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

NCT02000817 | Completed Phase 1 Results

• 2 other identifiers: 1165052013-003296-34
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 6

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.

Conditions

Diabetes Mellitus, Type 1

Keywords

Beta Cell; Monoclonal Antibody; Otelixizumab; Cytokine Release Syndrome; Epstein-Barr Virus; Diabetes Mellitus

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (17)

• Free Serum Otelixizumab Concentrations by Treatment

  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

  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

  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

  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

  Baseline (Day-1), Month 6 and Month 24

Study Arms (5)

Otelixizumab 9 mg

EXPERIMENTAL

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 18 mg

EXPERIMENTAL

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 27 mg

EXPERIMENTAL

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 36 mg

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Each subject will receive otelixizumab matching placebo diluted with 0.9% weight /volume sodium chloride intravenously daily for 6 consecutive days

Biological: Placebo

Interventions

Otelixizumab BIOLOGICAL

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

Otelixizumab 18 mg; Otelixizumab 27 mg; Otelixizumab 36 mg; Otelixizumab 9 mg

Placebo BIOLOGICAL

Placebo is available 0.9% w/v sodium chloride

Placebo

Eligibility Criteria

• Age: 16 Years - 27 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Parexel: collaborator

Study Sites (6)

GSK Investigational Site

Brussels, 1070, Belgium

Location

GSK Investigational Site

Brussels, 1090, Belgium

Location

GSK Investigational Site

Edegem, 2650, Belgium

Location

GSK Investigational Site

Ghent, 9000, Belgium

Location

GSK Investigational Site

Leuven, 3000, Belgium

Location

GSK Investigational Site

Liège, 4000, Belgium

Location

Related Publications (2)

• Keymeulen B, van Maurik A, Inman D, Oliveira J, McLaughlin R, Gittelman RM, Roep BO, Gillard P, Hilbrands R, Gorus F, Mathieu C, Van de Velde U, Wisniacki N, Napolitano A. A randomised, single-blind, placebo-controlled, dose-finding safety and tolerability study of the anti-CD3 monoclonal antibody otelixizumab in new-onset type 1 diabetes. Diabetologia. 2021 Feb;64(2):313-324. doi: 10.1007/s00125-020-05317-y. Epub 2020 Nov 4.

  PMID: 33145642 DERIVED

• Vlasakakis G, Napolitano A, Barnard R, Brown K, Bullman J, Inman D, Keymeulen B, Lanham D, Leirens Q, MacDonald A, Mezzalana E, Page K, Patel M, Savage CO, Zamuner S, van Maurik A. Target engagement and cellular fate of otelixizumab: a repeat dose escalation study of an anti-CD3epsilon mAb in new-onset type 1 diabetes mellitus patients. Br J Clin Pharmacol. 2019 Apr;85(4):704-714. doi: 10.1111/bcp.13842. Epub 2019 Feb 5.

  PMID: 30566758 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Cytokine Release Syndrome; Epstein-Barr Virus Infections; Diabetes Mellitus

Interventions

otelixizumab

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 7, 2013
• First Posted: December 4, 2013
• Study Start: March 12, 2014
• Primary Completion: September 27, 2018
• Study Completion: September 27, 2018
• Last Updated: June 24, 2019
• Results First Posted: June 24, 2019

Record last verified: 2019-03

Locations

BE (6)