Clinical Trial Results:
Open label phase II multicenter clinical trial to evaluate safety during accelerated dose escalation of an allergoid birch pollen preparation in patients with IgE mediated allergic rhinitis or rhinoconjunctivitis with or without controlled bronchial asthma
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Summary
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EudraCT number |
2015-005400-28 |
Trial protocol |
DE |
Global end of trial date |
20 Feb 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Feb 2019
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First version publication date |
21 Feb 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AL1502AV
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
ALLERGOPHARMA GMBH & CO. KG.
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Sponsor organisation address |
Hermann-Körner-Straße 52, Reinbek, Germany, 21465
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Public contact |
Clinical Trials Information, Allergopharma GmbH & Co. KG, 0049 40427650,
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Scientific contact |
Clinical Trials Information, Allergopharma GmbH & Co. KG, 0049 40427650,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 Aug 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Feb 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Evaluate the safety and tolerability of an accelerated dose escalation scheme with Allergovit birch in patients with seasonal allergic rhinitis or rhinoconjunctivitis caused by birch pollen with or without controlled bronchial asthma (acc. to the Global Initiative for Asthma [GINA] 2015).
Efficacy exploratory immunological parameters:
Evaluate the change of total specific IgG and specific IgG4 for Betula verrucosa between screening visit and final visit.
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Protection of trial subjects |
The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (ICH) guidance for Good Clinical Practice (GCP) and the applicable regulatory requirements.
Data Safety Monitoring Board (DSMB) was in place throughout the trial; DSMB consisted of 3 independent physicians, experienced in the field of allergy. The primary function of the DSMB was to ensure the subjects’ safety. The DSMB team reviewed an update of the safety data from all treated subjects.
Other than routine care, no specific measures were implemented for the protection of trial subjects.
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Background therapy |
Concomitant medication was defined as any medication other than the IMP that was taken during the clinical trial. All concomitant medications and procedures were reported in the eCRF, stating the indication, dosage and start and end date of therapy. Any changes in concomitant medications were documented and checked against the study inclusion and exclusion criteria. | ||
Evidence for comparator |
Abbreviations used in this document: AE=Adverse event AIT=Allergen immunotherapy DSMB=Data Safety Monitoring Board bpm=Beats per minute ICF=Informed consent form IMP=Investigational medicinal product MedDRA=Medical Dictionary for Regulatory Activities PEF=Peak flow measurement T=Treatment (as in T1 =Treatment visit 1, etc.) TU=Therapeutic units WAO=World Allergy Organization | ||
Actual start date of recruitment |
27 Jun 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 130
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Worldwide total number of subjects |
130
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EEA total number of subjects |
130
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
130
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Overall, 175 adult male and female subjects (18-64 y) were screened for eligibility; 130 subjects were randomised to treatment, according to the exclusion and inclusion criteria. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Screened and randomised to treatment, according to the exclusion and inclusion criteria. | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Accelerated dose escalation | ||||||||||||||||||||||||
Arm description |
Patient randomized to accelerated dose escalation with 4 injections were treated over a period of up to 12 weeks. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Allergovit® Birch
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Investigational medicinal product code |
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Other name |
Birch pollen allergoid
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
The IMP is an aluminium hydroxide-adsorbed allergoid preparation of Allergovit® Birch, provided in two stock concetrations (1000 TU/mL, 10,000TU/mL); injected volume was between 0.1 and 0.6 mL (depending on the stock concentration used). The forseen scheme could be adjusted according to the well-being of the patient and could be lower than the max dose (6000 TU).
PEF and vital signs were measured before and after each injection. The IMP was administered at the trial site, as slow, subcutaneous injection, under sterile measures, on the extensor side of the upper arm, above the elbow. After each administration of the IMP, patients remained under supervision for at least 120 min (accelerated dose escalation) and 30 min (standard dose escalation).
Accelerated dose escalation scheme every 7 days (injection number): 200 (1), 600 (2), 2000 (3), 6000 (4) TU.
Maintenance every 2 weeks after last dose: 6000 (5), 6000 (6) TU.
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Arm title
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Standard dose escalation | ||||||||||||||||||||||||
Arm description |
Patients randomized to standard dose escalation with 7 injections were treated for up to 15 weeks. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Allergovit® Birch
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Investigational medicinal product code |
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Other name |
Birch pollen allergoid
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
The IMP is an aluminium hydroxide-adsorbed allergoid preparation of Allergovit® Birch, provided in two stock concetrations (1000 TU/mL, 10,000TU/mL); injected volume was between 0.1 and 0.6 mL (depending on the stock concentration used). The forseen scheme could be adjusted according to the well-being of the patient and could be lower than the max dose (6000 TU).
