Trial Outcomes & Findings for Trial of Otelixizumab for Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-1 (NCT NCT00678886)

Last Updated: 2017-10-03

Results Overview

Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from Time 0 to 120 minutes, calculated using the trapezoidal rule. This reported AUC was normalized for time interval by dividing it by 120 minutes. This normalized AUC was calculated for each participant at Baseline, Week 12, and at Months 6, 12, 18, and 24. Data has been presented for meal stimulated C-peptide Area under assessment performed at Month 12. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Month 12.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

272 participants

Primary outcome timeframe

Baseline (0-120 minutes on Day 1) and Month 12 (0-120 minutes)

Results posted on

2017-10-03

Participant Flow

This study was conducted at 85 centers in 9 countries namely Canada (4), Germany (3), Denmark (1), Spain (5), Finland (2), United Kingdom (4), Italy (8), Sweden (11) and United States of America (47) from 29 July 2008 to 31 January 2012. A total of 240 participants with new-onset Type 1 diabetes mellitus (NOT1DM) were planned to be enrolled.

Participants were screened for a period of 35 days and a total of 272 participants were randomized in the study.

Participant milestones

Participant milestones
Measure	Adolescent (Placebo) Eligible adolescent participants received matching placebo to Otelixizumab administered as intravenous (IV) infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Adolescent (Otelixizumab) Eligible adolescent participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 milligram \[mg\], second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.	Adult (Placebo) Eligible adult participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive Days. Participants were followed-up for 24 months after the last dose.	Adult (Otelixizumab) Eligible adult participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg), second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Overall Study STARTED	10	19	81	162
Overall Study COMPLETED	10	19	72	153
Overall Study NOT COMPLETED	0	0	9	9

Reasons for withdrawal

Reasons for withdrawal
Measure	Adult (Placebo) Eligible adult participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive Days. Participants were followed-up for 24 months after the last dose.	Adult (Otelixizumab) Eligible adult participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg), second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Overall Study Withdrawal by Subject	4	6
Overall Study Physician Decision	1	1
Overall Study Lost to Follow-up	3	2
Overall Study Other	1	0

Baseline Characteristics

Trial of Otelixizumab for Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-1

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.	Total n=272 Participants Total of all reporting groups
Age, Continuous	25.2 Years STANDARD_DEVIATION 7.13 • n=5 Participants	24.7 Years STANDARD_DEVIATION 6.54 • n=7 Participants	24.9 Years STANDARD_DEVIATION 6.73 • n=5 Participants
Sex: Female, Male Female	31 Participants n=5 Participants	64 Participants n=7 Participants	95 Participants n=5 Participants
Sex: Female, Male Male	60 Participants n=5 Participants	117 Participants n=7 Participants	177 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	6 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) White	85 Participants n=5 Participants	169 Participants n=7 Participants	254 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (0-120 minutes on Day 1) and Month 12 (0-120 minutes)

Population: Intent-to-treat (ITT) population, comprised of all participants who were randomized and received any part of at least 1 infusion of study drug.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Change From Baseline in 2-hour Mixed Meal Stimulated C-peptide Area Under Curve [AUC] (Normalized for 120-minute Time Interval) at Month 12	-0.21 nanomoles per liter Standard Error 0.030	-0.21 nanomoles per liter Standard Error 0.021

SECONDARY outcome

Timeframe: Week 12 and Months 6 and 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

A participant was considered a responder if, at the given time point, the participant had HbA1c\<= 6.5%, and mean daily insulin use over 7 consecutive days \< 0.5 international units per kilogram per day (IU/kg/day) during the 2 weeks preceding the visit. Data has been presented from number of participants with their percentages who were responders at Week 12 and Months 6 and 12.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Number of Participants Who Were Responders for (Glycosylated Hemoglobin) HbA1c/Insulin Use Response at Week 12 and Months 6 and 12 Responders at Week 12	45 Participants	85 Participants
Number of Participants Who Were Responders for (Glycosylated Hemoglobin) HbA1c/Insulin Use Response at Week 12 and Months 6 and 12 Responders at Month 6	42 Participants	74 Participants
Number of Participants Who Were Responders for (Glycosylated Hemoglobin) HbA1c/Insulin Use Response at Week 12 and Months 6 and 12 Responders at Month 12	34 Participants	56 Participants

SECONDARY outcome

Timeframe: Week 12 and Months 6 and 12.

Population: ITT population.

Participants recorded their daily insulin use in their electronic diaries. In particular, insulin was recorded thoroughly and accurately for at least 7 consecutive days during the 2 weeks before the visits at Baseline, Week 12, and Months 6 and 12. During each of these visits, the investigator/designee accessed the invivodata DiaryPRO web site to review insulin-use data for the previous 2-week period to ensure completeness. If errors/gaps were identified (e.g., if the participant did not take insulin and not entered 0 units), the investigator/designee recorded the missing data from participant recall using a data clarification form (DCF). Paper diary to collect insulin use, were reviewed for completeness. Any missing data that could be recalled by the participant was entered. If the participant did not record any insulin use during the 2-week period before the visit, the site obtained an insulin use history for the previous 7 days and calculated the average daily insulin dose.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Mean Daily Insulin Use at Week 12 and Months 6 and 12. Mean daily insulin use at Week 12	0.34 IU/kg Standard Error 0.017	0.31 IU/kg Standard Error 0.013
Mean Daily Insulin Use at Week 12 and Months 6 and 12. Mean daily insulin use at Month 6	0.36 IU/kg Standard Error 0.022	0.36 IU/kg Standard Error 0.016
Mean Daily Insulin Use at Week 12 and Months 6 and 12. Mean daily insulin use at Month 12	0.42 IU/kg Standard Error 0.023	0.39 IU/kg Standard Error 0.017

SECONDARY outcome

Timeframe: Week 12 and Months 6 and 12

Population: ITT population.

