| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Childhood Onset Idiopathic Nephrotic Syndrome |
|
| E.1.1.1 | Medical condition in easily understood language |
Nephrotic syndrome is a kidney disorder that causes swelling in your body (especially in the face, legs and feet) and changes in your urine (too much protein).
|
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029164 |
| E.1.2 | Term | Nephrotic syndrome |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To evaluate the efficacy of obinutuzumab compared with MMF based on proportion of Participants with Sustained Complete Remission at 1 year (UPCR <= 0.2 g/g at Week 52) without occurrence of a relapse or any of the other intercurrent events |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of obinutuzumab compared with MMF based on overall relapse free survival (RFS), probability of RFS at Week 52, cumulative corticosteroid dose, number of relapses on randomized study treatment, proportion of participants experiencing edema associated relapse and proportion of patients in complete remission at 18 months
• To evaluate changes in fatigue of participants treated with obinutuzumab compared with MMF
• To evaluate changes in the quality of life of participants treated with obinutuzumab compared with MMF
• To evaluate edema over time
• To evaluate the safety of obinutuzumab compared with MMF
• To characterize the obinutuzumab pharmacokinetic (PK) profile
• To characterize obinutuzumab induced pharmacodynamics (PD) changes
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Must be age >= 2-25 years old
• Diagnosis of frequently relapsing nephrotic syndrome (FRNS) or steroid dependent nephrotic syndrome (SDNS) before the age of 18 years
• Must be in complete remission defined by the absence of edema, urinary protein to creatinine ratio (UPCR) <= 0.2 g/g at screening and have three consecutive daily urine dipstick readings of trace or negative for protein within the week prior to randomization
• Must have had at least one relapse in the 6 months prior to screening, after discontinuation of or while receiving oral corticosteroids and/or immunosuppressive therapy to prevent relapses
• Patients having received cyclophosphamide in the 6 months prior to randomization must have experienced at least 1 relapse subsequent to cyclophosphamide discontinuation
• Estimated glomerular filtration rate (eGFR) within normal range for age
• For females of childbearing potential: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraception, during the treatment period and for 18 months after the final dose of obinutuzumab and for 6 weeks after the final dose of MMF
• For males: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agree to refrain from donating sperm during the treatment period and for 90 days after the final dose of MMF
|
|
| E.4 | Principal exclusion criteria |
• Secondary nephrotic syndrome
• History of steroid resistant nephrotic syndrome
• History of genetic defects known to directly cause nephrotic syndrome
• Treatment with other immunosuppressive medications to prevent relapse, other than MMF or oral corticosteroids within 2 months prior to randomization
• Pregnancy or breastfeeding or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab, or within 6 weeks after the final dose of MMF
• Females of childbearing potential, including those who have had tubal ligation, must have a negative serum pregnancy test result within 28 days prior to initiation of study treatment and a negative urine pregnancy test at Day 1, prior to randomization
• History of organ or bone marrow transplant
• Participation in another therapeutic trial within 30 days of enrollment or 5 half-lives of the investigational drug
• Intolerance or contraindication to study therapies, including any of the following:
o History of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion
o Lack of peripheral venous access
o Intolerance or contraindication to oral or intravenous (IV) corticosteroids
o Intolerance or contraindication to MMF
• Patients demonstrating prior treatment failure to MMF as defined by two or more relapses in any 6-month period of time while receiving MMF for at least a 6-month duration
• Participants in the judgment of the investigator likely to require systemic corticosteroids for reasons other than idiopathic nephrotic syndrome during the study
• Receipt of any of the following excluded therapies:
o Cyclophosphamide, levamisole, mizoribine, tacrolimus, cyclosporine, or voclosporin during the 2 months prior to screening or during screening
o Any biologic B cell−depleting therapy (e.g., antiCD19, antiCD20, antiCD22, such as, but not limited to, rituximab, ocrelizumab, or ofatumumab within 9 months prior to the Day 1 baseline visit.
