A Study to Evaluate Ocrelizumab in Patients With Nephritis Due to Systemic Lupus Erythematosus (BELONG)

Study Overview
=================
Brief Summary
-----------------
This is a Phase III, randomized, double-blind, placebo-controlled, multicentre, parallel-group study designed to evaluate the efficacy and safety of ocrelizumab added to SOC (corticosteroid plus one of two immunosuppressant regimens) compared with placebo added to SOC in patients with WHO or ISN Class III or IV lupus nephritis.

Official Title
-----------------
A Randomised, Double-Blind, Placebo Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Two Doses of Ocrelizumab in Patients With WHO or ISN Class III or IV Nephritis Due to Systemic Lupus Erythematosus

Conditions
-----------------
Lupus Nephritis, Systemic Lupus Erythematosus

Intervention / Treatment
-----------------
* Drug: Corticosteroids
* Drug: Cyclophosphamide
* Drug: Mycophenolate Mofetil
* Drug: Ocrelizumab
* Drug: Placebo
* Drug: Azathioprine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 16 years or above at the time of the screening Ability and willingness to provide written informed consent and to comply with the schedule of protocol requirements Diagnosis of SLE Active lupus nephritis Exclusion Criteria: Currently active retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia, or dementia Severe renal impairment Lack of peripheral venous access Pregnancy or breast feeding mothers History of severe allergic or anaphylactic reactions to humanized, chimeric or murine monoclonal antibodies or i.v. immunoglobulin Known severe chronic pulmonary disease Evidence of significant uncontrolled concomitant diseases in any organ system not related to SLE, which, in the investigator's opinion, would preclude patient participation Concomitant condition which has required treatment with systemic corticosteroid (excluding topical or inhaled steroids) prior to screening Known HIV or chronic active Hepatitis B or chronic active Hepatitis C infection Known active infection of any kind prior to Day 1 History of serious recurrent or chronic infection 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). History of alcohol or drug abuse prior to screening Major surgery prior to screening, excluding diagnostic surgery Previous treatment with CAMPATH-1H Previous treatment with a BAFF directed treatment (e.g. anti-BLyS) prior to screening Previous treatment with a B-cell targeted therapy other than one directed at BAFF (e.g. anti-CD20, anti-CD22) Treatment with any investigational agent prior to screening Receipt of any live vaccines prior to Day 1 Intolerance or contraindication to oral or i.v. corticosteroids Positive hepatitis BsAg or hepatitis C serology. Patients who are HBsAg negative but HBcAb positive may be enrolled with a negative DNA test

