| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| 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 |
To investigate the ability of the ocrelizumab regimen in
combination with standard of care treatment (SOC) to induce a
complete or partial renal response, as assessed by renal function,
urinary sediment and proteinuria in patients with ISN/RPS or
WHO class III or IV lupus nephritis. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of ocrelizumab.
• To evaluate the PK, immunogenicity and PD parameters of ocrelizumab in this patient population.
• To evaluate corticosteroid sparing in patients receiving ocrelizumab.
• To evaluate the effect of ocrelizumab on extra-renal disease manifestations
• To evaluate the impact of ocrelizumab on symptoms and patient functioning using the SF-36, Facit Fatigue and modified Brief Pain Inventory (mBPI-SF). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age 16 years or above at the time of the screening unless the inclusion of minors is prohibited by the local regulations.
2. Ability and willingness to provide written informed consent (or to obtain consent from a parent guardian where applicable) and to comply with the schedule of protocol requirements.
3. Diagnosis of SLE according to ACR criteria. At least 4 criteria must have been present for the diagnosis of SLE. The 4 criteria do not have to be present at the time of screening.
4. Active lupus nephritis defined as follows: Biopsy proven (within 6 months prior to randomization) WHO or ISN Class III or IV LN (excluding III (C), IV-S (C) and IV-G (C), Patients are permitted to have co-existing Class V (see Table 1). Whenever possible, biopsies should be graded and reported following ISN/RPS classification scheme. AND The presence of: Urinary protein to Urinary creatinine ratio ≥ 1. The
proteinuria must not have improved by ≥ 50% in the preceding 6 months. The urine sample used to define this ratio is the 24 hour screening sample which is measured by the central laboratory. If collection and analysis of a 24 hour urine sample is not possible prior to randomization then a timed urine collection (at least 12 hours) should be obtained. Determination of eligibility based on a first-void morning ‘spot’ urine sample is acceptable if collection and analysis of a timed urine sample is not possible prior to randomization.
5. For patients of reproductive potential (males and females), a reliable means of contraception must be used for the duration of the study (e.g. hormonal contraceptive, intrauterine device, physical barrier) according to local guidelines and the treating physician’s recommendations. The relevant section of the product label for CYC, MMF or AZA (as appropriate) should be followed.
6. Female patients of childbearing potential must have a negative serum pregnancy test from the screening visit prior to enrollment at Day 1. |
|
| E.4 | Principal exclusion criteria |
1.Currently active retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia or dementia.
2.Severe renal impairment as defined by calculated GFR<25 mL/min, or the presence of oliguria (defined as a documented urine volume<400 mL/24hr) or renal biopsy results indicating chronic irreversible renal scarrin(either>50% of glomeruli with sclerosis or>50% interstitial fibrosis on renal biopsy).
3.Lack of peripheral venous access.
4.Pregnancy or breast feeding mothers.
5.History of severe allergic or anaphylactic reactions to humanized, chimeric or murine monoclonal antibodies or i.v. immunoglobulin.
6.Known severe chronic pulmonary disease(FEV1<50% predicted or functional dyspnea≥Grade3 on the MRC Dyspnea Scale).
7.Evidence of significant uncontrolled concomitant diseases in any organ system not related to SLE which, in the investigator’s opinion, would preclude patient participation.
8.Concomitant conditionwhich has required treatment with systemic corticosteroid at any time in the 52wks prior to screening.
9.Known HIV or chronic active HepatitisB or chronic active HepatitisC infection.
10.Known active, clinically significant infection of any kind or any major episode of infection requiring hospitalization or treatment with intravenous anti-infectives in the 14days prior to Day1. Patients may be enrolled in the presence of recent minor infections not requiring treatment with antibiotics, if in the Investigator’s opinion, the infection has resolved prior to Day1 and is unlikely to present additional risk to the subject.
11.History of serious recurrent or chronic infection.A chest radiograph will be performed during screening, if not performed in the 12wks prior to screening, to assess infection.If there is any evidence of pulmonary infection a chest radiograph should be performed.
12.History of cancer, including solid tumors, hematological malignancies and carcinoma in situ(except basal cell carcinoma, squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured).
13.History of alcohol or drug abuse in the 52wks prior to screening.
14.Major surgery in the 4wks prior to screening, excluding diagnostic surgery.
15. Previous treatment with CAMPATH-1H.
16.Previous treatment with a BAFF directed treatment in the 12mths prior to screening.
17.Previous treatment with a B-cell targeted therapy other than one directed at BAFF.
18.Treatment with any investigational agent in the 28days prior to screening or within five half-lives of the investigational drug(whichever is longer).
19.Receipt of any live vaccines in the 6wks prior to Day1(it is recommended that a patient’s vaccination record and the need for immunization prior to receiving ocrelizumab should be carefully investigated).
20.Intolerance or contraindication to oral or i.v. corticosteroids.21.Treatment with more than 1g CYC in the 6mths prior to screening period.
22.Receipt of more than 3g i.v. pulse methylprednisolone(cumulative dose)within the 12weeks prior to Screening.
23.Receipt of prednisone doses>20mg/day(or equivalent, including parenteral corticosteroids, except for pulse steroids as defined in exclusion criterion #22)for longer than 14days within a 12wks period prior to screening. During the 14days prior to screening patients may have been treated with high-dose oral prednison (up to 1mg/kg/day).
24.Treatment with a systemic calcineurin inhibitor within the 12wks prior to screening.
25.Aspartate aminotransferase or alanine aminotransferase or amylase>2.5times the upper limit of normal, unless caused by SLE. Patients with elevated serum amylase may be eligible if serum lipase is within normal limits and clinical signs of pancreatitis are not present.
26.Neutrophils<1.5×109/L.If the absolute neutrophil count is<1.5×109/L but the investigator has assessed the neutropenia is due to SLE, the patient may be eligible for the study. This determination will be made after discussion with the Medical Monitor. 27.Hemoglobin<7g/dL. 28.Platelet count<50×109/L . If the platelet count is<50×109/L but >10×109/L and the investigator believes this is due to SLE, the patient may be eligible for the study. This determination will be made after discussion with the Medical Monitor.
29.Positive serum hCG measured prior to the first ocrelizumab infusion.
30.Positive hepatitis BsAg or hepatitisC serology.Patients who are HBsAg negative but HBcAb positive may be enrolled with a negative DNA test. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is the proportion of patients with a clinical response in the following three mutually exclusive categories at Week 48:
1. Patients who achieve a Complete Renal Response (CRR)
2. Patients who achieve a Partial Renal Response (PRR)
3. Patients who do not achieve a Renal Response (neither a CRR nor a PRR) will be classed as non-responders [NR] at Week 48.
|
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Please refer to setion 3.1.6 "End of Study" of the Protocol |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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