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Clinical Trial Results:
Phase II, dose ranging, efficacy study of anti-thymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes (T1D)

Summary
EudraCT number	2019-003265-17
Trial protocol	BE DE FI SI AT IT DK
Global end of trial date	16 Dec 2024

Results information
Results version number	v1(current)
This version publication date	27 Jul 2025
First version publication date	27 Jul 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

S63466

ISRCTN number

US NCT number

NCT04509791

WHO universal trial number (UTN)

Other trial identifiers

University of Cambridge Department of Paediatrics : MELD-ATG 2020-1

Sponsor organisation name

University of Cambridge

Sponsor organisation address

Francis Crick Ave, Cambridge, United Kingdom,

Public contact

MELD-ATG Trial Coordinator, Univeristy of Cambridge, +44 01223762944, MELD-ATG@medschl.cam.ac.uk

Scientific contact

MELD-ATG Trial Coordinator, Univeristy of Cambridge, +44 01223762944, MELD-ATG@medschl.cam.ac.uk

Sponsor organisation name

University Hospitals Leuven

Sponsor organisation address

Herestraat 49, Leuven, Belgium, 3000

Public contact

MELD-ATG@uzleuven.be, University Hospitals Leuven Department of Clinical and Experimental Medicine, 0032 16342129, MELD-ATG@uzleuven.be

Scientific contact

MELD-ATG@uzleuven.be, University Hospitals Leuven Department of Clinical and Experimental Medicine, 0032 16342129, MELD-ATG@uzleuven.be

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

20 Feb 2025

Is this the analysis of the primary completion data?

Yes

Primary completion date

16 Dec 2024

Global end of trial reached?

Yes

Global end of trial date

16 Dec 2024

Was the trial ended prematurely?

Main objective of the trial

• To determine the changes in stimulated C-peptide response over the first two hours of a mixed meal tolerance test (MMTT) at 12 months for 2.5mg/kg ATG arm versus the placebo. • Conditional on finding a statistical difference between the 2.5mg/kg ATG arm and placebo, to identify the minimally effective dose (lowest dose significantly different to placebo) amongst the doses studied in the trial using change in stimulated C-peptide response over the first two hours of a MMTT at 12 months versus placebo.

Protection of trial subjects

Background therapy

insulin therapy

Evidence for comparator

Actual start date of recruitment

01 Sep 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Slovenia: 15

Country: Number of subjects enrolled

United Kingdom: 38

Country: Number of subjects enrolled

Austria: 13

Country: Number of subjects enrolled

Belgium: 43

Country: Number of subjects enrolled

Denmark: 15

Country: Number of subjects enrolled

Finland: 2

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Italy: 3

Worldwide total number of subjects

152

EEA total number of subjects

114

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment officially started in November 2020 (Belgium). Recruitment in Germany, the UK, Slovenia and Austria started in 2021. Recruitment in Denmark & Italy started in 2022. In 2023, recruitment started in Finland. Recruitment was officially completed in January 2024.

Screening details

Major inclusion criteria: T1DM diagnosis <9 weeks of planned treatment day 1, random C-peptide levels ≥200 pmol/L, presence of ≥1 diabetes-related autoantibody (GADA, IA-2A or ZnT8A) Major exclusion criteria: T2DM, evidence of tuberculosis infection, requiring use of immunosuppressive or immunomodulative agents (e.g. use of systemic steroids)

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Blinding implementation details

The web-based randomisation system Sealed Envelope was used for randomising. Both patients and the study teams were blinded to the treatment allocation. The pharmacy team was unblinded to the treatment allocation, in order to be able to prepare the infusion. The medical monitor was unblinded for safety review and the monitors for reviewing the study team and pharmacy teams. Emergency unblinding for safety reasons was possible during the entire trial (responsibility of the investigator).

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo -

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

IV sodium chloride solution (0.9%)

Middle dose 1 - 0.1mg/kg ATG

Arm description

Low dose Anti-thymocyte globulin (ATG) - 0.1mg/kg

Arm type

Experimental

Investigational medicinal product name

Anti-thymocyte globulin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

IV - Low dose Anti-thymocyte globulin - 0.1mg/kg in sodium chloride solution (0.9%)

Middle dose 2 - 0.5mg/kg ATG

Arm description

Low dose Anti-thymocyte globulin (ATG) - 0.5mg/kg

Arm type

Experimental

Investigational medicinal product name

Anti-thymocyte globulin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

IV - Low dose Anti-thymocyte globulin - 0.5mg/kg in sodium chloride solution (0.9%)

Middle dose 3 - 1.5mg/kg ATG

Arm description

Low dose Anti-thymocyte globulin (ATG) - 1.5mg/kg

Arm type

Experimental

Investigational medicinal product name

Anti-thymocyte globulin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

IV - Low dose Anti-thymocyte globulin - 1.0mg/kg in sodium chloride solution (0.9%)

High dose - 2.5mg/kg ATG

Arm description

High dose Anti-thymocyte globulin (ATG) - 2.5mg/kg

Arm type

Experimental

Investigational medicinal product name

Anti-thymocyte globulin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

IV - High dose Anti-thymocyte globulin - 2.5mg/kg in sodium chloride solution (0.9%)

Number of subjects in period 1 ^[1]	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Started	31	6	35	12	33
Completed	30	5	32	9	32
Not completed	1	1	3	3	1
Consent withdrawn by subject	1	-	1	1	-
Lost to follow-up	-	1	2	2	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The number of subject enrolled worldwide resembles the number of subjects that have been screened for this trial. The number of subjects in the baseline period resembles the number of subjects that have been screened and found to be eligible for participation in the trial and have therefore had a baseline visit during which baseline data were collected for primary and secondary outcomes. Statistical analyses were carried out according to a intention-to-treat principle.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Placebo -