HbA1c levels were recorded at Screening, Baseline (Day 1), Day 28, Week 8, Week 12, Months 4 to 12 and Month 24. Data has been presented for HbA1c levels at Week 12 and Months 6 and 12.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
HbA1c Level at Week 12 and Months 6 and 12 HbA1c levels at Month 12	6.83 Percentage Standard Error 0.146	7.02 Percentage Standard Error 0.108
HbA1c Level at Week 12 and Months 6 and 12 HbA1c levels at Month 6	6.60 Percentage Standard Error 0.138	6.77 Percentage Standard Error 0.100
HbA1c Level at Week 12 and Months 6 and 12 HbA1c levels at Week 12	6.45 Percentage Standard Error 0.124	6.54 Percentage Standard Error 0.094

SECONDARY outcome

Timeframe: Upto Month 12

Population: ITT population.

Hypoglycemic events reported by participants were classified as defined by the American Diabetes Association (ADA) Workgroup on Hypoglycemia as follows: Severe hypoglycemia: an event requiring assistance of another person to actively administer carbohydrate, glucagon/other resuscitative actions, documented symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration(PGC)\<=70 mg/dL, asymptomatic hypoglycemia: an event not accompanied by typical symptoms of hypoglycemia but with a measured PGC\<=70 mg/dL,probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia are not accompanied by a plasma glucose determination, but were presumably caused by a PGC\<=70 mg/dL and relative hypoglycemia: an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia, and interprets the symptoms as indicative of hypoglycemia, but with a measured PGC\>70 mg/dL.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Number of Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12 Severe hypoglycemia upto Month 12	2 Hypoglycemic events	5 Hypoglycemic events
Number of Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12 Documented symptomatic hypoglycemia upto Month 12	3092 Hypoglycemic events	6322 Hypoglycemic events
Number of Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12 Asymptomatic hypoglycemia upto Month 12	4718 Hypoglycemic events	9962 Hypoglycemic events
Number of Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12 Probable symptomatic hypoglycemia upto Month 12	84 Hypoglycemic events	93 Hypoglycemic events
Number of Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12 Relative hypoglycemia upto Month 12	85 Hypoglycemic events	211 Hypoglycemic events

SECONDARY outcome

Timeframe: Upto Month 12

Population: ITT population. Data has been presented for number of participants with their percentages with hypoglycemic events defined by hypoglycemic event categories from Baseline upto month 12.

Hypoglycemic events reported by participants were classified as defined by the ADA Workgroup on Hypoglycemia as Severe hypoglycemia: an event requiring assistance of another person to actively administer carbohydrate, glucagon/other resuscitative actions, documented symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration (PGC)\<=70 mg/dL, asymptomatic hypoglycemia: an event not accompanied by typical symptoms of hypoglycemia but with a measured PGC\<=70 mg/dL,probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia are not accompanied by a plasma glucose determination, but were presumably caused by a PGC\<=70 mg/dL and relative hypoglycemia: an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia, and interprets the symptoms as indicative of hypoglycemia, but with a measured PGC\>70 mg/dL. Only categories with values are presented.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Number of Participants With Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12 Severe hypoglycemia upto Month 12	2 Participants	4 Participants
Number of Participants With Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12 Documented symptomatic hypoglycemia upto Month 12	78 Participants	163 Participants
Number of Participants With Hypoglycemic Events Defined by Hypoglycemic Event Categories From Baseline Upto Month 12 Asymptomatic hypoglycemia upto Month 12	10 Participants	13 Participants

SECONDARY outcome

Timeframe: Week 12 and Months 6 and 12.

Population: ITT population. Only those participants available at the specified time points were analyzed.

The event frequency of glucose measurements that were hypoglycemic excursions were calculated per participant basis, using the number of occurrences where blood glucose was less than or equal to 70 mg/dL. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Number of Hypoglycemic Excursions (<=70 mg/dL) With Most Complete Glucose at Week 12 and Months 6 and 12. Number of hypoglycemic excursions at Week 12	2.3 Hypoglycemic excursions Standard Error 0.28	2.8 Hypoglycemic excursions Standard Error 0.27
Number of Hypoglycemic Excursions (<=70 mg/dL) With Most Complete Glucose at Week 12 and Months 6 and 12. Number of hypoglycemic excursions at Month 6	3.0 Hypoglycemic excursions Standard Error 0.36	2.9 Hypoglycemic excursions Standard Error 0.27
Number of Hypoglycemic Excursions (<=70 mg/dL) With Most Complete Glucose at Week 12 and Months 6 and 12. Number of hypoglycemic excursions at Month 12	2.9 Hypoglycemic excursions Standard Error 0.41	3.2 Hypoglycemic excursions Standard Error 0.32

SECONDARY outcome

Timeframe: Week 12 and Months 6 and 12.

