Trial Outcomes & Findings for Trial of Otelixizumab for Adolescents and Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-2 (NCT NCT01123083)

Last Updated: 2017-09-15

Results Overview

C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg per deciliter (mg/dL) and no higher than 200 mg/dL. 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 AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the value at Month 12 from the Baseline value.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

179 participants

Primary outcome timeframe

Baseline (Day 1) and Month 12

Results posted on

2017-09-15

Participant Flow

This study was conducted across 73 centers in 10 countries (Belgium, Canada, Germany, Denmark, Spain, Finland, United Kingdom, Italy, Sweden, and United States of America) from 17 May 2010 to 09 March 2012.

A total of 179 participants (125 adults and 54 adolescents) were randomized in this study and included in safety and intent-to-treat (ITT) population.

Participant milestones

Participant milestones
Measure	Placebo Eligible participants received Placebo matching otelixizumab 3.1 milligrams (mg) as intravenous (IV) infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Overall Study STARTED	61	118
Overall Study COMPLETED	50	103
Overall Study NOT COMPLETED	11	15

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Eligible participants received Placebo matching otelixizumab 3.1 milligrams (mg) as intravenous (IV) infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Overall Study Investigator recommendation	1	1
Overall Study Administrative reasons	0	4
Overall Study Lost to Follow-up	2	6
Overall Study Adverse Event	1	0
Overall Study Withdrew for another reason not covered	0	1
Overall Study Participant/legal representative request	7	3

Baseline Characteristics

Trial of Otelixizumab for Adolescents and Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-2

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=61 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Total n=179 Participants Total of all reporting groups
Age, Continuous	22.5 Years STANDARD_DEVIATION 8.22 • n=5 Participants	23.6 Years STANDARD_DEVIATION 8.34 • n=7 Participants	23.2 Years STANDARD_DEVIATION 8.29 • n=5 Participants
Sex: Female, Male Female	24 Participants n=5 Participants	50 Participants n=7 Participants	74 Participants n=5 Participants
Sex: Female, Male Male	37 Participants n=5 Participants	68 Participants n=7 Participants	105 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	2 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	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	54 Participants n=5 Participants	111 Participants n=7 Participants	165 Participants n=5 Participants
Race (NIH/OMB) More than one race	4 Participants n=5 Participants	2 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 (Day 1) and Month 12

Population: ITT population consisted of all participants who were randomized and received any part of at least 1 infusion of study drug. Only those participants available at the indicated time points were analyzed.

Outcome measures

Outcome measures
Measure	Placebo n=45 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=96 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide Area Under Curve (AUC) (Normalized for 120-minute Time Interval) at Month 12	-0.14 nanomoles per liter Standard Error 0.036	-0.23 nanomoles per liter Standard Error 0.026

SECONDARY outcome

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

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

C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg/dL and no higher than 200 mg/dL. 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 AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=61 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide AUC (Normalized for 120-minute Time Interval) at Week 12 and 6 Months Week 12	0.05 nanomoles per liter Standard Error 0.031	-0.05 nanomoles per liter Standard Error 0.023
Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide AUC (Normalized for 120-minute Time Interval) at Week 12 and 6 Months Month 6	-0.04 nanomoles per liter Standard Error 0.037	-0.10 nanomoles per liter Standard Error 0.027

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 12, Month 6, 12, 18

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

C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg/dL and no higher than 200 mg/dL. 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 AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=61 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 Week 12	0.0519 nanomoles per liter Standard Deviation 0.24430	-0.0472 nanomoles per liter Standard Deviation 0.23394
Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 Month 6	-0.0455 nanomoles per liter Standard Deviation 0.23802	-0.0945 nanomoles per liter Standard Deviation 0.29151
Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 Month 12	-0.1236 nanomoles per liter Standard Deviation 0.24362	-0.2331 nanomoles per liter Standard Deviation 0.30537
Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18 Month 18	-0.4125 nanomoles per liter Standard Deviation 0.17059	0.0502 nanomoles per liter Standard Deviation 0.25597

SECONDARY outcome

Timeframe: Month 3, 6 and 12

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

A participant was considered a responder when, at the given time point, the participant had: glycosylated hemoglobin (HbA1c) less than or equal to 6.5 percent and mean daily insulin use less than 0.5 international unit per kilogram per day (IU/kg/day) over 7 consecutive days during the 2 weeks preceding the visit.

