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RANDOMISED PILOT TRIAL OF

MYFORTIC FOR THE TREATMENT OF PRIMARY PROTEINURIC

GLOMERULONEPHRITIS

Short Title: Proteinuria in Glomerulonephritis: Myfortic (GloMY)

TRIAL PROTOCOL – VERSION 3.2

REC Ref No.: 10/S0703/27

ISRCTN11937028 EUDRACT No: 2009- 016003-26

Chief Investigator: Professor Lorraine Harper

Trial Sponsor: University Hospital Birmingham NHS Foundation Trust

Funded by an Educational Grant from Novartis Pharmaceuticals UK Ltd

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GloMY Trial Management Group

Nephrology

Professor Lorraine Harper (0121 414 7042) (University Hospital, Birmingham) l.harper@bham.ac.uk

Clinical Trials Statistics

Professor Keith Wheatley (0121 415 9119) Miss Natalie Ives (0121 415 9113) (CRUK Clinical Trials Unit, Birmingham) (University of Birmingham Clinical Trials Unit) k.wheatley@bham.ac.uk n.j.ives@bham.ac.uk

Data Monitoring and Ethics Committee Professor David Oliveira, Nephrologist (Chair ) (St George’s Hospital, London)

Dr Iain MacPhee, Nephrologist (St George’s Hospital, London)

Dr Louise Hillier, Statistician (Addenbrookes, Cambridge) (Warwick Trials Unit)

Trial Steering Committee Dr Wai Tse, (Independent Chair) Nephrologist, Derriford Hospital, Plymouth

Dr Richard Borrows, (Independent), Nephrologist, University Hospital, Birmingham

Dr Andrew Lewington (Independent), Nephrologist, St James’s Hospital, Leeds

Dr Jonathan Barratt, Nephrologist, Leicester General Hospital

Professor Steven Harper, Nephrologist, Southmead Hospital, Bristol

Dr David Jayne, Nephrologist, Addenbrooke’s Hospital, Cambridge

Dr Alan Salama, Nephrologist, Royal Free Hospital, London

Dr Simon Satchell, (Independent), Nephrologist, Southmead Hospital, Bristol

GloMY Study Office For general queries, supply of trial materials, and collection of data:

Birmingham Clinical Trials Unit (BCTU), College of Medical & Dental Sciences, Robert Aitken Institute, University of Birmingham, Edgbaston, Birmingham B15 2TT

Tel: 0121 415 9100 (answering machine outside office hours); Fax: 0121 415 9135 Trial Coordinator Mrs Elizabeth Brettell 0121 415 9130 e.a.brettell@bham.ac.uk Computing Mr Nick Hilken 0121 415 9121 n.h.hilken@bham.ac.uk Statistician Mr Andrew Howman 0121 415 9116 a.j.howman@bham.ac.uk

Randomisation Internet: https://www.trials.bham.ac.uk/GloMY

Telephone: 0800 953 0274 (toll free in UK) Or +44 (0)121 415 9137 (from outside the UK)

Clinical queries during office hours should be directed to one of the Clinical Co-ordinators, or to an

appropriate member of the Trial Management Group.

Other queries should be directed to the GloMY Study Office.

Trial Sponsor: University Hospitals Birmingham NHS Foundation Trust

REC reference: 10/S0703/27 EudraCT number: 2009-016003-26 ISRCTN number: ISRCTN11937028 Version Number: Protocol version: 3.2 dated 03/01/12 Previous versions: 3.1, 3.0, 2.1, 2.0, 1.0

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Contents

1. Trial Outline: Proteinuria in Glomerulonephritis: Myfortic (GloMY) ................................... 5 2. Background and Rationale ............................................................................................... 7 3. Trial Design and Objectives ............................................................................................. 9

3.1. Primary Trial Objective .............................................................................................. 9 3.2. Secondary Trial Objectives ....................................................................................... 9

4. Trial Procedures ............................................................................................................ 10 4.1. Entry Criteria ........................................................................................................... 10

4.1.1. Inclusion Criteria ............................................................................................... 10 4.1.2. Exclusion Criteria .............................................................................................. 10

4.2. Screening and Consent ........................................................................................... 10 4.3. Baseline Assessments ............................................................................................ 11 4.4. Internet, Telephone & Out-of-Hours Randomisation ............................................... 12 4.5. Blinding ................................................................................................................... 12 4.6. Interventions ............................................................................................................ 12

4.6.1. Treatment Arm .................................................................................................. 12 4.6.2. Standard Care .................................................................................................. 12

4.7. Other Treatments, Contraception and Dose Modification ........................................ 13 4.7.1. Prophylactic Therapies ..................................................................................... 13 4.7.2. Contraception ................................................................................................... 13 4.7.3. Dosage Modification ......................................................................................... 13 4.7.4. Treatment of Resistant Disease ........................................................................ 13 4.7.5. Treatment of Relapse ....................................................................................... 13

5. Outcome Measures of Efficacy ...................................................................................... 14 5.1. Patient Follow-Up and Assessments ....................................................................... 14

5.1.1. Scheduled Visits ............................................................................................... 14 5.1.2. End of Study ..................................................................................................... 14 5.1.3. Summary of Patient Assessments and Data Collection .................................... 14

5.2. Primary Outcome Measure of Efficacy .................................................................... 15 5.3. Secondary Outcome Measures of Efficacy ............................................................. 15 5.4. Endpoint Definitions ................................................................................................ 16 5.5. Criteria for Patient Discontinuation .......................................................................... 16

6. Safety Assessment and Reporting ................................................................................. 16 6.1. Definitions of Types of Adverse Events ................................................................... 16

6.1.1. Adverse Events (AEs) ....................................................................................... 16 6.1.2. Adverse Reactions (ARs) ................................................................................. 17 6.1.3. Serious Adverse Events (SAEs) ....................................................................... 17 6.1.4. Serious Adverse Reactions (SARs) .................................................................. 17 6.1.5. Suspected Unexpected Serious Adverse Reactions (SUSARs) ....................... 17

6.2. Assessing Severity and Causality of AEs and SAEs ............................................... 18 6.3. Reporting all Types of Adverse Events ................................................................... 18

6.3.1. Reporting Adverse Events/Reactions ............................................................... 18 6.3.2. Reporting Serious Adverse Events/Reactions .................................................. 18 6.3.3. Reporting SUSARs ........................................................................................... 18 6.3.4. Reporting Pregnancies ..................................................................................... 19

6.4. Pharmacovigilance Responsibilities ........................................................................ 19 7. Sample Size and Recruitment ....................................................................................... 20

7.1. Sample size ............................................................................................................. 20 7.2. Recruitment ............................................................................................................. 20

8. Statistical Analysis ......................................................................................................... 20 8.1 Data Monitoring and Ethics Committee .................................................................... 21

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9. Biomedical Studies ........................................................................................................ 21 9.1. Blood for Biomarkers ............................................................................................... 21 9.2. Urine for Biomarkers (optional) ............................................................................... 21 9.3. Renal Biopsy (optional) ........................................................................................... 21