Population: ITT population. Only those participants available at the specified time points were analyzed.

The greatest hypoglycemic excursions during an interval was calculated as 70 mg/dL minus the lowest recorded glucose level in the interval. If a participant had data recorded during the interval but did not have a value below 70 mg/dL, the participants greatest hypoglycemic excursion for that interval was 0 mg/dL. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Magnitude of Greatest Hypoglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Magnitude of excursion, Week 12	9.4 milligrams per deciliter Standard Error 0.92	10.8 milligrams per deciliter Standard Error 0.90
Magnitude of Greatest Hypoglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Magnitude of excursion, Month 6	11.9 milligrams per deciliter Standard Error 1.24	10.6 milligrams per deciliter Standard Error 0.77
Magnitude of Greatest Hypoglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Magnitude of excursion, Month 12	11.2 milligrams per deciliter Standard Error 1.20	11.0 milligrams per deciliter Standard Error 0.92

SECONDARY outcome

Timeframe: Week 12 and Months 6 and 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

Percentage of hypoglycemic excursions was calculated as the total number of observations that exceed the hypoglycemic excursion boundary (i.e.\<= 70 mg/dL) divided by the total number of glucose measurements recorded in a time interval for the intervals: Baseline to Week 12, post-Week 12 to Month 6, post-Month 6 to Month 12. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected. Data has been presented for number of participants with their percentages having hypoglycemic excursion.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Number of Participants With Hypoglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Percentage of participants with excursion,Week 12	72 Participants	127 Participants
Number of Participants With Hypoglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Percentage of participants with excursion,Month 6	57 Participants	121 Participants
Number of Participants With Hypoglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Percentage of participants with excursion,Month 12	56 Participants	111 Participants

SECONDARY outcome

Timeframe: Week 12 and Months 6 and 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

The event frequency of glucose measurements that were hyperglycemic excursions were calculated on a per participant basis using the number of occurrences where blood glucose was greater than the hyperglycemic tolerance limit. There were 3 hyperglycemic tolerance limits considered: 200 mg/dL, 130 mg/dL and 100 mg/dL. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold > 100 mg/dL at Week 12	34.0 Hyperglycemic excursions Standard Error 1.78	32.9 Hyperglycemic excursions Standard Error 1.15
Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold > 130 mg/dL at Week 12	20.5 Hyperglycemic excursions Standard Error 1.72	19.9 Hyperglycemic excursions Standard Error 1.01
Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold > 200 mg/dL at Week 12	5.7 Hyperglycemic excursions Standard Error 0.85	5.6 Hyperglycemic excursions Standard Error 0.59
Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold > 100 mg/dL at Month 6	33.5 Hyperglycemic excursions Standard Error 1.77	35.1 Hyperglycemic excursions Standard Error 1.41
Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold > 130 mg/dL at Month 6	20.8 Hyperglycemic excursions Standard Error 1.68	22.7 Hyperglycemic excursions Standard Error 1.25
Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold > 200 mg/dL at Month 6	6.5 Hyperglycemic excursions Standard Error 1.07	7.9 Hyperglycemic excursions Standard Error 0.85
Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold > 100 mg/dL at Month 12	35.6 Hyperglycemic excursions Standard Error 1.97	33.4 Hyperglycemic excursions Standard Error 1.27
Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold > 130 mg/dL at Month 12	24.0 Hyperglycemic excursions Standard Error 1.92	22.2 Hyperglycemic excursions Standard Error 1.05
Number of Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold > 200 mg/dL at Month 12	8.6 Hyperglycemic excursions Standard Error 1.42	6.9 Hyperglycemic excursions Standard Error 0.59

SECONDARY outcome

Timeframe: Week 12 and Months 6 and 12.

Population: ITT population. Only those participants available at the specified time points were analyzed.

The greatest hyperglycemic excursions during an interval was calculated as the largest recorded glucose level in the interval minus the hyperglycemic tolerance limit value (HGTLV). If a participant had data recorded during the interval but did not have a value above the HGTLV, the participants greatest hyperglycemic excursion for that interval was 0 mg/dL. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold> 100 mg/dL at Week 12	158.3 milligrams per deciliter Standard Error 9.26	158.4 milligrams per deciliter Standard Error 6.65
Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold> 130 mg/dL at Week 12	128.3 milligrams per deciliter Standard Error 9.26	128.4 milligrams per deciliter Standard Error 6.65
Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold> 200 mg/dL at Week 12	65.7 milligrams per deciliter Standard Error 8.51	65.7 milligrams per deciliter Standard Error 6.12
Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold> 100 mg/dL at Month 6	154.6 milligrams per deciliter Standard Error 9.34	175.7 milligrams per deciliter Standard Error 8.09
Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold> 130 mg/dL at Month 6	124.8 milligrams per deciliter Standard Error 9.31	145.7 milligrams per deciliter Standard Error 8.09
Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold> 200 mg/dL at Month 6	63.3 milligrams per deciliter Standard Error 8.32	80.1 milligrams per deciliter Standard Error 7.75
Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold> 100 mg/dL at Month 12	176.7 milligrams per deciliter Standard Error 10.02	177.5 milligrams per deciliter Standard Error 7.08
Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold> 130 mg/dL at Month 12	146.8 milligrams per deciliter Standard Error 10.00	147.5 milligrams per deciliter Standard Error 7.07
Magnitude of Greatest Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12. Threshold> 200 mg/dL at Month 12	81.8 milligrams per deciliter Standard Error 9.33	82.6 milligrams per deciliter Standard Error 6.61

