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INSTITUTE
Validation and Verification of the Allergen Biocube
Model with an Intranasal Corticosteroid
Keith Lane, Endri Angjeli, Paul Gomes MS, Mark B. Abelson MD, Tarek Shazley MD, Mayur M. Contractor - Ora Institute, Andover MA
Validation and Verification of
the Allergen Biocube Model
with an Intranasal Corticosteroid
300 Brickstone Square | Andover MA | 01810 | P: 978-685-8900 | F: 978-689-0020 | oraclinical.com
Validation and Verification of the Allergen Biocube
Model with an Intranasal Corticosteroid
INSTITUTE
Keith Lane, Endri Angjeli, Paul Gomes MS, Mark B. Abelson MD, Tarek Shazley MD, Mayur M. Contractor - Ora Institute, Andover MA
Purpose
Controlled clinical models have become an important tool in development and regulatory approval of new therapeutics for allergic rhinitis.
For example, Environmental Exposure Units (EEUs) have been used to study presentation of allergic rhinitis and to evaluate therapies in a
controlled setting. The ability to elicit allergic rhinitis in a controlled setting provides an opportunity for observation of therapeutic effects
in real time as well as a setting in which treatment effects can be precisely monitored. To date, EEUs have been used for Phase II and
post-marketing drug development studies. Despite this, these current models do not fully capitalize on their potential to quantify the disease
process or the degree to which test interventions modify that process.
Most EEUs suffer from a failure to mimic the normal environmental exposure of allergens that
occurs in allergic rhinitis. Often, allergen levels are inconsistent or are delivered doses that
may not be clinically relevant. This is likely a key factor in the inability of EEUs to generate
reproducible results in clinical studies. This problem is so significant that often the same EEU is
unable to duplicate results in similar or identical protocols. In addition, because of their large
size (typically 50-150 patients/unit), most current EEUs are ill-suited for capturing objective
endpoints with clinician involvement and direct patient observation.
In contrast to other EEUs, Ora has refined its controlled clinical model (Allergen BioCube,
ABC) toward two specific goals: (1) to effectively, reproducibly elicit allergic rhinitis signs
and symptoms in a well-defined patient population, and (2) to capture clinical effects of test
therapies in a controlled manner using both objective and subjective measures in smaller
patient populations.
Our goal is to achieve consistent and reproducible results through the use of precision control of our allergen concentration and flow
through the ABC, make objective measurements with the use of a dedicated clinician, and quantify clinical changes in a consistent and
straight forward manner. We believe that exercising greater control and using clinically significant exposure parameters allows us to more
reliably and efficiently show therapeutic drug effects with low standard deviations in data and within a smaller patient population. As
part of our second goal, we have developed a proprietary objective scale, the Nasal Inflammation Scale (NIS), to ensure accuracy and
reproducibility of assessments.
In this study, we established that our strategy to use precision control and quality together with clinician-informed quantitative measurements
produce excellent therapeutic intervention results. Using an intranasal corticosteroids with well-defined efficacy, Flonase®, and controlled
priming and test exposures to ragweed within the Ora ABC, we were able to show a significant decrease in instantaneous TNSS scores
between the treatment and placebo groups.
300 Brickstone Square | Andover MA | 01810 | P: 978-685-8900 | F: 978-689-0020 | oraclinical.com
Validation and Verification of the Allergen Biocube
Model with an Intranasal Corticosteroid
INSTITUTE
Keith Lane, Endri Angjeli, Paul Gomes MS, Mark B. Abelson MD, Tarek Shazley MD, Mayur M. Contractor - Ora Institute, Andover MA
Methods
A 6-visit IRB-approved single-center, double masked, placebo controlled study was conducted. The two groups included a Flonase®
group (N= 11)with a mean age of 42.9 (SD= 11.7) and a placebo group(N=10) with a mean age of 42.2 (SD= 10.9), all with a history of seasonal allergic symptomology and demonstrated sensitivity to ragweed (as defined by an Ora positive skin test). The study visits
included 1 screening visit, 2 priming (baseline) ABC visits, 2 ABC post-treatment test visits and a study completion and exit visit. Priming
visits are used to establish that subjects have a sufficient level of allergic response to ragweed pollen and to as a way to establish a
baseline TNSS score before treatment.
