Condition category
Urological and Genital Diseases
Date applied
17/06/2019
Date assigned
21/06/2019
Last edited
21/06/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

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effective in most of the patients, recurrent relapses happen in 75% of the patients when the steroid dose is reduced or withdrawn.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?
July 2019 for five years

Who is funding the study?
NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC), UK

Who is the main contact?
1. Ms Sonakshi Kadyan (scientific)
sonakshi.kadyan@addenbrookes.nhs.uk
2. Dr Daniella Lawson (public)

Trial website

Contact information

Type

Scientific

Primary contact

Ms Sonakshi Kadyan

ORCID ID

Contact details

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
01223 349007
sonakshi.kadyan@addenbrookes.nhs.uk

Type

Public

Additional contact

Dr Daniella Lawson

ORCID ID

Contact details

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
01223 250709
daniella.lawson@addenbrookes.nhs.uk

Additional identifiers

EudraCT number

2018-004611-50

ClinicalTrials.gov number

Nil known

Protocol/serial number

41605

Study information

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)

Acronym

TURING

Study hypothesis

Rituximab prolongs remission of nephrotic syndrome secondary to minimal change disease and focal segmental glomerular sclerosis

Ethics approval

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)

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

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

Phase

Phase III

Drug names

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 trial start date

01/11/2018

Overall trial end date

30/12/2025

Reason abandoned (if study stopped)

Eligibility

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 type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 112; UK Sample Size: 112

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

30/12/2024

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Addenbrookes Hospital
Cambridge University Hospitals NHS Foundation Trust Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

St Mary's Hospital
Imperial College Healthcare NHS Trust Praed Street
London
W2 1NY
United Kingdom

Trial participating centre

Royal Free Hospital
Royal Free London Nhs Foundation Trust Pond Street
London
NW3 2QG
United Kingdom

Trial participating centre

The Royal London Hospital
Barts Health NHS Trust Whitechapel Greater London
London
E1 1BB
United Kingdom

Trial participating centre

John Radcliffe Hospital
Oxford University Hospitals NHS Foundation Trust Headley Way Headington
Oxford
OX3 9DU
United Kingdom

Trial participating centre

King's College Hospital NHS Foundation Trust
Denmark Hill
London
SE5 9RS
United Kingdom

Trial participating centre

Royal Derby Hospital
University Hospitals Of Derby And Burton NHS Foundation Trust Uttoxeter Road
Derby
DE22 3NE
United Kingdom

Trial participating centre

Royal Stoke University Hospital
University Hospitals Of North Midlands NHS Trust Newcastle Road
Stoke-on-trent
ST4 6QG
United Kingdom

Trial participating centre

St George's Hospital
St George's University Hospitals NHS Foundation Trust Blackshaw Road Tooting
London
SW17 0QT
United Kingdom

Trial participating centre

Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom

Trial participating centre

Royal Preston Hospital
Sharoe Green Lane Fulwood
Preston
PR2 9HT
United Kingdom

Trial participating centre

Manchester University NHS Foundation Trust
Cobbett House Oxford Road
Manchester
M13 9WL
United Kingdom

Trial participating centre

Guy’s Hospital
Guy’s & St Thomas’ NHS Foundation Trust Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

Royal Liverpool University Hospital
Royal Liverpool and Broadgreen University Hospitals NHS Trust Prescot Street
Liverpool
L7 8XP
United Kingdom

Trial participating centre

York Hospital
York Teaching Hospital NHS Foundation Trust Wigginton Road
York
YO31 8HE
United Kingdom

Trial participating centre

Southmead Hospital
North Bristol NHS Trust Southmead Road Westbury-on-Trym
Bristol
BS10 5NB
United Kingdom

Trial participating centre

Royal Sussex County Hospital
Eastern Road
Brighton
BN2 5BE
United Kingdom

Trial participating centre

Broomfield Hospital
Court Road
Chelmsford
CM1 7ET
United Kingdom

Trial participating centre

St Helier Hospital
Wrythe Lane
Carshalton
SM5 1AA
United Kingdom

Trial participating centre

Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

Freeman Hospital
Freeman Road High Heaton
Newcastle-upon-tyne
NE7 7DN
United Kingdom

Trial participating centre

Lister Hospital
Coreys Mill Lane
Stevenage
SG1 4AB
United Kingdom

Trial participating centre

Royal Berkshire Hospital
London Road
Reading
RG1 5AN
United Kingdom

Trial participating centre

Hull Royal Infirmary
Anlaby Road
Hull
HU3 2JZ
United Kingdom

Trial participating centre

Northern General Hospital
Herries Road
Sheffield
S5 7AU
United Kingdom

Trial participating centre

Royal Devon & Exeter Hospital
Barrack Road
Exeter
EX2 5DW
United Kingdom

Trial participating centre

Walsgrave General Hospital
Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom

Trial participating centre

Derriford Hospital
Derriford Road
Plymouth
PL6 8DH
United Kingdom

Trial participating centre

Salford Royal
Stott Lane
Salford
M6 8HD
United Kingdom

Trial participating centre

St. James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Birmingham Women's And Children's NHS Foundation Trust
Steelhouse Lane
Birmingham
B4 6NH
United Kingdom

Trial participating centre

Gartnavel Royal Hospital
1055 Great Western Road
Glasgow
G12 0XH
United Kingdom

Trial participating centre

Cardiff & Vale University LHB
Heath Park
Cardiff
CF14 4XW
United Kingdom

Trial participating centre

NHS Ayrshire and Arran
PO Box 13 Boswell House 10 Arthur Street
Ayr
KA7 1QJ
United Kingdom

Trial participating centre

Queen Elizabeth Hospital
Gayton Road
Kings Lynn
PE30 4ET
United Kingdom

Sponsor information

Organisation

Cambridge University Hospitals NHS Foundation Trust

Sponsor details

Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
-
abc@email.com

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 17/83/06

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal

IPD sharing statement:
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.

Intention to publish date

30/12/2025

Participant level data

Stored in repository

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

17/06/2019: Trial’s existence confirmed by NIHR.