10. Research Governance ................................................................................................. 22 10.1. Sponsor ................................................................................................................. 22 10.2. Clinical Trials Unit .................................................................................................. 22 10.3. Confidentiality of Personal Data ............................................................................ 22 10.4. Long-Term Storage of Data ................................................................................... 22 10.5. Research Indemnity .............................................................................................. 22

11. Trial Organisation......................................................................................................... 22 11.1 Principal Investigator ........................................................................................... 22 11.2 Finance ................................................................................................................ 23 11.3 Cost Implications ................................................................................................. 23 11.4 Trial Communications .......................................................................................... 23 11.5 Clinical Queries ................................................................................................... 23 11.6 Publication ........................................................................................................... 23

12. References .................................................................................................................. 24

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1. Trial Outline: Proteinuria in Glomerulonephritis: Myfortic (GloMY)

Design: GloMY is a national, multi-centre, randomised controlled open-label pilot trial of Myfortic plus short course steroids versus standard care in patients with proteinuric primary focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). Currently standard care is a long course of steroids for patients with FSGS, and no treatment for patients with IgAN.

Aim of Study: To determine the feasibility of running a full-scale phase III randomised trial of Myfortic plus short course steroids versus standard care in patients with FSGS or IgAN, and to obtain preliminary comparative data on the efficacy of Myfortic plus short course steroids in inducing sustained response in patients with FSGS or IgAN.

Inclusion Criteria: Patients with new onset biopsy proven (within last year) primary FSGS with albumin less than the normal laboratory reference range OR patients with primary IgAN with biopsy findings E1 or M1 using the Oxford classification and a minimum of 8 glomeruli in the biopsy AND Proteinuria (Protein Creatinine Ratio, PCR>100mg/mmol or ACR>66mg/mmol) following at least 4 weeks treatment with maximal blood pressure treatment (to include angiotensin blockade) to target blood pressure <130/80 mmHg.

Randomisation: Randomisation is via the internet, using a computer generated minimisation algorithm.

Treatment Arms: Intervention group for both FSGS and IgAN patients (Myfortic and short course of steroids): Myfortic 720mg b.d continued for 2 years, along with prednisolone, starting at dose of 1mg/kg (up to a maximum of 60mg) tapered to 0mg by 10 weeks.

Standard care for FSGS patients (Long course of steroids - prednisolone): Prednisolone, starting at dose of 1mg/kg (up to a maximum of 60mg) until complete remission or a maximum of 6 months treatment. If complete remission is achieved, prednisolone will be tapered to 0mg over the following 10 weeks. In those achieving partial remission, prednisolone will be continued for a further month, and then tapered to 5mg over 8 weeks, and then maintained at 5mg until 2 years.

Standard care for IgAN patients: No treatment.

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Preliminary Efficacy Data: The primary measure of efficacy will be the proportion of patients achieving complete or partial remission by 24 weeks sustained (relapse free) for 12 months. Secondary measures of efficacy will be the proportion achieving partial remission and time to partial remission, proportion achieving complete remission and time to complete remission, time to relapse, proportion of patients requiring alternative cytotoxic agent or treatment failure and renal function (estimated Glomerular Filtration Rate, proteinuria). Data will also be collected on cumulative dose of corticosteroids, number of patients developing steroid induced diabetes, number of patients having serious infections and adverse events. Data will be collected at baseline, at weeks 2 and 4, and then every 4 weeks out to 6 months post-randomisation, and then every 12 weeks for at least 2 years.

Sample Size: As this is a pilot study, no formal sample size calculations have been performed. Recruitment of 100 patients with FSGS and IgAN over 24 months is planned (50 to Myfortic with short course steroids and 50 to standard care), with a minimum number of 40 patients with each disease type.

Study Duration: 48 months.

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2. Background and Rationale Glomerulonephritis is the third leading cause of end-stage renal failure in European populations (1). Its most frequent histological types are IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (2, 3). Proteinuria and baseline renal function are important predictors of renal dysfunction (4). Severity of proteinuria at onset and follow-up are associated with a poor outcome in primary glomerulonephritis (4). Reduction in proteinuria itself may reduce renal injury irrespective of the underlying primary renal injury. FSGS FSGS accounts for between 10% and 35% of adult cases of nephrotic syndrome (5), with an incidence of 1 to 2 per million population. Historically, the prognosis of untreated nephrotic patients with FSGS is poor, with 50% developing end-stage renal failure within 8 years, and spontaneous remissions are rare (6, 7). Patients who achieve complete remission have an improved prognosis (8). In studies, greater than 90% of patients with FSGS who achieve remission remained dialysis independent at 5 to 10 years compared with 53% of patients who failed to achieve remission (8, 9). Attainment of partial remission, although not as beneficial as complete remission, still confers long-term benefit for patients (10). Unfortunately, even in those who attain remission, relapse is common, occurring in up to 50% of patients. Relapse is more common in patients who achieve only a partial remission (10). Treatment with prednisolone for 4 to 8 weeks in patients with FSGS has a marginal effect on outcomes (11), but in more recent studies, high-dose prednisolone for longer periods of 4 to 5 months improved response rates from 15% to 60% (12). However, following treatment, steroid dependency is common, at least in children, due to the high rate of relapse. Although there have been no randomised controlled trials (RCTs) of immunosuppressive intervention in untreated primary FSGS compared with placebo, the current accepted standard care for patients with FSGS is prolonged steroids. Several case series have shown improvement in patients attaining remission compared to historical controls (9,13,14). Unfortunately, there are no good clinical trials comparing cytotoxic therapies with steroids in previously untreated disease. A small pilot study of the use of Mycophenolate in FSGS suggests that Mycophenolate is as effective as conventional treatment with steroids, but remission may occur faster with reduction in steroid exposure (15). RCTs have been performed in patients with steroid resistant FSGS. A meta-analysis concluded that cyclosporine may give benefit in steroid resistant FSGS, but there was concern about associated nephrotoxicity (15). IgAN Primary IgAN is the most common cause of idiopathic glomerulonephritis throughout the world, with approximately 20% of patients progressing to end-stage renal failure by 20 years. Biopsy proven IgAN has an incidence of 10 per million population in the UK. As with FSGS, severity of proteinuria is predictive of a poor outcome (16). Reduction of proteinuria to <1g/day confers substantial improvements in outcome. Improvements have been made in the management of IgAN since the introduction of angiotensin blockade, which in many patients is sufficient to reduce proteinuria to <1g/day (17). However, there are a substantial number of patients that have persistent proteinuria >1g/day; beyond blood pressure control and angiotensin blockade the management of these patients remains uncertain. A recent Cochrane review suggested that outcomes favour the use of immunosuppression, with steroids being the most promising (18). Long-term results of a RCT which used a regime of three pulses of 1g methylprednisolone at entry, 2 months and

