Idiopathic Angioedema
Conditions
Keywords
Angioedema, Idiopathic Angioedema, IAE
Brief summary
The overall hospitalizations for a diagnosis of angioedema doubled from the year 2000 to 2009. Although some of the cases represented hereditary angioedema or ace-inhibitor induced angioedema, the majority of episodes were idiopathic. Idiopathic Angioedema (IAE) can be life- threatening especially when affecting tissues within the respiratory tract. No clear guidelines exist for management of this important condition for clinicians. Current therapies typically include avoidance of potential triggers and use of medications either for prophylaxis or for acute events, such as antihistamines, corticosteroids, and epinephrine. There remains a critical need for therapeutic options to provide more effective prophylaxis.
Detailed description
This study is a randomized, double-blind, placebo-controlled, parallel group trial which will study the effects of omalizumab on patients with 2 or more episodes of Idiopathic Angioedema (IAE) in the past 6 months, despite current therapy. This study has three periods; screening, treatment, and follow-up. Subjects in the screening period will be consented and screened for eligibility criteria. 40 qualified individuals will enter the treatment period. Individuals will be randomized to either monthly subcutaneous administration of omalizumab 300mg (20 subjects) versus monthly placebo injection (20 subjects) in addition to their previously prescribed management plan for a total of 6 months. Individuals will then enter a follow-up period of 4 months. Study visits will occur monthly during the treatment period for update of clinical status and administration of omalizumab/placebo injection. After, the treatment period individuals will be seen twice for follow-up period. The entire study will consist of 10 study visits and will last approx. 10 months.
Interventions
DRUGOmalizumab
Omalizumab 300mg subcutaneous injection once monthly for 6 months. Total dose will be divided into two 150mg/1.2mL injections.
DRUGPlacebos
Placebo Group (Sodium Chloride 0.9%) two 1.2mL subcutaneous injections once monthly for 6 months.
Sponsors
Novartis Pharmaceuticals
University of Wisconsin, Madison
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults or adolescents who are 18 years or older at the time of screening with physician diagnosis of idiopathic angioedema * Minimum of two episodes of idiopathic angioedema in the past 6 months at the time of screening * Management of idiopathic angioedema with a stable controller treatment plan for the prior 6 months * Complement profile (C1 Esterase inhibitor panel) within normal reference values * If a woman is of child-bearing potential, she must agree to a reliable form of birth control including: abstinence, oral contraceptives (birth control pills), Depo-provera, an intrauterine device (IUD), or double-barrier contraception (partner using condom and participant using diaphragm, contraceptive sponge or cervical cap, and spermicidal)
Exclusion criteria
* Diagnosis of Hereditary Angioedema (HAE), Acquired Angioedema, or Ace-inhibitor associated angioedema, which are forms of angioedema with known mechanisms and alternate treatment options * Chronic Urticaria (itching and/or hives) with or without Angioedema which are known mast cell mediated processes previously shown to be responsive to the use of omalizumab * Previous usage of omalizumab in the last 3 months which can affect the patient-related outcomes and biomarker assessments if not washed out of the system * Patients, who in the judgment of the investigator, have a history or condition that might compromise patient safety or compliance, interfere with evaluations, or preclude completion of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean 7-day Angioedema Activity Score (AAS7) | baseline to end of treatment period at 6 months | The AAS7 Score is a measure of the frequency and intensity of angioedema episodes. The total possible range of scores over 7 days is 0-15 (mean day sum score) where higher scores indicate increased angioedema activity. |
| Presence of a 7-day Angioedema Activity Score (AAS7) Greater Than 0 Across All Treatment Visits | across all visits during treatment period (up to 6 months) | The AAS7 Score is a measure of the frequency and intensity of angioedema episodes. The total possible range of scores over 7 days is 0-15 (mean day sum score) where higher scores indicate increased angioedema activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Angioedema Quality of Life (AE-QoL) Questionnaire Across All Treatment Visits | across all visits during treatment period (up to 6 months) | The AE-QoL Questionnaire is a 17-item survey, the total possible range of scores is transformed to a scale of 1-100 where higher score indicate increased impairment. |
