12961797 true Does Interleukin-1 Receptor Antagonist Improve Outcome following aneurysmal Subarachnoid Haemorrhage (aSAH)? A Phase III trial SC IL-1Ra in SAH - phase III trial Treatment with IL-1Ra subcutaneously (SC) twice daily to patients with aneurysmal subarachnoid haemorrhage will improve clinical outcome at 6 months. Background and study aims Subarachnoid haemorrhage (SAH) is a bleed onto the surface of the brain. It is usually caused when a weakness (aneurysm) in the wall of a blood vessel within the brain suddenly bursts. It affects up to 6,000 people every year in the UK. Up to half of all patients do not survive long enough to receive hospital treatment and those who do survive, often suffer long-term issues that impact on their daily life. In the hours and days after SAH, patients are at risk of further brain damage due to inflammation (swelling). A protein called interleukin-1 (IL-1) is the main culprit and this triggers a number of other chemicals in the circulation which may lead to physical symptoms similar to stroke but can also cause problems with language, mood, anxiety and fatigue all of which impact most on recovery and returning to work. The effect of IL-1 can be blocked, reduced or even reversed by another protein present naturally in our body; interleukin-1 receptor antagonist (IL-1Ra). A company has produced a man-made version of IL-1Ra, which has been used for many years as an anti-inflammatory treatment for rheumatoid arthritis. Inflammation occurs very early after the initial haemorrhage and can continue for up to 21 days, which means IL-1Ra should be given early and through the risk period to prevent or reduce these symptoms. Our group has successfully tested IL-1Ra in patients with subarachnoid haemorrhage and found it reduces inflammation in the circulation and brain and we now want to establish whether IL-1Ra improves recovery after subarachnoid haemorrhage. The aim of this study is to treat patients with SAD using IL-1Ra subcutaneously twice daily to see if this can improve clinical outcomes. Who can participate? Adults aged 18 and older who have SAH. What does the study involve? Participants are randomly allocated to one of two groups. Those in the first group receive subcutaneous injections of IL-1Ra twice daily for up to 21 days from the onset of their symptoms. Those in the second group receive a placebo (a dummy) twice daily for 21 days. All participants continue to receive the standard care for subarachnoid haemorrhage and participation in this study will not affect or delay this care. Participants provide blood samples before the treatment, and after 3-5 days to measure levels of inflammatory markers in the blood. Participants are followed up for safety for 30 days and are followed up for six months to assess the impact of the treatment. What are the possible benefits and risks of participating? As this is a phase III study it will be made clear to participants that there is no evidence of benefit at this stage. Participants will also be advised that as this study is double-blind and randomised and it will not be known if they will receive study drug or placebo. Evidence from earlier phase studies showed that the study drug reduces inflammation associated with SAH and is safe to use. The results of this study will provide evidence whether reducing inflammation improves outcome and participants may be helping to provide the evidence that may change treatment for SAH in the future. Where is the study run from? This study is being run by the University of Manchester (UK) and takes place in hospitals in the UK. When is the study starting and how long is it expected to run for? July 2015 to April 2024 Who is funding the study? National Institute for Health Research (UK) Who is the main contact? Jane Pearson, SCIL@manchester.ac.uk Clinical outcome is measured using the modified Rankin Scale (mRS) questionnaire at 6 months. 1. Mood is measured using the Hospital Anxiety and Depression Scale questionnaire at 6 months 2. Fatigue is measured using the GM-SAT Fatigue question and Fatigue Severity Score questionnaire at 6 months 3. Quality of life is measured using the EQ-5D-5L questionnaire at 6 months Ethics approval required North West - Haydock Research Ethics Committee

3rd Floor - Barlow House, 4 Minshull Street

Manchester United Kingdom M1 3DZ 17/NW/0581 10.1186/ISRCTN12961797 2016-003725-42 214739 NCT03249207 CPMS: 35757 NCT03249207 2016-003725-42 214739 35757 Randomised; Interventional; Design type: Treatment, Drug Interventional Randomised controlled trial Treatment 2024-04-30T00:00:00.000Z United Kingdom England Scotland Wales Royal Stoke University Hospital

Newcastle Road

Stoke-on-Trent United Kingdom ST4 6QG Royal Hallamshire Hospital

Glossop Road

Sheffield United Kingdom S10 2JF University Hospital of Wales

Heath Park

Cardiff United Kingdom CF14 4XW Northern Care Alliance NHS Foundation Trust

Salford Royal Stott Lane

Salford United Kingdom M6 8HD RM3@2.16.840.1.113883.2.1.3.2.4.18.48 National Hospital for Neurology & Neurosurgery

Queen Square

London United Kingdom WC1N 3BG RRVN0@2.16.840.1.113883.2.1.3.2.4.18.48 Plymouth Hospital

