START: Study of Antithymocyte Globulin for Treatment of New-onset T1DM

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00515099
• Collaborator: Immune Tolerance Network (ITN) (Other)
• Enrollment: 58
• Locations: 9
• Arms: 2
• Duration (Months): 71
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Antithymocyte globulin (e.g., Thymoglobulin®) is an antibody preparation that is commonly used to treat and prevent organ transplant rejection. The START trial aims to determine whether antithymocyte globulin (ATG) treatment can halt the progression of newly diagnosed type 1 diabetes when given within 12 weeks of disease diagnosis.

Condition or Disease	Intervention/Treatment	Phase
New-onset Type 1 Diabetes Mellitus	Drug: Antithymocyte globulin; Drug: Placebo	Phase 2

Detailed Description

Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which the immune system mistakenly attacks the insulin-producing beta cells in the pancreas. Without these cells, the body cannot maintain proper blood glucose levels in response to daily activities, such as eating or exercise. Generally, at the time someone is diagnosed with T1DM, not all of a person's beta cells have been destroyed - between 15-40% remain healthy and are still able to produce insulin. Importantly, even small amounts of naturally produced insulin can improve blood sugar control, make daily management of diabetes less complicated, and reduce the risk of long term complications. Preserving the remaining precious beta cells is therefore the goal of the START trial.

The medication being tested in the START trial is antithymocyte globulin (e.g., Thymoglobulin®), a mixture of specialized proteins called antibodies. ATG attaches itself to white blood cells known as T cells, some of which are responsible for the immune system's attack on beta cells that occurs in T1DM. ATG can change how T cells work, and can eliminate a large proportion of the T cells from the bloodstream temporarily. Treatment of new onset T1DM with ATG is therefore expected to alter the behavior of the T cells to halt their attack, and also reduce T cell numbers, so that new T cells that grow in their place will learn to accept the beta cells, rather than attacking them.

Following an initial screening appointment, eligible participants will be randomly assigned to one of two groups: the Experimental Group will receive the study treatment while the Control Group that will receive placebo. Each participant has a 2 in 3 chance of being assigned to the treatment group, and a 1 in 3 chance of being assigned to the placebo. The START trial is a blinded study, so neither participants nor study physicians will know to which group an individual has been assigned. All participants will receive intensive diabetes management. Participants in both groups will be admitted to the hospital for 5-8 days to receive infusions of either the study drug or placebo.

The duration of the study is 2 years. Participants will have 8 follow-up appointments in the first year and 4 visits in the second year. Most of these visits will last 1- 2 hours. A review of interval health, a physical exam, an assessment of diabetes control including recent 5 day insulin use and blood sugar (e.g., glucose) testing, and blood collection for laboratory testing will occur at each visit. Four of the visits will last about 5 hours, during which participants will undergo mixed-meal tolerance testing (MMTT). This involves drinking a special drink, similar to a milkshake, and having blood specimens taken over a 4-hour period.

Subjects will be reimbursed for travel and parking expenses, and will receive compensation for their participation in the longer mixed meal tolerance test visits.

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Effect of Antithymocyte Globulin on Preserving Beta Cell Function in New Onset Type 1 Diabetes Mellitus
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Antithymocyte globulin This group received a total of 6.5 mg/kg of antithymocyte globulin (e.g., Thymoglobulin®) divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	Drug: Antithymocyte globulin; Daily 4-day escalating dose; Other Names: ATG Thymoglobulin® Rabbit antithymocyte globulin RATG
Placebo Comparator: Placebo This group received a saline solution to match the Thymoglobulin doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	Drug: Placebo; Daily 4-day saline solution; Other Names: Inactive drug (pharmacologically) Saline solution

Outcome Measures

Primary Outcome Measures

1. 2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) [Baseline (Pre-treatment initiation), Month 12]

   C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy primary endpoint.

Secondary Outcome Measures

1. 4-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT) [Baseline (Pre-treatment initiation), Month 12]

   C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 4-hour (e.g., 240 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy endpoint.

2. Insulin Use in Units Per Kilogram Body Weight Per Day [Baseline (Pre-treatment), Months 12 and 24]

   The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity.

3. Number of Participants Who Are Exogenous-Insulin-Free [Baseline (Pre-treatment), Months 12 , 18, and 24]

   The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity.

