Chronic Sinusitis, Nasal Polyposis
Conditions
Keywords
endoscopic sinus surgery, corticosteroid, chronic rhinosinusitis, mometasone furoate, polyposis
Brief summary
The RESOLVE II Study is a randomized, single-blind, parallel arm, concurrently controlled, multicenter study with 300 chronic sinusitis patients who had prior endoscopic sinus surgery but present with recurrent sinus obstruction.
Detailed description
The RESOLVE II Study is a randomized, sham-controlled, double-blind, parallel arm multicenter trial conducted in up to 45 clinical centers (academic and private) across the United States in 300 adults with chronic sinusitis, who are indicated for revision surgery because of recurring nasal obstruction/congestion symptoms and bilateral ethmoid polyposis.
Interventions
DRUGS8 Sinus Implant
In-office bilateral placement of the S8 Sinus Implant (mometasone furoate, 1350 mcg) in the ethmoid sinuses
DRUGMometasone furoate nasal spray
Mometasone furoate nasal spray (200mcg) once daily
PROCEDURESham
In-office bilateral sham procedure, consisting of advancement of a delivery system with the S8 Sinus Implant into the ethmoid sinuses followed by removal without deployment.
Sponsors
Intersect ENT
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Participants were blindfolded and earmuffed during the baseline procedure and follow-up endoscopic examinations. Implants were removed at Day 60 to allow blinded assessment of bilateral polyp grade at Day 90 by a centralized videoendoscopy review by a panel of 3 independent sinus surgeons.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: * Confirmed diagnosis of chronic sinusitis * Patient has undergone bilateral total ethmoidectomy at least 90 days prior to screening * Patient has Nasal Obstruction/Congestion score of at least 2 (scale from 0 to 3) on at least 5 days during the 7 days following informed consent, despite use of topical intranasal steroid irrigations or sprays for at least 14 days preceding scoring, as documented in medication records * Indication for repeat ESS: * Complaints of at least 2 symptoms of chronic sinusitis: nasal obstruction/congestion, post-nasal discharge, thick nasal discharge, facial pain/pressure, or decreased sense of smell * Endoscopic evidence of bilateral sinus obstruction due to polyposis (minimum grade 2 on each side) * History of high-dose steroid use and/or sinus steroid irrigations within the preceding 1 year
Exclusion criteria
* Patient has presence of polyposis grade 1, 1.5 or 4 on either side * Patient has presence of adhesions/synechiae grades 3 or 4 * Patient has known history of immune deficiency * Patient has concurrent condition such as cancer or HIV requiring active chemotherapy and/or immunotherapy management for the disease * Patient has oral-steroid dependent condition such as COPD, asthma or other condition * Patient has known history of allergy or intolerance to corticosteroids or mometasone furoate * Patient has presence of physical obstruction that would preclude access to either ethmoid sinus for implant delivery (e.g., severe septal deviation, septal spur, very small middle meatus, total obstruction of the nasal passage with severe scarring, polyposis) * Patient has clinical evidence of acute bacterial sinusitis * Patient has clinical evidence or suspicion of invasive fungal sinusitis * Patient has evidence of disease or condition expected to compromise survival or ability to complete follow-up assessments during the 90-day follow-up period * Patient is currently participating in another clinical trial or has already participated in this clinical trial * Patient has history of insulin dependent diabetes mellitus * Patient has previously undergone ESS and experienced a cerebrospinal fluid (CSF) leak or has residual compromised vision as a result of a complication in a prior ESS procedure * Patient has known dehiscence of the lamina papyracea * Patient has evidence of active viral illness * Patient has known history or diagnosis of glaucoma or ocular hypertension (prior ocular exam with IOP\>21 mm Hg and pressure lowering medication given) or posterior subcapsular cataract
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Nasal Obstruction/Congestion Score | Day 30 | Determined by patients using a daily diary on a scale from 0 (no symptoms) to 3 (severe symptoms) over a period of 7 days prior to the baseline and Day 30 visits. Negative values for change from baseline indicate reduction (improvement) in nasal obstruction/congestion symptoms. |
