Trial of Otelixizumab for Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-1

Diabetes Mellitus, Type 1 Clinical Trial

— DEFEND-1  

Official title:

Durable-Response Therapy Evaluation For Early or New-Onset Type 1 Diabetes - DEFEND

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00678886
• Other study ID #: 115495
• Secondary ID: TRX4006
• Status: Completed
• Phase: Phase 3
• First received: May 13, 2008
• Last updated: September 5, 2017
• Start date: July 29, 2008
• Est. completion date: January 31, 2012

Study information

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

Clinical Trial Summary

The purpose of this study is to find out if an 8-day series of otelixizumab infusions leads to greater improvement in insulin secretion as compared with placebo infusion. Insulin secretion will be assessed using mixed meal-stimulated C-peptide.

Subjects will be assigned to receive either otelixizumab or placebo at a ratio of 2:1 (2/3 otelixizumab, 1/3 placebo). These study agents will be administered as an addition to insulin, diet, and other physician determined standard of care treatments.

DEFEND-1 is now closed to enrollment.

DEFEND-2 will begin early in 2010. It is very similar to DEFEND-1 and will again require subjects with new onset type 1 diabetes. Please check back here for more details.

In the meantime, established and new onset type 1 diabetes patients in North America are welcome to consider the TTEDD study:

http://www.clinicaltrials.gov/ct2/show/NCT00451321?term=TTEDD&rank=1

Description:

The following visits are required:

• Screening Visits: 2 to 3 appointments will be conducted to determine eligibility. At 2 of these visits participants will drink a liquid meal and have blood tests done over the post-meal period.

• Dosing Visits: 8 outpatient visits on consecutive days, each lasting about 4-6 hours.

• Follow-up Visits: weekly for the first month, then every 2 weeks for 3 months, followed by monthly visits through 1 year. There will be 3 visits in the second year.

• The total duration of the study is 2 years.

• Glucose test strips, glucose monitors and PDAs to record insulin will be provided to all study subjects for the duration fo the study. Frequent glycemic monitoring will occur through lab testing and blood glucose self-monitoring to help facilitate tight glycemic control in all subjects.

Other known NCT identifiers

• NCT00893022

Recruitment information / eligibility

• Status: Completed
• Enrollment: 272
• Est. completion date: January 31, 2012
• Est. primary completion date: January 31, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 45 Years

Eligibility

Inclusion Criteria:

• Ages 12-45

• Diagnosis of diabetes mellitus, consistent with ADA criteria

• No more than 90 days between diagnosis and administration of study compounds

• Requires insulin for type 1 diabetes mellitus, or has required insulin at some time between diagnosis and administration of study compounds.

• Stimulated C-peptide level greater than 0.20 nmol/L and less than or equal to 3.50 nmol/L

• Positive for one or more of the autoantibodies typically associated with T1DM:

antibody to glutamic acid decarboxylase (anti-GAD); antibody to protein tyrosine phosphatase-like protein (anti-IA-2); zinc transporter autoantibodies (ZNT8); insulin autoantibodies (IAA). A subject who is positive for insulin autoantibodies (IAA) and negative for the other autoantibodies will only be eligible if the subject has used insulin for less than 7 days total.

Exclusion Criteria:

• Other, significant medical conditions based on the study doctor's evaluation

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

Biological:
• otelixizumab infusion plus physician determined standard of care
infusion
• placebo infusion plus physician determined standard of care
infusion