Derriford Hospital Derriford Road

Plymouth United Kingdom PL6 8DH NT711@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospital Southampton NHS Foundation Trust

Southampton General Hospital Tremona Road

Southampton United Kingdom SO16 6YD RHM@2.16.840.1.113883.2.1.3.2.4.18.48 Leeds General Infirmary

Great George Street

Leeds United Kingdom LS1 3EX 5N1C2@2.16.840.1.113883.2.1.3.2.4.18.48 St George's Hospital

Blackshaw Road

London United Kingdom SW17 0QT The Walton Centre NHS Foundation Trust

Lower Lane Fazakerley

Liverpool United Kingdom L9 7LJ Brighton and Sussex University Hospitals NHS Trust

Royal Sussex County Hospital Eastern Road

Brighton United Kingdom BN2 5BE RXH@2.16.840.1.113883.2.1.3.2.4.18.48 Nottingham University Hospitals NHS Trust

Trust Headquarters Queens Medical Centre Derby Road

Nottingham United Kingdom NG7 2UH RX1@2.16.840.1.113883.2.1.3.2.4.18.48 Charing Cross Hospital

Fulham Palace Road

London United Kingdom W6 8RF RDU92@2.16.840.1.113883.2.1.3.2.4.18.48 Barts Health NHS Trust

The Royal London Hospital 80 Newark Street

London United Kingdom E1 2ES R1H@2.16.840.1.113883.2.1.3.2.4.18.48 Southmead Hospital

Southmead Road Westbury-on-trym

Bristol United Kingdom BS10 5NB 5A316@2.16.840.1.113883.2.1.3.2.4.18.48 Lancashire Teaching Hospitals NHS Foundation Trust

Royal Preston Hospital Sharoe Green Lane Fulwood

Preston United Kingdom PR2 9HT RXN@2.16.840.1.113883.2.1.3.2.4.18.48 Addenbrookes

Addenbrookes Hospital Hills Road

Cambridge United Kingdom CB2 0QQ NV504@2.16.840.1.113883.2.1.3.2.4.18.48 Patient 1. Patients with CT positive spontaneous SAH admitted to a participating neurosurgical centre where written informed consent can be obtained and study drug can be administered within 72 hours of ictus 2. No concomitant health problems that, in the opinion of the PI or designee, would interfere with participation, administration of study drug or assessment of outcomes including safety 3. Willing and able to give informed consent or consent available from a patient representative for trial inclusion including agreement in principle to receive study drug and undergo all study assessments 4. Male or female aged 18 years or above Adult 18 Years All 1000 612 Current participant exclusion criteria as of 14/08/2023: 1. Unconfirmed or uncertain diagnosis of spontaneous SAH 2. Known active tuberculosis or active hepatitis 3. Known active malignancy 4. Known Still's Disease 5. Neutropenia (ANC <1.5 x 109/L ) 6. Abnormal renal function (creatinine clearance or estimated Glomerular Filtration Rate (eGFR) < 30 ml/minute) documented in the last 3 months prior to this SAH 7. Live vaccinations within the last 10 days of this SAH 8. Previous or concurrent treatment with IL-1Ra known at the time of trial entry or previous participation in this trial 9. Current treatment with TNF antagonists 10. Known to have participated in a clinical trial of an investigational agent or device in the 30 days prior to ictus 11. Known to have participated in a clinical trial of an investigational agent or device within 5 half-lives (of the previous agent or device) prior to ictus 12. Known to be pregnant or breastfeeding or inability to reliably confirm that the patient is not pregnant 13. Clinically significant serious concurrent medical condition, pre-morbid illnesses, or concurrent serious infection (including confirmed or suspected COVID-19 infection), at the PI’s (or designee’s) discretion, which could affect the safety or tolerability of the intervention 14. Known allergy to IL-1Ra or any of the excipients listed in the drug SmPC 15. Known allergy to other products that are produced by DNA technology using the microorganism E. coli (e.g. E.coli derived protein) 16. Current treatment with IL-6 or IL-1 inhibitors or drugs affecting the IL-1 axis 17. History of DRESS syndrome Previous participant exclusion criteria: 1. Unconfirmed or uncertain diagnosis of spontaneous SAH 2. Known active tuberculosis or active hepatitis 3. Known active malignancy 4. Neutropenia (ANC <1.5 x 109/L ) 5. Abnormal renal function (creatinine clearance or estimated Glomerular Filtration Rate (eGFR) < 30 ml/minute) documented in the last 3 months prior to this SAH 6. Live vaccinations within the last 10 days of this SAH 7. Previous or concurrent treatment with IL-1Ra known at the time of trial entry or previous participation in this trial 8. Previous or current treatment with medication suspected of interacting with IL-1Ra, listed in the drug SmPC 9. Known to have participated in a clinical trial of an investigational agent or device in the previous 30 days or 5 half-lives of enrolment (whichever is longer) of ictus, or for the period determined by the protocol of the trial / study the patient has taken part in 10. Known to be pregnant or breast feeding or inability to reliably confirm that the patient is not pregnant 11. Clinically significant serious concurrent medical condition, pre morbid illnesses, or concurrent serious infection, at the PI’s (or designee’s) discretion, which could affect the safety or tolerability of the intervention 12. Known allergy to IL-1Ra or any of the excipients listed in the drug SmPC 13. Known allergy to other products that are produced by DNA technology using the micro-organism E. coli (e.g. E.coli derived protein) 2018-05-31T00:00:00.000Z 2023-09-30T00:00:00.000Z Stroke Nervous System Diseases Stroke This is a double-blind, placebo-controlled trial. Patients with aneurysmal subarachnoid haemorrhage receive subcutaneous injections of IL-1Ra or placebo twice daily for up to 21 days from the onset of their symptoms. Blood samples are taken before the start of the intervention and after 3-5 days to measure levels of inflammatory markers in the blood. Participants are followed up for safety until day 30 after the start of the intervention and are followed up after six months to assess the impact of the intervention on clinical outcome. Other Phase III The data sharing plans for the current study are unknown and will be made available at a later date. Data sharing statement to be made available at a later date Protocol

