ORIGINAL ARTICLE
Steroid-eluting sinus implant for in-office treatment of recurrent polyposis: a pharmacokinetic study Randall Ow, MD1 , Eli Groppo, MD2 , Donald Clutter, MD, FACS3 and Anna K. Gawlicka, PhD4
Background: Long-term use of systemic glucocorticoid therapy has been associated with hypothalamic-pituitaryadrenal axis suppression and other systemic adverse events. This pharmacokinetic study evaluated the systemic safety and performance of a bioabsorbable sinus implant that gradually releases 1350 μg of mometasone furoate directly to the sinus mucosa. Methods: A prospective, single-center study treating 5 adult patients with recurrent polyposis aer bilateral total ethmoidectomy. Each patient received 2 steroid-releasing implants in-office under local/topical anesthesia. Plasma concentrations of mometasone furoate and cortisol were determined before placement and through 30-day followup, which also included endoscopic grading and patientreported outcomes. Results: Five patients (mean age 46.2 ± 9.2 standard deviation [SD] years; 60% male) underwent successful placement in all 10 ethmoid sinuses. There were no serious adverse events. The plasma concentrations of mometasone furoate were generally below the lower limit of quantification (LLOQ) of the assay (30 pg/mL). Cortisol concentrations at follow-up ranged from 3.9 to 5.7 mg/dL compared
C
urrent treatment options of chronic rhinosinusitis (CRS) with recurrent polyposis (CRSwNP) include antibiotics, systemic and topical steroids, allergy management, immunotherapy, and surgery.1–3 The myriad of clin-
Ear, Nose and Throat, Roseville, CA; 2 Sacramento Ear, Nose and Throat, Sacramento, CA; 3 Sacramento Ear, Nose and Throat, Folsom, CA; 4 Intersect ENT, Menlo Park, CA
1 Sacramento
Correspondence to: Randall Ow, MD, Sacramento Ear, Nose and Throat, 2 Medical Plaza Drive, Suite 225, Roseville, CA 95661; e-mail: [email protected] Funding sources for the study: Intersect ENT Potential conflict of interest: A. K. G. is an Intersect ENT employee. Public clinical trial registration: http://clinicaltrials.gov/show/NCT01894503. A Clinical Evaluation of the Safety and Performance of the Steroid-Releasing S8 Sinus Implant When Used in Post-Sinus Surgery Patients With Recurrent Sinus Polyps. Received: 2 July 2014; Revised: 4 August 2014; Accepted: 20 August 2014 DOI: 10.1002/alr.21414 View this article online at wileyonlinelibrary.com.
to 4.7 mg/dL at baseline. At 1 month, there was a significant improvement in bilateral polyp grade (p = 0.037), nasal obstruction score (p = 0.002), and 22-item Sino-Nasal Outcome Test (SNOT-22) (p = 0.010) compared to baseline. Conclusion: The reported 100% placement success, negligible systemic exposure to mometasone furoate released over time, lack of adrenal suppression, and the absence of serious adverse events suggest that the implant provides a valid and safe option for the in-office treatment of recurrent polyposis. Randomized, controlled, blinded clinical studies are underway to provide further evidence of safety C 2014 ARS-AAOA, LLC. and efficacy.
Key Words: corticosteroid; mometasone furoate; bioabsorbable; drugeluting; chronic rhinosinusitis; nasal polyps; endoscopic sinus surgery; localized drug delivery; cortisol How to Cite this Article: Ow R, Groppo E, Cluer D, Gawlicka AK. Steroid-eluting sinus implant for in-office treatment of recurrent polyposis: a pharmacokinetic study. Int Forum Allergy Rhinol. 2014;4:816–822.
ical management options demonstrates the lack of longterm effectiveness of any single treatment option.4 This is best explained by the multifactorial pathophysiology of CRS.5 Surgical treatment with polypectomy temporarily relieves ostiomeatal complex blockage but is not curative.6, 7 Systemic corticosteroids have been shown to enhance the efficacy of surgical approaches but result in numerous adverse events.8 The development of corticosteroids that are delivered directly to the nasal mucosa has addressed much of the concern about the systemic adverse effects associated with systemic corticosteroid therapy.1, 8, 9 However, intranasal topical preparations often fail, presumably because of impaired penetration of topical steroid to the target sinus anatomy due to blockage of ostiomeatal complex by polyposis, crusting, secretions, and/or edema, resulting in limited delivery of an adequate amount of drug.