4. Number of Participants With Major Hypoglycemic Event(s) Post Treatment Randomization/Initiation [Baseline (Pre-treatment), Months 12 , and 24]

   Major hypoglycemic events are defined as a glucose concentration <55 mg/dL (grades 2-5, NCI-CTCAE version 3.0), or clinically: involving seizure(s) or involving loss of consciousness (coma), or requiring assistance from another individual in order to recover.

5. 2-Hour and 4-Hour C-peptide Area Under the Curve (AUC) Results in Response to Standardized Mixed Meal Tolerance Test (MMTT) [Baseline (Pre-treatment), Month 24]

   C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) and 4-hour (e.g., 240 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the CDER at the FDA as a valid efficacy endpoint.

6. Hemoglobin A1c [Baseline (Pre-treatment), Months 12 and 24]

   Glycosylated hemoglobin (HbA1c) is a measure of the average plasma concentration of blood sugar (glucose) over the previous three months and measures the level of optimal management of underlying disease. An HbA1c of <\=5.6% is considered normal. HbA1c of 6.5% or higher is typical for individuals with Type 1 Diabetes mellitus (T1DM).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 35 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of type 1 diabetes (according to American Diabetes Association [ADA] criteria) within100 days of enrollment

• Positive for one or more autoantibodies (anti-glutamic acid decarboxylase [GAD], anti-insulin, or IA-2 autoantibodies)

• Peak stimulated C-peptide level >0.4 pmol/mL or >1.2ng/mL following an MMTT

• Serologic evidence of prior Epstein-Barr virus (EBV) infection (EBV seropositive)

• Willing to use acceptable forms of contraception

Exclusion Criteria:

• Any sign of active infection (e.g., hepatitis, tuberculosis, EBV, cytomegalovirus (CMV), or toxoplasmosis) at screening

• Positive for human immunodeficiency virus (HIV), tuberculosis, or hepatitis B surface antigen (HBsAg) at screening

• Prior history of any significant cardiac disease, such as congestive heart failure, arrhythmia, or structural defects, or suspicion thereof

• Use of glucocorticoids in the 28 days prior to study entry; or topical use of glucocorticoids

• Use of diabetes medications (other than insulin) that may affect glucose homeostasis, such as metformin, sulfonylureas, thiazolidinediones, or amylin

• Evidence of liver dysfunction

• Evidence of kidney disease

• Pregnancy or plan to become pregnant

• Leukopenia (<3,000 leukocytes/µL), neutropenia (<1,500neutrophils/µL), lymphopenia (<800 lymphocytes/µL), or thrombocytopenia (<125,000 platelets/µL).

• Prior treatment with rabbit ATG or known hypersensitivity or exposure to rabbit sera-derived products

• Vaccination with a live virus within the last 6 weeks before enrollment

• Prior or current therapy that is known to cause a significant, ongoing change in the course of T1DM or immunologic status

• Any condition that may compromise study participation or may confound the interpretation of the study results

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital/USC School of Medicine	Los Angeles	California	United States	90027
2	Children's Hospital and Research Center	Oakland	California	United States	92609
3	UCSD/San Diego Children's Hospital	San Diego	California	United States	92123
4	Diabetes Center at UCSF	San Francisco	California	United States	94143
5	Barbara Davis Center for Childhood Diabetes, University of Colorado	Aurora	Colorado	United States	80010
6	Emory Children's Center	Atlanta	Georgia	United States	30322
7	University of Minnesota	Minneapolis	Minnesota	United States	55455
8	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
9	University of Pennsylvania/Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Immune Tolerance Network (ITN)

Investigators

• Principal Investigator: Stephen Gitelman, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• National Institute of Allergy and Infectious Diseases (NIAID)
• Click here for the Immune Tolerance Network (ITN) Web site
• ITN TrialShare: open public access to study level information

Publications

• Greenbaum CJ, Mandrup-Poulsen T, McGee PF, Battelino T, Haastert B, Ludvigsson J, Pozzilli P, Lachin JM, Kolb H; Type 1 Diabetes Trial Net Research Group; European C-Peptide Trial Study Group. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care. 2008 Oct;31(10):1966-71. doi: 10.2337/dc07-2451. Epub 2008 Jul 15.
• Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, Lachin JM, Polonsky KS, Pozzilli P, Skyler JS, Steffes MW. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes. 2004 Jan;53(1):250-64. Erratum in: Diabetes. 2004 Jul;53(7):1934.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00515099
• Other Study ID Numbers: DAIT ITN028AI
• First Posted: Aug 13, 2007
• Last Update Posted: May 11, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): New-onset Type 1 Diabetes Mellitus; New-onset T1DM; New-onset Type 1 Diabetes; New-onset T1D; Newly Diagnosed Type 1 Diabetes Mellitus; Autoimmune diabetes; Thymoglobulin; ATG; Rabbit antithymocyte globulin
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Thymoglobulin; Antilymphocyte Serum

