Front-line therapy in CLL: assessment of ibrutinib-containing regimes

ISRCTN	ISRCTN01844152
DOI	https://doi.org/10.1186/ISRCTN01844152
EudraCT/CTIS number	2013-001944-76
Secondary identifying numbers	16675

Submission date: 08/08/2014
Registration date: 08/08/2014
Last edited: 19/12/2023

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

http://www.cancerresearchuk.org/about-cancer/trials/a-trial-ibrutinib-rituximab-chronic-lymphocytic-leukaemia-flair

Contact information

Dr Sue Bell
Public, Scientific, Principal Investigator

Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom

Phone	+44 (0)113 343 4033
Email	ctru_flair@leeds.ac.uk

Study information

Study design	Randomised; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	FLAIR: Front-Line therapy in CLL: Assessment of Ibrutinib-containing Regimes: a randomised controlled trial
Study acronym	FLAIR
Study hypothesis	Current hypothesis as of 13/11/2023 The trial originally aimed to compare the effect on progression-free survival (PFS) of ibrutinib plus rituximab (IR) with that of fludarabine, cyclophosphamide and rituximab (FCR) in patients with previously untreated chronic lymphocytic leukaemia (CLL). The amendment to include the additional trial arms will allow a comparison of PFS between ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR, and a comparison of minimal residual disease (MRD) negativity rates in I+V with those in I. A further amendment to allow genetically high-risk patients, defined by a detectable TP53 disruption (any 17p deletion and/or TP53 mutation), randomised to either I or I+V, will allow a comparison of MRD negativity rates between I and I+V in patients with TP53 abnormalities. _____ Previous hypothesis as of 07/09/2018: The trial originally aimed to compare the effect on progression-free survival (PFS) of ibrutinib plus rituximab (IR) with that of fludarabine, cyclophosphamide and rituximab (FCR) in patients with previously untreated chronic lymphocytic leukaemia (CLL). The amendment to include the additional trial arms will allow a comparison of PFS between ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR, and a comparison of minimal residual disease (MRD) negativity rates in I+V with those in I. _____ Previous hypothesis: The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of progression-free survival.
Ethics approval(s)	NRES Committee Yorkshire & The Humber - Leeds West, 17/06/2014, ref: 14/YH/0085
Condition	Chronic lymphocytic leukaemia
Intervention	Current intervention as of 13/11/2023 All arms are now closed to recruitment. Participants were randomised on a 1:1:1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and rituximab (FCR), ibrutinib plus rituximab (IR), ibrutinib monotherapy (I) or ibrutinib + venetoclax (I+V). FCR: fludarabine (oral), cyclophosphamide (oral) and rituximab (intravenous infusion). F (24 mg/m2/day) and C (150 mg/m2/day) are administered days 1-5 and R is administered at 375 mg/ m2 for day 1 cycle 1 and then at 500 mg/m2 for day 1 for cycles 2-6. Each cycle is repeated every 28 days and there are 6 cycles. IR: ibrutinib (oral) and rituximab. 6 cycles of R as per FCR. Ibrutinib (420 mg) is administered daily for 6 years. I: ibrutinib monotherapy is administered as per IR I+V: ibrutinib + venetoclax (oral): ibrutinib is administered as per IR. Venetoclax is given daily from week 9 onwards in weekly dose increments (20 mg, 50 mg, 100 mg, 200 mg and 400 mg) after which 400 mg is administered for 6 years. Follow up: baseline, 9 months post randomisation then every 6 months until 7 years or disease progression. All participants will be followed up at least annually until death. Participants with any 17p deletion and/or TP53 mutation will be randomised on a 1:1 basis to receive ibrutinib monotherapy (I) or ibrutinib + venetoclax (I+V). _____ Previous intervention as of 07/09/2018: Participants will be randomised on a 1:1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and rituximab (FCR), ibrutinib monotherapy (I) or ibrutinib + venetoclax (I+V). The IR arm has been closed to recruitment. _____ Previous intervention as of 29/06/2017: Participants will be randomised on a 1:1:1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and rituximab (FCR), ibrutinib plus rituximab (IR), ibrutinib monotherapy (I) or ibrutinib + venetoclax (I+V). Added 24/07/2017: FCR: fludarabine (oral), cyclophosphamide (oral) and rituximab (intravenous infusion). F (24mg/m2/day) and C (150mg/m2/day) are administered days 1-5 and R is administered at 375mg/ m2 for day 1 cycle 1 and then at 500mg/m2 for day 1 for cycles 2-6. Each cycle is repeated every 28 days and there are 6 cycles. IR: ibrutinib (oral) and rituximab. 6 cycles of R as per FCR. Ibrutinib (420mg) is administered daily for six years. I: ibrutinib monotherapy is administered as per IR I+V: ibrutinib + venetoclax (oral): ibrutinib is administered as per IR. Venetoclax is given daily from week 9 onwards in weekly dose increments (20mg, 50mg, 100mg, 200mg and 400mg) after which 400mg is administered for six years. Follow up: baseline, 9 months post randomisation then every six months until 7 years or disease progression. All participants will be followed up at least annually until death. _____ Previous intervention: Participants will be randomised on a 1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and rituximab (FCR) or ibrutinib plus rituximab (IR).
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Fludarabine, cyclophosphamide, rituximab, ibrutinib, venetoclax
