A prospective study to evaluate the safety and efficacy of AdvaCoat Mx sinus gel for treatment of chronic rhinosinusitis without nasal polyps.

Chronic rhinosinusitis (CRS) is a common disease, affecting 5 to 15% of urban
populations in Europe and approximately 12% of Americans under the age of 45
years. CRS is differentiated, though not clearly, as with or without nasal
polyps. Assessment of CRS for diagnostic evaluation and for the clinical
studies should include both subjective and objective measures to determine the
degree and duration of symptoms. Patients will score symptoms using a visual
analogue scale to measure subjective symptoms scores associated with chronic
sinusitis. Furthermore, CT scans and endoscopy have been widely used for
diagnosis and management of CRS.

Treatment of CRS includes topical and oral corticosteroids, oral antibiotics,
nasal decongestants, saline nasal and antral irrigations, antimycotics,
antihistamines, cromones and endoscopic surgery. Studies provide evidence to
suggest that CRS should be treated with a rigorous medical regimen before
surgery is considered. Indeed, relapse of symptoms may be prevented or
inhibited with medical therapy for a sustained period of time to delay or
prevent surgery. The goal of surgery is to facilitate sinus drainage, generally
by widening the sinus ostia and removing anatomic obstructions. Surgery should
be reserved for patients refractory to medical therapy. There is evidence that
the endoscopic sinus surgery is effective in improving symptoms and quality of
life in adult patients with CRS.

Various hyaluronan based biomaterials are now available and in common use to
provide a post-surgical nasal dressing. In addressing the issue of failed
medical therapy for CRS, a combination of a steroid with a hyaluronan applied
to the sinonasal tissues is considered for treatment of chronic rhinosinusitis
refractory to medical therapy.

The AdvaCoat Mx gel is intended to alleviate the symptoms of CRS after a single
application. To support safety, biocompatibility testing of the materials was
conducted in accordance with ISO 10993 Guidelines for the Biological Evaluation
of Medical Devices, and included cytotoxicity, irritation, sensitization and
acute toxicity. These tests demonstrated the device component of AdvaCoat Mx
gel to be biocompatible.

The purpose of the first part of the study is the evaluation of the first 9
subjects that will be conducted to confirm the 1.5 mL AdvaCoat Mx treatment
volume per side as the desired volume for the expanded portion of the study.

The purpose of the second part of this study is to evaluate the safety and
efficacy of AdvaCoat* Mx sinus gel. 80 subjects will be blinded in a three arm
study that will compare the safety and efficacy of AdvaCoat Mx to placebo gel
and saline placebo in a 2:1:1 randomization.

AdvaCoat Mx is a sustained release formulation of triamcinolone acetonide (TA)
applied to the ostiomeatal complex (OMC) for the relief of symptoms associated
with chronic rhinosinusitis. Upon application, the AdvaCoat Mx forms a gel
conforming to mucosal surfaces. The anticipated symptom relief from a single
dose is due to the sustained anti-inflammatory action of TA made possible by
the physical form of the product which provides localization and retention at
the OMC. The product has been developed to reduce the symptoms for CRS. The
current treatment of CRS (nasal spray with corticosteroids) has been used for a
long period of time, but is not well able to reach the ostiomeatal complex and
to result in relief of teh symptoms. The sponsor and the investigators hope to
prove that the product is safe and effective in reducing the symptoms for CRS.

The study will initiate as an open-label, AdvaCoat Mx volume escalation
evaluation of nine (9) subjects (9 subject cohort). The planned AdvaCoat Mx
volumes are 0.5 mL per side (1.0 mL total volume delivered), 1.0 mL per side
(2.0 mL total volume delivered) and 1.5 mL per side (3.0 mL total volume
delivered), to be delivered to each side of the Ostiomeatal Complex (OMC). The
evaluation of all subjects in the 9 subject cohort will be completed prior to
initiation of the blinded portion of the study (80 subject cohort). The 9
subject cohort is intended to confirm 1.5 mL AdvaCoat Mx per side as the
desired volume for the 80 subject cohort. In the absence of any treatment
related and/or serious adverse events, patients in the second part of the trial
will be treated with 1.5 ml AdvaCoat Mx per side.

Subjects in the first part of the trial will be treated with AdvaCoat Mx on
each side of the OMC as follows (two treatments per subject):
- 3 subjects will be treated with 0.5 mL per side (1.0 mL total volume
delivered) AdvaCoat Mx.
- After 1 week post-treatment of the third subject receiving 0.5 mL per side of
AdvaCoat Mx, 3 additional subjects will be treated with 1.0 mL per side (2.0 mL
total volume delivered) of AdvaCoat Mx.
- After 1 week post-treatment of the third subject receiving 1.0 mL per side
AdvaCoat Mx, 3 additional subjects will be treated with 1.5 mL per side (3.0 mL
total volume delivered) of AdvaCoat Mx.
- After 1 week post-treatment of the third subject receiving 1.5 mL per side of
AdvaCoat Mx, the sponsor will review any reported adverse events to confirm
acceptability of proceeding with treating 80 subjects in the blinded portion of
the study with 1.5 mL per side (3.0 mL total volume delivered) of AdvaCoat Mx.

Subjects will return for post-treatment follow-up at 1, 2 and 4 weeks. Daily
pain medication logs will be completed by the subject at home for the duration
of the study. Adverse events will be solicited at all visits.

The second part of the study is a prospective, multicenter, randomized,
controlled, single-blinded study to evaluate the safety and efficacy of
AdvaCoat* Mx sinus gel for the treatment of chronic rhinosinusitis without
nasal polyps.

The eligible patients will be treated as follows;
- If the patient fulfills all inclusion and exclusion criteria the sinus where
the gel will be applied will be cleared using suction.
- the patient will be randomised to teh control or treatment group (AdvaCoat
gel : placebo gel : placebo saline = 2:1:1).

Control group:
- Placebo (saline) will be applied to the ostiomeatal complex
- Placebo gel (only the gel componen of the AdvaCoat gel) will be applied to
the ostiomeatal complex

Treatment group:
- The AdvaCoat gel will be applied to teh ostiomeatal complex

The patients will be followed for 12 weeks and need to visit the hospital at 2,
8 and 12 weeks after the treatment for follow-up visits.

In total 89 patients will participate in this clinical trial. Half the 80
patient cohort will be treated with AdvaCoat, one quarter will be treated with
the placebo gel and one quarter with the placebo saline.

Potential risks associated with the use of AdvaCoat Mx may include those events
that have been reported in association with other absorbable hyaluronan nasal
dressings. Potential risks to subjects in this study include, but are not
limited to, the following: nasal obstruction, headache, epistaxis, infection
and local irritation or sensitivity to the product.

Potential adverse reactions which may be associated with any corticosteroid
therapy include conditions which affect the following systems: fluid and
electrolyte balance, musculoskeletal, gastrointestinal, dermatologic,
endocrine, ophthalmic, metabolic and other areas.

The patients need to visit the hospital 5 times. During the follow-up visits,
they only need to answer a few questions. The 80 patient cohort needs to
complete a questionnaire as well and during the visit at 8 weeks another CT
scan will be performed. At the last visit, all patients need to have another
endoscopy. However, this will not be much of a burden for the patients.