| Bilateral Polyp Grade | Day 90 | Polyp grade was determined by an independent panel of 3 sinus surgeons based on a centralized, blinded videoendoscopy review. Each sinus was graded from 0 (no visible polyps) to 4 (nasal polyps completely obstructing nasal cavity) and then the left and right values were added to obtain a total bilateral polyp grade, ranging from 0 to 8. Negative values for change from baseline indicated reduction (improvement) in bilateral polyp grade. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nasal Obstruction/Congestion Score | Day 90 | Determined by patients using a daily diary on a scale from 0 (no symptoms) to 3 (severe symptoms) over a period of 7 days prior to baseline and Day 90. Negative values for change from baseline indicated reduction (improvement) in nasal obstruction/congestion symptoms. |
| Percentage of Patients Indicated for Repeat Endoscopic Sinus Surgery (RESS) | Day 90 | Proportion of patients still indicated for RESS at day 90 despite ongoing use of mometasone furoate nasal spray based on clinical investigator assessment using study-specific criteria. To be indicated for RESS, patients had to: (1) complain of nasal obstruction/congestion (moderate to severe) and postnasal discharge, facial pain/pressure/fullness, or altered sense of smell/taste; (2) have endoscopic evidence of persisting nasal polyps (grade \>= 2 on each side); and (3) have received (required at baseline) or need a systemic steroid as noted during endoscopy. |
| Facial Pain/Pressure Score | Day 90 | Determined by patients on a 6-point Likert scale from 0 (absent) to 5 (very severe). Negative values for change from baseline indicated reduction (improvement) in facial pain/pressure symptoms. |
| Decreased Sense of Smell Score | Day 90 | Determined by patients on a 6-point Likert scale from 0 (absent) to 5 (very severe). Negative values for change from baseline indicated reduction (improvement) in sense of smell. |
| Ethmoid Sinus Obstruction | Day 90 | Percentage of the ethmoid sinus volume obstructed by scarring, polyps, or edema on endoscopy, as determined by an independent panel of 3 sinus surgeons based on a centralized, blinded videoendoscopy review using a 100-mm visual analogue scale (VAS), ranging from 0 (absence of obstruction) to 100 (complete obstruction). Negative values for change from baseline indicated reduction (improvement) in ethmoid sinus obstruction. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited at 40 sites across the US between December 2014 and May 2016, of which 34 sites enrolled at least 1 patient.
Pre-assignment details
Patients were considered enrolled into the study after signing the ICF and entered a 2-week screening period. A video-recorded screening endoscopy and symptom scoring, using a daily diary, were required to confirm patient eligibility. Video-endoscopies were assessed by an independent reviewer in order to confirm bilateral polyposis.
Participants by arm
| Arm | Count |
|---|---|
| Treatment In-office bilateral placement of the S8 Sinus Implant (mometasone furoate, 1350 mcg) in the ethmoid sinuses
Mometasone furoate nasal spray (200mcg) once daily | 201 |
| Control In-office bilateral sham procedure
Mometasone furoate nasal spray (200mcg) once daily | 99 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Control | Total | Treatment |
|---|---|---|---|
| Age, Continuous | 47.9 years STANDARD_DEVIATION 12.4 | 49.6 years STANDARD_DEVIATION 12.74 | 50.5 years STANDARD_DEVIATION 12.9 |
| Race/Ethnicity, Customized Race/Ethnicity Asian | 4 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Black | 13 Participants | 40 Participants | 27 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Other | 2 Participants | 8 Participants | 6 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White | 80 Participants | 244 Participants | 164 Participants |
| Sex: Female, Male Female | 43 Participants | 117 Participants | 74 Participants |
| Sex: Female, Male Male | 56 Participants | 183 Participants | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 201 | 0 / 99 |
| other Total, other adverse events | 53 / 201 | 28 / 99 |
| serious Total, serious adverse events | 1 / 201 | 0 / 99 |
Outcome results
Primary
Bilateral Polyp Grade
Polyp grade was determined by an independent panel of 3 sinus surgeons based on a centralized, blinded videoendoscopy review. Each sinus was graded from 0 (no visible polyps) to 4 (nasal polyps completely obstructing nasal cavity) and then the left and right values were added to obtain a total bilateral polyp grade, ranging from 0 to 8. Negative values for change from baseline indicated reduction (improvement) in bilateral polyp grade.
