Randomised Placebo-controlled Study of Grass Pollen Allergen Immunotherapy Tablet (AIT) for Seasonal Rhinitis: Time Course of Nasal, Cutaneous and Immunological Outcomes
Grass Pollen Allergen Immunotherapy Tablet (AIT) Time Course Study
Sponsors
Lead Sponsor
Collaborators
Source
Imperial College London
Oversight Info
Has Dmc
No
Is Fda Regulated Drug
No
Is Fda Regulated Device
No
Brief Summary
About 45 million people in Europe have allergic rhinitis (hay fever) - inflammation of the
nasal passages causing sneezing, runny nose, nasal congestion, itching and tearing of the
eyes. In the United Kingdom (UK), seasonal hay fever due to grass pollen allergy accounts for
approximately 7 times more doctors' appointments than asthma. The standard treatment for hay
fever consists of treating the symptoms with a nasal spray and an antihistamine. However, in
a survey taken in a UK general practice less than 40% of patients with hay fever reported
good symptom control with this standard treatment. For those patients with hay fever whose
symptoms are not well controlled by treatment with antihistamines and nasal sprays,
subcutaneous immunotherapy (SCIT) - (monthly injections of a grass allergen extract for a
period of 3-5 years) is an effective alternative, and is approved in the UK on a named
patient basis. More recently, allergen immunotherapy tablets (AITs) have been developed,
including grass pollen allergen tablets. These have been shown to be highly effective in the
treatment of hay fever, with the additional benefit of being convenient for patients, given
that they may be taken at home. Grazax® (manufactured by Allergologisk Laboratorium København
(ALK)-Abello, Denmark) has UK and European Union (EU) license for use in the treatment of
troublesome grass pollen induced hay fever. The aim of this research is to investigate the
effects of the AIT treatment on the immune system over time - which changes are taking place
and when in the course of treatment. This will provide insight into the complexities of the
development of allergen-specific immune tolerance - how harmful allergic responses against
innocuous substances such as grass pollen can be overridden.
Detailed Description
The study will be conducted over 44 months. We expect to screen 70 atopic patients in order
to enroll up to 50 suitable atopic participants to ensure randomisation of at least 40 atopic
participants following their baseline visit. Additionally, we shall recruit 20 healthy,
non-atopic volunteers. Individuals with moderate to severe grass pollen hay fever, with or
without associated seasonal asthma, will be recruited and screened after the pollen season
from September through March 2014. Atopic Participants will undergo baseline assessments in
December 2013 to March 2014. All screening assessments will be completed before eligible
participants are randomized to active or placebo treatment. Atopic participants will then
begin AIT treatment in February-March 2014 and continue treatment for 12 months. All atopic
participants will be provided with anti-allergic rescue medications (antihistamine tablets,
topical intranasal corticosteroids, and eye-drops) throughout the pollen season. Clinical
surrogate endpoint assessments and on specific time Points blood, nasal fluid and nasal
brushing sampling, will be performed at baseline (January-March 2014), at 4, 8, 12 and 16
weeks after starting the AIT, and at 6 and at 12 months (January-March 2015) of treatment.
Nasal mucosal biopsies will be taken at baseline, during the Peak pollen season, and 12
months of treatment. After 12 months of treatment, unblinding will take place. Those atopic
participants receiving active AIT treatment will continue therapy for another 12 months
followed by a withdrawal phase of 12 months. Blood samples and nasal biopsies will be taken
from these participants again at 24 and at 36 months from the initial start of treatment.
Those atopic participants on placebo will be offered 24 months of active treatment after
unblinding.
20 healthy, non-atopic participants will also be recruited and studied on a single day before
and after nasal challenge at one timepoint at 12 months. They will undergo the same clinical
and immunological measurements as for the 46 randomised subjects participating in the
clinical trial. The healthy subjects will undergo no therapeutic intervention and serve as
controls for the immunological measurements.
The study will receive monitoring by:
- the sponsor, Imperial College London
and audits by:
- Medicines for human use (clinical trials) regulations authority (MHRA)
We will assess the clinical data on paper case report forms and will use Inform as a database
in order to verify completeness of data entry.
