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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02000817
Recruitment Status : Completed
First Posted : December 4, 2013
Last Update Posted : October 9, 2018
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Biological: Otelixizumab Biological: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 12, 2014
Actual Primary Completion Date : September 27, 2018
Actual Study Completion Date : September 27, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arm Intervention/treatment
Experimental: Otelixizumab 9 mg
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
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

Experimental: Otelixizumab 18 mg
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
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

Experimental: Otelixizumab 27 mg
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
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

Experimental: Otelixizumab 36 mg
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
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

Placebo Comparator: Placebo
Each subject will receive otelixizumab matching placebo diluted with 0.9% weight /volume sodium chloride intravenously daily for 6 consecutive days
Biological: Placebo
Placebo is available 0.9% w/v sodium chloride




Primary Outcome Measures :
  1. INCIDENCE ADVERSE EVENTS RELATED TO CYTOKINE RELEASE SYNDROME (CRS) [ Time Frame: Upto 24 months ]
  2. EPSTEIN-BARR VIRUS (EBV) REACTIVATION [ Time Frame: Day -1, Day 6 and 21, week 6, Month 2, 3, 6 and 24 ]
    Blood samples will be drawn for EBV viral load detection by Polymerase chain reaction (PCR)

  3. ABNORMAL HEMATOLOGY PARAMETERS [ Time Frame: Day-1 to Month 24 ]
    Hematology parameters include; red blood cell count, absolute white blood cell count, Reticulocyte Count, Hemoglobin, Hematocrit, mean corpuscular volume, mean corpuscular haemoglobin, Mean corpuscular hemoglobin concentration, Neutrophils, Lymphocytes, Monocytes, Eosinophils, and Basophils

  4. ABNORMAL CLINICAL CHEMISTRY PARAMETERS [ Time Frame: Day-1 to Month 24 ]
    Clinical chemistry parameters include; blood urea nitrogen, creatinine, fasting glucose, sodium, potassium, chloride, total carbondioxide, calcium, alanine transaminase, aspartate transaminase, Gamma-glutamyltransferase, Alkaline phosphatase, Total and direct bilirubin, uric acid, albumin, and total protein

  5. ABNORMAL ECG CHANGES [ Time Frame: Day-1 to Month 24 ]
    Single 12-lead electrocardiogram (ECGs) will be obtained after the subject has been resting in the semi-supine position for at least 5 minutes at scheduled time points

  6. ABNORMAL VITAL SIGNS [ Time Frame: Day-1 to Month 24 ]
    Vital signs include; blood pressure, pulse rate, respiratory rate and temperature


Secondary Outcome Measures :
  1. FREE SERUM OTELIXIZUMAB MAXIMUM OBSERVED PLASMA CONCENTRATION (CMAX) [ Time Frame: Pre-dose, 0.5,1,2,4,6,8,9 or 12 and 16 hrs during infusion on Day 1; Pre-dose on Day 2 to Day 5; Pre dose and 1 hr on Day 6; and within first hour of visit on Day 14 ]
    Blood samples for PK assessments will be collected at the scheduled times points

  2. TIME TO FREE SERUM OTELIXIZUMAB MAXIMUM OBSERVED PLASMA CONCENTRATION (TMAX ) [ Time Frame: Pre-dose, 0.5,1,2,4,6,8,9 or 12 and 16 hrs during infusion on Day 1; Pre-dose on Day 2 to Day 5; Pre dose and 1 hr on Day 6; and within first hour of visit on Day 14 ]
    Blood samples for PK assessments will be collected at the scheduled times points

  3. FREE SERUM OTELIXIZUMAB AREA UNDER THE PLASMA CONCENTRATION-TIME CURVE AUC(0-T) [ Time Frame: Pre-dose, 0.5,1,2,4,6,8,9 or 12 and 16 hrs during infusion on Day 1; Pre-dose on Day 2 to Day 5; Pre dose and 1 hr on Day 6; and within first hour of visit on Day 14 ]
    Blood samples for PK assessments will be collected at the scheduled times points

  4. FREE SERUM OTELIXIZUMAB AUC UP TO THE LAST MEASURABLE CONCENTRATION (AUC(0- TAU) [ Time Frame: Pre-dose, 0.5,1,2,4,6,8,9 or 12 and 16 hrs during infusion on Day 1; Pre-dose on Day 2 to Day 5; Pre dose and 1 hr on Day 6; and within first hour of visit on Day 14 ]
    Blood samples for PK assessments will be collected at the scheduled times points

  5. FREE SERUM OTELIXIZUMAB APPARENT TERMINAL PHASE HALF-LIFE (T1/2) [ Time Frame: Pre-dose, 0.5,1,2,4,6,8,9 or 12 and 16 hrs during infusion on Day 1; Pre-dose on Day 2 to Day 5; Pre dose and 1 hr on Day 6; and within first hour of visit on Day 14 ]
    Blood samples for PK assessments will be collected at the scheduled times points

