Chronic Sinusitis With Nasal Polyps and Eosinophilia
Conditions
Keywords
Sinusitis, Rhinosinusitis, CRS, CRSwNP, CSNP-E, Nasal polyps, Nasal polyposis, Eosinophilia, Asthma
Brief summary
Phase 2, open-label, multi-center study to evaluate the clinical effects of oral administration of dexpramipexole for 6 months in subjects with chronic sinusitis with nasal polyps and eosinophilia.
Detailed description
This open-labelled study will evaluate the safety and preliminary efficacy of dexpramipexole for reducing the number of eosinophils in the peripheral blood and in improving nasal polyp score when administered to 20 subjects with chronic sinusitis with nasal polyps and eosinophilia. Subjects will received dexpramipexole for up to 6 months and will have safety tests performed monthly and will have efficacy evaluations performed at month 1, month 3, and month 6 after beginning study drug.
Interventions
DRUGdexpramipexole
Dexpramipexole capsule-shaped film-coated tablets at the dose strength of 150 mg administered orally as 1 tablet twice daily (300 mg/day)
Sponsors
Knopp Biosciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male or female \>18 or \<70 years of age * Willing to practice effective contraception during the study and be willing and able to continue contraception for 1 month (females) or 3 months (males) after the last dose of study treatment * Confirmed diagnosis of chronic sinusitis with nasal polyps * Documented history of nasal eosinophilia * Documented peripheral absolute eosinophil count \>300 cells/μL * Bilateral total polyp score of \>4 * Sino-nasal outcome test (SNOT-22) score of \>7 * Using an intranasal corticosteroid spray or irrigation (\< 1000 μg/day beclomethasone or equivalent)
Exclusion criteria
* Acute sinusitis, concurrent nasal infection, or subjects who have had a nasal or upper respiratory tract infection within 2 weeks prior to baseline * CT scan suggestive of allergic fungal rhinosinusitis * Nasal septal deviation that would occlude at least one nostril * Nasal surgery (including polypectomy) within 6 months prior to baseline * History of more than 5 sinonasal surgeries requiring general anesthesia * History of more than 2 sinonasal surgeries that changed the lateral wall of the nose * History of cystic fibrosis, primary ciliary's dysfunction or Kartagener's syndrome * History of diagnosis with a parasitic infection * Hospitalization or emergency treatment for the treatment of asthma two or more times in the 12 months prior to baseline * Hospitalization for an acute asthmatic attack within 4 weeks prior to baseline * Forced expiratory volume (FEV1) of \<60% of predicted normal range * Treatment with a systemic corticosteroid or intra-polyp corticosteroid within 8 weeks prior to baseline or anticipated need for systemic corticosteroids during the study treatment period * Utilization of rescue oral corticosteroids for asthma or chronic sinusitis exacerbation more than one time within the past 1 year * Treatment with an investigational drug in the previous 30 days or 5-half-lives, whichever is longer * Treatment with a monoclonal antibody therapy including omalizumab (Xolair®), within 5-half-lives * Treatment with zileuton (Zyflo®) within 4 weeks of baseline * Treatment with pramipexole (Mirapex®) within 4 weeks of baseline * History of malignancy, including solid tumors and hematologic malignancies (except basal cell and squamous cell cancers of the skin that have been completely excised and cured) * History of human immunodeficiency virus (HIV) or hepatitis B or C * History of unstable or severe cardiac, hepatic, or renal disease, or other medically significant illness * Medical or other condition likely to interfere with subject's ability to undergo study procedures, adhere to visit schedule or comply with study requirements * Absolute neutrophil count \<2000 cells/μL at screening, or any documented history of neutropenia * Total IgE \>1500 IU/ml at any visit prior to baseline * Renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) of ≤80 mg/dL at screening (estimation of creatinine clearance using the MDRD formula) * History of long QT syndrome or arrhythmia * Prolongation of QT/QTc interval (e.g., repeated demonstration of a QT/QTc interval \>450 ms) at screening or pre-dose on day 1 * Clinically important abnormalities in resting ECG that may interfere with the interpretation of QTc interval changes at screening or pre-dose on day 1, including any of the following: * PR interval \>210 ms; * QRS \>110 ms; * Heart rate \<45 bpm or \>100 bpm (average of 3 assessments). * Pregnant women or women breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Polyp Score (TPS) After 6 Months of Treatment | Baseline and Month 6 | The change in Nasal Polyp Score (NPS) score after 6 months of treatment is presented. A blinded Central Endoscopy Rater determined the NPS for each nare on a scale of 0 to 4, and the bilateral NPS scores were added to generate the Total Polyp Score (TPS) on a scale of 0 to 8. A lower TPS corresponds to a lower polyp burden. |