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4 months and 6 months treatment with prednisolone 0.5mg/kg on alternate days showed renal survival advantage over those treated with supportive care. Reduction in proteinuria was a better predictor of outcome than absolute proteinuria at entry in this study (19). However, 30% of patients failed to respond to steroids, and many physicians are reluctant to treat patients with IgAN with this regime due to the toxicity associated with high-dose prolonged steroids. Therefore, the current accepted standard care for patients with IgAN is no treatment beyond the routine management of blood pressure control, which should include angiotensin blockade. Part of the reluctance to treat patients with IgAN with immunosuppression has been due to difficulty in identifying those patients with IgAN likely to benefit from treatment. Recently a new classification of IgAN has been published which has identified robust histological features with predictive significance (20), which will allow identification of those patients who may respond to immunosuppression. However, the effect of cytotoxic therapy on long-term outcome is less clear. A recent meta-analysis reviewing the benefits of Mycophenolate suggested no statistical benefit on reduction of proteinuria. However, only four RCTs which recruited a total of 168 patients were included, the studies were heterogeneous and follow-up was short. In addition, a large number of patients had advanced chronic kidney disease (21). Hence, it is difficult to draw firm conclusions as to the effects of Mycophenolate in IgAN and larger studies are required using histological features that will allow identification of those individuals who may respond to intervention. In addition to glomerular scarring, tubulointerstitial disease is an important predictor of progression to end-stage renal failure in both FSGS and IgAN. Observational and experimental studies suggest albumin is a tubulointerstitial toxin. Studies in experimental models suggest that proteinuria induces a proinflammatory and profibrotic milieu within the tubulointerstitum by stimulating the production of proinflammatory and profibrotic cytokines, chemokines, and growth factors such as IL-8, RANTES, TGF- and monocyte chemotactic protein 1 (MCP-1) (22). MCP-1 release from tubules promotes the influx of macrophages (23). The benefits of immunosuppression in FSGS and IgAN may impact both at the glomerular and tubulointerstitial compartments. In primary glomerulonephritis, irrespective of cause, tubulointerstitial disease is characterised by tubular atrophy and interstitial scar formation with a prominent macrophage inflammatory infiltrate (24). Animal models indicate that this cell type has a central role in the initiation and progression of renal injury (25). The relationship between albuminuria, urinary MCP-1 and interstitial macrophage numbers is suggested to be strongest in those patients with lower levels of scarring and affected by disorders associated with distinct patterns of glomerular injury, such as IgAN and FSGS (26). Animal models of chronic renal disease with proteinuria suggest immunosuppressive agents may reduce proteinuria and inhibit tubulointerstitial damage (27). In addition, Mycophenolate inhibits accumulation of lymphocytes and macrophages which may have a central role in driving inflammation within the tubulointerstitum (25). Interestingly immunosuppressive agents may also have effects on podocytes improving proteinuria (28, 29). The need for GloMY: A multi-centre, randomised phase II trial It has been suggested that high-dose prolonged steroids could reduce proteinuria and improve renal survival in both FSGS and IgAN. However, physicians are often reluctant to utilise these regimes due to the toxicity associated with long course steroid regimes, which include diabetes, osteoporosis, increased risk of cardiovascular disease and obesity. Hypertension and diabetes are particularly important as they are important risk factors in the progression of FSGS to end-stage renal failure (4). A reduction in steroid exposure would be a significant advantage.

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Hypothesis We hypothesise that Myfortic combined with a short course of steroids will reduce proteinuria and prevent progression of tubulointerstitial inflammation in patients with primary proteinuric renal disease, FSGS and IgAN. Importance of the knowledge to be gained Knowledge to be gained from this study could be highly important. The optimisation of treatment strategies for patients with FSGS and IgAN has the potential to dramatically and directly affect clinical practice and patient outcomes. This is underscored by the current widely varied practice patterns regarding the use of corticosteroids and other cytotoxic therapies and the variable outcomes of these patient populations. Furthermore, the relative rarity of patients with these diseases has traditionally made it difficult to collect high quality data on interventions that affect hard, clinical endpoints.

3. Trial Design and Objectives Proteinuria in Glomerulonephritis: Myfortic (GloMY) is a national, multi-centre, randomised controlled open-label pilot trial of Myfortic plus short course steroids versus standard care in patients with proteinuric FSGS or IgAN. Current accepted standard care is a prolonged course of steroids in patients with FSGS, and is no treatment in patients with IgAN.

3.1. Primary Trial Objective To determine the feasibility of running a full-scale phase III randomised trial of Myfortic plus short course steroids in patients with FSGS or IgAN. The trial will also provide preliminary comparative data on the efficacy of Myfortic plus short course steroids in inducing sustained response (partial or complete) in a well-defined cohort of patients with primary proteinuric glomerulonephritis (FSGS and IgAN) that will inform the sample size required to design a large prospective randomised study investigating the effect of Myfortic. 3.2. Secondary Trial Objectives To obtain preliminary data on the efficacy of Myfortic plus short course steroids in:-

inducing full remission

sustaining remission

preventing the progression of chronic kidney disease

reducing proteinuria

treatment safety.

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This study will also enable the study forms to be piloted.

4. Trial Procedures See Appendix 1 for Trial Schema 4.1. Entry Criteria 4.1.1. Inclusion Criteria 1. Patients with new onset biopsy proven (within last year) primary FSGS with albumin

less than the normal laboratory reference range OR patients with primary IgAN with biopsy findings E1 or M1 using the Oxford classification (see Appendix 2) and a minimum of 8 glomeruli in the biopsy

AND 2. Proteinuria (Protein Creatinine Ratio, PCR>100mg/mmol or ACR>66mg/mmol)

following at least 4 weeks treatment with maximal blood pressure lowering therapy (to include angiotensin blockade) to target blood pressure <130/80 mmHg

3. If female and of childbearing potential, must:

Not be pregnant or breastfeeding

Agree to avoid pregnancy during and for 6 weeks following the last dose of study treatment

4. If male with a partner of childbearing potential, must:

Agree to use adequate, medically approved, contraceptive precautions during and for 6 weeks following the last dose of study treatment.