Outcome measures

Outcome measures
Measure	Placebo n=61 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Number of Participants With Responder Status Week 12	19 Participants	42 Participants
Number of Participants With Responder Status Month 6	11 Participants	26 Participants
Number of Participants With Responder Status Month 12	10 Participants	23 Participants

SECONDARY outcome

Timeframe: Baseline (Day 1) and Month 3, 6, 12

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

Mean daily insulin use over 7 consecutive days during the 2 weeks preceding each key visit was calculated as the mean of the values of amount of insulin used per day on each of the 7 consecutive days. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=61 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment Week 12	-0.04 International unit per kilogram (IU/kg) Standard Error 0.020	-0.08 International unit per kilogram (IU/kg) Standard Error 0.016
Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment Month 6	0.01 International unit per kilogram (IU/kg) Standard Error 0.027	-0.04 International unit per kilogram (IU/kg) Standard Error 0.021
Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment Month 12	0.01 International unit per kilogram (IU/kg) Standard Error 0.036	0.05 International unit per kilogram (IU/kg) Standard Error 0.028

SECONDARY outcome

Timeframe: Baseline (Day 1) and Month 3, 6, 12

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

HbA1c level was recorded at Baseline, Month 3, 6 and 12. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=61 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment Month 12	-0.61 Percentage of HbA1c Standard Error 0.188	-0.47 Percentage of HbA1c Standard Error 0.133
Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment Week 12	-0.82 Percentage of HbA1c Standard Error 0.140	-1.01 Percentage of HbA1c Standard Error 0.101
Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment Month 6	-0.65 Percentage of HbA1c Standard Error 0.185	-0.65 Percentage of HbA1c Standard Error 0.134

SECONDARY outcome

Timeframe: Baseline (Day 1) and Month 12

Population: ITT population.

Severe hypoglycemia was considered as an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Documented symptomatic hypoglycemia was considered as an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration less than or equal to 70 mg/dL and it was collected in (1) eCRF using two forms - for single event and for mutiple events, and (2) the IVRS system. The numbers of participant-reported hypoglycemic events per participant of severe hypoglycemia and documented symptomatic hypoglycemia have been reported.

Outcome measures

Outcome measures
Measure	Placebo n=61 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 Severe hypoglycemia	33 Events	11 Events
Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 Documented symptomatic hypoglycemia from IVRS	429 Events	690 Events
Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12 Documented symptomatic hypoglycemia from eCRF	822 Events	1300 Events

SECONDARY outcome

Timeframe: Baseline (Day 1) and Month 12

Population: ITT population.

Severe hypoglycemia was considered as an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Documented symptomatic hypoglycemia was considered as an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration less than or equal to 70 mg/dL and it was collected in (1) eCRF using two forms - for single event and for mutiple events, and (2) the IVRS system. The percentage of participant with incidence of severe hypoglycemia and documented symptomatic hypoglycemia have been reported.

Outcome measures

Outcome measures
Measure	Placebo n=61 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 Severe hypoglycemia	11.5 Percentage of participants	5.9 Percentage of participants
Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 Documented symptomatic hypoglycemia from IVRS	36.1 Percentage of participants	28.8 Percentage of participants
Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12 Documented symptomatic hypoglycemia from eCRF	45.9 Percentage of participants	43.2 Percentage of participants

SECONDARY outcome

Timeframe: Month 6 and 12

Population: ITT population. Only those participants available at the indicated 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 and 12. Baseline adjustment was used to reduce the potential impact of imbalances in Baseline levels between treatment groups on the treatment comparisons at later time points. For the O'Brien mean rank analysis at a particular time point, adjusted HbA1c values (for both treatment groups together) and adjusted mean daily insulin use values was 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. If otelixizumab treatment was effective on this composite endpoint, then the mean of the ranks sum in the otelixizumab group was smaller than the mean of the ranks sum in the placebo group.

Outcome measures

Outcome measures
Measure	Placebo n=61 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Composite Rank Sum: HbA1c and Exogenous Insulin Use at 6 and 12 Months Month 12	96 Rank Standard Deviation 51.2	110 Rank Standard Deviation 55.3
Composite Rank Sum: HbA1c and Exogenous Insulin Use at 6 and 12 Months Month 6	119 Rank Standard Deviation 48.4	110 Rank Standard Deviation 49.8

SECONDARY outcome

Timeframe: Month 6 and 12

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

O'Brien analyses was 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 and 12. The three variables was adjusted for Baseline values. Baseline adjustment was used to reduce the potential impact of imbalances in Baseline levels between treatment groups on the treatment comparisons at later time points. HbA1c and insulin use was ranked from smallest to largest, and C-peptide AUC was ranked from largest to smallest. If otelixizumab treatment was effective on the composite endpoint, then the mean of the ranks sum in the otelixizumab group was smaller than the mean of the ranks sum in the placebo group.