Primary outcome measure	Current primary outcome measure as of 07/09/2018: 1. Whether I+V is superior to FCR in terms of progression-free survival. 2. Whether I+V is superior to I in terms of Minimal Residual Disease negativity. The proportion of concurrently randomised participants who are MRD negative in the bone marrow at any time during the trial will be summarised by treatment arm and compared using a binary logistic regression model adjusted for the minimisation factors and trial stage, excluding centre, and Kaplan-Meier curves will be presented. The analysis of MRD negativity will be initially carried out at 2 years after the close of recruitment. Previous primary outcome measure: The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of progression-free survival, and whether IR toxicity rates are favourable.
Secondary outcome measures	Current secondary outcome measures as of 10/09/2018: 1. PFS of I+V in comparison with I. This is assessed using time from randomisation to first documented evidence of disease progression (as defined by IWCLL criteria) or death from any cause. Participants who do not progress will be censored at the last date they were known to be alive and progression-free. 2. PFS of I in comparison with FCR. This is assessed using time from randomisation to first documented evidence of disease progression (as defined by IWCLL criteria) or death from any cause. Participants who do not progress will be censored at the last date they were known to be alive and progression free. 3. Overall survival. This is assessed using time from randomisation to date of death from any cause. Participants not known to have died will be censored at the date they were last known to be alive. 4. Proportion of participants obtaining undetectable MRD, as defined by IWCLL criteria. A negative MRD is defined as the presence of <0.01% CLL cells in the bone marrow. Achievement of MRD negativity is defined as a MRD negative results at any time over the length of the trial. 5. Stopping I-containing therapy in MRD negative patients. Participants receiving I, IR or I+V who achieve MRD negativity in the bone marrow will be able to stop treatment. MRD levels will be monitored over time following stopping treatment. 6. Restarting I-containing therapy on MRD relapse. Those who relapse at the MRD level will restart treatment and will be assessed further for MRD response. 7. Response to therapy, as defined by IWCLL criteria. For participants randomised to FCR or IR, response is assessed at 3 months post-treatment with FCR or R and again at the end of treatment with ibrutinib for participants randomised to IR. For participants randomised to I or I+V, response is assessed at 9 months post-randomisation and again at the end of treatment. 8. Safety and toxicity assessed using adverse events reported throughout the trial, as graded by CTCAE V4.03 , and determined by routine clinical assessments at each centre. 9. Health-related quality of life. The EORTC QLQC30 and EORTC QLQCLL16 will be used to measure participant assessed QoL prior to randomisation, at the end of treatment with FCR and R (for participants randomised to FCR or IR) or at 6 months post-randomisation (for participants randomised to I or I+V), and then at 6-monthly visits. 10. Cost-effectiveness. The SF12 and EQ5D will be used to produce quality adjusted life years (QALYs). NHS resource use and participants’ out of pocket expenses will be collected via the Case Record Forms, as well as health economics patient questionnaires. These will be collected prior to randomisation, at the end of treatment with FCR and R (for participants randomised to FCR or IR) or at 6 months post-randomisation (for participants randomised to I or I+V), and then at 6-monthly visits. Previous secondary outcome measures as of 07/09/2018: 1. PFS of I+V in comparison with I 2. PFS of I in comparison with FCR 3. Overall survival 4. Proportion of participants obtaining undetectable MRD, as defined by IWCLL criteria 5. Stopping of I-containing therapy in MRD-negative patients. Participants who have an MRD negative result in the peripheral blood at any timepoint between 12 and 30 months post-randomisation will be eligible to stop treatment prior to the 6 years post-randomisation timepoint if they confirm MRD negativity in the bone marrow. 6. Time to MRD relapse for participants who stop I-containing treatment based on MRD negativity and then go on to relapse at the MRD 7. Response to therapy, as defined by IWCLL criteria. For each comparison, the best response for each participant at either 3 months post-treatment with FCR, 9 months post randomisation (for participants randomised to I or I+V) or the end of treatment (for I or I+V) will be summarised by treatment group and overall. The proportion of participants achieving a Complete Response (CR+CRi) and an Overall Response (at least a PR) at any stage during the trial will be summarised by treatment arm 8. Safety and toxicity. Safety analyses will summarise the AR, SAE, SAR and SUSAR rates per participant, by treatment received and overall for all participants randomised to stages II and III. ARs will be presented by CTCAE toxicity grade (V4.0.3). 9. Health-related quality of life assessed using all domains of the EORTC QLQ-C30 and the CLL-specific module, EORTC QLQ-CLL16. 10. Cost-effectiveness Previous secondary outcome measures: 1. Overall survival 2. Undetectable minimal residual disease 3. Response to therapy 4. Health-related quality of life 5. Cost-effectiveness
Overall study start date	01/08/2014
Overall study end date	01/01/2030

