TRX4 Monoclonal Antibody in Type 1 Diabetes (T1 DM) (TTEDD)

• ClinicalTrials.gov Identifier: NCT00451321
• Recruitment Status: Terminated
• First Posted: March 23, 2007
• Results First Posted: November 13, 2017
• Last Update Posted: November 13, 2017
• Sponsor: GlaxoSmithKline
• Collaborator: Juvenile Diabetes Research Foundation
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

The purpose of this study is to optimize several multi-dose regimens of otelixizumab, determine the highest biologically active dose, evaluate biomarkers and surrogates of efficacy, and to evaluate the effects of each multi-dose regimen of otelixizumab against standard safety and efficacy parameters.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 88 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: TRX4 Therapeutic Evaluation of Different Multi-Dose Regimens in Type 1 Diabetes Mellitus (TTEDD)
• Actual Study Start Date: July 31, 2006
• Actual Primary Completion Date: December 1, 2011
• Actual Study Completion Date: December 1, 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: otelixizumab	Drug: Otelixizumab; Infusion

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Month 24 ]
   AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include adverse events that result in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
2. Number of Participants With Cytokine Release AE [ Time Frame: Up to Month 24 ]
   AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Cytokine release AEs were defined as occurring during dosing or within a limited time window after the last dose.
3. Number of Participants With Abnormal Hematology Values of Potential Clinical Concern (PCC) [ Time Frame: Up to Month 48 ]
   Hematology parameters: hemoglobin, white blood cell (WBC) count, basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelet count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were assessed for abnormal PCC values. Data for abnormal parameters (high and low) is presented. Only those parameters for which at least one value of PCC was reported are summarized.
4. Number of Participants With Abnormal Clinical Chemistry Values of PCC [ Time Frame: Up to Month 48 ]
   Clinical chemistry parameters: alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, gamma-glutamyl transferase, lactate dehydrogenase, lipids, blood urea nitrogen, creatinine, uric acid, sodium, potassium, chloride, carbon dioxide, creatinine phosphokinase, albumin, calcium, magnesium, glucose, phosphate, bicarbonate and total protein were assessed for abnormal PCC values. Data for abnormal parameters (high and low) is presented. Only those parameters for which at least one value of PCC was reported are summarized.
5. Number of Participants With Abnormal Urinalysis Dipstick Results [ Time Frame: Up to Month 48 ]
   Urinalysis parameters: Occult blood, Glucose urine, Ketones, Leukocyte esterase, Nitrite, pH, Protein urine were assessed. Abnormal values for occult blood and ketones were presented as 1+, 2+ and 3+ (the plus sign increases with a higher level of parameters: 1+=slightly positive, 2+=positive, 3+=high positive). Abnormal glucose urine values were presented as 50, 100, 250 and 1000 mg/dL. Abnormal nitrite values were presented as 'positive', and abnormal urine protein values were presented as 30 and 100 mg/dL.
6. Mean Overall Maximum Cytokines Level [ Time Frame: Up to Week 8 ]
   Levels of cytokines: interferon (IFN)-gamma, interleukin (IL)-10, IL-6 and tumor necrosis factor (TNF)-alpha were assessed. One sample was collected at Baseline, on dose Day 1 at 1, 2, 3, and 8 hours post-end of infusion (EOI) and on all other dosing days at pre-dose, and 1, 2, 3, and 8 hour post-EOI. After the completion of dosing, on Day 21 and Week 8, only the IL-10 level was assessed in the cytokine blood sample.
7. Number of Participants With Positive Epstein Barr Virus (EBV) Viral Load [ Time Frame: Up to Month 18 ]
   EBV load was measured using quantitative polymerase chain reaction (PCR) method. If a participant had an EBV viral load of >100,000 copies/10^6 peripheral blood mononuclear cells (c/10^6 PBMC) lymphocytes at any time post-dose, the test was repeated immediately. Data for participants with abnormal viral load is presented.

Secondary Outcome Measures :

1. Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUClast) of Otelixizumab [ Time Frame: At Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour post-start of infusion (SOI). On Dose Day 5, at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI. ]
   Pharmacokinetic (PK) samples were obtained at Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour post-SOI. On Dose Day 5, samples were collected at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI. The lower limit of quantification was 0.019 micrograms per milliliter (µg/mL). The 'PK summary Population' was defined as participants in the 'All Subjects' Population for whom a pharmacokinetic sample was obtained and analyzed, and who received the full scheduled dose, as specified in the protocol. Only those participants available at the specified time points were analyzed.
2. Maximum Plasma Drug Concentration (Cmax) of Otelixizumab [ Time Frame: At Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour post-SOI. On Dose Day 5, at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI. ]
   PK samples were obtained at Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour post-SOI. On Dose Day 5, samples were collected at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI. The lower limit of quantification was 0.019 µg/mL. Only those participants available at the specified time points were analyzed.
3. Time of Last Quantifiable Drug Concentration (Tlast) and Time of Occurrence of Maximum Plasma Drug Concentration (Tmax) of Otelixizumab [ Time Frame: At Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour post-SOI. On Dose Day 5, at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI. ]
   PK samples were obtained at Baseline, and on all dose days except the final dose day, at pre-dose, EOI, and 4 hour SOI. On Dose Day 5, samples were collected at pre-dose, EOI, and 3.5, 4, 5, and 8-10 hour post-SOI. The lower limit of quantification was 0.019 µg/mL. Only those participants available at the specified time points were analyzed.
4. Mean Lymphocytes Subsets (CD19+ B Cells, CD4+CD25hiFoxP3+ T Cells, CD8+CD25+FoxP3+ T Cells) Count [ Time Frame: Day 8 and 28 ]
   One sample was collected at the screening visit and at Baseline. On dose Day 1, samples were collected at EOI and 4 hour post-SOI. On all other dosing days, samples were collected at pre-dose, EOI and 4 hour post-SOI. To obtain absolute counts for each lymphocyte subset (CD19+ B cells, CD4+CD25hiFoxP3+ T cells, CD8+CD25+FoxP3+ T cells) the proportion of total lymphocytes constituting that subset was multiplied by the total count for the same participant at the same time point. The data was collected on Baseline, Days 1 to 8, Days 14, 21, 28, Weeks 6, 8, 10, 12, Months 4, 5, 6, 12, 24, 36 and 48. However data for Days 8 and 28 is presented. The 'Pharmacodynamic (PD) summary population' was defined as participants in the 'All Subjects' Population for whom a PD sample was obtained and analyzed and who received the full scheduled dose, as specified in the protocol.
5. Mean Lymphocytes Subsets (CD4+ T Cells, CD8+ T Cells) Count [ Time Frame: Day 8 and 28 ]
   One sample was collected at the screening visit and at Baseline. On dose Day 1, samples were collected at EOI and 4 hour post-SOI. On all other dosing days, samples were collected at pre-dose, EOI and 4 hour post-SOI. To obtain absolute counts for each lymphocyte subset (CD4+ T cells, CD8+ T cells) the proportion of total lymphocytes constituting that subset was multiplied by the total count for the same participant at the same time point. The data was collected on Baseline, Days 1 to 8, Days 14, 21, 28, Weeks 6, 8, 10, 12, Months 4, 5, 6, 12, 24, 36 and 48. However data for Days 8 and 28 is presented.
6. Mean CD4+/CD8+ Ratio [ Time Frame: Day 8 and 28 ]
   One sample was collected at the screening visit and at Baseline. On dose Day 1, samples were collected at EOI and 4 hour post-SOI. On all other dosing days, samples were collected at pre-dose, EOI and 4 hour post-SOI. CD4+/CD8+ ratio was determined by dividing the absolute count of CD4+ T cells by the absolute count of CD8+ T cells for the same participant at the same time point. The data was collected on Baseline, Days 1 to 8, Days 14, 21, 28, Weeks 6, 8, 10, 12, Months 4, 5, 6, 12, 24, 36 and 48. However data for Days 8 and 28 is presented.
7. Percent Lymphocytes Subsets (CD25+CD8+Tregs) Count [ Time Frame: Day 8 and 28 ]
   One sample was collected at the screening visit and at Baseline. On dose Day 1, samples were collected at EOI and 4 hour post-SOI. On all other dosing days, samples were collected at pre-dose, EOI and 4 hour post-SOI. The data was collected on Baseline, Days 1 to 8, Days 14, 21, 28, Weeks 6, 8, 10, 12, Months 4, 5, 6, 12, 24, 36 and 48. However data for Days 8 and 28 is presented.
8. Amounts of Cell-bound Otelixizumab on CD4+ and CD8+ T Cells [ Time Frame: At the screening visit and at Baseline. On dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months. ]
   Samples were planned to analyze at the screening visit and at Baseline. Further on dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months.
9. Saturation of CD4+ and CD8+ T Cells With Otelixizumab [ Time Frame: At the screening visit and at Baseline. On dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months. ]
   Samples were planned to analyze at the screening visit and at Baseline. Further on dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months.
10. CD3/TCR Complexes on CD4+ and CD8+ T Cells [ Time Frame: At the Screen visit and at Baseline. On dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months. ]
    Samples were planned to analyze at the Screen visit and at Baseline. Further on dose Day 1, at EOI and 4 hour post-SOI. On all other dosing days, at pre-dose, EOI and 4 hour post-SOI up to 48 months.
11. Number of Participants With Detectable Anti-otelixizumab Antiglobulin Response [ Time Frame: Up to Month 48 ]
    Anti-otelixizumab antibody levels were determined by ELISA. Immunogenicity data was not collected for Cohort 5 (5 day dosing) participants.
12. Number of Participants With Use of Analgesics, Antihistamines and IV Hydration as Concomitant Medication During Dosing Days [ Time Frame: Up to Day 8 ]
    Ibuprofen (analgesic) was given orally as follows: 400-800 mg 2 hour before SOI, 400-800 mg 2 hour after SOI, 400-800 mg 6 hour after SOI, and 400-800 mg at bedtime. If ibuprofen was contraindicated, acetaminophen was used in place of ibuprofen. Acetaminophen doses were adjusted so as it did not exceed 1000 mg per 6 hour or 4000 mg per day. A non-sedating antihistamine (cetirizine) was administered approximately 1 hour prior to each infusion of study drug. The recommended initial dose of cetirizine was 5 mg or 10 mg per day in adults and children aged 12 years and older. Normal saline solution was administered IV as needed to maintain hydration.
13. Change From Baseline in Percent Glycosylated Hemoglobin (HbA1c) [ Time Frame: Baseline and up to Month 48 ]
    Participants were seen weekly during the first 4 weeks post-dose and then every other week through Week 12. After Week 12, visits occurred every 1 to 3 months through Month 18, which completes the Core Study up to Month 48 (follow up). Day 1 pre-dose value was considered as Baseline value. Change from Baseline was post-Baseline value minus Baseline value.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 45 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Adults 12 to 45 years old who are in good general health
• Confirmed diagnosis of insulin requiring type 1 diabetes mellitus with good glycemic control
• Measurable C-peptide levels