Reporting group title

Middle dose 1 - 0.1mg/kg ATG

Reporting group description

Low dose Anti-thymocyte globulin (ATG) - 0.1mg/kg

Reporting group title

Middle dose 2 - 0.5mg/kg ATG

Reporting group description

Low dose Anti-thymocyte globulin (ATG) - 0.5mg/kg

Reporting group title

Middle dose 3 - 1.5mg/kg ATG

Reporting group description

Low dose Anti-thymocyte globulin (ATG) - 1.5mg/kg

Reporting group title

High dose - 2.5mg/kg ATG

Reporting group description

High dose Anti-thymocyte globulin (ATG) - 2.5mg/kg

Reporting group values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG	Total
Number of subjects	31	6	35	12	33	117
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adults (18-64 years)	0	0	0	0	0	0
From 65-84 years	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0
Children (5-11)	6	0	7	1	7	21
Adolescents (12-17)	21	4	22	8	21	76
Adults (18-25)	4	2	6	3	5	20
Gender categorical
Units: Subjects
Female	10	3	22	8	20	63
Male	21	3	13	4	13	54
Ethnicity
Units: Subjects
Europe (excl Nordic countries)	26	6	27	9	27	95
Africa	1	0	1	1	1	4
Asia - including Turkey	0	0	2	1	1	4
Mixed	2	0	1	0	1	4
Nordic (Norway Sweden Denmark Finland Iceland Faro	2	0	4	1	3	10
Diabetes-related autoantibodies
Number of diabetes-related autoantibodies present at baseline
Units: Subjects
1 autoantibody	0	1	3	1	1	6
2 autoantibodies	5	1	8	1	10	25
3 autoantibodies	16	1	9	3	12	41
4 autoantibodies	10	3	15	7	10	45
BMI
Units: kg/m²
arithmetic mean (standard deviation)	20.18 ( 3.68 )	23.3 ( 3.76 )	19.39 ( 3.25 )	19.83 ( 3.77 )	19.62 ( 3.46 )	-
Glycated hemoglobin
Glycated hemoglobin (%) at baseline
Units: Percentage
arithmetic mean (standard deviation)	7.64 ( 1.1 )	7.2 ( 0.66 )	7.89 ( 1.32 )	7.97 ( 1.35 )	7.88 ( 1.17 )	-
Insulin dose-adjusted A1c
Insulin dose-adjusted A1c (IDAA1C) at baseline
Units: Index
arithmetic mean (standard deviation)	9.34 ( 1.78 )	8.32 ( 1.05 )	9.56 ( 2.02 )	9.45 ( 2.19 )	9.51 ( 1.67 )	-
C-peptide AUC
C-peptide AUC from 2-hour MMTT (nmol/L/min) at baseline
Units: nmol/L/min
median (inter-quartile range (Q1-Q3))	0.79 (0.62 to 0.97)	1.06 (0.8 to 1.63)	0.83 (0.67 to 1.15)	0.86 (0.70 to 1.30)	0.81 (0.68 to 0.95)	-
Time from T1D diagnosis to randomization
Time from T1D diagnosis to randomization in days
Units: days
median (inter-quartile range (Q1-Q3))	54 (47 to 57)	51 (43 to 58)	50 (40 to 56)	48 (34 to 57)	51 (40 to 56)	-

End points

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Reporting group title

Placebo

Reporting group description

Placebo -

Reporting group title

Middle dose 1 - 0.1mg/kg ATG

Reporting group description

Low dose Anti-thymocyte globulin (ATG) - 0.1mg/kg

Reporting group title

Middle dose 2 - 0.5mg/kg ATG

Reporting group description

Low dose Anti-thymocyte globulin (ATG) - 0.5mg/kg

Reporting group title

Middle dose 3 - 1.5mg/kg ATG

Reporting group description

Low dose Anti-thymocyte globulin (ATG) - 1.5mg/kg

Reporting group title

High dose - 2.5mg/kg ATG

Reporting group description

High dose Anti-thymocyte globulin (ATG) - 2.5mg/kg

Primary: Changes of C-peptide response during a MMTT - 12 months post treatment

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End point title

Changes of C-peptide response during a MMTT - 12 months post treatment

End point description

The differences in changes in area under the stimulated C-peptide response curve over the first 2 hours of a MMTT at 12 months post treatment.

End point type

Primary

End point timeframe

12 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: nmol/L/min
log mean (confidence interval 95%)	0.411403434 (0.348140202 to 0.474666666)	0.562477373 (0.417939595 to 0.70701505)	0.513130606 (0.451309393 to 0.574952020)	0.466454545 (0.360205959 to 0.572703232)	0.535193737 (0.473115656 to 0.597271717)

Primary outcome (placebo v. 2.5mg/kg dose)

Statistical analysis description

A mixed effects longitudinal model was used on the transformed ln(AUC C-peptide+1) data (baseline, 3-, 6- and 12-months) adjusting for baseline C-peptide data in the model as an outcome. The model assumes that the repeated measures follow a multivariate normal distribution and allows randomized participants with missing timepoint data to be incorporated under a Missing At Random (MAR) assumption.

