Clinical trial NCT02880852: Belimumab Phase I Study in Chinese Subjects With Systemic Lupus Erythematosus
Official title: A Single Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK1550188 in Chinese Subjects With Systemic Lupus Erythematosus (SLE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Systemic Lupus Erythematosus
Keywords: Systemic Lupus Erythematosus
Belimumab
Pharmacodynamics
safety tolerability
Pharmacokinetics
Chinese subjects
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-08-26
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: In China, Belimumab (GSK1550188) will be developed for a dosing regimen of once-monthly intravenous (IV) infusion for the treatment of SLE. This open-label, single dose study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of belimumab in Chinese SLE subjects. A total of approximately 20 subjects will be enrolled to receive IV infusion of 10 milligrams per kilogram (mg/kg) GSK1550188 on Day 0 for the treatment of SLE. Subjects will be followed for 84 days after the administration of drug.


Eligibility criteria: Inclusion Criteria:

* Subjects who give consent to this study participation and sign informed consent form.
* Subjects at least 18 years of age inclusive at screening visit.
* SLE Classification: Have a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) classification criteria, with 4 or more of the 11 ACR criteria present, serially or simultaneously during any interval or observation.
* SLE Treatment: Be on either no SLE medication or a stable SLE treatment regimen of any medication (alone or in combination) for a period of at least 2 months prior to Day 0; corticosteroids (prednisone or prednisone equivalent, up to 40 mg/day); immunosuppressive or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil hydrochloride, and mycophenolate sodium), mizoribine, calcineurin inhibitors (example \[e.g.\], tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 6-mercaptopurine, or thalidomide; anti-malarials (e.g., hydroxychloroquine, chloroquine, quinacrine) and non-steroidal anti-inflammatory drugs (NSAIDs).
* The subjects with positive test for anti-nuclear antibody (ANA) or anti-double stranded deoxyribonucleic acid (DNA) serum antibody.
* Males and females: A female subject is eligible to enter the study if she is: not pregnant or nursing; of non-childbearing potential (i.e., women who had a hysterectomy, are postmenopausal which is defined as 1 year without menses, have both ovaries surgically removed or have current documented tubal ligation); of childbearing potential (i.e., women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhoea \[even severe\], women who are perimenopausal or have just begun to menstruate. These women must have a negative serum pregnancy test at screening, and agree to one of the following: complete abstinence from penile-vaginal intercourse, when this is the female's preferred and usual lifestyle, from 2 weeks prior to administration of the 1st dose of investigational product (IP) until study complete; or consistent and correct use of one of the following acceptable methods of birth control for 1 month prior to the start of the IP and for 16 weeks after the last dose of IP: any intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1 percent (%) per year; oral contraceptives; double barrier method with vaginal spermicidal agent: condom and an occlusive cap (cervical cap/vault or diaphragm) with a vaginal spermicidal agent (foam/gel/film/cream/suppository); implants of etonogestrel or levonorgestrel; estrogenic vaginal ring; injectable progesterone; percutaneous contraceptive patch; male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for the female subject.
* Based on single or averaged corrected QT (QTc) interval values of triplicate ECGs obtained over a brief recording period: \[QTc corrected by Bazett's (QTcB) or QTc corrected by Fridericia's (QTcF) formula\] \<450 milliseconds (msec); or QTcB or QTcF \<480 msec in subjects with bundle branch block.

Exclusion Criteria:

* B-cell Therapy: Have received treatment with any B cell targeted therapy (e.g., rituximab, other anti-CD20 agents, anti-CD22 \[epratuzumab\], anti-CD52 \[alemtuzumab\], BLyS-receptor fusion protein \[BR3\], Transmembrane activator and calcium-modulator and cytophilin ligand interactor \[TACI\] Fc, or belimumab) at any time.
* The subject has received a biologic investigational or non-investigational agent within 12 months prior to Day 0.
* Received IV immunoglobulin (Ig), plasmapheresis, hemodialysis, intravenous cyclophosphamide, or high dose prednisone and its equivalents (\>60 mg/day) within 6 months prior to Day 0.
* The subject has received a non-biologic investigational agent within 2 months prior to Day 0.
* The subject is currently participating in another clinical study or post-marketing study in which the subject is or will be exposed to an investigational agent.
* The subject has severe lupus kidney disease (defined by proteinuria \>6 grams \[g\]/24 hours) within 6 months prior to the Screening visit.
* History of renal transplant.
* Active central nervous system (CNS) lupus \[including seizures, psychosis, organic brain syndrome, cerebrovascular accident (CVA), motor neuropathy, vasculitis\] requiring medical intervention within 6 months prior to Screening visit.
* Infections: Have required management of acute or chronic infections, as follows: currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria); hospitalization for treatment of infection within 2 months prior to Day 0; use of parenteral (IV or intramuscular \[IM\]) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 2 months prior to Day 0.
* The subject has hypogammaglobulinemia or immunoglobulin A (IgA) deficiency (IgA level \<10 mg/deciliter \[dL\]).
* Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies.
* Uncontrolled other diseases: History or clinical evidence of active significant acute or chronic diseases (i.e., cardiovascular, pulmonary, untreated hypertension, anemia, gastrointestinal, hepatic, renal, neurological, cancer, or infectious diseases) which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk.
* Have a planned surgical procedure, or a history of any other medical disease, or laboratory abnormalities, or conditions which would make the subject (in the opinion of the Investigator) unsuitable for the study.
* The subject has an abnormality on 12-lead ECG at screening which is clinically significant in the opinion of the investigator.
* Have evidence of current drug or alcohol abuse or dependence.
* AST and ALT \>=2x upper limit of normal (ULN); ALP and bilirubin \>1.5xULN (isolated bilirubin \>1.5ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Have a historically positive human immunodeficiency virus (HIV) test or test positive at screening for HIV.
* History of or positive test at screening visit for any of Hepatitis B surface antigen (HBsAg), anti- Hepatitis B core antibody (HBcAb) or anti-hepatitis C virus antibodies (HCVAb). If only anti-HBcAb result is positive, hepatitis B virus (HBV)-(DNA) test will be performed. If HBV-DNA results in negative, the patient is eligible.
* Laboratory Abnormalities: Have a Grade 3 or greater laboratory abnormality based on the protocol toxicity scale except for the following that are allowed:
* Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment.
* Stable Grade 3/4 proteinuria (=\<6 g/24 hour equivalent by spot urine protein to creatinine ratio allowed).
* Stable Grade 3 hypoalbuminemia due to lupus nephritis, and not related to liver disease or malnutrition.
* Stable Grade 3 neutropenia or stable Grade 3 white blood cell count.
* Subjects who have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months or who, in the investigator's opinion, pose a significant suicide risk.