During ABC visits, nasal pruritus, rhinorrhea, sneezing,
and congestion were assessed at 15 minute intervals using standardized 0-3 unit scales, and were combined to
generate
a
total
nasal
symptom
score
(TNSS)
(range: 0-12). In addition peak nasal inspiratory
flow
(PNIF)
(PEFR)
was
and
peak
evaluated
expiratory
before
entering
flow
and
rate
at
every hour in the ABC. Upon exiting the ABC, nasal
inflammation was graded by a clinician using the 0-4
nasal inflammation scale (NIS). Enrollment inclusion required that subjects in the priming visits to achieve a TNSS of > 6, a nasal congestion score of > 2,. Following the 2nd priming baseline
visit, subjects were randomized into treatment arms, the intranasal corticosteroid Flonase® or placebo, and asked to self administer treatment QD for two weeks. At the end of the two-week dosing, the 2 ABC post-treatment challenge visits were conducted and the same
data was collected. Subjects completed and exited the study after evaluation at visit 6.
Data was compared and analyzed in both unadjusted and adjusted (to Visit 3 baseline) methods.
300 Brickstone Square | Andover MA | 01810 | P: 978-685-8900 | F: 978-689-0020 | oraclinical.com
Validation and Verification of the Allergen Biocube
Model with an Intranasal Corticosteroid
INSTITUTE
Keith Lane, Endri Angjeli, Paul Gomes MS, Mark B. Abelson MD, Tarek Shazley MD, Mayur M. Contractor - Ora Institute, Andover MA
Results
Over the whole 180 minutes of the final post-treatment ABC exposure (Visit 5), mean TNSS score of the treatment group (TNSS= 2.59,
SE= 0.78) was significantly different from the mean TNSS score of the placebo group (TNSS= 5.08, SE= 0.81,Diff= -2.49, p= 0.026)
(Figure 1, Figure 2A). The mean unadjusted TNSS scores over the final 60 minutes Visit 5 (which represents a maximal exposure to allergen and a plateau of symptoms in both groups) for subjects in the treatment group (TNSS = 2.75, SE= 0.89) compared to mean
unadjusted TNSS scores of subjects in the placebo group (TNSS = 6.14, SE= 0.94) were significantly different as well (Diff= -3.39, p=
0.009) (Figure 2B). When values were adjusted to baseline pre-treatment (Visit 3) TNSS scores for the treatment group (TNSS = 8.22)
and placebo group (TNSS = 6.82), the difference between TNSS scores for the treatment group (TNSS= 2.51, SE= 0.92) and placebo
group (TNSS = 6.40, SE= 0.97) remained statistically significant (Diff= -3.89, p= 0.005). This overall significant difference and decrease
in TNSS achieved by significant decreases in all the contributing symptoms of TNSS (Table 1), (Figure 4).
Secondary endpoints included clinician graded nasal inflammation scores and objective Peak Nasal Inspiration Rate (PNIF) scores. Mean
change in NIS from baseline pre-ABC exposure to post-treatment ABC exposure was decreased for the treatment group (NIS= 0.85, SE=
0.41) as compared to the placebo group (NIS= 1.67, SE= 0.43), which did not reach statistical significance, but we believe is trending
towards significant difference (Diff= -0.82, p=0.166) (Figure 5A). Contrary to our predictions, there was no statistical significant difference
of PNIF scores between unadjusted scores for the treatment group (PNIF= 121.59, SE= 9.88) and the placebo group (PNIF= 108.50,
SE= 10.36, Diff= 13.09, p= 0.360); similarly there was no significant difference of adjusted PNIF scores between the treatment group
(PNIF= 116.41, SE= 8.53) and the placebo group (PNIF= 114.19, SE= 8.96, Diff= 2.22, p= 0.861) (Figure 5B).
Symptom
Treatment
Placebo
Difference
p value
Unadjusted
Nasal Congestion
Rhinorrhea
Sneezing
Nasal Pruritus
1.11. ± 0.28
0.69 ± 0.27
0.45 ± 0.25
0.49 ± 0.26
1.74 ± 0.29
1.60 ± 0.28
1.26 ± 0.26
1.54 ± 0.27
-0.63
-0.91
-0.81
-1.05
0.121
0.02
0.23
0.005
Adjusted
Nasal Congestion
Rhinorrhea
Sneezing
Nasal Pruritus
0.86 ± 0.28
0.58 ± 0.26
0.44 ± 0.24
0.44 ± 0.26
1.74 ± 0.29
1.73 ± 0.28
1.27 ± 0.25
1.60 ± 0.27
-1.15
-1.15
-0.83
-1.15
0.008
0.003
0.017
0.02
Table 1: C
ontributing Symptoms of TNSS
300 Brickstone Square | Andover MA | 01810 | P: 978-685-8900 | F: 978-689-0020 | oraclinical.com
Validation and Verification of the Allergen Biocube
Model with an Intranasal Corticosteroid
INSTITUTE
Keith Lane, Endri Angjeli, Paul Gomes MS, Mark B. Abelson MD, Tarek Shazley MD, Mayur M. Contractor - Ora Institute, Andover MA
Figure 1: Mean TNSS of treatment group (red) and placebo group (blue) over full 180 minutes of ABC exposure. Dashed line indicates TNSS level at pre-treatment baseline and solid
line indicates TNSS level at final post-treatment exposure.
6.14± 0.94
2.75± 0.89
TNSS
2.59± 0.78
TNSS
5.08± 0.81
*
A.
*
B.
Figure 2: 1 80 Minute Unadjusted Mean TNSS (A) and final 60 Minute Unadjusted Mean TNSS (B). The treatment group showed a significant difference in mean TNSS score
compared to the placebo group over both the full 180 minutes (Diff= -2.49, P= 0.026) and the final 60 minutes of exposure (Diff= -3.39, p= 0.009).
300 Brickstone Square | Andover MA | 01810 | P: 978-685-8900 | F: 978-689-0020 | oraclinical.com
Validation and Verification of the Allergen Biocube
Model with an Intranasal Corticosteroid
INSTITUTE
Keith Lane, Endri Angjeli, Paul Gomes MS, Mark B. Abelson MD, Tarek Shazley MD, Mayur M. Contractor - Ora Institute, Andover MA
Placebo
Flonase
Pre
Post
Figure 3: Representative turbinate inflammation before and after treatments in placebo group (left) and Flonase group (right).
300 Brickstone Square | Andover MA | 01810 | P: 978-685-8900 | F: 978-689-0020 | oraclinical.com
Validation and Verification of the Allergen Biocube
Model with an Intranasal Corticosteroid
INSTITUTE
Keith Lane, Endri Angjeli, Paul Gomes MS, Mark B. Abelson MD, Tarek Shazley MD, Mayur M. Contractor - Ora Institute, Andover MA
1.74± 0.29
1.73± 0.28
Symptom score
0.89± 0.28
1.60± 0.27
1.27± 0.25
0.58± 0.26
0.44± 0.26
0.44± 0.24
*
*
*
*
Figure 4: A
djusted mean scores of contributing symptoms of TNSS including nasal congestion, rhinorrhea, sneezing, and nasal pruritus. Statistically significant difference was
seen in the treatment group for all symptoms: nasal congestion (Diff= -1.15, p= 0.008), rhinorrhea (Diff= -1.15, p= 0.003), sneezing (Diff= -0.83 , p= 0.017), nasal pruritus
(Diff= -1.15, p= 0.02).
Symptom score
3
A.
1.67± 0.43
3 0.85± 0.41
2.5
2.5
2
2
1.5
1.5
1
1
0.5
0.5
0
0
Placebo
A.
A.
Score
Placebo
Treatment
Score
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
Treatment
B.
Liters/min
Score
B.
Placebo
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
Score
114.19± 8.96
Placebo
Treatment
116.41± 8.53
Treatment
B.
Figure 5: O
bjective measurements include nasal inflammation score (A.) and adjusted peak nasal inspiratory flow (B.). NIS did not show a fully statistical significant difference
between the treatment and placebo group (Diff= -0.82, p=0.166). PNIF showed no significant difference between the groups (Diff= 2.22, p= 0.861).
