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

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01030861
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), National Center for Research Resources (NCRR) (NIH), Juvenile Diabetes Research Foundation (Other), American Diabetes Association (Other)
• Enrollment: 76
• Locations: 19
• Arms: 2
• Actual Duration (Months): 106
• Patients Per Site: 4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The study will determine whether the anti-CD3 monoclonal antibody, teplizumab, can help to prevent or delay the onset of type 1 diabetes (T1D) in relatives determined to be at very high risk for developing the disease. Teplizumab has been studied in new onset type 1 diabetes for testing of efficacy and safety in previous studies; other studies are currently in progress. The results of previous studies indicate that teplizumab reduces the loss of insulin production during the first year after diagnosis in individuals with type 1 diabetes. The purpose of this study is to determine if teplizumab can interdict the immune process that causes the destruction of insulin secreting beta cells in the pancreas during the "pre-diabetic" state and thereby prevent or delay the onset of type 1 diabetes.

Condition or Disease	Intervention/Treatment	Phase
Autoantibody Positive; Non-diabetic Relatives at Risk for Type 1 Diabetes; High Risk; Impaired Glucose Tolerance	Drug: Teplizumab; Drug: Placebo infusion	Phase 2

Detailed Description

The study plans to enroll approximately 71 subjects between the ages of 8-45 years, over 2-3 years. The study is projected to last between 4-6 years, depending upon rate of enrollment and number of subjects who develop diabetes.

The main study objective is to determine whether intervention with teplizumab will prevent or delay the development of type 1 diabetes in high risk autoantibody positive non-diabetic relatives of individuals with T1D. Secondary outcomes are to include analyses of C-peptide and other measures from Oral Glucose Tolerance Testing (OGTT), safety, tolerability, and other mechanistic outcomes will be assessed during the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: AntiCD3 Mab (Teplizumab) For Prevention of Diabetes In Relatives At-Risk for Type 1 Diabetes Mellitus
• Actual Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Nov 1, 2018
• Actual Study Completion Date: Jun 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: teplizumab Intravenous infusions of teplizumab given for 14 consecutive days. Each infusion takes about 30 minutes and is followed by a 2 hour observation period.	Drug: Teplizumab; intravenous infusions
Placebo Comparator: Placebo infusion 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.	Drug: Placebo infusion; Placebo for Teplizumab

Outcome Measures

Primary Outcome Measures

1. Rate of New Diabetes Per Year [During follow-up, median 745 days, range 74 to 2683]

   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.

Secondary Outcome Measures

1. Number of Participants With Adverse Events [Baseline Visit to Diagnosis of Type 1 Diabetes median 745 days, range 74 to 2683]

   Adverse events categorized and graded via CTCAE.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Between ages of 8-45 years

• Have a relative with type 1 diabetes

• If first degree relative must be 8-45 years old (brother, sister, parent, offspring)

• If second degree relative must be between 8-20 years old (niece, nephew, aunt, uncle, grandchild, cousin)

• Abnormal glucose tolerance by OGTT confirmed with 7 weeks of baseline visit [fasting blood glucose greater than 110mg/dL or and less than 126 mg/dL OR 2 hour glucose greater or equal to 140 mg/dL and less than 200 mg/dL OR 30, 60, or 90 minute value on OGTT greater than or equal to 200 mg/dL]

• Presence of at least two confirmed diabetes autoantibodies

Exclusion Criteria:

• type 1 diabetes previously diagnosed or detected at screening [fasting glucose greater or equal to 126 mg/dL or 2 hour glucose greater or equal to 200 mg/dL]

• abnormalities in blood counts, liver enzymes, international normalised ratio (INR),

• positive purified protein derivative (PPD) test

• vaccination with live virus within 6 weeks of randomization

• evidence of acute infection based on laboratory testing or clinical evidence

• serological evidence of past current or past HIV , hepatitis B, or hepatitis C infection

• Be currently pregnant or lactating

• Prior treatment with study drug

• Prior treatment with other monoclonal antibody in past one year

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California in San Francisco	San Francisco	California	United States	94143
2	University of California-San Francisco	San Francisco	California	United States	94143
3	Stanford University	Stanford	California	United States	94305
4	Barbara Davis Center for Childhood Diabetes/ University of Colorado	Denver	Colorado	United States	80045
5	Yale University School of Medicine	New Haven	Connecticut	United States	06519
6	University of Florida	Gainesville	Florida	United States	32610
7	University of Miami	Miami	Florida	United States	33136
8	University of South Florida	Tampa	Florida	United States	33612
9	Indiana University	Indianapolis	Indiana	United States	46202
10	University of Minnesota	Minneapolis	Minnesota	United States	55455
11	The Children's Mercy Hospital	Kansas City	Missouri	United States	64108
12	Columbia University	New York	New York	United States	10032
13	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15201
14	Vanderbilt University	Nashville	Tennessee	United States	37232
15	University of Texas	Dallas	Texas	United States	75390-9072
16	Baylor College of Medicine	Houston	Texas	United States	77030
17	Benaroya Research Institute	Seattle	Washington	United States	982101
18	The Hospital for Sick Children	Toronto	Ontario	Canada	MSG-1X8
19	Forschergruppe Diabetes	Munich		Germany