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09a5ba33-6814-4d84-9747-9df7fc8ca075 c1f89d10-a733-46c5-afbf-44d595c1c4f1 714a31d3-a439-4460-b37d-26a9c70bc82a No Protocol file ISRCTN12961797_Protocol_v8.0_04June2020.pdf fb4ddde4-b9d1-41b9-a12f-3097c37fd3a9 true application/pdf 2017702 94a1164f927991739edfb3d8eeb796ce Protocol file ISRCTN12961797_Protocol_v9.0_13March2023.pdf beee5793-dca2-4733-bade-2dedf0c62b21 true application/pdf 1249774 5c964626ed28a65ec2facbe98e6384a3 Jane Pearson Scientific

Clinical Trial Manager Manchester Clinical Trials Unit The University of Manchester Jean McFarlane Building Oxford Road

Manchester United Kingdom M13 9PL +44 (0)161 918 2142 SCIL@manchester.ac.uk Public The University of Manchester University/education https://ror.org/027m9bs27 Non-commercial National Institute for Health Research http://dx.doi.org/10.13039/501100000272 91927162 true A two-arm randomised controlled trial of concurrent chemo-radiotherapy comparing twice-daily and once-daily radiotherapy schedules in patients with limited stage Small Cell Lung Cancer (SCLC) and good performance status CONVERT This study aims to establish a standard chemo-therapy regimen for patients with limited stage Small Cell Lung Cancer (SCLC) and good performance status. https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-to-find-the-best-way-to-give-radiotherapy-for-people-with-small-cell-lung-cancer Overall survival. Information for each of the primary and secondary objectives will be gained by assessing the patient prior to each cycle of chemotherapy, at a completion visit within 4 weeks of the final cycle, and then at follow-up visits which are 3 monthly for the first year, then six monthly thereafter until death. 1. Local progression-free survival 2. Metastasis-free survival 3. Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) toxicity 4. Chemotherapy dose intensity 5. Radiotherapy dose intensity Information for each of the primary and secondary objectives will be gained by assessing the patient prior to each cycle of chemotherapy, at a completion visit within 4 weeks of the final cycle, and then at follow-up visits which are 3 monthly for the first year, then six monthly thereafter until death. Old ethics approval format UK ethics approval on 21/12/2007 10.1186/ISRCTN91927162 NCT00433563 06-DOG07-68 NCT00433563 06-DOG07-68 Multicentre randomised active-controlled parallel-group unblinded phase III trial Interventional Randomised controlled trial Treatment 2019-02-15T00:00:00.000Z United Kingdom England Belgium Canada France Netherlands Poland Slovenia Spain The Christie NHS Foundation Trust