Time frame: Day 90
Population: Intent-to-treat population. Values were adjusted for steroid and surgical interventions by LOCF approach. Sensitivity analyses, including tipping point, were prespecified if missing values exceed 5%. There were 8 (2.7%) participants (6 treatment, 2 control) with missing values at Day 90. No imputation of missing values was performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Bilateral Polyp Grade | Baseline | 5.48 units on a scale | Standard Deviation 1.132 |
| Treatment | Bilateral Polyp Grade | Day 90 | 4.91 units on a scale | Standard Deviation 1.432 |
| Treatment | Bilateral Polyp Grade | Change from baseline | -0.56 units on a scale | Standard Deviation 1.059 |
| Control | Bilateral Polyp Grade | Baseline | 5.43 units on a scale | Standard Deviation 1.009 |
| Control | Bilateral Polyp Grade | Day 90 | 5.26 units on a scale | Standard Deviation 1.378 |
| Control | Bilateral Polyp Grade | Change from baseline | -0.15 units on a scale | Standard Deviation 0.907 |
Comparison: The between treatment group difference was estimated using the ANCOVA model with site and treatment group as fixed effects. The primary efficacy hypothesis was that the use of the S8 Sinus Implant would reduce the bilateral polyp grade compared to the control group. The null hypothesis was H0: β1=0 and alternative hypothesis was H1: β1 ≠ 0. Only a statistically significant, negative estimate of β1 was to constitute evidence of effectiveness.p-value: 0.007395% CI: [-0.6, -0.09]ANCOVA
Primary
Nasal Obstruction/Congestion Score
Determined by patients using a daily diary on a scale from 0 (no symptoms) to 3 (severe symptoms) over a period of 7 days prior to the baseline and Day 30 visits. Negative values for change from baseline indicate reduction (improvement) in nasal obstruction/congestion symptoms.
Time frame: Day 30
Population: Intent-to-treat population. Scoring for \>=4 days in 7 days before the baseline and Day 30 visits was required. Sensitivity analyses, including tipping point, were prespecified if missing values exceed 5%. There were 4 (1.3%) participants (2 treatment, 2 control) with missing values at Day 30. No imputation of missing values was performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Nasal Obstruction/Congestion Score | 30 Day | 1.56 units on a scale | Standard Deviation 0.743 |
| Treatment | Nasal Obstruction/Congestion Score | Change from baseline | -0.80 units on a scale | Standard Deviation 0.729 |
| Treatment | Nasal Obstruction/Congestion Score | Baseline | 2.36 units on a scale | Standard Deviation 0.488 |
| Control | Nasal Obstruction/Congestion Score | 30 Day | 1.79 units on a scale | Standard Deviation 0.674 |
| Control | Nasal Obstruction/Congestion Score | Baseline | 2.35 units on a scale | Standard Deviation 0.479 |
| Control | Nasal Obstruction/Congestion Score | Change from baseline | -0.56 units on a scale | Standard Deviation 0.619 |
Comparison: ANCOVA model with site and treatment group as fixed effects and contrasts constructed to estimate the difference between treatment groups. The primary efficacy hypothesis was that the use of the S8 Sinus Implant would reduce the Nasal Obstruction/Congestion score compared to the control group. The null hypothesis was H0: β1=0 and alternative hypothesis was H1: β1 ≠ 0. Only a statistically significant, negative estimate of β1 was to constitute evidence of effectiveness.p-value: 0.007495% CI: [-0.39, -0.06]ANCOVA
Secondary
Decreased Sense of Smell Score
Determined by patients on a 6-point Likert scale from 0 (absent) to 5 (very severe). Negative values for change from baseline indicated reduction (improvement) in sense of smell.