PEF and vital signs were measured before and after each injection. The IMP was administered at the trial site, as slow, subcutaneous injection, under sterile measures, on the extensor side of the upper arm, above the elbow. After each administration of the IMP, patients remained under supervision for at least 120 min (accelerated dose escalation) and 30 min (standard dose escalation).
Standard dose escalation scheme every 7 days (injection number): 100 (1), 200 (2), 400 (3), 800 (4), 1500 (5), 3000 (6), 6000 (7) TU.
Maintenance every 2 weeks after last dose: 6000 (8), 6000 (9) TU.
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Baseline characteristics reporting groups
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Reporting group title |
Accelerated dose escalation
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Reporting group description |
Patient randomized to accelerated dose escalation with 4 injections were treated over a period of up to 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard dose escalation
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Reporting group description |
Patients randomized to standard dose escalation with 7 injections were treated for up to 15 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Accelerated dose escalation
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Reporting group description |
Patient randomized to accelerated dose escalation with 4 injections were treated over a period of up to 12 weeks. | ||
Reporting group title |
Standard dose escalation
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Reporting group description |
Patients randomized to standard dose escalation with 7 injections were treated for up to 15 weeks. | ||
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End point title |
1_Treatment-emergent adverse events: causal relationship [1] | |||||||||
End point description |
Results shown represent the number of patients with AEs that were assesed by the investigator as
related to IMP.
When assessing the causality of an AE, the investigator had 2 options:
• Related to IMP
• Not related to IMP
The causality of an AE was suggested to be related, if:
• The AE occurred in a causal temporal relationship to IMP administration
• The localization of the AE implied a causal relationship to IMP administration
The results shown below reflect the number of patients and the numbers of AEs assessed by the investigator as related to the IMP.
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End point type |
Primary
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End point timeframe |
Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP
administration; up to 12 wks for patients in accelerated dose escalation and up to 15 wks for patients in standard dose escalation.
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| 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: This was a safety and tolerability trial. Thus, no hypotheses for the final analysis were formulated and the data were analyzed descriptively. This is in line with the ICH E9 guideline. |
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| Notes [2] - Safety Set Number of AEs assessed by the investigator as related to IMP N=238 [3] - Safety Set Number of AEs assessed by the investigator as related to IMP N=167 |
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| No statistical analyses for this end point | ||||||||||
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End point title |
2_Treatment-emergent adverse events: worst intensity [4] | ||||||||||||||||||
End point description |
Results shown represent the number of patients with AEs of intensities defined below.
AE intensity in this trial was assessed by the the investigator's clinical judgement.
AE intensity:
Mild=Transient symptoms, no interference with the patient’s daily activities.
Moderate=Marked symptoms, moderate interference with the patient’s daily activities.
Severe=Considerable interference with the patient’s daily activities.
The results shown below reflect the number of patients with AEs by intensity, as assessed by the investigator.
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End point type |
Primary
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End point timeframe |
Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP
administration; up to 12 wks for patients in accelerated dose escalation and up to 15 wks for patients in
standard dose escalation.
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| Notes [4] - 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: This was a safety and tolerability trial. Thus, no hypotheses for the final analysis were formulated and the data were analyzed descriptively. This is in line with the ICH E9 guideline. |
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| Notes [5] - Safety Set [6] - Safety Set |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
3_Treatment-emergent adverse event anaphylactic systemic reactions according to WAO | ||||||||||||||||||
End point description |
An AE was defined as a systemic reaction, if the type of event in the AE section of the eCRF was assessed as “anaphylactic reaction acc. WAO grade" and the WAO grade was documented as '1', '2', '3', '4' , or '5'.
Anaphylactic reactions are graded based on organ systems involved and severity according to the WAO Subcutaneous Immunotherapy Systemic Reaction Grading System. The WAO grading of anaphylactic reactions included in this trial is a modified WAO grading.
The results shown below reflect the number of patients and the numbers of AEs, assessed by the investigator as treatment-emergent AEs (anaphylactic systemic reactions) according to WAO.
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End point type |
Secondary
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End point timeframe |
Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP
administration; up to 12 wks for patients in accelerated dose escalation and up to 15 wks for patients in standard dose escalation.