Study Results

Participant Flow

Recruitment Details	Subjects were recruited during an approximate 40-month accrual period. Initially 66 subjects were planned, however enrollment closed early at 58 subjects on June 30, 2011 secondary to slow accrual (planned 30-month accrual period).
Pre-assignment Detail	Subjects ages 12 to 35 years who were first diagnosed with type 1 diabetes mellitus (T1DM) within 100 days of enrollment.

Arm/Group Title	Antithymocyte Globulin	Placebo
Arm/Group Description	This group received a total of 6.5 mg/kg of antithymocyte globulin (Thymoglobulin®) administered intravenously and divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	This group received a saline solution administered intravenously to match the antithymocyte globulin (Thymoglobulin®) doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.
Period Title: Overall Study
STARTED	38	20
COMPLETED	35	16
NOT COMPLETED	3	4

Baseline Characteristics

Arm/Group Title	Antithymocyte Globulin	Placebo	Total
Arm/Group Description	This group received a total of 6.5 mg/kg of antithymocyte globulin (Thymoglobulin®) administered intravenously and divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	This group received a saline solution administered intravenously to match the antithymocyte globulin (Thymoglobulin®) doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	Total of all reporting groups
Overall Participants	38	20	58
Age (Count of Participants)
<=18 years	19 50%	10 50%	29 50%
Between 18 and 65 years	19 50%	10 50%	29 50%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	19.4 (6.6)	20.5 (7.1)	19.8 (6.7)
Age, Customized (participants) [Number]
12 -15 Years	13 34.2%	6 30%	19 32.8%
16 - 21 Years	13 34.2%	6 30%	19 32.8%
22 - 35 Years	12 31.6%	8 40%	20 34.5%
Sex: Female, Male (Count of Participants)
Female	14 36.8%	9 45%	23 39.7%
Male	24 63.2%	11 55%	35 60.3%
Region of Enrollment (participants) [Number]
United States	38 100%	20 100%	58 100%