Comparison groups

High dose - 2.5mg/kg ATG v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.05 ^[2]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.124

Confidence interval

level

95%

sides

2-sided

lower limit

0.043

upper limit

0.205

Variability estimate

Standard error of the mean

Dispersion value

0.0415

Notes
[1] - The primary hypothesis of comparing 2.5mg/kg ATG to placebo. Assuming this SD and comparing 2.5mg/kg ATG to placebo on the transformed ln(AUC C-peptide+1) scale, 32 participants in each arm provided over 90% power at a 5% significance level to detect a change of 0.22 nmol/L/min using a two-sided two-sample t-test.
[2] - If the 2.5mg/kg dose was found not to be statistically significant, no further tests would have been carried out, forming a gatekeeping procedure for the primary endpoint and the family wise error rate controlled at 5%.

Primary outcome (placebo v. 0.5mg/kg dose)

Statistical analysis description

Given a significant effect for the 2.5mg/kg ATG versus placebo mean difference, the middle dose level (0.5mg/kg ATG) was compared to the placebo dose at the 5% level using the Wald test.

Comparison groups

Placebo v Middle dose 2 - 0.5mg/kg ATG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.05 ^[4]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.102

Confidence interval

level

95%

sides

2-sided

lower limit

0.021

upper limit

0.183

Variability estimate

Standard error of the mean

Dispersion value

0.041

Notes
[3] - Given a significant effect for the 2.5mg/kg ATG versus placebo mean difference, the middle dose level (0.5mg/kg ATG) was compared to the placebo dose at the 5% level using the Wald test.
[4] - If the 2.5mg/kg dose was found not to be statistically significant, no further tests would have been carried out, forming a gatekeeping procedure for the primary endpoint and the family wise error rate controlled at 5%.

Primary: Changes in CD4/CD8 ratio - 12 months post treatment

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End point title

Changes in CD4/CD8 ratio - 12 months post treatment

End point description

Changes in CD4/CD8 ratio - 12 months post treatment

End point type

Primary

End point timeframe

12 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: units
geometric mean (confidence interval 95%)	1.98045 (1.832757 to 2.128143)	2.257679 (1.969606 to 2.545753)	1.947787 (1.803551 to 2.092023)	1.489817 (1.273482 to 1.706152)	1.395302 (1.250049 to 1.540555)

Secondary - CD4/CD8 (placebo v. 2.5mg/kg dose)

Statistical analysis description

Comparable linear mixed effects models were fitted to secondary outcome, ratio of CD4/CD8. This secondary outcome was not included in the multiplicity control so individual findings should be interpreted as exploratory.

Comparison groups

Placebo v High dose - 2.5mg/kg ATG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05 ^[5]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.585

Confidence interval

level

95%

sides

2-sided

lower limit

-0.74

upper limit

-0.43

Variability estimate

Standard error of the mean

Dispersion value

0.079

Notes
[5] - This secondary outcome was not included in the multiplicity control so individual findings should be interpreted as exploratory.

Secondary - CD4/CD8 (placebo v. 0.5mg/kg dose)

Statistical analysis description

Comparable linear mixed effects models were fitted to secondary outcomes, CD4/CD8 ratio of absolute counts. This secondary outcome was not included in the multiplicity control so individual findings should be interpreted as exploratory.

Comparison groups

Placebo v Middle dose 2 - 0.5mg/kg ATG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05 ^[6]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.033

Confidence interval

level

95%

sides

2-sided

lower limit

-0.186

upper limit

0.12

Variability estimate

Standard error of the mean

Dispersion value

0.078

Notes
[6] - This secondary outcome was not included in the multiplicity control so individual findings should be interpreted as exploratory.

Secondary: Changes of C-peptide response during a MMTT - 3 months post treatment

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End point title

Changes of C-peptide response during a MMTT - 3 months post treatment

End point description

The differences in changes in area under the stimulated C-peptide response curve over the first 2 hours of a MMTT at 3 months post treatment.

End point type

Secondary

End point timeframe

3 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: nmol/L/min
log mean (confidence interval 95%)	0.576156262 (0.527184949 to 0.6251275)	0.708432626 (0.618357979 to 0.798507272)	0.6284462 (0.5808083 to 0.6760841)	0.6039400 (0.538042525 to 0.669837676)	0.6238126 (0.5760606 to 0.6715645)

No statistical analyses for this end point

Secondary: Changes of C-peptide response during a MMTT - 6 months post treatment

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End point title

Changes of C-peptide response during a MMTT - 6 months post treatment

End point description

The differences in changes in area under the stimulated C-peptide response curve over the first 2 hours of a MMTT at 6 months post treatment.

End point type

Secondary

End point timeframe

6 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	34	9	32
Units: nmol/L/min
log mean (confidence interval 95%)	0.5052018 (0.4495933 to 0.5608104)	0.661471212 (0.545831919 to 0.777110606)	0.5953023 (0.5412028 to 0.649401818)	0.5914197 (0.5082453 to 0.6745941)	0.587397777 (0.533288080 to 0.641507474)

No statistical analyses for this end point

Secondary: HbA1c (mmol/mol) - 3 months post treatment

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End point title

HbA1c (mmol/mol) - 3 months post treatment

End point description

Changes in HbA1c 3 months post treatment

End point type

Secondary

End point timeframe

3 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: mmol/mol
geometric mean (confidence interval 95%)	46.9532354 (43.5213982 to 50.3850835)	43.9032028 (35.9700494 to 51.8363672)	46.5149825 (43.2876378 to 49.7423271)	45.7195261 (40.3307750 to 51.1082663)	47.9692171 (44.7286156 to 51.2098186)

No statistical analyses for this end point

Secondary: HbA1c (mmol/mol) - 6 months post treatment

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End point title

HbA1c (mmol/mol) - 6 months post treatment

End point description

Changes in HbA1c 6 months post treatment

End point type

Secondary

End point timeframe

6 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: mmol/mol
log mean (confidence interval 95%)	50.6954671 (47.1621432 to 54.2287800)	42.9364016 (34.6840121 to 51.1887912)	45.7402257 (42.4184217 to 49.0620187)	46.6922509 (40.8662086 to 52.5182931)	48.2148026 (44.8391187 to 51.5904975)

