A Study of QLG1074 Combined With Background Therapy in Subjects With Active Lupus Nephritis

Official title

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of QLG1074 With Placebo in Achieving Renal Remission in Subjects With Active Lupus Nephritis

Overview

The purpose of this study is to assess the efficacy of QL1074 compared with placebo in achieving renal response after 52 weeks of therapy in subjects with Active Lupus Nephritis.

Detailed description

The aim of the current study is to investigate whether QL1074, added to the standard of care treatment in active lupus nephritis (LN), is able to reduce disease activity over a treatment period of 52 weeks. The background therapy will be mycophenolate mofetil (MMF) and initial treatment with IV methylprednisolone, followed by a reducing course of oral corticosteroids. Subjects with active LN will be eligible to enter the study. They are required to have a diagnosis of LN according to established diagnostic criteria and clinical and biopsy features suggestive of active nephritis. Efficacy will be assessed by the ability of the drug combination to reduce the level of proteinuria (as measured by Urine Protein Creatinine Ratio (UPCR)) while demonstrating an acceptable safety profile.

Interventions

• Drug Voclosporin（QL1074）
  QL1074 23.7 mg BlD will be administered as a fixed dose without the use of therapeutic drugmonitoring. The protocol contains provisions for management of dose based on safety concerns, in particular, BP and renal function，can be managed by dose reduction and temporary of QL1074 to interruption.
• Drug Placebo
  Placebo softgel capsules, identical to 7.9 mg QL1074, will be provided. The administration plan and dosage management regulations are the same as QL1074.

Primary outcome measures

• Number of Participants With Complete Renal Remission at Week 52 [Time frame: Week 52]

Secondary outcome measures (12)

• Time to Urine Protein Creatinine Ratio of ≤0.5 g/g(Number of Days) [Time frame: 52 Weeks]
• Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 g/g or Less [Time frame: 52 Weeks]
• Number of Subjects With Partial Renal Response at Week 52 [Time frame: Week 52]
• Time to 50% Reduction in UPCR (Number of Days) [Time frame: 52 Weeks]
• Number of Subjects With Partial Renal Response at Week 24 [Time frame: Week 24]
• Number of Subjects With Renal Response With Low Dose Steroids [Time frame: Week 24 and Week 52]
• Change From Baseline in UPCR [Time frame: Baseline and Weeks 2, 4, 8, 12, 16, 16, 20, 24, 30, 36, 42, 48 and 52.]
• Proportion of subjects experiencing a confirmed 30% decrease or more fom baseline in eGFR at each timepoint [Time frame: Baseline and Weeks 2, 4, 8, 12, 16, 16, 20, 24, 30, 36, 42, 48 and 52.]
• Change from baseline by visit in Serum Creatinine, Urine Protein, and estimated Glomerular Filtration rate. [Time frame: Baseline and Weeks 2, 4, 8, 12, 16, 16, 20, 24, 30, 36, 42, 48 and 52.]
• Change From Screening in Immunology Parameters (Complement 3 (C3), C4, and Anti-Double-Stranded DNA) [Time frame: Week 24 and Week 52]
• Change From Baseline in Patient Reported Outcomes [Time frame: Week 12, Week 24 and Week 52]
• Change From Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA - SLEDAI) [Time frame: Week 24 and Week 52]

Eligibility criteria

Inclusion criteria

• Written informed consent before any study-specific procedures are performed.
• Male or female subjects with a minimum age of 18 (or legal age of consent if >18 years) to 75 years of age, inclusive, at the time of screening (Visit 1).
• Previous diagnosis of systemic lupus erythematosus (SLE) according to the American College of Rheumatology criteria (1997)
• Subjects with evidence of active nephritis, According to the 2018 International Society of Nephrology/Society of Nephropathology (ISN/RPS) classification criteria for lupus nephritis, defined as follows:

• Kidney biopsy result within 2 years prior to screening indicating Class III, IV (alone or in combination with Class V), or Class V LN, Biopsy results must be reviewed with the Investigator to confirm eligibility.
• UPCR of a minimum of ≥1.5 mg/mg for Class III/IV or to a minimum of ≥2 mg/mg for Class V at screening.
• If the subject provides a biopsy report within 2 years but more than 6 months before screening, the UPCR needs to be doubled at least within 6 months before screening.
• According to the Investigators' evaluation, subject requires high-dose corticosteroids and immunosuppressive therapy.
• Subject is willing to take oral MMF for the duration of the study, either by continuing current MMF therapy or by initiating it on or before the Baseline Visit.
• Fertile subjects (both male and female) must agree to use reliable contraception methods with their partners from the time of signing the informed consent form until 3 months after the end of the trial; women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline.