International Forum of Allergy & Rhinology, Vol. 4, No. 10, October 2014
816
Pharmacokinetics of a steroid-eluting sinus implant
Mometasone furoate–eluting sinus implants represent an alternative option for local corticosteroid delivery to treat CRS patients who experience recurrent polyposis after endoscopic sinus surgery (ESS).10 The safety and efficacy of localized, controlled, steroid delivery to the sinus mucosa from a bioabsorbable sinus implant with 370 μg of mometasone furoate released over 1 month have been demonstrated in the perioperative setting in 3 clinical studies and a meta-analysis.11–14 The sinus implant used in this study was designed to be placed in the office setting to provide an immediate onset of action by dilating and maintaining an opening in middle meatus and ethmoid sinus, restoring ventilation, drainage, and reducing the sensation of nasal blockage and congestion. The implant was also designed to control inflammation and reestablish sinus patency by providing localized, controlled delivery of 1350 μg of mometasone furoate over 3 months with the maximum drug release over the first 30 days. The technical feasibility of in-office insertion of this higher drug–content implant and its initial safety and efficacy were demonstrated in a pilot study with 12 patients.15 The objective of the present study was to determine the safety and performance of the steroid-releasing sinus implant when used in post–sinus surgery patients who present with recurrent ethmoid sinus obstruction. Plasma concentrations of mometasone furoate and cortisol were measured over 30 days of maximum drug release to assess whether there was systemic exposure to the steroid using this route of administration.
Patients and methods Implant The steroid-eluting sinus implant used in this study was supplied by Intersect ENT (Menlo Park, CA) for investigational use and, at the time of this manuscript, was not for sale in the United States nor approved by the U. S. Food and Drug Administration (FDA). The implant is composed of a poly(lactide-co-glycolide) (PLGA) bioabsorbable polymer and has a self-expanding, non-obstructive design, which allows it to adjust to fit in a postoperative ethmoid sinus cavity (Fig. 1). The implant is similar in concept to the previously studied steroid-eluting implant (PROPEL Sinus Implant; Intersect ENT), with some unique differences to allow for treatment of polyp patients. In order to dilate an obstructed sinus cavity, the implant has greater radial strength owing to its arched design. The arched design also aids in retention by maintaining strength and apposition in the cavity as polypoid tissue recedes. Mometasone furoate is encapsulated in a biodegradable polymer matrix consisting of PLGA and a poly(ethylene glycol) excipient, which provides for gradual release of 1350 μg by diffusion of the drug over 3 months. The in vivo drug release characteristics, which were established in a rabbit model, were designed to release approximately 60% of the drug directly into the sinus tissue in the first 30 days to provide a rapid
817
International Forum of Allergy & Rhinology, Vol. 4, No. 10, October 2014
FIGURE 1. Steroid-eluting sinus implant with 1350 μg of mometasone furoate for in-office placement.
therapeutic effect concurrent with the mechanical opening of the sinus cavity. The timing of the maximum release was used as rationale for assessing systemic exposure over the first month in the present study. The remaining drug is released over the following 2 months to provide sustained control of sinus inflammation.
Study design This was a prospective, single-center study with 5 adult patients. Prior to patient enrollment, the study protocol and informed consent process were reviewed and approved by IntegReview Ethical Review Board, a fully accredited institutional review board in Austin, TX. The study was registered on ClinicalTrials.gov under identifier NCT01894503. Patients diagnosed with CRS were included if they had previously undergone bilateral total ethmoidectomy over 90 days prior to the study, presented with endoscopically confirmed bilateral sinus obstruction due to polyposis with a minimum grade 2 on at least 1 side, and in whom placement of the sinus implant was both feasible and medically appropriate. Patients were excluded if they had history of intolerance to corticosteroids, an oralsteroid–dependent condition (eg, chronic obstructive pulmonary disease [COPD]), history of immune deficiency, insulin-dependent diabetes, clinical evidence of either acute bacterial sinusitis or invasive fungal sinusitis, or had experienced a cerebrospinal fluid (CSF) leak or ocular complication during a previous ESS. Patients were also excluded if there was a physical obstruction precluding access to either ethmoid sinus for delivery of the study implants (eg, severe septal deviation, septal spur). Concomitant steroid medication use was strictly regulated in order to isolate, as much as possible, the safety,
Ow et al.
