Recent-Onset Type 1 Diabetes Trial Evaluating Efficacy and Safety of Teplizumab (PROTECT)

• ClinicalTrials.gov Identifier: NCT03875729
• Recruitment Status: Completed
• First Posted: March 15, 2019
• Results First Posted: April 24, 2024
• Last Update Posted: April 24, 2024
• Sponsor: Provention Bio, Inc.
• Information provided by (Responsible Party): Provention Bio, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Type 1 Diabetes Mellitus
• Interventions: Biological: teplizumab; Biological: Placebo
• Enrollment: 328

Participant Flow

Recruitment Details	The first participant was enrolled on April 5, 2019, and the last participant was enrolled on November 4, 2021.
Pre-assignment Details	Of 422 assessed for eligibility, 328 met inclusion criteria and were randomized to treatment.

Arm/Group Title	Placebo	Teplizumab
Arm/Group Description	Placebo: Control Placebo was administered via intravenous infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course approximately 6 months later at Day 182 (Week 26). Participants who were unable to receive the second 12-day course due to COronaVIrus Disease of 2019 (COVID-19) pandemic restrictions were given the second course at approximately 12 months (Week 52) in a modified dosing schedule. Each course of treatment included daily infusions for 12 days. The placebo solution consisted of the same formulation as the study drug but without teplizumab. Placebo was administered in the same dose volume and by the same treatment schedule as the active drug.	Teplizumab: Treatment Teplizumab was administered via intravenous infusion in two courses, with the first course starting on Day 1 (Week 1) and the second course approximately 6 months later at Day 182 (Week 26). Participants who were unable to receive the second 12-day course due to COronaVIrus Disease of 2019 (COVID-19) pandemic restrictions were given the second course at approximately 12 months (Week 52) in a modified dosing schedule. Each course of treatment included daily infusions for 12 days. Each course included: Day 1: 106 μg/m^2; Day 2: 425 μg/m^2; Days 3-12: 850 μg/m^2 Total per course: 9.0 mg/m^2 The doses of study drug were calculated based on the participant's body surface area (BSA) measured on the first day of each treatment course.
Period Title: Overall Study
Started	111	217
Completed	101	195
Not Completed	10	22
Reason Not Completed
Adverse Event	0	5
Withdrawal by Subject	8	11
Pregnancy	0	1
Lost to Follow-up	0	5
Personal reasons	2	0

Baseline Characteristics

Arm/Group Title		Placebo	Teplizumab	Total
Arm/Group Description		Placebo: Control	Teplizumab: Treatment	Total of all reporting groups
Overall Number of Baseline Participants		111	217	328
Baseline Analysis Population Description		Intent-to-treat population
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	<=18 years	111 100.0%	217 100.0%	328 100.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	111 participants	217 participants	328 participants
		12.3 (2.55)	12.0 (2.53)	12.1 (2.54)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	Female	42 37.8%	98 45.2%	140 42.7%
	Male	69 62.2%	119 54.8%	188 57.3%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	Hispanic or Latino	4 3.6%	14 6.5%	18 5.5%
	Not Hispanic or Latino	101 91.0%	193 88.9%	294 89.6%
	Unknown or Not Reported	6 5.4%	10 4.6%	16 4.9%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	White	94 84.7%	189 87.1%	283 86.3%
	Black or African American	6 5.4%	5 2.3%	11 3.4%
	Asian	3 2.7%	4 1.8%	7 2.1%
	American Indian or Alaskan Native	0 0.0%	1 0.5%	1 0.3%
	Native Hawiian or Other Pacific Islander	1 0.9%	0 0.0%	1 0.3%
	Multiple	0 0.0%	6 2.8%	6 1.8%
	Other	1 0.9%	4 1.8%	5 1.5%
	Not reported	6 5.4%	8 3.7%	14 4.3%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Canada	Number Analyzed	111 participants	217 participants	328 participants
		7	13	20
Belgium	Number Analyzed	111 participants	217 participants	328 participants
		4	1	5
United States	Number Analyzed	111 participants	217 participants	328 participants
		56	126	182
Czechia	Number Analyzed	111 participants	217 participants	328 participants
		10	17	27
Poland	Number Analyzed	111 participants	217 participants	328 participants
		15	33	48
United Kingdom	Number Analyzed	111 participants	217 participants	328 participants
		6	6	12
France	Number Analyzed	111 participants	217 participants	328 participants
		5	9	14
Germany	Number Analyzed	111 participants	217 participants	328 participants
		8	12	20
Peak C-peptide at screening; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	0.2 - 0.7 pmol/mL	47 42.3%	91 41.9%	138 42.1%
	>0.7 pmol/mL	64 57.7%	126 58.1%	190 57.9%
Age group at randomization; Measure Type: Count of Participants; Unit of measure: Participants
8 - 12 years	Number Analyzed	111 participants	217 participants	328 participants
		62 55.9%	120 55.3%	182 55.5%
>12 - 17 years	Number Analyzed	111 participants	217 participants	328 participants
		49 44.1%	97 44.7%	146 44.5%
Number of positive type 1 diabetes (T1D) autoantibodies; Measure Type: Count of Participants; Unit of measure: Participants
None	Number Analyzed	111 participants	217 participants	328 participants
		0 0.0%	1 0.5%	1 0.3%
One	Number Analyzed	111 participants	217 participants	328 participants
		3 2.7%	10 4.6%	13 4.0%
Two	Number Analyzed	111 participants	217 participants	328 participants
		13 11.7%	38 17.5%	51 15.5%
Three	Number Analyzed	111 participants	217 participants	328 participants
		30 27.0%	47 21.7%	77 23.5%
Four	Number Analyzed	111 participants	217 participants	328 participants
		39 35.1%	66 30.4%	105 32.0%
Five	Number Analyzed	111 participants	217 participants	328 participants
		26 23.4%	55 25.3%	81 24.7%
History of diabetic ketoacidosis (DKA); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	Yes	4 3.6%	0 0.0%	4 1.2%
	No	107 96.4%	217 100.0%	324 98.8%
Human leukocyte antigen (HLA) genotyping - DR3 [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	109 participants	215 participants	324 participants
	Positive	56 51.4%	96 44.7%	152 46.9%
	Negative	53 48.6%	119 55.3%	172 53.1%
		[1] Measure Analysis Population Description: Populations differs due to missing values.
Human leukocyte antigen (HLA) genotyping - DR4 [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	109 participants	215 participants	324 participants
	Positive	75 68.8%	137 63.7%	212 65.4%
	Negative	34 31.2%	78 36.3%	112 34.6%
		[1] Measure Analysis Population Description: Populations differs due to missing values.
Anti-glutamic acid decarboxylase 65 (GAD65) autoantibody; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	Positive	96 86.5%	183 84.3%	279 85.1%
	Negative	15 13.5%	34 15.7%	49 14.9%
Anti-islet antigen 2 (IA-2) autoantibody; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	Positive	87 78.4%	165 76.0%	252 76.8%
	Negative	24 21.6%	52 24.0%	76 23.2%
Anti-zinc transporter 8 (ZnT8) autoantibody; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	Positive	83 74.8%	162 74.7%	245 74.7%
	Negative	28 25.2%	55 25.3%	83 25.3%
Anti-insulin autoantibody; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	Positive	85 76.6%	144 66.4%	229 69.8%
	Negative	26 23.4%	73 33.6%	99 30.2%
Anti-islet cell cytoplasmic antibody (ICA); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	111 participants	217 participants	328 participants
	Positive	54 48.6%	112 51.6%	166 50.6%
	Negative	57 51.4%	105 48.4%	162 49.4%
Height; Mean (Standard Deviation); Unit of measure: Cm
	Number Analyzed	111 participants	217 participants	328 participants
		158.48 (14.977)	155.35 (15.358)	156.41 (15.279)
Weight; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	111 participants	217 participants	328 participants
		49.19 (15.889)	46.68 (14.992)	47.53 (15.323)
Body mass index (BMI); Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	111 participants	217 participants	328 participants
		19.063 (3.6415)	18.868 (3.4517)	18.934 (3.5127)
Body mass index (BMI) z-score [1]; Mean (Standard Deviation); Unit of measure: Z-score
	Number Analyzed	111 participants	217 participants	328 participants
		0.0557 (1.0957)	0.0627 (1.0723)	0.0603 (1.0786)
		[1] Measure Description: The body mass index (BMI) z-score is a measure of the relative BMI adjusted for child's age and sex and describes the distance the BMI measurement falls from the mean in standard deviation units. A z-score of 0 represents the mean BMI for that age and sex, and a positive score indicates a BMI is higher than the mean, and a negative z-score indicates a BMI is lower than the mean. Z-scores were derived using the growth chart from the general population (e.g., Centers for Disease Control and Prevention (CDC) Growth Charts, https://www.cdc.gov/growthcharts/clinical_charts.htm).
C-peptide area under concentration-time curve standardized by mixed meal tolerance test duration [1]; Mean (Standard Deviation); Unit of measure: pmol/mL
	Number Analyzed	111 participants	217 participants	328 participants
		0.7237 (0.3190)	0.7445 (0.3653)	0.7375 (0.3499)
		[1] Measure Description: The area under concentration-time curve (AUC) of C-peptide was measured after a 4-hour (4h) mixed meal tolerance test (MMTT). The AUC was computed using the trapezoidal rule and standardized by the duration of the MMTT test, i.e., AUC was divided by the last blood sample collection time (240 minutes or the last collection time for 4h MMTT).
Insulin use [1] [2]; Mean (Standard Deviation); Unit of measure: U/kg/day
	Number Analyzed	63 participants	126 participants	189 participants
		0.383 (0.2535)	0.447 (0.3093)	0.426 (0.2928)
		[1] Measure Description: Insulin use at baseline was calculated as the average daily use for participants who had at least 3 days of data recorded on the insulin diary before the start of the study.; [2] Measure Analysis Population Description: Insulin use at baseline was not calculated for participants who did not have at least 3 days of data recorded on the insulin diary before the start of the study.
Glycated hemoglobin (HbA1c) [1]; Mean (Standard Deviation); Unit of measure: Percentage of glycated hemoglobin
	Number Analyzed	110 participants	217 participants	327 participants
		9.18 (1.918)	8.90 (1.729)	9.00 (1.797)
		[1] Measure Analysis Population Description: Population differs due to missing value for one participant.
Time from type 1 diabetes (T1D) diagnosis to randomization; Mean (Standard Deviation); Unit of measure: Weeks
	Number Analyzed	111 participants	217 participants	328 participants
		5.20 (0.812)	5.37 (0.730)	5.31 (0.762)

Outcome Measures

1. Primary Outcome

Title	Change in C-peptide ln(AUC+1) Standardized by Duration of the Mixed Meal Tolerance Test (MMTT)
Description	The area under the concentration-time curve (AUC) of C-peptide was measured after a 4-hour mixed meal tolerance test (MMTT) and is a measure of endogenous insulin production and β cell function. The AUC was computed using the trapezoidal rule and standardized by the duration of the MMTT test, i.e., AUC was divided by the last blood sample collection time (240 minutes or the last collection time for 4h MMTT).
Time Frame	Baseline to Week 78

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) and Per Protocol (PP). The main reason participants were excluded from the PP population was for treatment compliance <80% (15 of 16 excluded participants in the placebo group and 32 of 37 in the teplizumab group). Other reasons included took prohibited medication (1 in placebo group, 3 in teplizumab group), received incorrect treatment (2 in teplizumab group), and pregnancy (1 in teplizumab group).

Arm/Group Title		Placebo	Teplizumab
Arm/Group Description:		Placebo: Control	Teplizumab: Treatment
Overall Number of Participants Analyzed		111	217
Least Squares Mean (95% Confidence Interval); Unit of Measure: pmol/mL
Intent-to-treat	Number Analyzed	111 participants	217 participants
		-0.2112; (-0.2437 to -0.1786)	-0.0859; (-0.1090 to -0.0628)
Per Protocol	Number Analyzed	95 participants	180 participants
		-0.2185; (-0.2501 to -0.1869)	-0.0800; (-0.1030 to -0.0570)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teplizumab
	Comments	This study was designed to show a difference of at least a 40% in C-peptide response between teplizumab and placebo. In geometric means, this translates to a value of (1.4×0.28) = 0.392. Consequently, approximately 300 participants were planned for enrollment, assuming 2-sided α=0.05, 90% power, 2:1 randomization, and a 10% dropout rate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	ITT: The ANCOVA model included treatment, age group at randomization, and baseline C-peptide ln(AUC+1) as independent variables. Missing data at Week 78 were multiply imputed using pattern-mixture model under the missing not at random assumption.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1253
	Confidence Interval	(2-Sided) 95%; 0.0852 to 0.1653
	Estimation Comments	Least squares mean (LSmean) difference = Teplizumab - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teplizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	PP: The ANCOVA model included treatment, age group at randomization, and baseline C-peptide ln(AUC+1) as independent variables. Missing data at Week 78 were multiply imputed using a pattern-mixture model under the missing not at random assumption.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.1385
	Confidence Interval	(2-Sided) 95%; 0.0994 to 0.1776
	Estimation Comments	Least squares mean (LSmean) difference = teplizumab - placebo

2. Secondary Outcome

Title	Average Daily Exogenous Insulin Use
Description	The average daily insulin use was calculated based on participants who have at least 3 days of insulin use recorded in the dairy for the Week 78 visit.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

Intent-to-treat and Per Protocol

Arm/Group Title		Placebo	Teplizumab
Arm/Group Description:		Placebo: Control	Teplizumab: Treatment
Overall Number of Participants Analyzed		111	217
Least Squares Mean (95% Confidence Interval); Unit of Measure: Units/kg/day
Intent-to-treat	Number Analyzed	111 participants	217 participants
		0.593; (0.470 to 0.716)	0.463; (0.363 to 0.562)
Per Protocol	Number Analyzed	95 participants	180 participants
		0.613; (0.538 to 0.687)	0.446; (0.390 to 0.502)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teplizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.085
	Comments	ITT: ANCOVA model included treatment, age group at randomization, and screening peak C-peptide category as independent variables. Missing data at Week 78 were multiply imputed using a pattern-mixture model under the missing not at random assumption.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.131
	Confidence Interval	(2-Sided) 95%; -0.280 to 0.018
	Estimation Comments	LSmean difference = teplizumab - placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teplizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	PP: ANCOVA model included treatment, age group at randomization, and screening peak C-peptide category as independent variables. Missing data at Week 78 were multiply imputed using a pattern-mixture model under the missing not at random assumption.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.167
	Confidence Interval	(2-Sided) 95%; -0.256 to -0.078
	Estimation Comments	LSmean difference = teplizumab - placebo.

3. Secondary Outcome

Title	Change in Glycated Hemoglobin (HbA1c) Levels (%)
Description	Change in percentage (%) glycated hemoglobin (HbA1c)
Time Frame	Baseline to Week 78

Outcome Measure Data

Analysis Population Description

Intent-to-treat and Per Protocol

Arm/Group Title		Placebo	Teplizumab
Arm/Group Description:		Placebo: Control	Teplizumab: Treatment
Overall Number of Participants Analyzed		111	217
Least Squares Mean (95% Confidence Interval); Unit of Measure: Percentage of glycated hemoglobin
Intent-to-treat	Number Analyzed	111 participants	217 participants
		-1.89; (-2.16 to -1.62)	-1.98; (-2.17 to -1.78)
Per Protocol	Number Analyzed	95 participants	180 participants
		-1.94; (-2.21 to -1.67)	-2.07; (-2.27 to -1.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teplizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.606
	Comments	ITT: ANCOVA model included treatment, age group at randomization, screening peak C-peptide category, baseline HbA1c as independent variables. Missing data were multiply imputed using a pattern-mixture model under the missing not at random assumption.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.42 to 0.24
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teplizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.454
	Comments	PP: ANOVA model included treatment, age group at randomization, screening peak C-peptide category, baseline HbA1c as independent variables. Missing data were multiply imputed using a pattern-mixture model under the missing not at random assumption.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.46 to 0.20
	Estimation Comments	LSmean difference = teplizumab - placebo.

4. Secondary Outcome

Title	Time in Range for Glycemia Control
Description	Time in range (%) for glycemia control was assessed using Continuous Glucose Monitoring (CGM). Time in range was defined as daily average percentage of time a participant's glucose is >= 70 mg/dL and <=180 mg/dL. Time in range was calculated based on participants who had at least 3 days of CGM data recorded for Week 78 visit with a range of at least 8 hours on a given day.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

Intent-to-treat and Per Protocol

Arm/Group Title		Placebo	Teplizumab
Arm/Group Description:		Placebo: Control	Teplizumab: Treatment
Overall Number of Participants Analyzed		111	217
Least Squares Mean (95% Confidence Interval); Unit of Measure: Percentage of time in range
Intent-to-treat	Number Analyzed	111 participants	217 participants
		62.65; (57.38 to 67.92)	67.36; (63.70 to 71.03)
Per Protocol	Number Analyzed	95 participants	180 participants
		61.44; (56.50 to 66.38)	67.61; (64.09 to 71.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teplizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.151
	Comments	ITT: The ANCOVA model included treatment, age group at randomization, and screening peak C-peptide category as independent variables. Missing data were multiply imputed using a pattern-mixture model under the missing not at random assumption.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.71
	Confidence Interval	(2-Sided) 95%; -1.72 to 11.15
	Estimation Comments	LSmean difference = teplizumab - placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teplizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.045
	Comments	PP: The ANCOVA model included treatment, age group at randomization, and screening peak C-peptide category as independent variables. Missing data were multiply imputed using a pattern-mixture model under the missing not at random assumption.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.17
	Confidence Interval	(2-Sided) 95%; 0.13 to 12.22
	Estimation Comments	LSmean difference = teplizumab - placebo.

5. Secondary Outcome

Title	Rate of Clinically Important Hypoglycemic Events
Description	Rate = clinically important hypoglycemic events/patient-year. A clinically important episode was defined as a blood glucose value of <54 mg/dL (3.0 mmol/L) (i.e., Level 2 Hypoglycemia, International Hypoglycemia Study Group, 2017) or a hypoglycemia event of severe cognitive impairment requiring external assistance (such as seizure, syncope, severe confusion with or without a confirmatory low blood glucose reading) (i.e., Level 3 Hypoglycemia, International Hypoglycemia Study Group 2017). Event rate was calculated for each participant as number of events / total study follow-up time. Total study follow-up time was calculated as (the date of last study contact - the first dose date + 1)/365.25. The summary is based on the data reported post-baseline in the Hypoglycemic Events Electronic Diary (eDiary).
Time Frame	During the entire study (from the first dose to the last study contact, up to 78 Weeks)

Outcome Measure Data

Analysis Population Description

Intent-to-treat and Per Protocol

Arm/Group Title		Placebo	Teplizumab
Arm/Group Description:		Placebo: Control	Teplizumab: Treatment
Overall Number of Participants Analyzed		111	217
Mean (95% Confidence Interval); Unit of Measure: Events/patient-year
Intent-to-treat	Number Analyzed	111 participants	217 participants
		4.24; (3.06 to 5.89)	4.68; (3.70 to 5.91)
Per protocol	Number Analyzed	95 participants	180 participants
		4.63; (3.31 to 6.49)	5.04; (3.94 to 6.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teplizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.634
	Comments	ITT: Estimates and p-values were obtained from a negative binomial regression model using rate of hypoglycemic episodes as dependent variable and treatment, age group at randomization, and screening peak C-peptide category as independent variables.
	Method	Negative binomial regression model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.64
	Estimation Comments	Rate ratio = teplizumab / placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teplizumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.690
	Comments	PP: Estimates and p-values were obtained from a negative binomial regression model using rate of hypoglycemic episodes as dependent variable and treatment age group at randomization, and screening peak C-peptide category as independent variables.
	Method	Rate ratio
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.65
	Estimation Comments	Rate ratio = teplizumab / placebo.

6. Secondary Outcome

Title	Number of Participants With Adverse Events of Special Interest (AESIs)
Description	AESIs are defined in the protocol and categories in the statistical analysis plan. Participants with multiple events are counted only once for each preferred term and category.
Time Frame	During the entire study (from the first dose to the last study contact, up to 78 Weeks)

Outcome Measure Data

Analysis Population Description

Safety population = all randomized study participants receiving any exposure to study drug.

Arm/Group Title	Placebo	Teplizumab
Arm/Group Description:	Placebo: Control	Teplizumab: Treatment
Overall Number of Participants Analyzed	111	217
Measure Type: Count of Participants; Unit of Measure: Participants
Treatment-emergent AESI	24 21.6%	63 29.0%
Participants with at least one >= grade 3 infection	2 1.8%	1 0.5%
Participants with at least one acute mononucleosis-like illness	3 2.7%	17 7.8%
Participants with at least one lymphoma or other malignancy, including benign tumors	1 0.9%	2 0.9%
Participants with at least one instance of severe hypoglycemic event	18 16.2%	29 13.4%
Participants with at least one >=grade 3 liver function abnormality	0 0.0%	8 3.7%
Participants with at least one >= grade 3 thrombocytopenia	0 0.0%	0 0.0%
Participants with at least one >= grade 3 neutropenia	0 0.0%	7 3.2%
Participants with at least one >= grade 4 allergic/hypersensitivity reaction	0 0.0%	0 0.0%
Participants with at least one >= grade 3 rash	0 0.0%	4 1.8%

7. Secondary Outcome

Title	Teplizumab Serum Concentrations
Description	PK samples were collected prior to dosing except for Day 9 in Course 1. An additional PK sample was collected 45 minutes after infusion on Day 9 in Course 1. Concentration values below Lower Limit of Quantification (2.50 ng/mL) were set to zero for summary statistics. Course 2 day numbers were set relative to the first day of dosing, regardless of normal or modified dosing schedule.
Time Frame	Pre-dose samples collected on Days 1, 4, 9, 12 and 28 for each of the two treatment courses, and one post-dose sample collected on Day 9 during the first treatment course.

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) population includes all randomized participants who received at least one dose of teplizumab with at least one valid pharmacokinetic sample.

Arm/Group Title		Teplizumab
Arm/Group Description:		Teplizumab: Treatment
Overall Number of Participants Analyzed		217
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
Course 1, Day 1	Number Analyzed	216 participants
		7.4271; (628.114%)
Course 1, Day 4	Number Analyzed	210 participants
		70.4769; (50.767%)
Course 1, Day 9	Number Analyzed	206 participants
		250.3928; (44.677%)
Course 1, Day 9 post-dose	Number Analyzed	59 participants
		636.4390; (33.171%)
Course 1, Day 12	Number Analyzed	208 participants
		305.6569; (47.048%)
Course 1, Day 28	Number Analyzed	186 participants
		25.0317; (79.953%)
Course 2, Day 1	Number Analyzed	121 participants
		5.5433; (522.457%)
Course 2, Day 4	Number Analyzed	123 participants
		82.0166; (50.333%)
Course 2, Day 9	Number Analyzed	119 participants
		145.9498; (75.737%)
Course 2, Day 12	Number Analyzed	121 participants
		108.2988; (107.776%)
Course 2, Day 28	Number Analyzed	118 participants
		13.2159; (181.421%)

8. Secondary Outcome

Title	Anti-teplizumab Antibody (ADA) Titers After Treatment Courses
Description	Baseline was defined as the most recent value collected prior to the first dose of study drug. Week 26 Day 187 and Weeks 27 and 34 are planned for subjects under the normal dosing schedule. Week 52 Day 369 and Weeks 53, 56, and 60 are planned for subjects under the modified dosing schedule.
Time Frame	Baseline through 78 Week

Outcome Measure Data

Analysis Population Description

The Immunogenicity population includes all randomized participants who received at least one dose of teplizumab with at least one valid serum Anti-teplizumab Antibody (ADA) sample.

Arm/Group Title		Teplizumab
Arm/Group Description:		Teplizumab: Treatment
Overall Number of Participants Analyzed		217
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Titer
Baseline	Number Analyzed	15 participants
		65.81; (182.3%)
Week 2	Number Analyzed	176 participants
		177.22; (278.2%)
Week 4	Number Analyzed	172 participants
		817.08; (275.0%)
Week 8	Number Analyzed	172 participants
		1040.58; (239.1%)
Week 26 Day 182	Number Analyzed	134 participants
		834.86; (226.1%)
Week 26 Day 187	Number Analyzed	124 participants
		807.26; (681.6%)
Week 27	Number Analyzed	167 participants
		9257.15; (222.3%)
Week 30	Number Analyzed	169 participants
		9985.29; (218.7%)
Week 34	Number Analyzed	162 participants
		7326.91; (237.0%)
Week 39	Number Analyzed	170 participants
		3701.64; (202.8%)
Week 52 Day 364	Number Analyzed	153 participants
		1398.22; (240.1%)
Week 52 Day 369	Number Analyzed	11 participants
		308.80; (207.5%)
Week 53	Number Analyzed	15 participants
		8043.22; (165.7%)
Week 56	Number Analyzed	18 participants
		14221.44; (241.8%)
Week 60	Number Analyzed	17 participants
		9040.49; (299.4%)
Week 65	Number Analyzed	150 participants
		996.15; (484.4%)
Week 78	Number Analyzed	140 participants
		672.13; (332.4%)

9. Secondary Outcome

Title	Incidence of Anti-drug Antibodies (ADA) After Treatment Courses
Description	Baseline is defined as the most recent value collected prior to the first dose of study drug. Week 26 Day 187 and Weeks 27 and 34 are planned for subjects under the normal dosing schedule. Week 52 Day 369 and Weeks 53, 56, and 60 are planned for subjects under the modified dosing schedule.
Time Frame	From baseline through Week 78

Outcome Measure Data

Analysis Population Description

The Immunogenicity population includes all randomized participants who received at least one dose of teplizumab with at least one valid serum Anti-teplizumab Antibody (ADA) sample.

Arm/Group Title		Teplizumab
Arm/Group Description:		Teplizumab: Treatment
Overall Number of Participants Analyzed		217
Measure Type: Count of Participants; Unit of Measure: Participants
Baseline	Number Analyzed	215 participants
	Positive	15 7.0%
	Negative	200 93.0%
Week 2	Number Analyzed	207 participants
	Positive	182 87.9%
	Negative	25 12.1%
Week 4	Number Analyzed	204 participants
	Positive	178 87.3%
	Negative	26 12.7%
Week 8	Number Analyzed	206 participants
	Positive	175 85.0%
	Negative	31 15.0%
Week 26 Day 182	Number Analyzed	192 participants
	Positive	139 72.4%
	Negative	53 27.6%
Week 26 Day 187	Number Analyzed	170 participants
	Positive	130 76.5%
	Negative	40 23.5%
Week 27	Number Analyzed	175 participants
	Positive	167 95.4%
	Negative	8 4.6%
Week 30	Number Analyzed	176 participants
	Positive	169 96.0%
	Negative	7 4.0%
Week 34	Number Analyzed	176 participants
	Positive	163 92.6%
	Negative	13 7.4%
Week 39	Number Analyzed	192 participants
	Positive	170 88.5%
	Negative	22 11.5%
Week 52 Day 364	Number Analyzed	192 participants
	Positive	155 80.7%
	Negative	37 19.3%
Week 52 Day 369	Number Analyzed	15 participants
	Positive	11 73.3%
	Negative	4 26.7%
Week 53	Number Analyzed	16 participants
	Positive	15 93.8%
	Negative	1 6.3%
Week 56	Number Analyzed	19 participants
	Positive	18 94.7%
	Negative	1 5.3%
Week 60	Number Analyzed	18 participants
	Positive	17 94.4%
	Negative	1 5.6%
Week 65	Number Analyzed	191 participants
	Positive	153 80.1%
	Negative	38 19.9%
Week 78	Number Analyzed	191 participants
	Positive	146 76.4%
	Negative	45 23.6%

Adverse Events

Time Frame	Treatment-emergent adverse events = from the first dose of study drug administration through the end of the study, up to 78 weeks
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Placebo	Teplizumab
Arm/Group Description	Safety population	Safety population
All-Cause Mortality
	Placebo	Teplizumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/111 (0.00%)	0/217 (0.00%)
Serious Adverse Events
	Placebo	Teplizumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	6/111 (5.41%)	12/217 (5.53%)
Cardiac disorders
Palpitation † 1	0/111 (0.00%)	1/217 (0.46%)
Gastrointestinal disorders
Vomiting † 1	0/111 (0.00%)	1/217 (0.46%)
Constipation † 1	1/111 (0.90%)	0/217 (0.00%)
Immune system disorders
Cytokine release syndrome † 1	0/111 (0.00%)	3/217 (1.38%)
Infections and infestations
Device related bacteraemia † 1	1/111 (0.90%)	0/217 (0.00%)
Gastroenteritis † 1	2/111 (1.80%)	0/217 (0.00%)
Injury, poisoning and procedural complications
Concussion † 1	0/111 (0.00%)	1/217 (0.46%)
Metabolism and nutrition disorders
Hypoglycaemia † 1	1/111 (0.90%)	1/217 (0.46%)
Hyperglycaemia † 1	0/111 (0.00%)	1/217 (0.46%)
Nervous system disorders
Syncope † 1	1/111 (0.90%)	0/217 (0.00%)
Psychiatric disorders
Suicidal ideation † 1	0/111 (0.00%)	2/217 (0.92%)
Suicide attempt † 1	0/111 (0.00%)	1/217 (0.46%)
Anxiety † 1	1/111 (0.90%)	0/217 (0.00%)
Renal and urinary disorders
Nephrolithiasis † 1	0/111 (0.00%)	1/217 (0.46%)
Skin and subcutaneous tissue disorders
Dermatitis atopic † 1	0/111 (0.00%)	1/217 (0.46%)
1 Term from vocabulary, 26.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	Teplizumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	88/111 (79.28%)	212/217 (97.70%)
Blood and lymphatic system disorders
Lymphopenia † 1	0/111 (0.00%)	50/217 (23.04%)
Neutropenia † 1	1/111 (0.90%)	28/217 (12.90%)
Leukopenia † 1	1/111 (0.90%)	26/217 (11.98%)
Anaemia † 1	5/111 (4.50%)	13/217 (5.99%)
Cardiac disorders
Tachycardia † 1	1/111 (0.90%)	12/217 (5.53%)
Gastrointestinal disorders
Nausea † 1	21/111 (18.92%)	92/217 (42.40%)
Vomiting † 2	15/111 (13.51%)	68/217 (31.34%)
Abdominal pain † 2	9/111 (8.11%)	37/217 (17.05%)
Abdominal pain upper † 2	12/111 (10.81%)	31/217 (14.29%)
Diarrhoea † 2	12/111 (10.81%)	31/217 (14.29%)
General disorders
Pyrexia † 1	11/111 (9.91%)	53/217 (24.42%)
Fatigue † 1	15/111 (13.51%)	22/217 (10.14%)
Chills † 1	0/111 (0.00%)	19/217 (8.76%)
Immune system disorders
Cytokine release syndrome † 1	1/111 (0.90%)	16/217 (7.37%)
Infections and infestations
COVID-19 † 2	26/111 (23.42%)	49/217 (22.58%)
Upper respiratory tract infection † 2	23/111 (20.72%)	44/217 (20.28%)
Nasopharyngitis † 2	14/111 (12.61%)	19/217 (8.76%)
Gastroenteritis † 2	10/111 (9.01%)	9/217 (4.15%)
Investigations
Lymphocyte count decreased † 1	5/111 (4.50%)	73/217 (33.64%)
White blood cell count decreased † 1	6/111 (5.41%)	53/217 (24.42%)
Neutrophil count decreased † 1	11/111 (9.91%)	33/217 (15.21%)
Alanine aminotransferase increased † 1	0/111 (0.00%)	28/217 (12.90%)
Aspartate Aminotransferase increased † 1	1/111 (0.90%)	20/217 (9.22%)
Metabolism and nutrition disorders
Hypoglycaemia † 1	81/111 (72.97%)	151/217 (69.59%)
Decreased appetite † 2	3/111 (2.70%)	11/217 (5.07%)
Musculoskeletal and connective tissue disorders
Pain in extremity † 2	6/111 (5.41%)	15/217 (6.91%)
Arthralgia † 2	5/111 (4.50%)	14/217 (6.45%)
Nervous system disorders
Headache † 1	21/111 (18.92%)	94/217 (43.32%)
Dizziness † 1	5/111 (4.50%)	11/217 (5.07%)
Renal and urinary disorders
Proteinuria † 1	3/111 (2.70%)	14/217 (6.45%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	12/111 (10.81%)	20/217 (9.22%)
Nasal congestion † 1	6/111 (5.41%)	19/217 (8.76%)
Oropharyngeal pain † 1	16/111 (14.41%)	19/217 (8.76%)
Rhinorrhoea † 1	4/111 (3.60%)	11/217 (5.07%)
Skin and subcutaneous tissue disorders
Rash † 1	5/111 (4.50%)	86/217 (39.63%)
Rash maculo-papular † 2	4/111 (3.60%)	29/217 (13.36%)
Pruritus † 2	9/111 (8.11%)	17/217 (7.83%)
Rash macular † 2	0/111 (0.00%)	11/217 (5.07%)
Dermatitis † 2	6/111 (5.41%)	9/217 (4.15%)
Erythema † 2	6/111 (5.41%)	7/217 (3.23%)
Vascular disorders
Hypotension † 1	10/111 (9.01%)	18/217 (8.29%)
1 Term from vocabulary, 26.0; 2 Term from vocabulary, MedDRA 26.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

Enrollment into the study was temporarily suspended due to COronaVIrus Disease of 2019 (COVID-19) pandemic restrictions. Participants who were unable to receive the second 12-day treatment course at 6 months due to COVID-19 pandemic restrictions were given the second course at approximately 12 months (modified dosing schedule).

More Information

Certain Agreements

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

There IS 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.

Sponsor has right to publish multi-center study results first, then PI may publish/present study results after Sponsor had at least 60 days and up to 105 days to review/comment/obtain intellectual property protection, PI has deleted all sponsor-requested references to confidential information, and PI has considered the Sponsor's proposed revisions in good faith and meets with the Sponsor to discuss/ resolve any disagreements regarding accuracy, data analyses or confidential information.

Results Point of Contact

• Name/Title: Clinical and Translational Medicine Lead
• Organization: Sanofi
• Phone: 1-703-344-2992
• EMail: laura.knecht@sanofi.com

Publications of Results:

Ramos EL, Dayan CM, Chatenoud L, Sumnik Z, Simmons KM, Szypowska A, Gitelman SE, Knecht LA, Niemoeller E, Tian W, Herold KC; PROTECT Study Investigators. Teplizumab and beta-Cell Function in Newly Diagnosed Type 1 Diabetes. N Engl J Med. 2023 Dec 7;389(23):2151-2161. doi: 10.1056/NEJMoa2308743. Epub 2023 Oct 18.

• Responsible Party: Provention Bio, Inc.
• ClinicalTrials.gov Identifier: NCT03875729
• Other Study ID Numbers: PRV-031-001
• First Submitted: March 13, 2019
• First Posted: March 15, 2019
• Results First Submitted: February 8, 2024
• Results First Posted: April 24, 2024
• Last Update Posted: April 24, 2024