No statistical analyses for this end point

Secondary: HbA1c (mmol/mol) - 12 months post treatment

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End point title

HbA1c (mmol/mol) - 12 months post treatment

End point description

Changes in HbA1c 12 months post treatment

End point type

Secondary

End point timeframe

12 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: mmol/mol
log mean (confidence interval 95%)	53.8019479 (50.2996515 to 57.3042443)	43.7714647 (35.4721023 to 52.0708161)	48.3601802 (45.0188570 to 51.7014924)	49.2193307 (43.0644458 to 55.3742157)	49.8691909 (46.4764031 to 53.2619788)

Secondary outcome HbA1c (placebo v. 2.5mg/kg dose)

Statistical analysis description

Comparable linear mixed effects models were fitted to secondary outcomes, glycated hemoglobin (%) (HbA1c). This secondary outcome was not included in the multiplicity control so individual findings should be interpreted as exploratory.

Comparison groups

Placebo v High dose - 2.5mg/kg ATG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05 ^[7]

Method

Mixed models analysis

Parameter type

Median difference (final values)

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.223

Notes
[7] - This secondary outcome was not included in the multiplicity control so individual findings should be interpreted as exploratory.

Secondary outcome HbA1c (placebo v. 0.5mg/kg dose)

Statistical analysis description

Comparison groups

Placebo v Middle dose 2 - 0.5mg/kg ATG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05 ^[8]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.93

upper limit

-0.07

Variability estimate

Standard error of the mean

Dispersion value

0.221

Notes
[8] - This secondary outcome was not included in the multiplicity control so individual findings should be interpreted as exploratory.

Secondary: Insulin use - 3 months post treatment

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End point title

Insulin use - 3 months post treatment

End point description

Changes in insuline use 3 months post treatment

End point type

Secondary

End point timeframe

3 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: units/24hr/kg
geometric mean (confidence interval 95%)	0.38407939 (0.31251384 to 0.45564485)	0.26222 (0.100212121 to 0.424227979)	0.401080505 (0.333150101 to 0.469010909)	0.415460808 (0.303360404 to 0.527561111)	0.4144191 (0.344957 to 0.4838813)

No statistical analyses for this end point

Secondary: Insulin use - 6 months post treatment

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End point title

Insulin use - 6 months post treatment

End point description

Changes in insuline use 6 months post treatment

End point type

Secondary

End point timeframe

6 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: units/24hr/kg
geometric mean (confidence interval 95%)	0.4735686 (0.40003848 to 0.5467524)	0.2778695 (0.1156906 to 0.4400483)	0.4447685 (0.3754506 to 0.5140863)	0.3759515 (0.2597446 to 0.4921584)	0.4194426 (0.3499787 to 0.4889064)

No statistical analyses for this end point

Secondary: Insulin use - 12 months post treatment

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End point title

Insulin use - 12 months post treatment

End point description

Changes in insuline use 12 months post treatment

End point type

Secondary

End point timeframe

12 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: units/24hr/kg
geometric mean (confidence interval 95%)	0.5380983 (0.4664981 to 0.6096986)	0.3946814 (0.2325022 to 0.5568606)	0.5253224 (0.455307 to 0.5953379)	0.4686962 (0.3479719 to 0.5894206)	0.5024111 (0.4322181 to 0.5726042)

Secondary - insulin use (placebo v. 2.5mg/kg dose)

Statistical analysis description

Comparable linear mixed effects models were fitted to secondary outcome, insulin use (mg/kg/24hrs). This secondary outcome was not included in the multiplicity control so individual findings should be interpreted as exploratory.

Comparison groups

Placebo v High dose - 2.5mg/kg ATG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05 ^[9]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.036

Confidence interval

level

95%

sides

2-sided

lower limit

-0.128

upper limit

0.056

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[9] - This secondary outcome was not included in the multiplicity control so individual findings should be interpreted as exploratory.

Secondary - insulin use (placebo v. 0.5mg/kg dose)

Statistical analysis description

Comparison groups

Placebo v Middle dose 2 - 0.5mg/kg ATG

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05 ^[10]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.013

Confidence interval

level

95%

sides

2-sided

lower limit

-0.104

upper limit

0.079

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[10] - This secondary outcome was not included in the multiplicity control so individual findings should be interpreted as exploratory.

Secondary: Changes in CD4/CD8 ratio - 3 months post treatment

Top of page

End point title

Changes in CD4/CD8 ratio - 3 months post treatment

End point description

Changes in CD4/CD8 ratio - 3 months post treatment

End point type

Secondary

End point timeframe

3 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: units
geometric mean (confidence interval 95%)	2.061071 (1.912452 to 2.20969)	2.018107 (1.730033 to 2.30618)	1.799619 (1.656212 to 1.943027)	1.537151 (1.331781 to 1.742521)	1.225702 (1.0806 to 1.370804)

No statistical analyses for this end point

Secondary: Changes in CD4/CD8 ratio - 6 months post treatment

Top of page

End point title

Changes in CD4/CD8 ratio - 6 months post treatment

End point description

Changes in CD4/CD8 ratio - 6 months post treatment

End point type

Secondary

End point timeframe

6 months post treatment

End point values	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Number of subjects analysed	30	5	32	9	32
Units: units
geometric mean (confidence interval 95%)	2.076863 (1.927256 to 2.22647)	2.056617 (1.768544 to 2.34469)	1.931648 (1.786584 to 2.076712)	1.633123 (1.4225777 to 1.84367)	1.271815 (1.126561 to 1.417068)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From time of written informed consent until 12 months post treatment