Outcome measures

Outcome measures
Measure	Placebo n=61 Participants Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 Participants Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Composite Rank Sum: C-Peptide AUC, HbA1c and Exogenous Insulin Use at 6 and 12 Months Month 6	206 Rank Standard Deviation 48.6	186 Rank Standard Deviation 41.6
Composite Rank Sum: C-Peptide AUC, HbA1c and Exogenous Insulin Use at 6 and 12 Months Month 12	180 Rank Standard Deviation 42.5	170 Rank Standard Deviation 46.0

Adverse Events

Placebo

Serious events: 4 serious events

Other events: 50 other events

Deaths: 0 deaths

Otelixizumab

Serious events: 11 serious events

Other events: 108 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=61 participants at risk Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 participants at risk Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Metabolism and nutrition disorders Hyperglycaemia	1.6% 1/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Metabolism and nutrition disorders Diabetic ketoacidosis	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Nervous system disorders Convulsion	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Nervous system disorders Headache	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Nervous system disorders Loss of consciousness	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Immune system disorders Cytokine release syndrome	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	1.7% 2/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma in situ	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid cancer	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Congenital, familial and genetic disorders Atrial septal defect	1.6% 1/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.00% 0/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Vomiting	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
General disorders Malaise	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Injury, poisoning and procedural complications Overdose	1.6% 1/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.00% 0/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Scoliosis	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Pregnancy, puerperium and perinatal conditions Pregnancy induced hypertension	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Psychiatric disorders Major depression	1.6% 1/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.00% 0/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.85% 1/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Psychiatric disorders Suicidal ideation	1.6% 1/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	0.00% 0/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.

Measure	Placebo n=61 participants at risk Eligible participants received Placebo matching otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.	Otelixizumab n=118 participants at risk Eligible participants received otelixizumab 3.1 mg as IV infusion, with each infusion given over a 30-minute period. Participants received a series of 8 infusions, 1 infusion per day over 8 consecutive days.
Nervous system disorders Headache	55.7% 34/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	78.0% 92/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Nervous system disorders Dizziness	6.6% 4/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	10.2% 12/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Infections and infestations Nasopharyngitis	24.6% 15/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	31.4% 37/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Infections and infestations Upper respiratory tract infection	26.2% 16/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	7.6% 9/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Infections and infestations Sinusitis	11.5% 7/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	2.5% 3/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Infections and infestations Influenza	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	7.6% 9/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Infections and infestations Pharyngitis streptococcal	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	5.1% 6/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Infections and infestations Urinary tract infection	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	5.1% 6/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Nausea	26.2% 16/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	32.2% 38/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Vomiting	3.3% 2/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	16.1% 19/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Abdominal pain	8.2% 5/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	9.3% 11/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Diarrhoea	1.6% 1/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	9.3% 11/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Gastrointestinal disorders Abdominal pain upper	1.6% 1/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	5.1% 6/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
General disorders Fatigue	18.0% 11/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	23.7% 28/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
General disorders Pyrexia	3.3% 2/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	17.8% 21/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
General disorders Chills	4.9% 3/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	13.6% 16/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
General disorders Malaise	6.6% 4/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	3.4% 4/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
General disorders Infusion site erythema	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	5.1% 6/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Myalgia	6.6% 4/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	9.3% 11/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Back pain	1.6% 1/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	10.2% 12/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	3.3% 2/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	5.9% 7/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	3.3% 2/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	5.9% 7/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	5.1% 6/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	5.1% 6/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	11.5% 7/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	13.6% 16/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Respiratory, thoracic and mediastinal disorders Cough	6.6% 4/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	7.6% 9/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Respiratory, thoracic and mediastinal disorders Nasal congestion	1.6% 1/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	5.9% 7/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Metabolism and nutrition disorders Hypoglycaemia	9.8% 6/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	10.2% 12/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.
Blood and lymphatic system disorders Lymphadenopathy	14.8% 9/61 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.	6.8% 8/118 • Adverse events (AEs) and serious adverse events (SAEs) were collected from dosing Days 1 to 8 and until study withdrawal. Safety population consisted of all participants for whom there was evidence that they received any part of at least 1 infusion of study drug.