Outcome Measures

1. Primary Outcome

Title	2-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT)
Description	C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy primary endpoint.
Time Frame	Baseline (Pre-treatment initiation), Month 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Antithymocyte Globulin	Placebo
Arm/Group Description	This group received a total of 6.5 mg/kg of antithymocyte globulin (Thymoglobulin®) administered intravenously and divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	This group received a saline solution administered intravenously to match the antithymocyte globulin (Thymoglobulin®) doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.
Measure Participants	38	20
Baseline (Pre-treatment initiation)	0.86 (0.37)	0.93 (0.50)
Month 12	0.66 (0.37)	0.69 (0.52)
Change from Baseline (Pre-treatment initiation)	-0.20 (0.29)	-0.24 (0.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antithymocyte Globulin, Placebo
	Comments	Primary imputation method used for missing Month 12 AUC. Measuring range for C-peptide is 0.05-30 ng/mL
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments	P-value is for testing treatment effect using an analysis of covariance with baseline ln(AUC+1) as a covariate and change in ln(AUC+1) from baseline as the outcome variable.
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	4-Hour C-peptide Area Under the Curve (AUC) Result in Response to Standardized Mixed Meal Tolerance Test (MMTT)
Description	C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 4-hour (e.g., 240 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the Center for Drug Evaluation and Research (CDER) at the FDA as a valid efficacy endpoint.
Time Frame	Baseline (Pre-treatment initiation), Month 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Antithymocyte Globulin	Placebo
Arm/Group Description	This group received a total of 6.5 mg/kg of antithymocyte globulin (Thymoglobulin®) administered intravenously and divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	This group received a saline solution administered intravenously to match the antithymocyte globulin (Thymoglobulin®) doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.
Measure Participants	38	20
Baseline (Pre-treatment initiation)	0.86 (0.30)	0.90 (0.37)
Month 12	0.67 (0.38)	0.63 (0.39)
Change from Baseline (Pre-treatment initiation)	-0.19 (0.30)	-0.27 (0.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antithymocyte Globulin, Placebo
	Comments	Missing Month 12 AUC values were not imputed. Measuring range for C-peptide is 0.05-30 ng/mL
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.40
	Comments	P-value is for testing treatment effect using an analysis of covariance with baseline In(AUC+1) as a covariate and change in In(AUC+1) from baseline as the outcome variable
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Insulin Use in Units Per Kilogram Body Weight Per Day
Description	The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity.
Time Frame	Baseline (Pre-treatment), Months 12 and 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Antithymocyte Globulin	Placebo
Arm/Group Description	This group received a total of 6.5 mg/kg of antithymocyte globulin (Thymoglobulin®) administered intravenously and divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	This group received a saline solution administered intravenously to match the antithymocyte globulin (Thymoglobulin®) doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.
Measure Participants	38	20
Baseline (Pre-treatment initiation)	0.34 (0.22)	0.42 (0.24)
Month 12	0.40 (0.24)	0.49 (0.26)
Change from Baseline to Month 12	0.07 (0.20)	0.08 (0.20)
Month 24	0.54 (0.31)	0.47 (0.21)
Change from Baseline to Month 24	0.19 (0.23)	0.06 (0.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antithymocyte Globulin, Placebo
	Comments	Comparison of groups for change from baseline (pre-treatment initiation) to Month 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments	P-value is for testing treatment effect using an analysis of covariance with baseline level as a covariate and change in insulin use from baseline as the outcome variable
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antithymocyte Globulin, Placebo
	Comments	Comparison of groups for change from baseline (pre-treatment initiation) to Month 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments	P-value is for testing treatment effect using an analysis of covariance with baseline level as a covariate and change in insulin use from baseline as the outcome variable
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Number of Participants Who Are Exogenous-Insulin-Free
Description	The need to use exogenous insulin is an indication that the body is not producing enough endogenous insulin. Higher amounts of insulin use indicate higher disease activity.
Time Frame	Baseline (Pre-treatment), Months 12 , 18, and 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Antithymocyte Globulin	Placebo
Arm/Group Description	This group received a total of 6.5 mg/kg of antithymocyte globulin (Thymoglobulin®) administered intravenously and divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	This group received a saline solution administered intravenously to match the antithymocyte globulin (Thymoglobulin®) doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.
Measure Participants	38	20
Baseline (Pre-treatment initiation)	1 2.6%	0 0%
Month 12	1 2.6%	0 0%
Month 18	1 2.6%	0 0%
Month 24	1 2.6%	0 0%

5. Secondary Outcome

Title	Number of Participants With Major Hypoglycemic Event(s) Post Treatment Randomization/Initiation
Description	Major hypoglycemic events are defined as a glucose concentration <55 mg/dL (grades 2-5, NCI-CTCAE version 3.0), or clinically: involving seizure(s) or involving loss of consciousness (coma), or requiring assistance from another individual in order to recover.
Time Frame	Baseline (Pre-treatment), Months 12 , and 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Antithymocyte Globulin	Placebo
Arm/Group Description	This group received a total of 6.5 mg/kg of antithymocyte globulin (Thymoglobulin®) administered intravenously and divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	This group received a saline solution administered intravenously to match the antithymocyte globulin (Thymoglobulin®) doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.
Measure Participants	38	20
Participants with Hypoglycemic Events Up to Mo. 12	23 60.5%	12 60%
Participants with Hypoglycemic Events Up to Mo. 24	30 78.9%	15 75%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antithymocyte Globulin, Placebo
	Comments	Comparison of groups up to Month 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.099
	Comments	P-value is for testing treatment effect using an analysis of covariance with baseline level as a covariate and change in insulin use from baseline as the outcome variable
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antithymocyte Globulin, Placebo
	Comments	Comparison of groups up to Month 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments	P-value is for testing treatment effect using an analysis of covariance with baseline level as a covariate and change in insulin use from baseline as the outcome variable
	Method	Fisher Exact
	Comments