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 1576; UK Sample Size: 1576; Planned sample size for genetically high-risk pathway: 64
Participant inclusion criteria	Current inclusion criteria as of 13/11/2023: For standard-risk pathway: 1. At least 18 years old. Maximum age of 75 years old. 2. B-CLL with a characteristic immunophenotype, including small lymphocytic lymphoma 3. Binet's Stages C, B or Progressive Stage A 4. Requiring therapy by the IWCLL criteria in that they must have at least one of the following: 4.1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia. 4.2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly 4.3. Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy 4.4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months as long as the lymphocyte count is over 30 x 10^9/L 4.5. A minimum of any one of the following disease-related symptoms must be present: 4.5.1. Unintentional weight loss more than or equal to 10% within the previous 6 months. 4.5.2. Significant fatigue (i.e. Eastern Cooperative Oncology Group PS 2 or worse; cannot work or unable to perform usual activities) 4.5.3. Fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection 4.5.4. Night sweats for more than 1 month without evidence of infection 5. Considered fit for treatment with FCR as determined by the treating clinician 6. World Health Organisation (WHO) performance status (PS) of 0, 1 or 2 7. Able to provide written informed consent 8. Biochemical values must be within the following limits within 14 days prior to randomization and at baseline: 8.1. Alanine aminotransferase (ALT) 3 x upper limit of normal (ULN). Aspartate aminotransferase (AST) 3 x ULN. 8.2. Total bilirubin = 1.5 x ULN, unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin For the genetically high-risk pathway 1. TP53 abnormality confirmed by central laboratory 2. At least 18 years old (no upper limit) 3. Meeting all the inclusion criteria for the standard risk pathway stated, with the exception of ‘considered fit for treatment with FCR as determined by the treating clinician’ _____ Previous inclusion criteria: 1. At least 18 years old. Maximum age of 75 years old. 2. B-CLL with a characteristic immunophenotype, including small lymphocytic lymphoma 3. Binets Stages C, B or Progressive Stage A 4. Requiring therapy by the IWCLL criteria in that they must have at least one of the following: 4.1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia. 4.2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly 4.3. Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy 4.4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months as long as the lymphocyte count is over 30 x 10^9/L 4.5. A minimum of any one of the following disease-related symptoms must be present: 4.5.1. Unintentional weight loss more than or equal to 10% within the previous 6 months. 4.5.2. Significant fatigue (i.e. Eastern Cooperative Oncology Group PS 2 or worse; cannot work or unable to perform usual activities) 4.5.3. Fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection 4.5.4. Night sweats for more than 1 month without evidence of infection 5. Considered fit for treatment with FCR as determined by the treating clinician 6. World Health Organisation (WHO) performance status (PS) of 0, 1 or 2 7. Able to provide written informed consent 8. Biochemical values must be within the following limits within 14 days prior to randomization and at baseline: 8.1. Alanine aminotransferase (ALT) 3 x upper limit of normal (ULN). Aspartate aminotransferase (AST) 3 x ULN. 8.2. Total bilirubin = 1.5 x ULN, unless bilirubin rise is due to Gilberts syndrome or of non-hepatic origin
Participant exclusion criteria	Current exclusion criteria as of 07/09/2018: 1. Prior therapy for CLL 2. History or current evidence of Richters transformation 3. Major surgery within 4 weeks prior to randomisation 4. Active infection 5. Above 20% P53 deletion, determined by FISH 6. Past history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies 7. Concomitant warfarin or equivalent vitamin K inhibitor - added 29/06/2017: or other oral anticoagulant treatment; anyone requiring anticoagulation treatment for greater than 6 months is not eligible for trial entry 8. Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 30 days after treatment with ibrutinib has finished, whichever is latest. Women must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction 9. Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 3 months after treatment with ibrutinib has finished, whichever is latest, unless they are surgically sterile 10. CNS involvement with CLL 11. Symptomatic cardiac failure not controlled by therapy, or unstable angina not adequately controlled by current therapy (in patients with a significant cardiac history the left ventricular function should be assessed and patients with severe impairment should be excluded) 12. Respiratory impairment (bronchiectasis or moderate COPD) 13. Other severe, concurrent diseases or mental disorders that could interfere with their ability to participate in the study 14. Inability to swallow oral medication 15. Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease etc) 16. Known HIV positive 17. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded 18. Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result 19. History of prior malignancy, with the exception of the following: 19.1. Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician 19.2. Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease 19.3. Adequately treated cervical carcinoma in situ without current evidence of disease 20. Persisting severe pancytopenia (neutrophils <0.5 x 10^9/l or platelets <50 x 10^9/l) unless due to direct marrow infiltration by CLL 21. Current treatment with prednisolone of >10 mg/day 22. Active haemolysis (patients with haemolysis controlled with prednisolone at a dose 10 mg or less per day can be entered into the trial) 23. Patients with a creatinine clearance of less than 30 ml/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula) 24. History of stroke or intracranial hemorrhage within 6 months prior to enrollment 25. Requirement for treatment with a strong CYP3A4/5 inhibitor or inducer 26. Cardiac event (eg. recent myocardial infarction, coronary artery stent) requiring dual antiplatelet treatment. 27. Allergy or inability to tolerate uric acid reducing agents (eg allopurinol/rasburicase). 28. Unwilling or unable to take PCP prophylaxis (eg cotrimoxazole). Previous exclusion criteria: 1. Prior therapy for CLL 2. History or current evidence of Richters transformation 3. Major surgery within 4 weeks prior to randomisation 4. Active infection 5. Above 20% P53 deletion, determined by FISH 6. Past history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies 7. Concomitant warfarin or equivalent vitamin K inhibitor - added 29/06/2017: or other oral anticoagulant treatment; anyone requiring anticoagulation treatment for greater than 6 months is not eligible for trial entry 8. Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 30 days after treatment with ibrutinib has finished, whichever is latest. Women must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction 9. Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 3 months after treatment with ibrutinib has finished, whichever is latest, unless they are surgically sterile 10. CNS involvement with CLL 11. Symptomatic cardiac failure not controlled by therapy, or unstable angina not adequately controlled by current therapy (in patients with a significant cardiac history the left ventricular function should be assessed and patients with severe impairment should be excluded) 12. Respiratory impairment (bronchiectasis or moderate COPD) 13. Other severe, concurrent diseases or mental disorders that could interfere with their ability to participate in the study 14. Inability to swallow oral medication 15. Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease etc) 16. Known HIV positive 17. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded 18. Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result 19. History of prior malignancy, with the exception of the following: 19.1. Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician 19.2. Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease 19.3. Adequately treated cervical carcinoma in situ without current evidence of disease 20. Persisting severe pancytopenia (neutrophils <0.5 x 10^9/l or platelets <50 x 10^9/l) unless due to direct marrow infiltration by CLL 21. Current treatment with prednisolone of >10 mg/day 22. Active haemolysis (patients with haemolysis controlled with prednisolone at a dose 10 mg or less per day can be entered into the trial) 23. Patients with a creatinine clearance of less than 30 ml/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula) 24. History of stroke or intracranial hemorrhage within 6 months prior to enrollment 25. Requirement for treatment with a strong CYP3A4/5 inhibitor or inducer
Recruitment start date	01/09/2014
Recruitment end date	31/10/2023