| Ratio to Baseline in Peripheral Blood Eosinophil Counts After 6 Months of Treatment | Baseline and Month 6 | Change in peripheral blood eosinophil (measured in cells/μL) from baseline to month 6 is presented as ratio to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | 6 months | Summary of subjects from the safety population who experienced potentially clinically significant values or changes in vital signs or weight |
| Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | 6 months | Summary of subjects from the safety population who experienced potentially significant values in electrocardiogram parameters |
| Change From Baseline in TPS After 3 Months of Treatment | Baseline and Month 3 | The change in Nasal Polyp Score (NPS) score after 3 months of treatment is presented. A blinded Central Endoscopy Rater determined the NPS for each nare on a scale of 0 to 4, and the bilateral NPS scores were added to generate the Total Polyp Score (TPS) on a scale of 0 to 8. A lower TPS corresponds to a lower polyp burden. |
| Ratio to Baseline in Peripheral Blood Eosinophil Counts After 3 Months of Treatment | Baseline and Month 3 | Change in peripheral blood eosinophil (measured in cells/μL) from baseline to month 3 is presented as ratio to baseline. |
| Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | 6 months | Summary of subjects from the safety population who experienced potentially clinically significant values in hand serum chemistry results |
Other
| Measure | Time frame | Description |
|---|---|---|
| Ratio to Baseline in Polyp Tissue Eosinophil Count After 6 Months of Treatment | Baseline and Month 6 | Change in polyp tissue eosinophil count measured as eosinophils/hpf (high powered field) from baseline to month 6 is presented as ratio to baseline. |
Countries
United States
Participant flow
Pre-assignment details
During a screening period of between 14 and 21 days, subjects were monitored symptoms of sinusitis and asthma. Subject who failed to meet the eligibility criteria during the screening period were disqualified.
Participants by arm
| Arm | Count |
|---|---|
| Dexpramipexole dexpramipexole 150 mg BID
dexpramipexole: Dexpramipexole capsule-shaped film-coated tablets at the dose strength of 150 mg administered orally as 1 tablet twice daily (300 mg/day) | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Dose interruption >1 month | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Protocol Violation (eligibility) | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Dexpramipexole |
|---|---|
| Age, Continuous | 46.1 years STANDARD_DEVIATION 9.78 |
| Age, Customized 50 to 65 years | 5 Participants |
| Age, Customized < 50 years | 14 Participants |
| Age, Customized > 65 years | 1 Participants |
| CSNP-E Symptoms Anterior and/or posterior mucopurulent drainage | 20 Participants |
| CSNP-E Symptoms Decreased sense of smell (anosmia) | 20 Participants |
| CSNP-E Symptoms Sinonasal obstruction/congestion | 20 Participants |
| Duration of symptoms > 10 years | 5 Participants |
| Duration of symptoms ≤ 1 year | 3 Participants |
| Duration of symptoms > 1 year to ≤ 5 years | 6 Participants |
| Duration of symptoms > 5 years to ≤ 10 years | 6 Participants |
| Duration of Symptoms (months) | 112.4 months STANDARD_DEVIATION 138.13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 18 / 20 |
| serious Total, serious adverse events | 1 / 20 |
Outcome results
Primary
Change From Baseline in Total Polyp Score (TPS) After 6 Months of Treatment
The change in Nasal Polyp Score (NPS) score after 6 months of treatment is presented. A blinded Central Endoscopy Rater determined the NPS for each nare on a scale of 0 to 4, and the bilateral NPS scores were added to generate the Total Polyp Score (TPS) on a scale of 0 to 8. A lower TPS corresponds to a lower polyp burden.