Adverse event reporting additional description

Any untoward medical occurrence in a participant or clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Placebo

Reporting group description

Placebo -

Reporting group title

Middle dose 1 - 0.1mg/kg ATG

Reporting group description

Low dose Anti-thymocyte globulin (ATG) - 0.1mg/kg

Reporting group title

Middle dose 2 - 0.5mg/kg ATG

Reporting group description

Low dose Anti-thymocyte globulin (ATG) - 0.5mg/kg

Reporting group title

Middle dose 3 - 1.5mg/kg ATG

Reporting group description

Low dose Anti-thymocyte globulin (ATG) - 1.5mg/kg

Reporting group title

High dose - 2.5mg/kg ATG

Reporting group description

High dose Anti-thymocyte globulin (ATG) - 2.5mg/kg

Serious adverse events	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	2 / 12 (16.67%)	5 / 33 (15.15%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Injury, poisoning and procedural complications
Overdose as per trial allocation
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Overdose as per trial allocation and as per protocol
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dose error
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Suspected serum sickness
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	2 / 33 (6.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation and urinary retention
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Myalgia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Subcutaneous infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	Placebo	Middle dose 1 - 0.1mg/kg ATG	Middle dose 2 - 0.5mg/kg ATG	Middle dose 3 - 1.5mg/kg ATG	High dose - 2.5mg/kg ATG
Total subjects affected by non serious adverse events
subjects affected / exposed	31 / 31 (100.00%)	6 / 6 (100.00%)	35 / 35 (100.00%)	12 / 12 (100.00%)	33 / 33 (100.00%)
Vascular disorders
Flushing
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	2	0	0	0	0
Hypertension
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Hypotension
alternative dictionary used: MedDRA 27
subjects affected / exposed	2 / 31 (6.45%)	0 / 6 (0.00%)	2 / 35 (5.71%)	1 / 12 (8.33%)	3 / 33 (9.09%)
occurrences all number	3	0	2	1	3
Phlebitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Surgical and medical procedures
Insulin therapy (admission to start insulin pump therapy)
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	1	0	1
Tooth extraction
alternative dictionary used: MedDRA 27
subjects affected / exposed	2 / 31 (6.45%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	2	0	0	1	0
General disorders and administration site conditions
Chills
alternative dictionary used: MedDRA 27
subjects affected / exposed	2 / 31 (6.45%)	0 / 6 (0.00%)	7 / 35 (20.00%)	3 / 12 (25.00%)	10 / 33 (30.30%)
occurrences all number	2	0	9	3	18
Face edema
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Fatigue
alternative dictionary used: MedDRA 27
subjects affected / exposed	4 / 31 (12.90%)	3 / 6 (50.00%)	7 / 35 (20.00%)	4 / 12 (33.33%)	8 / 33 (24.24%)
occurrences all number	11	4	9	5	14
Influenza-like illness
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	1 / 6 (16.67%)	2 / 35 (5.71%)	1 / 12 (8.33%)	4 / 33 (12.12%)
occurrences all number	1	1	3	1	6
Infusion site pruritus
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Injection site reaction
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Malaise
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	3 / 35 (8.57%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	2	0	3	0	2
Non-cardiac chest pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	1 / 6 (16.67%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	1	1	0	0
Peripheral edema
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	2
Pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	2 / 31 (6.45%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	2	0	0	0	0
Pyrexia
alternative dictionary used: MedDRA 27
subjects affected / exposed	10 / 31 (32.26%)	2 / 6 (33.33%)	18 / 35 (51.43%)	3 / 12 (25.00%)	18 / 33 (54.55%)
occurrences all number	13	2	23	5	30
Immune system disorders
Cytokine release syndrome
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	2 / 6 (33.33%)	8 / 35 (22.86%)	2 / 12 (16.67%)	11 / 33 (33.33%)
occurrences all number	0	2	9	3	16
Hypersensitivity
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Seasonal allergy
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Serum sickness
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	11 / 35 (31.43%)	6 / 12 (50.00%)	27 / 33 (81.82%)
occurrences all number	0	0	11	6	27
Reproductive system and breast disorders
Amenorrhea
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Dysmenorrhea
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	3 / 35 (8.57%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	7	0	1
Respiratory, thoracic and mediastinal disorders
Cough
alternative dictionary used: MedDRA 27
subjects affected / exposed	5 / 31 (16.13%)	0 / 6 (0.00%)	5 / 35 (14.29%)	1 / 12 (8.33%)	4 / 33 (12.12%)
occurrences all number	8	0	6	1	4
Dyspnea
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	1 / 33 (3.03%)
occurrences all number	1	0	0	1	1
Epistaxis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Laryngeal inflammation
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Nasal congestion
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	2 / 12 (16.67%)	1 / 33 (3.03%)
occurrences all number	0	2	0	2	1
Oropharyngeal pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	5 / 31 (16.13%)	1 / 6 (16.67%)	4 / 35 (11.43%)	2 / 12 (16.67%)	5 / 33 (15.15%)
occurrences all number	9	1	8	2	7
Rhinitis allergic
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	1	0	1
Rhinorrhea
alternative dictionary used: MedDRA 27
subjects affected / exposed	2 / 31 (6.45%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	4 / 33 (12.12%)
occurrences all number	2	0	0	1	5
Tachypnea
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Throat irritation
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Wheezing
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Psychiatric disorders
Anxiety
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Eating disorder
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Stress
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	2	0	0	0
Injury, poisoning and procedural complications
Accidental overdose
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Ankle fracture
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Dose calculation error
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	0 / 12 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	1	0	0	3
Fracture
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Head injury
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Infusion related reaction
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	4 / 35 (11.43%)	2 / 12 (16.67%)	5 / 33 (15.15%)
occurrences all number	2	0	4	3	6
Injury
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Limb injury
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Procedural pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	2	0	0	0	0
Soft tissue injury
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Upper limb fracture
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Wrist fracture
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Congenital, familial and genetic disorders
Gilbert's syndrome
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Cardiac disorders
Palpitations
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	2 / 6 (33.33%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	2	0	0	1
Tachycardia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	0	0	0	3
Nervous system disorders
Dizziness
alternative dictionary used: MedDRA 27
subjects affected / exposed	2 / 31 (6.45%)	1 / 6 (16.67%)	1 / 35 (2.86%)	2 / 12 (16.67%)	2 / 33 (6.06%)
occurrences all number	2	1	4	2	2
Headache
alternative dictionary used: MedDRA 27
subjects affected / exposed	18 / 31 (58.06%)	4 / 6 (66.67%)	24 / 35 (68.57%)	8 / 12 (66.67%)	23 / 33 (69.70%)
occurrences all number	53	9	64	18	48
Lethargy
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Migraine
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Paresthesia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Syncope
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Tremor
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Blood and lymphatic system disorders
Anemia
alternative dictionary used: MedDRA 27
subjects affected / exposed	4 / 31 (12.90%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	4 / 33 (12.12%)
occurrences all number	4	0	1	0	4
Leukocytosis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Leukopenia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Lymphadenopathy
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	2 / 33 (6.06%)
occurrences all number	1	0	0	0	3
Lymphopenia
alternative dictionary used: MedDRA 27
subjects affected / exposed	6 / 31 (19.35%)	2 / 6 (33.33%)	12 / 35 (34.29%)	5 / 12 (41.67%)	14 / 33 (42.42%)
occurrences all number	6	2	14	6	17
Monocytopenia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Neutropenia
