop more new treatments for COPD.
East Midlands - Leicester South Research Ethics Committee
Date of REC Opinion
13 Aug 2018
Further Information Favourable Opinion