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A Multicentre, Randomized, Double-blind, Parallel Group, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Reducing Oral Corticosteroid dependent Asthma.
This is a randomized, double-blind, parallel group, placebo-controlled study designed to evaluate the efficacy and safety of a fixed 300 mg dose of tralokinumab administered subcutaneously every 2 weeks in adult and adolescent subjects with oral corticosteroid dependent asthma. Approximately120 subjects will be randomized globally. Subjects will receive tralokinumab or placebo, administered via subcutaneous injection at the study site, over a 40-week treatment period.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tralokinumab | Experimental | Tralokinumab subcutaneous injection |
|
| Placebo | Placebo Comparator | Placebo subcutaneous injection |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tralokinumab | Biological | Tralokinumab dose |
| |
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change From Baseline in the Final Daily, Average, OCS Dose at Week 40 While Not Losing Asthma Control. | The 40-week treatment period consisted of 3 phases: an induction phase (Week 0 to Week 12) where patients remained on their optimised OCS dose; an OCS reduction phase (Week 12 to Week 32) where OCS dose reduction could have started at Week 12 with the possibility of dose titration every 4 weeks to reach the lowest possible OCS dose; and a maintenance phase (Week 32 to Week 40) where patients remained on the OCS dose reached at Week 32 to demonstrate asthma control was maintained after achieving the lowest OCS dose. Criteria used to assess asthma control included lung function assessments (forced expiratory volume in 1 second and morning peak expiratory flow), night awakenings, and the use of rescue medication and systemic corticosteroids. The least squares (LS) mean percent change from baseline in average daily OCS dose is presented. The final daily percent change from baseline was defined as {(Final daily average dose - baseline daily average dose)/baseline daily average dose}*100%. | Baseline (Week 0) and Week 40 |
| Measure | Description | Time Frame |
|---|---|---|
| The Number of Patients With Final Daily Average OCS Dose ≤5 mg at Week 40. | The 40-week treatment period consisted of 3 phases: an induction phase (Week 0 to Week 12) where patients remained on their optimised OCS dose; an OCS reduction phase (Week 12 to Week 32) where OCS dose reduction could have started at Week 12 with the possibility of dose titration every 4 weeks to reach the lowest possible OCS dose; and a maintenance phase (Week 32 to Week 40) where patients remained on the OCS dose reached at Week 32 to demonstrate asthma control was maintained after achieving the lowest OCS dose. The number of patients with a final daily average OCS dose ≤5.0 mg is presented. For patients prescribed a fixed daily dose, then the average OCS dose was defined as the prescribed dose. For patients on a regimen where a different amount of OCS was to be taken each day, then the average OCS dose was defined as the average amount prescribed to be taken each day. |
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Inclusion Criteria:
1) Age 12-75 2) Documented physician-diagnosed asthma. 3) Documented treatment with ICS at a total daily dose corresponding to ≥500µg fluticasone propionate dry powder formulation and a LABA. 4) Subjects must have received OCS for the treatment of asthma for 6 months prior to Visit 1 and on a stable OCS dose between ≥7.5 to ≤30mg daily or daily equivalent for at least one month prior to enrolment (Visit 1) . 5) Pre-BD FEV1 value <80% (<90% for patients 12-17 yrs of age) of their PNV. 6) Post-BD reversibility of ≥12% in FEV1.
Exclusion Criteria:
1) Clinically important pulmonary disease other than asthma. 2) History of anaphylaxis following any biologic therapy. 3) Hepatitis B, C or HIV. 4) Pregnant or breastfeeding. 5) History of cancer. 6) Current tobacco smoking or a history of tobacco smoking for ≥10 pack-years. 7) Previous receipt of tralokinumab.