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	4 / 35 (11.43%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	7	0	1
Neutrophilia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	0	0	0	2
Thrombocytopenia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	3 / 33 (9.09%)
occurrences all number	0	0	0	1	3
Ear and labyrinth disorders
Ear pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	2	0	0
Middle ear infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Vertigo
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Eye disorders
Chalazion
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Conjunctival hemorrhage
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Dry eye
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	1	0	0
Eye edema
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Eye pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	1	0	0
Periorbital edema
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Gastrointestinal disorders
Abdominal distension
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Abdominal pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	7 / 31 (22.58%)	3 / 6 (50.00%)	11 / 35 (31.43%)	4 / 12 (33.33%)	9 / 33 (27.27%)
occurrences all number	14	5	12	4	16
Celiac disease
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Constipation
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	2 / 12 (16.67%)	1 / 33 (3.03%)
occurrences all number	0	1	0	2	2
Diarrhea
alternative dictionary used: MedDRA 27
subjects affected / exposed	5 / 31 (16.13%)	0 / 6 (0.00%)	5 / 35 (14.29%)	1 / 12 (8.33%)	5 / 33 (15.15%)
occurrences all number	6	0	6	1	7
Dyspepsia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Dysphagia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Epigastric discomfort
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Nausea
alternative dictionary used: MedDRA 27
subjects affected / exposed	6 / 31 (19.35%)	1 / 6 (16.67%)	6 / 35 (17.14%)	1 / 12 (8.33%)	13 / 33 (39.39%)
occurrences all number	10	1	8	2	25
Oral mucosal blistering
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Tongue blistering
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Toothache
alternative dictionary used: MedDRA 27
subjects affected / exposed	2 / 31 (6.45%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	2	0	1	0	0
Vomiting
alternative dictionary used: MedDRA 27
subjects affected / exposed	4 / 31 (12.90%)	0 / 6 (0.00%)	7 / 35 (20.00%)	1 / 12 (8.33%)	10 / 33 (30.30%)
occurrences all number	4	0	8	2	18
Hepatobiliary disorders
Hyperbilirubinemia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	3	0	0	0
Skin and subcutaneous tissue disorders
Acne
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	2	0	1	0	1
Alopecia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	1	0	1
Angioedema
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0
Ecchymosis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Eczema
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	4 / 35 (11.43%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	5	0	1
Erythema
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0
Hyperhidrosis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Lipohypertrophy
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Night sweats
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Skin pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	2
Perioral dermatitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Pruritus
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	4 / 35 (11.43%)	3 / 12 (25.00%)	10 / 33 (30.30%)
occurrences all number	1	0	4	3	10
Purpura
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Rash
alternative dictionary used: MedDRA 27
subjects affected / exposed	8 / 31 (25.81%)	2 / 6 (33.33%)	6 / 35 (17.14%)	1 / 12 (8.33%)	3 / 33 (9.09%)
occurrences all number	9	4	8	1	3
Skin hypopigmentation
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Skin ulcer
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Spider naevus
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Urticaria
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	0	1	0	2
Vitiligo
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0
Renal and urinary disorders
Cystitis non-infective
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Dysuria
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Urinary retention
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	3 / 35 (8.57%)	3 / 12 (25.00%)	1 / 33 (3.03%)
occurrences all number	0	0	3	3	1
Back pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Bone pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	0	0	1	1	0
Joint effusion
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Muscle spasms
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Muscular weakness
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0
Musculoskeletal stiffness
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0
Myalgia
alternative dictionary used: MedDRA 27
subjects affected / exposed	8 / 31 (25.81%)	3 / 6 (50.00%)	4 / 35 (11.43%)	2 / 12 (16.67%)	10 / 33 (30.30%)
occurrences all number	13	3	5	2	10
Neck pain
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0
Pain in extremity
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	2 / 33 (6.06%)
occurrences all number	1	0	0	0	3
Infections and infestations
Acrodermatitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Bronchitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	0	0	1	1	0
COVID-19 infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	3 / 31 (9.68%)	1 / 6 (16.67%)	3 / 35 (8.57%)	2 / 12 (16.67%)	2 / 33 (6.06%)
occurrences all number	3	1	3	2	3
Conjunctivitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	3 / 35 (8.57%)	1 / 12 (8.33%)	1 / 33 (3.03%)
occurrences all number	1	0	3	1	1
Enterobiasis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Epstein-Barr virus infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Eye infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Fungal foot infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Gastroenteritis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	1	0	1
Impetigo
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	9 / 31 (29.03%)	2 / 6 (33.33%)	9 / 35 (25.71%)	3 / 12 (25.00%)	12 / 33 (36.36%)
occurrences all number	12	3	14	4	15
Infective exacerbation of asthma
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Influenza
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	2	0	0
Laryngitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	2 / 31 (6.45%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	2	0	0	0	1
Lymph gland infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Nail infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	2	0	2
Nasopharyngitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	11 / 31 (35.48%)	0 / 6 (0.00%)	10 / 35 (28.57%)	0 / 12 (0.00%)	9 / 33 (27.27%)
occurrences all number	17	0	17	0	19
Oral herpes
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0
Otitis media
alternative dictionary used: MedDRA 27
subjects affected / exposed	2 / 31 (6.45%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	2	0	1	0	0
Parasitic gastroenteritis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Paronychia
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Pharyngitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	4 / 31 (12.90%)	0 / 6 (0.00%)	1 / 35 (2.86%)	1 / 12 (8.33%)	1 / 33 (3.03%)
occurrences all number	5	0	1	1	2
Rhinitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	2 / 31 (6.45%)	0 / 6 (0.00%)	2 / 35 (5.71%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	2	0	3	0	3
Scarlet fever
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Sepsis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Skin infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	0	0	1
Tonsilitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	3 / 35 (8.57%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	4	0	0
Tooth infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	1 / 6 (16.67%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0
Tracheobronchitis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Upper respiratory tract infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	2 / 33 (6.06%)
occurrences all number	2	0	0	0	2
Urinary tract infection
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	2	0	0	0	0
Varicella
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	1
Vulvovaginal candidiasis
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	1	0	1
Metabolism and nutrition disorders
Decreased appetite
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0
Hyperglycemia
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	0 / 35 (0.00%)	0 / 12 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	0	0	1
Hypoglycemia
alternative dictionary used: MedDRA 27
subjects affected / exposed	1 / 31 (3.23%)	0 / 6 (0.00%)	1 / 35 (2.86%)	0 / 12 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	1	0	0
Iron deficiency
alternative dictionary used: MedDRA 27
subjects affected / exposed	0 / 31 (0.00%)	0 / 6 (0.00%)	1 / 35 (2.86%)	1 / 12 (8.33%)	0 / 33 (0.00%)
occurrences all number	0	0	1	1	0

