Teplizumab for Prevention of Type 1 Diabetes In Relatives "At-Risk"

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ClinicalTrials.gov Identifier: NCT01030861

Recruitment Status : Completed

First Posted : December 14, 2009

Results First Posted : August 5, 2020

Last Update Posted : August 5, 2020

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Sponsor:

Collaborators:

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Center for Research Resources (NCRR)

Juvenile Diabetes Research Foundation

American Diabetes Association

Information provided by (Responsible Party):

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions	Autoantibody Positive Non-diabetic Relatives at Risk for Type 1 Diabetes High Risk Impaired Glucose Tolerance
Interventions	Drug: Teplizumab Drug: Placebo infusion
Enrollment	76

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Teplizumab	Placebo Infusion
Arm/Group Description	Intravenous infusions of teplizumab...	Intravenous infusion of placebo (sa...
Arm/Group Description	Intravenous infusions of teplizumab given for 14 consecutive days. Each infusion takes about 30 minutes and is followed by a 2 hour observation period. Teplizumab: intravenous infusions	Intravenous infusion of placebo (saline) will be given for 14 consecutive days. Infusions will take approximately 30 minutes and will be followed by a two hour observation period. Placebo infusion: Placebo for Teplizumab
Period Title: Overall Study
Started	44	32
Completed	44	32
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Teplizumab	Placebo Infusion	Total
Arm/Group Description		Intravenous infusions of teplizumab...	Intravenous infusion of placebo (sa...	Total of all reporting groups
Arm/Group Description		Intravenous infusions of teplizumab given for 14 consecutive days. Each infusion takes about 30 minutes and is followed by a 2 hour observation period. Teplizumab: intravenous infusions	Intravenous infusion of placebo (saline) will be given for 14 consecutive days. Infusions will take approximately 30 minutes and will be followed by a two hour observation period. Placebo infusion: Placebo for Teplizumab	Total of all reporting groups
Overall Number of Baseline Participants		44	32	76
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Median (Inter-Quartile Range) Unit of measure: Years
	Number Analyzed	44 participants	32 participants	76 participants
		14 (8.5 to 49.5)	13 (8.6 to 45.0)	13.9 (11.5 to 20.0)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	44 participants	32 participants	76 participants
	Female	19 43.2%	15 46.9%	34 44.7%
	Male	25 56.8%	17 53.1%	42 55.3%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	44 participants	32 participants	76 participants
	Hispanic or Latino	1 2.3%	1 3.1%	2 2.6%
	Not Hispanic or Latino	43 97.7%	31 96.9%	74 97.4%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	44 participants	32 participants	76 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	2 6.3%	2 2.6%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	44 100.0%	30 93.8%	74 97.4%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Relationship to person with type 1 diabetes Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	44 participants	32 participants	76 participants
Sibling(s)		24 54.5%	16 50.0%	40 52.6%
Identical twin		4 9.1%	0 0.0%	4 5.3%
Offspring		6 13.6%	6 18.8%	12 15.8%
Parent		6 13.6%	3 9.4%	9 11.8%
Sibling and another first degree relative		2 4.5%	3 9.4%	5 6.6%
Second degree relative		2 4.5%	3 9.4%	5 6.6%
Third degree relative or further removed		0 0.0%	1 3.1%	1 1.3%
Autoantibodies Positive Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	44 participants	32 participants	76 participants
Anti-GAD65 harmonized		40 90.9%	28 87.5%	68 89.5%
Micro insulin		20 45.5%	11 34.4%	31 40.8%
Anti-IA-2 harmonized		27 61.4%	24 75.0%	51 67.1%
Islet Cell Cytoplasmic Autoantibodies (ICA)		29 65.9%	28 87.5%	57 75.0%
Anti-ZnT8		32 72.7%	24 75.0%	56 73.7%
Glycated hemoglobin level Median (Inter-Quartile Range) Unit of measure: Percentage of glycated hemoglobin
	Number Analyzed	44 participants	32 participants	76 participants
		5.2 (4.9 to 5.4)	5.3 (5.1 to 5.4)	5.2 (5.0 to 5.4)

