Investigation of Otelixizumab in New-Onset, Autoimmune Type 1 Diabetes Mellitus Patients

Study Overview
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Brief Summary
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The aim of this Phase I/IIa study is to identify a safe and tolerable dosage regimen of intravenously administered otelixizumab. In addition, the C-peptide decline in new onset type 1 diabetes mellitus (NOT1DM) patients and possible immunological mechanisms will be investigated with a view to identifying trends and early immunological biomarkers which could predict response in halting/slowing Beta-cell destruction in this patient population. This exploratory study will explore the safety and tolerability between the well tolerated but non-efficacious cumulative dose of 3.1 mg and a cumulative dose of 48 mg at which efficacy based on C-peptide analysis was demonstrated, albeit with evidence of Epstein Barr Virus (EBV) reactivation and Cytokine Release Syndrome (CRS). Exploration of the tolerability dose response is considered a necessary first step to determining the therapeutic index of otelixizumab.

Official Title
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A Single Blind, Randomised, Placebo Controlled, Repeat Dose, Dose Escalating Study Investigating Safety, Tolerability Pharmacokinetics, Pharmacodynamics and the Beta-Cell Preserving Effect of Otelixizumab in New-Onset, Autoimmune Type 1 Diabetes Mellitus Patients

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Biological: Otelixizumab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. All subjects must weigh at least 31 kg. Diagnosis of diabetes mellitus (DM) according to Amerrican Diabetes Association (ADA) and World Health Organization (WHO) criteria and consistent with Type 1a (autoimmune) Diabetes Mellitus (T1DM), 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. Currently requires insulin treatment for T1DM and has received intensive insulin therapy for at least 7 days prior to screening. Positive for at least one auto-antibody 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. Evidence of residual functioning Beta-cells as measured by mixed meal stimulated C peptide peak level >= 0.2 nanomole/litre (nmol/L). 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 study protocol. 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. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in study protocol. This criterion must be followed from 2 weeks prior to dosing and for 60 days after the last dose of study drug. Willing to follow the procedures outlined in the protocol. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) < 2xupper limit of normal (ULN); alkaline phosphatase and bilirubin <= 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent). Subjects eligible for enrolment in the study must meet all of the following criteria: QTc <450msec or QTc <480msec for patients with bundle branch block. The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purposes of data analysis, QTcF will be used as primary. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period. Screening total lymphocyte counts within the normal range in two separate samples taken at least three days apart (eg screening and Day -1). Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. In the case of minors (under 18 years) written informed consent must also be obtained from a parent or Legally Acceptable Representative (LAR). Exclusion Criteria: A positive pre-study Hepatitis B surface antigen or core antibody or positive Hepatitis C antibody result within 3 months of screening Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). A positive test for Human Immunodeficiency Virus (HIV) 1 and/or 2 antibody. 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). Exposure to more than four new investigational drugs within 12 months prior to the first dosing day. 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 GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation. Where participation in the study would result in donation of blood or blood products in excess of 500 milliliter (mL) within a 3 month period. Lactating females. Subject is mentally or legally incapacitated. History of thrombocytopenia. The subject has received immunizationion 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 The subject has had significant systemic infection during the 6 weeks before the first dose of study drug (e.g., infection requiring hospitalization, major surgery, or intravenous (i.v.) antibiotics to resolve; other infections, e.g., bronchitis, sinusitis, localized 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). Current or prior malignancy, other than non-melanoma skin cancer. Patient has undergone a splenectomy Radiological evidence of active tuberculosis (TB). 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. 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 re test, the abnormality is resolved or becomes clinically insignificant. Positive EBV capsid Ab IgM in absence of a positive EBV EBNA Ab IgG EBV viral load of> 10,000 copies per 10^6 peripheral blood mononuclear cells (PBMCs) as determined by quantitative polymerase chain reaction (qPCR) Immunoglobulin G (IgG) negative for EBV. A positive result on an Immuno-Assay test for syphilis; and, if result of Immuno-assay test is positive, then a confirmatory test will be performed. Have used any atypical antipsychotic drug (e.g., risperidone, quetiapine, or clozapine) within the 30 days before signing the Informed Consent Form (ICF). Have previously received otelixizumab or any other anti cluster of differentiation (CD)3 monoclonal antibody, e.g. muromonab, or teplizumab, and are 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). Previous or current exposure to biologic cell-depleting therapies (e.g. anti-CD11a, anti-CD22, anti-CD20, anti- B lymphocyte stimulator/ B-cell activating factor (BLyS/BAFF), anti-CD3, anti-CD5, anti-CD52) including investigational agents, and planning to use any such antibody for the planned duration of study participation (2 years after the last dose of study drug). Predisposition to thromboembolic disease, or thromboembolic event (excluding superficial) in the past 12 months. Is currently receiving corticoid treatment or has received systemic corticoid treatment within a month of screening, History of Graves disease Prior allergic reaction, including anaphylaxis, to any human, humanised, chimeric, or rodent antibody. Have undergone any major surgical procedure within 30 days before the first dose of study drug, and/or planning to undergo any such surgery within 3 months after the last dose of study drug. Any condition or situation that, in the investigator's judgment, is likely to cause the subject to be unable or unwilling to participate in study procedures or to complete all scheduled assessments.