Sponsors and Collaborators

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

Investigators

• Study Chair: Carla J Greenbaum, MD, Type 1 Diabetes TrialNet

Study Documents (Full-Text)

• Study Protocol - Jun 25, 2014
• Statistical Analysis Plan - Mar 27, 2018

More Information

Additional Information:

• Type 1 Diabetes TrialNet

Publications

None provided.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT01030861
• Other Study ID Numbers: TrialNet - tep (IND); UC4DK106993
• First Posted: Dec 14, 2009
• Last Update Posted: Aug 5, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): type 1 diabetes; pre-diabetic; autoantibody positive; at risk for type 1 diabetes; glucose intolerance; relatives of people with type 1 diabetes
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Intolerance

Study Results

Participant Flow

Arm/Group Title	Teplizumab	Placebo Infusion
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 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 Participants	44	32	76
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	14	13	13.9
Sex: Female, Male (Count of Participants)
Female	19 43.2%	15 46.9%	34 44.7%
Male	25 56.8%	17 53.1%	42 55.3%
Ethnicity (NIH/OMB) (Count of 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%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	2 6.3%	2 2.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	44 100%	30 93.8%	74 97.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Relationship to person with type 1 diabetes (Count of Participants)
Sibling(s)	24 54.5%	16 50%	40 52.6%
Identical twin	4 9.1%	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%	1 3.1%	1 1.3%
Autoantibodies Positive (Count of 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%	51 67.1%
Islet Cell Cytoplasmic Autoantibodies (ICA)	29 65.9%	28 87.5%	57 75%
Anti-ZnT8	32 72.7%	24 75%	56 73.7%
Glycated hemoglobin level (percentage of glycated hemoglobin) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of glycated hemoglobin]	5.2	5.3	5.2

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 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 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
Measure Participants	44	32
Number [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.
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 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
Measure Participants	44	32
Count of Participants [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 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 (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/32 (0%)
Serious Adverse Events
	Teplizumab		Placebo Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/44 (18.2%)		1/32 (3.1%)
Gastrointestinal disorders
Gastroenteritis	1/44 (2.3%)	1	0/32 (0%)	0
Obstruction, GI	1/44 (2.3%)	1	0/32 (0%)	0
Obstruction, GU	0/44 (0%)	0	1/32 (3.1%)	1
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils	1/44 (2.3%)	1	0/32 (0%)	0
Infection with unknown ANC	1/44 (2.3%)	1	0/32 (0%)	0
Musculoskeletal and connective tissue disorders
Fracture	1/44 (2.3%)	1	0/32 (0%)	0
Chest Wall Pain	1/44 (2.3%)	1	0/32 (0%)	0
Pain	1/44 (2.3%)	1	0/32 (0%)	0
Nervous system disorders
Dizziness	1/44 (2.3%)	1	0/32 (0%)	0
Skin and subcutaneous tissue disorders
Infection - Skin	1/44 (2.3%)	1	0/32 (0%)	0
Other (Not Including Serious) Adverse Events
	Teplizumab		Placebo Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/44 (97.7%)		23/32 (71.9%)
Blood and lymphatic system disorders
Lymphopenia	1/44 (2.3%)	1	0/32 (0%)	0
Hemoglobin	2/44 (4.5%)	6	0/32 (0%)	0
Leukocytes (total WBC)	8/44 (18.2%)	13	0/32 (0%)	0
Lymphopenia	30/44 (68.2%)	73	2/32 (6.3%)	5
Leukocytes	2/44 (4.5%)	2	0/32 (0%)	0
Neutrophils/granulocytes (ANC/AGC)	4/44 (9.1%)	5	1/32 (3.1%)	6
Cardiac disorders
Hypertension	2/44 (4.5%)	2	1/32 (3.1%)	1
Cardiac Arrhythmia - Other (Specify in Event Details)	0/44 (0%)	0	1/32 (3.1%)	1
Cardiac Arrhythmia	0/44 (0%)	0	1/32 (3.1%)	1
Hypotension	0/44 (0%)	0	1/32 (3.1%)	1
Palpitations	0/44 (0%)	0	1/32 (3.1%)	2
Ear and labyrinth disorders
Otitis, middle ear (non-infectious)	0/44 (0%)	0	1/32 (3.1%)	2
Endocrine disorders
Thyroid function, low (hypothyroidism)	1/44 (2.3%)	1	0/32 (0%)	0
Hypoglycemia	0/44 (0%)	0	2/32 (6.3%)	3
Eye disorders
Vitreous hemorrhage	1/44 (2.3%)	1	0/32 (0%)	0
Ocular surface disease	2/44 (4.5%)	4	1/32 (3.1%)	2
Conjunctivitis	0/44 (0%)	0	1/32 (3.1%)	1
Eyelid dysfunction	0/44 (0%)	0	1/32 (3.1%)	2
Gastrointestinal disorders
Dental: periodontal disease	1/44 (2.3%)	1	0/32 (0%)	0
Diarrhea	2/44 (4.5%)	2	0/32 (0%)	0
Stomach Pain	1/44 (2.3%)	2	0/32 (0%)	0
Heartburn/dyspepsia	1/44 (2.3%)	2	0/32 (0%)	0
Nausea	2/44 (4.5%)	3	1/32 (3.1%)	2
Obstruction, GI	1/44 (2.3%)	3	0/32 (0%)	0
Vomiting	2/44 (4.5%)	3	2/32 (6.3%)	3
Dental: teeth	0/44 (0%)	0	2/32 (6.3%)	4
Dental: teeth development	0/44 (0%)	0	1/32 (3.1%)	1
General disorders
Fatigue (asthenia, lethargy, malaise)	1/44 (2.3%)	1	0/32 (0%)	0
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	2/44 (4.5%)	3	0/32 (0%)	0
Flu-like syndrome	2/44 (4.5%)	7	0/32 (0%)	0
Pain	10/44 (22.7%)	13	4/32 (12.5%)	6
Weight gain	1/44 (2.3%)	1	0/32 (0%)	0
Hepatobiliary disorders
Elevated Bilirubin	0/44 (0%)	0	1/32 (3.1%)	2
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	3/44 (6.8%)	4	0/32 (0%)	0
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	2/44 (4.5%)	2	0/32 (0%)	0
Alpha-Gal Allergy	1/44 (2.3%)	1	0/32 (0%)	0
Cytokine release syndrome/acute infusion reaction	1/44 (2.3%)	3	0/32 (0%)	0
Infections and infestations
Infection with Normal ANC	12/44 (27.3%)	34	4/32 (12.5%)	13
Infection with unknown ANC	5/44 (11.4%)	9	1/32 (3.1%)	3
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	2/44 (4.5%)	2	1/32 (3.1%)	1
AST, SGOT(serum glutamic oxaloacetic transaminase)	1/44 (2.3%)	1	1/32 (3.1%)	1
Bilirubin (hyperbilirubinemia)	0/44 (0%)	0	2/32 (6.3%)	3
Cholesterol, serum-high (hypercholesteremia)	0/44 (0%)	0	1/32 (3.1%)	1
Musculoskeletal and connective tissue disorders
Fracture	3/44 (6.8%)	6	1/32 (3.1%)	1
Joint Pain	1/44 (2.3%)	1	3/32 (9.4%)	5
Myositis (inflammation/damage of muscle)	1/44 (2.3%)	4	0/32 (0%)	0
Nervous system disorders
Mood alteration	2/44 (4.5%)	4	2/32 (6.3%)	6
Cognitive Disturbance	1/44 (2.3%)	1	0/32 (0%)	0
Neuropathy: motor	1/44 (2.3%)	2	1/32 (3.1%)	2
Seizure	1/44 (2.3%)	1	0/32 (0%)	0
Neuropathy: sensory	0/44 (0%)	0	1/32 (3.1%)	2
Personality/behavioral	0/44 (0%)	0	1/32 (3.1%)	1
Syncope (fainting)	0/44 (0%)	0	1/32 (3.1%)	1
Renal and urinary disorders
Kidney Stones	1/44 (2.3%)	1	0/32 (0%)	0
Reproductive system and breast disorders
Breast function/lactation	0/44 (0%)	0	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm, wheezing	4/44 (9.1%)	4	0/32 (0%)	0
Cough	3/44 (6.8%)	5	0/32 (0%)	0
Dyspnea (shortness of breath)	2/44 (4.5%)	2	0/32 (0%)	0
Hypoxia	1/44 (2.3%)	1	0/32 (0%)	0
Nasal cavity/paranasal sinus reactions	2/44 (4.5%)	4	0/32 (0%)	0
Pneumonitis/pulmonary infiltrates	1/44 (2.3%)	1	0/32 (0%)	0
Pulmonary/Upper Respiratory Infection	4/44 (9.1%)	5	1/32 (3.1%)	2
Skin and subcutaneous tissue disorders
Folliculitis	1/44 (2.3%)	1	0/32 (0%)	0
Injection site reaction/extravasation changes	1/44 (2.3%)	1	0/32 (0%)	0
Pruritus/itching	4/44 (9.1%)	5	1/32 (3.1%)	2
Rash/desquamation	13/44 (29.5%)	41	0/32 (0%)	0
Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)	2/44 (4.5%)	2	0/32 (0%)	0
Rash: hand-foot skin reaction	1/44 (2.3%)	2	0/32 (0%)	0
Urticaria (hives, welts, wheals)	1/44 (2.3%)	2	0/32 (0%)	0
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	0/44 (0%)	0	2/32 (6.3%)	4
Nail changes	0/44 (0%)	0	1/32 (3.1%)	1
Vascular disorders
Thrombosis	0/44 (0%)	0	1/32 (3.1%)	1
Phlebitis (including superficial thrombosis)	0/44 (0%)	0	1/32 (3.1%)	2

Limitations/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.