Outcome Measures

1.Primary Outcome


Title	Rate of New Diabetes Per Year
Description	Rate at which criteria are met for diabetes onset as defined by the Am...
Description	Rate at which criteria are met for diabetes onset as defined by the American Diabetes Association (ADA) based on glucose testing or the presence of unequivocal hyperglycemia with acute metabolic decompensation.
Time Frame	During follow-up, median 745 days, range 74 to 2683

Outcome Measure Data

Analysis Population Description

Relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease.


Arm/Group Title	Teplizumab	Placebo Infusion
Arm/Group Description:	Intravenous infusions of teplizumab...	Intravenous infusion of placebo (sa...
Arm/Group Description:	Intravenous infusions of teplizumab given for 14 consecutive days. Each infusion takes about 30 minutes and is followed by a 2 hour observation period. Teplizumab: intravenous infusions	Intravenous infusion of placebo (saline) will be given for 14 consecutive days. Infusions will take approximately 30 minutes and will be followed by a two hour observation period. Placebo infusion: Placebo for Teplizumab
Overall Number of Participants Analyzed	44	32
Measure Type: Number Unit of Measure: N diabetes per 100 participant years
	43	72

2.Secondary Outcome


Title	Number of Participants With Adverse Events
Description	Adverse events categorized and graded via CTCAE.
Description	Adverse events categorized and graded via CTCAE.
Time Frame	Baseline Visit to Diagnosis of Type 1 Diabetes median 745 days, range 74 to 2683

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Teplizumab	Placebo Infusion
Arm/Group Description:	Intravenous infusions of teplizumab...	Intravenous infusion of placebo (sa...
Arm/Group Description:	Intravenous infusions of teplizumab given for 14 consecutive days. Each infusion takes about 30 minutes and is followed by a 2 hour observation period. Teplizumab: intravenous infusions	Intravenous infusion of placebo (saline) will be given for 14 consecutive days. Infusions will take approximately 30 minutes and will be followed by a two hour observation period. Placebo infusion: Placebo for Teplizumab
Overall Number of Participants Analyzed	44	32
Measure Type: Count of Participants Unit of Measure: Participants
	43 97.7%	23 71.9%

Adverse Events

Time Frame	Adverse Event data were collected for individual participants, beginning with the Baseline Visit and ending with the documented Diagnosis of Type 1 Diabetes (the primary study endpoint), median 745 days, range 74 to 2683.
Adverse Event Reporting Description	CTCAE