300 Brickstone Square | Andover MA | 01810 | P: 978-685-8900 | F: 978-689-0020 | oraclinical.com
INSTITUTE
Validation and Verification of the Allergen Biocube
Model with an Intranasal Corticosteroid
Keith Lane, Endri Angjeli, Paul Gomes MS, Mark B. Abelson MD, Tarek Shazley MD, Mayur M. Contractor - Ora Institute, Andover MA
Conclusion
New clinical models should be validated in accordance with the two “V’s and three “R’s”, (validation, verification, reproducibility, reliability, repeatability.) The Allergen BioCube has been previously tested to ensure reliable and reproducible pollen levels as well as a repeatable and consistent clinical response to allergen exposure. Additionally, we have verified that the ABC induces allergic rhinitis consistent
with the natural environment, through an environmental comparison study. The final step in the validation of the ABC was to verify that a
known and efficacious therapy, a nasal corticoid, could demonstrate therapeutic efficacy in the unit.
Despite a small sample size, we were able to achieve significant improvement with regards to the mean TNSS primary endpoints subjects in the therapeutic arm. The level of control over exposure parameters and used of precise measurements at multiple time points has
allowed us to capture a strong drug effect with a low amount of standard error in the data. Our data shows that there was a significant
difference in TNSS scores between the two groups when accounting for TNSS scores throughout the whole final post-treatment exposure,
as well as a statistical significant difference during the last 60 minutes. Those last 60 minutes, simulating prolonged exposure to allergen
and allowing time for symtoms to fully set in, is the time period when subject’s symptoms become steady and the measureable difference between the groups is more reliable. The precision of our model has narrowed standard error and increased the effectiveness of
our measurements to a point where can evaluate effects on individual symptoms. Furthermore, the importance of producing a clinically
significant environment in which to mimic the true environmental form of the disease was essential in the success of this study and one of
the strengths of the Ora ABC.
While we were not able to achieve a statistically significant change with regards to clinician graded nasal inflammation, the trend of the
result was encouraging. With the use of a nasal steroid, the full effect of the medication may take longer than two weeks, thus longer
term evaluation of nasal inflammation may be necessary to see a more robust effect. More importantly, Ora is the first group to use such
objective measurements in an EEU study and we will continue to develop the model to further improve upon these encouraging results.
The higher level of inherent variation in the nasal inflammation data and method of measurement suggests to us that with a slightly larger
sample size, this specific objective measurement would be able to show significant changes as seen by similar levels of standard error
and variation as mean TNSS scores. We are encouraged be the results of the NIS measurements as the means were nearly clinically significant, and we look forward to refining the scale and method for its use in future studies. The advantage to using an endpoint such as the
NIS opposed to measurements such as PNIF, as other EEUs have used, is the involvement of clinician expertise. PNIF data from this study
showed that the endpoint is highly variable and unreliable, and from a clinical standpoint, may be very dependent on subject technique.
Our data shows improvements in TNSS compared to placebo in both objective and subjective measurements indicating that the subjects
experienced symptomatic effects of allergen exposure and the expected therapeutic benefit of the intranasal steroid, which our model
was able to capture. Furthermore, the results are comparable to published values of efficacy measure in environmental studies, verifying
that, our model can be used to assess efficacy of therapeutics designed to treat signs and symptoms of allergic rhinitis1. The use of more
precise models such as the ABC enables us to capture high quality data in a manner, with fewer subjects, which reliably reflect the subjects’ experience, including the effects of drug treatments.
The overall level of precision achieved though our model also makes it possible to test the various efficacies of multiple products and dosing levels at once, as well as the ability to quickly build efficacy libraries for these products, allowing for future benchmark comparison.
In future studies, we will also be able to deliver multiple allergens at the same time, including both seasonal and perennial varieties. This
capacity allows us to produce a more clinically relevant model for sensitization, priming, and allergy induction. The Ora ABC model
delivers results in a highly efficient manner, without the use of hundreds of patients and is a powerful tool in the future of allergy pharmaceutical development.
1. Zieglmayera, P., Zieglmayerb, R., Bareillec, P., Rousellc, V., Salmonc, E., Horaka, F. 2008. Fluticasone furoate versus placebo in symptoms of grass-pollen allergic
rhinitis induced by exposure in the Vienna Challenge Chamber. Current Medical Research and Opinion. 24(6): 1833–1840.
300 Brickstone Square | Andover MA | 01810 | P: 978-685-8900 | F: 978-689-0020 | oraclinical.com