The Inform database also includes normal ranges of parameters if relevant.
Standard Operating Procedures are in place regarding clinical measures (e.g. nasal allergen
challenges, nasal biopsies etc.) as well as data management (e.g. the Trial Master File),
reporting of adverse events and data collection. All involved investigators are informed
about these procedures and have current Good Clinical Practice (GMC) instructions.
Statistical analysis will be with non-parametric statistics taking into account treatment
effect baseline values and visit number. Inclusion of 20 participants per group will give
greater than 90% power (p=0.05) to detect a 40% reduction in the early phase response (EPR)
after nasal challenge (AUC of the TNSS in the first 60 minutes after challenge, a 40%
reduction in the skin late phase response (LPR), and a 50% increase in grass pollen allergen
specific immunoglobulin G4 (IgG4) for AIT vs. placebo.
Based on more recent nasal allergen challenge studies (Scadding et al, unpublished data; mean
4.63, standard deviation 1.65 for AUC 0-60 minutes post grass pollen nasal challenge in 14
allergic volunteers), inclusion of 13 patients per group will provide 80% power to detect a
40% reduction in AUC after challenge, whereas inclusion of 22 patients per group will provide
80% power to detect a 30% reduction.
Further based on a recent study (Scadding et al, unpublished data; mean 70.14, standard
deviation 14.17 for cross-sectional area in cm2 at 8 hours for skin late phase response to
intradermal grass pollen injection), inclusion of 7 participants per group will provide 80%
power to detect a 30% reduction, whereas inclusion of 10 participants per group will provide
90% power to detect a 30% reduction.
Intent-to-treat (ITT) sample will be defined as all randomized participants. ITT participants
will be analysed with the group to which they were randomized, regardless of the medication
actually received. If participants drop out post randomisation, they will be invited to
complete study assessments throughout the duration of the trial.
Per-protocol (PP) sample will be defined as ITT sample participants who remain in the study
for 12 months and in whom the primary endpoints were assessed. Participants in the PP sample
must be compliant with study medication, defined as taking 75% or more of their study
medication for the duration of the study. Compliance with study medication will be as
assessed by pill count for returned AIT/placebo. Participants in the PP sample will be
analysed with the group to which they were randomized. The non-atopics will also be included
in the PP sample.
Safety sample (SS) will be defined as all enrolled participants.
Analysis of study data will be conducted to address all objectives of the trial and other
interrelationships among all data elements of interest to the investigators and of relevance
to the objectives of the study. Primary analysis of treatment effect will be conducted under
the intention-to-treat (ITT) principle of eligible patients, whereby outcome data from all
eligible patients will be included regardless of treatment compliance. In addition to the
analyses described in sections below, summary descriptive statistics will be provided in the
following manner: continuous data will be summarized descriptively by mean, standard
deviation, median, and range; categorical data will be presented as enumerations and
percentages.
Analysis of primary endpoint:
The primary endpoint will be analysed using the ITT and the PP sample. The analysis of the
primary endpoint will compare the mean EPR to nasal challenge recorded by the TNSS during the
first 60 minutes after the nasal challenge, at 12 months of therapy. Comparison between
active and placebo groups will be assessed using ANOVA at the 0.05 level of significance.
Analysis of secondary endpoint:
All secondary analyses will be treated as supportive. P-values will be presented for the
secondary endpoints but will not be adjusted for multiplicity and should be interpreted with
caution. Findings will be evaluated in the context of the available body of knowledge and
with respect to other findings.