Arm/Group Title	Teplizumab		Placebo Infusion
Arm/Group Description	Intravenous infusions of teplizumab...		Intravenous infusion of placebo (sa...
Arm/Group Description	Intravenous infusions of teplizumab given for 14 consecutive days. Each infusion takes about 30 minutes and is followed by a 2 hour observation period. Teplizumab: intravenous infusions		Intravenous infusion of placebo (saline) will be given for 14 consecutive days. Infusions will take approximately 30 minutes and will be followed by a two hour observation period. Placebo infusion: Placebo for Teplizumab
All-Cause Mortality
	Teplizumab		Placebo Infusion
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/44 (0.00%)		0/32 (0.00%)
Serious Adverse Events Serious Adverse Events
	Teplizumab		Placebo Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/44 (18.18%)		1/32 (3.13%)
Gastrointestinal disorders
Gastroenteritis ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Obstruction, GI ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Obstruction, GU ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Infection with unknown ANC ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Musculoskeletal and connective tissue disorders
Fracture ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Chest Wall Pain ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Pain ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Nervous system disorders
Dizziness ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Skin and subcutaneous tissue disorders
Infection - Skin ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Teplizumab		Placebo Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/44 (97.73%)		23/32 (71.88%)
Blood and lymphatic system disorders
Lymphopenia ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Hemoglobin ^†	2/44 (4.55%)	6	0/32 (0.00%)	0
Leukocytes (total WBC) ^†	8/44 (18.18%)	13	0/32 (0.00%)	0
Lymphopenia ^†	30/44 (68.18%)	73	2/32 (6.25%)	5
Leukocytes ^†	2/44 (4.55%)	2	0/32 (0.00%)	0
Neutrophils/granulocytes (ANC/AGC) ^†	4/44 (9.09%)	5	1/32 (3.13%)	6
Cardiac disorders
Hypertension ^†	2/44 (4.55%)	2	1/32 (3.13%)	1
Cardiac Arrhythmia - Other (Specify in Event Details) ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Cardiac Arrhythmia ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Hypotension ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Palpitations ^†	0/44 (0.00%)	0	1/32 (3.13%)	2
Ear and labyrinth disorders
Otitis, middle ear (non-infectious) ^†	0/44 (0.00%)	0	1/32 (3.13%)	2
Endocrine disorders
Thyroid function, low (hypothyroidism) ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Hypoglycemia ^†	0/44 (0.00%)	0	2/32 (6.25%)	3
Eye disorders
Vitreous hemorrhage ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Ocular surface disease ^†	2/44 (4.55%)	4	1/32 (3.13%)	2
Conjunctivitis ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Eyelid dysfunction ^†	0/44 (0.00%)	0	1/32 (3.13%)	2
Gastrointestinal disorders
Dental: periodontal disease ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Diarrhea ^†	2/44 (4.55%)	2	0/32 (0.00%)	0
Stomach Pain ^†	1/44 (2.27%)	2	0/32 (0.00%)	0
Heartburn/dyspepsia ^†	1/44 (2.27%)	2	0/32 (0.00%)	0
Nausea ^†	2/44 (4.55%)	3	1/32 (3.13%)	2
Obstruction, GI ^†	1/44 (2.27%)	3	0/32 (0.00%)	0
Vomiting ^†	2/44 (4.55%)	3	2/32 (6.25%)	3
Dental: teeth ^†	0/44 (0.00%)	0	2/32 (6.25%)	4
Dental: teeth development ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
General disorders
Fatigue (asthenia, lethargy, malaise) ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L) ^†	2/44 (4.55%)	3	0/32 (0.00%)	0
Flu-like syndrome ^†	2/44 (4.55%)	7	0/32 (0.00%)	0
Pain ^†	10/44 (22.73%)	13	4/32 (12.50%)	6
Weight gain ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Hepatobiliary disorders
Elevated Bilirubin ^†	0/44 (0.00%)	0	1/32 (3.13%)	2
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever) ^†	3/44 (6.82%)	4	0/32 (0.00%)	0
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip) ^†	2/44 (4.55%)	2	0/32 (0.00%)	0
Alpha-Gal Allergy ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Cytokine release syndrome/acute infusion reaction ^†	1/44 (2.27%)	3	0/32 (0.00%)	0
Infections and infestations
Infection with Normal ANC ^†	12/44 (27.27%)	34	4/32 (12.50%)	13
Infection with unknown ANC ^†	5/44 (11.36%)	9	1/32 (3.13%)	3
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase) ^†	2/44 (4.55%)	2	1/32 (3.13%)	1
AST, SGOT(serum glutamic oxaloacetic transaminase) ^†	1/44 (2.27%)	1	1/32 (3.13%)	1
Bilirubin (hyperbilirubinemia) ^†	0/44 (0.00%)	0	2/32 (6.25%)	3
Cholesterol, serum-high (hypercholesteremia) ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Musculoskeletal and connective tissue disorders
Fracture ^†	3/44 (6.82%)	6	1/32 (3.13%)	1
Joint Pain ^†	1/44 (2.27%)	1	3/32 (9.38%)	5
Myositis (inflammation/damage of muscle) ^†	1/44 (2.27%)	4	0/32 (0.00%)	0
Nervous system disorders
Mood alteration ^†	2/44 (4.55%)	4	2/32 (6.25%)	6
Cognitive Disturbance ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Neuropathy: motor ^†	1/44 (2.27%)	2	1/32 (3.13%)	2
Seizure ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Neuropathy: sensory ^†	0/44 (0.00%)	0	1/32 (3.13%)	2
Personality/behavioral ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Syncope (fainting) ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Renal and urinary disorders
Kidney Stones ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Reproductive system and breast disorders
Breast function/lactation ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm, wheezing ^†	4/44 (9.09%)	4	0/32 (0.00%)	0
Cough ^†	3/44 (6.82%)	5	0/32 (0.00%)	0
Dyspnea (shortness of breath) ^†	2/44 (4.55%)	2	0/32 (0.00%)	0
Hypoxia ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Nasal cavity/paranasal sinus reactions ^†	2/44 (4.55%)	4	0/32 (0.00%)	0
Pneumonitis/pulmonary infiltrates ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Pulmonary/Upper Respiratory Infection ^†	4/44 (9.09%)	5	1/32 (3.13%)	2
Skin and subcutaneous tissue disorders
Folliculitis ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Injection site reaction/extravasation changes ^†	1/44 (2.27%)	1	0/32 (0.00%)	0
Pruritus/itching ^†	4/44 (9.09%)	5	1/32 (3.13%)	2
Rash/desquamation ^†	13/44 (29.55%)	41	0/32 (0.00%)	0
Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) ^†	2/44 (4.55%)	2	0/32 (0.00%)	0
Rash: hand-foot skin reaction ^†	1/44 (2.27%)	2	0/32 (0.00%)	0
Urticaria (hives, welts, wheals) ^†	1/44 (2.27%)	2	0/32 (0.00%)	0
Bruising (in absence of Grade 3 or 4 thrombocytopenia) ^†	0/44 (0.00%)	0	2/32 (6.25%)	4
Nail changes ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Vascular disorders
Thrombosis ^†	0/44 (0.00%)	0	1/32 (3.13%)	1
Phlebitis (including superficial thrombosis) ^†	0/44 (0.00%)	0	1/32 (3.13%)	2
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