Time frame: Day 90
Population: Intent-to-treat population. Values were adjusted for steroid and surgical interventions by LOCF approach. There were 5 (1.7%) participants (3 treatment, 2 control) with missing values at Day 90. No imputation of missing values was performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Decreased Sense of Smell Score | Change from baseline | -1.20 units on a scale | Standard Deviation 1.659 |
| Treatment | Decreased Sense of Smell Score | Baseline | 4.1 units on a scale | Standard Deviation 1.38 |
| Treatment | Decreased Sense of Smell Score | Day 90 | 2.9 units on a scale | Standard Deviation 1.96 |
| Control | Decreased Sense of Smell Score | Change from baseline | -0.76 units on a scale | Standard Deviation 1.599 |
| Control | Decreased Sense of Smell Score | Baseline | 4.1 units on a scale | Standard Deviation 1.36 |
| Control | Decreased Sense of Smell Score | Day 90 | 3.4 units on a scale | Standard Deviation 1.86 |
Comparison: ANCOVA model with site and treatment group as fixed effects and contrasts constructed to estimate the difference between treatment groups. The null hypothesis was H0: β1=0 and alternative hypothesis was H1: β1 ≠ 0. Only a statistically significant, negative estimate of β1 was to constitute evidence of effectiveness.p-value: 0.04795% CI: [-0.85, -0.06]ANCOVA
Secondary
Ethmoid Sinus Obstruction
Percentage of the ethmoid sinus volume obstructed by scarring, polyps, or edema on endoscopy, as determined by an independent panel of 3 sinus surgeons based on a centralized, blinded videoendoscopy review using a 100-mm visual analogue scale (VAS), ranging from 0 (absence of obstruction) to 100 (complete obstruction). Negative values for change from baseline indicated reduction (improvement) in ethmoid sinus obstruction.
Time frame: Day 90
Population: Intent-to-treat population. Values were adjusted for steroid and surgical interventions by LOCF approach. There were 8 (2.7%) participants (6 treatment, 2 control) with missing values at Day 90. No imputation of missing values was performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Ethmoid Sinus Obstruction | Baseline | 69.2 units on a scale | Standard Deviation 19.87 |
| Treatment | Ethmoid Sinus Obstruction | Day 90 | 57.7 units on a scale | Standard Deviation 23.57 |
| Treatment | Ethmoid Sinus Obstruction | Change from baseline | -11.3 units on a scale | Standard Deviation 18.11 |
| Control | Ethmoid Sinus Obstruction | Baseline | 67.0 units on a scale | Standard Deviation 18.55 |
| Control | Ethmoid Sinus Obstruction | Day 90 | 64.8 units on a scale | Standard Deviation 23.14 |
| Control | Ethmoid Sinus Obstruction | Change from baseline | -1.9 units on a scale | Standard Deviation 14.36 |
Comparison: ANCOVA model with site and treatment group as fixed effects and contrasts constructed to estimate the difference between treatment groups.The null hypothesis was H0: β1 = 0 and the alternative hypothesis was H1: β1 ≠ 0. Although the alternative hypothesis was specified as 2-sided, only a statistically significant, negative estimate of β1 constituted evidence of effectiveness. The 2-sided alpha for this test was 0.05.p-value: 0.000795% CI: [-12.1, -3.83]ANCOVA
Secondary
Facial Pain/Pressure Score
Determined by patients on a 6-point Likert scale from 0 (absent) to 5 (very severe). Negative values for change from baseline indicated reduction (improvement) in facial pain/pressure symptoms.
