Evaluation of the Safety and Tolerability of Re-dosing With Intravenous (iv) Otelixizumab in Adult Subjects With Newly Diagnosed Type 1 Diabetes Mellitus
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 3
- 主要终点
- Mean Change From Baseline in Value of Albumin and Total Protein
研究概览
简要总结
The purpose of this study to assess the safety and tolerability of re-dosing at 6 months with otelixizumab (given as an 8-day series of intravenous infusions) in adult subjects with newly diagnosed type 1 diabetes mellitus
详细描述
The primary objective of this phase IIa, open-label, multi-centre study is to assess the safety, tolerability and immunogenicity of re-dosing at 6 months with an 8 consecutive day series of otelixizumab intravenous (IV) infusions in 8 adult subjects with newly diagnosed type 1 diabetes mellitus (T1DM). Although it is hoped that the β cell preserving effect of otelixizumab will be long-lasting, it is possible that the effect may decline over time and thus T1DM subjects may require re-treatment. Six months is the minimum time expected between treatments.
After baseline assessments, eligible subjects will receive 8 consecutive days of otelixizumab infusions, each given over a 30 minute period. Prophylaxis for cytokine release syndrome AEs will be given. At Month 6, following a review of any new medical conditions, concomitant medications, lymphocyte count, Epstein Barr Virus (EBV) viral load and other re-dosing eligibility criteria, subjects will be re-treated with the same dosing regimen. Subjects will be followed for 24 months in this study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, aged 18 to 45 years. Women are allowed if they are of non-childbearing potential or agree to use one of the contraception methods listed in the protocol.
- •Diagnosis of type 1 autoimmune diabetes mellitus according to ADA and WHO criteria
- •No more than 90 days between diagnosis and the first dose of study drug.
- •Currently requires insulin for T1DM treatment, or has required insulin at some time between diagnosis and the first dose of study drug.
- •Positive for one or more of the autoantibodies typically associated with T1DM: antibody to glutamic acid decarboxylase (anti-GAD); antibody to protein tyrosine phosphatase-like protein (anti-IA-2); or insulin autoantibodies (IAA). A subject who is positive for insulin autoantibodies (IAA) and negative for the other autoantibodies will only be eligible if the subject has used insulin for less than 7 days total.
- •Stimulated C-peptide level greater than 0.20 nmol/L and less than or equal to 3.50 nmol/L
- •Body mass index not greater than 32 kg/m
- •QTc <450 millisecond (msec) or <480msec for patients with Bundle Branch Block
排除标准
- •Pregnant, breastfeeding, or planning to become pregnant from the beginning of the screening period or at least 14 days prior to initial dosing until at least 60 days after the last dose of the second treatment course of study drug.
- •Current or prior malignancy, other than non-melanoma skin cancer (subject must have had fewer than 5 occurrences of non-melanoma skin cancer, and the last occurrence must not be within 3 months of study entry).
- •Clinically significant abnormal laboratory values during the Screening period, other than those due to T1DM. Permitted ranges for selected laboratory values are shown in the protocol. A clinically significant abnormal value will not result in exclusion if, upon re test, the abnormality is resolved or becomes clinically insignificant.
- •Significant and/or active disease in any body system likely to increase the risk to the subject or interfere with the subject's participation in or completion of the study. Examples of significant diseases include, but are not limited to, coronary artery disease, congestive heart failure, uncontrolled hypertension, renal failure, emphysema, history of bleeding peptic ulcers, history of seizure(s), addiction to illicit drugs, and alcohol abuse.
- •Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), presence of hepatitis B surface antigen (HBsAg), positive hepatitis C test result within 3 months of screening
- •Significant systemic infection during the 6 weeks before the first dose of study drug (e.g., infection requiring hospitalisation, major surgery, or IV antibiotics to resolve; other infections, e.g., bronchitis, sinusitis, localised cellulitis, candidiasis, or urinary tract infections, must be assessed on a case-by-case basis by the investigator regarding whether they are serious enough to warrant exclusion).
- •History of current or past active tuberculosis infection and or latent tuberculosis infection. Further details are given in the protocol.
- •A positive test for human immunodeficiency virus (HIV) antibody or risk factors which predispose subject to HIV infection.
- •EBV viral load greater than or = to 10,000 copies per 10xe6 peripheral blood mononuclear cells (PBMCs) as determined by quantitative polymerase chain reaction (qPCR). If there is any clinical suspicion that a subject who is EBV seronegative and with EBV PCR <10,000 copies per 10xe6 PBMCs has symptoms consistent with infectious mononucleosis prior to administration of study drug, then a monospot test result must be negative before the subject can be dosed.
- •A positive test for syphilis.
