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Clinical Trial Results:
The Influence of Polyvalent Mechanical Bacterial Lysate (ISMIGEN®) on Clinical Course of Asthma and Related Immunological parameters in Asthmatic Children (EOLIA Study): Randomized, Double Blind, Placebo-Controlled, Multicentre, Parallel-Group Study

Summary
EudraCT number	2013-000737-12
Trial protocol	PL
Global end of trial date	08 Jun 2015
Results information
Results version number	v1(current)
This version publication date	20 Jun 2021
First version publication date	20 Jun 2021
Other versions
Summary report(s)	EOLIA-Clinical trial report synopsis-final version-09-Jun-2016

Trial information Top of page
Trial identification
Sponsor protocol code	LPI-1201
Additional study identifiers
ISRCTN number	-
US NCT number	NCT02541331
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Lallemand Pharma AG
Sponsor organisation address	Via Selva, 2, MASSAGNO, Switzerland, 6900
Public contact	Dr Frédéric DURMONT, Lallemand Pharma AG, 41 919 804 613, officelp@lallemand.com
Scientific contact	Dr Bernard GOUT, BG ClinicalS, 33 682 578 160, b.gout@bgclinicals.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	Yes
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	08 Apr 2016
Is this the analysis of the primary completion data?	No
Global end of trial reached?	Yes
Global end of trial date	08 Jun 2015
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	The primary objective of this study is to evaluate in IgE-dependent allergic asthmatic children the efficacy of Ismigen® versus Placebo to improve the asthma control level measured by the ACT/P-ACT (Asthma Control Test/ Paediatric Asthma Control Test) score after a 3-month treatment as add-on to routine asthma therapy.
Protection of trial subjects	Study performed in compliance with GCP Patients were followed according to routine practices for paediatric asthma. To minimize pain induced by blood drawing procedures, an anaesthetic patch was systematically proposed to the patients participating in the biological assessments. Moreover, the volume of blood draws was strickly in compliance with the European Paediatric Regulation.
Background therapy	All patients were treated with Inhaled Cortico Steroid (ICS)+ Long Acting Beta-2 Agonist (LABA) or ICS + Short Acting Beta-2 Agonist (SABA) prn for asthma attacks.
Evidence for comparator	No comparator. The design of this randomised trial was placebo controlled.
Actual start date of recruitment	14 Jul 2014
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Poland: 152
Worldwide total number of subjects	152
EEA total number of subjects	152
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	110
Adolescents (12-17 years)	42
Adults (18-64 years)	0
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	All patients were recruted in Poland between 14/07/2014 and 26/09/2014. Four investigation sites were involved: one site at the University Children Hospital of Lublin and three in private clinical practices (site 2- Lublin, Site 3- Chelm, Site 4- Zawadzkie). All patients were screened from the general paediatric allergic asthma population.
Pre-assignment
Screening details	The screening of the patients was performed during routine medical follow up for asthmatic children.
Period 1
Period 1 title	Screening/inclusion
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Investigator, Monitor, Data analyst, Carer, Assessor, Subject
Blinding implementation details	Allocation of product to the patients was performed according to a randomisation list. Placebo and active were indistinguishable.
Arms
Are arms mutually exclusive	Yes
Arm title	Ismigen
Arm description	Active
Arm type	Experimental
Investigational medicinal product name	Polyvalent Mechanical Bacterial Lysate (PMBL)
Investigational medicinal product code	J07AX
Other name	Ismigen
Pharmaceutical forms	Sublingual tablet
Routes of administration	Sublingual use
Dosage and administration details	The study treatment was administered sublingually for a period of three months. The first ten days of each month, one tablet per day was given at home, in the morning between 6.00 and 9.00 am before any feeding. The patients were instructed to keep the preparation under the tongue for at least 5-7 minutes to ensure prolonged contact with the sublingual mucosae.
Arm title	Placebo
Arm description	Placebo
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code	N/A
Other name
Pharmaceutical forms	Sublingual tablet
Routes of administration	Sublingual use
Dosage and administration details	The study treatment ( Placebo) was administered sublingually for a period of three months. The first ten days of each month, one tablet per day was given at home, in the morning between 6.00 and 9.00 am before any feeding. The patients were instructed to keep the preparation under the tongue for at least 5-7 minutes to ensure prolonged contact with the sublingual mucosae.
Number of subjects in period 1 Ismigen Placebo Started 75 77 Completed 75 77
Period 2
Period 2 title	Biology visit (V2)
Is this the baseline period?	No
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Investigator, Monitor, Subject, Data analyst, Carer, Assessor
Blinding implementation details	same as in previous period. Note that only a subset of voluntary patients was involved in the biology subset (21 Ismigen and 28 Placebo). Due to impossibility to create a period with this lowest patients number as compared to period 3, period 2 has been entered as concerning the whole cohorte. The data are reported in the end point section with the number of patients who performed the visit.
Arms
Are arms mutually exclusive	Yes
Arm title	Ismigen
Arm description	Active
Arm type	Experimental
Investigational medicinal product name	Polyvalent Mechanical Bacterial Lysate (PMBL)
Investigational medicinal product code	J07AX
Other name	Ismigen
Pharmaceutical forms	Sublingual tablet
Routes of administration	Sublingual use
Dosage and administration details	The study treatment was administered sublingually for a period of three months. The first ten days of each month, one tablet per day was given at home, in the morning between 6.00 and 9.00 am before any feeding. The patients were instructed to keep the preparation under the tongue for at least 5-7 minutes to ensure prolonged contact with the sublingual mucosae.
Arm title	Placebo
Arm description	Placebo
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code	N/A
Other name
Pharmaceutical forms	Sublingual tablet
Routes of administration	Sublingual use
Dosage and administration details	The study treatment ( Placebo) was administered sublingually for a period of three months. The first ten days of each month, one tablet per day was given at home, in the morning between 6.00 and 9.00 am before any feeding. The patients were instructed to keep the preparation under the tongue for at least 5-7 minutes to ensure prolonged contact with the sublingual mucosae.
Number of subjects in period 2 Ismigen Placebo Started 75 77 Completed 75 76 Not completed 0 1      Consent withdrawn by subject - 1
Period 3
Period 3 title	End of Treatment V3
Is this the baseline period?	No
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Monitor, Data analyst, Carer, Assessor
Blinding implementation details	Same as previous period
Arms
Are arms mutually exclusive	Yes
Arm title	Ismigen
Arm description	Active
Arm type	Experimental
Investigational medicinal product name	Polyvalent Mechanical Bacterial Lysate (PMBL)
Investigational medicinal product code	J07AX
Other name	Ismigen
Pharmaceutical forms	Sublingual tablet
Routes of administration	Sublingual use
Dosage and administration details	The study treatment was administered sublingually for a period of three months. The first ten days of each month, one tablet per day was given at home, in the morning between 6.00 and 9.00 am before any feeding. The patients were instructed to keep the preparation under the tongue for at least 5-7 minutes to ensure prolonged contact with the sublingual mucosae.
Arm title	Placebo
Arm description	Placebo
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code	N/A
Other name
Pharmaceutical forms	Sublingual tablet
Routes of administration	Sublingual use
Dosage and administration details	The study treatment ( Placebo) was administered sublingually for a period of three months. The first ten days of each month, one tablet per day was given at home, in the morning between 6.00 and 9.00 am before any feeding. The patients were instructed to keep the preparation under the tongue for at least 5-7 minutes to ensure prolonged contact with the sublingual mucosae.
Number of subjects in period 3 Ismigen Placebo Started 75 76 Completed 72 76 Not completed 3 0      Consent withdrawn by subject 1 -      Adverse event, non-fatal 2 -
Period 4
Period 4 title	Follow up 3 months V4
Is this the baseline period?	No
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Monitor, Data analyst, Carer, Assessor
Blinding implementation details	Same as previous period
Arms
Are arms mutually exclusive	Yes
Arm title	Ismigen
Arm description	Active
Arm type	Experimental
Investigational medicinal product name	Polyvalent Mechanical Bacterial Lysate (PMBL)
Investigational medicinal product code	J07AX
Other name	Ismigen
Pharmaceutical forms	Sublingual tablet
Routes of administration	Sublingual use
Dosage and administration details	The study treatment was administered sublingually for a period of three months. The first ten days of each month, one tablet per day was given at home, in the morning between 6.00 and 9.00 am before any feeding. The patients were instructed to keep the preparation under the tongue for at least 5-7 minutes to ensure prolonged contact with the sublingual mucosae.
Arm title	Placebo
Arm description	Placebo
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code	N/A
Other name
Pharmaceutical forms	Sublingual tablet
Routes of administration	Sublingual use
Dosage and administration details	The study treatment ( Placebo) was administered sublingually for a period of three months. The first ten days of each month, one tablet per day was given at home, in the morning between 6.00 and 9.00 am before any feeding. The patients were instructed to keep the preparation under the tongue for at least 5-7 minutes to ensure prolonged contact with the sublingual mucosae.
Number of subjects in period 4 Ismigen Placebo Started 72 76 Completed 71 75 Not completed 1 1      Prohibited concomitant medication 1 -      Protocol deviation - 1
Period 5
Period 5 title	Follow up 6 months V5
Is this the baseline period?	No
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Investigator, Monitor, Data analyst, Carer, Assessor, Subject
Blinding implementation details	Same as previous period
Arms
Are arms mutually exclusive	Yes
Arm title	Ismigen
Arm description	Active
Arm type	Experimental
Investigational medicinal product name	Polyvalent Mechanical Bacterial Lysate (PMBL)
Investigational medicinal product code	J07AX
Other name	Ismigen
Pharmaceutical forms	Sublingual tablet
Routes of administration	Sublingual use
Dosage and administration details	The study treatment was administered sublingually for a period of three months. The first ten days of each month, one tablet per day was given at home, in the morning between 6.00 and 9.00 am before any feeding. The patients were instructed to keep the preparation under the tongue for at least 5-7 minutes to ensure prolonged contact with the sublingual mucosae.
Arm title	Placebo
Arm description	Placebo
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code	N/A
Other name
Pharmaceutical forms	Sublingual tablet
Routes of administration	Sublingual use
Dosage and administration details	The study treatment ( Placebo) was administered sublingually for a period of three months. The first ten days of each month, one tablet per day was given at home, in the morning between 6.00 and 9.00 am before any feeding. The patients were instructed to keep the preparation under the tongue for at least 5-7 minutes to ensure prolonged contact with the sublingual mucosae.
Number of subjects in period 5 Ismigen Placebo Started 71 75 Completed 70 75 Not completed 1 0      Prohibited concomitat medication 1 -