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 27 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: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Otelixizumab 9 mg<br>Each subject will receive otelixizumab 1.5 mg diluted with 0.9% weight /volume sodium chloride intravenously daily for 6 consecutive days (cumulative dose-9 mg) | Biological: Otelixizumab<br>* Otelixizumab is available at unit dose strength of 5 milligram/mL provided as 1 mL solution per vial to be diluted to 0.1 mg/mL in 0.9% sodium chloride. The 0.1 mg/mL solution is to be administered by intravenous infusion using a syringe pump and an in-line 0.2 micron filter by study personnel following specified regimens<br>|
| Experimental: Otelixizumab 18 mg<br>Each subject will receive otelixizumab 3 mg diluted with 0.9% weight /volume sodium chloride intravenously daily for 6 consecutive days (cumulative dose-18 mg) | Biological: Otelixizumab<br>* Otelixizumab is available at unit dose strength of 5 milligram/mL provided as 1 mL solution per vial to be diluted to 0.1 mg/mL in 0.9% sodium chloride. The 0.1 mg/mL solution is to be administered by intravenous infusion using a syringe pump and an in-line 0.2 micron filter by study personnel following specified regimens<br>|
| Experimental: Otelixizumab 27 mg<br>Each subject will receive otelixizumab 4.5 mg diluted with 0.9% weight /volume sodium chloride intravenously daily for 6 consecutive days (cumulative dose-27 mg) | Biological: Otelixizumab<br>* Otelixizumab is available at unit dose strength of 5 milligram/mL provided as 1 mL solution per vial to be diluted to 0.1 mg/mL in 0.9% sodium chloride. The 0.1 mg/mL solution is to be administered by intravenous infusion using a syringe pump and an in-line 0.2 micron filter by study personnel following specified regimens<br>|
| Experimental: Otelixizumab 36 mg<br>Each subject will receive otelixizumab 1.5 mg diluted with 0.9% weight /volume sodium chloride intravenously daily for 6 consecutive days (cumulative dose-36 mg) | Biological: Otelixizumab<br>* Otelixizumab is available at unit dose strength of 5 milligram/mL provided as 1 mL solution per vial to be diluted to 0.1 mg/mL in 0.9% sodium chloride. The 0.1 mg/mL solution is to be administered by intravenous infusion using a syringe pump and an in-line 0.2 micron filter by study personnel following specified regimens<br>|
| Placebo Comparator: Placebo<br>Each subject will receive otelixizumab matching placebo diluted with 0.9% weight /volume sodium chloride intravenously daily for 6 consecutive days | Biological: Placebo<br>* Placebo is available 0.9% w/v sodium chloride<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) Related to Cytokine Release Syndrome (CRS) | An 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. On treatment AEs have been reported. Safety Population comprised of all participants who received at least one dose of study treatment. | Up to Day 14 | 
| Epstein-Barr Virus (EBV) Viral Load Detection | Blood samples were collected for analysis of EBV viral load and detection was done by polymerase chain reaction (PCR). | Week 3, Week 6, Week 8, Week 12, Week 24 and Week 96 | 
| Number of Participants With Abnormal Laboratory Results | Blood samples were collected to analyze the laboratory parameters which included alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, calcium, chloride, creatinine, direct bilirubin, glucose, potassium, protein, sodium, urate, urea nitrogen, basophil, eosinophil, mean corpuscular haemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), erythrocytes, haematocrit, haemoglobin, leukocytes, lymphocytes, monocytes, neutrophils, platelets and reticulocytes. | Up to Month 24 | 
| Number of Participants With Increase in QT Interval Corrected for Heart Rate (QTc) | 12-lead electrocardiograms (ECGs) were obtained in semi-supine position after 5 minutes rest for the participants at indicated time points to measure QTc. | Up to Month 24 | 
| Number of Participants With Abnormal Vital Sign Results | Vital signs were measured in semi-supine position after 5 minutes rest for the participants at indicated time points. Vital signs included systolic, diastolic blood pressure, pulse rate and respiratory rate | Up to Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Free Serum Otelixizumab Concentrations by Treatment | Blood samples were collected at designated timepoints. Free serum Otelixizumab concentrations were calculated by linear and semi-logarithmic individual serum concentration-time profiles. Fully treated population comprised of all randomized participants who received the full 6 days of treatment based on actual exposure data. NA indicates that data could not be calculated as >30% of samples were below the limit of quantification. | Pre-dose on Day 1,2,3,4,5,6 and 14; 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 16 hours post-dose on Day 1, and 1 hour post-dose on Day 6. | 