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| Name | Affiliation | Role |
|---|---|---|
| William W Busse, M.D. | University of Wisconsin School of Medicine and Public Health, Department of Medicine, Allergy & Immunology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | New Haven | Connecticut | 06520 | United States | ||
| Research Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30442714 | Background | Busse WW, Brusselle GG, Korn S, Kuna P, Magnan A, Cohen D, Bowen K, Piechowiak T, Wang MM, Colice G. Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma. Eur Respir J. 2019 Jan 31;53(2):1800948. doi: 10.1183/13993003.00948-2018. Print 2019 Feb. | |
| 29536781 | Derived | Panettieri RA Jr, Wang M, Braddock M, Bowen K, Colice G. Tralokinumab for the treatment of severe, uncontrolled asthma: the ATMOSPHERE clinical development program. Immunotherapy. 2018 Mar 1;10(6):473-490. doi: 10.2217/imt-2017-0191. Epub 2018 Mar 14. |
| Label | URL |
|---|---|
| Related Info | View source |
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218 patients were screened. Prior to randomisation, patients completed a run-in period or run-in/oral corticosteroid (OCS) optimisation period (reached their minimum effective dose of OCS and remained stable on that dose for 2 weeks). 140 patients were randomised to study treatment. All randomised patients received study treatment.
First patient enrolled: 19 February 2015; Last patient last visit: 07 September 2017. Study performed at 56 sites in 7 countries. Patients were maintained on their currently prescribed inhaled corticosteroid long-acting β2-agonist therapy and any additional asthma controller medications throughout the study period.
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| ID | Title | Description |
|---|---|---|
| FG000 | Tralokinumab | Tralokinumab 300 milligrams (mg) administered by subcutaneous (SC) injection every two weeks (Q2W) over a 40-week treatment period. |
| FG001 | Placebo | Placebo was administered by SC injection over a 40-week treatment period. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 22, 2016 | Mar 1, 2018 |
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| Other |
Placebo dose |
|
| At Week 40 |
| The Number of Patients With ≥50% Reduction in Final Average Daily OCS Dose at Week 40. | The 40-week treatment period consisted of 3 phases: an induction phase (Week 0 to Week 12) where patients remained on their optimised OCS dose; an OCS reduction phase (Week 12 to Week 32) where OCS dose reduction could have started at Week 12 with the possibility of dose titration every 4 weeks to reach the lowest possible OCS dose; and a maintenance phase (Week 32 to Week 40) where patients remained on the OCS dose reached at Week 32 to demonstrate asthma control was maintained after achieving the lowest OCS dose. The number of patients with ≥50% reduction in average daily OCS dose is presented. The final daily percent change from baseline was defined as {(Final daily average dose - baseline daily average dose)/baseline daily average dose}*100%. If this resulted in a value of -50% or less (more negative), that patient was classified as having at least a 50% reduction in final daily average OCS dose. | At Week 40 |
| Annual Asthma Exacerbation Rate (AAER) up to Week 40. | AAER up to Week 40 in the tralokinumab group was compared to that seen in the placebo group. The response variable was the number of exacerbations the patient experienced up to Week 40, with the logarithm of the time at risk in years of experiencing an exacerbation included as offset in the model. AAER = number of exacerbations*365.25/(follow-up date - date of randomisation + 1). Asthma exacerbation was defined as a worsening of asthma that led to any of the following:
| Baseline (Week 0) up to Week 40 |
| Clearwater |
| Florida |
| 33765 |
| United States |
| Research Site | St Louis | Missouri | 63141 | United States |
| Research Site | Rochester | New York | 14618 | United States |
| Research Site | The Bronx | New York | 10461 | United States |
| Research Site | Durham | North Carolina | 27705 | United States |
| Research Site | Monroeville | Pennsylvania | 15146 | United States |
| Research Site | Philadelphia | Pennsylvania | 19140 | United States |
| Research Site | Anderson | South Carolina | 29621 | United States |
| Research Site | Spartanburg | South Carolina | 29303 | United States |
| Research Site | Boerne | Texas | 78006 | United States |
| Research Site | Dallas | Texas | 75246 | United States |
| Research Site | San Antonio | Texas | 78212 | United States |
| Research Site | Tyler | Texas | 75708 | United States |
| Research Site | Richmond | Virginia | 23225 | United States |
| Research Site | Brussels (Anderlecht) | 1070 | Belgium |
| Research Site | Ghent | 9000 | Belgium |
| Research Site | Hasselt | 3500 | Belgium |
| Research Site | Leuven | 3000 | Belgium |
| Research Site | Woluwé-St-Lambert | 1200 | Belgium |
| Research Site | Grenoble | 38043 | France |
| Research Site | Lille | 59037 | France |
| Research Site | Lyon | 69317 | France |
| Research Site | Nantes | 44093 | France |
| Research Site | Pessac | 33604 | France |
| Research Site | Berlin | 10717 | Germany |
| Research Site | Berlin | 10969 | Germany |
