Anti-CD3 mAb Treatment of Recent Onset Type 1 Diabetes

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00378508
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Juvenile Diabetes Research Foundation (Other)
• Enrollment: 63
• Locations: 4
• Arms: 2
• Duration (Months): 83
• Patients Per Site: 15.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a randomized placebo controlled study to test whether a single 14 course of treatment with the anti-CD3 monoclonal antibody, hOKT3gamma1(Ala-Ala),Teplizumab will prevent the loss of insulin secretory capacity in individuals with Type 1 diabetes of 4 - 12 months duration since diagnosis.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: mAb hOKT3gamma1(Ala-Ala), Teplizumab; Drug: Placebo Arm	Phase 2

Detailed Description

The study design is a double blind placebo controlled trial that will enroll subjects between the ages of 8 - 30 who have had the diagnosis of Type 1 diabetes made 4 - 12 months prior to enrollment. A single 14 course of treatment with mAb hOKT3gamma1(Ala-Ala), Teplizumab will be given. The primary endpoint is the C-peptide response to a mixed meal at 12 months. A total of 60 subjects will be enrolled (30 in the drug treatment and 30 in the placebo groups) at 4 study sites: Yale University,the University of California at San Francisco, Children's Hospital of Philadelphia, and the Barbara Davis Diabetes Center.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of hOKT3gamma1(Ala-Ala) Teplizumab for Treatment of Patients With Recent Onset Type 1 Diabetes
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 The course of Teplizumab comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.	Drug: mAb hOKT3gamma1(Ala-Ala), Teplizumab; This is a randomized, two-arm, double blind placebo controlled phase II trial in which 60 participants with recent-onset T1DM are randomized at a 1:1 ratio to receive Teplizumab or placebo over a 14 day treatment period. The course of Teplizumab comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2.; Other Names: mAb hOKT3gamma1(Ala-Ala), MGA031, Teplizumab
Placebo Comparator: 2 Normal saline infusion	Drug: Placebo Arm

Outcome Measures

Primary Outcome Measures

1. C-peptide Area Under the Curve (AUC) Response to a Mixed Meal Tolerance Test (MMTT) at 12 Months [At month 12 post-treatment]

   C-peptide secretory response was calculated as ln[(Area Under the Curve of the C-peptide from the 240 minute MMTT/240 +1] For presentation, the C-peptide data were converted to the AUC as pmol/ml. This is adjusted for baseline.

2. C-peptide Area Under the Curve (AUC) Response to a Mixed Meal Tolerance Test (MMTT) at Baseline [At Baseline (before treatment)]

   C-peptide secretory response was calculated as ln[(Area Under the Curve of the C-peptide from the 240 minute MMTT/240 +1] For presentation, the C-peptide data were converted to the AUC as pmol/ml. This baseline data was used to adjust for the C-peptide AUC primary endpoint measure at 12 months.

Secondary Outcome Measures

1. Hemoglobin A1c [At 12 months post-treatment]

2. Average Insulin Use Over 12 Months [After 12 months post-treatment]

3. Baseline Insulin Use [At baseline (before treatment)]

4. Baseline Hemoglobin A1c [At baseline (before treatment)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• age 8 - 30,

• duration of diabetes 4 - 12 months,

• weight greater than 27.5 kg,

• stimulated C-peptide >= 0.2 pmol/ml

Exclusion Criteria:

• asthma,

• history of hepatitis C, hepatitis B, HIV

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California at San Francisco	San Francisco	California	United States	94143
2	Barbara Davis Diabetes Center	Aurora	Colorado	United States	80045
3	Yale University	New Haven	Connecticut	United States	06520
4	Children's Hospital of Philadelphia (CHOP)	Philadelphia	Pennsylvania	United States	10194

Sponsors and Collaborators

• Yale University
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Juvenile Diabetes Research Foundation

Investigators

• Principal Investigator: Kevan C Herold, Yale University
• Principal Investigator: Jeffrey A Bluestone, PhD, University of California at San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

• Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes. 2005 Jun;54(6):1763-9.
• Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002 May 30;346(22):1692-8.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT00378508
• Other Study ID Numbers: Delay-Study 5; R01DK057846
• First Posted: Sep 20, 2006
• Last Update Posted: Aug 13, 2021
• Last Verified: Aug 1, 2021

• Keywords provided by Yale University: immune therapy; autoimmunity; insulin secretion; diabetes mellitus
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from 4 clinical sites and were eligible if they were between the ages of 8-30 and diagnosed with Type 1 Diabetes for at least 4 months, but not more than 12 months prior to enrollment.

