| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lupus nephritis is a specific kind of kidney inflammation (called nephritis) that affects children and adults with systemic lupus erythematosus (SLE). SLE is an autoimmune condition. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025140 |
| E.1.2 | Term | Lupus nephritis |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Based on published data, including our pilot data and the huge experience of the detrimental effects of steroids, we plan to test the hypothesis that in steroid naïve patients with a new flare of lupus nephritis, the addition of Rituximab to mycophenolate mofetil (MMF) but without oral steroids, is at least as effective at inducing a response as the standard of care therapy comprising MMF and oral steroids. Full details are given in A57.
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| E.2.2 | Secondary objectives of the trial |
The clinical study aims to address the following questions:
1. Is the combination of Rituximab and mycophenolate mofetil without oral steroids superior to mycophenolate mofetil and oral steroids with respect to safety as judged by:
a) fewer serious infections
b) fewer serious adverse events
c) fewer metabolic abnormalities especially the new onset of diabetes, weight gain, bone thinning (osteoporosis) and, in children, reduced growth rate?
2. Is the combination of Rituximab and mycophenolate mofetil without oral steroids non inferior to mycophenolate mofetil and oral steroids in bringing active lupus nephritis under control over time as judged by:
a) the proportion of patients achieving partial renal response (PR) at week 52 (see A58 for definitions)
b) the time to complete remission
c) the time to partial remission
d) the proportion of patients achieving partial remission who on repeat kidney biopsy have achieved a full histological remission i.e. no active disease on biopsy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adults aged 18-75 years old and children aged 12-17 years old with active lupus nephritis ISN/RPS Class III A or A/C, Class IV-G A or A/C, Class IV-S A or A/C, and / or Class V on kidney biopsy done within previous 8 weeks.
2. Urine protein:creatinine ratio >100mg/mmol (>1mg/mg) at visit -1 or any time with 14 days before visit -1.
3. No contraindications to the use of IV methyl prednisolone, mycophenolate mofetil, oral steroids or rituximab or any other required medications.
4. Able to provide informed consent.
5. Willingness to use a medically acceptable form of contraception (progesterone only pill, progesterone implants, oral contraceptive if not contraindicated, intrauterine contraceptive device, barrier methods) if female and at risk of pregnancy. |
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| E.4 | Principal exclusion criteria |
1) Aged <12 years or >75 years
2) Obsolescence of >50% of the glomeruli or tubulointerstitial scarring of >50%
3) Severe “critical” SLE flare defined as:
a) BILAG 2004 A flare in CNS system
b) or any SLE manifestation requiring more immunosuppression than allowed within the protocol in the physician's opinion
4) Pregnancy
5) Breast feeding
6) Patients should not be on or require maintenance steroids and should not have had more than 4 weeks of steroids in the period immediately preceding recruitment irrespective of dose
7) Patients that have had more than 1.5g of IV methyl prednisolone in the previous 4 weeks
8) Prior use within 12 months of visit -1 of therapeutic monoclonal antibody, or B or T cell modulating ‘biologic’ use
9) Prior use within 6 months of visit -1 of Intravenous immunoglobulin / plasma exchange
OR Cyclophosphamide
10) eGFR <30mls/min/1.73m2
11) Active infections, including but not limited to the human immunodeficiency virus (HIV), and hepatitis B (including prior infection as judged by positive Hepatitis B core antibody) or Hepatitis C or tuberculosis
12) Receipt of a live-attenuated vaccine within 3 months of study enrolment
13) In the investigator’s opinion, patients that are at high risk for infection (including but not limited to indwelling catheter, dysphagia with aspiration, decubitus ulcer, history of prior aspiration pneumonia or recurrent severe urinary tract infection)
14) Prior history of invasive fungal infections
15) History of any cancer
16) In female patients, known history of cervical dysplasia CIN Grade III cervical high risk human papillomavirus or abnormal cervical cytology other than abnormal squamous cells of undetermined significance (ASCUS) within the past 3 years. The patient will be eligible after the condition has resolved (e.g., follow-up HPV test is negative or cervical abnormality has been effectively treated >1 year ago)
17) Any concomitant medical condition that in the investigator’s opinion, or after discussion with the CI, places the participant at risk by participating in this study.
18) Comorbidities requiring systemic corticosteroid therapy.
