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Clinical Trial Results:
A multi centre randomised placebo-controlled double-blind clinical trial for the evaluation of efficacy of specific immunotherapy with an aluminium hydroxide-adsorbed recombinant hypoallergenic derivative of the major birch pollen allergen r Bet v1-FV on Bet v 1 associated soy allergy

Summary
EudraCT number	2009-011737-27
Trial protocol	DE
Global end of trial date	18 Jul 2014

Results information
Results version number	v1(current)
This version publication date	18 Jul 2020
First version publication date	18 Jul 2020
Other versions
Summary report(s)	2015-07-13_BASALIT_Ergebnisbericht_in_Arzneimittelpruefungen_final1.0

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

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Trial information

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Sponsor protocol code

BASALIT

ISRCTN number

ISRCTN67316358

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University Leipzig

Sponsor organisation address

Ritterstr. 26, Leipzig, Germany, 04109

Public contact

Jan Christoph Simon, Prof., MD, University Leipzig Klinik für Dermatologie, Venerologie und Allergologie, jan.simon@medizin.uni-leipzig.de

Scientific contact

Regina Treudler, Prof., MD, University Leipzig Klinik für Dermatologie, Venerologie und Allergologie, regina.treudler@medizin.uni-leipzig.de

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

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

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

Analysis stage

Final

Date of interim/final analysis

19 Jan 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Jul 2014

Global end of trial reached?

Yes

Global end of trial date

18 Jul 2014

Was the trial ended prematurely?

Main objective of the trial

To determine the efficacy of specific subcutaneous immunotherapy (SCIT) against birch allergen Bet v 1 on birch pollen associated soy allergy.

Protection of trial subjects

For the analyses of the clinical endpoints, patients will undergo several allergological tests, all of which will be perfomed in a standardized matter according to current position papers. . This will include questionnaires, skin prick tests, blood draws for in vitro tests and oral provocation tests with soy-containing or placebo meals.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Feb 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 56

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

All patients are undergoing initial screening and baseline examinations (up to 9 months) before intervention phase - including double blind placebo controlled food challenge (DBPCFC).

Screening details

The aim was to include a total number of 84 patients with evaluable data with regard to the primary and secondary endpoints after intervention with rBet v1 or placebo. To obtain reliable information, about 385 patients were planned to be recruited and screened for eligibility.

Number of subjects started

195 ^[1]

Number of subjects completed

Reason: Number of subjects

Screening failure: 139

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 139 of these patients are Screening failures.

Period 1 title

intervention (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Verum

Arm description

Arm type

Experimental

Investigational medicinal product name

rBet v1-FV

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Duration of intervention per patient will be divided into three phases: up-dosing; prolongation; maintenance Up-dosing will start with initial injections of 0.15 ml (strength A), continues with increasing dosages of strength A (5 µg/ml) and then of strength B (100 mg/ml). Injections will be administered at weekly intervals (+7 days) according to the dosage schedule, with a maximum dose of 0.8 ml of strength B. During prolongation, there will be gradually increased injection intervals: 7 (+7 days) 14 (+/-7days), 28 (+/-7 days). Thereafter, injections will be applied every 28 (+ 14 days) resulting in the maintenance phase, which is scheduled for nine injections during 38 weeks.

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Duration of intervention per patient will be divided into three phases: up-dosing; prolongation; maintenance The same time schedule and injection regimes as in verum arm. During prolongation, there will be gradually increased injection intervals: 7 (+7 days) 14 (+/-7days), 28 (+/-7 days). Thereafter, injections will be applied every 28 (+ 14 days) resulting in the maintenance phase, which is scheduled for nine injections during 38 weeks.