4.1.2. Exclusion Criteria 1. Age <18 years 2. Secondary causes of FSGS 3. Secondary IgAN 4. Deteriorating renal function >20μmol/l each week for 3 weeks or more 5. Estimated Glomerular Filtration Rate (eGFR) <20 ml/min (using modification of diet in

renal disease (MDRD) equation) 6. Poor blood pressure control (e.g. blood pressure ≥140/90 mmHg) 7. Greater than 2 weeks of corticosteroid therapy for renal disease 8. Previous treatment with immunosuppression therapies for renal disease 9. Unable to receive immunosuppression treatments due to malignancy or active

infection 10. Patients with systemic infection unless specific anti-infective therapy is employed 11. Diabetes 12. Known to have hepatitis B or C 13. Known to be HIV positive 14. Neutropenia 15. Inability to give informed consent. 4.2. Screening and Consent Potential participants will undergo a screening evaluation by a study physician or qualified study nurse to determine if the patient meets all of the inclusion criteria and none of the exclusion criteria. The screening visit requires documentation of PCR or ACR, blood pressure and blood pressure therapy, serum creatinine/eGFR, serum albumin, serum HbA1c, documentation of random glucose <12mmol/l, assessment of treatment with glucocorticoids in the last 28 days, a pregnancy test (where applicable), clinical assessment of hepatitis B, C and HIV status and available pertinent histology results. Those patients whose blood pressure control requires an increase in medication will return

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for repeat screening 4 weeks later. There will be central review of biopsy, although this is not necessary for inclusion. To measure BP the patient needs to be rested for 5 minutes (i.e. seated) and then their BP is measured on three occasions separated by 1 minute. Usually the first BP reading is elevated and the true BP is obtained from averaging the 2nd and 3rd readings. If it is in accordance with the site’s local practice it is acceptable to use mean daytime BP measurements taken from 24 ambulatory measurements and also mean daytime BP measurements taken at home, if the patient has white coat hypertension. Informed consent will be sought from all eligible patients. Detailed study information and the consent form for the main trial and the biomedical studies will be reviewed with eligible patients (see Appendices 3 and 4 for FSGS patients, see Appendices 5 and 6 for IgAN patients). After disclosure of the study details and the potential risks and benefits of participating in the study, patients will be given adequate time (at least 24 hours) to consider consenting to participate in the main trial and to consent for the procurement of biological specimens. Importantly, patients may opt out of participating in the urine biomarker study, but still participate in the main GloMY trial. The patient’s general practitioner will be informed in writing of the patient’s participation in the GloMY trial with the patient’s consent (see Appendix 7). 4.3. Baseline Assessments Patients who agree to participate and give informed consent will undergo a baseline visit as soon as possible (prior to randomisation). Baseline data will include basic demographic information, laboratory and clinical data (see Appendix 8):- 1. Date of birth, sex 2. Height/Weight 3. Medications 4. Blood pressure To measure BP the patient needs to be rested for 5 minutes (i.e.

seated) and then their BP is measured on three occasions separated by 1 minute. Usually the first BP reading is elevated and the true BP is obtained from averaging the 2nd and 3rd readings. If it is in accordance with the site’s local practice it is acceptable to use mean daytime BP measurements taken from 24hr ambulatory measurements and also mean daytime BP measurements taken at home, if the patient has white coat hypertension.

Routine practice blood and urine samples will be taken to measure: 5. PCR/ACR 6. Serum creatinine and albumin 7. eGFR 8. HBA1c Additional study blood and urine samples will be taken and renal tissue previously used for diagnostic purposes will be retrieved: (see Section 9: Biomedical Studies) 9. Blood for biomarkers stored for future analysis 10. Urine for biomarkers stored for future analysis 11. Quantitative assessment of fibrosis on diagnostic biopsy.

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4.4. Internet, Telephone & Out-of-Hours Randomisation Patients will be randomised between the two treatment groups (Myfortic plus short course steroids or standard care) in a one-to-one ratio via the University of Birmingham Clinical Trials Unit (BCTU) on-line randomisation service. This secure internet-based central randomisation service is available 24 hours a day and will ensure concealment of treatment allocation. Randomisation will use a computer-based algorithm with minimisation. There will be a separate minimisation for each diagnosis (FSGS and IgAN), and minimisation will be by the prognostic factors of age (≤60 vs. >60 years), severity of renal disease at presentation (eGFR≤50 vs. >50ml/min) and proteinuric range (PCR≤300 vs. >300mg/mmol/ACR≤200 vs ACR>200mg/mmol) to ensure balance of patients across the two arms within each of FSGS and IgAN disease groups Informed consent must be obtained by the local investigator or other qualified local research staff before randomisation is performed. The investigator should then log into the on-line randomisation service at https://www.trials.bham.ac.uk/GloMY, which will ask the investigator to confirm the eligibility criteria and supply the minimisation parameters. The patients will then be randomised to either Myfortic and short course steroids or standard care (a long course of steroids if FSGS or no treatment if IgAN). The patient will also be assigned a unique trial identification number to be used on all trial related material for the patient. Confirmation of the treatment allocation and trial identification number will be forwarded to the trial coordinator, the local investigator and the local pharmacy via e-mail immediately upon randomisation. In the event that access to the internet is unavailable, the investigator may call the BCTU (0800 953 0274) during normal office hours (9am to 5pm) who will access the randomisation program and inform the investigator of the treatment allocation and ensure that the randomisation information reaches the appropriate study personnel. A back-up paper randomisation will also be available at the BCTU. 4.5. Blinding Patients and health care providers will not be blinded to randomised treatment allocation due to the differences in the steroid regimens being assessed. However, the end-points are objective and therefore unlikely to be significantly influenced by the lack of blinding. However, the renal biopsy assessment will be performed by a pathologist who will be blinded to randomised treatment allocation. 4.6. Interventions 4.6.1. Treatment Arm Participants in the intervention group (Myfortic and short course of steroids) will be treated with Myfortic 720mg b.d continued for 2 years. Prednisolone will be administered at a starting dose of 1mg/kg (up to a maximum of 60mg) tapered to 0mg by 10 weeks. See Appendix 9 for prednisolone tapering schedule. 4.6.2. Standard Care 4.6.2.1. FSGS Participants in the standard care group will receive a long course of prednisolone, starting at 1mg/kg (up to a maximum of 60mg), until complete remission or a maximum of 6 months treatment. If complete remission is achieved, prednisolone will be tapered to 0mg over the following 10 weeks. In those achieving a partial remission, long course prednisolone will be continued for a further month, and then tapered to 5mg over 8 weeks

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and maintained at 5mg until 2 years. See Appendix 9 for long course prednisolone tapering schedule. In patients with NO reduction in proteinuria at 16 weeks, additional immunosuppressant therapy (such as cyclosporine or tacrolimus) may be introduced at the investigator’s discretion as per local practice. 4.6.2.2. IgAN No treatment. Note: Definitions of complete remission, partial remission, relapse and resistant disease are given in Section 5.4. 4.7. Other Treatments, Contraception and Dose Modification Additional treatments will be administered according to local practice. Blood pressure target of 130/80 should be maintained throughout the study 4.7.1. Prophylactic Therapies Infection prophylaxis such as with septrin, fracture prophylaxis such as with calcium and vitamin D supplementation and treatment with bisphosphonates will be recommended for consideration, but implementation will be left to local practice. 4.7.2. Contraception Male and female patients will be expected to use reliable, medically approved methods of contraception for the duration of the study treatment (and for up to six weeks afterwards); if they are unable to do this, they will be asked to refrain from sexual intercourse. 4.7.3. Dosage Modification Renal function and age: No dose adjustments are required. Leucopenia: Myfortic should be withheld if the total white blood cell (WBC) count is <4x109/L. Myfortic may be restarted at 50% dose once the WBC count is >4x109/L on two consecutive tests or >5x109/L on at least one test. After an episode of leucopenia, WBC counts should be monitored at least weekly for at least four weeks. Other: Dose alterations in corticosteroids and Myfortic should be made as per local practice in the event of infectious complications, side-effects of treatment or new onset diabetes. 4.7.4. Treatment of Resistant Disease Resistant disease, defined as failure to reduce PCR by >50% after 6 months of treatment, should be treated as per local practice and will be viewed as treatment failure. 4.7.5. Treatment of Relapse Relapse, as defined by increase in PCR >50% of remission level and a level >100mg/mmol maintained on 2 separate occasions at least 2 weeks apart should have induction steroid therapy re-introduced and maintained until remission. Tapering of steroid therapy should be as previously stated and maintained at 5mg per day (see Appendix 9). In those patients treated only with steroids, an alternative immunosuppressant therapy (such as cyclosporine or tacrolimus) may be introduced at the investigator’s discretion as per local practice.