| Research Site | Frankfurt | 60596 | Germany |
| Research Site | Hamburg | 22299 | Germany |
| Research Site | Hanover | 30625 | Germany |
| Research Site | Mainz | 55131 | Germany |
| Research Site | München | 80331 | Germany |
| Research Site | München-Pasing | 81241 | Germany |
| Research Site | Amsterdam | 1105 AZ | Netherlands |
| Research Site | Groningen | 9728 NT | Netherlands |
| Research Site | Leeuwarden | 8934 AD | Netherlands |
| Research Site | Bystra | 43-360 | Poland |
| Research Site | Krakow | 31-011 | Poland |
| Research Site | Krakow | 31-209 | Poland |
| Research Site | Lodz | 90-141 | Poland |
| Research Site | Lubin | 59-300 | Poland |
| Research Site | Ostrowiec Świętokrzyski | 27-400 | Poland |
| Research Site | Rzeszów | 35-051 | Poland |
| Research Site | Wroclaw | 50-220 | Poland |
| Research Site | Wroclaw | 53-301 | Poland |
| Research Site | Dnipro | 49007 | Ukraine |
| Research Site | Kharkiv | 61002 | Ukraine |
| Research Site | Kharkiv | 61035 | Ukraine |
| Research Site | Kyiv | 03680 | Ukraine |
| Research Site | Kyiv | 04201 | Ukraine |
| Research Site | Vinnytsia | 21001 | Ukraine |
| Related Info | View source |
| COMPLETED | Patients who completed treatment and patients who discontinued treatment but completed the study. |
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| NOT COMPLETED |
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All patients in the full analysis set (FAS) who received any study treatment (tralokinumab or placebo) were included in the baseline analysis.
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| ID | Title | Description |
|---|---|---|
| BG000 | Tralokinumab | Tralokinumab 300 mg administered by SC injection Q2W over a 40-week treatment period. |
| BG001 | Placebo | Placebo was administered by SC injection over a 40-week treatment period. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percent Change From Baseline in the Final Daily, Average, OCS Dose at Week 40 While Not Losing Asthma Control. | The 40-week treatment period consisted of 3 phases: an induction phase (Week 0 to Week 12) where patients remained on their optimised OCS dose; an OCS reduction phase (Week 12 to Week 32) where OCS dose reduction could have started at Week 12 with the possibility of dose titration every 4 weeks to reach the lowest possible OCS dose; and a maintenance phase (Week 32 to Week 40) where patients remained on the OCS dose reached at Week 32 to demonstrate asthma control was maintained after achieving the lowest OCS dose. Criteria used to assess asthma control included lung function assessments (forced expiratory volume in 1 second and morning peak expiratory flow), night awakenings, and the use of rescue medication and systemic corticosteroids. The least squares (LS) mean percent change from baseline in average daily OCS dose is presented. The final daily percent change from baseline was defined as {(Final daily average dose - baseline daily average dose)/baseline daily average dose}*100%. | The FAS included all randomised patients who received at least one dose of study treatment, irrespective of their protocol adherence and continued participation in the study. | Posted | Least Squares Mean | Standard Error | Percent change from baseline | Baseline (Week 0) and Week 40 |
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| Secondary | The Number of Patients With Final Daily Average OCS Dose ≤5 mg at Week 40. | The 40-week treatment period consisted of 3 phases: an induction phase (Week 0 to Week 12) where patients remained on their optimised OCS dose; an OCS reduction phase (Week 12 to Week 32) where OCS dose reduction could have started at Week 12 with the possibility of dose titration every 4 weeks to reach the lowest possible OCS dose; and a maintenance phase (Week 32 to Week 40) where patients remained on the OCS dose reached at Week 32 to demonstrate asthma control was maintained after achieving the lowest OCS dose. The number of patients with a final daily average OCS dose ≤5.0 mg is presented. For patients prescribed a fixed daily dose, then the average OCS dose was defined as the prescribed dose. For patients on a regimen where a different amount of OCS was to be taken each day, then the average OCS dose was defined as the average amount prescribed to be taken each day. | The FAS included all randomised patients who received at least one dose of study treatment, irrespective of their protocol adherence and continued participation in the study. | Posted | Count of Participants | Participants | At Week 40 |
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| Secondary | The Number of Patients With ≥50% Reduction in Final Average Daily OCS Dose at Week 40. | The 40-week treatment period consisted of 3 phases: an induction phase (Week 0 to Week 12) where patients remained on their optimised OCS dose; an OCS reduction phase (Week 12 to Week 32) where OCS dose reduction could have started at Week 12 with the possibility of dose titration every 4 weeks to reach the lowest possible OCS dose; and a maintenance phase (Week 32 to Week 40) where patients remained on the OCS dose reached at Week 32 to demonstrate asthma control was maintained after achieving the lowest OCS dose. The number of patients with ≥50% reduction in average daily OCS dose is presented. The final daily percent change from baseline was defined as {(Final daily average dose - baseline daily average dose)/baseline daily average dose}*100%. If this resulted in a value of -50% or less (more negative), that patient was classified as having at least a 50% reduction in final daily average OCS dose. | The FAS included all randomised patients who received at least one dose of study treatment, irrespective of their protocol adherence and continued participation in the study. | Posted | Count of Participants | Participants | At Week 40 |