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Ismigen
Reporting group description	Active
Reporting group title	Placebo
Reporting group description	Placebo
Reporting group values Ismigen Placebo Total Number of subjects 75 77 152 Age categorical The study was performed in a population of allergic asthmatic children of both genders aged 6 to 16 years with uncontrolled or partly controlled asthma (ACT/P-ACT score ≤ 19). Units: Subjects     Children 6-11 years 56 54 110     Adolescents 12-16 years 19 23 42 Age continuous Age (years) at baseline Units: years     arithmetic mean (standard deviation) 9.4 ± 2.7 9.8 ± 2.6 - Gender categorical Gender at baseline (M/F) Units: Subjects     Female 26 20 46     Male 49 57 106 ACT/P-ACT asthma control test and paediatric asthma control test Units: arbitrary     arithmetic mean (standard deviation) ± ± - Respiratory infections The mean number of respiratory infection per patient during the past 12 months was calculated and referred to baseline characteristic. Units: arbitrary     arithmetic mean (standard deviation) ± ± - PAQLQ score 2 questionnaires available: PAQLQ self-administered version and PAQLQ interviewer-administered version . These tests measure asthma-related quality of life with the 23-item Polish validated version of the PAQLQ for children. Units: arbitrary units     arithmetic mean (standard deviation) ± ± - PACQLQ score PACQLQ measures how caregivers are limited in their own quality of life by their child’s asthma.The maximal score is 7, which indicates optimal quality of life. Units: arbitrary units     arithmetic mean (standard deviation) ± ± - Red blood cells Red blood cells count measured at baseline Units: T/L     arithmetic mean (standard deviation) ± ± - White blood cells count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) ± ± - neutrophils count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) ± ± - Basophils count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) ± ± - Eosiniophils count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) ± ± - Lymphocytes count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) ± ± - Monocytes count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) ± ± - Platelet count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) ± ± - serum IgE level Serum IgE was measured for patients biology subset Units: IU/ml     arithmetic mean (standard deviation) ± ± - Serum IgA level Measured at baseline for patients of the biology subset Units: g/l     arithmetic mean (standard deviation) ± ± - Serum IgM level It was measured at baseline for the biology subset Units: g/l     arithmetic mean (standard deviation) ± ± - Serum IgG level it was measured at baseline for patients of the biology subset Units: g/l     arithmetic mean (standard deviation) ± ± - Serum IgG1 level it was measured at baseline for patients of the biology subset Units: g/l     arithmetic mean (standard deviation) ± ± - Serum IgG2 level It was measured at baseline for the patients of the biology subset Units: g/l     arithmetic mean (standard deviation) ± ± - Serum IgG3 level It was measured at baseline for the biology subset Units: g/l     arithmetic mean (standard deviation) ± ± - Serum IgG4 level It was measured at baseline for the biology subset Units: g/l     arithmetic mean (standard deviation) ± ± - Serum specific IgG Specific IgG against Ismigen antigens were measured for patients of the biology subset Units: arbitrary units     arithmetic mean (standard deviation) ± ± - Serum specific IgG 500 The same as previous but with a 1:500 dilutions of antigens Units: arbitrary units     arithmetic mean (standard deviation) ± ± - Serum specific IgA The serum specific IgA against Ismigen antigens was measured as baseline for patients of the biology subset. Units: arbitrary units     arithmetic mean (standard deviation) ± ± - Serum specific IgA 500 level The same as previous but with 1:500 dilutions of Ismigen antigens Units: arbitrary units     arithmetic mean (standard deviation) ± ± - Serum specific IgM Specific IgM against Ismigen antigens were measured at baseline for patients of the biology subset. Units: arbitrary units     arithmetic mean (standard deviation) ± ± - Serum specific IgM 500 The same as previous but with 1:500 dilutions of Ismigen antigens Units: arbitrary units     arithmetic mean (standard deviation) ± ± - T reg expressing CD4+, FoxP3 and high level of CD25 Phenotype of T lymphocytes: flow cytometric analysis for patients of the biology subset. Units: cells/mm3     arithmetic mean (standard deviation) ± ± - Cytotoxic lymphocytes count Flow cytometric analysis: phenotype of circulating cytotoxic T lymphocytes Units: cells/mm3     arithmetic mean (standard deviation) ± ± - NK cells count Phenotype analysis as previously described Units: Cells/mm3     arithmetic mean (standard deviation) ± ± - Late activated T Lymphocytes % CD3+ Phenotype analysis as previously described Units: percent of CD3+ cells     arithmetic mean (standard deviation) ± ± - Early activated T lymphocytes % CD45+ Phenotype analysis: CD3+CD69+%CD45+ Units: % of CD45+     arithmetic mean (standard deviation) ± ± - Early activated T lymphocytes % CD3+ Phenotype analysis: CD3+CD69+%CD3+ Units: % of CD3+ cells     arithmetic mean (standard deviation) ± ± - Early activated T helper lymphocytes% CD45+ CD4+CD69+%CD45: Assessment at baseline: phenotype analysis as previously described for other lymphocytes types Units: % of CD45+ cells     arithmetic mean (standard deviation) ± ± -
Subject analysis sets
Subject analysis set title	FAS Ismigen baseline
Subject analysis set type	Full analysis
Subject analysis set description	The FAS population includes all patients of the Safety set having at least one evaluation of the primary criterion post administration.
Subject analysis set title	FAS Placebo baseline
Subject analysis set type	Full analysis
Subject analysis set description	The FAS population includes all patients of the Safety set having at least one evaluation of the primary criterion post administration.
Subject analysis set title	FAS Ismigen V2
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Placebo V2
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Ismigen V3
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Placebo V3
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Ismigen V4
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Placebo V4
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Ismigen V5
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Placebo V5
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis sets values FAS Ismigen baseline FAS Placebo baseline FAS Ismigen V2 FAS Placebo V2 FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects 74 76 21 28 74 76 74 76 74 76 Age categorical The study was performed in a population of allergic asthmatic children of both genders aged 6 to 16 years with uncontrolled or partly controlled asthma (ACT/P-ACT score ≤ 19). Units: Subjects     Children 6-11 years 56 54     Adolescents 12-16 years 18 22 Age continuous Age (years) at baseline Units: years     arithmetic mean (standard deviation) 9.3 ± 2.7 9.8 ± 2.6 ± ± ± ± ± ± ± ± Gender categorical Gender at baseline (M/F) Units: Subjects     Female 25 19     Male 49 57 ACT/P-ACT asthma control test and paediatric asthma control test Units: arbitrary     arithmetic mean (standard deviation) 16.8 ± 2.4 16.8 ± 2.4 ± ± ± ± ± ± ± ± Respiratory infections The mean number of respiratory infection per patient during the past 12 months was calculated and referred to baseline characteristic. Units: arbitrary     arithmetic mean (standard deviation) 3.9 ± 1.3 4 ± 1.3 ± ± ± ± ± ± ± ± PAQLQ score 2 questionnaires available: PAQLQ self-administered version and PAQLQ interviewer-administered version . These tests measure asthma-related quality of life with the 23-item Polish validated version of the PAQLQ for children. Units: arbitrary units     arithmetic mean (standard deviation) 5.8 ± 0.9 5.7 ± 1.1 ± ± ± ± ± ± ± ± PACQLQ score PACQLQ measures how caregivers are limited in their own quality of life by their child’s asthma.The maximal score is 7, which indicates optimal quality of life. Units: arbitrary units     arithmetic mean (standard deviation) 4.6 ± 1.2 4.5 ± 1.2 ± ± ± ± ± ± ± ± Red blood cells Red blood cells count measured at baseline Units: T/L     arithmetic mean (standard deviation) 4.80 ± 0.40 4.76 ± 0.38 ± ± ± ± ± ± ± ± White blood cells count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) 6.64 ± 1.70 6.89 ± 3.48 ± ± ± ± ± ± ± ± neutrophils count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) 2.87 ± 1.19 3.09 ± 2.8 ± ± ± ± ± ± ± ± Basophils count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) 0.04 ± 0.02 0.03 ± 0.02 ± ± ± ± ± ± ± ± Eosiniophils count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) 0.65 ± 0.39 0.41 ± 0.26 ± ± ± ± ± ± ± ± Lymphocytes count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) 2.4 ± 0.62 2.72 ± 1.05 ± ± ± ± ± ± ± ± Monocytes count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) 0.67 ± 0.19 0.64 ± 0.54 ± ± ± ± ± ± ± ± Platelet count Assessment at baseline Units: G/L     arithmetic mean (standard deviation) 283.6 ± 38.9 286.5 ± 60.4 ± ± ± ± ± ± ± ± serum IgE level Serum IgE was measured for patients biology subset Units: IU/ml     arithmetic mean (standard deviation) 1624.0 ± 3921.2 502.8 ± 580.4 ± ± ± ± ± ± ± ± Serum IgA level Measured at baseline for patients of the biology subset Units: g/l     arithmetic mean (standard deviation) 1.56 ± 0.57 1.47 ± 0.49 ± ± ± ± ± ± ± ± Serum IgM level It was measured at baseline for the biology subset Units: g/l     arithmetic mean (standard deviation) 0.99 ± 0.38 1.07 ± 0.60 ± ± ± ± ± ± ± ± Serum IgG level it was measured at baseline for patients of the biology subset Units: g/l     arithmetic mean (standard deviation) 11.5 ± 2.2 9.8 ± 1.8 ± ± ± ± ± ± ± ± Serum IgG1 level it was measured at baseline for patients of the biology subset Units: g/l     arithmetic mean (standard deviation) 7.6 ± 1.7 6.9 ± 1.5 ± ± ± ± ± ± ± ± Serum IgG2 level It was measured at baseline for the patients of the biology subset Units: g/l     arithmetic mean (standard deviation) 3.1 ± 1.2 2.2 ± 0.8 ± ± ± ± ± ± ± ± Serum IgG3 level It was measured at baseline for the biology subset Units: g/l     arithmetic mean (standard deviation) 0.39 ± 0.15 0.43 ± 0.15 ± ± ± ± ± ± ± ± Serum IgG4 level It was measured at baseline for the biology subset Units: g/l     arithmetic mean (standard deviation) 1.34 ± 1.06 0.71 ± 0.63 ± ± ± ± ± ± ± ± Serum specific IgG Specific IgG against Ismigen antigens were measured for patients of the biology subset Units: arbitrary units     arithmetic mean (standard deviation) 8.1 ± 4.3 8.6 ± 5.6 ± ± ± ± ± ± ± ± Serum specific IgG 500 The same as previous but with a 1:500 dilutions of antigens Units: arbitrary units     arithmetic mean (standard deviation) 6.0 ± 3.7 5.4 ± 3.1 ± ± ± ± ± ± ± ± Serum specific IgA The serum specific IgA against Ismigen antigens was measured as baseline for patients of the biology subset. Units: arbitrary units     arithmetic mean (standard deviation) 4.6 ± 2.0 4.8 ± 2.0 ± ± ± ± ± ± ± ± Serum specific IgA 500 level The same as previous but with 1:500 dilutions of Ismigen antigens Units: arbitrary units     arithmetic mean (standard deviation) 2.8 ± 1.1 3.0 ± 1.3 ± ± ± ± ± ± ± ± Serum specific IgM Specific IgM against Ismigen antigens were measured at baseline for patients of the biology subset. Units: arbitrary units     arithmetic mean (standard deviation) 8.9 ± 3.7 9.7 ± 3.4 ± ± ± ± ± ± ± ± Serum specific IgM 500 The same as previous but with 1:500 dilutions of Ismigen antigens Units: arbitrary units     arithmetic mean (standard deviation) 3.9 ± 1.1 4.3 ± 2.1 ± ± ± ± ± ± ± ± T reg expressing CD4+, FoxP3 and high level of CD25 Phenotype of T lymphocytes: flow cytometric analysis for patients of the biology subset. Units: cells/mm3     arithmetic mean (standard deviation) 55.5 ± 22.7 71.8 ± 28.9 ± ± ± ± ± ± ± ± Cytotoxic lymphocytes count Flow cytometric analysis: phenotype of circulating cytotoxic T lymphocytes Units: cells/mm3     arithmetic mean (standard deviation) 615.6 ± 264.1 744.2 ± 372.4 ± ± ± ± ± ± ± ± NK cells count Phenotype analysis as previously described Units: Cells/mm3     arithmetic mean (standard deviation) 239.9 ± 161.5 286.0 ± 244.1 ± ± ± ± ± ± ± ± Late activated T Lymphocytes % CD3+ Phenotype analysis as previously described Units: percent of CD3+ cells     arithmetic mean (standard deviation) 18.9 ± 5.4 19.2 ± 5.4 ± ± ± ± ± ± ± ± Early activated T lymphocytes % CD45+ Phenotype analysis: CD3+CD69+%CD45+ Units: % of CD45+     arithmetic mean (standard deviation) 7.7 ± 3.3 8.1 ± 3.9 ± ± ± ± ± ± ± ± Early activated T lymphocytes % CD3+ Phenotype analysis: CD3+CD69+%CD3+ Units: % of CD3+ cells     arithmetic mean (standard deviation) 11.4 ± 4.3 11.5 ± 5.8 ± ± ± ± ± ± ± ± Early activated T helper lymphocytes% CD45+ CD4+CD69+%CD45: Assessment at baseline: phenotype analysis as previously described for other lymphocytes types Units: % of CD45+ cells     arithmetic mean (standard deviation) 3.8 ± 7.4 1.2 ± 0.7 ± ± ± ± ± ± ± ±