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| Notes [7] - Safety Set Number of events Overall N=4 Escalation phase N=3 Maintenance phase N=1 [8] - Safety Set Number of events Overall N=3 Escalation phase N=3 Maintenance phase N=0 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
4_Lung function test: PEF | ||||||||||||||||||||||||
End point description |
PEF measurements were performed as part of safety measures. The visit and the injection were
rescheduled if a patient did not demonstrate PEF of ≥70% of predicted normal prior to the injection.
PEF was determined at all study visits as follows.
Accelerated dose escalation scheme: before, and 15, 30, 60, 120 min after injection
Standard dose escalation scheme: before, and 15, 30 min after injection
PEF results were similar at all study visits in both groups.
Results shown below are representative for the study visits: first injection day (T1) before, end of injection (after 30 min standard or after 120 min accelerated dose escalation phase); last injection day (T9 Standard dose and T9 accelerated dose, before and after 30 min standard and before or after 120 min accelerated dose escalation phase).
The mean and median PEF results were similar between the treatment groups at all the time points.
The number of patients contributing to the data at each data point is shown.
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End point type |
Secondary
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End point timeframe |
PEF was measured at the screening visit, during treatment, any additional visits, and final visit, at times
specified below under the heading 'Description'.
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| Notes [9] - Safety Set 1st d bfr=63 1st d 120 min aft=63 Lst d bfr=59 Lst d 120 min aft=59 [10] - Safety Set 1st d bfr=67 1st d 30 min aft=66 Lst d bfr=64 Lst d 30 min aft=64 |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
5_Tolerability: Likert scale (Investigator) | |||||||||||||||||||||||||||
End point description |
At the final visit, the tolerability was assessed by the investigator using a 5 point Likert scale, as defined
below.
Likert scale score system: 1=Very bad; 2=Bad; 3=Average; 4=Good; 5=Very good.
The values represent the number of patients, according to the investigators' assessment.
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End point type |
Secondary
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End point timeframe |
At the final visit.
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| Notes [11] - Safety Set used for analysis for both treatment groups |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
6_Tolerability: Likert scale (Patient) | |||||||||||||||||||||||||||
End point description |
At the final visit, the tolerability was assessed by the patient using a 5 point Likert scale, as defined below.
Likert scale score system: 1=Very bad; 2=Bad; 3=Average; 4=Good; 5=Very good.
The values represent the number of patients, according to the patient's own assessment.
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End point type |
Secondary
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End point timeframe |
At the final visit.
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| Notes [12] - Safety Set used for analysis for both treatment groups |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
7_Treatment-emergent adverse events: local reactions | |||||||||||||||||||||
End point description |
Local reactions (AEs) at the injection site > 5 cm or leading to distinct discomfort interfering with the patient’s daily activities.
Results shown represent the number of patients with AEs, characterized as local reactions at injection site and related to IMP.
The AEs were: Injection site swelling, Injection site erythema, Injection site pruritus, Injection site pain, Injection site warmth, Discomfort, Injection site anaesthesia, Injection site haematoma, Injection site hypoaesthesia, Injection site induration, Injection site paraesthesia, Injection site rash, Injection site reaction, Injection site urticaria.
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End point type |
Secondary
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End point timeframe |
Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP
administration; up to 12 wks for patients in accelerated dose escalation and up to 15 wks for patients in
standard dose escalation.
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| Notes [13] - Safety set used for analysis for both treatment groups |
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
8_Small local reactions not considered as AE | |||||||||||||||
End point description |
Number of patients with or without any small local reactions (≥ 2.5 cm and ≤ 5 cm) that were not considered as AEs.
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End point type |
Secondary
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End point timeframe |
Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP
administration; up to 12 wks for patients in accelerated dose escalation and up to 15 wks for patients in standard dose escalation.
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| Notes [14] - Safety Set used for analysis for both treatment groups |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
9_Vital signs - Heart rate | |||||||||||||||||||||||||||
End point description |
Clinical chemistry, vital signs, physical examination - are summarized in one representative endpoint.
Shown is the heart rate; the time points are as described for the end point 6.
The number of patients contributing to the data at each data point is shown.
There were no relevant differences between the treatment groups for vital signs and for laboratory parameters.
Vital signs measured:
Arterial BP, diastolic BP, heart rate, respiratory rate
Laboratory parameters:
• Clinical chemistry: creatinine, total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase
• Blood sugar: glucose (fasting or non fasting; status to be assessed only for determination of eligibility of the subject for the trial)
• Hematology: differential blood cell count, hemoglobin, leukocytes, platelets
• Urine analysis: protein, glucose, blood (hemoglobin), leukocytes, beta-human chorionic gonadotropin (women of childbearing potential only).
