The use of rituximab in the treatment of nephrotic glomerulonephritis (TURING)
| ISRCTN | ISRCTN16948923 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16948923 |
| EudraCT/CTIS number | 2018-004611-50 |
| Secondary identifying numbers | 41605 |
- Submission date
- 17/06/2019
- Registration date
- 21/06/2019
- Last edited
- 15/10/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Urological and Genital Diseases
Plain English Summary
Background and study aims
Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are rare auto-immune kidney diseases that lead the patient to develop nephrotic syndrome and if untreated can result in substantial morbidity including kidney failure and death. All the current treatments have serious limitations and glucocorticoids are the mainstay of treatment in MCD/FSGS. Although they are effective in most of the patients, recurrent relapses happen in 75% of the patients when the steroid dose is reduced or withdrawn. Frequent relapses result in high cumulative steroid exposure, which in turn increases the risk of obesity, diabetes, infection and osteoporosis.
There is a critical need for steroid alternative treatments in MCD/FSG patients that are both effective and safe, and do not adversely affect kidney function. Rituximab is the most promising candidate treatment. It is currently a licensed treatment for other auto-immune diseases where it has an excellent safety profile. Moreover, randomised trial evidence already supports the use of rituximab in children with MCD/FSGS. This study, TURING, will assess if giving rituximab to an adult patient with nephrotic syndrome caused by MCD/FSGS is safe, effective to prevent relapses of the disease and determine how long patients remain well. TURING will help doctors to decide the best course of treatment for future patients.
Who can participate?
Aged 16 or older who have new or relapsing nephrotic syndrome as a consequence of minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS)
What does the study involve?
Participants will be randomised to either receiving three doses of rituximab infusion or placebo along with receiving standard of care treatment for their disease. Participants are only eligible for the study if they are experiencing a relapse of their disease. If they are randomised to the placebo arm and subsequently relapse again while in the trial, they may be eligible to receive open-label rituximab infusions (identical to the study assessments within the main study.
What are the possible benefits and risks of participating?
Participants have the benefit of accessing rituximab which is currently not licensed or funded by NHS England for use in adults with relapsing nephrotic syndrome.
Where is the study run from?
Cambridge Clinical Trials Unit based at Cambridge University Hospitals NHS Foundation Trust
When is the study starting and how long is it expected to run for?
November 2019 to April 2026
Who is funding the study?
NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC), UK
Who is the main contact?
1. Katrina Gatley (scientific), katrina.gatley1@nhs.net
2. Hira Siddiqui (public), hira.siddiqui@nhs.net
Contact information
Scientific
Cambridge Clinical Trials Unit
Cambridge University Hospitals NHS Foundation Trust
Addenbrooke's Hospital
Coton House Level 6, Box 401
Hills Road
Cambridge
CB2 0QQ
United Kingdom
| Phone | +44 (0)1223 349007 |
|---|---|
| katrina.gatley1@nhs.net |
Public
Cambridge Clinical Trials Unit
Cambridge University Hospitals NHS Foundation Trust
Addenbrooke's Hospital
Coton House Level 6, Flat 63
Hills Road
Cambridge
CB2 0QQ
United Kingdom
| Phone | +44 (0)1223 250709 |
|---|---|
| hira.siddiqui@nhs.net |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| 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 below to request a patient information sheet |
| Scientific title | A randomised, two-arm (1:1 ratio), double blind, placebo controlled phase III trial to assess the efficacy, safety, cost and cost-effectiveness of rituximab in treating de novo or relapsing NS in patients with MCD/FSGS (TURING) |
| Study acronym | TURING |
| Study hypothesis | Rituximab prolongs remission of nephrotic syndrome secondary to minimal change disease and focal segmental glomerular sclerosis |
| Ethics approval(s) | Approved 14/06/2019, London - City & East Research Ethics Committee (Bristol Research Ethics Committee Centre, Whitefriars, Level 3, Block B, Lewins Mead, Bristol, BS1 2NT; +44(0)207 104 8171; nrescommittee.london-cityandeast@nhs.net) |