SECONDARY outcome

Timeframe: Week 12 and Months 6 and 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

Percentage of hyperglycemic excursions was calculated as the total number of observations that exceed the hyperglycemic excursion boundary (i.e. \> HGTLV) divided by the total number of glucose measurements recorded in a time interval for the intervals: Baseline to Week 12, post-Week 12 to Month 6, post-Month 6 to Month 12. Most complete glucose interval was the 7 day period with the maximum number of days with at least 4 recordings per day. If these results were in more than one 7 day period, then the 7 day period with the largest average number of daily recordings (out of those with the maximum number of days with at least 4 recordings per day) was selected. If there were 2 or more 7 day periods that have the same number of days with at least 4 recordings and the same maximum average number of glucose recordings, the period that ended closest to the day of the study was selected. Data for number of participants with their percentages are presented.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Threshold> 100 mg/dL at Week 12	90 Participants	177 Participants
Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Threshold> 130 mg/dL at Week 12	90 Participants	177 Participants
Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Threshold> 200 mg/dL at Week 12	65 Participants	130 Participants
Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Threshold> 100 mg/dL at Month 6	80 Participants	166 Participants
Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Threshold> 130 mg/dL at Month 6	79 Participants	166 Participants
Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Threshold> 200 mg/dL at Month 6	57 Participants	139 Participants
Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Threshold> 100 mg/dL at Month 12	78 Participants	161 Participants
Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Threshold> 130 mg/dL at Month 12	77 Participants	160 Participants
Number of Participants With Hyperglycemic Excursions With Most Complete Glucose at Week 12 and Months 6 and 12 Threshold> 200 mg/dL at Month 12	60 Participants	131 Participants

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 12, Months 6 and 12.

Population: ITT population.

Average daily risk range is a measure for evaluation of blood glucose variability that was designed to be equally sensitive to hypoglycemia and hyperglycemia. The ADRR was assessed over 30-day periods prior to Baseline and at key visits Week 12 and Months 6 and 12. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Week 12 and Months 6 and 12.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Change From Baseline in Average Daily Risk Range (ADRR) at Week 12 and Months 6 and 12. ADRR at Month 6	2.03 Ratio Standard Error 1.133	2.86 Ratio Standard Error 0.801
Change From Baseline in Average Daily Risk Range (ADRR) at Week 12 and Months 6 and 12. ADRR at Week 12	-0.41 Ratio Standard Error 0.826	0.71 Ratio Standard Error 0.599
Change From Baseline in Average Daily Risk Range (ADRR) at Week 12 and Months 6 and 12. ADRR at Month 12	3.29 Ratio Standard Error 1.038	4.22 Ratio Standard Error 0.732

SECONDARY outcome

Timeframe: Month 6 and 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

O'Brien mean rank analyses was performed on a two-part composite of the baseline-adjusted HbA1c level and the baseline-adjusted mean total daily insulin use per kg body weight in the otelixizumab group compared with the placebo group at Months 6, 12. For the O'Brien mean rank analysis at a particular time point, adjusted HbA1c values (for both treatment groups together) was ranked from smallest to largest, and adjusted mean daily insulin use values were ranked from smallest to largest. For each participant, the HbA1c and insulin use ranks were added together, producing a composite rank. A treatment comparison test was then performed on the composite ranks.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Composite Rank Summary for HbA1c and Exogenous Insulin Use at Month 6 and Month 12 Composite rank summary, Month 12	245 Composite rank score Standard Deviation 120.0	244 Composite rank score Standard Deviation 115.2
Composite Rank Summary for HbA1c and Exogenous Insulin Use at Month 6 and Month 12 Composite rank summary, Month 6	238 Composite rank score Standard Deviation 123.3	247 Composite rank score Standard Deviation 113.7

SECONDARY outcome

Timeframe: Month 6 and 12

Population: ITT population. Only those participants available at the specified time points were analyzed.

O'Brien analyses will be performed on a three-part composite of HbA1c level, C-peptide AUC, and mean daily Insulin use in the otelixizumab group compared with the placebo group at Months 6 and12. For the O'Brien mean rank analysis at a particular time point, HbA1c and insulin use will be ranked from smallest to largest, and C-peptide AUC will be ranked from largest to smallest. For each participant, the C-Peptide AUC, ranks for HbA1c and insulin use were added together, producing a composite rank. A treatment comparison test was then performed on the composite ranks.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Composite Rank Summary for C-Peptide AUC, HbA1c and Exogenous Insulin Use at Month 6 and Month 12 Month 6	365 Composite rank score Standard Deviation 83.8	373 Composite rank score Standard Deviation 105.6
Composite Rank Summary for C-Peptide AUC, HbA1c and Exogenous Insulin Use at Month 6 and Month 12 Month 12	360 Composite rank score Standard Deviation 85.1	366 Composite rank score Standard Deviation 95.4

SECONDARY outcome

Timeframe: Day 1, Day 4, Day 8

Population: ITT population. Only those participants available at the specified time points were analyzed.