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.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Carla Greenbaum, MD
Organization:	Benaroya Research Institute
Phone:	206-342-6933
EMail:	cjgreen@benaroyaresearch.org

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Leung SS, Borg DJ, McCarthy DA, Boursalian TE, Cracraft J, Zhuang A, Fotheringham AK, Flemming N, Watkins T, Miles JJ, Groop PH, Scheijen JL, Schalkwijk CG, Steptoe RJ, Radford KJ, Knip M, Forbes JM. Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells. Diabetes. 2022 Sep 1;71(9):1994-2008. doi: 10.2337/db22-0177.

Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, Gitelman SE, Gottlieb PA, Krischer JP, Linsley PS, Marks JB, Moore W, Moran A, Rodriguez H, Russell WE, Schatz D, Skyler JS, Tsalikian E, Wherrett DK, Ziegler AG, Greenbaum CJ; Type 1 Diabetes TrialNet Study Group. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019 Aug 15;381(7):603-613. doi: 10.1056/NEJMoa1902226. Epub 2019 Jun 9. Erratum In: N Engl J Med. 2020 Feb 6;382(6):586.

Layout table for additonal information

Responsible Party:	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:	NCT01030861
Other Study ID Numbers:	TrialNet - tep (IND) UC4DK106993 ( U.S. NIH Grant/Contract )
First Submitted:	December 11, 2009
First Posted:	December 14, 2009
Results First Submitted:	July 2, 2020
Results First Posted:	August 5, 2020
Last Update Posted:	August 5, 2020

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