Belimumab Phase I Study in Chinese Subjects With Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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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.

Official Title
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A Single Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK1550188 in Chinese Subjects With Systemic Lupus Erythematosus (SLE)

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Belimumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belimumab 10 mg/kg<br>In this open label study, a single dose of 10 mg/kg Belimumab will be administered intravenously in Chinese subjects with systemic lupus erythematosus. | Drug: Belimumab<br>* Belimumab will be provided as white uniform lyophilized cake in vials with unit dose strength of 400 mg/vial plus excipients (citric acid/sodium citrate/sucrose/polysorbate) for reconstitution in 4.8 milliliter sterile water for injection (SWFI). Belimumab will be administered as 10 mg/kg intravenous infusion for over 1 hour on Day 0.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Concentration (Cmax) of Belimumab | Blood samples were collected at the indicated timepoints to calculate Cmax of belimumab. | 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 | 
| 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 | Blood samples were collected at the indicated timepoints to calculate AUC (0 to t) and AUC (0 to inf) of belimumab. | 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 | 
| Terminal Phase Half-life (t1/2) of Belimumab | Blood samples were collected at the indicated time points to calculate t1/2 of belimumab. | 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 | 
| Terminal Phase Rate Constant (Lambda z) of Belimumab | Blood samples were collected at the indicated time points to calculate lambda z of belimumab. | 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 | 
| Systemic Clearance (CL) of Belimumab | Blood samples were collected at the indicated time points to calculate CL of belimumab. | 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 | 
| Volume of Distribution (Vz) of Belimumab | Blood samples were collected at the indicated time points to calculate Vz of belimumab. | 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 | 
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. 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 a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant, or associated with liver injury and impaired liver function. | Up to Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 84 in Vital Signs- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Vital signs included SBP and DBP. SBP and DBP were measured with the participant in the sitting position. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Change From Baseline to Day 84 in Vital Sign- Pulse Rate | Vital signs included pulse rate. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Change From Baseline to Day 84 in Vital Sign- Temperature | Vital signs included temperature. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Number of Participants With Abnormal-clinically Significant 12-lead Electrocardiogram (ECG) Findings | ECG parameters included heart rate, PR interval, QRS interval, QT interval and corrected QT (QTc) interval. Number of participants with abnormal-clinically significant 12-lead ECG findings are presented. | Up to Day 84 | 
| 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 | Clinical chemistry parameters included ALT, ALP, AST, GGT and lactate dehydrogenase. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Change From Baseline to Day 84 in Clinical Chemistry Parameters- Albumin and Protein | Clinical chemistry parameters included albumin and protein. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Change From Baseline to Day 84 in Clinical Chemistry Parameters- Bilirubin, Creatinine, Direct Bilirubin, Indirect Bilirubin and Urate | Clinical chemistry parameters included bilirubin, creatinine, direct bilirubin, indirect bilirubin and urate. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Change From Baseline to Day 84 in Clinical Chemistry Parameters- Calcium, Calcium Corrected, Carbon Dioxide, Chloride, Magnesium, Phosphate, Potassium, Sodium, Urea and Glucose | Clinical chemistry parameters included calcium, calcium corrected, carbon dioxide, chloride, magnesium, phosphate, potassium, sodium, urea and glucose. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Change From Baseline to Day 84 in Hematology Laboratory Parameters- Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets | Hematology parameters included basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Change From Baseline to Day 84 in Hematology Parameter- Erythrocytes | Hematology parameter included erythrocytes. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Change From Baseline to Day 84 in Hematology Parameter- Hematocrit | Hematology parameter included hematocrit. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Change From Baseline to Day 84 in Hematology Parameter- Hemoglobin | Hematology parameter included hemoglobin. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. | Baseline (pre-dose on Day 0) to Day 84 | 
| Number of Participants With Positive Urinalysis Dipstick Results | Urinalysis was done by the dipstick method to detect the presence of protein, glucose, ketones and occult blood in urine. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameter of urine occult blood, urine protein and urine ketones can be read as negative, Trace, 1+, 2+, 3+ and 4+, indicating proportional concentrations in the urine sample; results for urinalysis parameter of urine glucose can be read as negative, Trace, 1+ or 1/4 gram per Liter (g/L), 2+ or 1/2 g/L, 3+ or 1 g/L and 4+ indicating proportional concentrations in the urine sample. *a indicates two participants did not take the urinalysis test at Day 14 on scheduled date but took an unscheduled sample at the next visit (Day 21) and *b indicates one participant did not take the urinalysis test at Day 28 on scheduled date but took an unscheduled sample at the next visit (Day 42). Only those participants with positive results have been presented. | Day 0 (24 hours), Day 14, Day 21, Day 28, Day 42, Day 56 and Day 84 | 
| Percent Change From Baseline to Day 84 in B Cell Subsets (Cluster of Differentiation [CD]19 and CD 20+) for Pharmacodynamic Assessment | Immunoglobulin B cell subsets included CD19 and CD 20+. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. Percent change from Baseline was calculated as 100 multiplied by [(Post-Baseline Visit Value minus Baseline) / Baseline]. Pharmacodynamic population comprised of participants who received the study medication and for whom pharmacodynamic data was available. | Baseline (pre-dose on Day 0) to Day 84 | 
| Percent Change From Baseline to Day 84 in B Cell Subsets (CD20+/27+ Memory and CD20+/27-naïve) for the Pharmacodynamic Assessment | Immunoglobulin B cell subset included CD20+/27+ memory and CD20+/27-naïve. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. Percent change from Baseline was calculated as 100 multiplied by [(Post-Baseline Visit Value minus Baseline) / Baseline]. | Baseline (pre-dose on Day 0) to Day 84 | 
| 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 | Immunoglobulin B cell subset inlcuded Norm CD19+/27Br/38Br SLE subset, Norm CD20+/138+plasmacytoid, Norm CD20+/69+activated and Norm CD20-/CD138+plasma cell. Baseline was pre-dose on Day 0. Change from Baseline was defined as the post-Baseline value minus the Baseline value. Percent change from Baseline was calculated as 100 multiplied by [(Post-Baseline Visit Value minus Baseline) / Baseline]. | Baseline (pre-dose on Day 0) to Day 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Lupus Erythematosus, Belimumab, Pharmacodynamics, safety tolerability, Pharmacokinetics, Chinese subjects