Levels of cytokine (TNFα, IL-6, IL-10) were measured at Baseline and at 2 hours after end of infusion (EOI) on Day 1, Day 4, Day 8 . Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Day 1, Day 4 and Day 8.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Change From Baseline in Level of Cytokines Interleukin (IL-6), IL-10 and Tumor Necrosis Factor-alpha (TNF-a) at Day 1, Day 4, Day 8 TNF-a levels, Day 8, 2 hours after EOI	0.135 picograms per milliliter Standard Error 0.2649	3.614 picograms per milliliter Standard Error 0.8920
Change From Baseline in Level of Cytokines Interleukin (IL-6), IL-10 and Tumor Necrosis Factor-alpha (TNF-a) at Day 1, Day 4, Day 8 IL-6 levels, Day 8, 2 hours after EOI	0.45 picograms per milliliter Standard Error 0.448	14.59 picograms per milliliter Standard Error 5.266
Change From Baseline in Level of Cytokines Interleukin (IL-6), IL-10 and Tumor Necrosis Factor-alpha (TNF-a) at Day 1, Day 4, Day 8 IL-6 levels, Day 1, 2 hours after EOI	0.76 picograms per milliliter Standard Error 0.680	2.78 picograms per milliliter Standard Error 0.544
Change From Baseline in Level of Cytokines Interleukin (IL-6), IL-10 and Tumor Necrosis Factor-alpha (TNF-a) at Day 1, Day 4, Day 8 IL-6 levels, Day 4, 2 hours after EOI	-0.13 picograms per milliliter Standard Error 0.251	3.01 picograms per milliliter Standard Error 1.107
Change From Baseline in Level of Cytokines Interleukin (IL-6), IL-10 and Tumor Necrosis Factor-alpha (TNF-a) at Day 1, Day 4, Day 8 IL-10 levels, Day 1, 2 hours after EOI	0.15 picograms per milliliter Standard Error 0.342	4.61 picograms per milliliter Standard Error 1.770
Change From Baseline in Level of Cytokines Interleukin (IL-6), IL-10 and Tumor Necrosis Factor-alpha (TNF-a) at Day 1, Day 4, Day 8 IL-10 levels, Day 4, 2 hours after EOI	0.55 picograms per milliliter Standard Error 0.629	1.35 picograms per milliliter Standard Error 0.575
Change From Baseline in Level of Cytokines Interleukin (IL-6), IL-10 and Tumor Necrosis Factor-alpha (TNF-a) at Day 1, Day 4, Day 8 IL-10 levels, Day 8, 2 hours after EOI	1.84 picograms per milliliter Standard Error 1.019	25.57 picograms per milliliter Standard Error 7.196
Change From Baseline in Level of Cytokines Interleukin (IL-6), IL-10 and Tumor Necrosis Factor-alpha (TNF-a) at Day 1, Day 4, Day 8 TNF-a levels, Day 1, 2 hours after EOI	-0.126 picograms per milliliter Standard Error 0.0719	2.320 picograms per milliliter Standard Error 0.3996
Change From Baseline in Level of Cytokines Interleukin (IL-6), IL-10 and Tumor Necrosis Factor-alpha (TNF-a) at Day 1, Day 4, Day 8 TNF-a levels, Day 4, 2 hours after EOI	0.111 picograms per milliliter Standard Error 0.2381	1.509 picograms per milliliter Standard Error 0.5740

SECONDARY outcome

Timeframe: Baseline (pre-dose on Day 1) and up to 12 Months

Population: ITT population. Only those participants available at the specified time points were analyzed.