- •Had a potent immunosuppressive agent (e.g., systemic high-dose corticosteroids on a chronic basis, methotrexate, cyclosporine, or anti-TNF agents) within the 30 days before the first dose of study drug, or expecting to require such treatment within 3 months after the last dose of study drug. (Intranasal, inhaled, and topical corticosteroid medications are permitted if used at recommended dosages.)
- •Used an atypical antipsychotic drug (e.g., risperidone [Risperdal], quetiapine [Seroquel], or clozapine [Clozaril]) within the 30 days before first dose of study drug, or expecting to require such treatment during the study.
- •Received a vaccine within the 30 days before the first dose of study drug, or expecting to require a vaccine during the dosing period or the 30 days after the last dose of study drug.
- •Previously received otelixizumab or any other anti CD3 monoclonal antibody, e.g., OKT3 (muromonab or Orthoclone), ChAglyCD3, or hOKT3γ1 (ala ala), or not willing to refrain from using any such antibody for the planned duration of study participation (18 months after the last dose of study drug).
- •Previously received an anti lymphocyte monoclonal antibody, such as anti-CD20, anti-thymocyte globulin (ATG), rituximab (Rituxan), or alemtuzumab (Campath), or planning to use any such antibody during the planned duration of study participation (18 months after the last dose of study drug).
- •Had an investigational drug within the 3 months before the first dose of study drug or planning to take an investigational drug within18 months of the last dose of study drug.
- •Have donated any plasma or blood within 45 days before the first dose of study drug.
- •Prior allergic reaction, including anaphylaxis, to any human, humanised, chimeric, or rodent antibody.
- •Undergone a major surgical procedure within 30 days before the first dose of study drug, or planning to undergo any such surgery within 3 months after the last dose of study drug.
结局指标
主要结局
Mean Change From Baseline in Value of Albumin and Total Protein
时间窗: Baseline and up to Month 24
Clinical chemistry parameters were planned to be analyzed from Baseline to Month 24. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Number of Participants With Any Adverse Events (AEs) and Serious AEs (SAEs)
时间窗: Up to Month 24
AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include adverse events that result in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Study was early terminated and participant withdrew on study Day 164.
Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
时间窗: Baseline and up to Month 24
Blood pressure was assessed at sitting position at Baseline and 1 to 7 hours of post-infusion of first treatment period. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Change From Baseline in Respiration Rate
时间窗: Baseline and up to Month 24
Respiration rate was assessed at sitting position at Baseline and post-treatment. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Change From Baseline in Temperature
时间窗: Baseline and up to Month 24
Temperature was recorded at sitting position at Baseline and post treatment. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Change From Baseline in Red Blood Cell Count
时间窗: Baseline and up to Month 24
Hematology parameters were planned to be analyzed from Baseline to Month 24. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Change From Baseline in Heart Rate
时间窗: Baseline and up to Month 24
Heart rate was recorded at sitting position at Baseline and post-treatment period. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Number of Participants With Values Outside the Normal Range for Vitals
时间窗: Up to Month 24
Vital included assessment of SBP, DBP, respiration rate, heart rate and temperature were assessed at sitting position. Participant did not received re-dose of second treatment period and withdrew on study Day 164 because of early study termination.
Mean Change From Baseline in Value of Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatinine Kinase, Follicle Stimulating Hormone, Gamma Glutamyl Tranferase and Lactate Dehydrogenase
时间窗: Baseline and up to Month 24
Clinical chemistry parameters were planned to be analyzed from Baseline to Month 24. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Change From Baseline in Value of Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid
时间窗: Baseline and up to Month 24
Clinical chemistry parameters were planned to be analyzed from Baseline to Month 24. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Change From Baseline in Value of Calcium, Chloride, Carbon Dioxide Content/Bicarbonate, Glucose, Potassium, Magnesium, Sodium, Inorganic Phosphorus and Urea/Blood Urea Nitrogen
时间窗: Baseline and up to Month 24
Clinical chemistry parameters were planned to be analyzed from Baseline to Month 24. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Epstein-Barr Virus (EBV) Viral Load
时间窗: Up to Month 24
Levels of EBV were assessed periodically using Quantitative Polymerase Chain Reaction. If a participant had an EBV viral load of \>=10,000 copies per 10\^6 Peripheral Blood Mononuclear Cells (PBMCs) at any visit, the test was repeated as soon as possible to confirm this result. If the result was confirmed, the test was repeated weekly for 2 weeks or until the count decreases to \< 10,000 copies per 10\^6 PBMCs, whichever was longer. The EBV Load remained zero throughout the study. Participant did not received re-dose of second treatment period and withdrew on study Day 164 because of early study termination. The viral load was to measure using unit copies per 10\^6 Peripheral Blood Mononuclear Cells (PBMCs)
Mean Change in Total Lymphocyte Count
时间窗: Baseline and up to Month 24
Total lymphocyte count was planned to be analyzed up to Month 24.