| Condition | Nephrotic syndrome, caused by minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) |
| Intervention | 112 patients with new presentation or relapsing MCD/FSGS will be recruited. They will be randomised to receive rituximab (2 x 1g starting within 4 weeks of start of protocolised prednisolone regimen (Day 0), followed by 1g at 26 weeks) or placebo (2 doses starting within 4 weeks of start of protocolised prednisolone treatment followed by last done at 26 weeks). All patients will receive standard of care treatment with prednisolone, with a protocolised dosing regimen. All trial visits will align with standard of care clinic visits where ever possible. There are approximately 15 visits (based on 24 month participation in trial) of which approx 12 will coincide with standard of care visits for this patient population. The infusion visits of which there are 3 in the main study and then an additional 3 in the open label phase are in addition to standard of care and travel and refreshments will be covered for these. Participants will have blood and urine tests at the hospitals as standard and the results will be be shared as part of the study. Participants will be required to provide four 24-hour urine collection samples to detect proteinuria. Once they have achieved remission they will also be required to carry out weekly urine protein dipstick testing. Kits will be provided by the sites and instructions will be provided via PIS and Urine dipstick test diaries. The advantage of this frequency of testing is that participants will be aware of a potential relapse sooner than if they were not doing this testing and will be able to get medical treatment quickly. Data collection will include proteinuria (protein in urine), serum albumin, renal function and quality of life. The primary endpoint will be time from partial remission to relapse. Follow up will continue until all patients have completed at least 24 months of follow-up or have relapsed. An open label phase (OLP) will be open to patients in the placebo arm who reach the primary endpoint of relapse during the two year follow up visits. Sites will be unblinded to treatment identities per patient at this point and if the relapsed patient is found to be on the placebo arm; they will be offered rituximab therapy which will follow the protocolised pathway as per main study ( 3 doses in total over 26 weeks). Participants who qualify for OLP will only be required to attend hospital for infusions and AE checks. Travel and refreshment costs will be covered. Blood and urine test as standard will be extracted directly from online renal registries and participants will have consented to this. Patients who relapse but are found to have been randomised to the rituximab arm will be reverted to standard of care pathways for their disease. Patients who have not responded to treatment by achieving partial or complete remission at the week 16 visit will leave the trial and return to standard of care treatment. These patients will not receive the third dose of rituximab or placebo at week 26 as they have not demonstrated steroid responsiveness, and ongoing treatment with prednisolone with or without rituximab is likely to be futile. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Rituximab |
| Primary outcome measure | Time from partial or complete remission (whichever documented first) to relapse of nephrotic syndrome (assessed via blood and urine test to confirm relapse) |
| Secondary outcome measures | An evaluation of the effect of rituximab on: 1. Proportion of patients achieving partial or complete remission 2. Time to partial or complete remission from Day 0 (SPPR) 3. Serious adverse events (AEs) 4. AE of Special Interest, including infection and steroid-associated side effects 5. Change in urinary PCR/24 hour proteinuria 6. Change in serum albumin 7. Kidney function as assessed by the change in Glomerular filtration rate (GFR) from Day 0 - Start of Protocolised Prednisolone Regimen (SPPR) to 24 months and to trial end 8. Health Status (EQ-5D-5L) 9. Resource use, cost and cost-effectiveness |
| Overall study start date | 01/11/2018 |
| Overall study end date | 30/04/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 16 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 112; UK Sample Size: 112 |
| Total final enrolment | 150 |
| Participant inclusion criteria | 1. Age 16 years or older. 2. NS at trial entry (serum albumin < 35g/l and protein creatinine ratio (PCR) > 300mg/mmol) secondary to MCD/FSGS with, 3. De novo disease or relapsing disease in a patient previously steroid or calcineurin inhibitor (CNI) responsive. 4. Latest biopsy (at any time) proven MCD/FSGS. 5. Ability to provide written informed consent. 6. Agreed to be enrolled in the National Registry of Rare Kidney Disease (RaDaR). |
| Participant exclusion criteria | 1. MCD or FSGS due to secondary causes, including obesity-driven hyperfiltration, remnant kidneys, malignancy of a type likely to be associated with MCD /FSGS and genetic polymorphisms known to be associated with nephrosis 2. MCD/FSGS secondary to malignancy, including lymphoproliferative disorders 3. Family history of MCD or FSGS in a first degree relative 4. Previous rituximab within 18 months preceding Day 0 (SPPR), or 12 months if there is evidence of B cell return in peripheral lymphocyte subsets 5. Previous cyclophosphamide within 6 months preceding Day 0 (SPPR) 6. Prednisolone daily dose equal to or greater than 60mg, with a course length of greater than4 weeks, immediately prior to randomisation 7. Evidence of current or past infection with Hepatitis B, C or HIV (unless appropriate prophylaxis is given and no replicating virus is detected) 8. Positive serum pregnancy test (within 14 days prior to treatment with IMP in main trial and rituximab in OLP) 9. Evidence of active severe infection 10. Severe heart failure or severe, uncontrolled cardiac disease 11. Pregnant or breast-feeding women 12. Live vaccine administration in the four weeks prior to enrolment and while remaining on IMP treatment 13. Previous/known hypersensitivity to prednisolone or IMP or to murine proteins (and any excipients as described in section 6.1 of the SmPC) 14. Co-enrolment in another clinical trial of an investigational medicinal product 15. Any other reason which, in the opinion of the Principal Investigator (PI), renders the patient unsuitable for the trial 16. An increase in CNI dose in the four weeks preceding randomisation |
| Recruitment start date | 01/07/2019 |
| Recruitment end date | 31/03/2024 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Praed Street
London
W2 1NY
United Kingdom
Pond Street
London
NW3 2QG
United Kingdom
Whitechapel
Greater London
London
E1 1BB
United Kingdom
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
London
SE5 9RS
United Kingdom
Uttoxeter Road
Derby
DE22 3NE
United Kingdom
Newcastle Road
Stoke-on-trent
ST4 6QG
United Kingdom
Blackshaw Road
Tooting
London
SW17 0QT
United Kingdom
Leicester
LE1 5WW
United Kingdom
Fulwood
Preston
PR2 9HT
United Kingdom
Oxford Road
Manchester
M13 9WL
United Kingdom
Great Maze Pond
London
SE1 9RT
United Kingdom
Prescot Street
Liverpool
L7 8XP
United Kingdom
Wigginton Road
York
YO31 8HE
United Kingdom
Southmead Road
Westbury-on-Trym
Bristol
BS10 5NB
United Kingdom
Brighton
BN2 5BE
United Kingdom
Chelmsford
CM1 7ET
United Kingdom
Carshalton
SM5 1AA
United Kingdom
Birmingham
B15 2TH
United Kingdom
Nottingham
NG7 2UH
United Kingdom
High Heaton
Newcastle-upon-tyne
NE7 7DN
United Kingdom
Stevenage
SG1 4AB
United Kingdom
Reading
RG1 5AN
United Kingdom
Hull
HU3 2JZ
United Kingdom
Sheffield
S5 7AU
United Kingdom
Exeter
EX2 5DW
United Kingdom
Coventry
CV2 2DX
United Kingdom
Plymouth
PL6 8DH
United Kingdom
Salford
M6 8HD
United Kingdom
Leeds
LS9 7TF
United Kingdom
Birmingham
B4 6NH
United Kingdom
Glasgow
G12 0XH
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Boswell House
10 Arthur Street
Ayr
KA7 1QJ
United Kingdom
Kings Lynn
PE30 4ET
United Kingdom
Sponsor information
Hospital/treatment centre
Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
England
United Kingdom
| abc@email.com | |
"ROR" |
https://ror.org/04v54gj93 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 30/12/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Stored in repository |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository. The database will be hosted by the University of Cambridge server and access will be restricted to delegated individuals only. |
Editorial Notes
15/10/2024: The following changes were made to the trial record:
1. The overall end date was changed from 31/10/2024 to 30/04/2026.
2. The total final enrolment was added.
3. The intention to publish date was changed from 30/12/2025 to 30/12/2027.
22/04/2024: The following changes were made:
1. The recruitment end date was changed from 30/12/2024 to 31/03/2024.
2. The study contacts were updated.
3. The study overall end date was changed from 30/12/2025 to 31/10/2024.
20/11/2023: The contact was updated.
17/06/2019: Trial’s existence confirmed by NIHR.