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| Secondary | Annual Asthma Exacerbation Rate (AAER) up to Week 40. | AAER up to Week 40 in the tralokinumab group was compared to that seen in the placebo group. The response variable was the number of exacerbations the patient experienced up to Week 40, with the logarithm of the time at risk in years of experiencing an exacerbation included as offset in the model. AAER = number of exacerbations*365.25/(follow-up date - date of randomisation + 1). Asthma exacerbation was defined as a worsening of asthma that led to any of the following:
| The FAS included all randomised patients who received at least one dose of study treatment, irrespective of their protocol adherence and continued participation in the study. | Posted | Number | 95% Confidence Interval | Adjusted rate (events/year) | Baseline (Week 0) up to Week 40 |
|
40 weeks.
Data is reported for adverse events with an onset date ≥ the first day of study treatment and ≤ (the last day of study treatment + 2 weeks). Patient population was the safety analysis set which included all patients who received at least one dose of study treatment.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tralo 300 mg Q2W | Tralokinumab 300 mg administered by SC injection Q2W over a 40-week treatment period. | 0 | 70 | 9 | 70 | 55 | 70 |
| EG001 | Placebo | Placebo was administered by SC injection over a 40-week treatment period. | 0 | 70 | 16 | 70 | 44 | 70 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Colitis | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
| |
| Hand fracture | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
| |
| Rib fracture | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
| |
| Pulmonary function test abnormal | Investigations | MedDRA 20.0 | Systematic Assessment |
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| Weight decreased | Investigations | MedDRA 20.0 | Systematic Assessment |
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| Rotator cuff syndrome | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
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| Tendonitis | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
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| Breast cancer female | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 20.0 | Systematic Assessment |
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| Uterine leiomyoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 20.0 | Systematic Assessment |
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| Acute kidney injury | Renal and urinary disorders | MedDRA 20.0 | Systematic Assessment |
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| Vaginal prolapse | Reproductive system and breast disorders | MedDRA 20.0 | Systematic Assessment |
| |
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | General disorders | MedDRA 20.0 | Systematic Assessment |
| |
| Injection site erythema | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Injection site pain | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Injection site pruritus | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
| |
| Oral candidiasis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
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| Sinusitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
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| Viral upper respiratory tract infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
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| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
| |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA 20.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Global Clinical Lead | AstraZeneca | +1 301-398-0582 | ClinicalTrialTransparency@astrazeneca.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 7, 2017 | Mar 1, 2018 | SAP_001.pdf |
| ID | Term |
|---|---|
| D001249 | Asthma |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| ID | Term |
|---|---|
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
| D012130 | Respiratory Hypersensitivity |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| C574065 | tralokinumab |
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| >=65 years |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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The null hypothesis was that the average percentage change in OCS dose on tralokinumab was equal to the average percentage change in OCS dose on placebo.
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Placebo was administered by SC injection over a 40-week treatment period.
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