Time frame: Day 90
Population: Intent-to-treat population. Values were adjusted for steroid and surgical interventions by LOCF approach. There were 5 (1.7%) participants (3 treatment, 2 control) with missing values: 3 at baseline (1 treatment, 1 control)) and 2 at Day 90 (1 treatment, 1 control) No imputation of missing values was performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Facial Pain/Pressure Score | Baseline | 1.9 units on a scale | Standard Deviation 1.4 |
| Treatment | Facial Pain/Pressure Score | Day 90 | 1.1 units on a scale | Standard Deviation 1.25 |
| Treatment | Facial Pain/Pressure Score | Change from baseline | -0.77 units on a scale | Standard Deviation 1.209 |
| Control | Facial Pain/Pressure Score | Baseline | 2.2 units on a scale | Standard Deviation 1.42 |
| Control | Facial Pain/Pressure Score | Day 90 | 1.2 units on a scale | Standard Deviation 1.2 |
| Control | Facial Pain/Pressure Score | Change from baseline | -0.90 units on a scale | Standard Deviation 1.269 |
Comparison: ANCOVA model with site and treatment group as fixed effects and contrasts constructed to estimate the difference between treatment groups. The null hypothesis was H0: β1=0 and alternative hypothesis was H1: β1 ≠ 0. Only a statistically significant, negative estimate of β1 was to constitute evidence of effectiveness.p-value: 0.913ANCOVA
Secondary
Nasal Obstruction/Congestion Score
Determined by patients using a daily diary on a scale from 0 (no symptoms) to 3 (severe symptoms) over a period of 7 days prior to baseline and Day 90. Negative values for change from baseline indicated reduction (improvement) in nasal obstruction/congestion symptoms.
Time frame: Day 90
Population: Intent-to-treat population. Scoring for \>=4 of 7 days immediately preceding the baseline and Day 90 visits was required. There were 34 (11.3%) participants with missing scores: 23 treatment and 10 control at Day 90 and 1 (treatment) at baseline. No imputation of missing values was performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Nasal Obstruction/Congestion Score | Baseline | 2.36 units on a scale | Standard Deviation 0.488 |
| Treatment | Nasal Obstruction/Congestion Score | Day 90 | 1.42 units on a scale | Standard Deviation 0.814 |
| Treatment | Nasal Obstruction/Congestion Score | Change from baseline | -0.93 units on a scale | Standard Deviation 0.798 |
| Control | Nasal Obstruction/Congestion Score | Baseline | 2.35 units on a scale | Standard Deviation 0.479 |
| Control | Nasal Obstruction/Congestion Score | Day 90 | 1.68 units on a scale | Standard Deviation 0.812 |
| Control | Nasal Obstruction/Congestion Score | Change from baseline | -0.69 units on a scale | Standard Deviation 0.791 |
Comparison: ANCOVA model with site and treatment group as fixed effects and contrasts constructed to estimate the difference between treatment groups. The null hypothesis was H0: β1=0 and the alternative hypothesis was H1: β1 ≠ 0. Only a statistically significant, negative estimate of β1 was to constitute evidence of effectiveness.p-value: 0.024895% CI: [-0.48, -0.07]ANCOVA
Secondary
Percentage of Patients Indicated for Repeat Endoscopic Sinus Surgery (RESS)
Proportion of patients still indicated for RESS at day 90 despite ongoing use of mometasone furoate nasal spray based on clinical investigator assessment using study-specific criteria. To be indicated for RESS, patients had to: (1) complain of nasal obstruction/congestion (moderate to severe) and postnasal discharge, facial pain/pressure/fullness, or altered sense of smell/taste; (2) have endoscopic evidence of persisting nasal polyps (grade \>= 2 on each side); and (3) have received (required at baseline) or need a systemic steroid as noted during endoscopy.
Time frame: Day 90
Population: Intent-to-treat population, consisting of all patients in whom an implant or sham procedure was attempted. 2 participants did not complete Day 90 visit. No imputation of missing values was performed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment | Percentage of Patients Indicated for Repeat Endoscopic Sinus Surgery (RESS) | Baseline | 201 Participants |
| Treatment | Percentage of Patients Indicated for Repeat Endoscopic Sinus Surgery (RESS) | Day 90 | 78 Participants |
| Control | Percentage of Patients Indicated for Repeat Endoscopic Sinus Surgery (RESS) | Baseline | 99 Participants |
| Control | Percentage of Patients Indicated for Repeat Endoscopic Sinus Surgery (RESS) | Day 90 | 62 Participants |
Comparison: Test: H0: OR = 1 vs. OR ≠ 1 by Cochrane-Mantel-Haenszel testp-value: 0.000495% CI: [1.63, 4.44]Cochran-Mantel-Haenszel