Time frame: Baseline and Month 6
Population: All subjects who had a Month 3 evaluation (on study drug Day 77 or later) for TPS and peripheral blood eosinophil count. Last observation carried forward (LOCF) was used to replace missing data due to drop out. Only Month 3 data or later (assessment date Day 77 or later and within 7 days of last dose) were used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexpramipexole | Change From Baseline in Total Polyp Score (TPS) After 6 Months of Treatment | 0.07 units on a scale | Standard Deviation 1.751 |
p-value: 0.885t-test, 2 sided
Primary
Ratio to Baseline in Peripheral Blood Eosinophil Counts After 6 Months of Treatment
Change in peripheral blood eosinophil (measured in cells/μL) from baseline to month 6 is presented as ratio to baseline.
Time frame: Baseline and Month 6
Population: All subjects who had a Month 3 evaluation (on study drug Day 77 or later) for TPS and peripheral blood eosinophil count. Last observation carried forward (LOCF) was used to replace missing data due to drop out. Only Month 3 data or later (assessment date Day 77 or later and within 7 days of last dose) were used.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Dexpramipexole | Ratio to Baseline in Peripheral Blood Eosinophil Counts After 6 Months of Treatment | 0.06 ratio to baseline |
Comparison: Null hypothesis is the ratio of Month 6 to Baseline within the dexpramipexole group equals '1'.p-value: <0.001t-test, 2 sided
Secondary
Change From Baseline in TPS After 3 Months of Treatment
The change in Nasal Polyp Score (NPS) score after 3 months of treatment is presented. A blinded Central Endoscopy Rater determined the NPS for each nare on a scale of 0 to 4, and the bilateral NPS scores were added to generate the Total Polyp Score (TPS) on a scale of 0 to 8. A lower TPS corresponds to a lower polyp burden.
Time frame: Baseline and Month 3
Population: All subjects who had a Month 3 evaluation (on study drug Day 77 or later) for total eosinophil count and total polyp score
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dexpramipexole | Change From Baseline in TPS After 3 Months of Treatment | 0.0 units on a scale | Standard Deviation 1.414 |
p-value: 1t-test, 2 sided
Secondary
Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations
Summary of subjects from the safety population who experienced potentially clinically significant values in hand serum chemistry results
Time frame: 6 months
Population: The safety population included all subjects who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | HIGH: Hematocrit - Females >=54% | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | LOW: Hematocrit - Females <= 32% | 2 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | LOW: Albumin <= 25 g/L | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | HIGH: Alanine aminotransferase (ALT) >= 1.5 x ULN | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | HIGH: Aspartate aminotransferase (AST) >= 1.5 x ULN | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | HIGH: Total bilirubin >= 1.5 x ULN | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | HIGH: Glucose>= 9.7 mmol/L | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | LOW: Glucose <= 2.2 mmol/L | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | HIGH: Eosinophils > 1.6 x 10(9)/L | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | HIGH: Hemoglobin - Females >=175g/L | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | LOW: Hemoglobin - Females <= 95g/L | 2 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | HIGH: Lymphocytes > 12 x 10(9)/L | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | LOW: Lymphocytes < 0.8 x 10(9)/L | 2 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Clinical Laboratory Evaluations | LOW: Neutrophils < 1.5 x 10(9)/L | 0 Participants |
Secondary
Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight
Summary of subjects from the safety population who experienced potentially clinically significant values or changes in vital signs or weight
Time frame: 6 months
Population: The safety population included all subjects who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Diastolic Blood Pressure: decrease from pre-dosing of more than 20 mmHg | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Heart Rate: >120 beats per minute | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Systolic Blood Pressure: >180 mmHg | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Systolic Blood Pressure: increase from pre-dosing of more than 40 mmHg | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Systolic Blood Pressure: <90 mmHg | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Systolic Blood Pressure: decrease from pre-dosing of more than 30 mmHg | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Diastolic Blood Pressure: >105 mmHg | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Diastolic Blood Pressure: increase from pre-dosing of more than 30 mmHg | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Diastolic Blood Pressure: <50 mmHg | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Heart Rate: increase from pre-dosing of more than 20 beats per minute | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Heart Rate: <50 beats per minute | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Heart Rate: decrease from pre-dosing of more than 20 beats per minute | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Temperature: >38ºC and an increase from pre-dosing of at least 1ºC | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Body Weight: >7% increase from baseline value | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Clinically Significant Values in Vital Signs and Weight | Body Weight: <=7% decrease from baseline value | 0 Participants |
Secondary
Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters
Summary of subjects from the safety population who experienced potentially significant values in electrocardiogram parameters
Time frame: 6 months
Population: The safety population included all subjects who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | QTcF: >450 msec | 2 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | QTcF: >480 msec | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | QTcF: > 450 msec and ≤ 450 msec at baseline | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | QTcF: > 480 msec and ≤ 480 msec at baseline | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | QTcF: > 450 msec and change from baseline > 30 msec | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | QTcF: > 480 msec and change from baseline > 30 msec | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | QTcF change from baseline: >30 msec | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | QTcF change from baseline: >60 msec | 0 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | Rhythm abnormalities: Sinus rhythm | 17 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | Rhythm abnormalities: Sinus bradycardia | 3 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | Rhythm abnormalities: Premature atrial complexes, conducted or non-conducted sinus rhythm | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | ST-T abnormalities: Nonspecific T wave abnormality | 3 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | ST-T abnormalities: Early repolarization | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | ST-T abnormalities: Early repolarization, considered normal variant | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | ST-T abnormalities: Nonspecific ST deviation | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | ST-T abnormalities: Nonspecific ST deviation, prolonged QTcF interval | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | ST-T abnormalities: Nonspecific T wave abnormality, prolonged QTcF interval | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | ST-T abnormalities: Prolonged QTcF interval | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | Conduction abnormality: First degree AV block | 2 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | Conduction abnormality: Complete right bundle branch block | 1 Participants |
| Dexpramipexole | Number of Subjects With Potentially Significant Values in Electrocardiogram Parameters | Conduction abnormality: Complete right bundle branch block first degree AV block | 1 Participants |
Secondary
Ratio to Baseline in Peripheral Blood Eosinophil Counts After 3 Months of Treatment
Change in peripheral blood eosinophil (measured in cells/μL) from baseline to month 3 is presented as ratio to baseline.
Time frame: Baseline and Month 3
Population: All subjects who had a Month 3 evaluation (on study drug Day 77 or later) for total eosinophil count
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Dexpramipexole | Ratio to Baseline in Peripheral Blood Eosinophil Counts After 3 Months of Treatment | 0.05 ratio |
Comparison: Null hypothesis is the ratio of Month 3 to Baseline within the dexpramipexole group equals '1'.p-value: <0.001t-test, 2 sided
Other Pre-specified
Ratio to Baseline in Polyp Tissue Eosinophil Count After 6 Months of Treatment
Change in polyp tissue eosinophil count measured as eosinophils/hpf (high powered field) from baseline to month 6 is presented as ratio to baseline.
Time frame: Baseline and Month 6
Population: All subjects who had a Month 3 evaluation (on study drug Day 77 or later) for TPS and peripheral blood eosinophil count (Efficacy Population). Additionally, subjects with \<5 eos/hpf at screening or baseline visit are not included in this analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Dexpramipexole | Ratio to Baseline in Polyp Tissue Eosinophil Count After 6 Months of Treatment | 0.03 ratio to baseline |
Comparison: Null hypothesis is the ratio of Month 6 to Baseline within the dexpramipexole group equals '1'; 68% confidence interval is equal to plus/minus 1 standard errorp-value: 0.001Wilcoxon Signed Rank Test (paired)