Overall Status
Completed
Start Date
2013-09-01
Completion Date
2017-03-01
Primary Completion Date
2017-03-01
Phase
Phase 2
Study Type
Interventional
Primary Outcome
Measure |
Time Frame |
|
Total Nasal Symptom Score After Nasal Allergen Challenge (NAC) |
60 minutes post-challenge after 12 months of treatment |
Secondary Outcome
Measure |
Time Frame |
|
Early Phase Intradermal Test |
after 12 months of treatment |
|
Late Phase Intradermal Test |
after 12 months of treatment |
|
Change From Baseline in Delta Peak Nasal Inspiratory Flow in L/Min |
60 minutes post-challenge after 12 months of treatment |
|
End of Season Global Rhinitis Symptoms |
after treatment at 12 months |
Enrollment
46
Condition
Intervention
Intervention Type
Drug
Intervention Name
Description
The active treatment arm will receive active grass pollen immunotherapy tablet (AIT), Grazax Oral Lyophilisate 75,000 SQ-T once daily.
Arm Group Label
Grazax
Other Name
Grazax 75,000 SQ-T oral lyophilisate
Allergen Immunotherapy Tablet
SQ Standardized Grass Allergy Immunotherapy
Intervention Type
Drug
Intervention Name
Description
This arm will receive Grazax placebo once daily which contains the same composition as in the active Grazax tablet with the only difference being the exclusion of the grass pollen allergen extract.
Arm Group Label
Grazax Placebo
Other Name
Grazax Placebo tablet
Eligibility
Criteria
Atopic Participants:
Inclusion Criteria:
- age 18 to 65
- grass pollen-induced allergic rhinoconjunctivitis for at least 2 years with peak
symptoms in May-July.
- moderate to severe rhinoconjunctivitis symptoms with or without mild seasonal asthma
interfering with usual daily activities/sleep.
- rhinoconjunctivitis that remains troublesome despite treatment with either
antihistamines or nasal corticosteroids during the grass pollen season.
- Positive skin prick test response (wheal diameter ≥ 3 mm) to timothy grass pollen.
- Positive specific immunoglobulin E (IgE), defined as IgE immunoCAP ≥ 0.7 Immuno Solid
Phase Allergenchip (ISAC) standardized units (ISU), against timothy grass pollen.
- if applicable a negative urine pregnancy test and willingness to use an effective form
of contraception for the duration of involvement in the study.
- The ability to give informed consent and comply with study procedures.
- A positive grass pollen nasal allergen challenge test as defined by a total nasal
symptom score (TNSS) of at least 7/12 after 5 minutes with an allergen dose of 5,000
bioequivalent units (BU)/ml.
Exclusion Criteria:
- Previous grass pollen allergen immunotherapy.
- Prebronchodilator forced expiratory volume at one second (FEV1) < 70% of predicted
value out of grass-pollen season.
- A clinical history of symptomatic allergic rhinitis and/or asthma caused by an
allergen to which the participant is regularly exposed.
- Perennial asthma requiring regular inhaled corticosteroids.
- Seasonal symptoms outside the grass-pollen season.
- History of emergency visit or hospital admission for asthma in the previous 12 months.
- History of chronic obstructive pulmonary disease.
- History of significant recurrent acute sinusitis.
- History of chronic sinusitis.
- At screening visit evidence for upper respiratory tract infection.Participants may be
re-evaluated for eligibility after symptoms resolve.
- Current smokers or a history of ≥ 5 pack years.
- History of life-threatening anaphylaxis or angioedema.
- Ongoing systemic immunosuppressive treatment.
- The use of any investigational drug within 30 days of the screening visit.
- The presence of any medical condition that the investigator deems incompatible with
participation in the study.
- History of fish allergy with positive skin test and/or positive specific IgE test to
vertebrate/finned fish.
- Contraindications taking Grazax.
Non-Atopic:
Inclusion Criteria:
- age 18 to 65.
- Negative skin prick test response to timothy grass pollen and panel of aeroallergens.
- Negative specific IgE, defined as IgE immunoCAP < 0.35 ISU, against timothy grass
pollen.
- If applicable a negative urine pregnancy test at the time of screening and willingness
to use an effective form of contraception for the duration of involvement in the
study.
- The ability to give informed consent and comply with study procedures.
Exclusion criteria:
- Previous grass pollen allergen immunotherapy.
- Prebronchodilator FEV1 < 70% of predicted value out of grass-pollen season.
- symptomatic allergic rhinitis and/or asthma caused by an allergen to which the
participant is regularly and perennially exposed (e.g. cat dander).