Proportion of Anti-otelixizumab Neutralizing Antibodies
时间窗: Up to Month 24
Antibodies to otelixizumab were planned to be measured at Baseline and at specified post-Baseline visits using a validated immunoassay. If a positive result was detected, the samples were analyzed further in a neutralizing antibody assay to determine if the antibodies were neutralizing. The 12 and 24 month samples were only be taken if a participant had a positive result for antibodies at the last tested time point (Month 9) or if the Month 9 test results were not available.
Mean Change From Baseline in Value of Estradiol
时间窗: Baseline and up to Month 24
Clinical chemistry parameters were planned to be analyzed from Baseline to Month 24. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count and White Blood Cell Count
时间窗: Baseline and up to Month 24
Hematology parameters were planned to be analyzed from Baseline to Month 24. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Change From Baseline in Glycosylated Hemoglobin Value
时间窗: Baseline and up to Month 24
Hematology parameters were planned to be analyzed from Baseline to Month 24. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Change From Baseline in Hemoglobin Value
时间窗: Baseline and up to Month 24
Hematology parameters were planned to be analyzed from Baseline to Month 24. Day 1 value was considered to be Baseline value. Change from Baseline was planned to be calculated as any post-Baseline value minus Baseline value.
Mean Change in Circulating Peripheral T Lymphocytes
时间窗: Days 1, 4 and 8 of each treatment course
Circulating peripheral T lymphocytes were planned to be measured before, during and after dose 1, 4 and 8 of first treatment course. Because of the early termination of the study the data was not analyzed.
Mean Change in CD4+ and CD8+ T-cell Counts
时间窗: Days 1, 4 and 8 of each treatment course
CD4+ and CD8+ T cells were planned to be measured before, during and after dose 1, 4 and 8 of first treatment course. Because of the early termination of the study the data was not analyzed.
Mean Change in Circulating Peripheral CD4+ and CD8+ Subset Counts
时间窗: Days 1, 4 and 8 of each treatment course
Circulating peripheral CD4+ and CD8+ T cells were planned to be measured before, during and after dose 1, 4 and 8 of first treatment course. Because of the early termination of the study the data was not analyzed.
Mean Serum Levels of Anti-otelixizumab Binding Antibodies
时间窗: Up to Month 24
Antibodies to otelixizumab were planned to be measured at Baseline and at specified post-Baseline visits using a validated immunoassay. If a positive result was detected, the samples were analyzed further in a neutralizing antibody assay to determine if the antibodies were neutralizing. The 12 and 24 month samples were only be taken if a participant had a positive result for antibodies at the last tested time point (Month 9) or if the Month 9 test results were not available.
次要结局
- Mean Individual Serum Concentrations of Otelixizumab(Pre-dose and EOI on Dosing Day 1, EOI on Dosing Days 2, 3, 5-7 and Pre-dose, EOI, 6 hours post SOI on Dosing days 4 and 8 of each treatment course)
- Mean Circulating CD4+ and CD8+ Subset Counts(Days 1, 4 and 8 of each treatment course)
- Area Under the Serum Concentration-time Curve [AUC(0-tlast)] of Otelixizumab(Pre-dose and EOI on Dosing Day 1, EOI on Dosing Days 2, 3, 5-7 and Pre-dose, EOI, 6 hours post SOI on Dosing days 4 and 8 of each treatment course)
- Mean Circulating Peripheral T Lymphocytes Count(Day 1, 4 and 8 of each treatment course)
- Time to Cmax (Tmax) of Otelixizumab(Pre-dose and EOI on Dosing Day 1, EOI on Dosing Days 2, 3, 5-7 and Pre-dose, EOI, 6 hours post SOI on Dosing days 4 and 8 of each treatment course)
- Terminal Phase Half-life (Thalf) of Otelixizumab(Pre-dose and EOI on Dosing Day 1, EOI on Dosing Days 2, 3, 5-7 and Pre-dose, EOI, 6 hours post SOI on Dosing days 4 and 8 of each treatment course)
- Mean Saturation of CD3 Antigen on Peripheral Blood T Cells(Days 1, 4 and 8 of each treatment course)
- Maximum Observed Serum Concentration (Cmax) of Otelixizumab(Pre-dose and EOI on Dosing Day 1, EOI on Dosing Days 2, 3, 5-7 and Pre-dose, EOI, 6 hours post SOI on Dosing days 4 and 8 of each treatment course)
- Time of Last Observed Quantifiable Concentration (Tlast) of Otelixizumab(Pre-dose and EOI on Dosing Day 1, EOI on Dosing Days 2, 3, 5-7 and Pre-dose, EOI, 6 hours post SOI on Dosing days 4 and 8 of each treatment course)