Locations

Countries of recruitment

England
Northern Ireland
Scotland
United Kingdom
Wales

Study participating centres

Clinical Trials Research Unit (CTRU)

Leeds
LS2 9JT
United Kingdom

Aberdeen Royal Infirmary

Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom

Addenbrookes Hospital

Hills Road
Cambridge
CB2 0QQ
United Kingdom

Altnagelvin Hospital

WHSCT
Glenshane Road
Glenshane
Londonderry
BT47 6SB
United Kingdom

Barnet General Hospital

Wellhouse Lane
Hertfordshire
Barnet
EN5 3DJ
United Kingdom

Colchester General Hospital

Department of Haematology
Colchester General Hospital
Turner Road
Colchester
Essex
Colchester
CO4 5JL
United Kingdom

Basingstoke and North Hampshire Hospital

Aldermaston Road
Basingstoke
RG24 9NA
United Kingdom

Royal Hampshire County Hospital

Romsey Road
Winchester
SO22 5DG
United Kingdom

Beatson Oncology Centre

1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Victoria Hospital, Glasgow

52 Grange Road
Glasgow
G42 9LF
United Kingdom

Royal Alexandra Hospital

Corsebar Road
Paisley
PA2 9PN
United Kingdom

Belfast City Hospital

Belfast Health and Social Care Trust
51 Lisburn Road
Belfast
BT9 7AB
United Kingdom

Birmingham Heartlands Hospital

Birmingham
B9 5SS
United Kingdom

Good Hope Hospital

Rectory Road
Sutton Coldfield
B75 7RR
United Kingdom

Blackpool Victoria Hospital

Whinney Heys Road
Lancashire
Blackpool
FY3 8NR
United Kingdom

Borders General Hospital

Melrose
TD6 9BS
United Kingdom

Bradford Royal Infirmary

Bradford Teaching Hospitals NHS Foundation Trust
Duckworth Lane
West Yorkshire
BD9 6RJ
Bradford
BD9 6RJ
United Kingdom

Bristol Haematology and Oncology Centre

Horfield Road
Bristol
BS2 8ED
United Kingdom

Calderdale Royal Hospital

Salterhebble
Halifax
HX3 0PW
United Kingdom

Huddersfield Royal Infirmary

Acre Street
Lindley
Huddersfield
HD3 3EA
United Kingdom

Castle Hill Hospital

Castle Road
Cottingham
HU16 5JQ
United Kingdom

Gloucestershire Royal Hospital

Great Western Road
Gloucester
GL1 3NN
United Kingdom

Cheltenham General Hospital

Sandford Road
Cheltenham
GL53 7AN
United Kingdom

Christie Hospital

Christie NHS Foundation Trust
Wilmslow Road
Manchester
M20 4BX
United Kingdom

Churchill Hospital

Oxford Cancer Centre & Cancer Research UK
Oxford University Hospitals NHS Trust
Oxford
OX3 7LE
United Kingdom

