A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Obinutuzumab in Adolescents With Active Class III or IV Lupus Nephritis and the Safety and PK of Obinutuzumab in Pediatric Participants

Official title

A Phase II, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Obinutuzumab in Adolescent Patients With Active Class III or IV Lupus Nephritis, Including an Evaluation of Open Label Safety and PK in a Cohort of Pediatric Patients (Aged 5 to < 12)

Overview

This phase II, randomized, double-blind, placebo-controlled study is designed to evaluate the safety, efficacy and pharmacokinetics (PK) of obinutuzumab in adolescent participants (AP) aged 12 to less than 18 with biopsy-confirmed proliferative lupus nephritis (LN). It will also evaluate open label safety and PK of obinutuzumab in pediatric participants (PP), aged 5 to \<12 with LN.

Interventions

• Drug Obinutuzumab
  Obinutuzumab will be administered by IV infusion at a dose of 1000 mg on Day 1, Day 14, Week 24, Week 26 and Week 52.
• Drug Placebo
  Placebo matching obinutuzumab will be administered by IV on Day 1, Day 14, Week 24, Week 26 and Week 52.
• Drug Mycophenolate Mofetil
  Mycophenolate Mofetil (MMF) will be taken by home administration orally at a target dose of 1200 mg/m\^2/day to a maximum of 2.5g/day from baseline (Day 1) onwards.
• Drug Acetaminophen/paracetamol
  Acetaminophen 1000 mg will be administered as pre-medication prior to infusions.
• Drug Diphenhydramine hydrochloride (HCl)
  Diphenhydramine HCl 50 mg will be administered as pre-medication prior to infusions.
• Drug Methylprednisolone
  Methylprednisolone 80 mg IV will be administered as pre-medication prior to infusions.
• Drug Prednisone
  Oral prednisone or equivalent corticosteroid will be taken by home administration daily to a maximum dose of 60mg/day followed by a guided taper to 5mg/day or less by Week 24.

Primary outcome measures

• Percentage of Participants who Achieve a Complete Renal Response (CRR) (AP) [Time frame: Week 76]
• Percentage of Participants with Adverse Events (PP) [Time frame: Baseline to Week 76]

Secondary outcome measures (12)

• Percentage of Participants Achieving a CRR (AP) [Time frame: Weeks 24 and 52]
• Percentage of Participants who Achieve CRR with Successful Prednisone Taper (AP) [Time frame: Week 76]
• Percentage of Participants who Achieve a PRR (AP) [Time frame: Week 76]
• Percentage of Participants Achieving an Overall Response (CRR or PRR) (AP) [Time frame: Weeks 24, 52, and 76]
• Change in UPCR (AP) [Time frame: Baseline to Week 76]
• Change in eGFR (AP) [Time frame: Baseline to Week 76]
• Time to Onset of CRR over the Course of 76 weeks (AP) [Time frame: Up to Week 76]
• Percentage of Participants who Experience Treatment Failure (AP) [Time frame: Week 12 to Week 76]
• Change in anti-dsDNA titers (AP) [Time frame: Baseline to Week 76]
• Change in C3 Complement Levels (AP) [Time frame: Baseline to Week 76]
• Change in C4 Complement Levels (AP) [Time frame: Baseline to Week 76]
• Percentage of Participants with Adverse Events According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 (AP) [Time frame: Baseline to Week 76]

Eligibility criteria

Inclusion criteria

• Participants who are age 12 to <18 years at the time of randomization
• Participants who are age 5 to <12 years (younger participant cohort) at the time of randomization once recruitment is open. (Investigators will be notified by the Sponsor when recruitment is open to this younger population)
• International Society of Nephrology and the Renal Pathology Society (ISN/RPS) 2003 Class III or IV active LN demonstrated on renal biopsy performed in the 12 months prior to or during screening
• Class V disease may be present in addition to Class III or IV LN, but participants with isolated Class V disease are not eligible
• Diagnosis of SLE according to the Systemic Lupus International Collaborating Clinics (SLICC) 2012 criteria
• Significant proteinuria defined by a UPCR above > 0.5 based on a first-morning void (FMV) collection at screening
• During the 12 months prior to or during screening, all participants must have received at least one dose of pulse-range IV methylprednisolone (typically 30 mg/kg, maximum of 1000 mg per dose) or equivalent for the treatment of the current episode of active LN.