| Mean Visual Analog Scale | baseline to end of treatment period at 6 months | The effect of treatment compared to placebo on the change in IAE severity from baseline to the end of the treatment period as recorded on a 0-100 visual analog scale. Lower numbers indicate increased severity. |
| Presence of Visual Analog Scale Less Than 100 Across All Treatment Visits | across all visits during treatment period (up to 6 months) | The effect of treatment compared to placebo on the change in IAE severity from baseline to the end of the treatment period as recorded on a 0-100 visual analog scale. Lower numbers indicate increased severity. |
| Mean Number of IAE Episodes 2 Weeks Prior to Randomization | baseline to end of treatment period at 6 months | Idiopathic angioedema (IAE) refers to episodes of angioedema without urticaria for which no explanation can be found despite a thorough investigation. Patients are sometimes referred to as having IAE while further investigations are being performed, and therefore this term does not necessarily represent a distinct condition, but rather a diagnostic challenge in which the pathway of swelling is yet to be determined. |
| Number of IAE Events Across All Treatment Visits | across all visits during treatment period (up to 6 months) | — |
| Number of Participants Who Visited Urgent Care or Emergency Room | baseline, end of treatment period at 6 months, follow up at 9 months | Count of participants who visited urgent care or the emergency room is participant reported. The baseline measure is for the 6 months prior to study, at the 6 month time point for the time on study, and the 9 month time point for the previous 3 months on study. |
| Number of Participants Who Used Rescue Medication or Corticosteroids | baseline, end of treatment period at 6 months, follow up at 9 months | — |
| Number of Times Rescue Medications Were Used During the Treatment Period | up to 26 weeks | — |
| Change in Duration of IAE Episodes | baseline to end of treatment period at 6 months | Duration of IAE Episodes is participant reported for the 6 months prior to study (baseline) and again at the 6 month time point for the time on study. |
| Mean Angioedema Quality of Life (AE-QoL) Questionnaire | baseline to end of treatment period at 6 months | The AE-QoL Questionnaire is a 17-item survey, the total possible range of scores is transformed to a scale of 1-100 where higher score indicate increased impairment. |
Countries
United States
Participant flow
Recruitment details
Participants were screened and enrolled at the University of Wisconsin-Madison Allergy and Asthma Clinical Research Unit from March 2017 to April 2019.
Pre-assignment details
Two participants were screened and enrolled but not randomized to an arm to start the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo contains sodium chloride 0.9% and will be provided by Novartis. Placebo will be administered as a subcutaneous injection.
Placebos: Placebo Group (Sodium Chloride 0.9%) two 1.2mL subcutaneous injections once monthly for 6 months. | 5 |
| Omalizumab Omalizumab is a sterile, white, preservative-free, lyophilized powder, contained in a single-use vial that will be reconstituted with sterile water for injection (SWFI), USP, and administered as a subcutaneous injection. Each omalizumab vial contains 202.5 mg of omalizumab, 145.5 mg sucrose, 2.8 mg L-histidine hydrochloride monohydrate, 1.8 mg L-histidine, and 0.5 mg polysorbate 20. Each vial is designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP.
Omalizumab: Omalizumab 300mg subcutaneous injection once monthly for 6 months. Total dose will be divided into two 150mg/1.2mL injections. | 5 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Omalizumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 4 Participants | 7 Participants |
| Age, Continuous | 53 years | 53.8 years | 53.4 years |
| Duration of IAE Episodes | 14.3 hours | 21.1 hours | 17.7 hours |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 171.18 centimeters | 180.86 centimeters | 176.02 centimeters |
| Number of IAE Episodes in past 6 months | 15.2 IAE Episodes | 10.6 IAE Episodes | 12.9 IAE Episodes |
| Number of Urgent Care / Emergency Department Visits in past 6 months | 0.6 visits | 0.2 visits | 0.4 visits |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 10 Participants |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
| Weight | 93.4 kg | 91.2 kg | 92.3 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 0 / 5 | 1 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Mean 7-day Angioedema Activity Score (AAS7)
The AAS7 Score is a measure of the frequency and intensity of angioedema episodes. The total possible range of scores over 7 days is 0-15 (mean day sum score) where higher scores indicate increased angioedema activity.