Basildon Hospital

Basildon
SS16 5NL
United Kingdom

Countess of Chester Hospital

Chester
CH2 1UL
United Kingdom

Craigavon Area Hospital

68 Lurgan Road
Portadown
BT63 5QQ
United Kingdom

Croydon University Hospital

530 London Road
Croydon
CR7 7YE
United Kingdom

Derriford Hospital

Plymouth
PL6 8DH
United Kingdom

Doncaster Royal Infirmary

Armthorpe Road
Doncaster
DN2 5LT
United Kingdom

East Surrey Hospital

Canada Avenue
Redhill
Surrey
Redhill
RH1 5RH
United Kingdom

Epsom General Hospital

Dorking Road
Epsom
KT18 7EG
United Kingdom

St Helier Hospital

Wrythe Lane
Carshalton
SM5 1AA
United Kingdom

George Eliot Hospital

College Street
Nuneaton
CV10 7DJ
United Kingdom

Glan Clwyd Hospital

Bodelwyddan
Rhyl
LL18 5UJ
United Kingdom

Lincoln County Hospital

Haematology Department
Lincoln County Hospital
Greetwell Road
Lincoln
Lincolnshire (E Mid)
Lincoln
LN2 5QY
United Kingdom

Grantham & District Hospital

Manthorpe Road
Grantham
NG31 8DG
United Kingdom

Pilgrim Hospital

Sibsey Road
Boston
PE21 9QS
United Kingdom

Harrogate District Hospital

Lancaster Park Road
Harrogate
HG2 7SX
United Kingdom

Hammersmith Hospital

Imperial College Healthcare NHS Trust
Du Cane Road
London
W12 0HS
United Kingdom

Ipswich Hospital

Ipswich Hospital NHS Trust
Heath Road
Suffolk
Ipswich
IP4 5PD
United Kingdom

James Cook University Hospital

Marton Road
Middlesbrough
TS4 3BW
United Kingdom

James Paget Hospital

Great Yarmouth
NR31 6LA
United Kingdom

Kings College Hospital

Denmark Hill
London
SE5 9RS
United Kingdom

Princess Royal University Hospital

Farnborough Common
Orpington
BR6 8ND
United Kingdom

Kings Mill Hospital

Mansfield Road
Nottinghamshire
Sutton-In-Ashfield
NG17 4JL
United Kingdom

Leicester Royal Infirmary

Leicester General Infirmary
Gwendolen Road
Leicester
LE5 4PW
Leicester
LE5 4PW
United Kingdom

Manchester Royal Infirmary

Oxford Road
Manchester
M13 9WL
United Kingdom

Milton Keynes General Hospital

Standing Way
Eaglestone
Milton Keynes
MK6 5LD
United Kingdom

Monklands Hospital

Monkscourt Avenue
Airdrie
ML6 0JS
United Kingdom

Musgrove Park Hospital

Taunton
TA1 5DA
United Kingdom

Nevill Hall Hospital

Brecon Road
Abergavenny
NP7 7EG
United Kingdom

Northampton General Hospital

Northampton
NN1 5BD
United Kingdom

Nottingham University Hospitals

City Hospital Campus
Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Peterborough City Hospital

Peterborough & Stamford NHS FT
Bretton Gate
Peterborough
PE3 9GZ
United Kingdom

Poole Hospital

Poole Hospital NHS Foundation Trust
Longfleet Road
Dorset
Poole
BH15 2JB
United Kingdom

Royal Bournemouth Hospital

Castle Lane East
Bournemouth
BH7 7DW
United Kingdom

Queen Elizabeth Hospital Birmingham

University Hospital Birmingham NHS Foundation Trust
Queen Elizabeth Hospital
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom

Queen Elizabeth Hospital Gateshead

Sheriff Hill
Gateshead
NE9 6SX
United Kingdom

Queen's Hospital Romford

Haematology & Oncology Department
Queens Hospital
Rom Valley Way
Essex
Romford
RM7 0AG
United Kingdom

Raigmore Hospital

Department of Haematology
Old Perth Road
Inverness
IV2 3UJ
United Kingdom

Rotherham District General Hospital

Moorgate Road
Oakwood
Rotherham
S60 2UD
Rotherham
S60 2UD
United Kingdom

Queen Alexandra Hospital

Portsmouth
PO6 3LY
United Kingdom

Royal Cornwall Hospital

Truro
TR1 3LJ
United Kingdom

Royal Derby Hospital

Uttoxeter Road
Derby
DE22 3NE
United Kingdom

Royal Devon and Exeter Hospital

Barrack Road
Devon
Exeter
EX2 5DW
United Kingdom

Royal Gwent Hospital

Block 3, Pathology
Royal Gwent Hospital
Newport
Gwent
NP20 2UB
Newport
NP20 2UB
United Kingdom