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OCR 400 mg + SOC<br>Participants received Ocrelizumab 400 mg i.v. infusion on Days 1 and 15, followed by 400 mg i.v. at Week 16 and then every 16 weeks plus SOC regimen. | Drug: Corticosteroids<br>* Intravenous and oral repeating dose<br>Drug: Cyclophosphamide<br>* Cyclophosphamide was administered at a IV dose 500 mg every 2 weeks for up to 6 doses followed by maintenance treatment with azathioprine.<br>Drug: Mycophenolate Mofetil<br>* Mycophenolate Mofetil was administered orally at maximum dose of 3 g/day.<br>Drug: Ocrelizumab<br>* Ocrelizumab was administed at a dose and as per schedule in arm description<br>Drug: Azathioprine<br>* Azathioprine was administered at a dose up to 2 mg/kg/day with a maximum dose of 200 mg.<br>|
| Experimental: OCR 1000 mg + SOC<br>Participants received Ocrelizumab 1000 mg i.v. infusion on Days 1 and 15, followed by 1000 mg i.v. at Week 16 and then every 16 weeks plus SOC regimen. | Drug: Corticosteroids<br>* Intravenous and oral repeating dose<br>Drug: Cyclophosphamide<br>* Cyclophosphamide was administered at a IV dose 500 mg every 2 weeks for up to 6 doses followed by maintenance treatment with azathioprine.<br>Drug: Mycophenolate Mofetil<br>* Mycophenolate Mofetil was administered orally at maximum dose of 3 g/day.<br>Drug: Ocrelizumab<br>* Ocrelizumab was administed at a dose and as per schedule in arm description<br>Drug: Azathioprine<br>* Azathioprine was administered at a dose up to 2 mg/kg/day with a maximum dose of 200 mg.<br>|
| Placebo Comparator: Placebo + SOC<br>Participants received placebo i.v. infusion on Days 1 and 15, followed by placebo infusion at Week 16 and then every 16 weeks plus SOC regimen. | Drug: Corticosteroids<br>* Intravenous and oral repeating dose<br>Drug: Cyclophosphamide<br>* Cyclophosphamide was administered at a IV dose 500 mg every 2 weeks for up to 6 doses followed by maintenance treatment with azathioprine.<br>Drug: Mycophenolate Mofetil<br>* Mycophenolate Mofetil was administered orally at maximum dose of 3 g/day.<br>Drug: Placebo<br>* Placebo was administered as per schedule in arm description<br>Drug: Azathioprine<br>* Azathioprine was administered at a dose up to 2 mg/kg/day with a maximum dose of 200 mg.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieved Complete Renal Response (CRR) | CRR was defined as: 1. Normal serum creatinine (and with no more than a 25 percent [%] increase from Baseline); 2. Improvement in urinary protein:urinary creatinine ratio to less than or equal to (≤) 0.5. PRR was defined as at least 50 percent (%) reduction in proteinuria from Baseline, without more than 25% increase of serum creatinine at Week 48, compared with Baseline. If Baseline urine protein:urine creatinine ratio was greater than (>) 3, a urine protein:urine creatinine ratio of less than (<) 3 needed to be achieved. | Week 48 | 
| Percentage of Participants Who Achieved Overall Response | Overall response rate (ORR) equals (=) CRR + PRR. CRR was defined as: 1. Normal serum creatinine (and with no more than a 25% increase from baseline) 2. Improvement in urinary protein:urinary creatinine ratio to ≤0.5. PRR was defined as at least 50 % reduction in proteinuria from Baseline, without more than 25% increase of serum creatinine at Week 48, compared with Baseline. If Baseline urine protein:urine creatinine ratio is >3, a urine protein:urine creatinine ratio of <3 needs to be achieved. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Renal Response (Partial or Complete) by Week 36, and Sustain or Improve This Response Until Week 48 |  | Weeks 36, 40, 44, and 48 | 
| Time To Complete Renal Response | Time to complete renal response was proposed to be analyzed using a stratified log rank test with race and SOC as stratification factors. Comparisons of ocrelizumab versus placebo were to be expressed as p-values, estimated hazard ratios, adjusted proportions of participants who achieved a complete renal response and their 95% confidence intervals. Kaplan-Meier curves were to be produced. Due to early termination of the study the analyses were not performed. | Baseline up to Week 48 | 
| Area Under the Curve (AUC) of Calculated Glomerular Filtration Rate (cGFR) Between Baseline and Week 48 | The improvement of AUC of cGFR was to be measured between Baseline and Week 48. This was to be analyzed with Analysis of Covariance (ANCOVA) with race and SOC as covariates. | Baseline and Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and Week 48 | 
| Percentage of Participants Who Achieved A Reduction In Systemic Lupus Erythematosis Disease Activity Index (SLEDAI) -2K Score | SLEDAI-2K measures disease activity at the visit or within the preceding 10 days. It comprised of 24 descriptors, covering 9 organ systems, and reflects disease activity over the previous 10 days.The total SLEDAI-2K score falls between 0 and 105, with higher scores representing higher disease activity | Baseline and Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 | 
| Time to First Renal Flare In Those Participants Who Demonstrated at Least a Partial Renal Response | Renal flares may be either proteinuric or nephritic as defined below: Proteinuric Flares are defined as follows:In participants who achieve a urine protein:urine creatinine (Upr:Ucr) ≤ 0.5, an increase to Upr:Ucr >1; In participants with an Upr:Ucr >0.5, a doubling of Upr:Ucr (with a minimum increase to Upr:Ucr >2). Nephritic Flare defined as: Increase in serum creatinine of ≥30% from the lowest value achieved in the study accompanied by Increase Upr:Ucr >1 Or New/worsening active urine sediment on two consecutive occasions, in the absence of urinary tract infection or other causes of hematuria. | Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 | 
| Percentage of Participants Who Achieved Clinically Meaningful Improvement in the Physical and Mental Component Scores of the Short Form 36 (SF36) From Baseline to Week 48 | The SF36 Health Survey is a 36-item, patient-reported survey of patient health. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. A score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. The eight sections are: vitality, physical functioning, bodily pain, general health perceptions physical role functioning, emotional role functioning, social role functioning, and mental health. | Baseline and Weeks 1, 12, 24, 36, and 48 | 