Exclusion criteria

• Severe, active central nervous system (CNS) SLE, including retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke, cerebellar ataxia, or dementia
• Sclerosis in >50% of glomeruli on renal biopsy
• Purely chronic Class III(c) or Class IV(c) disease on renal biopsy, defined as the absence of any active lesions
• Presence of rapidly progressive glomerulonephritis
• Pure Class V LN
• Intolerance or contraindication to study therapies
• Active infection of any kind (excluding fungal infection of nail beds) 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 HIV infection and other severe Immunodeficiency blood disorders
• History of serious recurrent or chronic infection
• History of or current cancer, including solid tumors, hematological malignancies, and carcinoma in situ (except basal cell carcinoma and squamous cell carcinoma of the skin that have been excised and cured) within the past 5 years
• Significant or uncontrolled concomitant medical disease which, in the investigator's opinion, would preclude participant participation
• Currently active alcohol or drug abuse or history of alcohol or drug abuse

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 11 centers

• Loma Linda University health — Loma Linda
• UCSF Benioff Childrens Hospital — San Francisco
• Children's Hospital Colorado, Anchutz Medical Campus — Aurora
• Emory Children's Center — Atlanta
• Indiana University Health University Hospital — Indianapolis
• Louisiana State University — Shreveport
• Hackensack University Medical Center — Hackensack
• Cohen Children's Medical Center of New York — Queens
• … and 3 more centers

Brazil · 5 centers

• Ser Servicos Especializados Em Reumatologia — Salvador
• Hospital Universitário Onofre Lopes - UFRN — Petrópolis
• Centro de Pesquisa São Lucas — Campinas
• Hospital das Clinicas - FMUSP — São Paulo
• Universidade Federal de Sao Paulo - UNIFES — São Paulo

France · 4 centers

• CH de Bicêtre — Le Kremlin-Bicêtre
• Hôpital Robert Debré — Paris
• Hop Necker Enfants Malades — Paris
• CHU de Toulouse - Hôpital des Enfants — Toulouse

Spain · 4 centers

• Hospital Sant Joan De Deu — Esplugas de Llobregat
• Hospital Ramon y Cajal — Madrid
• Hospital de La Paz — Madrid
• Hospital Universitario la Fe: Servicio de Reumatologia Pediatrica — Valencia

Italy · 3 centers

• Ospedale Pediatrico Bambino Gesu — Rome
• IRCCS G. Gaslini — Genoa
• Clinica Pediatrica II De Marchi — Milan

Mexico · 3 centers

• CREA Hospital Mexico Americano — Guadalajara
• Clinstile S.A de C.V. — Mexico City
• Hospital Universitario Dr. Jose Eleuterio Gonzalez — Monterrey

South Africa · 3 centers

• Red Cross War Memorial Children?s Hospital — Cape Town
• Groote Schuur Hospital — Cape Town
• Panaroma Medical Center — Panorama

United Kingdom · 3 centers

• Royal Hospital For Children — Glasgow
• Alder Hey Childrens Hospital — Liverpool
• Great Ormond Street Hospital for Children — London

Canada · 2 centers

• The Hospital for Sick Children — Toronto
• Hospital Sainte-Justine — Montreal

Peru · 2 centers

• Instituto de Ginecología y Reproducción — Lima
• Clinica El Golf — San Isidro

Poland · 2 centers

• Uniwersyteckie Centrum Kliniczne — Gdansk
• Szpital Specjalistyczny dla Dzieci i Doroslych — Torun

Russia · 1 center

• Saint-Petersburg State — St-peterburg

Publications

• Dossier C, Bonneric S, Baudouin V, Kwon T, Prim B, Cambier A, Couderc A, Moreau C, Deschenes G, Hogan J. Obinutuzumab in Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome in Children. Clin J Am Soc Nephrol. 2023 Dec 1;18(12):1555-1562. doi: 10.2215/CJN.0000000000000288. Epub 2023 Sep 6. PMID 37678236

Identifiers

NCT: NCT05039619 · WA42985 · 2021-000097-29 · 2023-505825-15-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