6. Secondary Outcome

Title	2-Hour and 4-Hour C-peptide Area Under the Curve (AUC) Results in Response to Standardized Mixed Meal Tolerance Test (MMTT)
Description	C-peptide is a substance released by the pancreas into the bloodstream in equal amounts to insulin and reflects how much insulin pancreatic beta cells are making. The standardized MMTT evaluates whether beta cells are producing endogenous insulin. The MMTT was performed in the morning and blood samples for C-peptide collected at baseline (pre-meal) and 15, 30, 60, 90, 120, 150, 180, 210,and 240 minutes post-meal. Results of the stimulated 2-hour (e.g., 120 minutes) and 4-hour (e.g., 240 minutes) post-meal C-peptide AUC are provided. Larger numbers are preferable (better) in these AUC results: more insulin being produced reflects less severe disease. C-peptide levels in the serum (e.g., AUC following a standardized MMTT) compared to control group at 1 year post treatment initiation for the evaluation of investigational products intended to preserve endogenous beta-cell function in T1DM trials is recognized by the CDER at the FDA as a valid efficacy endpoint.
Time Frame	Baseline (Pre-treatment), Month 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Antithymocyte Globulin	Placebo
Arm/Group Description	This group received a total of 6.5 mg/kg of antithymocyte globulin (Thymoglobulin®) administered intravenously and divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	This group received a saline solution administered intravenously to match the antithymocyte globulin (Thymoglobulin®) doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.
Measure Participants	38	20
Baseline (Pre-treatment initiation)	0.86 (0.37)	0.93 (0.50)
2-hour AUC Month 24	0.58 (0.43)	0.61 (0.67)
Change from 2-hr MMTT Baseline	-0.27 (0.31)	-0.32 (0.32)
4-hour AUC Month 24	0.56 (0.36)	0.59 (0.63)
Change from 4-hr MMTT Baseline	-0.26 (0.28)	-0.31 (0.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antithymocyte Globulin, Placebo
	Comments	2-Hour AUC change from baseline (pre-initiation treatment) to Month 24. Primary imputation method used for missing Month 24 AUC. Measuring range for C-peptide is 0.05-30 ng/mL.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.38
	Comments	P-value is for testing treatment effect using an analysis of covariance with baseline In(AUC+1) as a covariate and change in In(AUC+1) from baseline as the outcome variable
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antithymocyte Globulin, Placebo
	Comments	4-Hour AUC change from baseline (pre-initiation treatment) to Month 24. Missing Month 24 AUC values were not imputed. Measuring range for C-peptide is 0.05-30 ng/mL.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments	P-value is for testing treatment effect using an analysis of covariance with baseline In(AUC+1) as a covariate and change in In(AUC+1) from baseline as the outcome variable
	Method	ANCOVA
	Comments