| Percentage of Participants Who Achieved Clinically Meaningful Improvement in Fatigue Using the Functional Assessment of Chronic Illness Therapy (Facit) Fatigue Questionnaire From Baseline to Week 48 | The FACIT Fatigue Scale is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a four point Likert scale (4 = not at all fatigued to 0 = very much fatigued). | Baseline and Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 | 
| Percentage of Participants Who Achieved Clinically Meaningful Improvement in Pain Using the Modified Brief Pain Inventory Short Form (mBPI-SF) From Baseline to Week 48 | m-BPI-sf is a self-administered 11-point Likert rating scale to rate pain in the past 24 hours. A single item pertains to worst pain in the past 24 hours with a range of 0 (no pain) to 10 (worst imaginable pain). | Baseline and Weeks 1, 12, 24, 36, and 48 | 
| Health Care Visits Over the 48-Week Treatment Period | The number of health care visits (including doctor's office visits, Emergency room/ Accident and Emergency [ER/A&E] visits and hospitalizations) over the 48-week treatment period were recorded. | Weeks 1, 24, and 48 | 
| Percentage of Participants Who Achieved a CRR or PRR And Who Received A Corticosteroid Dose of <10 Milligrams Per Day (mg/Day) From Week 24 to Week 48 | CRR was defined as: 1. Normal serum creatinine (and with no more than a 25% increase from Baseline) 2. Inactive urinary sediment 3. Improvement in urinary protein:urinary creatinine ratio to ≤0.5. PRR was defined as at least 50% reduction in proteinuria from Baseline, without more than 25% increase of serum creatinine at Week 48, compared with Baseline. If Baseline urine protein:urine creatinine ratio was >3, a urine protein:urine creatinine ratio of <3 needed to be achieved. | Week 48 | 
| Percentage of Participants Who Achieved a CRR or PRR And Who Received a Corticosteroid Dose of <5 mg/Day by Week 48 | CRR was defined as: 1. Normal serum creatinine (and with no more than a 25% increase from Baseline) 2. Inactive urinary sediment 3. Improvement in urinary protein:urinary creatinine ratio to ≤0.5. PRR was defined as at least 50% reduction in proteinuria from Baseline, without more than 25% increase of serum creatinine at Week 48, compared with Baseline. If Baseline urine protein:urine creatinine ratio was >3, a urine protein: urine creatinine ratio of <3 needed to be achieved. | Week 48 | 
| Average Corticosteroid Burden Measured by AUC of the Cumulative Corticosteroid Dose Between 16 and 48 Weeks | AUC is the area under the curve (mathematically known as definite integral) in a plot of concentration of drug in blood plasma against time. AUC was to be used to determine the average corticosteroid burden. | Weeks 16, 20, 24, 28, 32, 36, 40, 44, and 48 | 
| Percentage of Participants Who Stopped Immunosuppressants After Week 48 | The number of participants who stopped immunosuppressants were to be determined by survey. | Week 48 | 
| Mean Absolute Counts of Cluster of Differentiation (CD) 19 Positive (+) Cells Per Visit | CD19 is a cell surface molecule which assembles with the antigen receptor of B lymphocytes. It is a critical signal transduction molecule that regulates B lymphocyte development, activation, and differentiation. CD19+ cells were measured as cells per microliter (cells/uL). | Baseline, Day 15, Week 4, 16, 32, 48, and by infusion (pre and post infusion) on Day 1, 15, Week 16, 32 | 
| Percentage of Participants With CD19+ Absolute B Cell Counts <10 Cells Per Microliter (Cells/uL) | CD19 is a cell surface molecule which assembles with the antigen receptor of B lymphocytes. It is a critical signal transduction molecule that regulates B lymphocyte development, activation, and differentiation. 0 represents 0% of participants. | Baseline, Day 15, Week 4, 16, 32, 48, and by infusion (pre and post infusion) on Day 1, 15, Week 16, 32 | 
| Percentage of Participants With CD19+ Absolute B Cell Counts <20 Cells/uL by Visit | CD19 is a cell surface molecule which assembles with the antigen receptor of B lymphocytes. It is a critical signal transduction molecule that regulates B lymphocyte development, activation, and differentiation. n = number of participants analyzed at the specified visit. 0 represents 0% of participants. | Baseline, Day 15, Week 4, 16, 32, 48, and by infusion (pre and post infusion) on Day 1, 15, Week 16, 32 | 
| Percentage of Participants With CD19+ Absolute B Cell Counts Less Than the Lower Limit of Normal (LLN) by Visit | CD19 is a cell surface molecule which assembles with the antigen receptor of B lymphocytes. It is a critical signal transduction molecule that regulates B lymphocyte development, activation, and differentiation. <LLN = 80 cells/uL. | Baseline, Day 15, Week 4, 16, 32, 48, and by infusion (pre and post infusion) on Day 1, 15, Week 16, 32 | 
| Percentage of Participants Achieving a Major Clinical Response or a Partial Clinical Response | A major clinical response was defined as British Isles Lupus Assessment Group (BILAG) C scores or better at Week 24 without developing any new A or two new B scores up to Week 24 and maintenance of this response without developing a moderate or severe flare between Week 24 and Week 48. A partial clinical response was defined as BILAG C scores or better at Week 24 and maintaining this response without developing a flare for 16 consecutive weeks. The BILAG is an organ-specific 86-question assessment based on the principle of the doctor's intent to treat, which requires an assessment of improved (1), the same (2), worse (3), or new (4) over the last month. Within each organ system, multiple manifestations and laboratory tests are combined into a single score for that organ. The resulting scores for each organ can be A through E, where A is very active disease, B is moderate activity, C is mild stable disease, D is resolved activity, and E indicates the organ was never involved. | Baseline and Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SLE, Lupus, BELONG