performance, and pharmacokinetic proprieties of the sinus implant. Because plasma mometasone furoate was monitored during the study, the use of mometasone furoate in any form, topical or inhalation, was not allowed 14 days prior to the implant procedure and until 30 days after the procedure. Additionally, in the 14-day run-in period leading up to the implant procedure, the use of high-dose steroids (eg, oral steroids, budesonide irrigations/drops, or nebulized/aerosolized steroids) was not allowed. There was also a 30-day restriction for use of parenteral steroid (eg, triamcinolone injection) prior to the procedure. During 30-day follow-up, high-dose steroids such as oral steroids, budesonide irrigations/drops, or other nebulized/aerosolized steroids were restricted. Patients were encouraged to use saline sprays or irrigations as needed. If infection was suspected, treatment with antibiotics was permitted at any time during the study. Patients were allowed to use a stabilized regimen of allergy-related medications such as leukotriene inhibitors or immunotherapy, topical intranasal steroid sprays, and orally-inhaled steroids for control of asthma, except those containing mometasone furoate. Each patient received 2 steroid-eluting sinus implants, which were placed bilaterally in an office setting. Topical/local anesthesia consisted of spraying the nasal cavity with 4% lidocaine (or equivalent) and oxymetazoline nasal decongestant, followed by middle meatal placement of cottonoids or pledgets soaked in 4% lidocaine and decongestant solution. Local injection into the sinus tissue and nasal septum was permitted as necessary to ensure patient comfort. Implant delivery success rate was defined as successful access and deployment of the implant to the target ethmoid sinus. Patients returned for periodic examination and blood draws. Plasma samples were collected in the morning on days 3, 7, 14, 21, and 30 by a certified phlebotomist with K2 EDTA anticoagulant and kept frozen at –80°C until analysis. Adverse events were recorded and tabulated through day 30. Follow-up examinations at days 7, 14, 21, and 30 included endoscopic grading by clinical investigators and patient-reported outcomes. The endoscopic evaluations were performed during each study visit, and recorded on standardized case report forms. Percent ethmoid sinus obstruction was estimated on a 100-mm visual analog scale (VAS) ranging from 0 (absence of obstruction) to 100 (complete obstruction). Middle turbinate position was graded on a 4-point categorical scale as either medialized, normal, partially lateralized, or lateralized. Adhesion/scarring severity was graded on a 5-point scale as either 0 (none), 1 (small but non-obstructing, no separation required), 2 (obstructing, but easily separated), 3 (dense and obstructing, separation difficult), or 4 (severe: complete adhesion of the middle turbinate to the lateral nasal wall). Polyps were graded on a 5-point scale as either 0 (no visible nasal polyps), 1 (small amount of nasal polyps confined in middle meatus, clinically insignificant, not requiring treatment), 2 (expanded amount of nasal polyps confined in middle
meatus), 3 (nasal polyps extending beyond middle meatus, within the sphenoethmoid recess not totally obstructing, or both), or 4 (nasal polyps completely obstructing the nasal cavity). Patient-reported outcomes were assessed using the Nasal Obstruction/Congestion Questionnaire and Sino-Nasal Outcome Test-22 (SNOT-22) with scores ranging from 0 (none) to 5 (problem as bad as it can be). The SNOT-22 total normalized score was calculated by adding the scores for all questions answered and then dividing by the number of questions answered. The treatment effect size was calculated as mean change between scores before and after treatment divided by baseline standard deviation (SD).16 By convention, an effect difference of >0.2 was considered small, >0.5 moderate, and >0.8 was considered a “large” improvement in health-related quality of life.16 The mometasone furoate assay was performed by Biopharmaceutical Research Inc. (BRI, Vancouver, BC, Canada) according to the previously developed and validated method for detection of nominal concentrations ranging from 30 pg/mL to 2000 pg/mL using a Waters Micromass Quattro micro mass spectrometer coupled with a Waters ACQUITY UPLC System (Waters Corp., Milford, MA).14 Plasma cortisol was assayed using an enzyme-linked immunosorbent assay kit (Oxford Biomed Research) by BRI in accordance with a previously validated protocol.14
