Chronic Idiopathic Urticaria
Conditions
Keywords
Chronic Idiopathic Urticaria
Brief summary
The investigators are recruiting for a chronic hives study. This research is being done to test whether an investigational drug called AstraZeneca drug (AZD)1981 may be helpful for treating people with Chronic Idiopathic Urticaria who continue to have symptoms despite taking antihistamines. The word investigational means that AZD1981 is not approved for marketing by the Food and Drug Administration (FDA). The FDA is allowing the use of AZD1981 in this study. People with chronic hives lasting for at least 6 months and without a known cause may join. The study involves 6 visits over 8 weeks. Approximately 48 participants expected to take part in this study at the Johns Hopkins Asthma and Allergy Clinic. All participants will be treated with the study medication and/or placebo for 8 weeks. The results of this trial may have a benefit others with Chronic Idiopathic Urticaria who don't respond well to antihistamines by generating experience and data to support the design of a larger, multicenter trial investigating the efficacy of AZD1981 in treating antihistamine refractory CIU.
Detailed description
The investigators propose to use AZD1981 in subjects with chronic idiopathic urticaria (CIU) who are otherwise uncontrolled on first-line, oral antihistamine therapy. The skin lesion pathology in CIU shows a perivascular infiltrate of lymphocytes (both Th2 and Th1), eosinophils, and basophils, and closely resembles an allergen-induced late-phase reaction. Further, murine studies show that the chemoattractant receptor-homologous molecule expressed on Th2 (CRTh2) pathway is important in leukocyte recruitment following allergen challenge of the skin. Our proposed hypothesis is that AZD1981 in CIU will reduce CRTh2-expressing, leukocyte recruitment to the skin and reduce leukocyte activation through CRTh2, thus reducing the signs and symptoms in CIU refractory to control with antihistamines.
Interventions
DRUGAZD1981
AZD1981 is an oral, potent, selective, reversible antagonist of CRTh2 (Chemoattractant Receptor Homologous Molecule expressed on Th2 cells).
DRUGPlacebo
Sugar pill manufactured to mimic AZD1981 10 mg tablet
Sponsors
AstraZeneca
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Females must be surgically sterile or postmenopausal or using a highly effective form of birth control throughout the duration of the study * Females must have a negative urine pregnancy test at screening * Must meet the criteria for Chronic Idiopathic Urticaria (CIU) as defined by itching and hives for \>3 days per week for over 6 weeks with no clear cause * CIU symptoms must have started at least 6 months prior to starting the study * Must have moderate to severe CIU, using a standardized survey, despite taking antihistamines
Exclusion criteria
* Pregnant females or females who plan to become pregnant during the study * Drug or alcohol abuse within the past 3 years * Use of any investigational drug with 30 days of the start of the study * Eczema or other skin conditions associated with itching (besides hives) * Inability to comply with follow-up procedures * Use of the following therapies in the past 30 days: hydroxychloroquine, sulfasalazine, dapsone, methotrexate, cyclophosphamide, Intravenous Immunoglobulin (IVIG), plasmapheresis, cyclosporine, oral or systemic steroids, or other monoclonal antibody therapies * Use of doxepin within the past 2 weeks * Use of either H2 antihistamines and leukotriene receptor antagonists within 7 days before starting the study (unless already on these medications for Gastroesophageal Reflux Disease (GERD), asthma or allergic rhinitis) * Inability to take diphenhydramine (Benadryl) * Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks or interfere with ability to comply with study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change in Diary-based Clinical Symptoms as Measured by the Urticaria Activity Score 7 (UAS7) | 7 Days | The UAS score, which is the sum of pruritus and hives, will be used to calculate the UAS7. UAS is a validated measure of Chronic Spontaneous Urticaria (CSU) disease activity which scores the intensity of pruritus (0-3, with 0 = no itch and 3 is severe itch) and number of hives (0-3 0 means no hives and 3 means greater than 50 hives) with a maximum value of 6 for a given day. The UAS7 is the sum of the daily average UAS scores (average of a.m. and p.m.) for 7 days with a minimum score of 0 and a maximum value of 42. The UAS7 is a sum of the daily average (average of a.m. and p.m.) for 7 days. The baseline score was established during the second placebo therapy week and compared to the final week of the 4 week active treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With Adverse Events | 8 weeks | The safety of AZD1981 will be assessed using the following outcome measures: incidence and severity of treatment-emergent adverse events and serious adverse events, clinical laboratory measures, and vital signs. In particular we will measure CBC's with differential at baseline and week 4 and liver function tests every 2 weeks based on past trial experience of dose-related toxicity. |
| The Ability of AZD1981 to Inhibit Prostaglandin D2 (PGD2)-Induced Eosinophil Shape | Baseline, End of treatment, end of washout | The measure of Eosinophil shape change was assessed by cell scatter characteristics using a flow cytometer. Cellular scatter was established with buffer and then several doses of PGD2 stimulation. |
Countries
United States
Participant flow
Pre-assignment details
This study involved a 1-week screening period and a 2-week single-blind placebo run-in before randomization to active or placebo treatment. 10/38 enrolled subjects were excluded based on low disease activity (n=5), inability to remain solely on daily H1 antihistamine (n=4), and noncompliance (n=1).
Participants by arm
| Arm | Count |
|---|---|
| AZD1981 AZD1981 for oral administration will be available in tablet form. AZD1981 tablets will be provided in 10 mg strengths.
The drug will be self-administered by the subject. Subjects will take 4 tablets in the morning, 4 tablets in the afternoon, and 4 tablets in the evening.
The tablets should be swallowed whole with a glass of water.