Exclusion criteria

• Estimated glomerular filtration rate (eGFR) as calculated by the Chronic Kidney Disease Epidemiology Collaboration equation of ≤45 mL/minute/1.73 m2 at screening.
• urrently taking or planning to use drugs or treatments listed in the Prohibited Drugs (Section 5.5) during the trial, including not completing the required washout.
• Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to require dialysis during the study period.
• A previous kidney transplant or planned transplant within study treatment period.
• Any known hypersensitivity or contraindication to any of the drugs planned to be used (including but not limited to: MMF, Mycophenolate Sodium, Cyclosporine, Voclosporin, Corticosteroids) or any components of these drug products.
• Current or medical history of:

• The subject has a history of drug abuse or alcohol abuse within 2 years before the screening period;
• Malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision. Subjects with cervical dysplasia that is cervical intraepithelial neoplasia 1, but have been treated with conization or loop electrosurgical excision procedure and have had a normal repeat Papanicolaou test are allowed;
• Lymphoproliferative disease or previous total lymphoid irradiation;
• Severe viral infection (e.g., cytomegalovirus, hepatitis B virus, hepatitis C virus) within 3 months of screening; or known HIV infection. Severe viral infection is defined as active disease requiring antiviral therapy;
• Active tuberculosis (TB), or known history of TB/evidence of old TB if not taking prophylaxis with isoniazid;
• Other known clinically significant active medical conditions, such as:

• Severe cardiovascular disease including congestive heart failure, history of cardiac dysrhythmia, congenital long QT syndrome or Hypertension with poor control (systolic blood pressure ≥165mmHg and/or diastolic blood pressure ≥105mmHg after treatment with 2 or more drugs). QT interval duration corrected for heart rate using method of Fridericia exceeding 480 msec in the presence of a normal QRS interval (<110 msec) at time of screening will result in exclusion;
• Liver dysfunction (aspartate aminotransferase, alanine aminotransferase, or bilirubin ≥2.5 times the upper limit of normal) at screening and, if abnormal at screening, then confirmed that the levels have returned to <2.5 times upper limit of normal before randomization;
• Chronic obstructive pulmonary disease or asthma requiring oral steroids;
• Bone marrow insufficiency unrelated to active SLE (according to Investigator judgment) with white blood cell count <2.5×109/L; absolute neutrophil count <1.3×109/L; thrombocytopenia (platelet count <50×109/L);
• According to the evaluation of the investigator, the subject suffered from active bleeding;
• Patients with infections requiring intravenous antibiotic treatment (antibacterial drugs, antiviral drugs, antifungal drugs, or antiparasitic drugs) during screening;
• According to the researchers' assessment, the subjects have other congenital or acquired immune diseases (except for SLE and LN), for which the condition or the treatment of the condition may affect the study assessments or outcomes (e.g., scleroderma with significant pulmonary hypertension; any condition for which additional immunosuppression is indicated). Overlapping conditions for which the condition or treatment is not expected to affect assessments or outcomes (e.g.,Sjögren's syndrome) are not excluded.
• No vaccines using live vaccines or attenuated live vaccines are allowed in the 4 weeks before the screening and while taking the study treatment.
• According to the evaluation of the investigators, there have been significant, unstable or poorly controlled physical/mental illnesses or traumas that may affect the progress or results of the trial within the first 6 months of the screening period.
• Women who are pregnant or breastfeeding.
• Participated in another drug or device trial within 4 weeks before the screening period or within 5 half-lives of the drug (whichever is longer).
• The subject has participated in previous clinical trials of Voclosporin, was randomly assigned to a group, and received treatment with the trial drug.
• According to the assessment of the investigators, there may be conditions that affect the results of the trial or that the risks to the subjects outweigh the benefits.

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

Quadruple blind

Primary purpose

Treatment

Study locations

China · 10 centers

• The First Affiliated Hospital of Bengbu Medical University — Bengbu
• The People's Hospital of Bozhou — Bozhou
• Anhui Provincial Hospital — Hefei
• The Second Affiliated Hospital of Anhui Medical University — Hefei
• Chincse PLA General Hosptial — Beijing
• Peking University First Hospital — Beijing
• Fujian Medical University Union Hospital — Fuzhou
• The First Affiliated Hospital of Dalian Medical University — Dalian
• … and 2 more centers

Identifiers

NCT: NCT06406205 · QLG1074-301

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