Locations

Country	Name	City	State
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Oakville	Ontario
Canada	GSK Investigational Site	Pointe-Claire	Quebec
Canada	GSK Investigational Site	Smiths Falls	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Denmark	GSK Investigational Site	Arhus C
Finland	GSK Investigational Site	Tampere
Finland	GSK Investigational Site	Turku
Germany	GSK Investigational Site	Bad Lauterberg	Niedersachsen
Germany	GSK Investigational Site	Bad Nauheim	Hessen
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg
Italy	GSK Investigational Site	Latina	Lazio
Italy	GSK Investigational Site	Milano
Italy	GSK Investigational Site	Monserrato	Sardegna
Italy	GSK Investigational Site	Palermo	Sicilia
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Roma
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Gerona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Sant Joan
Spain	GSK Investigational Site	Tarrasa, Barcelona
Sweden	GSK Investigational Site	Göteborg
Sweden	GSK Investigational Site	Halmstad
Sweden	GSK Investigational Site	Harnosand
Sweden	GSK Investigational Site	Karlskrona
Sweden	GSK Investigational Site	Karlstad
Sweden	GSK Investigational Site	Kristianstad
Sweden	GSK Investigational Site	Motala
Sweden	GSK Investigational Site	Stockholm
Sweden	GSK Investigational Site	Umeå
Sweden	GSK Investigational Site	Växjö
United Kingdom	GSK Investigational Site	Bath	Somerset
United Kingdom	GSK Investigational Site	Blackburn
United Kingdom	GSK Investigational Site	Bristol
United Kingdom	GSK Investigational Site	Hull
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Newcastle upon Tyne
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Baltimore	Kansas
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Boca Raton	Florida
United States	GSK Investigational Site	Boise	Idaho
United States	GSK Investigational Site	Buffalo	New York
United States	GSK Investigational Site	Charleston	South Carolina
United States	GSK Investigational Site	Chattanooga	Tennessee
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Columbia	Missouri
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Costa Mesa	California
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Dayton	Ohio
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Eugene	Oregon
United States	GSK Investigational Site	Gulfport	Mississippi
United States	GSK Investigational Site	Honolulu	Hawaii
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Hurst	Texas
United States	GSK Investigational Site	Idaho Falls	Idaho
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Jupiter	Florida
United States	GSK Investigational Site	Kalamazoo	Michigan
United States	GSK Investigational Site	Kansas City	Missouri
United States	GSK Investigational Site	Langhorne	Pennsylvania
United States	GSK Investigational Site	Little Rock	Arkansas
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Memphis	Tennessee
United States	GSK Investigational Site	Mentor	Ohio
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Mineola	New York
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	Neptune City	New Jersey
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Ogden	Utah
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Orange	California
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Pembroke Pines	Florida
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Portland	Oregon
United States	GSK Investigational Site	Rapid City	South Dakota
United States	GSK Investigational Site	Riverside	California
United States	GSK Investigational Site	Rochester	New York
United States	GSK Investigational Site	Saint Louis	Missouri
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	Santa Ana	California
United States	GSK Investigational Site	Schertz	Texas
United States	GSK Investigational Site	Tacoma	Washington
United States	GSK Investigational Site	Topeka	Kansas
United States	GSK Investigational Site	Torrance	California
United States	GSK Investigational Site	Trinity	Florida
United States	GSK Investigational Site	Tulsa	Oklahoma
United States	GSK Investigational Site	Walnut Creek	California
United States	GSK Investigational Site	Washington, D.C.	District of Columbia
United States	GSK Investigational Site	Winter Park	Florida
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,  Denmark,  Finland,  Germany,  Italy,  Spain,  Sweden,  United Kingdom, 

References & Publications (2)