7. Secondary Outcome

Title	Hemoglobin A1c
Description	Glycosylated hemoglobin (HbA1c) is a measure of the average plasma concentration of blood sugar (glucose) over the previous three months and measures the level of optimal management of underlying disease. An HbA1c of <\=5.6% is considered normal. HbA1c of 6.5% or higher is typical for individuals with Type 1 Diabetes mellitus (T1DM).
Time Frame	Baseline (Pre-treatment), Months 12 and 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Antithymocyte Globulin	Placebo
Arm/Group Description	This group received a total of 6.5 mg/kg of antithymocyte globulin (Thymoglobulin®) administered intravenously and divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.	This group received a saline solution administered intravenously to match the antithymocyte globulin (Thymoglobulin®) doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4, 2 mg/kg.
Measure Participants	38	20
Baseline (Pre-treatment initiation)	6.7 (1.3)	6.8 (1.2)
Month 12	6.9 (1.6)	7.7 (1.8)
Change from Baseline to Month 12	0.1 (1.8)	1.0 (1.5)
Month 24	7.5 (1.5)	8.2 (2.4)
Change from Baseline to Month 24	0.6 (1.8)	1.4 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antithymocyte Globulin, Placebo
	Comments	Comparison of groups for change from Baseline to Month 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments	P-value is for testing treatment effect using an analysis of covariance with baseline level as a covariate and change in HbA1c from baseline as the outcome variable
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antithymocyte Globulin, Placebo
	Comments	Comparison of groups for change from Baseline to Month 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.16
	Comments	P-value is for testing treatment effect using an analysis of covariance with baseline level as a covariate and change in HbA1c from baseline as the outcome variable
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	From baseline (e.g., when informed consent signed) through study completion. The first participant enrolled in September 2007 and the last participant last visit for the study occurred in July 2013.
Adverse Event Reporting Description	Adverse Events (AEs) could be discovered through any of these methods: Observing the participant. Questioning the participant in an objective manner. Receiving an unsolicited complaint from the participant.
Arm/Group Title	Antithymocyte Globulin		Placebo
Arm/Group Description	This group received a total of 6.5 mg/kg of antithymocyte globulin (Thymoglobulin®) administered intravenously and divided into four doses as follows: Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4 2 mg/kg.		This group received a saline solution administered intravenously to match the antithymocyte globulin (Thymoglobulin®) doses given to the active treatment group, on Day 1, 0.5 mg/kg; Day 2, 2 mg/kg; Day 3, 2 mg/kg; and Day 4 2 mg/kg.
All Cause Mortality
	Antithymocyte Globulin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Antithymocyte Globulin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/38 (23.7%)		4/20 (20%)
Immune system disorders
Cytokine release syndrome	1/38 (2.6%)	1	0/20 (0%)	0
Serum sickness	2/38 (5.3%)	2	0/20 (0%)	0
Infections and infestations
Appendicitis	1/38 (2.6%)	1	0/20 (0%)	0
Gastroenteritis viral	0/38 (0%)	0	1/20 (5%)	1
Salmonellosis	1/38 (2.6%)	1	0/20 (0%)	0
Viral infection	1/38 (2.6%)	1	0/20 (0%)	0
Injury, poisoning and procedural complications
