| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Lupus Eritematoso Sistémico |
|
| 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 the standard-of-care treatment (SOC) to improve the signs and symptoms of moderate to severe SLE in patients with active disease. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of ocrelizumab in combination with SOC.
• To evaluate the pharmacokinetics, immunogenicity and pharmacodynamic effects of ocrelizumab in this population.
• To evaluate corticosteroid sparing in patients receiving ocrelizumab.
• To evaluate the effect of ocrelizumab on the frequency of disease flares.
• 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 |
Patients must meet the following criteria to be eligible for study entry. Documentation of each specific criterion must be present in the patient’s chart notes or records:
1. Age 16 years or above at the time of screening
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 current American College of Rheumatology (ACR) criteria. At least 4 criteria must be present, one of which must be a current positive ANA (titer at least 1:160).
4. Active disease at screening, as defined by the presence of EITHER a BILAG A score in at least one organ system domain other than the renal domain OR BILAG B scores in at least two organ system domains.
5. Background use of one of the following immunosuppressive drug for at least 60 days prior to Day 1 (AZA: 1-3 mg/kg/day, MMF: 1-3 g/day or MTX: 7.5-25 mg/week)
with a maximum change of no more than 50 mg of AZA daily, 500 mg MMF daily, or 5 mg MTX weekly in the 30 days prior to Day 1.
6. 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 AZA, MMF or MTX (as appropriate) should be followed.
7. 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 |
Exclusion Related to SLE
1. Presence of active moderate to severe glomerulonephritis, as defined by proteinuria > 1 g/24 hr or urinary protein to urinary creatinine ratio (Upr:Ucr) > 1 and presence of either RBC casts or > 10 RBC/hpf (in the absence of infection or menstrual hematuria).
2. Currently active retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia, or dementia.
Exclusions Related to General Health
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 ≥ Grade 3 on the MRC Dyspnea Scale).
7. Evidence of significant or uncontrolled concomitant diseases in any organ system not related to SLE (e.g. renal thrombosis, atherosclerotic cardiovascular disease, diabetes mellitus, accelerated hypertension, poorly controlled COPD or asthma, etc), which, in the investigator’s opinion, would impair patient participation.
8. Concomitant condition (e.g. asthma, Crohn’s disease, etc) which has required treatment with systemic corticosteroid (excluding topical or inhaled) at any time in the 52 weeks prior to screening.
9. Known HIV or chronic active Hepatitis B or chronic active Hepatitis C infection.
10. Known active infection of any kind (but excluding fungal infection of nail beds or oral thrush which has resolved before Day 1) within 30 days prior to Day. In addition, any major episode of infection requiring hospitalization or treatment with intravenous anti-infectives in the 30 days prior to Day 1 or oral anti-infectives in the 14 days prior to Day 1.
11. History of serious recurrent or chronic infection. A chest radiograph will be performed during screening, if not performed in the 12 weeks 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 of the skin that has been excised and cured).
13. History of alcohol or drug abuse in the 52 weeks prior to screening.
14. Major surgery in the 4 weeks prior to screening excluding diagnostic surgery.
Exclusions Related to Medications
15. Previous treatment with CAMPATH-1H.
16. Previous treatment with a BAFF directed treatment (e.g. anti-BLyS) in the 12 months prior to screening.
17. Previous treatment with a B-cell targeted therapy other than one directed at BAFF (e.g. anti-CD20, anti-CD22).
18. Treatment with any investigational agent, other than those above, in the 28 days prior to screening or five half-lives of the investigational drug (whichever is longer).
19. Receipt of any live vaccine in the 6 weeks prior to Day 1 (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 a second immunosuppressive or immunomodulatory drug (e.g., sulfasalazine, dapsone) in the 8 weeks prior to Day 1 (12 weeks prior to Day 1 for
leflunomide or 4 weeks prior to Day 1 after 11 days of standard cholestyramine or activated charcoal drug removal).
22. Prednisone dose of ≥ 0.7 mg/kg/day (or equivalent) for > 7 of the previous 30 days prior to screening.
23. Treatment with cyclophosphamide or a calcineurin inhibitor (e.g. cyclosporin, tacrolimus) in the 12 weeks prior to screening.
Exclusions Related to Laboratory Findings
24. Aspartate aminotransferase or alanine aminotransferase or amylase > 2.5 times 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.
25. Neutrophils < 1.5 × (10x10x10)/μL (measured prior to initiation or increase in corticosteroid). If the absolute neutrophil count is < 1.5 × (10x10x10)/μL but the investigator believes 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.
26. Hemoglobin < 7 g/dl.
27. Platelet count < 50 000/μL. If the platelet count is <50 000/μL but > 10,000/μL 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.
28. Positive serum hCG measured prior to the first ocrelizumab
infusion.
29. Serum creatinine > 2.5 mg/dL.
30. Positive hepatitis BsAg or hepatitis C 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 proportion of patients at Week 48 with a clinical response in the following (mutually exclusive) categories:
1. Major clinical response (MCR)
2. Partial clinical response (PCR)
3. Non-responder (NR)
|
|
| 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 | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 section 3.1.5 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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