TRX4 Monoclonal Antibody in Type 1 Diabetes (T1 DM)

Diabetes Mellitus, Type 1 Clinical Trial

— TTEDD  

Official title:

TRX4 Therapeutic Evaluation of Different Multi-Dose Regimens in Type 1 Diabetes Mellitus (TTEDD)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00451321
• Other study ID #: 115493
• Secondary ID: TRX4005
• Status: Terminated
• Phase: Phase 2
• First received: March 21, 2007
• Last updated: October 11, 2017
• Start date: July 31, 2006
• Est. completion date: December 1, 2011

Study information

• Verified date: October 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 88
• Est. completion date: December 1, 2011
• Est. primary completion date: December 1, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

Drug:
• Otelixizumab
Infusion

Locations

Country	Name	City	State
Canada	GSK Investigational Site	Toronto	Ontario
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Gulfport	Mississippi
United States	GSK Investigational Site	Jacksonville	Florida
United States	GSK Investigational Site	Kalamazoo	Michigan
United States	GSK Investigational Site	Mentor	Ohio
United States	GSK Investigational Site	Minneapolis	Minnesota
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Pinellas Park	Florida
United States	GSK Investigational Site	Rapid City	South Dakota
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	Walnut Creek	California
United States	GSK Investigational Site	Washington, D.C.	District of Columbia
United States	GSK Investigational Site	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
GlaxoSmithKline	Juvenile Diabetes Research Foundation

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	Up to Month 24
Primary	Number of Participants With Cytokine Release AE	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.	Up to Month 24
Primary	Number of Participants With Abnormal Hematology Values of Potential Clinical Concern (PCC)	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.	Up to Month 48
Primary	Number of Participants With Abnormal Clinical Chemistry Values of PCC	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.	Up to Month 48
Primary	Number of Participants With Abnormal Urinalysis Dipstick Results	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.	Up to Month 48
Primary	Mean Overall Maximum Cytokines Level	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.	Up to Week 8
Primary	Number of Participants With Positive Epstein Barr Virus (EBV) Viral Load	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.	Up to Month 18
Secondary	Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUClast) of Otelixizumab	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.	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.
Secondary	Maximum Plasma Drug Concentration (Cmax) of Otelixizumab	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.	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.
Secondary	Time of Last Quantifiable Drug Concentration (Tlast) and Time of Occurrence of Maximum Plasma Drug Concentration (Tmax) of Otelixizumab	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.	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.
Secondary	Mean Lymphocytes Subsets (CD19+ B Cells, CD4+CD25hiFoxP3+ T Cells, CD8+CD25+FoxP3+ T Cells) Count	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.	Day 8 and 28
Secondary	Mean Lymphocytes Subsets (CD4+ T Cells, CD8+ T Cells) Count	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.	Day 8 and 28
Secondary	Mean CD4+/CD8+ Ratio	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.	Day 8 and 28
Secondary	Percent Lymphocytes Subsets (CD25+CD8+Tregs) Count	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.	Day 8 and 28
Secondary	Amounts of Cell-bound Otelixizumab on CD4+ and CD8+ T Cells	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.	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.
Secondary	Saturation of CD4+ and CD8+ T Cells With Otelixizumab	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.	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.
Secondary	CD3/TCR Complexes on CD4+ and CD8+ T Cells	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.	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.
Secondary	Number of Participants With Detectable Anti-otelixizumab Antiglobulin Response	Anti-otelixizumab antibody levels were determined by ELISA. Immunogenicity data was not collected for Cohort 5 (5 day dosing) participants.	Up to Month 48
Secondary	Number of Participants With Use of Analgesics, Antihistamines and IV Hydration as Concomitant Medication During Dosing Days	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.	Up to Day 8
Secondary	Change From Baseline in Percent Glycosylated Hemoglobin (HbA1c)	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.	Baseline and up to Month 48