Blood samples were drawn for lymphocyte subset evaluations at Baseline and at 2hours after EOI on Day 4, pre-dose and after E0I on Day 8, Day 14, Day 21, Day 28, Week 6, Week 8, Week 10, Week 12, Month 6 and Month 12. Percentages of relevant lymphocyte subsets were determined by flow cytometry. The lymphocyte subsets assessed included CD8+CD25+ T lymphocytes, as well as the subsets of lymphocytes of these type that were positive for FoxP3, a protein that was expressed at high levels in the cytoplasm of regulatory T cells. CD4+CD25hiFoxP3+ T lymphocytes, a cell type was of interest because it played a regulatory role in T1DM. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at the time of assessment.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Day 4, 2 hours after EOI	118.8 Percent change Interval 32.1 to 366.9	53.4 Percent change Interval 3.4 to 235.9
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Day 8 pre-dose	94.4 Percent change Interval 25.9 to 199.9	49.7 Percent change Interval 9.4 to 148.5
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Day 8, 2 hours after EOI	113.2 Percent change Interval 28.8 to 2127.6	40.1 Percent change Interval 2.1 to 3737.0
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Day 14	114.5 Percent change Interval 26.5 to 2384.4	101.3 Percent change Interval 15.5 to 10906.4
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Day 21	114.6 Percent change Interval 34.8 to 489.8	101.9 Percent change Interval 0.0 to 44228.1
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Day 28	95.1 Percent change Interval 7.0 to 1612.7	101.7 Percent change Interval 2.1 to 6363.7
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Week 6	104.1 Percent change Interval 0.0 to 514.2	106.6 Percent change Interval 0.0 to 7010.9
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Week 8	110.1 Percent change Interval 29.1 to 1602.3	107.1 Percent change Interval 4.7 to 15806.4
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Week 10	109.9 Percent change Interval 8.6 to 1820.9	102.7 Percent change Interval 7.4 to 9943.6
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Week 12	102.5 Percent change Interval 9.8 to 1018.7	85.5 Percent change Interval 2.9 to 9911.7
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Month 6	137.9 Percent change Interval 19.5 to 1409.6	133.3 Percent change Interval 19.8 to 10357.4
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25+FoxP3+ T, Month 12	122.0 Percent change Interval 9.5 to 628.7	106.9 Percent change Interval 0.4 to 31690.3
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Day 4, 2 hours after EOI	151.9 Percent change Interval 12.6 to 400.8	60.8 Percent change Interval 1.5 to 364.5
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Day 8 pre-dose	93.8 Percent change Interval 13.6 to 521.7	43.5 Percent change Interval 3.6 to 675.0
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Day 8, 2 hours after EOI	110.7 Percent change Interval 18.6 to 3577.8	35.9 Percent change Interval 0.0 to 321279.0
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Day 14	118.4 Percent change Interval 8.8 to 1502.5	109.7 Percent change Interval 5.8 to 1364664.0
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Day 21	110.0 Percent change Interval 9.7 to 1720.2	98.8 Percent change Interval 0.0 to 1479653.0
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Day 28	101.1 Percent change Interval 2.1 to 949.9	108.7 Percent change Interval 0.0 to 62190.9
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Week 6	106.9 Percent change Interval 0.0 to 2508.7	110.7 Percent change Interval 0.0 to 9573.5
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Week 8	131.7 Percent change Interval 14.1 to 843.2	120.3 Percent change Interval 0.5 to 175040.0
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Week 10	97.7 Percent change Interval 1.5 to 2356.8	107.0 Percent change Interval 0.0 to 128591.0
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Week 12	113.6 Percent change Interval 1.9 to 1310.2	90.9 Percent change Interval 0.1 to 1045228.0
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Month 6	150.9 Percent change Interval 6.1 to 25639.5	153.2 Percent change Interval 5.5 to 1544544.0
Percent Change From Baseline in Circulating Peripheral Lymphocytes CD4+CD25+FoxP3+ T Cells and CD4+CD25hiFoxP3+ T Cells in Type 1 Diabetes Mellitus (TIDM) up to Month 12 CD4+CD25hiFoxP3+ T Cells, Month 12	166.4 Percent change Interval 5.1 to 1748.9	160.6 Percent change Interval 0.0 to 78843.4

SECONDARY outcome

Timeframe: Baseline (pre-dose on Day 1), Day 4 and Day 8

Population: ITT population. Only those participants available at the specified time points were analyzed.

The amount of cell-bound otelixizumab was determined by flow cytometry. The extent of T cell receptor alpha beta (TCRαβ) expression was determined using an antibody that bound to TCRαβ but did not compete with otelixizumab for binding sites at the expected range of concentrations. The MESF of the anti-TCRαβ antibody was used to quantify the number of CD3/TCR complexes present on T cells. Free otelixizumab binding sites (sites not occupied by otelixizumab) were detected by staining with biotinylated otelixizumab. The MESF of bound biotinylated otelixizumab was directly proportional to the availability of free otelixizumab binding sites. MESF of bound antibody on CD4+ T cells was a direct measurement of cell-bound otelixizumab on CD4+ T cells. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Day 1, Day 4 and Day 8.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Percent Change From Baseline in Cell-bound Otelixizumab on CD4+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 1, 2 hours after EOI	125.1 Percent change Standard Error 18.00	914.8 Percent change Standard Error 269.18
Percent Change From Baseline in Cell-bound Otelixizumab on CD4+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 4, 2 hours after EOI	174.3 Percent change Standard Error 41.95	2719.8 Percent change Standard Error 369.41
Percent Change From Baseline in Cell-bound Otelixizumab on CD4+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 8, pre-dose	151.5 Percent change Standard Error 39.49	471.5 Percent change Standard Error 98.53
Percent Change From Baseline in Cell-bound Otelixizumab on CD4+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 8, 2 hours after EOI	167.9 Percent change Standard Error 47.67	1387.5 Percent change Standard Error 274.21

SECONDARY outcome

Timeframe: Baseline (Pre-dose Day 1), Day 4, Day 8

Population: ITT population. Only those participants available at the specified time points were analyzed.