Data analysis All data were entered into a validated electronic database capture system, 100% monitored, and analyzed by an independent biostatistician. Descriptive statistics and graphical summaries were used to summarize the data. Continuous variables were presented as means with SD or median with ranges. Categorical variables were presented as counts and percentages. The sample size of 5 patients was consistent with a previously published pharmacokinetic study14 and considered adequate to assess whether there was quantifiable systemic exposure to mometasone furoate when delivered via this route of administration. The change from baseline was tested using paired t-test and considered statistically significant if p value was
Steroid-eluting sinus implant for in-office treatment of recurrent polyposis: a pharmacokinetic study Randall Ow, MD1 , Eli Groppo, MD2 , Donald Clutter, MD, FACS3 and Anna K. Gawlicka, PhD4
Background: Long-term use of systemic glucocorticoid therapy has been associated with hypothalamic-pituitaryadrenal axis suppression and other systemic adverse events. This pharmacokinetic study evaluated the systemic safety and performance of a bioabsorbable sinus implant that gradually releases 1350 μg of mometasone furoate directly to the sinus mucosa. Methods: A prospective, single-center study treating 5 adult patients with recurrent polyposis aer bilateral total ethmoidectomy. Each patient received 2 steroid-releasing implants in-office under local/topical anesthesia. Plasma concentrations of mometasone furoate and cortisol were determined before placement and through 30-day followup, which also included endoscopic grading and patientreported outcomes. Results: Five patients (mean age 46.2 ± 9.2 standard deviation [SD] years; 60% male) underwent successful placement in all 10 ethmoid sinuses. There were no serious adverse events. The plasma concentrations of mometasone furoate were generally below the lower limit of quantification (LLOQ) of the assay (30 pg/mL). Cortisol concentrations at follow-up ranged from 3.9 to 5.7 mg/dL compared
C
urrent treatment options of chronic rhinosinusitis (CRS) with recurrent polyposis (CRSwNP) include antibiotics, systemic and topical steroids, allergy management, immunotherapy, and surgery.1–3 The myriad of clin-
Ear, Nose and Throat, Roseville, CA; 2 Sacramento Ear, Nose and Throat, Sacramento, CA; 3 Sacramento Ear, Nose and Throat, Folsom, CA; 4 Intersect ENT, Menlo Park, CA
1 Sacramento
Correspondence to: Randall Ow, MD, Sacramento Ear, Nose and Throat, 2 Medical Plaza Drive, Suite 225, Roseville, CA 95661; e-mail: [email protected] Funding sources for the study: Intersect ENT Potential conflict of interest: A. K. G. is an Intersect ENT employee. Public clinical trial registration: http://clinicaltrials.gov/show/NCT01894503. A Clinical Evaluation of the Safety and Performance of the Steroid-Releasing S8 Sinus Implant When Used in Post-Sinus Surgery Patients With Recurrent Sinus Polyps. Received: 2 July 2014; Revised: 4 August 2014; Accepted: 20 August 2014 DOI: 10.1002/alr.21414 View this article online at wileyonlinelibrary.com.
to 4.7 mg/dL at baseline. At 1 month, there was a significant improvement in bilateral polyp grade (p = 0.037), nasal obstruction score (p = 0.002), and 22-item Sino-Nasal Outcome Test (SNOT-22) (p = 0.010) compared to baseline. Conclusion: The reported 100% placement success, negligible systemic exposure to mometasone furoate released over time, lack of adrenal suppression, and the absence of serious adverse events suggest that the implant provides a valid and safe option for the in-office treatment of recurrent polyposis. Randomized, controlled, blinded clinical studies are underway to provide further evidence of safety C 2014 ARS-AAOA, LLC. and efficacy.
Key Words: corticosteroid; mometasone furoate; bioabsorbable; drugeluting; chronic rhinosinusitis; nasal polyps; endoscopic sinus surgery; localized drug delivery; cortisol How to Cite this Article: Ow R, Groppo E, Cluer D, Gawlicka AK. Steroid-eluting sinus implant for in-office treatment of recurrent polyposis: a pharmacokinetic study. Int Forum Allergy Rhinol. 2014;4:816–822.
ical management options demonstrates the lack of longterm effectiveness of any single treatment option.4 This is best explained by the multifactorial pathophysiology of CRS.5 Surgical treatment with polypectomy temporarily relieves ostiomeatal complex blockage but is not curative.6, 7 Systemic corticosteroids have been shown to enhance the efficacy of surgical approaches but result in numerous adverse events.8 The development of corticosteroids that are delivered directly to the nasal mucosa has addressed much of the concern about the systemic adverse effects associated with systemic corticosteroid therapy.1, 8, 9 However, intranasal topical preparations often fail, presumably because of impaired penetration of topical steroid to the target sinus anatomy due to blockage of ostiomeatal complex by polyposis, crusting, secretions, and/or edema, resulting in limited delivery of an adequate amount of drug.