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

You S, Candon S, Kuhn C, Bach JF, Chatenoud L. CD3 antibodies as unique tools to restore self-tolerance in established autoimmunity their mode of action and clinical application in type 1 diabetes. Adv Immunol. 2008;100:13-37. doi: 10.1016/S0065-2776(08)00802-X. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in 2-hour Mixed Meal Stimulated C-peptide Area Under Curve [AUC] (Normalized for 120-minute Time Interval) at Month 12	Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from Time 0 to 120 minutes, calculated using the trapezoidal rule. This reported AUC was normalized for time interval by dividing it by 120 minutes. This normalized AUC was calculated for each participant at Baseline, Week 12, and at Months 6, 12, 18, and 24. Data has been presented for meal stimulated C-peptide Area under assessment performed at Month 12. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Month 12.	Baseline (0-120 minutes on Day 1) and Month 12 (0-120 minutes)
Secondary	Number of Participants Who Were Responders for (Glycosylated Hemoglobin) HbA1c/Insulin Use Response at Week 12 and Months 6 and 12	A participant was considered a responder if, at the given time point, the participant had HbA1c<= 6.5%, and mean daily insulin use over 7 consecutive days < 0.5 international units per kilogram per day (IU/kg/day) during the 2 weeks preceding the visit. Data has been presented from number of participants with their percentages who were responders at Week 12 and Months 6 and 12.	Week 12 and Months 6 and 12
Secondary	Mean Daily Insulin Use at Week 12 and Months 6 and 12.	Participants recorded their daily insulin use in their electronic diaries. In particular, insulin was recorded thoroughly and accurately for at least 7 consecutive days during the 2 weeks before the visits at Baseline, Week 12, and Months 6 and 12. During each of these visits, the investigator/designee accessed the invivodata DiaryPRO web site to review insulin-use data for the previous 2-week period to ensure completeness. If errors/gaps were identified (e.g., if the participant did not take insulin and not entered 0 units), the investigator/designee recorded the missing data from participant recall using a data clarification form (DCF). Paper diary to collect insulin use, were reviewed for completeness. Any missing data that could be recalled by the participant was entered. If the participant did not record any insulin use during the 2-week period before the visit, the site obtained an insulin use history for the previous 7 days and calculated the average daily insulin dose.	Week 12 and Months 6 and 12.
Secondary	HbA1c Level at Week 12 and Months 6 and 12	HbA1c levels were recorded at Screening, Baseline (Day 1), Day 28, Week 8, Week 12, Months 4 to 12 and Month 24. Data has been presented for HbA1c levels at Week 12 and Months 6 and 12.	Week 12 and Months 6 and 12
Secondary	Number of Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12	Hypoglycemic events reported by participants were classified as defined by the American Diabetes Association (ADA) Workgroup on Hypoglycemia as follows: Severe hypoglycemia: an event requiring assistance of another person to actively administer carbohydrate, glucagon/other resuscitative actions, documented symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration(PGC)<=70 mg/dL, asymptomatic hypoglycemia: an event not accompanied by typical symptoms of hypoglycemia but with a measured PGC<=70 mg/dL,probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia are not accompanied by a plasma glucose determination, but were presumably caused by a PGC<=70 mg/dL and relative hypoglycemia: an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia, and interprets the symptoms as indicative of hypoglycemia, but with a measured PGC>70 mg/dL.	Upto Month 12
Secondary	Number of Participants With Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12	Hypoglycemic events reported by participants were classified as defined by the ADA Workgroup on Hypoglycemia as Severe hypoglycemia: an event requiring assistance of another person to actively administer carbohydrate, glucagon/other resuscitative actions, documented symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration (PGC)<=70 mg/dL, asymptomatic hypoglycemia: an event not accompanied by typical symptoms of hypoglycemia but with a measured PGC<=70 mg/dL,probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia are not accompanied by a plasma glucose determination, but were presumably caused by a PGC<=70 mg/dL and relative hypoglycemia: an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia, and interprets the symptoms as indicative of hypoglycemia, but with a measured PGC>70 mg/dL. Only categories with values are presented.	Upto Month 12
Secondary	Number of Hypoglycemic Excursions (<=70 mg/dL) With Most Complete Glucose at Week 12 and Months 6 and 12.	The event frequency of glucose measurements that were hypoglycemic excursions were calculated per participant basis, using the number of occurrences where blood glucose was less than or equal to 70 mg/dL. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected.	Week 12 and Months 6 and 12.
Secondary	Magnitude of Greatest Hypoglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12.	The greatest hypoglycemic excursions during an interval was calculated as 70 mg/dL minus the lowest recorded glucose level in the interval. If a participant had data recorded during the interval but did not have a value below 70 mg/dL, the participants greatest hypoglycemic excursion for that interval was 0 mg/dL.; Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected.	Week 12 and Months 6 and 12.
Secondary	Number of Participants With Hypoglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12	Percentage of hypoglycemic excursions was calculated as the total number of observations that exceed the hypoglycemic excursion boundary (i.e.<= 70 mg/dL) divided by the total number of glucose measurements recorded in a time interval for the intervals: Baseline to Week 12, post-Week 12 to Month 6, post-Month 6 to Month 12. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected. Data has been presented for number of participants with their percentages having hypoglycemic excursion.	Week 12 and Months 6 and 12
Secondary	Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12.	The event frequency of glucose measurements that were hyperglycemic excursions were calculated on a per participant basis using the number of occurrences where blood glucose was greater than the hyperglycemic tolerance limit. There were 3 hyperglycemic tolerance limits considered: 200 mg/dL, 130 mg/dL and 100 mg/dL. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected.	Week 12 and Months 6 and 12
Secondary	Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12.	The greatest hyperglycemic excursions during an interval was calculated as the largest recorded glucose level in the interval minus the hyperglycemic tolerance limit value (HGTLV). If a participant had data recorded during the interval but did not have a value above the HGTLV, the participants greatest hyperglycemic excursion for that interval was 0 mg/dL. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected.	Week 12 and Months 6 and 12.
Secondary	Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12	Percentage of hyperglycemic excursions was calculated as the total number of observations that exceed the hyperglycemic excursion boundary (i.e. > HGTLV) divided by the total number of glucose measurements recorded in a time interval for the intervals: Baseline to Week 12, post-Week 12 to Month 6, post-Month 6 to Month 12. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected. Data for number of participants with their percentages are presented.	Week 12 and Months 6 and 12
Secondary	Change From Baseline in Average Daily Risk Range (ADRR) at Week 12 and Months 6 and 12.	Average daily risk range is a measure for evaluation of blood glucose variability that was designed to be equally sensitive to hypoglycemia and hyperglycemia. The ADRR was assessed over 30-day periods prior to Baseline and at key visits Week 12 and Months 6 and 12. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Week 12 and Months 6 and 12.	Baseline (Day 1) and Week 12, Months 6 and 12.
Secondary	Composite Rank Summary for HbA1c and Exogenous Insulin Use at Month 6 and Month 12	O'Brien mean rank analyses was performed on a two-part composite of the baseline-adjusted HbA1c level and the baseline-adjusted mean total daily insulin use per kg body weight in the otelixizumab group compared with the placebo group at Months 6, 12. For the O'Brien mean rank analysis at a particular time point, adjusted HbA1c values (for both treatment groups together) was ranked from smallest to largest, and adjusted mean daily insulin use values were ranked from smallest to largest. For each participant, the HbA1c and insulin use ranks were added together, producing a composite rank. A treatment comparison test was then performed on the composite ranks.	Month 6 and 12
Secondary	Composite Rank Summary for C-Peptide AUC, HbA1c and Exogenous Insulin Use at Month 6 and Month 12	O'Brien analyses will be performed on a three-part composite of HbA1c level, C-peptide AUC, and mean daily Insulin use in the otelixizumab group compared with the placebo group at Months 6 and12. For the O'Brien mean rank analysis at a particular time point, HbA1c and insulin use will be ranked from smallest to largest, and C-peptide AUC will be ranked from largest to smallest. For each participant, the C-Peptide AUC, ranks for HbA1c and insulin use were added together, producing a composite rank. A treatment comparison test was then performed on the composite ranks.	Month 6 and 12
Secondary	Change From Baseline in Level of Cytokines Interleukin (IL-6), IL-10 and Tumor Necrosis Factor-alpha (TNF-a) at Day 1, Day 4, Day 8	Levels of cytokine (TNFa, IL-6, IL-10) were measured at Baseline and at 2 hours after end of infusion (EOI) on Day 1, Day 4, Day 8 . Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Day 1, Day 4 and Day 8.	Day 1, Day 4, Day 8
Secondary	Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12	Blood samples were drawn for lymphocyte subset evaluations at Baseline and at 2hours after EOI on Day 4, pre-dose and after E0I on Day 8, Day 14, Day 21, Day 28, Week 6, Week 8, Week 10, Week 12, Month 6 and Month 12. Percentages of relevant lymphocyte subsets were determined by flow cytometry. The lymphocyte subsets assessed included CD8+CD25+ T lymphocytes, as well as the subsets of lymphocytes of these type that were positive for FoxP3, a protein that was expressed at high levels in the cytoplasm of regulatory T cells. CD4+CD25hiFoxP3+ T lymphocytes, a cell type was of interest because it played a regulatory role in T1DM. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment.	Baseline (pre-dose on Day 1) and up to 12 Months
Secondary	Percent Change From Baseline in Cell-bound Otelixizumab on CD4+ T Cells at Day 1, Day 4, Day 8	The amount of cell-bound otelixizumab was determined by flow cytometry. The extent of T cell receptor alpha beta (TCRaß) expression was determined using an antibody that bound to TCRaß but did not compete with otelixizumab for binding sites at the expected range of concentrations. The MESF of the anti-TCRaß antibody was used to quantify the number of CD3/TCR complexes present on T cells. Free otelixizumab binding sites (sites not occupied by otelixizumab) were detected by staining with biotinylated otelixizumab. The MESF of bound biotinylated otelixizumab was directly proportional to the availability of free otelixizumab binding sites. MESF of bound antibody on CD4+ T cells was a direct measurement of cell-bound otelixizumab on CD4+ T cells. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Day 1, Day 4 and Day 8.	Baseline (pre-dose on Day 1), Day 4 and Day 8
Secondary	Percent Change From Baseline in CD3/TCR Saturation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8	The extent of saturation of CD3/TCR receptors on CD4+ and CD8+ lymphocytes was determined by flow cytometry. The extent of TCRaß expression was determined using an antibody that bound to TCRaß but did not compete with otelixizumab for binding sites at the expected range of concentrations. The MESF of the anti-TCRaß antibody was used to quantify the number of CD3/TCR complexes present on T cells. The MESF of bound biotinylated otelixizumab was directly proportional to the availability of free otelixizumab binding sites. MESF of free CD3 sites on CD4+ T cells and CD8+ T cells was direct measurement of saturation of the CD3/TCR complex on CD4+ T cells and CD8+ T cells. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Day 1, Day 4 and Day 8.	Baseline (Pre-dose Day 1), Day 4, Day 8
Secondary	Percent Change From Baseline in CD3/TCR Modulation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8	The extent of modulation of CD3/TCR receptors on CD4+ and CD8+ lymphocytes was determined by flow cytometry. The extent of TCRaß expression was determined using an antibody that bound to TCRaß but did not compete with otelixizumab for binding sites at the expected range of concentrations. The MESF of the anti-TCRaß antibody was used to quantify the number of CD3/TCR complexes present on T cells. The MESF of bound biotinylated otelixizumab was directly proportional to the availability of free otelixizumab binding sites.CD3/TCR complexes on CD4+ and CD8+ T cells were detected with a non-competing antibody. Changes in the MESF of TCR expression was a direct measurement of TCR modulation. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Day 1, Day 4 and Day 8.	Baseline (Pre-dose Day 1), Day 4, Day 8

External Links

•   Website containing information on DEFEND study