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5. Outcome Measures of Efficacy 5.1. Patient Follow-Up and Assessments Each patient will be followed until study close with a minimum duration of follow-up of 2 years. Patient recruitment is anticipated to take 2 years, so the maximum duration of follow-up is 4 years (i.e. 208 weeks). Patients will be followed more frequently when they begin the trial when the interventions are being initiated and treatment is designed to induce remission. 5.1.1. Scheduled Visits Patients will be seen for trial follow-up assessments at weeks 2 and 4, and then every 4 weeks out to 6 months post-randomisation, and then every 12 weeks for at least 2 years or until the end of the study (defined as when the last randomised patient has completed 2 years follow-up) (See Section 5.1.2. on End of Study). During these study visits, basic clinical and laboratory data will be collected (see Appendix 10):-

Medications (including glucocorticoid dose)

Blood pressure target BP to be maintained at 130/80

Adverse events

Routine blood and urine samples to measure PCR/ACR, serum creatinine and albumin, serum HbA1c (at six-monthly intervals) and eGFR

Pregnancy test if applicable (every 3 months) Additional study blood and urine samples, and renal tissue (see Section 9: Biomedical Studies)

Blood sample to be stored for future analysis of biomarkers (every 6 months out to 2 years)

Urine sample for to be stored for future analysis of biomarkers (at 6 months, 1 and 2 years and at relapse (if applicable) - optional).

At the 2 year assessment, patients will be asked if they would be willing to have a repeat renal biopsy as part of the study - optional. Patients will be given an information sheet (see Appendix 11) on this procedure, and given time to consider to consenting to having the renal biopsy. Those patients who agree to have a renal biopsy at 2 years will be asked to complete a separate consent form (see Appendix 12). The patient’s general practitioner will be informed in writing of the patient having this renal biopsy with the patient’s consent (see Appendix 13).

Patients receiving Myfortic should have white blood counts monitored as per routine clinical practice as described in the update to date Summary of Product Characteristics (SmPC) (http://emc.medicines.org.uk/). 5.1.2. End of Study The end of the trial for regulatory purposes is defined as the date of the last follow-up visit at 2 years, of the last randomised patient undergoing protocol based therapy. If a patient has not been reviewed in the last 3 months, we will request that they are seen for a final study visit. At this end of study visit, basic clinical and laboratory data as detailed in Section 5.1.1 will be collected (see Appendix 10). 5.1.3. Summary of Patient Assessments and Data Collection Patients will be seen at weeks 2 and 4, and then every 4 weeks out to 6 months post-randomisation, and then every 12 weeks for at least 2 years or until the end of the study (see section 5.1.2 for definition of End of Study).

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Table 1: Patient Follow-Up Assessment Schedule and Data Collection*

Follow-up Schedule

At week 2, 4, then every 4 weeks for 6

months

Every 12 weeks for at least 2 years or until end of

studyλ

End of study visit

Ω

At Entry (Baseline)

Approximate Assessment Weeks: 2, 4, 8, 12, 16, 20, 24

Approximate Assessment Weeks: 38, 52, 64, 76, 88, 104, 116, 128, 140, 156,

168, 180, 192, 208

Informed Consent X

Basic demographics (e.g. DoB/age, sex)

X - - -

Medications X X X X

Blood pressure X X X X

Routine practice blood sample for serum creatinine and albumin, serum HbA1c (at six-monthly intervals) and eGFR

X X X X

Routine practice urine sample for PCR/ACR

X X X X

Urine sample for pregnancy test

X At 12 and 24 weeks X -

Adverse events - X X X

Blood sample to be stored for future analysis of biomarkers.

X At 24 weeks At 52, 76 and 104 weeks -

For patients who consent to the optional biomedical studies

Additional urine sample to be stored for future analysis of biomarkers

X At 24 weeks At 52 and 104 weeks (and at relapse if applicable)

-

Renal biopsy X† At 104 weeks -

For patients who are randomised to Myfortic

Complete blood counts X (also at Week 1, 3, 6, and 10)

X (also at Week 28, 32, 40, 44 to Week 48)

λ Follow-up for all patients will end once the last randomised patient has completed 2 years follow-up. With recruitment planned to take 2

years, this means the longest a patient will be followed-up is 4 years (i.e. 208 weeks) post-randomisation. Ω If at the end of the study, a patient has not been reviewed in the last 3 months, the patient should be seen for a (final) end of study visit.

† All patients must have had a renal biopsy within 1 year prior to entry into the study, which will undergo quantitative assessment of fibrosis.

* CRF completion should be as close as possible to the clinic assessment due date. However all CRFs will be accepted unless they cross over with the next clinic assessment timepoint.

5.2. Primary Outcome Measure of Efficacy The primary measure of efficacy will be the proportion of patients achieving a complete or partial remission by 24 weeks sustained (relapse free) for 12 months. 5.3. Secondary Outcome Measures of Efficacy Secondary measures of efficacy include:

Proportion achieving partial remission

Time to partial remission

Proportion achieving complete remission

Time to complete remission

Time to relapse

Proportion of patients requiring alternative cytotoxic agent or treatment failure

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Time to patients requiring alternative cytotoxic agent or treatment failure

Change in renal function as measured by eGFR

Change in proteinuria as determined by change in PCR

Cumulative dose of corticosteroids

Proportion of patients developing steroid induced diabetes

Severe adverse events (SAE) (and time to first SAE)

Serious infections

Proportion of patients who withdrew due to study drug intolerance For biomedical studies:

Analysis of blood for biomarkers of indicators of response

Analysis of urine for biomarkers of indicators of response.

Percentage change in interstitial fibrosis on renal biopsy (central scoring measured by Sirius red).

