Clinical trial NCT00678886: Trial of Otelixizumab for Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-1
Official title: Durable-Response Therapy Evaluation For Early or New-Onset Type 1 Diabetes - DEFEND
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 1
Keywords: Type 1 diabetes
new onset type 1 diabetes
T1DM
Type l diabetes
juvenile diabetes
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Juvenile Diabetes Research Foundation
First posted: 2008-05-16
Enrollment: 272
Sex: ALL
Minimum age (years): 12
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in 2-hour Mixed Meal Stimulated C-peptide Area Under Curve [AUC] (Normalized for 120-minute Time Interval) at Month 12
timeFrame: Baseline (0-120 minutes on Day 1) and Month 12 (0-120 minutes)
Secondary outcomes:
measure: Number of Participants Who Were Responders for (Glycosylated Hemoglobin) HbA1c/Insulin Use Response at Week 12 and Months 6 and 12
timeFrame: Week 12 and Months 6 and 12
measure: Mean Daily Insulin Use at Week 12 and Months 6 and 12.
timeFrame: Week 12 and Months 6 and 12.
measure: HbA1c Level at Week 12 and Months 6 and 12
timeFrame: Week 12 and Months 6 and 12
measure: Number of Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12
timeFrame: Upto Month 12
measure: Number of Participants With Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12
timeFrame: Upto Month 12
measure: Number of Hypoglycemic Excursions (<=70 mg/dL) With Most Complete Glucose at Week 12 and Months 6 and 12.
timeFrame: Week 12 and Months 6 and 12.
measure: Magnitude of Greatest Hypoglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12.
timeFrame: Week 12 and Months 6 and 12.
measure: Number of Participants With Hypoglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12
timeFrame: Week 12 and Months 6 and 12
measure: Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12.
timeFrame: Week 12 and Months 6 and 12
measure: Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12.
timeFrame: Week 12 and Months 6 and 12.
measure: Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12
timeFrame: Week 12 and Months 6 and 12
measure: Change From Baseline in Average Daily Risk Range (ADRR) at Week 12 and Months 6 and 12.
timeFrame: Baseline (Day 1) and Week 12, Months 6 and 12.
measure: Composite Rank Summary for HbA1c and Exogenous Insulin Use at Month 6 and Month 12
timeFrame: Month 6 and 12
measure: Composite Rank Summary for C-Peptide AUC, HbA1c and Exogenous Insulin Use at Month 6 and Month 12
timeFrame: Month 6 and 12
measure: 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
timeFrame: Day 1, Day 4, Day 8
measure: 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
timeFrame: Baseline (pre-dose on Day 1) and up to 12 Months
measure: Percent Change From Baseline in Cell-bound Otelixizumab on CD4+ T Cells at Day 1, Day 4, Day 8
timeFrame: Baseline (pre-dose on Day 1), Day 4 and Day 8
measure: Percent Change From Baseline in CD3/TCR Saturation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8
timeFrame: Baseline (Pre-dose Day 1), Day 4, Day 8
measure: Percent Change From Baseline in CD3/TCR Modulation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8
timeFrame: Baseline (Pre-dose Day 1), Day 4, Day 8
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Little Rock
country: United States
facility: GSK Investigational Site
state: Arkansas
city: Costa Mesa
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Orange
country: United States
facility: GSK Investigational Site
state: California
city: Riverside
country: United States
facility: GSK Investigational Site
state: California
city: Santa Ana
country: United States
facility: GSK Investigational Site
state: California
city: Torrance
country: United States
facility: GSK Investigational Site
state: California
city: Walnut Creek
country: United States
facility: GSK Investigational Site
state: California
city: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: Washington, D.C.
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Boca Raton
country: United States
facility: GSK Investigational Site
state: Florida
city: Jupiter
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Pembroke Pines
country: United States
facility: GSK Investigational Site
state: Florida
city: Trinity
country: United States
facility: GSK Investigational Site
state: Florida
city: Winter Park
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Honolulu
country: United States
facility: GSK Investigational Site
state: Hawaii
city: Boise
country: United States
facility: GSK Investigational Site
state: Idaho
city: Idaho Falls
country: United States
facility: GSK Investigational Site
state: Idaho
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Kansas
city: Topeka
country: United States
facility: GSK Investigational Site
state: Kansas
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Worcester
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Kalamazoo
country: United States
facility: GSK Investigational Site
state: Michigan
city: Gulfport
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Columbia
country: United States
facility: GSK Investigational Site
state: Missouri
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Missouri
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Omaha
country: United States
facility: GSK Investigational Site
state: Nebraska
city: Neptune City
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Buffalo
country: United States
facility: GSK Investigational Site
state: New York
city: Mineola
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Rochester
country: United States
facility: GSK Investigational Site
state: New York
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Dayton
country: United States
facility: GSK Investigational Site
state: Ohio
city: Mentor
country: United States
facility: GSK Investigational Site
state: Ohio
city: Tulsa
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Eugene
country: United States
facility: GSK Investigational Site
state: Oregon
city: Portland
country: United States
facility: GSK Investigational Site
state: Oregon
city: Langhorne
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Charleston
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Rapid City
country: United States
facility: GSK Investigational Site
state: South Dakota
city: Chattanooga
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Hurst
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Schertz
country: United States
facility: GSK Investigational Site
state: Texas
city: Ogden
country: United States
facility: GSK Investigational Site
state: Utah
city: Tacoma
country: United States
facility: GSK Investigational Site
state: Washington
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Oakville
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Smiths Falls
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Pointe-Claire
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Arhus C
country: Denmark
facility: GSK Investigational Site
city: Tampere
country: Finland
facility: GSK Investigational Site
city: Turku
country: Finland
facility: GSK Investigational Site
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Bad Nauheim
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Bad Lauterberg
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Latina
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Monserrato
country: Italy
facility: GSK Investigational Site
state: Sardegna
city: Palermo
country: Italy
facility: GSK Investigational Site
state: Sicilia
city: Milano
country: Italy
facility: GSK Investigational Site
city: Roma
country: Italy
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Gerona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Sant Joan
country: Spain
facility: GSK Investigational Site
city: Tarrasa, Barcelona
country: Spain
facility: GSK Investigational Site
city: Göteborg
country: Sweden
facility: GSK Investigational Site
city: Halmstad
country: Sweden
facility: GSK Investigational Site
city: Harnosand
country: Sweden
facility: GSK Investigational Site
city: Karlskrona
country: Sweden
facility: GSK Investigational Site
city: Karlstad
country: Sweden
facility: GSK Investigational Site
city: Kristianstad
country: Sweden
facility: GSK Investigational Site
city: Motala
country: Sweden
facility: GSK Investigational Site
city: Stockholm
country: Sweden
facility: GSK Investigational Site
city: Umeå
country: Sweden
facility: GSK Investigational Site
city: Växjö
country: Sweden
facility: GSK Investigational Site
city: Bath
country: United Kingdom
facility: GSK Investigational Site
state: Somerset
city: Blackburn
country: United Kingdom
facility: GSK Investigational Site
city: Bristol
country: United Kingdom
facility: GSK Investigational Site
city: Hull
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Newcastle upon Tyne
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
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. No abstract available.