Arm/Group Title	Saline Infusions (Placebo)	Teplizumab Infusion (Active)
Arm/Group Description	The course of normal saline infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.	The course of teplizumab infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.
Period Title: Overall Study
STARTED	29	34
Randomized	29	34
Received Intervention/Placebo	28	31
COMPLETED	27	31
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Saline Infusions (Placebo)	Teplizumab Infusions (Active)	Total
Arm/Group Description	The course of normal saline infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.	The course of teplizumab infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.	Total of all reporting groups
Overall Participants	27	31	58
Age, Customized (participants) [Number]
<15 years	20 74.1%	18 58.1%	38 65.5%
>=15 years	7 25.9%	13 41.9%	20 34.5%
Sex/Gender, Customized (participants) [Number]
Female	10 37%	15 48.4%	25 43.1%
Male	17 63%	16 51.6%	33 56.9%

Outcome Measures

1. Primary Outcome

Title	C-peptide Area Under the Curve (AUC) Response to a Mixed Meal Tolerance Test (MMTT) at 12 Months
Description	C-peptide secretory response was calculated as ln[(Area Under the Curve of the C-peptide from the 240 minute MMTT/240 +1] For presentation, the C-peptide data were converted to the AUC as pmol/ml. This is adjusted for baseline.
Time Frame	At month 12 post-treatment

Outcome Measure Data

Analysis Population Description

This endpoint was compared in the modified intent to treat population which included all subjects with at least one post-randomization mixed meal tolerance test (MMTT)

Arm/Group Title	Teplizumab Infusions (Active)	Saline Infusions (Placebo)
Arm/Group Description	The course of teplizumab infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.	The course of normal saline infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.
Measure Participants	31	27
Least Squares Mean (95% Confidence Interval) [pmol/ml]	0.451	0.371

2. Secondary Outcome

Title	Hemoglobin A1c
Time Frame	At 12 months post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Teplizumab Infusions (Active)	Saline Infusions (Placebo)
Arm/Group Description	The course of teplizumab infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.	The course of normal saline infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.
Measure Participants	31	27
Least Squares Mean (95% Confidence Interval) [percentage of hemogloblin A1c]	6.85	7.35

3. Secondary Outcome

Title	Average Insulin Use Over 12 Months
Time Frame	After 12 months post-treatment

Outcome Measure Data

Analysis Population Description

This endpoint was compared in the modified intent to treat population which included all subjects with at least one post-randomization mixed meal tolerance test (MMTT)

Arm/Group Title	Teplizumab Infusions (Active)	Saline Infusion (Placebo)
Arm/Group Description	The course of teplizumab infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.	The course of normal saline infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.
Measure Participants	31	27
Least Squares Mean (95% Confidence Interval) [U/kg/d]	0.475	0.574

4. Primary Outcome

Title	C-peptide Area Under the Curve (AUC) Response to a Mixed Meal Tolerance Test (MMTT) at Baseline
Description	C-peptide secretory response was calculated as ln[(Area Under the Curve of the C-peptide from the 240 minute MMTT/240 +1] For presentation, the C-peptide data were converted to the AUC as pmol/ml. This baseline data was used to adjust for the C-peptide AUC primary endpoint measure at 12 months.
Time Frame	At Baseline (before treatment)

Outcome Measure Data

Analysis Population Description

This endpoint was compared in the modified intent to treat population which included all subjects with at least one post-randomization mixed meal tolerance test (MMTT)

Arm/Group Title	Teplizumab Infusions (Active)	Saline Infusions (Placebo)
Arm/Group Description	The course of teplizumab infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.	The course of normal saline infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.
Measure Participants	31	27
Least Squares Mean (95% Confidence Interval) [pmol/ml]	0.593	0.554

5. Secondary Outcome

Title	Baseline Insulin Use
Time Frame	At baseline (before treatment)

Outcome Measure Data

Analysis Population Description

This endpoint was compared in the modified intent to treat population which included all subjects with at least one post-randomization mixed meal tolerance test (MMTT)

Arm/Group Title	Teplizumab Infusions (Active)	Saline Infusion (Placebo)
Arm/Group Description	The course of teplizumab infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.	The course of normal saline infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.
Measure Participants	31	27
Least Squares Mean (95% Confidence Interval) [U/kg/d]	0.405	0.386