The extent of saturation of CD3/TCR receptors on CD4+ and CD8+ lymphocytes was determined by flow cytometry. The extent of TCRαβ expression was determined using an antibody that bound to TCRαβ but did not compete with otelixizumab for binding sites at the expected range of concentrations. The MESF of the anti-TCRαβ antibody was used to quantify the number of CD3/TCR complexes present on T cells. The MESF of bound biotinylated otelixizumab was directly proportional to the availability of free otelixizumab binding sites. MESF of free CD3 sites on CD4+ T cells and CD8+ T cells was direct measurement of saturation of the CD3/TCR complex on CD4+ T cells and CD8+ T cells. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Day 1, Day 4 and Day 8.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Percent Change From Baseline in CD3/TCR Saturation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 1, 2 hours after EOI	93.4 Percent change Standard Error 2.40	90.9 Percent change Standard Error 3.82
Percent Change From Baseline in CD3/TCR Saturation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 4, 2 hours after EOI	109.7 Percent change Standard Error 11.91	50.2 Percent change Standard Error 4.90
Percent Change From Baseline in CD3/TCR Saturation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 8, pre-dose	97.7 Percent change Standard Error 10.66	59.0 Percent change Standard Error 5.31
Percent Change From Baseline in CD3/TCR Saturation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 8, 2 hours after EOI	98.0 Percent change Standard Error 13.03	21.7 Percent change Standard Error 3.33
Percent Change From Baseline in CD3/TCR Saturation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD8+ T cells, Day 1, 2 hours after EOI	92.4 Percent change Standard Error 2.38	91.4 Percent change Standard Error 3.82
Percent Change From Baseline in CD3/TCR Saturation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD8+ T cells, Day 4, 2 hours after EOI	116.7 Percent change Standard Error 14.53	51.6 Percent change Standard Error 5.23
Percent Change From Baseline in CD3/TCR Saturation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD8+ T cells, Day 8, pre-dose	97.4 Percent change Standard Error 11.84	60.8 Percent change Standard Error 6.11
Percent Change From Baseline in CD3/TCR Saturation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD8+ T cells, Day 8, 2 hours after EOI	98.2 Percent change Standard Error 14.63	23.0 Percent change Standard Error 3.72

SECONDARY outcome

Timeframe: Baseline (Pre-dose Day 1), Day 4, Day 8

Population: ITT population. Only those participants available at the specified time points were analyzed.

The extent of modulation of CD3/TCR receptors on CD4+ and CD8+ lymphocytes was determined by flow cytometry. The extent of TCRαβ expression was determined using an antibody that bound to TCRαβ but did not compete with otelixizumab for binding sites at the expected range of concentrations. The MESF of the anti-TCRαβ antibody was used to quantify the number of CD3/TCR complexes present on T cells. The MESF of bound biotinylated otelixizumab was directly proportional to the availability of free otelixizumab binding sites.CD3/TCR complexes on CD4+ and CD8+ T cells were detected with a non-competing antibody. Changes in the MESF of TCR expression was a direct measurement of TCR modulation. Baseline assessments were carried out on the morning of Day 1, before the start of the first infusion of study drug. Change from Baseline was calculated by subtracting the Baseline value from the post-randomization value at Day 1, Day 4 and Day 8.

Outcome measures

Outcome measures
Measure	Placebo n=91 Participants Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 Participants Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Percent Change From Baseline in CD3/TCR Modulation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 1, 2 hours after EOI	94.2 Percent change Standard Error 2.95	91.1 Percent change Standard Error 2.90
Percent Change From Baseline in CD3/TCR Modulation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 4, 2 hours after EOI	103.8 Percent change Standard Error 8.93	70.8 Percent change Standard Error 3.89
Percent Change From Baseline in CD3/TCR Modulation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 8, pre-dose	101.4 Percent change Standard Error 6.09	61.0 Percent change Standard Error 2.65
Percent Change From Baseline in CD3/TCR Modulation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD4+ T cells, Day 8, 2 hours after EOI	103.4 Percent change Standard Error 5.87	32.2 Percent change Standard Error 2.52
Percent Change From Baseline in CD3/TCR Modulation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD8+ T cells, Day 1, 2 hours after EOI	95.2 Percent change Standard Error 2.72	93.7 Percent change Standard Error 3.06
Percent Change From Baseline in CD3/TCR Modulation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD8+ T cells, Day 4, 2 hours after EOI	111.1 Percent change Standard Error 10.56	77.1 Percent change Standard Error 4.33
Percent Change From Baseline in CD3/TCR Modulation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD8+ T cells, Day 8, pre-dose	101.8 Percent change Standard Error 6.19	62.3 Percent change Standard Error 2.68
Percent Change From Baseline in CD3/TCR Modulation on CD4+ T Cells and CD8+ T Cells at Day 1, Day 4, Day 8 CD8+ T cells, Day 8, 2 hours after EOI	103.0 Percent change Standard Error 6.05	36.2 Percent change Standard Error 2.52

Adverse Events

Placebo

Serious events: 6 serious events

Other events: 81 other events

Deaths: 0 deaths

Otelixizumab

Serious events: 15 serious events

Other events: 173 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=91 participants at risk Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 participants at risk Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Infections and infestations Anal abscess	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Infections and infestations Appendicitis	1.1% 1/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.00% 0/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Infections and infestations Gastroenteritis viral	1.1% 1/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.00% 0/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Infections and infestations Septic embolus	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Infections and infestations Tonsillitis	1.1% 1/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.00% 0/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Infections and infestations Viral upper respiratory tract infection	1.1% 1/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.00% 0/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Immune system disorders Cytokine release syndrome	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	1.7% 3/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Injury, poisoning and procedural complications Alcohol poisoning	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Injury, poisoning and procedural complications Ligament rupture	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Anal fistula	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Gastritis erosive	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Metabolism and nutrition disorders Hypoglycaemic seizure	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Nervous system disorders Neurological symptom	1.1% 1/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.00% 0/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Nervous system disorders Paraesthesia	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Psychiatric disorders Alcohol abuse	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Psychiatric disorders Major depression	1.1% 1/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.00% 0/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Hepatobiliary disorders Cholelithiasis	1.1% 1/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.00% 0/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Pregnancy, puerperium and perinatal conditions Abortion missed	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	0.55% 1/181 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.