Royal Hallamshire Hospital

Glossop Road
Sheffield
S10 2JF
United Kingdom

Royal Lancaster Infirmary

Ashton Road
Lancaster
LA1 4RP
United Kingdom

Royal Liverpool University Hospital

Prescot Street
Liverpool
L7 8XP
United Kingdom

Royal Marsden Hospital

London
London
SW3 6JJ
United Kingdom

Royal Oldham Hospital

Central Admin, Pennine Square
Rochdale Road
Oldham
OL1 2JH
United Kingdom

Royal Stoke University Hospital

Stoke-on-Trent
ST4 6QG
United Kingdom

Royal Surrey County Hospital

Egerton Road
Guildford
GU2 7XX
United Kingdom

Royal United Hospital

Bath
BA1 3NG
United Kingdom

Russells Hall Hospital

Georgina Unit
High Street
Pensnett
Dudley
DY1 2HQ
United Kingdom

Salford Royal Hospital

Salford Royal Hospital NHS Foundation Trust
Stott Lane
Salford
Manchester
M6 8HD
Salford
M6 8HD
United Kingdom

Salisbury District Hospital

Salisbury
SB2 8BJ
United Kingdom

Sandwell General Hospital

Lyndon
West Midlands
West Bromwich
B71 4HJ
United Kingdom

Scunthorpe General Hospital

Cliff Gardens
Scunthorpe
DN15 7BH
United Kingdom

Diana, Princess of Wales Hospital

Scartho Road
Grimsby
DN33 2BA
United Kingdom

Singleton Hospital

Sketty Lane
Swansea
SA2 8QA
United Kingdom

Southampton General Hospital

Tremona Road
Southampton
SO16 6YD
United Kingdom

St Bartholomew's Hospital

West Smithfield
London
EC1A 7BE
United Kingdom

St. James's University Hospital

Department of Haematology, Level 3 Bexley Wing
St. James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

St George's Hospital

London
SW17 0QT
United Kingdom

Stoke Mandeville Hospital

CCHU
Mandeville Road
Buckinghamshire
Aylesbury
HP21 8AL
United Kingdom

Torbay District General Hospital

Lawes Bridge
South Devon
Torquay
TQ2 7AA
United Kingdom

University College London Hospital

235 Euston Road
London
NW1 2BU
United Kingdom

University Hospital Aintree

Lower Lane
Liverpool
L9 7AL
United Kingdom

University Hospital of Wales

Heath Park
Cardiff
CF14 4XW
United Kingdom

University Hospital Coventry

Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom

Victoria Hospital Kirkcaldy

Fife Area Labs
Victoria Hospital (Kirkcaldy)
Hayfield Road
Kirkcaldy
Fife
KY2 5AH
Kirkcaldy
KY2 5AH
United Kingdom

Queen Margaret Hospital

Whitefield Road
Dunfermline
KY12 0SU
United Kingdom

Watford General Hospital

Watford
WD18 0HB
United Kingdom

West Middlesex University Hospital

Isleworth
TW7 6AF
United Kingdom

West Wales General Hospital

Glangwili General Hospital, Chemotherapy Day Unit, Dolgwili Road, Carmarthen, SA31 2AF
Glangwili General Hospital
Dolgwilli Road
Carmarthen
Carmarthenshire
SA31 2AF
Carmarthen
SA31 2AF
United Kingdom

Western General Hospital

Crewe Road
Edinburgh
EH4 2XU
United Kingdom

Worcestershire Royal Hospital

Charles Hastings Way
Worcester
WR5 1DD
United Kingdom

Worthing Hospital

Lyndhurst Road
Worthing
BN11 2DH
United Kingdom

St Richards Hospital

Spitalfield Lane
Chichester
PO19 6SE
United Kingdom

Wythenshawe Hospital

Department of Haematology
University Hospital of South Manchester NHS Foundation Trust
Southmoor Road
Wythenshawe
Manchester
M23 9LT
United Kingdom