6. Secondary Outcome

Title	Baseline Hemoglobin A1c
Time Frame	At baseline (before treatment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Teplizumab Infusions (Active)	Saline Infusions (Placebo)
Arm/Group Description	The course of teplizumab infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.	The course of normal saline infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.
Measure Participants	31	27
Least Squares Mean (95% Confidence Interval) [percentage of hemoglobin A1c]	6.32	7.1

Adverse Events

Time Frame	The adverse event data was collected throughout the duration of the study which was approximately 6 years.
Arm/Group Title	Saline Infusions (Placebo)		Teplizumab Infusion (Active)
Arm/Group Description	The course of a saline infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.		The course of teplizumab infusion comprises daily doses of 51 µg/m2, 103 µg/m2, 207 µg/m2, 413 µg/m2, and 10 of 826 µg/m2 over a 14 day treatment period.
All Cause Mortality
	Saline Infusions (Placebo)		Teplizumab Infusion (Active)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Saline Infusions (Placebo)		Teplizumab Infusion (Active)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		1/34 (2.9%)
Immune system disorders
Drug Related Hypersensitivity	0/29 (0%)		1/33 (3%)
Other (Not Including Serious) Adverse Events
	Saline Infusions (Placebo)		Teplizumab Infusion (Active)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/29 (100%)		25/34 (73.5%)
Blood and lymphatic system disorders
Leukopenia	9/29 (31%)		10/33 (30.3%)
Lymphopenia	10/29 (34.5%)		15/33 (45.5%)
Neutropenia	7/29 (24.1%)		7/33 (21.2%)
Cardiac disorders
Tachycardia	2/29 (6.9%)		3/34 (8.8%)
Eye disorders
Conjunctivitis	2/29 (6.9%)		1/34 (2.9%)
Gastrointestinal disorders
Abdominal Discomfort	2/29 (6.9%)		1/34 (2.9%)
Abdominal Pain	6/29 (20.7%)		3/34 (8.8%)
Abdominal Pain (Upper)	9/29 (31%)		2/34 (5.9%)
Aphthous Stomatitis	2/29 (6.9%)		1/34 (2.9%)
Constipation	2/29 (6.9%)		0/34 (0%)
Diarrhea	6/29 (20.7%)		3/34 (8.8%)
Nausea	11/29 (37.9%)		14/33 (42.4%)
Oral Pain	3/29 (10.3%)		2/33 (6.1%)
Vomiting	12/29 (41.4%)		6/34 (17.6%)
General disorders
Catheter Related Complication	3/29 (10.3%)		1/34 (2.9%)
Catheter Site Pain	3/29 (10.3%)		0/34 (0%)
Catheter Site Rash	3/29 (10.3%)		1/34 (2.9%)
Chills	1/29 (3.4%)		3/34 (8.8%)
Edema Peripheral	0/29 (0%)		3/34 (8.8%)
Fatigue	3/29 (10.3%)		8/34 (23.5%)
Influenza Like Illness	7/29 (24.1%)		4/33 (12.1%)
Nodule	2/29 (6.9%)		0/33 (0%)
Pain	2/29 (6.9%)		1/33 (3%)
Pyrexia	6/29 (20.7%)		8/34 (23.5%)
Immune system disorders
Cytokine Release Syndrome	2/29 (6.9%)		1/34 (2.9%)
Infections and infestations
Nasopharyngitis	4/29 (13.8%)		2/33 (6.1%)
Pharyngitis Streptococcal	0/29 (0%)		2/33 (6.1%)
Upper Respiratory Tract Infection	7/29 (24.1%)		10/34 (29.4%)
Injury, poisoning and procedural complications
Arthropod Bite	2/29 (6.9%)		1/34 (2.9%)
Contusion	1/29 (3.4%)		4/34 (11.8%)
Excoriation	4/29 (13.8%)		2/34 (5.9%)
Investigations
