NOT1DM is an autoimmune disease. This means that the immune system, the part of the body which usually helps to fight infections, mistakenly attacks cells that produce insulin in the body. Insulin is necessary for the uptake of sugar from the blood MedDRA version: 18.0 Level: LLT Classification code 10003814 Term: Autoimmune disease, not elsewhere classified System Organ Class: 100000004870
Conditions
Interventions
Product Name: Otelixizumab
Product Code: GSK2136525
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Otelixizumab
CAS Number: 88191-44-2
Current Sponsor code: GSK2136525
Other descripti
Sponsors
GlaxoSmithKline Research & Development Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. Male or female aged between 16 and 27 years of age inclusive, at the time of signing the informed consent. NOTE: Subjects aged 16 to 17 years must be Tanner Stage = 2 (see SPM). All subjects must weigh at least 31 kg. 2. Diagnosis of diabetes mellitus according to ADA and WHO criteria and consistent with Type 1a (autoimmune) DM, with an interval of approximately 28 days (not more than 32 days) between the initial diagnosis and the first dose of study drug). Written documentation of the diagnosis of DM, including the date of diagnosis, must be obtained from the diagnosing physician. 3. Currently requires insulin treatment for T1DM and has received insulin therapy for at least 7 days prior to screening. 4. Positive for at least one autoantibody associated with T1DM: antibody to glutamic acid decarboxylase (anti GAD), antibody to protein tyrosine phosphatase-like protein (anti IA 2), antibody to islet-cell antigen (ICA) or ZnT8 Autoantibody. 5. Evidence of residual functioning ß cells as measured by mixed meal stimulated C peptide peak level = 0.2 nmol/L. 6. A female subject is eligible to participate if she has a negative pregnancy test as determined by a urine hCG test at screening or prior to dosing AND - Agrees to use one of the contraception methods listed in Section 4.3.1. Female subjects must agree to use contraception for 2 weeks prior to dosing and for 60 days after the last dose of study drug. - OR has only same-sex partners (refrains from heterosexual intercourse), when this is her preferred and usual lifestyle. 7. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in Section 4.3.1. This criterion must be followed from 2 weeks prior to dosing and for 60 days after the last dose of study drug. 8. Willing to follow the procedures outlined in the protocol. 9. AST and ALT 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1. A positive pre-study Hepatitis B surface antigen or core antibody or positive Hepatitis C antibody result within 3 months of screening. 2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). 3. A positive test for HIV 1 and/or 2 antibody. 4. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). 5. Exposure to more than four new investigational drugs within 12 months prior to the first dosing day. 6. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or CRO/GSK Medical Monitor, contraindicates their participation. 7. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 3 month period. 8. Lactating females. 9. Subject is mentally or legally incapacitated. 10. History of thrombocytopenia. 11. The subject has received immunization with a vaccine within 4 weeks before the first dose of study drug or requires a vaccine within 30 days after the last dose of study drug 12. The subject has had significant systemic infection during the 6 weeks before the first dose of study drug (e.g., infection requiring hospitalisation, major surgery, or i.v. 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). 13. Current or prior malignancy, other than non-melanoma skin cancer. 14. Patient has undergone a splenectomy 15. Radiological evidence of active tuberculosis (TB). 16. 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. 17. Clinically significant (based on Investigator’s discretion in consultation with the Medical Monitor if second opinion required) abnormal laboratory values during the screening period, other than those due to T1DM. A clinically significant abnormal value will not result in exclusion if, upon retest, the abnormality is resolved or becomes clinically insignificant. 18. Positive EBV capsid Ab IgM in absence of a positive EBV EBNA Ab IgG 19. EBV viral load of> 10,000 copies per 106 peripheral blood mononuclear cells (PBMCs) as determined by quantitative polymerase chain reaction (qPCR).. 20. IgG negative for EBV. 21. A positive result on a test for syphilis; and if result of the first test is positive, then a confirmatory test using another method will be performed. 22. Have used any atypical antipsychotic drug (e.g., risperidone [Risperdal], quetiapine [Seroquel], or clozapine [Clozaril]) within the 30 days before signing the ICF. 23.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the effect of a single course of otelixizumab treatment on the acute and long term safety and tolerability of otelixizumab in NOT1DM patients.;Secondary Objective: Secondary Objectives (Pharmacokinetic) -To assess the pharmacokinetics of repeat dose administration of otelixizumab over 14 days in NOT1DM patients. Secondary Objectives (Efficacy) -To assess the effect of a single course of otelixizumab treatment on the rate of decline of pancreatic Beta-cell function over 24 months in NOT1DM patients. -To assess the effect of a single course of otelixizumab treatment on the rate of decline of C-peptide response and insulin sensitivity of Beta-cell function determined after a hyperglycemic clamp over 24 months in NOT1DM patients. -To assess the effect of a single course of otelixizumab treatment on exogenous insulin use for otelixizumab over 24 months in NOT1DM patients. -To assess the effect of a single course of otelixizumab treatment on glycaemic control over 24 months in NOT1DM patients. Secondary Objectives (Pharmacodynamic)-Please refer to protocol P 21-22 for further information. ;Primary end point(s): • Incidence of adverse events (AEs) particularly those related to Cytokine release syndrome (CRS) • Epstein-Barr virus (EBV) reactivation • Changes in laboratory values, electrocardiograms (ECGs) and vital signs ;Timepoint(s) of evaluation of this end point: Up to 24 Months. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Pharmacokinetic: -Free serum otelixizumab concentrations over Days 1-14 and summary PK parameters. Efficacy: - Change from baseline in C-peptide and glucose AUC (0-120) after a Mixed Meal Tolerance Test at Month 3, 6, 12, 18 and 24. - Change from baseline in C-Peptide AUC and glucose hyperglycemic phase [H60 to H140 minutes] and insulin sensitivity (IS) index after a hyperglycemic clamp at Months 6 and 24. - Change from baseline in mean daily insulin use over 7 consecutive days during the week preceding all visits or phone calls. - Change from baseline in HbA1c level - Body weight Day -1, Months 12-24, -Hypoglycemic and hyperglycemic events over Months 1-24. Pharmacodynamic: - Relative change from baseline (%) in CD4+ and CD8+ cells, free CD3 and bound otelixizumab on CD4+ and CD8+ cells on Days 1 through 14. - Change from baseline in anti-drug antibody levels at Months 3 and 6. Exploratory Endpoints - Change from baseline in absolute lymphocyte counts and subsets (CD3+ CD4+, CD3+ CD8+, and CD19+ cells) and phenotype (eg effector, memory, regulatory T cells, eg CD45RA, CCR7+) over week 6 to Month 24. - Change from baseline in demethylated FoxP3 expression in whole blood over week 6 to Month 24. - Change from baseline in absolute numbers of HLA-A2-restricted CD8 T lymphocytes reactive to specific auto-antigens (by multimer) over week 6 to Month 24. - Change from baseline in frequency of cytokine producing cells following in vitro stimulation with auto-antigens (by ELISPOT) over week 6 to Month 24. - Change from baseline in auto-antibody titres (using a panel of common autoantibodies associated with T1DM antigens and possibly other auto-antigens) and serum analytes (such as cytokines/ chemokines) over week 6 to Month 24. - Change from baseline in T cell clonal repertoire by TCR deep sequencing over week 6 to Month 24. - Change from baseline in serum by measuring relative levels of unmethylated INS DNA and/or other biomarkers for ?- cell | — |
Countries
Belgium
Contacts
Public ContactClincial Trials Helpdesk
GlaxoSmithKline Research & Development Ltd
Outcome results
None listed