| Change From Baseline in C-Peptide Weighted Mean (Area Under Curve From 0 to 120 Minutes [AUC0-120 Minutes]) From Mixed Meal Tolerance Test | Blood samples were collected at indicated time points to assess levels of C-peptide. Day -1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Mixed meal-stimulated C-peptide AUC was calculated from area under C-peptide/time curve from time 0 to 120 minutes, using trapezoidal rule. ITT treated population comprised of all randomized participants who received at least one dose of study treatment. | Baseline (Day-1), Month 3, Month 6, Month 12, Month 18 and Month 24 | 
| Change From Baseline in Glucose Weighted Mean (Area Under Curve From 0 to 120 Minutes, AUC0-120 Minutes) From Mixed Meal Tolerance Test | Blood samples were collected at indicated time points to assess levels of glucose. Day -1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Mixed meal-stimulated glucose was calculated from area under the glucose /time curve from time 0 to 120 minutes, using trapezoidal rule. | Baseline (Day-1), Month 3, Month 6, Month 12, Month 18 and Month 24 | 
| Change From Baseline in C-Peptide Weighted Mean (Area Under Curve From 60 to 140 Minutes, [AUC 60-140 Minutes]) From Hyperglycemic Clamp Test | Blood samples were collected at indicated time points to assess levels of C-peptide during hyperglycemic (H) phase. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from specified time point value. C-peptide AUC was calculated from area under C-peptide/time curve from time H60 to H140 minutes. | Baseline (Day-1), Month 6, Month 24 | 
| Change From Baseline in Glucose Weighted Mean (Area Under Curve From 60 to 140 Minutes, AUC60-140 Minutes) From Hyperglycemic Clamp Test | Blood samples were collected at indicated time points to assess levels of glucose during hyperglycemic (H) phase. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Glucose AUC was calculated from area under the C-peptide/time curve from time H60 to H140 minutes. | Baseline (Day-1), Month 6 and Month 24 | 
| Change From Baseline in Insulin Sensitivity (IS) Index From Hyperglycemic Clamp Test | Insulin sensitivity index is defined as the ratio of glucose metabolized and average insulin concentration multiplied by 100 by hyperglycemic clamp test. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. | Baseline (Day-1), Month 6, Month 24 | 
| Change From Baseline in Mean Daily Insulin Use | Participants were asked to record their daily insulin usage thoroughly and accurately in a diary from 7 days prior to study visit. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. | Baseline (Day-1), Week 2, Week 3, Week 6, Week 8, Week 12, Week 24, Week 36, Week 48, Week 72 and Week 96 | 
| Change From Baseline in Hemoglobin A1c | Hemoglobin A1C levels were measured at indicated time points. Day-1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. | Baseline (Day-1), Month 6, Month 12 and Month 24 | 
| Absolute Body Weight | Body weight was measured at indicated time points. | Day-1, Month 12, Month 18 and Month 24 | 
| Time-normalized Number of Hypoglycemic and Hyperglycemic Events | As per American Diabetes Association (ADA), hypoglycemia is defined as blood glucose level <= 70 milligram/deciliter (mg/dl) and hyperglycemia is defined as blood glucose level > 250 mg/dL. Hypoglycaemic and hyperglycaemic events will be recorded in a diary whenever they occur, along with the start and stop dates. Mean number of events is defined as the average number of events reported per subject. Normalization is expressed by dividing number of events by length of reporting period in month (1 month = 30 days). | Up to Month 24 | 
| Relative Change From Baseline in Percentage (%) in CD4+ Cells | Whole blood samples were collected and analyzed by flow cytometry. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Relative change from Baseline (percentage) was calculated as change from Baseline relative to Baseline in percentage. | Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14 | 
| Relative Change From Baseline in Percentage (%) in CD8+ Cells | Whole blood samples were collected and analyzed by flow cytometry. Day1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Relative change from baseline (%) was calculated as change from Baseline relative to Baseline in %. NA indicates that standard deviation could not be calculated for a single participant. | Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14 | 
| Change From Baseline in Free CD3 on CD8+ Cells | Whole blood samples were drawn and analyzed by flow cytometry. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. NA indicates that standard deviation could not be calculated for a single participant. | Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14 | 
| Change From Baseline in Free CD3 on CD4+ Cells | Whole blood samples were drawn and analyzed by flow cytometry. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. NA indicates that standard deviation could not be calculated for a single participant. | Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14 | 
| Change From Baseline in Bound CD3 Copies on CD4+ Cells | Whole blood samples were drawn and analyzed by flow cytometry. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. NA indicates that standard deviation could not be calculated for a single participant. | Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14 | 
| Change From Baseline in Bound CD3 Copies on CD8+ Cells | Whole blood samples were drawn and analyzed by flow cytometry. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. NA indicates that standard deviation could not be calculated for a single participant. | Day 1 (30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 12 hours, 16 hours), Day 2, Day 3, Day 4, Day 5, Day 6 (1 hour), Day 14 | 
| Number of Participants With Anti-drug Antibody Binding | Samples were analyzed for the presence of anti-Otelixizumab antibodies using a validated immunoelectrochemiluminescent (ECL) assay. | Day-1, Month 3 and Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Beta Cell, Monoclonal Antibody, Otelixizumab, Cytokine Release Syndrome, Epstein-Barr Virus, Diabetes Mellitus