o Any biologic therapy (other than antiCD19, antiCD20, antiCD22) such as, but not limited to belimumab, daratumumab, ustekinumab, anifrolumab, secukinumab, or atacicept during the 2 months prior to
screening or during screening
o Oral inhibitors of Janus associated kinase (JAK), Bruton’s tyrosine kinase (BTK), or tyrosine kinase 2 (TYK2), including baricitinib, tofacitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib or any investigational agent during the 2 months prior to screening or during screening
o Any live vaccine during the 28 days prior to screening or during screening
• Active infection of any kind or any major episode of infection requiring hospitalization or treatment with IV anti-infective medications within 4 weeks prior to screening, or completion of oral anti-infectives within 2 weeks prior to randomization
• History of or currently active primary or secondary immunodeficiency, including known history of human immunodeficiency virus (HIV) infection and other severe Immunodeficiency blood disorders
• History of progressive multifocal leukoencephalopathy
• History of or current cancer, including solid tumors, hematological malignancies, and carcinoma in situ within the past 5 years
• Major surgery requiring hospitalization during the 4 weeks prior to screening or during screening
• High risk for clinically significant bleeding or any condition requiring plasmapheresis, intravenous immunoglobulin, or acute blood product transfusions
• Evidence of any significant or uncontrolled concomitant disease that, in the investigator’s judgment, would preclude participant’s participation, including but not limited to nervous system, respiratory, cardiac, hepatic, endocrine, malignant, or gastrointestinal disorders
• Currently active alcohol or drug abuse or history of alcohol or drug abuse
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Proportion of Participants with Sustained Complete Remission at 1 year, defined as first morning void UPCR <= 0.2 g/g at Week 52 without occurrence of a relapse or any other intercurrent events as defined below:
1. Relapse after Week 8.
2. Any systemic corticosteroids usage for > 14 days in a 30-day period after Week 8
3. Initiation of any rescue therapy for INS, as determined by the investigator’s best medical judgment, other than systemic corticosteroids at any time after randomization
4. Treatment discontinuation due to lack of efficacy at any time after randomization
5. Death at any time after randomization
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Overall relapse free survival (RFS)
2. Probability of RFS at Week 52
3. Cumulative corticosteroid dose (prednisone or equivalent adjusted for time on study)
4. Number of relapses
5. Proportion of participants experiencing edema associated relapse during the 52-week treatment period
6. Proportion of patients with sustained complete remission at Week 76
7. Mean change in “General Fatigue” domain of Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue scale total score from baseline to Week 52
8. Mean change in “Physical Functioning” domain of PedsQL Quality of Life Inventory from baseline to Week 52
9. Mean change in Cure Glomerulonephropathy Network (CureGN) Edema Scale from baseline over time to Week 52
10. Incidence, nature, and severity of adverse events, with severity determined according to AE intensity (mild, moderate, severe, life-threatening) and National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading if applicable from baseline to Week 52
11. Incidence of laboratory or vital sign abnormalities from baseline to Week 52
12. Serum concentrations of obinutuzumab at specified timepoints
13. Proportion of participants achieving B cell depletion [highly sensitive flow cytometry (HSFC)] at specified timepoints
14. Total peripheral B cell and B cell subsets (e.g., memory B cells) counts and change from baseline at specified timepoints
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.-5. At Week 52
6. At Week 76
7-11. Baseline to Week 52
12. At Days 1, 15 28, 84, 168, 182, 224, 364, and at early study discontinuation visit
13-14. At Days 1, 15, 28, 84, 168, 224, 364 and at early study discontinuation
|
|
| 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 | No |
| 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 | 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 | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Belgium |
| Brazil |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| Turkey |
| United States |
|
| 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
|
as the date when the last participant last visit (LPLV) occurs or the date at which the last data point required for statistical analysis of SFU is received from the last participant, whichever occurs later. The LPLV will occur when the last participant enrolled completes the SFU requirements, up to a maximum of 18 months from the last obinutuzumab infusion.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 13 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