19) Current substance abuse.
20) IgG below lower limit of local laboratory range |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome is to demonstrate non-inferiority in the proportion of patients achieving complete renal response (CR) at week 52 in Rituximab arm of the study compared with the Control arm.
Where CR is defined as:
- uPCR ≤50mg/mmol (=<0.5mg/mg) in a spot urine
AND
- eGFR ≥60ml/min, or if <60ml/min at screening, not fallen by >20% compared to screening/randomisation (whichever worse)
AND
- In the Rituximab arm without the need to prescribe oral steroids within 1 year, except for one course of oral prednisolone maximum 30mg for a maximum of 14 days OR one intramuscular, one intravenous injection or two intra-articular injections of steroids, each maximum 120mg methylprednisolone or equivalent (in addition to the planned IV methyl prednisolone in the protocol)
OR
- in the steroid arm without the need for additional steroids over and above the prescribed taper, except for one course of oral prednisolone maximum 30mg for a maximum of 14 days OR one intramuscular, one intravenous injection or two intra-articular injections of steroids, maximum 120mg methylprednisolone or equivalent (in addition to the planned IV methyl prednisolone in the protocol).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary outcome will be evaluated at 52 weeks. |
|
| E.5.2 | Secondary end point(s) |
Secondary outcomes
To explore if:
Does steroid sparing reduce adverse events?:
1. Proportion of patients with Serious Infectious Episodes
2. Proportion of patients with Serious Adverse Events (AEs)
3. Proportion of patients with evidence of metabolic abnormalities including:
o New onset diabetes
o Development of osteopenia or osteroporosis on bone density scan
o Change in weight, BMI, waist /hip ratio
o Paediatric – deviation from expected growth velocity
Disease control over time:
4. The proportion of patients achieving partial renal response (PR) at week 52 where PR is defined as:
- eGFR - no more than a 20% decrease from the baseline value,
AND
- if not nephrotic at baseline (urine PCR <300mg/mmol (3mg/mg)), 50% improvement in spot urine PCR
OR
- if nephrotic at baseline (urine PCR >300mg/mmol (3mg/mg)), 50% improvement in spot urine PCR AND urine PCR <300mg/mmol
5. Time to CR
6. Time to PR where PR is defined as above.
7. Proportion of patients in PR who achieve histological remission as judged by absence of proliferative lesions and no new subendothelial or subepithelial deposits on repeat biopsies
8. Proportion of patients with renal flare where flare is identified by:
proteinuria >50% increase
AND
above 100mg/mmol for 2 consecutive visits
AND/OR
- in those with normal renal function and normal urinary sediment, a fall of >20% in eGFR on 2 occasions
- where possible flare should be proven by repeat renal biopsy.
9. Cumulative steroid exposure (to include all oral and IV steroids from first dose of Rituximab)
10. Deviation from the steroid taper in steroid arm and/or introduction of steroids in the steroid-free arm
11. Proportion of patients achieving a response as defined by the SLE responder index (SRI) at week 52 and annually thereafter as defined by: a >4 point reduction in SELENA-SLEDAI score, no new BILAG A organ domain score and no more than I new BILAG B score and no worsening in physician’s global assessment (PGA) by >10% and must not have received non-protocol treatment.
12.Proportion of patients achieving a response as defined by the BILAG-based Composite Lupus Assessment (BICLA) at week 52 and annually thereafter as defined by: BILAG-2004 improvement (BILAG A to B/C/D, BILAG B to C/D and no BILAG worsening, no deterioration in SLEDAI total score, no worsening in physician’s global assessment (PGA) by >10% and must not have received non-protocol treatment.
13. An important exploratory outcome will be to evaluate whether removing oral steroids from the treatment of lupus nephritis improves quality of life for patients? This will be assessed using adult quality of life measures including LUPUSQoL, SF-36, EQ5D and for children the SMILEY measure. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Time points are at 1, 2 and where available 3 and 4 years and along the way for “time to” end points. All patients will be followed for a minimum of 2 years but patients entered early will be offered follow up until the last patient recruited has reached the 2 year time point i.e. up to a maximum of 4 years. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 29 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Canada |
| Russian Federation |
| United Arab Emirates |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Recruitment is predicted to take 2 years and minimum follow up is for 2 years so 4 years from first patient recruited. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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