Time frame: baseline to end of treatment period at 6 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Mean 7-day Angioedema Activity Score (AAS7) | baseline (2 weeks prior to randomization) | 2.8 score on a scale |
| Placebo | Mean 7-day Angioedema Activity Score (AAS7) | 6 months | 0.69 score on a scale |
| Omalizumab | Mean 7-day Angioedema Activity Score (AAS7) | baseline (2 weeks prior to randomization) | 1.6 score on a scale |
| Omalizumab | Mean 7-day Angioedema Activity Score (AAS7) | 6 months | 0.20 score on a scale |
Primary
Presence of a 7-day Angioedema Activity Score (AAS7) Greater Than 0 Across All Treatment Visits
The AAS7 Score is a measure of the frequency and intensity of angioedema episodes. The total possible range of scores over 7 days is 0-15 (mean day sum score) where higher scores indicate increased angioedema activity.
Time frame: across all visits during treatment period (up to 6 months)
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Placebo | Presence of a 7-day Angioedema Activity Score (AAS7) Greater Than 0 Across All Treatment Visits | 38 participant visits |
| Omalizumab | Presence of a 7-day Angioedema Activity Score (AAS7) Greater Than 0 Across All Treatment Visits | 4 participant visits |
p-value: 0.00395% CI: [2.77, 126.47]Regression, Logistic
Secondary
Change in Duration of IAE Episodes
Duration of IAE Episodes is participant reported for the 6 months prior to study (baseline) and again at the 6 month time point for the time on study.
Time frame: baseline to end of treatment period at 6 months
Population: 1 participant in the placebo arm was lost to follow up at the 6 month measure, but was able to be analyzed for the Primary Outcome
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Change in Duration of IAE Episodes | baseline (2 weeks prior to randomization) | 14.3 hours |
| Placebo | Change in Duration of IAE Episodes | 6 months | 3.25 hours |
| Omalizumab | Change in Duration of IAE Episodes | baseline (2 weeks prior to randomization) | 21.1 hours |
| Omalizumab | Change in Duration of IAE Episodes | 6 months | 0.5 hours |
Secondary
Mean Angioedema Quality of Life (AE-QoL) Questionnaire
The AE-QoL Questionnaire is a 17-item survey, the total possible range of scores is transformed to a scale of 1-100 where higher score indicate increased impairment.
Time frame: baseline to end of treatment period at 6 months
Population: 1 participant in the placebo arm was lost to follow up at the 6 month measure, but was able to be analyzed for the Primary Outcome
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Mean Angioedema Quality of Life (AE-QoL) Questionnaire | baseline (2 weeks prior to randomization) | 28.25 score on a scale |
| Placebo | Mean Angioedema Quality of Life (AE-QoL) Questionnaire | 6 months | 19.12 score on a scale |
| Omalizumab | Mean Angioedema Quality of Life (AE-QoL) Questionnaire | baseline (2 weeks prior to randomization) | 21.47 score on a scale |
| Omalizumab | Mean Angioedema Quality of Life (AE-QoL) Questionnaire | 6 months | 8.53 score on a scale |
Secondary
Mean Angioedema Quality of Life (AE-QoL) Questionnaire Across All Treatment Visits
The AE-QoL Questionnaire is a 17-item survey, the total possible range of scores is transformed to a scale of 1-100 where higher score indicate increased impairment.
Time frame: across all visits during treatment period (up to 6 months)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Angioedema Quality of Life (AE-QoL) Questionnaire Across All Treatment Visits | 19.0 score on a scale | Standard Deviation 12.9 |
| Omalizumab | Mean Angioedema Quality of Life (AE-QoL) Questionnaire Across All Treatment Visits | 8.5 score on a scale | Standard Deviation 10.4 |
p-value: 0.0395% CI: [1.24, 17.63]Regression, Linear
Secondary
Mean Number of IAE Episodes 2 Weeks Prior to Randomization
Idiopathic angioedema (IAE) refers to episodes of angioedema without urticaria for which no explanation can be found despite a thorough investigation. Patients are sometimes referred to as having IAE while further investigations are being performed, and therefore this term does not necessarily represent a distinct condition, but rather a diagnostic challenge in which the pathway of swelling is yet to be determined.