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Were there any global substantial amendments to the protocol? Yes

02 Sep 2020

V2.0 • 11.3.1 updated to comply with recommendations from Clinical Trial Facilitation Group (CTFG) regarding contraception for women of childbearing potential. • 12.4.3 CTCAE V5.0 to be used for clinical assessment of AE severity. • 16.4 updated with additional information on trial termination criteria. • 17.2 source data requirements updated according to sponsor requirements • 11.4 and Appendix 5 updated to include the maximum volume per visit for blood sampling • Clarification throughout regarding physical exam and vital sign requirements per visit.

13 Jan 2021

V3.0 (UK only) • 2.1 updated to include pharmacy contributors • 2.2 updated to include Trial Statistician • 3.0 abbreviations updated (PT and APTT) • 8.2 and trial design figure updated to clarify the trial design • 9.1.2 Exclusion criterion #3 updated: - Evidence of renal dysfunction with creatinine greater than 1.5 times the ULN at screening, adjusted for the age of the patient - New addition: Clinically significant clotting disorder, according to local reference ranges • 9.2.2 updated to remove repetition regarding trial design now covered in 8.2 • 9.2.4 updated to remove requirement to discuss with CI before emergency unblinding by investigators • 11.4, 11.7, 11.8 and 11.9 updated to add clotting tests (PT and APTT) and updated of schedule of assessments • Correction of heading numbers in section 11 and minor typos throughout

11 Feb 2021

V4.0 Protocol V4.0 includes the above changes made for Protocol V3.0, and in addition: • 2.2 Updated trial coordination contacts • 5.0 treatment preparation conditions corrected in trial flow chart • 8.6.2 addition of total daily insulin dose (units/kg) to secondary objectives • 8.7.3 Addition of RNA profiling to the exploratory outcome measures • 9.1.2 Exclusion criterion #3 updated to include: o Any history of malignancies, other than skin: “other than skin” removed o Known allergy to ATG or to similar products: New addition: “or hypersensitivity to rabbit proteins or to any of the excipients” o Pregnant and breastfeeding women • 10.1.1.7: Update on ATG administration: “This includes the requirement for administering IMP and observing the participant in a hospital setting under medical supervision” • 10.1.1.9: Update on the use of drugs: “Drugs not listed in 10.1.1.9 will be also permitted per investigators discretion and should be listed in the eCRF” • 11.4.1 Clarification regarding hepatitis B (surface antigen) and hepatitis C (antibody) serology testing requirements • 13.1.1.2: Update of management of allergic reactions • 13.1.2.3: Addition of anaphylaxis and management • 13.1.4 Haematological effects management diagram corrected • 17.1 Removal of the statement that the eCRF allows “live (immediate) entry during participant’s trial visit”

17 Feb 2021

V4.1 • 13.1.4: Old haematological effects management figure had not been deleted in error in V4.0. Corrected.

18 Feb 2021

V5.0 (Germany only) Response to German PEI Deficiencies 5.0 18 FEB 2021 • 3.0 abbreviations updated (PT and APTT) • 4.0 Synopsis updated (trial design, exclusion criteria, clotting studies, withdrawal criteria) • 8.2 Trial design clarified, including updated trial diagram • 9.1.2 Exclusion criteria updated: o #3 – now includes “Clinically significant clotting disorder, according to local reference ranges” o #9 – removal of “except skin” o #13 – addition of “hypersensitivity to rabbit proteins or to any of the excipients” o #15 – new exclusion criteria added for pregnant and breastfeeding women • 9.2.4 updated to remove requirement to discuss with CI before emergency unblinding by investigators • 9.3 “Discontinuation from trial follow up visits should be the last possible solution” added • 10.1.1.7 Requirement for administering IMP and observing the participant in a hospital setting under medical supervision and that medical personnel and equipment must be readily at hand to provide emergency treatment if necessary • 10.1.1.9 “Drugs not listed in 10.1.1.9 will be also permitted per investigators discretion and should be listed in the eCRF” added • 11.4, 11.7 and 11.8 updated to add clotting tests (PT and APTT) • 11.9 Schedule of Assessments updated to include PT and APTT • 13.1.2.2 Allergic reactions grade 3 now require permanent treatment discontinuation • 13.1.2.3 New section on management of anaphylaxis • Correction of heading numbers in section 11

01 Apr 2022

V6.0 • Alignment of Protocol V5.0 (Germany only) and Protocol V4.1 Changes made for V4.1 to align with V5.0: o Section 10.1.1.7 ATG preparation, dose and administration: Medical personnel and equipment must be readily at hand to provide emergency treatment if necessary, including in case of anaphylaxis (protocol section 13.1.2.3). Changes made for V5.0 to align with V4.1: o Update on the trial coordination, Protocol contributions and contact details o Section 4. Trial synopsis: - Total daily insulin dose is part of the secondary objectives - Creatinine levels should be evaluated according/adjusted to the age of the patients - Screening for Hepatitis B and C adapted (Hepatitis B: screening for surface antigen, Hepatitis C: screening for antibodies) o Section 5. - Trial flow chart corrected o Section 8.6.2 Secondary objective - total daily insulin dose added to the secondary objectives o Section 8.7.3 Exploratory outcome measures: RNA profiling is added o Section 9.1.2 Creatinine levels should be evaluated according/adjusted to the age of the patient o Section 9.2 Information on cohorts is removed (already subject to Section 8.2) o Section 11.4.1 Screening assessments: correction in screening for Hepatitis B and C o Section 13.1.4 - Haematological effects management diagram corrected o Section 17.1 - Removal of the statement that the eCRF allows “live (immediate) entry during participant’s trial visit” • Contact details section adapted • Section 4. Trial Synopsis: Unblinding procedure: The independent medical safety monitor, monitors, trial statisticians and pharmacy will be unblended Update on physical examination during the follow-up visits • Section 4. Trial Synopsis: Update on the procedure of approach • Section 9.2.3: Unblinding procedure: The independent medical safety monitor, monitors, trial statisticians and pharmacy will be unblinded • Section 10.3.1 Pharmacy responsibilities

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

http://www.ncbi.nlm.nih.gov/pubmed/34876434

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Clinical trials

Clinical Trial Results: Phase II, dose ranging, efficacy study of anti-thymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes (T1D)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Changes of C-peptide response during a MMTT - 12 months post treatment

Primary: Changes of C-peptide response during a MMTT - 12 months post treatment

Primary: Changes in CD4/CD8 ratio - 12 months post treatment

Primary: Changes in CD4/CD8 ratio - 12 months post treatment

Secondary: Changes of C-peptide response during a MMTT - 3 months post treatment

Secondary: Changes of C-peptide response during a MMTT - 3 months post treatment

Secondary: Changes of C-peptide response during a MMTT - 6 months post treatment

Secondary: Changes of C-peptide response during a MMTT - 6 months post treatment

Secondary: HbA1c (mmol/mol) - 3 months post treatment

Secondary: HbA1c (mmol/mol) - 3 months post treatment

Secondary: HbA1c (mmol/mol) - 6 months post treatment

Secondary: HbA1c (mmol/mol) - 6 months post treatment

Secondary: HbA1c (mmol/mol) - 12 months post treatment

Secondary: HbA1c (mmol/mol) - 12 months post treatment

Secondary: Insulin use - 3 months post treatment

Secondary: Insulin use - 3 months post treatment

Secondary: Insulin use - 6 months post treatment

Secondary: Insulin use - 6 months post treatment

Secondary: Insulin use - 12 months post treatment

Secondary: Insulin use - 12 months post treatment

Secondary: Changes in CD4/CD8 ratio - 3 months post treatment

Secondary: Changes in CD4/CD8 ratio - 3 months post treatment

Secondary: Changes in CD4/CD8 ratio - 6 months post treatment

Secondary: Changes in CD4/CD8 ratio - 6 months post treatment

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Clinical Trial Results:
Phase II, dose ranging, efficacy study of anti-thymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes (T1D)