International Forum of Allergy & Rhinology, Vol. 4, No. 10, October 2014
816
Pharmacokinetics of a steroid-eluting sinus implant
Mometasone furoate–eluting sinus implants represent an alternative option for local corticosteroid delivery to treat CRS patients who experience recurrent polyposis after endoscopic sinus surgery (ESS).10 The safety and efficacy of localized, controlled, steroid delivery to the sinus mucosa from a bioabsorbable sinus implant with 370 μg of mometasone furoate released over 1 month have been demonstrated in the perioperative setting in 3 clinical studies and a meta-analysis.11–14 The sinus implant used in this study was designed to be placed in the office setting to provide an immediate onset of action by dilating and maintaining an opening in middle meatus and ethmoid sinus, restoring ventilation, drainage, and reducing the sensation of nasal blockage and congestion. The implant was also designed to control inflammation and reestablish sinus patency by providing localized, controlled delivery of 1350 μg of mometasone furoate over 3 months with the maximum drug release over the first 30 days. The technical feasibility of in-office insertion of this higher drug–content implant and its initial safety and efficacy were demonstrated in a pilot study with 12 patients.15 The objective of the present study was to determine the safety and performance of the steroid-releasing sinus implant when used in post–sinus surgery patients who present with recurrent ethmoid sinus obstruction. Plasma concentrations of mometasone furoate and cortisol were measured over 30 days of maximum drug release to assess whether there was systemic exposure to the steroid using this route of administration.
Patients and methods Implant The steroid-eluting sinus implant used in this study was supplied by Intersect ENT (Menlo Park, CA) for investigational use and, at the time of this manuscript, was not for sale in the United States nor approved by the U. S. Food and Drug Administration (FDA). The implant is composed of a poly(lactide-co-glycolide) (PLGA) bioabsorbable polymer and has a self-expanding, non-obstructive design, which allows it to adjust to fit in a postoperative ethmoid sinus cavity (Fig. 1). The implant is similar in concept to the previously studied steroid-eluting implant (PROPEL Sinus Implant; Intersect ENT), with some unique differences to allow for treatment of polyp patients. In order to dilate an obstructed sinus cavity, the implant has greater radial strength owing to its arched design. The arched design also aids in retention by maintaining strength and apposition in the cavity as polypoid tissue recedes. Mometasone furoate is encapsulated in a biodegradable polymer matrix consisting of PLGA and a poly(ethylene glycol) excipient, which provides for gradual release of 1350 μg by diffusion of the drug over 3 months. The in vivo drug release characteristics, which were established in a rabbit model, were designed to release approximately 60% of the drug directly into the sinus tissue in the first 30 days to provide a rapid
817
International Forum of Allergy & Rhinology, Vol. 4, No. 10, October 2014
FIGURE 1. Steroid-eluting sinus implant with 1350 μg of mometasone furoate for in-office placement.
therapeutic effect concurrent with the mechanical opening of the sinus cavity. The timing of the maximum release was used as rationale for assessing systemic exposure over the first month in the present study. The remaining drug is released over the following 2 months to provide sustained control of sinus inflammation.
Study design This was a prospective, single-center study with 5 adult patients. Prior to patient enrollment, the study protocol and informed consent process were reviewed and approved by IntegReview Ethical Review Board, a fully accredited institutional review board in Austin, TX. The study was registered on ClinicalTrials.gov under identifier NCT01894503. Patients diagnosed with CRS were included if they had previously undergone bilateral total ethmoidectomy over 90 days prior to the study, presented with endoscopically confirmed bilateral sinus obstruction due to polyposis with a minimum grade 2 on at least 1 side, and in whom placement of the sinus implant was both feasible and medically appropriate. Patients were excluded if they had history of intolerance to corticosteroids, an oralsteroid–dependent condition (eg, chronic obstructive pulmonary disease [COPD]), history of immune deficiency, insulin-dependent diabetes, clinical evidence of either acute bacterial sinusitis or invasive fungal sinusitis, or had experienced a cerebrospinal fluid (CSF) leak or ocular complication during a previous ESS. Patients were also excluded if there was a physical obstruction precluding access to either ethmoid sinus for delivery of the study implants (eg, severe septal deviation, septal spur). Concomitant steroid medication use was strictly regulated in order to isolate, as much as possible, the safety,
Ow et al.
