Otelixizumab is being developed for the treatment of patients with autoimmune T1DM with residual beta cell function (RBCF), with the goal of preserving RBCF in this patient population. There are currently no approved treatments for this indication. Approved treatments for T1DM in the EU are insulins or insulin analogues. MedDRA version: 14.0 Level: LLT Classification code 10012608 Term: Diabetes mellitus insulin-dependent System Organ Class: 10027433 - Metabolism and nutrition disorders
Conditions
Interventions
Product Name: Otelixizumab
Product Code: GSK2136525
Pharmaceutical Form: Solution for infusion
CAS Number: 881191-44-2
Current Sponsor code: GSK 2136525
Other descriptive name: Otelixizumab
Concentrat
Sponsors
Tolerx, Inc.
GlaxoSmithKline
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.No condition that, in the investigator’s judgment, is likely to cause the subject to be unable to understand the information in the assent form or Informed Consent Document (ICD) or provide informed consent. Such conditions would include, but are not limited to, psychoses or mental retardation with an IQ below 65. 2.Informed Consent Document signed by the subject if the subject is legally an adult. If the subject is legally a minor, ICD signed the subject’s parent, both parents, or guardian and assent form signed by the subject, in accordance with the regulatory and legal requirements of the participating country. 3.Male or female, aged 12 to 45 years, inclusive, at the time of anticipated first dose of study drug. Subjects aged 12 to 17 years must be Tanner Stage >/= 2. All subjects must weigh at least 31 kg. 4.a. Diagnosis of diabetes mellitus according to ADA and WHO criteria (Appendix 1), with an interval of = 90 days between the initial diagnosis and the first dose of study drug. Documentation of the diagnosis of DM, including the date of diagnosis, must be obtained from the diagnosing physician. 4.b*. History and clinical course consistent with type 1a (autoimmune) DM. 5.Currently requires insulin treatment for T1DM, or has required insulin for DM treatment at some time between the date of diagnosis and the first dose of study drug. 6.Willing to undergo intensive insulin therapy and to self-monitor blood glucose levels at least 4 times daily from Screening through Month 24 and 7 times daily over 7 consecutive days during the 2 weeks before the visits at Baseline, Week 12, and Months 6, 12, 18, and 24. 7.Willing to record home insulin use, blood glucose levels, and signs and symptoms of hypoglycemic excursions using an electronic personal device assistant, complying with all data transmission requirements, for the planned duration of study participation (2 years after the last dose of study drug). 8.Willing to remain at the study center on each day of dosing until all assessments are complete, or longer if deemed medically necessary by the investigator. Willing to remain at the study center to undergo the mixed meal tolerance test (MMTT) at intervals of 3-12 months. 9.Positive for one or more of the following autoantibodies typically associated with T1DM: antibody to glutamic acid decarboxylase (anti GAD); antibody to protein tyrosine phosphatase-like protein (anti IA 2); zinc transporter autoantibodies; insulin autoantibodies (IAA). A subject who is positive for insulin autoantibodies (IAA) and negative for the other autoantibodies will not be eligible if the subject has used insulin for a total of 7 days or more. 10.Evidence of residual functioning ß cells as measured by a stimulated C peptide level > 0.20 nmol/L during the Screening or Predose MMTT when blood glucose level is > 70 mg/dL and = 200 mg/dL. 11.Maximum stimulated C-peptide level = 3.50 nmol/L. 12.For subjects aged 18 years or older at Screening, Body Mass Index (BMI) < 32. For subjects under 18 at Screening, BMI < 95th percentile for age and sex according to United States Center for Disease Control and Prevention. If a potential subject is identified who is in generally good health other than T1DM, and for whom non contraindicating medical issues exist, yet who does not strictly meet all eligibility criteria, the Sponsor reserves the right to allow participation in the study after review and discussion of the patient's medical status with the Inve
Exclusion criteria