5.4. Endpoint Definitions Complete Remission: PCR<50mg/mmol (ACR<33mg/mmol) maintained on 2 occasions at least 2 weeks apart, stable renal function and normalisation on albumin. Partial Remission: At least 50% reduction in PCR or PCR<100mg/mmol (ACR <66mg/mmol) maintained on 2 occasions at least 2 weeks apart, stable renal function. Time to partial remission will be based on date of lowest PCR maintained on at least 2 separate occasions at least 2 weeks apart. Relapse: Increase in PCR/ACR>50% of remission level and PCR level>100mg/mmol (ACR>66mg/mmol) maintained on 2 separate occasions at least 2 weeks apart. Stable renal function: eGFR within 15% of initial level. Resistant disease: Failure to reduce PCR by >50% by 6 months. 5.5. Criteria for Patient Discontinuation In the event that a patient withdraws their consent to participate in the trial we will ask that we be allowed to collect vital status information from the patient and/or their family physician or general practitioner. All other patients will be followed until the end of the study or trial termination (whichever occurs first).

6. Safety Assessment and Reporting 6.1. Definitions of Types of Adverse Events Within the GloMY trial, both Myfortic and the steroid prednisolone are defined as Investigational Medicinal Products (IMP). 6.1.1. Adverse Events (AEs)

An AE is any untoward medical occurrence in a patient or clinical trial patient administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a (investigational) medicinal product, whether or not related to the medicinal product.

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Expected AEs are those listed in the current Summary of Product Characteristics (SmPC; for licensed drugs) or Investigators Brochure (IB; for an unapproved IMP or licensed IMP for non-licensed use). Information on the current expected events is given in Appendix 14.

The following are not AEs:

A pre-existing condition (unless it worsens significantly during treatment)

Diagnostic and therapeutic procedures, such as surgery (although the medical condition for which the procedure was performed must be reported if new).

6.1.2. Adverse Reactions (ARs)

An AR is an AE judged by the reporting investigator as having a reasonable causal relationship to a medicinal product. The expression “reasonable causal relationship” means in general that there is evidence or argument to suggest a causal relationship. 6.1.3. Serious Adverse Events (SAEs)

An SAE is any AE that:

Results in death

Is life threatening*

Requires in-patient hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Results in a congenital anomaly or a birth defect. *Life-threatening in this context refers to an event in which the patient was at risk of death at the time of event; it does not refer to an event which hypothetically might have caused death if it were more serious.

Expected SAEs are those listed in the current SmPC or IB for the study drugs. Information on the current expected events is given in Appendix 14. Events NOT considered to be SAEs are hospitalisations for:

Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition

Treatment, which was elective or pre-planned, for a pre-existing condition that is unrelated to the indication under study, and has not worsened.

Note: Death from any cause should be reported on an SAE form (Appendix 15) and returned to the GloMY Trial Office at the BCTU. 6.1.4. Serious Adverse Reactions (SARs)

An SAR is an SAE judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to an IMP. The expression “reasonable causal relationship” means in general that there is evidence or argument to suggest a causal relationship. Factors to consider when assessing causality of SARs are i) the nature of the reaction; ii) timing of the reaction; and iii) the relationship to the dose. 6.1.5. Suspected Unexpected Serious Adverse Reactions (SUSARs)

A SUSAR is an SAR, which is of a type or severity which is NOT consistent with the up-to-date product information in the SmPC or IB. Information on the current expected events is given in Appendix 14. Please always use the most recent updated SmPC. Up-to-date SmPCs of licensed products are available at http://emc.medicines.org.uk/.

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6.2. Assessing Severity and Causality of AEs and SAEs

All AEs and SAEs should be evaluated by a doctor to determine severity and causality between the IMP and/or concomitant therapy and the AE.

The term “severe” is often used to describe the intensity (severity) of a specific event. This is not the same as “serious,” which is based on patient/event outcome or action criteria.

6.3. Reporting all Types of Adverse Events 6.3.1. Reporting Adverse Events/Reactions

Adverse events relating to the patients underlying disease and its treatment will be assessed at each study visit, and recorded on the follow-up form (see Appendix 10). The BCTU will provide details of all adverse events to the Data Monitoring and Ethics Committee (DMEC) for their review on an annual basis.

6.3.2. Reporting Serious Adverse Events/Reactions

All SAEs must be recorded on the SAE form (see Appendix 15) and faxed to the BCTU on 0121 415 9135 within 24 hours of the research staff becoming aware of the event. Please ensure that the local Principal Investigator has assigned causality and expectedness to the SAE before reporting. For each SAE, the following information will be collected:

Full details in medical terms with a diagnosis, if possible

(Information on the current expected events is given in Appendix 14.)

Action taken

Outcome

Causality, in the opinion of the investigator*

Whether the event would be considered expected or unexpected* (refer to the most recent and relevant SmPC or IB).

*Assessment of causality and expectedness must be made by a doctor. If a doctor is unavailable, initial reports without causality and expectedness assessment should be submitted to the BCTU by a healthcare professional within 24 hours, but must be followed up by medical assessment as soon as possible thereafter.

Any SAEs ongoing or still present at the end of the study must be followed up at least until the final outcome is determined, even if this means that follow-up for that patient continues after the study has ended. 6.3.3. Reporting SUSARs

SAEs classed by the local investigator as both suspected to be related to the trial drugs and unexpected are SUSARs, and are subject to expedited reporting. The investigator should complete a SAE form (see Appendix 15), and fax to the BCTU within 24 hours of the research staff becoming aware of the event.

The Chief Investigator (or nominated individual) will undertake urgent review of SUSARs within 24 hours of the event being reported to the BCTU and may request further information immediately from the patient’s clinical team. The Chief Investigator will not overrule the causality, expectedness or seriousness assessment given by the local investigator but may comment on these.

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The BCTU will report all SUSARs to the MHRA and the MREC, and all SUSARs in patients receiving Myfortic to Novartis. If the SUSAR resulted in death or was life-threatening this will be done within 7 days of the initial report being received, or within 15 days for any other SUSAR. The reporting of SUSARs to Novartis will be done within 3 days of the SUSAR report being received at the BCTU.

If information is incomplete at the time of initial reporting, the BCTU will request follow-up information, including information for analysis of causality, from the local investigator and will send the follow-up information to the MHRA, MREC and Novartis within an additional 8 days for fatal or life-threatening SUSARs, and as soon as possible for any others.

6.3.4. Reporting Pregnancies If any female taking part in the study becomes pregnant, then these should be reported to the BCTU, who will inform Novartis within 3 days of this report. 6.4. Pharmacovigilance Responsibilities

Local Investigator:

Medical judgement in assigning seriousness, expectedness and causality to AEs.

To fax SAE form to BCTU within 24 hours of becoming aware, and to provide further follow-up information as soon as available.

To report SAEs to local committees if required, in line with local arrangements.

To report all adverse drug reactions suspected to be related to other licensed drugs used in standard care using the yellow card system.

To sign an Investigator’s Agreement accepting these responsibilities.