Comminuted fracture	0/38 (0%)	0	1/20 (5%)	1
Investigations
CD4 lymphocytes decreased	1/38 (2.6%)	1	0/20 (0%)	0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	1/38 (2.6%)	1	0/20 (0%)	0
Diabetic ketoacidosis	0/38 (0%)	0	1/20 (5%)	1
Hyperglycaemia	2/38 (5.3%)	4	1/20 (5%)	1
Hypoglycaemia	2/38 (5.3%)	2	0/20 (0%)	0
Ketosis	1/38 (2.6%)	1	0/20 (0%)	0
Nervous system disorders
Syncope	1/38 (2.6%)	1	0/20 (0%)	0
Psychiatric disorders
Affective disorder	0/38 (0%)	0	1/20 (5%)	1
Bipolar disorder	1/38 (2.6%)	1	0/20 (0%)	0
Depression	1/38 (2.6%)	4	1/20 (5%)	1
Major depression	0/38 (0%)	0	1/20 (5%)	1
Mood altered	1/38 (2.6%)	1	0/20 (0%)	0
Substance abuse	0/38 (0%)	0	1/20 (5%)	1
Suicidal ideation	0/38 (0%)	0	1/20 (5%)	1
Skin and subcutaneous tissue disorders
Exfoliative rash	1/38 (2.6%)	2	0/20 (0%)	0
Vascular disorders
Axillary vein thrombosis	1/38 (2.6%)	1	0/20 (0%)	0
Other (Not Including Serious) Adverse Events
	Antithymocyte Globulin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/38 (100%)		20/20 (100%)
Blood and lymphatic system disorders
Leukopenia	14/38 (36.8%)	20	0/20 (0%)	0
Lymphadenopathy	1/38 (2.6%)	1	2/20 (10%)	2
Lymphopenia	38/38 (100%)	48	0/20 (0%)	0
Neutropenia	9/38 (23.7%)	10	2/20 (10%)	4
Thrombocytopenia	5/38 (13.2%)	5	0/20 (0%)	0
Cardiac disorders
Bradycardia	0/38 (0%)	0	1/20 (5%)	1
Ear and labyrinth disorders
Ear pain	0/38 (0%)	0	1/20 (5%)	1
Middle ear effusion	0/38 (0%)	0	1/20 (5%)	2
Eye disorders
Eye irritation	0/38 (0%)	0	1/20 (5%)	1
Ocular hyperaemia	3/38 (7.9%)	3	0/20 (0%)	0
Visual impairment	0/38 (0%)	0	1/20 (5%)	1
Gastrointestinal disorders
Abdominal pain	3/38 (7.9%)	3	1/20 (5%)	1
Abdominal pain lower	1/38 (2.6%)	1	1/20 (5%)	1
Abdominal pain upper	3/38 (7.9%)	3	1/20 (5%)	1
Constipation	5/38 (13.2%)	6	0/20 (0%)	0
Diarrhoea	5/38 (13.2%)	5	3/20 (15%)	3
Dyspepsia	2/38 (5.3%)	2	3/20 (15%)	3
Gastritis	2/38 (5.3%)	2	0/20 (0%)	0
Gastrooesophageal reflux disease	2/38 (5.3%)	2	0/20 (0%)	0
Nausea	7/38 (18.4%)	8	5/20 (25%)	7
Oral disorder	2/38 (5.3%)	4	0/20 (0%)	0
Toothache	1/38 (2.6%)	1	1/20 (5%)	1
Vomiting	3/38 (7.9%)	4	3/20 (15%)	3
General disorders
Catheter site pain	5/38 (13.2%)	5	1/20 (5%)	1
Chest discomfort	3/38 (7.9%)	3	1/20 (5%)	1
Chest pain	2/38 (5.3%)	2	1/20 (5%)	1
Face oedema	0/38 (0%)	0	1/20 (5%)	1
Fatigue	3/38 (7.9%)	4	4/20 (20%)	5
Influenza like illness	2/38 (5.3%)	2	3/20 (15%)	3
Infusion site pain	1/38 (2.6%)	1	1/20 (5%)	1
Infusion site swelling	0/38 (0%)	0	1/20 (5%)	1
Injection site discolouration	0/38 (0%)	0	1/20 (5%)	1
Injection site hypertrophy	2/38 (5.3%)	2	0/20 (0%)	0
Malaise	2/38 (5.3%)	2	1/20 (5%)	1
Pain	2/38 (5.3%)	2	1/20 (5%)	1
Pyrexia	6/38 (15.8%)	6	1/20 (5%)	1
Hepatobiliary disorders
Hyperbilirubinaemia	3/38 (7.9%)	3	0/20 (0%)	0
Immune system disorders
Cytokine release syndrome	36/38 (94.7%)	36	1/20 (5%)	1
Seasonal allergy	7/38 (18.4%)	8	2/20 (10%)	2
Serum sickness	36/38 (94.7%)	37	0/20 (0%)	0
Infections and infestations
Bronchitis	4/38 (10.5%)	5	0/20 (0%)	0
Ear infection	2/38 (5.3%)	2	0/20 (0%)	0
Eye infection	0/38 (0%)	0	1/20 (5%)	2
Gastroenteritis	2/38 (5.3%)	2	1/20 (5%)	1
Gingival infection	0/38 (0%)	0	1/20 (5%)	1
Influenza	3/38 (7.9%)	3	0/20 (0%)	0
Nasopharyngitis	5/38 (13.2%)	5	1/20 (5%)	1
Oral herpes	1/38 (2.6%)	1	1/20 (5%)	1
Otitis media	0/38 (0%)	0	1/20 (5%)	1
Pharyngitis	2/38 (5.3%)	2	2/20 (10%)	2
Pharyngitis streptococcal	2/38 (5.3%)	3	2/20 (10%)	2
Pneumonia	0/38 (0%)	0	1/20 (5%)	1
Sinusitis	5/38 (13.2%)	7	1/20 (5%)	1
Upper respiratory tract infection	16/38 (42.1%)	32	7/20 (35%)	16