Exclusion criteria: 1. Pregnant, breastfeeding, or planning to become pregnant during the 60 days after the last dose of study drug. 2. If of childbearing potential (defined as women who are premenopausal [have had at least 1 menstrual period during the past 1 year] and have not had a hysterectomy or tubal ligation), not using adequate contraception if sexually active. 3. Significant systemic infection during the 6 weeks before the first dose of study drug. 4. 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 history of current within 3 months of study entry). 5. History of current or past active tuberculosis infection or latent tuberculosis infection. This can be met with a positive purified protein derivative (PPD) test result during Screening or a documented positive result within 6 months prior to dosing. 6. 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. 7. Clinically significant abnormal laboratory values during the Screening period, other than those due to T1DM. 8. Positive results for Hepatitis B surface antigen and for antibodies to Hepatitis B core antigen, and Hepatitis C. 9. Positive results for antibodies to HIV I and II, and considered by the investigator to be at high risk for HIV infection. 10. EBV viral load of > 10,000 copies per 10ex6 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 10ex6 PBMCs has symptoms consistent with infectious mononucleosis prior to administration of study drug, then a monospot test result must be positive. 11. A positive result on the Rapid Plasma Reagin (RPR) test for syphilis; or, if result of RPR test is positive, a negative confirmatory test (for example, fluorescent treponemal antibody absorbed [FTA-ABS] test). 12. Have used any investigational drug within the 3 months before the first dose of study drug, and planning to take any investigational drug for the planned duration of study participation (2 years after the last dose of study drug). 13. Have used any 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, and expected 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.) 14. Have received a vaccine within the 30 days before the first dose of study drug, and expected to require a vaccine during the dosing period or the 14 days after the last dose of the study drug. 15. Have previously received otelixizumab or any other anti-CD3 monoclonal antibody, e.g., OKT3 (muromonab or Orthoclone®), ChAglyCD3, or hOKT3?1 (ala-ala), and not willing to refrain from using any such antibody for the planned duration of study participation (2 years after the last dose of study drug). 16. Have previously received any anti-lymphocyte monoclonal antibody, such as anti- CD20, anti-thymocyte globulin (ATG), rituximab (Rituxan®), or alemtuzumab (Campath®), and not planning to use any such antibody for the planned duration
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to demonstrate that subjects who receive an 8-day series of otelixizumab infusions have greater improvement than subjects who receive placebo in endogenous insulin secretion, as assessed by area under the concentration-time curve (AUC) for mixed meal-stimulated C-peptide, at 12 months after study drug administration.;Secondary Objective: Secondary objectives are: 1. To assess exogenous insulin use for the otelixizumab and placebo groups and for selected subpopulations; 2. To assess glycemic control, as measured by HbA1c, for the otelixizumab and placebo groups and for selected subpopulations; 3. To assess the safety of an 8-day series of otelixizumab infusions, especially with regards to adverse events (AEs), hypoglycemic and hyperglycemic excursions, and Epstein-Barr virus monitoring; and 4. To assess the pharmacodynamic effects of an 8-day series of otelixizumab infusions, especially with regards to absolute counts and percentages of lymphocyte subsets, CD3/T cell receptor (TCR) saturation and modulation, and serum levels of cytokines and cellular mediators.;Primary end point(s): The primary efficacy endpoint is change from baseline in 2-hour mixed meal stimulated C-peptide AUC at Month 12. Mixed meal-stimulated C-peptide AUC at Week 12 and Months 6, 18 and 24 will be analyzed using the same approach. C-peptide AUC change status (decreased, unchanged, or increased from baseline) will also be assessed at Week 12 and months 6, 12, 18 and 24.;Timepoint(s) of evaluation of this end point: 12 Months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Responder status (HbA1c <6.5%, insulin use ,0.5IU/kg/Day), mean daily insulin use, HbA1c, incidence of hypoglycaemic events, number and magnitude of hypoglycaemic excursions;Timepoint(s) of evaluation of this end point: Week 12, Month 6, Month 12 | — |
Countries
Canada, Denmark, Finland, Germany, Italy, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactEU GSK Clinical Trials Call Centre
GlaxoSmithKline
Outcome results
None listed