Manchester United Kingdom M20 4BX Patient 1. Either sex, aged greater than or equal to 18 years 2. Estern Cooperative Oncology Group (ECOG) Performance Status (PS) grade 0 - 1. Patients with PS 2 whose general condition is explained by obstructive/bulky disease likely to improve after the first cycle of chemotherapy can be included at the discretion of the local investigator. Patients with PS 2 as a result of comorbid conditions will be excluded 3. Histologically or cytologically confirmed SCLC 4. No patients with mixed small-cell and non-small-cell histologic features 5. No history of previous malignancy in the last 5 years (except non melanomatous skin or in-situ cervix carcinoma). Patients with previous malignancies (except breast cancer) and in remission for at least 5 years can be included 6. Limited stage disease (Veterans Administration Lung Cancer Study Group), i.e., patients whose disease can be encompassed within a radical radiation portal 7. No pleural or pericardial effusions proven to be malignant 8. Radiotherapy (RT) target volume acceptable by the local radiotherapist 9. Pulmonary function: 9.1. Forced Expiratory Volume in one second (FEV1) greater than 1 litre or 40% predicted value 9.2. Carbon Monoxide Transfer Coefficient (KCO) (Carbon Monoxide Diffusing capacity in the whole Lung per unit Alveolar Volume [DLCO/VA]) greater than 40% predicted 10. Maximum of one of the following adverse biochemical factors: 10.1. Serum alkaline phosphatase more than 1.5 times the Upper Limit of Normal (ULN) 10.2. Serum sodium less than lower limit of normal 10.3. Serum lactate dehydrogenase (LDH) greater than upper limit of normal (added 09/04/2008) 11. Normal serum creatinine and calculated creatinine clearance greater than or equal to 50 ml/min. If calculated creatinine clearance is less than 50 ml/mn according to the Cockroft and Gault formula, an Ethylenediaminetetraacetic Acid (EDTA) clearance should be performed 12. Adequate haematological function: 12.1. Neutrophils greater than 1.5 x 10^9/l 12.2. Platelets greater than 100 x 10^9/l 13. No other previous or concomitant illness or treatment which in the opinion of the clinician will interfere with the trial treatments or comparisons 14. No prior surgical resection of the primary tumour, no prior radiotherapy for lung cancer 15. Considered fit to receive any of the trial regimens 16. Female patients must satisfy the investigator that they are not pregnant, or are not of child-bearing potential, or are using adequate contraception. Men must also use adequate contraception, as etoposide is clastogenic 17. Patients must not be breastfeeding 18. Patient has read the patient information sheet and has signed the consent form 19. Patients available for follow-up Adult 18 Years All 532 547 Does not comply with the above inclusion criteria. 2008-04-07T00:00:00.000Z 2013-11-29T00:00:00.000Z Limited stage small cell lung cancer Cancer Lung cancer Control arm: 1. Between 4 and 6 cycles of cisplatin and etoposide (cisplatin 25 mg/m^2 intravenous [iv] day 1 - 3 or 75 mg/m^2 day 1, etoposide 100 mg/m^2 iv day 1 - 3) 2. Concurrent twice daily (BD) radiotherapy 45 Gy, 30 twice-daily fractions over 3 weeks, 5 days per week from day 22 of cycle 1 3. Prophylactic Cranial Irradiation (PCI) will be given if indicated Experimental arm: 1. Between 4 and 6 cycles of cisplatin and etoposide (cisplatin 25 mg/m^2 iv day 1 - 3 or 75 mg/m^2 day 1, etoposide 100 mg/m^2 iv day 1 - 3) 2. Concurrent once daily (OD) radiotherapy 66 Gy in 33 daily fractions over 6.5 weeks, 5 days per week from day 22 of cycle 1 3. Prophylactic Cranial Irradiation (PCI) will be given if indicated Patients will undergo screening examinations and will then be randomised to a treatment arm. Treatment will begin within 2 weeks of randomisation. During chemoradiotherapy treatment the patient will be assessed prior to each cycle via physical exam and blood tests, with chest X-rays prior to cycles 1, 3 and 5. Research staff will monitor any toxicities and record treatment and toxicity details on a Case Report Form (CRF). The patient will be seen again within 4 weeks of the final cycle for assessment, response to treatment will be evaluated and prophylactic cranial irradiation given if indicated. The patient will then enter the follow-up phase of the study - during follow-up patients will be seen at 3 monthly intervals for 12 months, and six monthly thereafter until death. Drug Phase III Cisplatin, etoposide 2017 Results article in https://www.ncbi.nlm.nih.gov/pubmed/28362511 sub-study results 2017 Results article in https://www.ncbi.nlm.nih.gov/pubmed/28642008 results 2019 Results article in https://www.ncbi.nlm.nih.gov/pubmed/30520977 secondary results 2016 Protocol article in https://www.ncbi.nlm.nih.gov/pubmed/26792218 protocol Results https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-to-find-the-best-way-to-give-radiotherapy-for-people-with-small-cell-lung-cancer

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663683bc-f2dc-43ea-95b4-8cea88c8e52a b58bf51b-f99a-4684-9c1b-3b904b661066 c33f94de-af9e-4ccb-8cb9-0cbb28a8c319 No Helen Bradley Scientific

Manchester Clinical Trials Unit The University of Manchester Room 1.316, Jean McFarlane Building Oxford Road

Manchester United Kingdom M13 9PL +44 0161 306 8239 helen.bradley@manchester.ac.uk Public Christie Hospital NHS Foundation Trust Hospital/treatment centre https://ror.org/03v9efr22 Non-commercial Cancer Research UK http://dx.doi.org/10.13039/501100000289