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Ismigen
Reporting group description	Active
Reporting group title	Placebo
Reporting group description	Placebo
Reporting group title	Ismigen
Reporting group description	Active
Reporting group title	Placebo
Reporting group description	Placebo
Reporting group title	Ismigen
Reporting group description	Active
Reporting group title	Placebo
Reporting group description	Placebo
Reporting group title	Ismigen
Reporting group description	Active
Reporting group title	Placebo
Reporting group description	Placebo
Reporting group title	Ismigen
Reporting group description	Active
Reporting group title	Placebo
Reporting group description	Placebo
Subject analysis set title	FAS Ismigen baseline
Subject analysis set type	Full analysis
Subject analysis set description	The FAS population includes all patients of the Safety set having at least one evaluation of the primary criterion post administration.
Subject analysis set title	FAS Placebo baseline
Subject analysis set type	Full analysis
Subject analysis set description	The FAS population includes all patients of the Safety set having at least one evaluation of the primary criterion post administration.
Subject analysis set title	FAS Ismigen V2
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Placebo V2
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Ismigen V3
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Placebo V3
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Ismigen V4
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Placebo V4
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Ismigen V5
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline
Subject analysis set title	FAS Placebo V5
Subject analysis set type	Full analysis
Subject analysis set description	idem baseline