AZD1981: AZD1981 is an oral, potent, selective, reversible antagonist of CRTh2 (Chemoattractant Receptor Homologous Molecule expressed on Th2 cells). | 14 |
| Placebo The placebo will be available in tablet form. The placebo contains the same ingredients as the AZD1981 with the exception of the active compound.
The placebo will be self-administered by the subject. Subjects will take 4 tablets in the morning, 4 tablets in the afternoon, and 4 tablets in the evening.
The tablets should be swallowed whole with a glass of water.
Placebo: Sugar pill manufactured to mimic AZD1981 10 mg tablet | 12 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | AZD1981 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 12 Participants | 26 Participants |
| Age, Continuous | 41.85 years | 45.17 years | 43.38 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 12 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 4 Participants | 10 Participants |
| Region of Enrollment United States | 14 participants | 12 participants | 26 participants |
| Sex: Female, Male Female | 10 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 12 |
| other Total, other adverse events | 9 / 14 | 8 / 12 |
| serious Total, serious adverse events | 0 / 14 | 0 / 12 |
Outcome results
Primary
The Change in Diary-based Clinical Symptoms as Measured by the Urticaria Activity Score 7 (UAS7)
The UAS score, which is the sum of pruritus and hives, will be used to calculate the UAS7. UAS is a validated measure of Chronic Spontaneous Urticaria (CSU) disease activity which scores the intensity of pruritus (0-3, with 0 = no itch and 3 is severe itch) and number of hives (0-3 0 means no hives and 3 means greater than 50 hives) with a maximum value of 6 for a given day. The UAS7 is the sum of the daily average UAS scores (average of a.m. and p.m.) for 7 days with a minimum score of 0 and a maximum value of 42. The UAS7 is a sum of the daily average (average of a.m. and p.m.) for 7 days. The baseline score was established during the second placebo therapy week and compared to the final week of the 4 week active treatment period.
Time frame: 7 Days
Population: One placebo subject had diary data compromised by device malfunction so only full data for 11 subjects were analyzed
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD1981 | The Change in Diary-based Clinical Symptoms as Measured by the Urticaria Activity Score 7 (UAS7) | Baseline | 20.46 UAS7 Scores | Standard Error 3.655 |
| AZD1981 | The Change in Diary-based Clinical Symptoms as Measured by the Urticaria Activity Score 7 (UAS7) | End of Treatment | 18.83 UAS7 Scores | Standard Error 3.779 |
| AZD1981 | The Change in Diary-based Clinical Symptoms as Measured by the Urticaria Activity Score 7 (UAS7) | End of Washout | 15.79 UAS7 Scores | Standard Error 3.726 |
| Placebo | The Change in Diary-based Clinical Symptoms as Measured by the Urticaria Activity Score 7 (UAS7) | Baseline | 24.59 UAS7 Scores | Standard Error 3.463 |
| Placebo | The Change in Diary-based Clinical Symptoms as Measured by the Urticaria Activity Score 7 (UAS7) | End of Treatment | 18 UAS7 Scores | Standard Error 3.614 |
| Placebo | The Change in Diary-based Clinical Symptoms as Measured by the Urticaria Activity Score 7 (UAS7) | End of Washout | 19 UAS7 Scores | Standard Error 3.465 |
Secondary
The Ability of AZD1981 to Inhibit Prostaglandin D2 (PGD2)-Induced Eosinophil Shape
The measure of Eosinophil shape change was assessed by cell scatter characteristics using a flow cytometer. Cellular scatter was established with buffer and then several doses of PGD2 stimulation.
Time frame: Baseline, End of treatment, end of washout
Population: Insufficient samples were obtained for one active and 2 placebo patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD1981 | The Ability of AZD1981 to Inhibit Prostaglandin D2 (PGD2)-Induced Eosinophil Shape | Baseline | 1521.317 Mean fluorescence units area under curve | Standard Deviation 138.146 |
| AZD1981 | The Ability of AZD1981 to Inhibit Prostaglandin D2 (PGD2)-Induced Eosinophil Shape | End of Treatment | 1435.540 Mean fluorescence units area under curve | Standard Deviation 137.752 |
| AZD1981 | The Ability of AZD1981 to Inhibit Prostaglandin D2 (PGD2)-Induced Eosinophil Shape | End of Washout | 1508.367 Mean fluorescence units area under curve | Standard Deviation 116.085 |
| Placebo | The Ability of AZD1981 to Inhibit Prostaglandin D2 (PGD2)-Induced Eosinophil Shape | Baseline | 1472.867 Mean fluorescence units area under curve | Standard Deviation 184.401 |
| Placebo | The Ability of AZD1981 to Inhibit Prostaglandin D2 (PGD2)-Induced Eosinophil Shape | End of Treatment | 1456.602 Mean fluorescence units area under curve | Standard Deviation 157.485 |
| Placebo | The Ability of AZD1981 to Inhibit Prostaglandin D2 (PGD2)-Induced Eosinophil Shape | End of Washout | 1406.221 Mean fluorescence units area under curve | Standard Deviation 108.539 |
Secondary
The Number of Participants With Adverse Events
The safety of AZD1981 will be assessed using the following outcome measures: incidence and severity of treatment-emergent adverse events and serious adverse events, clinical laboratory measures, and vital signs. In particular we will measure CBC's with differential at baseline and week 4 and liver function tests every 2 weeks based on past trial experience of dose-related toxicity.
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1981 | The Number of Participants With Adverse Events | 9 participants with adverse events |
| Placebo | The Number of Participants With Adverse Events | 8 participants with adverse events |