Chief Investigator (or nominated individual in their absence):

To assign causality and expected nature of SAEs where it has not been possible to obtain local assessment.

To review all events assessed as SAEs or SUSARs in the opinion of the local investigator. In the event of disagreement between local assessment and Chief Investigator review with regards to SUSAR status, local assessment will not be overruled, but Chief Investigator may add comments prior to reporting to MHRA.

Birmingham Clinical Trials Unit:

To report SUSARs to MHRA, MREC and Novartis within the required timelines.

To report all SAEs/SARs in patients receiving Myfortic, regardless of whether the event is suspected to be related to Myfortic, to Novartis within 3 days.

To notify Investigators of all SUSARs which compromise patient safety.

To report pregnancies to Novartis within 3 days.

To prepare annual safety reports to MHRA, MREC, Trial Steering Committee (TSC), Trial Sponsor and Novartis.

To prepare SAE reports for the DMEC at intervals to be decided by the DMEC.

To provide Investigators with updated IBs annually and other relevant information supplied by Novartis and others.

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Trial Steering Committee:

To periodically review blinded safety data and liaise with the DMEC regarding safety issues.

The TSC may close the trial on the recommendation of the independent DMEC in the event of clear evidence of harm or benefit for one treatment regimen.

Data Monitoring and Ethics Committee:

To review the un-blinded overall safety data to identify safety issues which may not be apparent on an individual case basis.

To review interim analyses.

To advise the TSC of the safety of the trial.

Novartis:

To report all SUSARs related to Myfortic to the Global Regulatory Authorities (except MHRA), within the required timelines.

To notify the BCTU of any relevant information or of any relevant safety matters which may affect the use of the IMP by a Trial Site. Such notifications shall be made in a timely manner and any action required may require agreement between Novartis, the Chief Investigator, the BCTU and the Sponsor.

7. Sample Size and Recruitment 7.1. Sample size As this is a pilot study, no formal sample size calculations have been performed. Recruitment of 100 patients with FSGS and IgAN over 24 months is planned (50 to Myfortic with short course steroids and 50 to standard care), with a minimum number of 40 patients with each disease type. 7.2. Recruitment The study will take place in multiple centres throughout the UK – 25 centres are planned to recruit patients. Patients recruitment is anticipated to take 2 years, but recruitment will be reviewed after one year if recruitment rates are lower than expected (i.e. <30 per year). The maximum period of recruitment will be 2 years. This will provide preliminary evidence of the treatment effect size and ability to recruit to the study.

8. Statistical Analysis Patients will be analysed in the treatment group to which they were randomised on the intention-to-treat principle. Disease types (FSGS or IgAN) will be analysed separately. For categorical variables (e.g. response rates), relative risks and 95% confidence intervals will be calculated. For continuous variables (e.g. PCR, eGFR), means and mean changes with 95% confidence intervals will be calculated (medians will be used if the data is non-parametric). The pattern of change over time will be evaluated using repeated measures analysis, with treatment allocation, time and the interaction term between treatment and time as independent variables. Time to event data (e.g. time to remission or relapse) will be analysed using log-rank methods, with hazard ratios and 95% confidence intervals being calculated. Since this is a pilot study, no formal hypothesis testing will be performed, and evidence of efficacy will be assessed using point estimates and 95% confidence intervals.

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Safety analyses will be performed by assessing the 95% confidence interval of the number of adverse events between treatment groups. 8.1 Data Monitoring and Ethics Committee An independent DMEC will be established for this trial and will include at least one member who is a statistician (preferably with experience in clinical trial methodology) and two experts in glomerulonephritis. The DMEC will meet at least annually to review all collected data (both efficacy and adverse event data) and may meet more frequently if required after analysis of the available data. The DMEC will advise the independent TSC whether to continue, modify or close the clinical trial.

9. Biomedical Studies Biomedical studies are an important component of the GloMY trial. The GloMY study provides an opportunity to identify biomarkers that are predictive of disease progression and predictive of a response to Myfortic and corticosteroids. Additional blood and urine samples will be requested from all patients at the time of entry into the trial, renal biopsies will be requested at trial entry and at 2 years. 9.1. Blood for Biomarkers In GloMY, blood will be analysed for potential biomarkers of response to treatment and progression of disease. Blood samples: An additional blood sample will be collected at trial entry and at the 6 months, 1 year, 18 months and 2 year follow-up assessments. Blood samples should be collected and prepared according to the guidelines in Appendix 16. 9.2. Urine for Biomarkers (optional) Urine samples will also be analysed for potential biomarkers of indicators of response. Urine samples: An additional urine sample will be collected at trial entry and at the 6 months, 1 year and 2 year follow-up assessments (and at relapse if applicable) provided the patient has consented for this. Urine samples should be collected and prepared according to the guidelines in Appendix 16. 9.3. Renal Biopsy (optional) Provided that the patient has not withheld consent, biopsy sections, from the time of diagnosis that are already fixed and stained should be forwarded to the trials office. Slides plus the associated proforma should be labelled with the patient’s initials, GloMY trial number and date of birth but not with their name. Slides should be sent to:

GloMY Study Office, Birmingham Clinical Trials Unit, College of Medical & Dental Sciences, Robert Aitken Institute, University of Birmingham, Edgbaston, Birmingham, B15 2TT.

At 2 years, patients will be asked to consent to having a repeat renal biopsy. If the patient consents to this, the anonymised biopsy plus the proforma should be sent to the GloMY Study office as detailed above. All anonymised biopsies will be reviewed centrally at the Department of Cellular Pathology, The John Radcliffe Hospital, Oxford.

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No other specimens (other than those detailed here) will be collected that are not considered to be part of the current standard of care. Importantly, patients may opt out of participating in the urine biomarker and renal biopsy biomedical studies, but still participate in the main part of the GloMY trial.

10. Research Governance The conduct of the trial will be in accordance with the UK Clinical Trial Regulations. 10.1. Sponsor National sponsorship will be provided by the University Hospitals Birmingham NHS Foundation Trust upon signing of the Clinical Study Site Agreement with each trial site. 10.2. Clinical Trials Unit Data from this trial will be handled by the Birmingham Clinical Trials Unit, a full-time research facility dedicated to, and with substantial experience in, the design and conduct of randomised clinical trials. The Birmingham Clinical Trials Unit recognises the responsibilities of a data management centre with respect to the ethical practice of research and the adequate protection of human subjects. 10.3. Confidentiality of Personal Data The trial will collect personal data about participants, and medical records will be reviewed for all patients and routine physical examinations will be performed. Participants will be informed that their trial data and information will be securely stored at the trial office at the Birmingham Clinical Trials Unit, and will be asked to consent to this. The Birmingham Clinical Trials Unit abides by the UK law Data Protection Act 1998. The data will be stored on a secure computer database, and all personal information obtained for the study will be held securely and treated as strictly confidential. Any data processed outside of the Birmingham Clinical Trials Unit will be anonymised. 10.4. Long-Term Storage of Data In line with Good Clinical Practice guidelines, all essential documentation and data will be retained for at least 15 years and until at least 2 years after the last approval of a marketing application in the European Union. 10.5. Research Indemnity GloMY was developed by members of the GloMY Trial Management Group and is funded by an educational grant from Novartis Pharmaceuticals UK Ltd. The University Hospital Birmingham NHS Foundation Trust is the trial ‘sponsor’. As it is not an industry-sponsored trial, ABPI guidelines on indemnity do not apply and there are no special arrangements for compensation for any non-negligent harm suffered by patients as a result of participating in the study. The normal NHS indemnity liability arrangements for clinician initiated research will, therefore, operate – see NHS Executive Health Service Guidelines HSG (96) 48, 8th November 1996. It should be noted, however, that negligent liability remains the responsibility of the hospital, whether or not a patient is part of a clinical trial, because of the duty of care that the hospital has for their patients.