End points Top of page

Primary: ACT/P-ACT change from baseline Top of page
End point title	ACT/P-ACT change from baseline
End point description	The main analysis is the target improvement in asthma control level as measured by the mean ACT or P-ACT score at 12 weeks. The ACT or P-ACT will be described at baseline and at 12 weeks as well as the mean change. If the value at 12 weeks is not available, the value at premature withdrawal visit will be used. The mean change will be compared between the treatment groups using an ANCOVA with the baseline as covariate. The same analysis will be performed at 24 weeks (3 months follow up) and 36 weeks (6 months follow up)
End point type	Primary
End point timeframe	End of Treatment V3, Follow up 3 months V4, Follow up 6 months V5
End point values FAS Ismigen baseline FAS Placebo baseline FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 74 76 74 76 74 76 74 76 Units: arbitrary     arithmetic mean (standard deviation) 16.8 ± 2.4 16.8 ± 2.4 21.0 ± 3.5 21.1 ± 3.0 22.3 ± 3.5 22.3 ± 3.1 23.0 ± 2.7 22.3 ± 3.3
Statistical analysis title	ACT/P-ACT Evolution at end of treatment
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	150
Analysis specification	Post-hoc
Analysis type	superiority [1]
P-value	= 0.9432 [2]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-7
upper limit	12
Variability estimate	Standard deviation
Notes [1] - Mean changes compared between groups using an ANCOVA with baseline as covariate. If non normal distributions (Shapiro-Wilk’s test), non-parametric covariance analysis (based on ranks): i)to compute the ranks of the response variable (change from baseline) and covariate (baseline value) in the combined treatment group ii) to calculate residuals from linear regression of response ranks on the covariate ranks. Mantel-Haenzel mean score statistic compares the mean values of residuals. [2] - The absolute changes in P-ACT/ACT scores between baseline and 12 w were similar in both groups (FAS ) after the 3 months treatment period. The asthma status for most of the patients could be categorized as “controlled” according to the mean ACT/P-ACT
Statistical analysis title	ACT/P-ACT evolution at V4
Statistical analysis description	The change from baseline at 24 weeks, will be described and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) will be used.
Comparison groups	FAS Ismigen V4 v FAS Placebo V4
Number of subjects included in analysis	150
Analysis specification	Post-hoc
Analysis type	superiority [3]
P-value	= 0.6472 [4]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-6
upper limit	13
Variability estimate	Standard deviation
Notes [3] - Same as previous [4] - The absolute changes in P-ACT/ACT scores between baseline and 24 w were similar in both groups (FAS after 3 months follow up). The asthma status for most of the patients could be categorized as “controlled” according to the mean ACT/P-ACT.
Statistical analysis title	ACT/P-ACT evolution at V5
Statistical analysis description	Same as previous at 36 weeks (6 months follow up)
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	150
Analysis specification	Post-hoc
Analysis type	superiority [5]
P-value	= 0.2112 [6]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [5] - Same as previous (cf 24 weeks) [6] - The absolute changes in P-ACT/ACT scores between baseline and 36 w were similar in both groups (FAS ) after the 6 months follow up p. The asthma status for most of the patients could be categorized as “controlled” according to the mean ACT/P-ACT.

Primary: ACT/P-ACT change from baseline Top of page

Secondary: Number of respiratory tract infections Top of page
End point title	Number of respiratory tract infections
End point description
End point type	Secondary
End point timeframe	The number of respiratory tract infections is recorded at each study times (Post treatment, 6 months and 9 months follow up) and the mean number per patient is calculated.
End point values FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 72 76 71 75 70 75 Units: arbitrary     arithmetic mean (standard deviation) 07 ± 0.8 0.7 ± 0.9 0.5 ± 0.7 0.6 ± 0.8 0.8 ± 0.9 0.7 ± 0.8
Statistical analysis title	Mean number of respiratory infections at V3
Statistical analysis description	The mean number of respiratory infections per patient will be described at each time (12 weeks, 24 weeks, 36 weeks and all the study) and comparison between treatment groups using a Student's t test or Wilcoxon’s test in case of non-normality)
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	148
Analysis specification	Post-hoc
Analysis type	superiority [7]
P-value	= 0.712 [8]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [7] - The mean number of respiratory infections per patient after the treatment period will be compared between treatment groups using a Student's t test or Wilcoxon’s test in case of non-normality) [8] - No effect of Ismigen treatment on the mean number of respiratory infections after the treatment period
Statistical analysis title	Mean number of respiratory infections at V4
Statistical analysis description	Same as previous
Comparison groups	FAS Placebo V4 v FAS Ismigen V4
Number of subjects included in analysis	146
Analysis specification	Post-hoc
Analysis type	superiority [9]
P-value	= 0.368 [10]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [9] - Same as previous [10] - No effect of Ismigen treatment on the mean number of respiratory tract infections at 24 weeks
Statistical analysis title	Mean number of respiratory infections at V5
Statistical analysis description	Same as previous
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	145
Analysis specification	Post-hoc
Analysis type	superiority [11]
P-value	= 0.948 [12]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [11] - Same as previous [12] - No effect of Ismigen treatment on mean number of respiratory infections at V5

Secondary: Number of respiratory tract infections Top of page

Secondary: Number of asthma exacerbations Top of page
End point title	Number of asthma exacerbations
End point description	Asthma exacerbations were defined as follows: -a Mild/Moderate exacerbation requires: • transient increase in ICS/B2-agonists/Anticholinergics use for ≥ 2 days or • Emergency room visits: but no systemic corticosteroids -a severe exacerbation requires: • Hospitalization or Emergency room visit, requiring systemic corticosteroids • Systemic corticosteroids (tablets or injection), ≥ 3 days (but < 7 days).
End point type	Secondary
End point timeframe	The mean number of asthma exacerbation was recorded at the End of Treatment, at 3 months follow up and at 6 months follow up.
End point values FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 72 76 71 75 70 75 Units: arbitary units     arithmetic mean (standard deviation) 0.3 ± 0.6 0.8 ± 1.1 0.4 ± 0.7 0.6 ± 0.9 0.4 ± 0.7 0.6 ± 1.1
Statistical analysis title	Mean nb of asthma exacerbation at V3
Statistical analysis description	The mean number of asthma exacerbations per patient were compared between treatment groups using a Student's t test or Wilcoxon’s test in case of non-normality) at the End of Treatment
Comparison groups	FAS Placebo V3 v FAS Ismigen V3
Number of subjects included in analysis	148
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.009 [13]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [13] - The mean number of asthma exacerbation was significantly lower in the Ismigen group as compared to Placebo group at V3
Statistical analysis title	Mean nb of asthma exacerbation at V4
Statistical analysis description	Same as previous at the 3 months follow up period
Comparison groups	FAS Ismigen V4 v FAS Placebo V4
Number of subjects included in analysis	146
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.168 [14]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [14] - The mean number of asthma exacerbation was not significantly different in the Ismigen group as compared to the Placebo group at the 3 months follow up visit.
Statistical analysis title	Mean nb of asthma exacerbation at V5
Statistical analysis description	Same as previous for the 6 months follow up period.
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	145
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.444 [15]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [15] - The mean number of asthma exacerbation was not significantly different in the Ismigne group as compared to the Placebo group

Secondary: Number of asthma exacerbations Top of page

Secondary: Number of asthma exacerbation related to infection Top of page
End point title	Number of asthma exacerbation related to infection
End point description	Exacerbations related and unrelated to infections “As per study procedures, and in the absence of laboratory investigations for infections, exacerbations were reported as “related to infection” when occurring during the course of an infection and as “unrelated to infection” in the absence of clinical symptoms of infection.”
End point type	Secondary
End point timeframe	End of Treatment, 3 months follow up, 6 months follow up
End point values FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 72 76 71 75 70 75 Units: arbitrary unit     arithmetic mean (standard deviation) 0.2 ± 0.5 0.4 ± 0.8 0.1 ± 0.4 0.2 ± 0.6 0.2 ± 0.5 0.3 ± 0.7
Statistical analysis title	Comparison of mean nb of AEX related to inf at V3
Statistical analysis description	The mean number of asthma exacerbations (AEX) related to infection (Inf) per patient was compared between treatment groups using a Student's t test or Wilcoxon’s test in case of non-normality at the End of Treatment
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	148
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.034 [16]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [16] - The mean number of asthma exacerbations related to infection was significantly lower in the Ismigen group at the End of Treatment.
Statistical analysis title	Comparison of mean nb of AEX related to inf at V4
Statistical analysis description	Same as previous
Comparison groups	FAS Ismigen V4 v FAS Placebo V4
Number of subjects included in analysis	146
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.126 [17]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [17] - No difference between groups
Statistical analysis title	Comparison of mean nb of AEX related to inf at V5
Statistical analysis description	Same as previous
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	145
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.274 [18]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [18] - No difference between groups

Secondary: Number of asthma exacerbation related to infection Top of page

Secondary: Asthma exacerbations unrelated to infection Top of page
End point title	Asthma exacerbations unrelated to infection
End point description	Exacerbations related and unrelated to infections “As per study procedures, and in the absence of laboratory investigations for infections, exacerbations were reported as “related to infection” when occurring during the course of an infection and as “unrelated to infection” in the absence of clinical symptoms of infection.”
End point type	Secondary
End point timeframe	The mean number of asthma exacerbation unrelated to infections was calculated at the End of Treament, at 3 months and 6 months follow up and for the all duration of the study
End point values FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 72 76 71 75 70 75 Units: arbitrary unit     arithmetic mean (standard deviation) 0.1 ± 0.3 0.3 ± 0.7 0.1 ± 0.4 0.2 ± 0.6 0.2 ± 0.5 0.3 ± 0.7
Statistical analysis title	Comparison of mean nb of AEX unrelated at V3
Statistical analysis description	The mean number of asthma exacerbations unrelated to infections per patient were compared between treatment groups using a Student's t test or Wilcoxon’s test in case of non-normality
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	148
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.057 [19]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [19] - Results non significantly different between groups but a trend in favor of ismigen group.
Statistical analysis title	Comparison of mean nb of AEX unrelated at V4
Statistical analysis description	Same as previous for this period
Comparison groups	FAS Ismigen V4 v FAS Placebo V4
Number of subjects included in analysis	146
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.442 [20]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [20] - No significant difference between groups
Statistical analysis title	Comparison of mean nb of AEX unrelated at V5
Statistical analysis description	Same as previous for this study period
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	145
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.924 [21]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [21] - No significant difference between groups