Measure	Placebo n=91 participants at risk Eligible participants received matching placebo to Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per Day over 8 consecutive days. Participants were followed-up for 24 months after the last dose.	Otelixizumab n=181 participants at risk Eligible participants received Otelixizumab administered as IV infusions, with each infusion given over a 30-minute period. Participants received a series of 8 infusions as first dose (Day 1 of 0.1 mg, second dose (Day 2 of 0.2 mg), third dose (Day 3 of 0.3 mg), fourth, fifth, sixth, seventh and eight dose (on Days 4,5,6,7,8 of 0.5 mg per Day) 1 infusion per Day over 8 consecutive days . The total amount of Otelixizumab administered was 3.1 mg. Participants were followed-up for 24 months after the last dose.
Nervous system disorders Headache	49.5% 45/91 • Number of events 117 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	85.6% 155/181 • Number of events 441 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Nausea	22.0% 20/91 • Number of events 32 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	33.1% 60/181 • Number of events 91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Infections and infestations Nasopharyngitis	31.9% 29/91 • Number of events 42 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	26.5% 48/181 • Number of events 83 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
General disorders Fatigue	22.0% 20/91 • Number of events 32 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	23.2% 42/181 • Number of events 58 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	26.4% 24/91 • Number of events 35 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	13.8% 25/181 • Number of events 35 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Vomiting	14.3% 13/91 • Number of events 15 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	19.3% 35/181 • Number of events 40 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
General disorders Pyrexia	11.0% 10/91 • Number of events 10 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	18.8% 34/181 • Number of events 45 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Myalgia	15.4% 14/91 • Number of events 27 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	11.6% 21/181 • Number of events 32 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Infections and infestations Upper respiratory tract infection	11.0% 10/91 • Number of events 15 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	12.2% 22/181 • Number of events 29 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Blood and lymphatic system disorders Lymphadenopathy	14.3% 13/91 • Number of events 20 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	9.9% 18/181 • Number of events 37 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
General disorders Chills	6.6% 6/91 • Number of events 9 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	13.3% 24/181 • Number of events 32 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Nervous system disorders Dizziness	13.2% 12/91 • Number of events 20 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	9.9% 18/181 • Number of events 23 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Metabolism and nutrition disorders Hypoglycaemia	8.8% 8/91 • Number of events 16 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	12.2% 22/181 • Number of events 83 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Respiratory, thoracic and mediastinal disorders Cough	11.0% 10/91 • Number of events 11 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	10.5% 19/181 • Number of events 24 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	2.2% 2/91 • Number of events 4 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	11.0% 20/181 • Number of events 23 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Diarrhoea	8.8% 8/91 • Number of events 9 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	7.2% 13/181 • Number of events 19 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Back pain	5.5% 5/91 • Number of events 5 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	7.2% 13/181 • Number of events 16 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Infections and infestations Sinusitis	4.4% 4/91 • Number of events 4 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	6.6% 12/181 • Number of events 17 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Respiratory, thoracic and mediastinal disorders Nasal congestion	7.7% 7/91 • Number of events 9 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	4.4% 8/181 • Number of events 13 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Investigations Blood creatine phosphokinase increased	6.6% 6/91 • Number of events 6 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	4.4% 8/181 • Number of events 8 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	5.5% 5/91 • Number of events 5 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	5.0% 9/181 • Number of events 11 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Infections and infestations Pharyngitis	9.9% 9/91 • Number of events 13 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	2.2% 4/181 • Number of events 4 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Skin and subcutaneous tissue disorders Rash macular	3.3% 3/91 • Number of events 3 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	5.5% 10/181 • Number of events 17 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
General disorders Malaise	2.2% 2/91 • Number of events 2 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	5.5% 10/181 • Number of events 13 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Skin and subcutaneous tissue disorders Rash papular	0.00% 0/91 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	6.6% 12/181 • Number of events 15 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	2.2% 2/91 • Number of events 2 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	5.5% 10/181 • Number of events 11 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Psychiatric disorders Insomnia	5.5% 5/91 • Number of events 5 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	2.8% 5/181 • Number of events 6 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Respiratory, thoracic and mediastinal disorders Sinus congestion	5.5% 5/91 • Number of events 5 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	2.8% 5/181 • Number of events 7 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.
Infections and infestations Viral infection	6.6% 6/91 • Number of events 9 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.	1.7% 3/181 • Number of events 4 • Upto Month 24 Safety was used for analysis which comprised of all participants who received any part of at least 1 infusion of study drug.