11. Trial Organisation 11.1 Principal Investigator

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Each centre should nominate one person to act as the Local Principal Investigator, who will be responsible for obtaining local R&D Department approval at their centre. Site agreements will be contingent upon the provision of evidence that study personnel have completed Good Clinical Practice training. 11.2 Finance GloMY is funded by an educational grant from Novartis and organised by the Department of Health funded University of Birmingham Clinical Trials Unit. 11.3 Cost Implications The GloMY trial can offer no financial support to the collaborating hospitals for treatments. However, GloMY should not involve any extra research costs for participating hospitals, as no additional follow-up visits or investigations are needed other than those that would normally be required for standard patient care. 11.4 Trial Communications Trial investigators will be informed of trial progress in the form of twice yearly electronic newsletters, annual investigators’ meetings and electronic mail (emerging issues). 11.5 Clinical Queries During office hours, the clinical coordinators (see inside front cover for contact details) provide an on-call service for any clinical queries about the trial.

11.6 Publication A meeting will be held after the end of the study to allow discussion of the main results among the collaborators prior to publication. The success of GloMY depends on the collaboration of nephrologists and nurses. For this reason, chief credit for the results of this pilot study will be given not to the central organisers, but to all those who have collaborated in the study.

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12. References 1.Couchoud C, Stengel B, Landais P, Aldigier JC, de Cornelissen F, Dabot C, et al. The renal epidemiology and information network (REIN): a new registry for end-stage renal disease in France. Nephrol Dial Transplant 2006;21(2):411-8. 2.Heaf J, Lokkegaard H, Larsen S. The epidemiology and prognosis of glomerulonephritis in Denmark 1985-1997. Nephrol Dial Transplant 1999;14(8):1889-97. 3.Simon P, Ramee MP, Boulahrouz R, Stanescu C, Charasse C, Ang KS, et al. Epidemiologic data of primary glomerular diseases in western France. Kidney Int 2004;66(3):905-8. 4.Moranne O, Watier L, Rossert J, Stengel B. Primary glomerulonephritis: an update on renal survival and determinants of progression. QJM 2008;101(3):215-24. Epub 2008 Feb 2. 5.Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis 1997;30(5):621-31. 6.Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am J Kidney Dis 1995;25(4):534-42. 7.Korbet SM, Schwartz MM, Lewis EJ. Primary focal segmental glomerulosclerosis: clinical course and response to therapy. Am J Kidney Dis 1994;23(6):773-83. 8.Chun MJ, Korbet SM, Schwartz MM, Lewis EJ. Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants. J Am Soc Nephrol 2004;15(8):2169-77. 9.Stirling CM, Mathieson P, Boulton-Jones JM, Feehally J, Jayne D, Murray HM, et al. Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis in five UK renal units. QJM 2005;98(6):443-9. Epub 2005 May 6. 10.Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC. Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. J Am Soc Nephrol 2005;16(4):1061-8. Epub 2005 Feb 16. 11.Yoshikawa N, Ito H, Akamatsu R, Matsuyama S, Hasegawa O, Nakahara C, et al. Focal segmental glomerulosclerosis with and without nephrotic syndrome in children. J Pediatr 1986;109(1):65-70. 12.Korbet SM. Treatment of primary focal segmental glomerulosclerosis. Kidney Int 2002;62(6):2301-10. 13.Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am J Kidney Dis 1995;25(4):534-42. 14.Cattran DC, Rao P. Long-term outcome in children and adults with classic focal segmental glomerulosclerosis. Am J Kidney Dis 1998;32(1):72-9. 15.Braun N, Schmutzler F, Lange C, Perna A, Remuzzi G, Risler T, et al. Immunosuppressive treatment for focal segmental glomerulosclerosis in adults. Cochrane Database Syst Rev 2008(3):CD003233. 16.Barratt J, Feehally J. IgA nephropathy. J Am Soc Nephrol 2005;16(7):2088-97. Epub 2005 Jun 1. 17. Barratt J, Feehally J. Treatment of IgA nephropathy. Kidney Int 2006;69(11):1934-8. 18.Samuels JA, Strippoli GF, Craig JC, Schena FP, Molony DA. Immunosuppressive agents for treating IgA nephropathy. Cochrane Database Syst Rev 2003(4):CD003965. 19.Pozzi C, Andrulli S, Del Vecchio L, Melis P, Fogazzi GB, Altieri P, et al. Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial. J Am Soc Nephrol 2004;15(1):157-63. 20.Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int 2009. 21.Xu G, Tu W, Jiang D, Xu C. Mycophenolate Mofetil Treatment for IgA Nephropathy: A Meta-Analysis. Am J Nephrol 2008;29(5):362-367. 22.Remuzzi G. Nephropathic nature of proteinuria. Curr Opin Nephrol Hypertens 1999;8(6):655-63. 23.Sean Eardley K, Cockwell P. Macrophages and progressive tubulointerstitial disease. Kidney Int 2005;68(2):437-55. 24.Hooke D, Gee D, Atkins R. Leukocyte analysis using monoclonal antibodies in glomerulonephritis. Kidney Int 1987;31:964-972. 25.Rodriguez-Iturbe B, Pons H, Herrera-Acosta J, Johnson RJ. Role of immunocompetent cells in nonimmune renal diseases. Kidney Int 2001;59(5):1626-40. 26.Eardley KS, Zehnder D, Quinkler M, Lepenies J, Bates RL, Savage CO, et al. The relationship between albuminuria, MCP-1/CCL2, and interstitial macrophages in chronic kidney disease. Kidney Int 2006;69(7):1189-97. 27.Morath C, Schwenger V, Beimler J, Mehrabi A, Schmidt J, Zeier M, et al. Antifibrotic actions of mycophenolic acid. Clin Transplant 2006;20 Suppl 17:25-9. 28.Xing CY, Saleem MA, Coward RJ, Ni L, Witherden IR, Mathieson PW. Direct effects of dexamethasone on human podocytes. Kidney Int 2006;70(6):1038-45. Epub 2006 Jul 12. 29.Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 2008;14(9):931-8.