Secondary: Asthma exacerbations unrelated to infection Top of page

Secondary: Number of day per patient with asthma exacerbations Top of page
End point title	Number of day per patient with asthma exacerbations
End point description	Mean of the total duration of asthma exacerbations per patient
End point type	Secondary
End point timeframe	The number of days with asthma exacerbation was measured at all study times: End of Treatment, Follow up 3months, Follow up 6 months
End point values FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 18 32 22 30 19 24 Units: day     arithmetic mean (standard deviation) 10.6 ± 10.7 12 ± 8.5 8.4 ± 5.4 10.4 ± 6.2 9.7 ± 5.3 11.5 ± 9.7
Statistical analysis title	Comparison of mean number of days with AEX at V3
Statistical analysis description	The number of days with exacerbation per patient wil be compared between treatment groups using a Student's t test or Wilcoxon’s test in case of non-normality
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	50
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.292 [22]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [22] - The mean number of days with asthma exacerbations per patient was not significantly different between groups at the End of treatment. To be noticed however that the number of patients with asthma exacerbation was lower in the ismigen group
Statistical analysis title	Comparison of mean nb of days with AEX at V4
Statistical analysis description	-The number of days with exacerbation per patient at V4 will be compared between treatment groups using a Student's t test or Wilcoxon’s test in case of non-normality
Comparison groups	FAS Ismigen V4 v FAS Placebo V4
Number of subjects included in analysis	52
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.209 [23]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [23] - No difference between groups
Statistical analysis title	Comparison of mean nb of days with AEX at V5
Statistical analysis description	Same as previous
Comparison groups	FAS Placebo V5 v FAS Ismigen V5
Number of subjects included in analysis	43
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.787 [24]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [24] - No difference between groups

Secondary: Number of day per patient with asthma exacerbations Top of page

Secondary: Mean duration of asthma exacerbation per event Top of page
End point title	Mean duration of asthma exacerbation per event
End point description	A mean duration of AEX duration (days) per event was calculated.
End point type	Secondary
End point timeframe	This endpoint was measured at the End of Treatment, Follow up 3 months and 6 months
End point values FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 18 32 22 30 19 24 Units: day     arithmetic mean (standard deviation) 8.7 ± 6.3 6.7 ± 3.8 6.4 ± 3.1 6.7 ± 4.5 6.6 ± 3.3 6.4 ± 4.1
Statistical analysis title	Comparison of mean duration of AEX at V3
Statistical analysis description	The mean duration per event (days) was compared between treatment groups using a Student's t test or Wilcoxon’s test in case of non-normality at V3
Comparison groups	FAS Placebo V3 v FAS Ismigen V3
Number of subjects included in analysis	50
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.149 [25]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [25] - No difference between groups
Statistical analysis title	Comparison of mean duration of AEX at V4
Statistical analysis description	Same as previous
Comparison groups	FAS Ismigen V4 v FAS Placebo V4
Number of subjects included in analysis	52
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.705 [26]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [26] - No difference beetween groups
Statistical analysis title	Comparison of mean duration of AEX at V5
Statistical analysis description	Same as previous
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	43
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.531 [27]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [27] - No difference between groups

Secondary: Mean duration of asthma exacerbation per event Top of page

Secondary: Number of school days lost because of asthma exacerbation Top of page
End point title	Number of school days lost because of asthma exacerbation
End point description
End point type	Secondary
End point timeframe	The number of school days lost or days without normal activities because of asthma exacerbation was determined at V3, V4, V5
End point values FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 18 32 22 30 19 24 Units: days     arithmetic mean (standard deviation) 3.0 ± 3.7 4.1 ± 5.1 2.1 ± 2.5 3.6 ± 4.9 5.1 ± 4.7 4.5 ± 5.4
Statistical analysis title	Comparison of school days lost at V3
Statistical analysis description	Comparison between groups of the number of school days lost or without normal activities because of asthma exacerbation at the End of treatment
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	50
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.523 [28]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [28] - No significant difference between groups
Statistical analysis title	Comparison of school days lost at V4
Statistical analysis description	same as previous
Comparison groups	FAS Ismigen V4 v FAS Placebo V4
Number of subjects included in analysis	52
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.455 [29]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [29] - No significant difference between groups
Statistical analysis title	Comparison of school days lost at V5
Statistical analysis description	same as previous
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	43
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.456 [30]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [30] - No significant difference

Secondary: Number of school days lost because of asthma exacerbation Top of page

Secondary: Number of days of SABA use for exacerbation relief Top of page
End point title	Number of days of SABA use for exacerbation relief
End point description
End point type	Secondary
End point timeframe	The mean nb of days of SABA use for AEX relief per patient was calculated for the all duration of the study Were considered as SABA: pure ß2 agonist or combined inhaled/nebulized SABA+ inhaled/nebulized anticholinergics or Symbicort for exacerbations.
End point values FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 37 47 Units: days     arithmetic mean (standard deviation) 11.5 ± 11.2 15.6 ± 10.2
Statistical analysis title	Comparison of the number of days of SABA use
Statistical analysis description	The number of days of SABA used for asthma exacerbation was compared between groups.
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	84
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.016 [31]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [31] - The mean number of days of SABA use for exacerbation relief from V1 to V5 was statistically lower in the Ismigen group as compared to the Placebo group.

Secondary: Number of days of SABA use for exacerbation relief Top of page

Secondary: Time to first asthma exacerbation Top of page
End point title	Time to first asthma exacerbation
End point description
End point type	Secondary
End point timeframe	This endpoint was measured for the all duration of the study, from baseline to V5
End point values FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 42 49 Units: weeks     arithmetic mean (standard deviation) 25 ± 1.4 19.7 ± 1.7
Statistical analysis title	comparison of time to first asthma exacerbation
Statistical analysis description	The time to first mild/moderate or severe asthma exacerbation is defined by the time between the start date of treatment and the date of the first mild/moderate or severe asthma exacerbation. For patients with no mild/moderate or severe asthma exacerbation, they are censored at the last assessment date. The global survival (period without exacerbation) is estimated using a survival analysis (Kaplan-Meier).
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	91
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.0905 [32]
Method	Logrank
Confidence interval
Notes [32] - No difference between groups

Secondary: Time to first asthma exacerbation Top of page

Secondary: Time to second asthma exacerbation Top of page
End point title	Time to second asthma exacerbation
End point description
End point type	Secondary
End point timeframe	The time to second asthma exacerbation is measured between baseline and V5
End point values FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 42 49 Units: weeks     arithmetic mean (standard deviation) 32.7 ± 0.9 25.9 ± 1.4
Statistical analysis title	Comparaison of time to second asthma exacerbation
Statistical analysis description	The time to second mild/moderate or severe asthma exacerbation is defined by the time between the start date of treatment and the date of the second mild/moderate or severe asthma exacerbation. For patients with no mild/moderate or severe asthma exacerbation, they will be censored at the last assessment date. The global survival (period without exacerbation) is estimated using a survival analysis (Kaplan-Meier) .
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	91
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.0024 [33]
Method	Logrank
Confidence interval
Notes [33] - The time to onset of second asthma exacerbation is significantly longer for the Ismigen® group

Secondary: Time to second asthma exacerbation Top of page

Secondary: Time to third asthma exacerbation Top of page
End point title	Time to third asthma exacerbation
End point description
End point type	Secondary
End point timeframe	The time to third asthma exacerbation is measured between baseline and V5.
End point values FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 42 49 Units: weeks     arithmetic mean (standard deviation) 35.3 ± 0.6 31.5 ± 1.2
Statistical analysis title	Comparison of time to third asthma exacerbation
Statistical analysis description	The time to third mild/moderate or severe asthma exacerbation is defined by the time between the start date of treatment and the date of the third mild/moderate or severe asthma exacerbation . For patients with no mild/moderate or severe asthma exacerbation, they are censored at the last assessment date. The global survival (period without exacerbation) is estimated using a survival analysis (Kaplan-Meier).
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	91
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.0004 [34]
Method	Logrank
Confidence interval
Notes [34] - The time to onset of third asthma exacerbation is significantly longer for the Ismigen® group

Secondary: Time to third asthma exacerbation Top of page

Secondary: Evolution of PAQLQ score between baseline and 36w Top of page
End point title	Evolution of PAQLQ score between baseline and 36w
End point description
End point type	Secondary
End point timeframe	The evolution of PAQLQ score was evaluated between baseline and 36 weeks
End point values FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 70 75 Units: arbitrary unit     arithmetic mean (standard deviation) 0.6 ± 0.8 0.7 ± 0.1
Statistical analysis title	Comparison of evolution of PAQLQ scores
Statistical analysis description	Changes from baseline (absolute)is calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) is used.
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	145
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.5673 [35]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [35] - No significant difference between groups

Secondary: Evolution of PAQLQ score between baseline and 36w Top of page

Secondary: Evolution of PACQLQ between baseline and 36 w Top of page
End point title	Evolution of PACQLQ between baseline and 36 w
End point description
End point type	Secondary
End point timeframe	Scores will be calculated and described at each time (inclusion and 36 weeks). For patients prematurely withdrawn, the questionnaire performed at premature withdrawal visit will be used for the 36 weeks visit. Changes from baseline will be calculated .
End point values FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 70 75 Units: Arbitrary unit     arithmetic mean (standard deviation) 1.3 ± 1.2 1.2 ± 1.1
Statistical analysis title	Comparison of evolution of PACQLQ score
Statistical analysis description	Changes from baseline are calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) is used.
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	145
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.2172 [36]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [36] - No significant difference between groups

Secondary: Evolution of PACQLQ between baseline and 36 w Top of page

Secondary: Evolution of red blood cells count Top of page
End point title	Evolution of red blood cells count
End point description
End point type	Secondary
End point timeframe	The evolution of blood cells count between baseline and 12 weeks has been calculated.
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 20 28 Units: T/L     arithmetic mean (standard deviation) -0.02 ± 0.27 0.06 ± 0.29
Statistical analysis title	Comparison of the evolution of red BLC
Statistical analysis description	Changes from baseline was calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	48
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.4178 [37]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [37] - no significant difference

Secondary: Evolution of red blood cells count Top of page

Secondary: Evolution of white blood cells count Top of page
End point title	Evolution of white blood cells count
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 20 28 Units: G/L     arithmetic mean (standard deviation) 0.4 ± 1.51 0.13 ± 3.53
Statistical analysis title	Comparison of the evolution of white BCC
Statistical analysis description	As previously explained for red blood cells
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	48
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.9046 [38]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [38] - No significant difference between groups

Secondary: Evolution of white blood cells count Top of page

Secondary: Evolution of neutrophils count Top of page
End point title	Evolution of neutrophils count
End point description
End point type	Secondary
End point timeframe	Evolution between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 20 28 Units: G/L     arithmetic mean (standard deviation) 0.27 ± 1.28 0.33 ± 2.53
Statistical analysis title	Comparison of evolution of neutrophils
Statistical analysis description	Same as described for other blood cells
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	48
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.4697 [39]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [39] - No difference between groups

Secondary: Evolution of neutrophils count Top of page

Secondary: Evolution of basophils count Top of page
End point title	Evolution of basophils count
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 20 28 Units: G/L     arithmetic mean (standard deviation) 0 ± 0.02 0 ± 0.01
Statistical analysis title	Comparison of evolution of basophils count
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	48
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.9838 [40]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [40] - no significant difference

Secondary: Evolution of basophils count Top of page

Secondary: Evolution of lymphocytes count Top of page
End point title	Evolution of lymphocytes count
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 20 28 Units: G/L     arithmetic mean (standard deviation) 0.12 ± 0.49 -0.3 ± 0.86
Statistical analysis title	Comparison of the evolution of lymphocytes count
Statistical analysis description	Same as previously described for other blood cells count.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	48
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.0141 [41]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [41] - The evolution of the lymphocytes count was significantly different between groups. The lymphocytes number increased in the Ismigen group whereas it decreased in the Placebo group.

Secondary: Evolution of lymphocytes count Top of page

Secondary: Evolution of the eosinophils count Top of page
End point title	Evolution of the eosinophils count
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 20 28 Units: G/L     arithmetic mean (standard deviation) 0.01 ± 0.21 0.06 ± 0.27
Statistical analysis title	Comparison of the evolution of eosinophils count
Statistical analysis description	Same as previously described for other blood cells counts.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	48
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.8243 [42]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [42] - no significant difference between groups

Secondary: Evolution of the eosinophils count Top of page

Secondary: Evolution of monocytes count Top of page
End point title	Evolution of monocytes count
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 20 28 Units: G/L     arithmetic mean (standard deviation) 0.01 ± 0.21 0.04 ± 0.57
Statistical analysis title	Comparison of the evolution of monocytes count
Statistical analysis description	Same as previously described for other blood cells count
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	48
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.5564 [43]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [43] - No significant difference between groups.

Secondary: Evolution of monocytes count Top of page

Secondary: Evolution of platelet count Top of page
End point title	Evolution of platelet count
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and 12 weeks
End point values FAS Placebo V3 FAS Ismigen V4 Number of subjects analysed 20 28 Units: G/L     arithmetic mean (standard deviation) 0.7 ± 38.2 -13.2 ± 45.3
Statistical analysis title	Comaprison of the evolution of platelet counts
Statistical analysis description	Same as previously described for other blood cells count
Comparison groups	FAS Placebo V3 v FAS Ismigen V4
Number of subjects included in analysis	48
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.2621 [44]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [44] - No significant difference

Secondary: Evolution of platelet count Top of page

Secondary: Evolution of IgE level Top of page
End point title	Evolution of IgE level
End point description
End point type	Secondary
End point timeframe	The evolution of serum IgE level was measured between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: IU/ml     arithmetic mean (standard deviation) 216.5 ± 574.3 -16.7 ± 257.1
Statistical analysis title	Comparison of evolution of IgE level
Statistical analysis description	Changes from baseline was calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.2995 [45]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [45] - No significant difference between groups

Secondary: Evolution of IgE level Top of page

Secondary: Evolution of IgA level Top of page
End point title	Evolution of IgA level
End point description
End point type	Secondary
End point timeframe	The evolution between baseline and 12 weeks was calculated for each arm
End point values FAS Placebo V3 FAS Ismigen V4 Number of subjects analysed 21 28 Units: g/l     arithmetic mean (standard deviation) 0.08 ± 0.2 0.08 ± 0.33
Statistical analysis title	Comparison of the evolution of IgA level
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Placebo V3 v FAS Ismigen V4
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.5828 [46]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [46] - no difference between groups

Secondary: Evolution of IgA level Top of page

Secondary: Evolution of IgM level Top of page
End point title	Evolution of IgM level
End point description
End point type	Secondary
End point timeframe	Same as for other non specific serum immunoglobulines
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: g/l     arithmetic mean (standard deviation) 0.05 ± 0.14 0.03 ± 0.28
Statistical analysis title	Comparison of evolution of IgM level
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.6998 [47]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [47] - No significant differences between groups

Secondary: Evolution of IgM level Top of page

Secondary: Evolution of IgG level Top of page
End point title	Evolution of IgG level
End point description
End point type	Secondary
End point timeframe	the evolution was measured between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: g/l     arithmetic mean (standard deviation) 0.1 ± 1.1 0.3 ± 0.9
Statistical analysis title	Compairison of the evolution of IgG level at V3
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.6649 [48]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [48] - No difference between groups

Secondary: Evolution of IgG level Top of page

Secondary: Evolution of IgG1 level Top of page
End point title	Evolution of IgG1 level
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: g/l     arithmetic mean (standard deviation) 0 ± 0.8 0.2 ± 0.8
Statistical analysis title	Comparison of the evolution of IgG1 level
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.5966 [49]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [49] - non significant difference between groups

Secondary: Evolution of IgG1 level Top of page

Secondary: Evolution of IgG2 level Top of page
End point title	Evolution of IgG2 level
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: g/l     arithmetic mean (standard deviation) 0.1 ± 0.2 0.1 ± 0.2
Statistical analysis title	Comparison of the evolution of IgG2 level
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.7402 [50]
Method	ANCOVA
Parameter type	Median difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [50] - No significant difference between groups

Secondary: Evolution of IgG2 level Top of page

Secondary: Evolution of IgG3 level Top of page
End point title	Evolution of IgG3 level
End point description
End point type	Secondary
End point timeframe	The evolution was calculated between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: g/l     arithmetic mean (standard deviation) 0.03 ± 0.09 0.03 ± 0.08
Statistical analysis title	Comparison of the evolution of IgG3 level
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.2762 [51]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [51] - No significant difference between groups

Secondary: Evolution of IgG3 level Top of page

Secondary: Evolution of IgG4 level Top of page
End point title	Evolution of IgG4 level
End point description
End point type	Secondary
End point timeframe	The evolution was calculated between baseline and 12 weeks
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: g/l     arithmetic mean (standard deviation) -0.02 ± 0.2 0.08 ± 0.28
Statistical analysis title	Comparison of evolution of IgG4 level
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.3571 [52]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [52] - No significant difference between groups

Secondary: Evolution of IgG4 level Top of page

Secondary: Evolution of specific IgG level Top of page
End point title	Evolution of specific IgG level
End point description
End point type	Secondary
End point timeframe	The change from baseline of this laboratory parameter was described at 3 weeks and 12 weeks.
End point values FAS Ismigen V2 FAS Placebo V2 FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 17 26 19 27 Units: arbitrary units     arithmetic mean (standard deviation) 1.2 ± 3.1 0.6 ± 2.9 0.2 ± 2.9 0.5 ± 2.7
Statistical analysis title	Comparison of evolution of specific IgG at V2
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Placebo V2 v FAS Ismigen V2
Number of subjects included in analysis	43
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.4923 [53]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [53] - No significant difference between groups
Statistical analysis title	Comparison of evolution of specific IgG at V3
Statistical analysis description	Same as previous
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	46
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.7593 [54]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [54] - No significant difference between groups

Secondary: Evolution of specific IgG level Top of page

Secondary: Evolution of specific IgG 500 level Top of page
End point title	Evolution of specific IgG 500 level
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and 3 weeks then 12 weeks.
End point values FAS Ismigen V2 FAS Placebo V2 FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 17 26 19 27 Units: arbitrary units     arithmetic mean (standard deviation) 0 ± 1.7 0.3 ± 1.4 0.4 ± 2.6 0.4 ± 1
Statistical analysis title	Comparison of evolution of specific IgG500 at V2
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V2 v FAS Placebo V2
Number of subjects included in analysis	43
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.731 [55]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [55] - No significant difference between groups.
Statistical analysis title	Comparison of evolution of IgG500 at V3
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	46
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.3189 [56]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [56] - No significant difference between groups.

Secondary: Evolution of specific IgG 500 level Top of page

Secondary: Evolution of specific IgA level Top of page
End point title	Evolution of specific IgA level
End point description
End point type	Secondary
End point timeframe	The evolution of specific IgA level was between baseline and 3 weeks and between baseline and 12 weeks.
End point values FAS Ismigen V2 FAS Placebo V2 FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 17 26 19 27 Units: arbitrary units     arithmetic mean (standard deviation) 0.5 ± 2.6 0.1 ± 1.6 0.3 ± 1.9 0 ± 1.5
Statistical analysis title	Comparison of the evolution of specific IgA at V2
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V2 v FAS Placebo V2
Number of subjects included in analysis	43
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.8525 [57]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [57] - No significant difference between groups
Statistical analysis title	Comparison of the evolution of specific IgA at V3
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	46
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.6794 [58]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [58] - No significant difference between groups

Secondary: Evolution of specific IgA level Top of page

Secondary: Evolution of specific IgA 500 level Top of page
End point title	Evolution of specific IgA 500 level
End point description
End point type	Secondary
End point timeframe	The evolution of specific IgA500 was calculated between baseline and V2 and between baseline and V3
End point values FAS Ismigen V2 FAS Placebo V2 FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 17 26 17 27 Units: arbitrary units     arithmetic mean (standard deviation) 0.8 ± 2.5 0 ± 1.5 0.1 ± 1.6 -0.1 ± 1.1
Statistical analysis title	Comparison of the evolution of IgA500 at V2
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V2 v FAS Placebo V2
Number of subjects included in analysis	43
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.6538 [59]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [59] - No significant difference between groups
Statistical analysis title	Comparison of evolution of specific IgG500 at V3
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	44
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.9069 [60]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [60] - No signifiant difference between groups

Secondary: Evolution of specific IgA 500 level Top of page

Secondary: Evolution of specific IgM level Top of page
End point title	Evolution of specific IgM level
End point description
End point type	Secondary
End point timeframe	The evolution of the specific IgM level was calculated between baseline and V2 and between baseline and V3
End point values FAS Ismigen V2 FAS Placebo V2 FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 17 26 19 27 Units: arbitrary units     arithmetic mean (standard deviation) -0.7 ± 0.2 -0.5 ± 2.1 0.4 ± 3 0.3 ± 1.5
Statistical analysis title	Comparison of the evolution of specific IgM at V2
Comparison groups	FAS Ismigen V2 v FAS Placebo V2
Number of subjects included in analysis	43
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.6892 [61]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [61] - No significant difference
Statistical analysis title	Comparison of the evolution of specific IgM at V3
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	46
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.4485 [62]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [62] - No significant difference between groups

Secondary: Evolution of specific IgM level Top of page

Secondary: Evolution of specific IgM 500 level Top of page
End point title	Evolution of specific IgM 500 level
End point description
End point type	Secondary
End point timeframe	The evolution of specific IgM500 level was calculated between baseline and V2 and between baseline and V3
End point values FAS Ismigen V2 FAS Placebo V2 FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 17 26 19 27 Units: arbitrary units     arithmetic mean (standard deviation) 0.1 ± 1.1 -0.3 ± 1.7 0.3 ± 1.4 0.3 ± 1.6
Statistical analysis title	Comparison of evolution of specific IgM500 at V2
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V2 v FAS Placebo V2
Number of subjects included in analysis	43
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.6547 [63]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [63] - No significant difference
Statistical analysis title	Comparison of evolution of specific IgM500 at V3
Statistical analysis description	Changes from baseline were calculated and compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) was used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	46
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.8737 [64]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [64] - No significant difference between groups

Secondary: Evolution of specific IgM 500 level Top of page

Secondary: Evolution of Treg counts at V3 Top of page
End point title	Evolution of Treg counts at V3
End point description
End point type	Secondary
End point timeframe	The evolution of Treg level was measured between baseline and V3
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: cells/mm3     arithmetic mean (standard deviation) 6.5 ± 37.3 -0.8 ± 24.8
Statistical analysis title	Comparison of the evolution of Treg counts
Statistical analysis description	The change from baseline at each time 12 weeks is compared between the treatment groups using an ANCOVA with the baseline as covariate. In case of non normal distributions (evaluated by Shapiro-Wilk’s test), a non-parametric analysis of covariance (based on ranks) is used.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.0395 [65]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [65] - The evolution of the level of T regulatory cells (Treg) expressing CD4, FoxP3 and high level of CD25 was significantly different between groups (p=0.0395). An increase was observed in treated patients while a reduction was detected in Placebo.

Secondary: Evolution of Treg counts at V3 Top of page

Secondary: Evolution of cytotoxic T lymphocytes counts at V3 Top of page
End point title	Evolution of cytotoxic T lymphocytes counts at V3
End point description
End point type	Secondary
End point timeframe	Evolution between baseline and V3
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: cells/mm3     arithmetic mean (standard deviation) 136.6 ± 324.3 -92.7 ± 282.8
Statistical analysis title	Comparison of the evolution of Cytotoxic T lymp
Statistical analysis description	As previously described for treg
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.0181 [66]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [66] - The evolution of CD3+CD8+ lymphocyte count was significantly different between groups (p=0.0181). An increase was observed in treated patients while a reduction was detected in Placebo.

Secondary: Evolution of cytotoxic T lymphocytes counts at V3 Top of page

Secondary: Evolution of NK cells count at V3 Top of page
End point title	Evolution of NK cells count at V3
End point description
End point type	Secondary
End point timeframe	Evolution between baseline and V3
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: cells/mm3     arithmetic mean (standard deviation) 19.1 ± 114.8 -35 ± 164
Statistical analysis title	Comparison of evolution of NK cells count
Statistical analysis description	As previously described for other white blood cells phenotypes
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.0463 [67]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [67] - The evolution of NK cells CD3-CD16+CD56+ (count) was significantly different between groups (p=0.0463). An increase was observed in Ismigen® treated patients while a reduction was detected in Placebo.

Secondary: Evolution of NK cells count at V3 Top of page

Secondary: Evolution of late activated T lymphocytes % CD3+ at V3 Top of page
End point title	Evolution of late activated T lymphocytes % CD3+ at V3
End point description
End point type	Secondary
End point timeframe	Evolution between baseline and V3 of late activated lymphocytes % CD3+ (CD3+CD25+%CD3+)
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: percent of CD3+ cells     arithmetic mean (standard deviation) -0.6 ± 5.3 0.7 ± 4.1
Statistical analysis title	Comparison of (CD3+CD25+)%CD3+ at V3
Statistical analysis description	As previously described for other white blood cells phenotypes
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.0243 [68]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [68] - The evolution of T cells CD3+CD25+ (% of T cells CD3+) was significantly different between groups (p=0.0243). A reduction was observed in the treated group while in the Placebo group an increase was detected.

Secondary: Evolution of late activated T lymphocytes % CD3+ at V3 Top of page

Secondary: Evolution of early activated T lymphocytes%CD45+ at V3 Top of page
End point title	Evolution of early activated T lymphocytes%CD45+ at V3
End point description
End point type	Secondary
End point timeframe	Evolution was measured between baseline and V3
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: % of CD45+ cells     arithmetic mean (standard deviation) -1.1 ± 3.8 2.3 ± 11.5
Statistical analysis title	Comparison of evolution of (CD3+CD69+)%CD45+
Statistical analysis description	As previously described for other phenotypes
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.0129 [69]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [69] - The evolution of T cells CD3+CD69+ (% of lymphocytes CD45+) was significantly different between groups (p=0.0129). A reduction was observed in the treated group while in the Placebo group an increase was detected.

Secondary: Evolution of early activated T lymphocytes%CD45+ at V3 Top of page

Secondary: Evolution of early activated T lymphocytes% CD3+ at V3 Top of page
End point title	Evolution of early activated T lymphocytes% CD3+ at V3
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and V3
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: % of CD3+ cells     arithmetic mean (standard deviation) -2.2 ± 5.2 2.5 ± 15.3
Statistical analysis title	Comparison of evolution of (CD3+CD69+)%CD+3
Statistical analysis description	Same as previously described for other phenotypes.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.014 [70]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [70] - The evolution of T cells CD3+CD69+ (% of T cells CD3+) was significantly different between groups (p=0.0140). A reduction was observed in the treated group while in the Placebo group an increase was detected.

Secondary: Evolution of early activated T lymphocytes% CD3+ at V3 Top of page

Secondary: Evolution of early activated T helper lymphocytes%CD45+ at V3 Top of page
End point title	Evolution of early activated T helper lymphocytes%CD45+ at V3
End point description
End point type	Secondary
End point timeframe	The evolution was measured between baseline and V3
End point values FAS Ismigen V3 FAS Placebo V3 Number of subjects analysed 21 28 Units: % of CD45+ cells     arithmetic mean (standard deviation) -1.1 ± 2 -0.1 ± 2.6
Statistical analysis title	Comparison of the evolution of CD4+CD69+%CD45+
Statistical analysis description	Same as previously described for other phenotypes.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	49
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.019 [71]
Method	ANCOVA
Parameter type	Mean difference (net)
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-
Variability estimate	Standard deviation
Notes [71] - The evolution of T cells CD4+CD69+ lymphocytes expressed as % of CD45+ cells was significantly different between groups: this percentage decreased in Ismigen® group whereas only a slight decrease was observed in the Placebo group .

Secondary: Evolution of early activated T helper lymphocytes%CD45+ at V3 Top of page

Secondary: Total duration of infections (per patient) Top of page
End point title	Total duration of infections (per patient)
End point description
End point type	Secondary
End point timeframe	The total duration of infections was measured at V3, V4, V5
End point values FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 35 32 28 36 35 39 Units: days     arithmetic mean (standard deviation) 10.2 ± 5.3 10.9 ± 6.8 8.5 ± 4.9 10.0 ± 6.3 10.0 ± 5.5 12.2 ± 12
Statistical analysis title	Comparison of total duration of RI at V3
Statistical analysis description	The total duration of infections per patient (days) was compared between treatment groups using a Student's t test or Wilcoxon’s test in case of non-normality.
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	67
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.89 [72]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [72] - No significant difference between groups.
Statistical analysis title	Comparison of total duration of RI at V4
Statistical analysis description	Same as previously described.
Comparison groups	FAS Ismigen V4 v FAS Placebo V4
Number of subjects included in analysis	64
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.471 [73]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [73] - No significant difference between groups
Statistical analysis title	Comparison of total duration of RI at V5
Statistical analysis description	Same as previously described.
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	74
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.884 [74]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [74] - No significant difference between groups

Secondary: Total duration of infections (per patient) Top of page

Secondary: Number of school days lost because of respiratory infections Top of page
End point title	Number of school days lost because of respiratory infections
End point description	School days lost or without normal activities.
End point type	Secondary
End point timeframe	This parameter was calculated at V3, V4, V5
End point values FAS Ismigen V3 FAS Placebo V3 FAS Ismigen V4 FAS Placebo V4 FAS Ismigen V5 FAS Placebo V5 Number of subjects analysed 35 32 28 36 35 39 Units: days     arithmetic mean (standard deviation) 3.6 ± 4.2 4.8 ± 4.8 2.6 ± 3.0 5.8 ± 5.1 5.7 ± 4.7 5.9 ± 6.2
Statistical analysis title	Comparison of school days lost because RI at V3
Statistical analysis description	The number of school days lost (or days without normal activity) was compared between treatment groups using a Student's t test or Wilcoxon’s test in case of non-normality)
Comparison groups	FAS Ismigen V3 v FAS Placebo V3
Number of subjects included in analysis	67
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.375 [75]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [75] - No significant difference between groups
Statistical analysis title	Comparison of school days lost because of RI at V4
Statistical analysis description	Same as previously described
Comparison groups	FAS Ismigen V4 v FAS Placebo V4
Number of subjects included in analysis	64
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.008 [76]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [76] - The number of school days lost was significantly lower in Ismigen® group as compared to Placebo group. However, the relevance of this isolated result should be questioned.
Statistical analysis title	Comparison of school days lost because RI at V5
Statistical analysis description	Same as previously described
Comparison groups	FAS Ismigen V5 v FAS Placebo V5
Number of subjects included in analysis	74
Analysis specification	Post-hoc
Analysis type	superiority
P-value	= 0.646 [77]
Method	Wilcoxon (Mann-Whitney)
Confidence interval
Notes [77] - No significant difference between groups

Secondary: Number of school days lost because of respiratory infections Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Adverse events were reported at all study times: V2, V3, V4, V5
Adverse event reporting additional description	All the AE, SAE reported in the diary or reported during the visit by the patients, discovered during the visit or notified by a hospital department were recorded in the CRF after validation by the investigator. In case of SAE (no SUSAR occurred during the study), SAE forms were filled until resolution or stabilization of the SAE.
Assessment type	Non-systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	18
Reporting groups
Reporting group title	Ismigen
Reporting group description	Treatment emergent adverse events were reported all over the study for all the patients of the Ismigen group who have taken at least 1 Ismigen tablet (safety population): 75 patients in the Ismigen group and 76 patients in the Placebo group.
Reporting group title	Placebo
Reporting group description	Treatment emergent adverse events were reported all over the study for all the patients of the Placebo group who have taken at least 1 Ismigen tablet (safety population).
Serious adverse events Ismigen Placebo Total subjects affected by serious adverse events      subjects affected / exposed 1 / 75 (1.33%) 3 / 76 (3.95%)      number of deaths (all causes) 0 0      number of deaths resulting from adverse events 0 0 Nervous system disorders VIIth nerve paralysis alternative assessment type: Systematic      subjects affected / exposed 1 / 75 (1.33%) 0 / 76 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders Status asthmaticus alternative assessment type: Systematic      subjects affected / exposed 0 / 75 (0.00%) 1 / 76 (1.32%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Infections and infestations Influenza alternative assessment type: Systematic      subjects affected / exposed 0 / 75 (0.00%) 1 / 76 (1.32%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Laryngitis alternative assessment type: Systematic      subjects affected / exposed 0 / 75 (0.00%) 1 / 76 (1.32%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Ismigen Placebo Total subjects affected by non serious adverse events      subjects affected / exposed 71 / 75 (94.67%) 67 / 76 (88.16%) General disorders and administration site conditions Pyrexia      subjects affected / exposed 6 / 75 (8.00%) 3 / 76 (3.95%)      occurrences all number 6 3 Respiratory, thoracic and mediastinal disorders Asthma      subjects affected / exposed 42 / 75 (56.00%) 49 / 76 (64.47%)      occurrences all number 79 146 Rhinitis allergic      subjects affected / exposed 10 / 75 (13.33%) 14 / 76 (18.42%)      occurrences all number 15 22 Infections and infestations Nasopharyngitis      subjects affected / exposed 38 / 75 (50.67%) 35 / 76 (46.05%)      occurrences all number 56 63 Pharyngitis      subjects affected / exposed 22 / 75 (29.33%) 25 / 76 (32.89%)      occurrences all number 36 32 Bronchitis      subjects affected / exposed 13 / 75 (17.33%) 19 / 76 (25.00%)      occurrences all number 13 28 Laryngitis      subjects affected / exposed 8 / 75 (10.67%) 4 / 76 (5.26%)      occurrences all number 11 5 Sinusitis      subjects affected / exposed 7 / 75 (9.33%) 8 / 76 (10.53%)      occurrences all number 7 11 Acute sinusitis      subjects affected / exposed 4 / 75 (5.33%) 1 / 76 (1.32%)      occurrences all number 4 1 Influenza      subjects affected / exposed 0 / 75 (0.00%) 5 / 76 (6.58%)      occurrences all number 0 5 Tonsillitis      subjects affected / exposed 6 / 75 (8.00%) 2 / 76 (2.63%)      occurrences all number 8 3

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? No
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
Due to the limited blood sample volume available in accordance with paediatric regulation , samples were insufficient for most patients to perform cytokines measurements planned in the protocol. Available results are included in the full report.
Online references
http://www.ncbi.nlm.nih.gov/pubmed/20920766 http://www.ncbi.nlm.nih.gov/pubmed/16936237 http://www.ncbi.nlm.nih.gov/pubmed/17353040 http://www.ncbi.nlm.nih.gov/pubmed/8901365 http://www.ncbi.nlm.nih.gov/pubmed/8901364 http://www.ncbi.nlm.nih.gov/pubmed/15796091 http://www.ncbi.nlm.nih.gov/pubmed/17346436 http://www.ncbi.nlm.nih.gov/pubmed/22023774 http://www.ncbi.nlm.nih.gov/pubmed/26028631 http://www.ncbi.nlm.nih.gov/pubmed/14979609 http://www.ncbi.nlm.nih.gov/pubmed/16522452

More information Top of page