Exclusion Criteria:

• Females must not be pregnant or lactating and willing to practice contraception
• No prior malignancy, other than non-melanoma skin cancer
• Body Mass Index (BMI) > 32 at screening

Contacts and Locations

Locations

United States, Alabama

GSK Investigational Site

Birmingham, Alabama, United States, 35294

United States, California

GSK Investigational Site

Walnut Creek, California, United States, 94598

United States, Colorado

GSK Investigational Site

Aurora, Colorado, United States, 80045

United States, District of Columbia

GSK Investigational Site

Washington, D.C., District of Columbia, United States, 20037

United States, Florida

GSK Investigational Site

Jacksonville, Florida, United States, 32207

GSK Investigational Site

Pinellas Park, Florida, United States, 33781

United States, Illinois

GSK Investigational Site

Chicago, Illinois, United States, 60637

United States, Maryland

GSK Investigational Site

Baltimore, Maryland, United States, 21201

United States, Massachusetts

GSK Investigational Site

Worcester, Massachusetts, United States, 1655

United States, Michigan

GSK Investigational Site

Kalamazoo, Michigan, United States, 49048

United States, Minnesota

GSK Investigational Site

Minneapolis, Minnesota, United States, 55455

United States, Mississippi

GSK Investigational Site

Gulfport, Mississippi, United States, 39501

United States, Nebraska

GSK Investigational Site

Omaha, Nebraska, United States, 68131

United States, Ohio

GSK Investigational Site

Mentor, Ohio, United States, 44060

United States, South Dakota

GSK Investigational Site

Rapid City, South Dakota, United States, 57701

United States, Texas

GSK Investigational Site

San Antonio, Texas, United States, 78229-4801

Canada, Ontario

GSK Investigational Site

Toronto, Ontario, Canada, M4G 3E8

Sponsors and Collaborators

GlaxoSmithKline

Juvenile Diabetes Research Foundation

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

More Information

Additional Information:

Click here for more information on the TTEDD study 

Study Data/Documents: Statistical Analysis Plan 

Identifier: 115493
For additional information about this study please refer to the GSK Clinical Study Register

Clinical Study Report 

Identifier: 115493
For additional information about this study please refer to the GSK Clinical Study Register

Individual Participant Data Set 

Identifier: 115493
For additional information about this study please refer to the GSK Clinical Study Register

Annotated Case Report Form 

Identifier: 115493
For additional information about this study please refer to the GSK Clinical Study Register

Study Protocol 

Identifier: 115493
For additional information about this study please refer to the GSK Clinical Study Register

Informed Consent Form 

Identifier: 115493
For additional information about this study please refer to the GSK Clinical Study Register

Dataset Specification 

Identifier: 115493
For additional information about this study please refer to the GSK Clinical Study Register

Publications:

Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005 Jun 23;352(25):2598-608. doi: 10.1056/NEJMoa043980.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00451321
• Other Study ID Numbers: 115493; TRX4005 ( Other Identifier: Tolerx )
• First Posted: March 23, 2007
• Results First Posted: November 13, 2017
• Last Update Posted: November 13, 2017
• Last Verified: October 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Keywords provided by GlaxoSmithKline:

type 1 diabetes mellitus; diabetes mellitus type 1; type 1 diabetes; diabetes mellitus; diabetes

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases