Childhood Idiopathic Nephrotic Syndrome
Conditions
Brief summary
This open-label, randomized multicenter study is to assess the efficacy, safety, and pharmacokinetics (PK)/pharmacodynamics (PD) of obinutuzumab compared with mycophenolate mofetil (MMF) in children and young adults (aged \>= 2-25 years) with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS).
Interventions
DRUGObinutuzumab
Obinutuzumab will be administered as per schedule specified in the respective arm.
DRUGMMF
MMF will be administered as per schedule specified in the respective arm.
DRUGPrednisone
Participants taking prednisone or equivalent at randomization will follow a guided tapering schedule to reach the goal of 0mg/day by Weeks 4-6 (and no later than Week 8 following randomization and continue without prednisone through Week 52.
DRUGMethylprednisolone
Methylprednisolone 80 mg (or 1.5 mg/kg if \</=45 kg) IV will be administered as premedication prior to infusions.
DRUGAcetaminophen/ Paracetamol
Acetaminophen 15 mg/kg (maximum dose 1000 mg) will be administered PO as premedication prior to infusions.
Diphenhydramine HCl 0.5-1 mg/kg (maximum dose 50 mg) will be administered PO or IV as premedication prior to infusions.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
* 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, 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 * Participants 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
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 a 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 * Participants 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Complete Remission at Week 52 | At Week 52 | Sustained complete remission was defined as first morning void urine protein-to-creatinine ratio (UPCR) ≤0.2 gram/gram (g/g) at Week 52 without the occurrence of relapse or any other intercurrent event (IE) (except treatment discontinuation for any reason \[TDAR\]). Participants with following IE were considered non-responders (except TDAR): After Week 8: 1) Relapse=Any of the following events: First-morning void UPCR ≥ 2 g/g; or dipstick urinalysis (UA) ≥3+ for 3 consecutive days (home-monitoring) \& most recent urine sample determined to have UPCR \>0.2 g/g as measured by the central laboratory ; or dipstick UA protein ≥ 3+ on any single day with edema \& urine sample determined to have UPCR \> 0.2 g/g as measured by the central laboratory. 2) Any systemic corticosteroids usage for \>14 days in 30-day period. After randomization: 1) Initiation of any rescue therapy for idiopathic nephrotic syndrome (INS), as per investigator other than systemic corticosteroids. 2) Death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Relapse-free Survival (RFS) | Up to approximately 127.3 weeks | Overall RFS was defined as the time from randomization to first relapse or death. Relapse was defined as any of the following events: First-morning void UPCR ≥2 g/g; or dipstick UA ≥3+ for 3 consecutive days (home-monitoring) and the most recent urine sample determined to have UPCR \>0.2 g/g as measured by the central laboratory; or dipstick UA protein ≥3+ on any single day with edema and urine sample determined to have UPCR \> 0.2 g/g as measured by the central laboratory. Participants who withdrew their consent were censored at the time of withdrawal. Participants who were lost to follow-up were censored at the last assessment during scheduled or unscheduled visits. Kaplan-Meier (KM) estimates were used to evaluate the median RFS. |
| Cumulative Corticosteroid Dose From Baseline to Week 52 | Baseline up to Week 52 | Cumulative corticosteroid dose was defined as the total dose received (mg/kg) of prednisone or equivalent, regardless of intercurrent events (relapse, rescue therapy, treatment discontinuation for any reason, and systemic corticosteroid usage for \> 14 days) in participants prior to experiencing death. Topical, intraarticular, or inhaled corticosteroids and IV methylprednisolone given as a pre-medication were not included in this analysis. |
| Relapses From Baseline to Week 52 | Baseline up to Week 52 | Relapses were evaluated using adjusted rate ratio from baseline to Week 52, regardless of IEs (relapse, TDAR \& systemic corticosteroid usage for \>14 days) in participants before receiving rescue therapy (RT)/experiencing death. Total number of relapses occurring during treatment period were evaluated by accounting for number of relapses experienced \& participant's follow-up time. Participant level relapse \& follow-up time data were aggregated, \& rate of relapses was compared between the two arms. Rate of relapse was analyzed using a negative binomial model with a log link \& log of each participant's follow up time as offset variable. Relapse=any of the following events: First-morning void UPCR ≥2 g/g; or dipstick UA ≥3+ for 3 consecutive days (home-monitoring) \& most recent urine sample determined to have UPCR \>0.2 g/g as measured by the central laboratory; or dipstick UA protein ≥ 3+ on any single day with edema \& urine sample determined to have UPCR \>0.2 g/g per central laboratory. |
| Percentage of Participants With Sustained Complete Remission at Week 76 | At Week 76 | Sustained complete remission=first morning void UPCR ≤ 0.2 g/g at Week 76 without the occurrence of relapse or any other IE (except TDAR). Relapse=Any of the following events: First-morning void UPCR ≥ 2 g/g; or dipstick UA ≥3+ for 3 consecutive days (home-monitoring) \& the most recent urine sample determined to have UPCR \> 0.2 g/g as measured by the central laboratory; or dipstick UA protein ≥ 3+ on any single day with edema \& urine sample determined to have UPCR \> 0.2 g/g as measured by the central laboratory. Other IEs include: Any systemic corticosteroids usage for \>14 days in a 30 day period; Initiation of any rescue therapy for INS, other than systemic corticosteroids; Death or TDAR. Participants with FRNS/SDNS who were randomized into the study at least 24 weeks prior to the date of randomization for the final participant in the study were only analyzed in this endpoint. Percentages have been rounded off. |
| Probability of RFS at Week 52 | At Week 52 | Probability of RFS at Week 52 was defined as the percentage of participants remaining free of relapse or death at Week 52. Relapse was defined as any of the following events: First-morning void UPCR ≥2 g/g; or dipstick UA ≥3+ for 3 consecutive days (home-monitoring) and the most recent urine sample determined to have UPCR \> 0.2 g/g as measured by the central laboratory; or dipstick UA protein ≥ 3+ on any single day with edema and urine sample determined to have UPCR \> 0.2 g/g as measured by the central laboratory. Participants who withdrew their consent were censored at the time of withdrawal. Participants who were lost to follow-up were censored at the last assessment during scheduled or unscheduled visits. K-M method was used to estimate the RFS rate at Week 52. Percentages have been rounded off. |
| Percentage of Participants Experiencing Edema Associated Relapse During the 52-week Treatment Period | Baseline up to Week 52 | Edema-associated relapse definition is the same as the definition of relapse except that the edema-associated relapse definition additionally requires that participant edema is present and documented in the eCRF at the time of the relapse event. Relapse=any of the following events: First-morning void UPCR ≥ 2 g/g; or dipstick UA ≥3+ for 3 consecutive days (home-monitoring) \& the most recent urine sample determined to have UPCR \> 0.2 g/g, measured by the central laboratory; or dipstick UA protein ≥ 3+ on any single day with edema \& urine sample determined to have UPCR \> 0.2 g/g as measured by the central laboratory. Percentages have been rounded off. |
| Mean Change From Baseline to Week 52 in Cure Glomerulonephropathy Network (CureGN) Edema Scale | Baseline up to Week 52 | Mean Change in CureGN Edema scale was defined as the mean change in total edema severity from baseline to Week 52, regardless of relapse, systemic corticosteroids usage for \>14 days in a 30 day period, and treatment discontinuation due to any reason, in participants prior to receiving rescue therapy and assuming death has not occurred. The CureGN edema scale was used to assess the total edema severity. Participants were asked to report the location of edema they experienced over the last month from eight different body areas (whole body, face, hands, arms, abdomen, genitalia, legs, feet) and rate its severity on a 6-point Likert scale (0=absent to 5=worst imaginable), with total scores ranging from 0-40. Higher score indicated worst edema severity. Adjusted mean change in the CureGN edema scale scores from baseline to Week 52 has been reported. |
| Mean Change From Baseline to Week 52 in "General Fatigue" Domain of Pediatric Quality of Life Inventory (PedsQL)-Multidimensional Fatigue Scale (MFS) Total Score | Baseline up to Week 52 | Mean Change in "General Fatigue" domain of PedsQL-MFS total score was defined as the mean change in total score of the "General Fatigue" domain from baseline to Week 52, regardless of relapse, systemic corticosteroids usage for \>14 days in a 30-day period, \& treatment discontinuation due to any reason, in participants prior to receiving rescue therapy \& assuming death did not occur. PedsQL MFS is an 18-item, self-reported measure designed to assess fatigue in participants with acute or chronic health conditions. This was a standard version with a 1-month recall period. The measure assessed three components of fatigue: General Fatigue (6 items), Sleep/Rest Fatigue (6 items), \& Cognitive Fatigue (6 items). General fatigue scores were based on a 5-point Likert response format, ranging from 0 (Never) to 4 (Almost Always) \& transformed to 0-100 total score. Higher score=less fatigue. Adjusted mean change in general fatigue domain scores from baseline to Week 52 has been reported. |
| Mean Change From Baseline to Week 52 in "Physical Functioning (PF)" Domain of PedsQL-4.0 Generic Core Scale | Baseline up to Week 52 | Mean Change in PF domain of PedsQL = mean change in the PF score from baseline to Week 52, regardless of relapse, systemic corticosteroids usage for \>14 days in a 30-day period, \& treatment discontinuation due to any reason, in participants prior to receiving rescue therapy \& assuming death did not occur. The PedsQL 4.0 Generic Core Scale is a 23 item measure used to assess health-related quality of life, over a recall of either one month (standard version) or 7 days (acute version). The 4 core domains include PF (8 items), Emotional Functioning (5 items), Social Functioning (5 items), and School Functioning (5 items). Items are rated on a 5-point Likert scale ranging from 0 (never a problem) to 4 (almost always a problem). Once completed, items are reverse scored \& linearly transformed to 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0, with higher scores=better health-related quality of life. Adjusted mean change in PF domain scores from baseline to Week 52 has been reported. |
| 52-week Treatment Period: Number of Participants With Adverse Events (AEs) | Up to Week 52 | An AE was defined as any untoward medical occurrence in a participant or clinical study participant temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. As pre-specified in the SAP, analysis excludes AEs reported following rescue treatment other than corticosteroids. |
| Maximum Serum Concentration (Cmax) of Obinutuzumab | Weeks 0-24 and Weeks 24-52 | Samples were collected pre- and post-infusion at Weeks 0, 2, 24, and 26 and single samples were collected at Weeks 4, 12, 32, and 52. Data reported is averaged over the weeks specified in the time frame. |
| Trough Concentration (Ctrough) of Obinutuzumab | Weeks 0-24 and Weeks 24-52 | Samples were collected pre- and post-infusion at Weeks 0, 2, 24, and 26 and single samples were collected at Weeks 4, 12, 32, and 52. Data reported is averaged over the weeks specified in the time frame. |
| Area Under the Concentration-Time Curve of Obinutuzumab From Time 0 to 52 Weeks (AUC0-52) | Weeks 0-52 | Samples were collected pre- and post-infusion at Weeks 0, 2, 24, and 26 and single samples were collected at Weeks 4, 12, 32, and 52. Data reported is averaged over the weeks specified in the time frame. |
| Percentage of Participants Achieving B-cell Depletion Analyzed Using High Sensitivity Flow Cytometry (HSFC) Over Time | Up to approximately 3 years | — |
| Total Peripheral B-cell and B-cell Subsets Counts Over Time | Up to approximately 3 years | — |
| Change From Baseline in Total Peripheral B-cell and B-cell Subsets Counts | Baseline up to approximately 3 years | — |
Countries
Belgium, Brazil, China, France, Italy, Japan, Poland, Spain, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 85 participants with childhood onset of frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS) took part in the study at 32 investigative sites across 9 countries. The study is still ongoing.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive either obinutuzumab or mycophenolate mofetil (MMF) during the 52-week treatment period.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 10.4 years STANDARD_DEVIATION 4.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 23 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 47 Participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 41 |
| other Total, other adverse events | 42 / 44 | 34 / 41 |
| serious Total, serious adverse events | 7 / 44 | 3 / 41 |
Outcome results
None listed