performance, and pharmacokinetic proprieties of the sinus implant. Because plasma mometasone furoate was monitored during the study, the use of mometasone furoate in any form, topical or inhalation, was not allowed 14 days prior to the implant procedure and until 30 days after the procedure. Additionally, in the 14-day run-in period leading up to the implant procedure, the use of high-dose steroids (eg, oral steroids, budesonide irrigations/drops, or nebulized/aerosolized steroids) was not allowed. There was also a 30-day restriction for use of parenteral steroid (eg, triamcinolone injection) prior to the procedure. During 30-day follow-up, high-dose steroids such as oral steroids, budesonide irrigations/drops, or other nebulized/aerosolized steroids were restricted. Patients were encouraged to use saline sprays or irrigations as needed. If infection was suspected, treatment with antibiotics was permitted at any time during the study. Patients were allowed to use a stabilized regimen of allergy-related medications such as leukotriene inhibitors or immunotherapy, topical intranasal steroid sprays, and orally-inhaled steroids for control of asthma, except those containing mometasone furoate. Each patient received 2 steroid-eluting sinus implants, which were placed bilaterally in an office setting. Topical/local anesthesia consisted of spraying the nasal cavity with 4% lidocaine (or equivalent) and oxymetazoline nasal decongestant, followed by middle meatal placement of cottonoids or pledgets soaked in 4% lidocaine and decongestant solution. Local injection into the sinus tissue and nasal septum was permitted as necessary to ensure patient comfort. Implant delivery success rate was defined as successful access and deployment of the implant to the target ethmoid sinus. Patients returned for periodic examination and blood draws. Plasma samples were collected in the morning on days 3, 7, 14, 21, and 30 by a certified phlebotomist with K2 EDTA anticoagulant and kept frozen at –80°C until analysis. Adverse events were recorded and tabulated through day 30. Follow-up examinations at days 7, 14, 21, and 30 included endoscopic grading by clinical investigators and patient-reported outcomes. The endoscopic evaluations were performed during each study visit, and recorded on standardized case report forms. Percent ethmoid sinus obstruction was estimated on a 100-mm visual analog scale (VAS) ranging from 0 (absence of obstruction) to 100 (complete obstruction). Middle turbinate position was graded on a 4-point categorical scale as either medialized, normal, partially lateralized, or lateralized. Adhesion/scarring severity was graded on a 5-point scale as either 0 (none), 1 (small but non-obstructing, no separation required), 2 (obstructing, but easily separated), 3 (dense and obstructing, separation difficult), or 4 (severe: complete adhesion of the middle turbinate to the lateral nasal wall). Polyps were graded on a 5-point scale as either 0 (no visible nasal polyps), 1 (small amount of nasal polyps confined in middle meatus, clinically insignificant, not requiring treatment), 2 (expanded amount of nasal polyps confined in middle
meatus), 3 (nasal polyps extending beyond middle meatus, within the sphenoethmoid recess not totally obstructing, or both), or 4 (nasal polyps completely obstructing the nasal cavity). Patient-reported outcomes were assessed using the Nasal Obstruction/Congestion Questionnaire and Sino-Nasal Outcome Test-22 (SNOT-22) with scores ranging from 0 (none) to 5 (problem as bad as it can be). The SNOT-22 total normalized score was calculated by adding the scores for all questions answered and then dividing by the number of questions answered. The treatment effect size was calculated as mean change between scores before and after treatment divided by baseline standard deviation (SD).16 By convention, an effect difference of >0.2 was considered small, >0.5 moderate, and >0.8 was considered a “large” improvement in health-related quality of life.16 The mometasone furoate assay was performed by Biopharmaceutical Research Inc. (BRI, Vancouver, BC, Canada) according to the previously developed and validated method for detection of nominal concentrations ranging from 30 pg/mL to 2000 pg/mL using a Waters Micromass Quattro micro mass spectrometer coupled with a Waters ACQUITY UPLC System (Waters Corp., Milford, MA).14 Plasma cortisol was assayed using an enzyme-linked immunosorbent assay kit (Oxford Biomed Research) by BRI in accordance with a previously validated protocol.14
Data analysis All data were entered into a validated electronic database capture system, 100% monitored, and analyzed by an independent biostatistician. Descriptive statistics and graphical summaries were used to summarize the data. Continuous variables were presented as means with SD or median with ranges. Categorical variables were presented as counts and percentages. The sample size of 5 patients was consistent with a previously published pharmacokinetic study14 and considered adequate to assess whether there was quantifiable systemic exposure to mometasone furoate when delivered via this route of administration. The change from baseline was tested using paired t-test and considered statistically significant if p value was