Time frame: baseline to end of treatment period at 6 months
Population: 1 participant in the placebo arm was lost to follow up at the 6 month measure, but was able to be analyzed for the Primary Outcome
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Mean Number of IAE Episodes 2 Weeks Prior to Randomization | baseline (2 weeks prior to randomization) | 1 episodes |
| Placebo | Mean Number of IAE Episodes 2 Weeks Prior to Randomization | 6 months | 0.5 episodes |
| Omalizumab | Mean Number of IAE Episodes 2 Weeks Prior to Randomization | baseline (2 weeks prior to randomization) | 0.4 episodes |
| Omalizumab | Mean Number of IAE Episodes 2 Weeks Prior to Randomization | 6 months | 0.2 episodes |
Secondary
Mean Visual Analog Scale
The effect of treatment compared to placebo on the change in IAE severity from baseline to the end of the treatment period as recorded on a 0-100 visual analog scale. Lower numbers indicate increased severity.
Time frame: baseline to end of treatment period at 6 months
Population: 1 participant in the placebo arm was lost to follow up at the 6 month measure, but was able to be analyzed for the Primary Outcome
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Mean Visual Analog Scale | baseline (2 weeks prior to randomization) | 91 score on a scale |
| Placebo | Mean Visual Analog Scale | 6 months | 88.75 score on a scale |
| Omalizumab | Mean Visual Analog Scale | baseline (2 weeks prior to randomization) | 84 score on a scale |
| Omalizumab | Mean Visual Analog Scale | 6 months | 97 score on a scale |
Secondary
Number of IAE Events Across All Treatment Visits
Time frame: across all visits during treatment period (up to 6 months)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Number of IAE Events Across All Treatment Visits | 1.8 count of events | Standard Deviation 2.3 |
| Omalizumab | Number of IAE Events Across All Treatment Visits | 0.2 count of events | Standard Deviation 0.5 |
p-value: 0.00595% CI: [1.9, 25.3]Regression, Linear
Secondary
Number of Participants Who Used Rescue Medication or Corticosteroids
Time frame: baseline, end of treatment period at 6 months, follow up at 9 months
Population: Data not collected due to study communications.
Secondary
Number of Participants Who Visited Urgent Care or Emergency Room
Count of participants who visited urgent care or the emergency room is participant reported. The baseline measure is for the 6 months prior to study, at the 6 month time point for the time on study, and the 9 month time point for the previous 3 months on study.
Time frame: baseline, end of treatment period at 6 months, follow up at 9 months
Population: Data not collected due to study communications.
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Number of Participants Who Visited Urgent Care or Emergency Room | baseline (2 weeks prior to randomization) | — |
| Unknown | Number of Participants Who Visited Urgent Care or Emergency Room | 6 months | — |
| Unknown | Number of Participants Who Visited Urgent Care or Emergency Room | 9 months | — |
Secondary
Number of Times Rescue Medications Were Used During the Treatment Period
Time frame: up to 26 weeks
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Placebo | Number of Times Rescue Medications Were Used During the Treatment Period | Number of times rescue H1-antagonist used | 13 instances of rescue medication use |
| Placebo | Number of Times Rescue Medications Were Used During the Treatment Period | Number of times Rescue Systemic Steroid used | 5 instances of rescue medication use |
| Placebo | Number of Times Rescue Medications Were Used During the Treatment Period | Number of times rescue H2-antagonist used | 14 instances of rescue medication use |
| Omalizumab | Number of Times Rescue Medications Were Used During the Treatment Period | Number of times Rescue Systemic Steroid used | 0 instances of rescue medication use |
| Omalizumab | Number of Times Rescue Medications Were Used During the Treatment Period | Number of times rescue H1-antagonist used | 7 instances of rescue medication use |
| Omalizumab | Number of Times Rescue Medications Were Used During the Treatment Period | Number of times rescue H2-antagonist used | 1 instances of rescue medication use |
Secondary
Presence of Visual Analog Scale Less Than 100 Across All Treatment Visits
The effect of treatment compared to placebo on the change in IAE severity from baseline to the end of the treatment period as recorded on a 0-100 visual analog scale. Lower numbers indicate increased severity.
Time frame: across all visits during treatment period (up to 6 months)
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Placebo | Presence of Visual Analog Scale Less Than 100 Across All Treatment Visits | 17 participant visits |
| Omalizumab | Presence of Visual Analog Scale Less Than 100 Across All Treatment Visits | 4 participant visits |
p-value: 0.0395% CI: [1.49, 720.54]Regression, Logistic