Primary outcomes:
measure: Maximum Observed Concentration (Cmax) of Belimumab
timeFrame: Day 0 (pre-dose, 5 minutes, 1 hour, 6 hours, 24 hours), and on Days 1, 7, 14, 21, 28, 42, 56, and 84 post-dose
measure: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0 to t]) and Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0 to Inf]) of Belimumab
timeFrame: Day 0 (pre-dose, 5 minutes, 1 hour, 6 hours, 24 hours), and on Days 1, 7, 14, 21, 28, 42, 56, and 84 post-dose
measure: Terminal Phase Half-life (t1/2) of Belimumab
timeFrame: Day 0 (pre-dose, 5 minutes, 1 hour, 6 hours, 24 hours), and on Days 1, 7, 14, 21, 28, 42, 56, and 84 post-dose
measure: Terminal Phase Rate Constant (Lambda z) of Belimumab
timeFrame: Day 0 (pre-dose, 5 minutes, 1 hour, 6 hours, 24 hours), and on Days 1, 7, 14, 21, 28, 42, 56, and 84 post-dose
measure: Systemic Clearance (CL) of Belimumab
timeFrame: Day 0 (pre-dose, 5 minutes, 1 hour, 6 hours, 24 hours), and on Days 1, 7, 14, 21, 28, 42, 56, and 84 post-dose
measure: Volume of Distribution (Vz) of Belimumab
timeFrame: Day 0 (pre-dose, 5 minutes, 1 hour, 6 hours, 24 hours), and on Days 1, 7, 14, 21, 28, 42, 56, and 84 post-dose
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to Day 84
Secondary outcomes:
measure: Change From Baseline to Day 84 in Vital Signs- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Change From Baseline to Day 84 in Vital Sign- Pulse Rate
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Change From Baseline to Day 84 in Vital Sign- Temperature
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Number of Participants With Abnormal-clinically Significant 12-lead Electrocardiogram (ECG) Findings
timeFrame: Up to Day 84
measure: Change From Baseline to Day 84 in Clinical Chemistry Parameters- Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Change From Baseline to Day 84 in Clinical Chemistry Parameters- Albumin and Protein
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Change From Baseline to Day 84 in Clinical Chemistry Parameters- Bilirubin, Creatinine, Direct Bilirubin, Indirect Bilirubin and Urate
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Change From Baseline to Day 84 in Clinical Chemistry Parameters- Calcium, Calcium Corrected, Carbon Dioxide, Chloride, Magnesium, Phosphate, Potassium, Sodium, Urea and Glucose
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Change From Baseline to Day 84 in Hematology Laboratory Parameters- Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Change From Baseline to Day 84 in Hematology Parameter- Erythrocytes
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Change From Baseline to Day 84 in Hematology Parameter- Hematocrit
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Change From Baseline to Day 84 in Hematology Parameter- Hemoglobin
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Number of Participants With Positive Urinalysis Dipstick Results
timeFrame: Day 0 (24 hours), Day 14, Day 21, Day 28, Day 42, Day 56 and Day 84
measure: Percent Change From Baseline to Day 84 in B Cell Subsets (Cluster of Differentiation [CD]19 and CD 20+) for Pharmacodynamic Assessment
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Percent Change From Baseline to Day 84 in B Cell Subsets (CD20+/27+ Memory and CD20+/27-naïve) for the Pharmacodynamic Assessment
timeFrame: Baseline (pre-dose on Day 0) to Day 84
measure: Percent Change From Baseline to Day 84 in Immunoglobulins B Cell Subset (Normalized [Norm] CD19+/27BRIGHT[Br]/38Br SLE Subset, Norm CD20+/138+Plasmacytoid, Norm CD20+/69+Activated and Norm CD20-/CD138+Plasma Cell) for Pharmacodynamic Assessment
timeFrame: Baseline (pre-dose on Day 0) to Day 84
Other outcomes:
Locations:
city: Shanghai
country: China
facility: GSK Investigational Site
city: Suzhou
country: China
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Zhang J, Wan W, Miao L, Wu J, Dong J, Shen Y, Xiong C, Li C, Xue Y, Cao G, Ma P. Pharmacokinetics, Pharmacodynamics and Safety of Belimumab in Chinese Patients with Systemic Lupus Erythematosus: A Phase I, Open-Label Study. Rheumatol Ther. 2020 Mar;7(1):191-200. doi: 10.1007/s40744-020-00193-9. Epub 2020 Jan 17.
citation: Gupta SV, Fanget MC, MacLauchlin C, Clausen VA, Li J, Cloutier D, Shen L, Robbie GJ, Mogalian E. Clinical and Preclinical Single-Dose Pharmacokinetics of VIR-2218, an RNAi Therapeutic Targeting HBV Infection. Drugs R D. 2021 Dec;21(4):455-465. doi: 10.1007/s40268-021-00369-w. Epub 2021 Nov 6.
citation: Zhou X, Lee TI, Zhu M, Ma P. Prediction of Belimumab Pharmacokinetics in Chinese Pediatric Patients with Systemic Lupus Erythematosus. Drugs R D. 2021 Dec;21(4):407-417. doi: 10.1007/s40268-021-00363-2. Epub 2021 Oct 9.