- Perennial asthma requiring regular inhaled corticosteroids.
- Seasonal symptoms outside or during the grass-pollen season.
- History of emergency visit or hospital admission for asthma in the previous 12 months.
- History of chronic obstructive pulmonary disease.
- History of significant recurrent acute sinusitis.
- History of chronic sinusitis.
- At screening visit, current symptoms of upper respiratory tract infection.
Participants may be re-evaluated for eligibility after symptoms resolve.
- Current smokers or a history of ≥ 5 pack years.
- History of life-threatening anaphylaxis or angioedema.
- Ongoing systemic immunosuppressive treatment.
- The use of any investigational drug within 30 days of the screening visit.
- The presence of any medical condition that the investigator deems incompatible with
participation in the study.
Gender
All
Minimum Age
18 Years
Maximum Age
65 Years
Healthy Volunteers
Accepts Healthy Volunteers
Overall Official
Last Name |
Role |
Affiliation |
|
Stephen R Durham, Prof. |
Principal Investigator |
Imperial College London |
Location
Facility |
|
NHS Royal Brompton Hospital London SW3 6NP United Kingdom |
Location Countries
Country
United Kingdom
Verification Date
2019-11-01
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Sponsor
Keywords
Has Expanded Access
No
Condition Browse
Secondary Id
2013-003732-72
13/EM/0351
Number Of Arms
2
Intervention Browse
Mesh Term
Immunologic Factors
Arm Group
Arm Group Label
Grazax
Arm Group Type
Active Comparator
Description
The active treatment arm will receive active grass pollen immunotherapy tablet (AIT), Grazax Oral Lyophilisate 75,000 standardised quality units tablet (SQ-T) once daily.
Arm Group Label
Grazax Placebo
Arm Group Type
Placebo Comparator
Description
This arm will receive Grazax placebo once daily which contains the same composition as in the active Grazax tablet with the only difference being the exclusion of the grass pollen allergen extract.
Results Reference
Citation
Steveling EH, Lao-Araya M, Koulias C, Scadding G, Eifan A, James LK, Dumitru A, Penagos M, Calderón M, Andersen PS, Shamji M, Durham SR. Protocol for a randomised, double-blind, placebo-controlled study of grass allergen immunotherapy tablet for seasonal allergic rhinitis: time course of nasal, cutaneous and immunological outcomes. Clin Transl Allergy. 2015 Dec 17;5:43. doi: 10.1186/s13601-015-0087-2. eCollection 2015.
PMID
26682038
Firstreceived Results Date
N/A
Acronym
Pollen+
Patient Data
Sharing Ipd
No
Firstreceived Results Disposition Date
N/A
Study Design Info
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Other
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Study First Submitted
December 4, 2013
Study First Submitted Qc
December 4, 2013
Study First Posted
December 9, 2013
Last Update Submitted
November 14, 2019
Last Update Submitted Qc
November 14, 2019
Last Update Posted
December 4, 2019
Results First Submitted
October 2, 2019
Results First Submitted Qc
November 14, 2019
Results First Posted
December 4, 2019
Provided Document Section
Provided Document
Document Type
Statistical Analysis Plan
Document Has Protocol
No
Document Has Icf
No
Document Has Sap
Yes
Document Date
May 4, 2015
Document Url
https://ClinicalTrials.gov/ProvidedDocs/27/NCT02005627/SAP_000.pdf
Document Type
Study Protocol
Document Has Protocol
Yes
Document Has Icf
No
Document Has Sap
No
Document Date
October 1, 2015
Document Url
https://ClinicalTrials.gov/ProvidedDocs/27/NCT02005627/Prot_001.pdf
Document Type
Informed Consent Form
Document Has Protocol
No
Document Has Icf
Yes
Document Has Sap
No
Document Date
October 1, 2015
Document Url
https://ClinicalTrials.gov/ProvidedDocs/27/NCT02005627/ICF_002.pdf
ClinicalTrials.gov processed this data on December 10, 2019
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Study Phase
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In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.