York Hospital

Wiggington Road
York
YO31 8HE
United Kingdom

Ysbyty Gwynedd

Penrhosgarnedd
Bangor
LL57 1PW
United Kingdom

Ysbyty Maelor

Wrexham Maelor Hospital
Croesnewydd Road
Wrexham
LL13 7TD
United Kingdom

Sponsor information

University of Leeds (UK)
University/education

Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
Leeds
LS2 9JT
England
United Kingdom

"ROR"	https://ror.org/024mrxd33

Funders

Funder type

Charity

Cancer Research UK; Grant Codes: C18027/A15790
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Janssen Pharmaceuticals
Private sector organisation / For-profit companies (industry)

Alternative name(s): Janssen Pharmaceutica NV, JANSSEN-CILAG NV, Janssen Belgium, Janssen, Janssen Pharmaceuticals
Location: Belgium

AbbVie Ltd

No information available

Results and Publications

Intention to publish date	31/12/2024
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Planned publication in a high-impact peer reviewed journal in 2024.
IPD sharing plan	Individual participant data for all trial participants (excluding any trial-specific participant opt-outs) will be made available for secondary research purposes at the end of the trial, i.e. usually when all primary and secondary endpoints have been met and all key analyses are complete. Data will only be shared for participants who have given consent to use of their data for secondary research. Requests to access trial data should be made to CTRU-DataAccess@leeds.ac.uk in the first instance. Requests will be reviewed (based on the above principles) by relevant stakeholders. No data will be released before an appropriate agreement is in place setting out the conditions of release. The agreement will govern data retention requirements, which will usually stipulate that data recipients must delete their copy of the data at the end of the planned project.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article	protocol	22/08/2017		Yes	No
Protocol article	protocol update	08/01/2021	11/01/2021	Yes	No
Interim results article	interim results	04/05/2023	09/05/2023	Yes	No
HRA research summary			28/06/2023	No	No
Results article		10/12/2023	19/12/2023	Yes	No

Editorial Notes

19/12/2023: Publication reference added.
13/11/2023: The following changes have been made:
1. The public and scientific contact and principal investigator have been changed.
2. The study hypothesis has been changed.
3. The intervention has been changed.
4. The participant inclusion criteria have been changed.
5. The target number of participants has been changed from "Planned Sample Size: 1576; UK Sample Size: 1576" to "Planned Sample Size: 1576; UK Sample Size: 1576; Planned sample size for genetically high-risk pathway: 64".
6. The recruitment end date has been changed from 01/01/2021 to 31/10/2023.
7. The IPD sharing plan has been added.
09/05/2023: Publication reference added.
11/01/2021: Publication reference added.
13/07/2020: The recruitment end date was changed from 30/06/2020 to 01/01/2021.
20/02/2020: The recruitment end date has been changed from 01/01/2020 to 30/06/2020.
03/04/2019: The condition has been changed from "Topic: Cancer; Subtopic: Haematological Oncology; Disease: Leukaemia (chronic)" to "Chronic lymphocytic leukaemia" following a request from the NIHR.
10/09/2018: The secondary outcome measures have been changed.
07/09/2018: The following changes have been made:
1. The study hypothesis has been changed.
2. The interventions have been changed.
3. The primary outcome measures have been changed.
4. The secondary outcome measures have been changed.
5. The participant exclusion criteria have been changed.
6. 103 UK trial centres have been added.
19/10/2017: Publication reference added.
24/07/2017: Publication and dissemination plan added.
29/06/2017: The following changes were made to the trial record:
1. The title was changed from 'Front-Line therapy in CLL: Assessment of Ibrutinib + Rituximab' to 'Front-Line therapy in CLL: Assessment of Ibrutinib-containing Regimes'.
2. The overall trial end date was changed from 01/08/2018 to 01/01/2030.
3. The target number of participants was changed from 754 to 1576.
4. The recruitment end date was changed from 01/08/2018 to 01/01/2020.
5. AbbVie Ltd was added as a funder.
18/10/2016: The recruitment start date was changed from 01/08/2014 to 01/09/2014.