Viral infection	5/38 (13.2%)	10	3/20 (15%)	3
Injury, poisoning and procedural complications
Arthropod bite	1/38 (2.6%)	1	1/20 (5%)	1
Contusion	1/38 (2.6%)	1	1/20 (5%)	1
Excoriation	4/38 (10.5%)	5	0/20 (0%)	0
Fibula fracture	1/38 (2.6%)	1	1/20 (5%)	1
Foot fracture	2/38 (5.3%)	2	0/20 (0%)	0
Hand fracture	0/38 (0%)	0	1/20 (5%)	1
Joint sprain	3/38 (7.9%)	3	0/20 (0%)	0
Sunburn	2/38 (5.3%)	3	1/20 (5%)	1
Investigations
Alanine aminotransferase increased	2/38 (5.3%)	3	0/20 (0%)	0
Aspartate aminotransferase increased	2/38 (5.3%)	4	0/20 (0%)	0
CD4 lymphocytes decreased	37/38 (97.4%)	37	0/20 (0%)	0
Glycosylated haemoglobin increased	0/38 (0%)	0	1/20 (5%)	1
Haptoglobin increased	2/38 (5.3%)	2	0/20 (0%)	0
T-lymphocyte count decreased	2/38 (5.3%)	2	0/20 (0%)	0
Weight decreased	0/38 (0%)	0	1/20 (5%)	1
Metabolism and nutrition disorders
Hyperglycaemia	7/38 (18.4%)	8	1/20 (5%)	3
Hypoglycaemia	31/38 (81.6%)	493	16/20 (80%)	201
Musculoskeletal and connective tissue disorders
Arthralgia	4/38 (10.5%)	4	3/20 (15%)	4
Back pain	4/38 (10.5%)	5	5/20 (25%)	6
Muscle spasms	2/38 (5.3%)	2	1/20 (5%)	1
Musculoskeletal pain	1/38 (2.6%)	1	3/20 (15%)	3
Myalgia	4/38 (10.5%)	4	2/20 (10%)	3
Pain in extremity	2/38 (5.3%)	3	2/20 (10%)	2
Rotator cuff syndrome	0/38 (0%)	0	1/20 (5%)	1
Nervous system disorders
Dizziness	4/38 (10.5%)	4	2/20 (10%)	2
Dysaesthesia	0/38 (0%)	0	1/20 (5%)	1
Headache	18/38 (47.4%)	25	10/20 (50%)	15
Lethargy	0/38 (0%)	0	1/20 (5%)	1
Migraine	1/38 (2.6%)	1	1/20 (5%)	1
Somnolence	0/38 (0%)	0	2/20 (10%)	3
Pregnancy, puerperium and perinatal conditions
Pregnancy	2/38 (5.3%)	2	0/20 (0%)	0
Psychiatric disorders
Affective disorder	0/38 (0%)	0	1/20 (5%)	1
Agitation	0/38 (0%)	0	1/20 (5%)	1
Anxiety	1/38 (2.6%)	1	1/20 (5%)	1
Attention deficit/hyperactivity disorder	0/38 (0%)	0	1/20 (5%)	1
Depression	3/38 (7.9%)	3	3/20 (15%)	3
Insomnia	2/38 (5.3%)	2	0/20 (0%)	0
Restlessness	2/38 (5.3%)	2	0/20 (0%)	0
Renal and urinary disorders
Proteinuria	0/38 (0%)	0	2/20 (10%)	2
Reproductive system and breast disorders
Dysmenorrhoea	1/38 (2.6%)	1	1/20 (5%)	1
Ovarian cyst	2/38 (5.3%)	3	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	1/38 (2.6%)	1	1/20 (5%)	1
Bronchospasm	0/38 (0%)	0	1/20 (5%)	1
Cough	8/38 (21.1%)	10	4/20 (20%)	5
Epistaxis	1/38 (2.6%)	1	1/20 (5%)	1
Nasal congestion	3/38 (7.9%)	4	3/20 (15%)	4
Oropharyngeal pain	9/38 (23.7%)	13	5/20 (25%)	6
Pharyngeal erythema	0/38 (0%)	0	1/20 (5%)	1
Productive cough	0/38 (0%)	0	1/20 (5%)	1
Rhinitis allergic	2/38 (5.3%)	4	1/20 (5%)	1
Rhinorrhoea	1/38 (2.6%)	1	3/20 (15%)	3
Sinus congestion	4/38 (10.5%)	4	1/20 (5%)	1
Tonsillar hypertrophy	0/38 (0%)	0	1/20 (5%)	1
Skin and subcutaneous tissue disorders
Acne	7/38 (18.4%)	8	1/20 (5%)	1
Blister	1/38 (2.6%)	1	1/20 (5%)	1
Dermatitis contact	2/38 (5.3%)	2	3/20 (15%)	3
Eczema	1/38 (2.6%)	1	1/20 (5%)	1
Ingrowing nail	2/38 (5.3%)	2	0/20 (0%)	0
Lipoatrophy	0/38 (0%)	0	1/20 (5%)	2
Lipohypertrophy	0/38 (0%)	0	2/20 (10%)	4
Pruritus	4/38 (10.5%)	4	3/20 (15%)	4
Rash	7/38 (18.4%)	8	2/20 (10%)	3
Rash papular	3/38 (7.9%)	3	0/20 (0%)	0
Rash pruritic	1/38 (2.6%)	1	1/20 (5%)	5
Urticaria	2/38 (5.3%)	2	2/20 (10%)	2
Vascular disorders
Flushing	0/38 (0%)	0	1/20 (5%)	1
Hot flush	0/38 (0%)	0	1/20 (5%)	1
Hypotension	0/38 (0%)	0	3/20 (15%)	3

Limitations/Caveats

Enrollment for this trial was closed at 58 participants and did not meet the planned sample size of 66 participants due to slow accrual.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.