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End point type |
Secondary
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End point timeframe |
Vital signs: screening (baseline), before and after each IMP administration, at dose escalation, and at the final/premature termination visit.
Laboratory parameters: screening (baseline) and at the final/premature termination visit.
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| Notes [15] - Safety Set 1st d bfr=63 1st d 120 min aft=63 Lst d bfr=59 Lst d 120 min aft=59 Final d=62 [16] - Safety Set 1st d bfr=67 1st d 30 min aft=66 Lst d bfr=64 Lst d 30 min aft=64 Final d=66 |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
10_Number of patients reaching the maintenance dose without dose adjustment | ||||||||||||||||||
End point description |
Number of patients reaching 1st injection of the planned maintenance dose without or with dose reductions.
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End point type |
Secondary
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End point timeframe |
Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP
administration; up to 12 wks for patients in accelerated dose escalation and up to 15 wks for patients in standard dose escalation.
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| Notes [17] - Safety Set used for analysis for both treatment groups |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
11_Treatment-emergent adverse events: leading to dose reduction | |||||||||
End point description |
Results shown represent the number of patients with AEs that led to dose reduction.
The AEs were: Eye swelling, Injection site erythema, Injection site pain, Injection site pruritus, Injection site swelling, Hypersensitivity, Rhinitis.
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End point type |
Secondary
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End point timeframe |
Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP
administration; up to 12 wks for patients in accelerated dose escalation and up to 15 wks for patients in
standard dose escalation.
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| Notes [18] - Safety Set AEs leading to leading to dose reduction N=30 [19] - Safety Set AEs leading to leading to dose reduction N=4 |
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| No statistical analyses for this end point | ||||||||||
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End point title |
12_Treatment-emergent adverse events: premature trial discontinuation | |||||||||
End point description |
Results shown represent the number of patients with AEs that led to premature trial discontinuation.
The AEs were: Injection site erythema, Injection site swelling.
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End point type |
Secondary
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End point timeframe |
Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP
administration; up to 12 wks for patients in accelerated dose escalation and up to 15 wks for patients in
standard dose escalation.
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| Notes [20] - Safety Set AEs leading to premature trial discontinuation N=2 [21] - Safety Set AEs leading to premature trial discontinuation N=0 |
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| No statistical analyses for this end point | ||||||||||
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End point title |
13_Immunologic parameter total specific IgG (Betula verrucosa) | ||||||||||||
End point description |
Exploratory immunological parameter.
The change of specific total IgG and specific IgG for Betula verrucosa was determined between the screening visit (baseline) and the final visit of the study.
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End point type |
Other pre-specified
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End point timeframe |
At screening (baseline) and at the final visit/premature termination of the study.
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| Notes [22] - Exploratory Immunological Parameters Set was used for evaluation of both treatment groups |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
14_Immunologic parameter total specific IgG4 (Betula verrucosa) | ||||||||||||
End point description |
Exploratory immunological parameter.
The change of specific total IgG and specific IgG4 for Betula verrucosa was determined between
the screening visit and the final visit of the study.
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End point type |
Other pre-specified
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End point timeframe |
At screening (baseline) and at the final visit/premature termination of the study.
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| Notes [23] - Exploratory Immunological Parameters Set was used for evaluation of both treatment groups |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP
administration or trial-related procedure.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
Accelerated dose escalation
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Reporting group description |
Patient randomized to accelerated dose escalation with 4 injections were treated over a period of up to 12 weeks. AEs with onset during or after 1st administration of trial medication were defined as treatment-emergent. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard dose escalation
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Reporting group description |
Patients randomized to standard dose escalation with 7 injections were treated for up to 15 weeks. AEs with onset during or after 1st administration of trial medication were defined as treatment-emergent. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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08 Dec 2016 |
In the protocol version final 1.0 dated 15th January 2016; two trial parts were originally planned.
During the first trial part from May 2016 – December 2016 adult patients were planned to be enrolled. In December 2016, an interim analysis of the data obtained within in the dose escalation phase of the first trial part had been planned. It should have been decided, whether the second trial part enrolling additional adults and also adolescents or children could be performed. The sponsor decided to waive then 2nd trial part in adolescents and children due to changes in the product strategy, despite no safety concerns obtained from the first part of the study. The protocol was amended accordingly, describing the trial conduct in adults only.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