Dropout before intervention

Arm description

these patients (one per arm) were excluded from analysis acc. to statistical analysis plan

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Verum	Placebo	Dropout before intervention
Started	37	17	2
Completed	37	17	2

Baseline characteristics

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Reporting group title

Verum

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

Dropout before intervention

Reporting group description

these patients (one per arm) were excluded from analysis acc. to statistical analysis plan

Reporting group values	Verum	Placebo	Dropout before intervention	Total
Number of subjects	37	17	2	56
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	37	17	2	56
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age continuous
Age at Screening
Units: years
arithmetic mean (standard deviation)	37.8 ( 14.6 )	37.4 ( 13.8 )	39 ( 25.5 )	-
Gender categorical
Gender
Units: Subjects
Female	25	12	2	39
Male	12	5	0	17
hyposensitization in history
Units: Subjects
yes	25	10	1	36
no	12	7	1	20
Food allergies
Units: Subjects
against <=4 foods	3	4	0	7
5 to <=10	17	7	2	26
>10	17	6	0	23
Skin prick test soy
standardized commercially available soy drink used
Units: Subjects
positive	36	16	2	54
negative	1	1	0	2
skin prick test birch
Units: Subjects
positive	36	17	2	55
negative	1	0	0	1
total IgE at BL
Units: kU/L
median (inter-quartile range (Q1-Q3))	163 (74 to 375)	147 (67 to 242)	124 (53.9 to )	-
specific IgF ab Bet v 1
Units: kU/L at BL
median (inter-quartile range (Q1-Q3))	34 (17 to 66)	28 (16 to 64)	22 (7.1 to )	-
specific IgE ab Gly m 4
Units: kU/L at BL
median (inter-quartile range (Q1-Q3))	9 (4 to 16)	6 (4 to 11)	3.1 (2.3 to )	-
BMI
Units: kg/m²
arithmetic mean (standard deviation)	24.5 ( 3.7 )	23.8 ( 3.6 )	22.8 ( 0.13 )	-

End points

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Reporting group title

Verum

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

Dropout before intervention

Reporting group description

these patients (one per arm) were excluded from analysis acc. to statistical analysis plan

Primary: LOAEL obj

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End point title

LOAEL obj ^[1] ^[2]

End point description

Performance of a double-blind placebo-controlled food challenge: 9 standardized meals within a food challenge were applied to the patient in predefined schedule within various hours of a day; the order of active (with increasing contents of soy) or placebo (withouth any soy but the same size, texture and colour of meals) food challenge was randomized and both challenges took place on 2 different days near in time; both the appearance of objective and/ or subjective symptoms were assessed by the investigators and/or reported by the patients after any meal incorporated and the lowest level identified in which signs/ symptoms occurred; the "Lowest observe adverse effect levels (LOAEL)" inducing objective signs/ subjective symptoms were regarded as two primary endpoints without hierarchy

End point type

Primary

End point timeframe

after the end of the intervention period

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: see attached Chart/document for statistics from the main publication
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: both dropouts before intervention started; no data available

End point values	Verum	Placebo
Number of subjects analysed	33	15
Units: gram(s) of soy
median (inter-quartile range (Q1-Q3))	24.7 (24.7 to 24.7)	24.7 (2.2 to 24.7)

Attachments

Basalit_statistics_main-results.pdf

No statistical analyses for this end point

Primary: LOAEL subj

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End point title

LOAEL subj ^[3] ^[4]

End point description

2nd primary end point; analysis with Bonferroni-Holm correction for multiplicity

End point type

Primary

End point timeframe

after the end of intervention

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: see attached Chart/document for statistics from the main publication
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: both dropouts before intervention started; no data available

End point values	Verum	Placebo
Number of subjects analysed	33 ^[5]	15 ^[6]
Units: gram(s) of soy
median (inter-quartile range (Q1-Q3))	4.7 (0.7 to 24.7)	2.2 (2.2 to 24.7)

Notes
[5] - in 4 patients refused to perform the DBPCFC after their ent of intervention
[6] - 2 patients refused to perform the DBPCFC after therin end of intervention

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events are recorded during intervention period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

rBet v 1

Reporting group description

experimental arm

Reporting group title

placebo injections

Reporting group description

control arm

Serious adverse events	rBet v 1	placebo injections
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 37 (16.22%)	2 / 17 (11.76%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Investigations
Arthroscopy
subjects affected / exposed	1 / 37 (2.70%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Brain contusion
subjects affected / exposed	1 / 37 (2.70%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	1 / 37 (2.70%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism arterial
subjects affected / exposed	1 / 37 (2.70%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Papilloma excision
subjects affected / exposed	1 / 37 (2.70%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Migraine
subjects affected / exposed	1 / 37 (2.70%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion
subjects affected / exposed	0 / 37 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Vascular stent thrombosis
subjects affected / exposed	1 / 37 (2.70%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 37 (2.70%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	rBet v 1	placebo injections
Total subjects affected by non serious adverse events
subjects affected / exposed	30 / 37 (81.08%)	15 / 17 (88.24%)
Nervous system disorders
Headache
subjects affected / exposed	11 / 37 (29.73%)	6 / 17 (35.29%)
occurrences all number	25	17
General disorders and administration site conditions
Fatigue
subjects affected / exposed	4 / 37 (10.81%)	1 / 17 (5.88%)
occurrences all number	4	4
Influenza like illness
subjects affected / exposed	4 / 37 (10.81%)	2 / 17 (11.76%)
occurrences all number	5	2
Injection site erythema
subjects affected / exposed	3 / 37 (8.11%)	1 / 17 (5.88%)
occurrences all number	3	4
Injection site pain
subjects affected / exposed	1 / 37 (2.70%)	3 / 17 (17.65%)
occurrences all number	4	3
Injection site pruritus
subjects affected / exposed	5 / 37 (13.51%)	1 / 17 (5.88%)
occurrences all number	15	4
Injection site swelling
subjects affected / exposed	5 / 37 (13.51%)	1 / 17 (5.88%)
occurrences all number	10	2
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	8 / 37 (21.62%)	2 / 17 (11.76%)
occurrences all number	11	2
Nausea
subjects affected / exposed	2 / 37 (5.41%)	1 / 17 (5.88%)
occurrences all number	3	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 37 (18.92%)	2 / 17 (11.76%)
occurrences all number	8	3
Oropharyngeal pain
subjects affected / exposed	4 / 37 (10.81%)	2 / 17 (11.76%)
occurrences all number	4	2
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	6 / 37 (16.22%)	0 / 17 (0.00%)
occurrences all number	8	0
Pruritus
subjects affected / exposed	6 / 37 (16.22%)	0 / 17 (0.00%)
occurrences all number	7	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	5 / 37 (13.51%)	3 / 17 (17.65%)
occurrences all number	5	3
Infections and infestations
Conjunctivitis
subjects affected / exposed	7 / 37 (18.92%)	1 / 17 (5.88%)
occurrences all number	9	1
Nasopharyngitis
subjects affected / exposed	24 / 37 (64.86%)	10 / 17 (58.82%)
occurrences all number	62	21
Sinusitis
subjects affected / exposed	5 / 37 (13.51%)	1 / 17 (5.88%)
occurrences all number	5	3

More information

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Were there any global substantial amendments to the protocol? Yes

25 Jun 2010

changes in: - eligibility criteria - Decision rules for patients’ inclusion to interventional SCIT - Modification in covariates used during statistical analyses

11 Mar 2011

addition of new trial site

14 Mar 2012

Because of weak recruitment of patients a cost-neutral prolongation of study was performed in agreement with BMBF - Projekträger im DLR Changes in defintion of adverse events Further trial sites will be involved in order to increase the recruitment rate of patients. Addition of one exclusion criterion: according to Leitlinien der Deutschen Gesellschaft Allergologie und klinische Immunologie (DGAKI)

Were there any global interruptions to the trial? No

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

In 2013 the manufacturer (Allergopharma Joachim Ganzer KG) announced that rBet v1-FV was no longer available to continue with the trial intervention. For that reason, the recruitment of patients was stopped prematurely.

http://www.ncbi.nlm.nih.gov/pubmed/27998002
http://www.ncbi.nlm.nih.gov/pubmed/27748994
http://www.ncbi.nlm.nih.gov/pubmed/22527380

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