Activated Partial Thromboplastin Time Prolonged	3/29 (10.3%)		4/34 (11.8%)
Alanine Aminotransferase Decreased	0/29 (0%)		2/34 (5.9%)
Alanine Aminotransferase Increased	5/29 (17.2%)		5/34 (14.7%)
Aspartate Aminotransferase Increased	5/29 (17.2%)		4/34 (11.8%)
Blood Albumin Decreased	7/29 (24.1%)		7/34 (20.6%)
Blood Alkaline Phosphatase Increased	3/29 (10.3%)		3/34 (8.8%)
Blood Bicarbonate Decreased	3/29 (10.3%)		1/34 (2.9%)
Blood Calcium Decreased	1/29 (3.4%)		3/34 (8.8%)
Blood Calcium Increased	2/29 (6.9%)		0/34 (0%)
Blood Creatinine Increased	4/29 (13.8%)		2/34 (5.9%)
Blood Potassium Decreased	0/29 (0%)		2/34 (5.9%)
Blood Sodium Decreased	4/29 (13.8%)		2/34 (5.9%)
Blood Urea Increased	2/29 (6.9%)		0/34 (0%)
Carbon Dioxide Abnormal	2/29 (6.9%)		0/34 (0%)
Cardiac Murmur	0/29 (0%)		2/34 (5.9%)
Gamma-glutamyltransferase Increased	2/29 (6.9%)		1/34 (2.9%)
Glycosylated Hemoglobin Increased	2/29 (6.9%)		3/34 (8.8%)
Hemoglobin Decreased	7/29 (24.1%)		10/34 (29.4%)
International Normalized Ratio Increased	4/29 (13.8%)		2/33 (6.1%)
Laboratory Test Abnormal	3/29 (10.3%)		1/33 (3%)
Lymphocyte Count Decreased	0/29 (0%)		5/33 (15.2%)
Lymphocyte Count Increased	2/29 (6.9%)		0/33 (0%)
Mean Cell Hemoglobin Increased	2/29 (6.9%)		0/33 (0%)
Platelet Count Decreased	1/29 (3.4%)		6/33 (18.2%)
Red Blood Cell Count Decreased	2/29 (6.9%)		0/34 (0%)
White Blood Cell Count Decreased	0/29 (0%)		3/34 (8.8%)
Metabolism and nutrition disorders
Hyperglycemia	2/29 (6.9%)		2/34 (5.9%)
Hypocalcemia	3/29 (10.3%)		3/34 (8.8%)
Hypoglycemia	3/29 (10.3%)		6/34 (17.6%)
Hyponatremia	2/29 (6.9%)		0/34 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/29 (13.8%)		3/34 (8.8%)
Musculoskeletal Pain	0/29 (0%)		3/33 (9.1%)
Myalgia	2/29 (6.9%)		0/33 (0%)
Neck Pain	2/29 (6.9%)		0/33 (0%)
Pain in Extremity	4/29 (13.8%)		5/33 (15.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin Papilloma	2/29 (6.9%)		1/34 (2.9%)
Nervous system disorders
Dizziness	5/29 (17.2%)		4/34 (11.8%)
Headache	20/29 (69%)		15/34 (44.1%)
Psychiatric disorders
Anxiety	10/29 (34.5%)		11/34 (32.4%)
Renal and urinary disorders
Hematuria	2/29 (6.9%)		0/34 (0%)
Ketonuria	3/29 (10.3%)		0/33 (0%)
Reproductive system and breast disorders
Dysmenorrhea	0/29 (0%)		2/34 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	4/29 (13.8%)		4/34 (11.8%)
Nasal Congestion	2/29 (6.9%)		5/33 (15.2%)
Pharyngolaryngeal Pain	6/29 (20.7%)		6/33 (18.2%)
Rhinitis Allergic	5/29 (17.2%)		2/34 (5.9%)
Skin and subcutaneous tissue disorders
Acne	1/29 (3.4%)		2/34 (5.9%)
Dry Skin	1/29 (3.4%)		4/34 (11.8%)
Erythema	2/29 (6.9%)		1/34 (2.9%)
Lipohypertrophy	1/29 (3.4%)		3/33 (9.1%)
Petechiae	2/29 (6.9%)		0/33 (0%)
Pruritus	9/29 (31%)		11/34 (32.4%)
Rash	16/29 (55.2%)		18/34 (52.9%)
Rash Generalized	0/29 (0%)		4/34 (11.8%)
Rash Papular	2/29 (6.9%)		3/34 (8.8%)
Skin Disorder	0/29 (0%)		2/34 (5.9%)
Skin Exfoliation	4/29 (13.8%)		6/34 (17.6%)
Urticaria	2/29 (6.9%)		2/34 (5.9%)
Vascular disorders
Hypotension	3/29 (10.3%)		2/34 (5.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.