  6. CHANGE FROM BASELINE IN GLUCOSE AFTER A MIXED MEAL TOLERANCE TEST [ Time Frame: Baseline and Month 24 ]
    Blood samples for glucose analysis will be collected before (-10 minutes), and after a mixed meal tolerance test at 0, 15, 30, 60, 90 and 120 minutes on Month 3, 6, 12, 18 and 24

  7. CHANGE FROM BASELINE IN C-PEPTIDE AFTER A MIXED MEAL TOLERANCE TEST [ Time Frame: Baseline and Month 24 ]
    Blood samples for C-peptide analysis will be collected before (-10 minutes), and after a mixed meal tolerance test at 0, 15, 30, 60, 90 and 120 minutes on Month 3, 6, 12, 18 and 24

  8. CHANGE FROM BASELINE IN C-PEPTIDE AUC HYPERGLYCEMIC PHASE [ Time Frame: Baseline and Month 24 ]
    Plasma C-peptide levels in blood will be measured during high (H) sugar levels at the following time points: H0, H60, H90, H120 and H140 minutes on Day -1, Month 6 and 24

  9. CHANGE FROM BASELINE IN C-PEPTIDE AUC EUGLYCEMIC PHASE [ Time Frame: Baseline and Month 24 ]
    Plasma C-peptide levels in blood will be measured during low (L) sugar levels at the following time points: L150, L165, L180 minutes on Day -1, Month 6 and 24.

  10. CHANGE FROM BASELINE IN INSULIN SENSITIVITY (IS) INDEX AFTER A HYPERGLYCEMIC CLAMP [ Time Frame: Baseline and Month 24 ]
    Blood will be collected for glucose measurement at Day -1, Month 6 and 24.

  11. CHANGE FROM BASELINE IN MEAN DAILY INSULIN USE OVER 7 CONSECUTIVE DAYS DURING THE WEEK PRECEDING THE VISIT OR TELEPHONE CALL [ Time Frame: Baseline and Month 24 ]
    It will be measured at day -1, month 6 and month 24

  12. CHANGE FROM BASELINE IN HBA1C LEVEL [ Time Frame: Baseline and Month 60 ]
    Subjects will be asked to report verbally their HbA1c at Month 36, 48 and 60

  13. BODY WEIGHT [ Time Frame: Day -1 and Months 2 to 24 ]
    Body weight will be measured at Day-1, and at Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 and Month 24

  14. NUMBER OF HYPOGLYCEMIC EVENTS [ Time Frame: Day 1 to Month 24 ]
  15. NUMBER OF HYPERGLYCEMIC EVENTS [ Time Frame: Day 1 to Month 24 ]
  16. CHANGE FROM BASELINE CD4 + CELLS [ Time Frame: Day 1 through to Day 14 ]
  17. NUMBER OF SUBJECTS WITH CHANGE CD8+ CELLS [ Time Frame: Day 1 through to Day 14 ]
  18. CHANGE IN FREE CD3 CELLS [ Time Frame: Day 1 through to Day 14 ]
  19. NUMBER OF SUBJECTS WITH CHANGE IN BOUND OTELIXIZUMAB ON CD4+ [ Time Frame: Day 1 through to Day 14 ]
  20. NUMBER OF SUBJECTS WITH CHANGE IN BOUND OTELIXIZUMAB ON CD8+ [ Time Frame: Day 1 through to Day 14 ]
  21. CHANGE FROM BASELINE IN ANTI-DRUG ANTIBODY LEVELS AT MONTHS 3 [ Time Frame: Baseline and Month 6 ]
    It will be measured at Day -1, Month 3 and 6



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Ages Eligible for Study:   16 Years to 27 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02000817


Locations
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Belgium
GSK Investigational Site
Brussels, Belgium, 1090
GSK Investigational Site
Bruxelles, Belgium, 1070
GSK Investigational Site
Edegem, Belgium, 2650
GSK Investigational Site
Gent, Belgium, 9000
GSK Investigational Site
Leuven, Belgium, 3000
GSK Investigational Site
Liège, Belgium, 4000
Sponsors and Collaborators
GlaxoSmithKline
Parexel
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02000817     History of Changes
Other Study ID Numbers: 116505
First Posted: December 4, 2013    Key Record Dates
Last Update Posted: October 9, 2018
Last Verified: October 2018

Keywords provided by GlaxoSmithKline:
Beta Cell
Monoclonal Antibody
Otelixizumab
Cytokine Release Syndrome
Epstein-Barr Virus
Diabetes Mellitus

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases