A Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Adults and Adolescents With Uncontrolled Asthma

Uncontrolled Asthma Clinical Trial

— STRATOS1  

Official title:

A Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Adults and Adolescents With Asthma Inadequately Controlled on Inhaled Corticosteroid Plus Long-Acting β2-Agonist.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02161757
• Other study ID #: D2210C00007
• Status: Completed
• Phase: Phase 3
• Start date: June 13, 2014
• Est. completion date: July 18, 2017

Study information

• Verified date: July 2018
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A 52-Week, Multicentre, Randomized, Double-Blind, Parallel Group, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Adults and Adolescents with Asthma Inadequately Controlled on Inhaled Corticosteroid Plus Long-Acting β2-Agonist

Description:

This is a randomized, double-blind, parallel group, placebo-controlled study designed to evaluate efficacy and safety of tralokinumab administered subcutaneously in subjects with uncontrolled asthma on inhaled corticosteroid plus long-acting β2-agonist and having a history of asthma exacerbations.

Approximately 1140 subjects will be randomized globally. Subjects will receive tralokinumab, or placebo, administered via subcutaneous injection at the study site, over a 52-week treatment period.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1207
• Est. completion date: July 18, 2017
• Est. primary completion date: February 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 75 Years

Eligibility

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 equivalents) and a LABA

4. Morning pre-BD FEV1 value of =40 and <80% value (<90% for patients 12 to 17 years of age) of their PNV.

5. Post-BD reversibility of =12% and =200 mL in FEV1

6. ACQ-6 score =1.5

Exclusion Criteria:

1. 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

Related Conditions & MeSH terms

• Asthma
• Uncontrolled Asthma

Intervention

Biological:
• Tralokinumab
Subcutaneous injection

Other:
• Placebo
Subcutaneous injection

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Caba
Argentina	Research Site	Cap. Fed
Argentina	Research Site	Ciudad Autonomade Buenos Aires
Argentina	Research Site	Concepción del Uruguay
Argentina	Research Site	Córdoba
Argentina	Research Site	Mendoza
Argentina	Research Site	Mendoza
Argentina	Research Site	Quilmes
Argentina	Research Site	Rosario
Argentina	Research Site	San Miguel de Tucuman
Belgium	Research Site	Brussels (Anderlecht)
Belgium	Research Site	Erpent
Belgium	Research Site	Leuven
Belgium	Research Site	Liège
Bulgaria	Research Site	Dupnitsa
Bulgaria	Research Site	Kozloduy
Bulgaria	Research Site	Pazardzhik
Bulgaria	Research Site	Pernik
Bulgaria	Research Site	Ruse
Bulgaria	Research Site	Sliven
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Stara Zagora
Bulgaria	Research Site	Varna
Bulgaria	Research Site	Veliko Tarnovo
Bulgaria	Research Site	Vratsa
Bulgaria	Research Site	Yambol
Colombia	Research Site	Armenia
Colombia	Research Site	Bogotá
Colombia	Research Site	Bogotá
Colombia	Research Site	Cali
Germany	Research Site	Aschaffenburg
Germany	Research Site	Augsburg
Germany	Research Site	Bad Lippspringe
Germany	Research Site	Geesthacht
Germany	Research Site	Herford
Germany	Research Site	Landsberg
Germany	Research Site	Leipzig
Germany	Research Site	München-Pasing
Germany	Research Site	Reinfeld
Germany	Research Site	Rodgau-Dudenhofen
Germany	Research Site	Warendorf
Hungary	Research Site	Balassagyarmat
Hungary	Research Site	Edelény
Hungary	Research Site	Farkasgyepü
Hungary	Research Site	Komárom
Hungary	Research Site	Létavértes
Hungary	Research Site	Miskolc
Hungary	Research Site	Pécs
Hungary	Research Site	Pécs
Hungary	Research Site	Százhalombatta
Korea, Republic of	Research Site	Bucheon-si
Korea, Republic of	Research Site	Cheongju-si
Korea, Republic of	Research Site	Daegu
Korea, Republic of	Research Site	Incheon
Korea, Republic of	Research Site	Incheon
Korea, Republic of	Research Site	Jeju-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Suwon-si
Peru	Research Site	Cusco
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Poland	Research Site	Bedzin
Poland	Research Site	Bydgoszcz
Poland	Research Site	Chorzów
Poland	Research Site	Gdansk
Poland	Research Site	Gdansk
Poland	Research Site	Grudziadz
Poland	Research Site	Kielce
Poland	Research Site	Kraków
Poland	Research Site	Lódz
Poland	Research Site	Lubin
Poland	Research Site	Lublin
Poland	Research Site	Lublin
Poland	Research Site	Mrozy
Poland	Research Site	Olsztyn
Poland	Research Site	Ostrów Wielkopolski
Poland	Research Site	Ostrowiec Swietokrzyski
Poland	Research Site	Oswiecim
Poland	Research Site	Pulawy
Poland	Research Site	Racibórz
Poland	Research Site	Skierniewice
Poland	Research Site	Staszów
Poland	Research Site	Warszawa
Poland	Research Site	Wielun
Poland	Research Site	Wolomin
Poland	Research Site	Wroclaw
Poland	Research Site	Wroclaw
Poland	Research Site	Zamosc
Poland	Research Site	Zgierz
Slovakia	Research Site	Humenne
Slovakia	Research Site	Kezmarok
Slovakia	Research Site	Presov
Slovakia	Research Site	Sabinov
Slovakia	Research Site	Topolcany
Spain	Research Site	Alicante
Spain	Research Site	Badalona
Spain	Research Site	Hospitalet de Llobregat(Barcel
Spain	Research Site	Santander
Spain	Research Site	Valencia
Taiwan	Research Site	Changhua
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	New-Taipei
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Yilan
Ukraine	Research Site	Chernivtsi
Ukraine	Research Site	Chernivtsi
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Lutsk
Ukraine	Research Site	Lviv
Ukraine	Research Site	Odesa
Ukraine	Research Site	Vinnytsia
Ukraine	Research Site	Zaporizhzhya
Ukraine	Research Site	Zaporizhzhya
United States	Research Site	Albany	Georgia
United States	Research Site	Anderson	South Carolina
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Arcadia	California
United States	Research Site	Arlington	Virginia
United States	Research Site	Asheville	North Carolina
United States	Research Site	Atlanta	Georgia
United States	Research Site	Bangor	Maine
United States	Research Site	Birmingham	Alabama
United States	Research Site	Boerne	Texas
United States	Research Site	Bowling Green	Kentucky
United States	Research Site	Brockton	Massachusetts
United States	Research Site	Brooklyn	New York
United States	Research Site	Charlotte	North Carolina
United States	Research Site	Chesterfield	Missouri
United States	Research Site	Clearwater	Florida
United States	Research Site	Colorado Springs	Colorado
United States	Research Site	Columbus	Ohio
United States	Research Site	Coral Gables	Florida
United States	Research Site	Cornelius	North Carolina
United States	Research Site	Corsicana	Texas
United States	Research Site	Cutler Bay	Florida
United States	Research Site	Dallas	Texas
United States	Research Site	Denver	Colorado
United States	Research Site	Denver	Colorado
United States	Research Site	Farmington Hills	Michigan
United States	Research Site	Flint	Michigan
United States	Research Site	Fort Lauderdale	Florida
United States	Research Site	Fort Wayne	Indiana
United States	Research Site	Fort Worth	Texas
United States	Research Site	Fort Worth	Texas
United States	Research Site	Greenville	South Carolina
United States	Research Site	Hialeah	Florida
United States	Research Site	Hialeah	Florida
United States	Research Site	Hickory	North Carolina
United States	Research Site	Homestead	Florida
United States	Research Site	Homestead	Florida
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Jacksonville	Florida
United States	Research Site	Johnston	Rhode Island
United States	Research Site	Kissimmee	Florida
United States	Research Site	Lampasas	Texas
United States	Research Site	Las Vegas	Nevada
United States	Research Site	Lawrenceville	Georgia
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	McKinney	Texas
United States	Research Site	Meridian	Idaho
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Middleburg Heights	Ohio
United States	Research Site	Missoula	Montana
United States	Research Site	Monroeville	Pennsylvania
United States	Research Site	Murray	Utah
United States	Research Site	Myrtle Beach	South Carolina
United States	Research Site	New Haven	Connecticut
United States	Research Site	Newport Beach	California
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Ormond Beach	Florida
United States	Research Site	Pembroke Pines	Florida
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Phoenix	Arizona
United States	Research Site	Plano	Texas
United States	Research Site	Poway	California
United States	Research Site	Providence	Rhode Island
United States	Research Site	Provo	Utah
United States	Research Site	Richland	Washington
United States	Research Site	Richmond	Virginia
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Salt Lake City	Utah
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	San Jose	California
United States	Research Site	Scottdale	Pennsylvania
United States	Research Site	Shelby	North Carolina
United States	Research Site	South Bend	Indiana
United States	Research Site	South Burlington	Vermont
United States	Research Site	Spartanburg	South Carolina
United States	Research Site	Tacoma	Washington
United States	Research Site	Toledo	Ohio
United States	Research Site	Tustin	California
United States	Research Site	Twin Falls	Idaho
United States	Research Site	Union	New Jersey
United States	Research Site	Uniontown	Pennsylvania
United States	Research Site	Warwick	Rhode Island
United States	Research Site	Wildomar	California
United States	Research Site	Winston-Salem	North Carolina
United States	Research Site	Winter Park	Florida
United States	Research Site	Ypsilanti	Michigan
Vietnam	Research Site	Can Tho
Vietnam	Research Site	Ha Noi
Vietnam	Research Site	Hanoi
Vietnam	Research Site	Ho Chi Minh
Vietnam	Research Site	Hochiminh

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Vietnam,  Argentina,  Belgium,  Bulgaria,  Colombia,  Germany,  Hungary,  Korea, Republic of,  Peru,  Poland,  Slovakia,  Spain,  Taiwan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Annualised Asthma Exacerbation Rate (AAER) up to Week 52	Asthma exacerbation was defined as a worsening of asthma that led to any of the following: Use of systemic corticosteroids for at least 3 days; a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids.; An emergency room (ER) or urgent care (UC) visit (defined as evaluation and treatment for <24 hours in an ER or UC centre) due to asthma that required systemic corticosteroids (see above).; An inpatient hospitalisation (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for =24 hours) due to asthma.; AAER = number of exacerbations*365.25 / (follow-up date - date of randomisation + 1) (where maximum follow-up time for a patient was approximately 52 weeks).; AAER in the tralokinumab group was compared to that seen in the placebo group up to Week 52 using a negative binomial model; rate ratios and rate reductions are both presented for comparative statistical analyses.	Baseline (Week 0) up to Week 52
Secondary	Percent Change From Baseline to Week 52 in Pre-dose/Pre-bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1)	Lung function was assessed by FEV1 which was measured by spirometry. Spirometry was performed by the Investigator or authorised delegate according to American Thoracic Society/European Respiratory Society guidelines. The mean percent change from baseline in pre-BD FEV1 at Week 52 is presented.	Baseline (Week 0) and Week 52
Secondary	Change From Baseline to Week 52 in Total Asthma Symptom Score (Bi-weekly Means)	Asthma symptoms during night-time and daytime were recorded by the patient each morning and evening in the Asthma Daily Diary. Symptoms were recorded using a 4-point response scale, which ranged from 0 to 3, where 0 indicated no asthma symptoms. Asthma symptom daytime score (recorded in the evening), night-time score (recorded in the morning), and total score were calculated separately. The daily asthma symptom total score was calculated by taking the sum of the night-time and daytime asthma symptom scores recorded each day, ranging from 0 to 6. A lower symptom score indicated a better outcome. The change from baseline in bi-weekly mean daily asthma symptom total score is presented.	Baseline (Week 0) and Week 52
Secondary	Change From Baseline to Week 52 in Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) Total Score	The AQLQ(S)+12 is a questionnaire that measures health-related quality of life for patients with asthma aged 12 and older. The questionnaire comprises 32 questions and has 4 separate domains (asthma symptoms, activity limitations, emotional function and environmental stimuli). Patients were asked to recall their experiences during the previous 2 weeks and to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The total score was calculated as the mean response to all questions, ranging from 1 (severe impairment) to 7 (no impairment). Individual AQLQ(S)+12 total score changes of =0.5 were considered to be clinically meaningful. The mean change from baseline in AQLQ(S)+12 score at Week 52 is presented.	Baseline (Week 0) and Week 52
Secondary	Change From Baseline to Week 52 in Asthma Control Questionnaire-6 (ACQ-6) Score	The ACQ-6 questionnaire is a shortened version of the ACQ (omitting FEV1 measurement) that assesses asthma symptoms (night-time awakenings, symptoms on waking, activity limitation, dyspnoea, wheezing) and rescue short-acting ß2-agonists medication use during the past week. Questions were weighted equally and scored on a 7-point scale from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score was the mean of the responses, ranging from 0 (totally controlled) to 6 (severely uncontrolled). Mean scores of =0.75 indicate well-controlled asthma, scores between 0.75 and =1.5 indicate partly controlled asthma and a score >1.5 indicates not well-controlled asthma. Individual changes of at least 0.5 were considered to be clinically meaningful. The mean change from baseline in ACQ-6 score at Week 52 is presented.	Baseline (Week 0) and Week 52
Secondary	AAER Associated With an ER/UC Visit, or a Hospitalisation up to Week 52	The annual rate of exacerbations associated with an ER/UC visit or hospitalisation up to Week 52 are presented for non-adjudicated data (i.e. events assessed by the Investigator and recorded in the electronic case report form).; AAER = Number of Exacerbations*365.25 / (Follow-up date - Date of randomisation + 1) (where maximum follow-up time for a patient was approximately 52 weeks).	Baseline (Week 0) up to Week 52
Secondary	Change From Baseline in European Quality of Life - 5 Dimension 5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) Scores at Week 52	The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The patient was asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also included a VAS, where the patient was asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state. The mean change from baseline in EQ-5D-5L VAS scores at Week 52 is presented.	Baseline (Week 0) and Week 52
Secondary	Change From Baseline in Total Asthma Rescue Medication Use at Week 52 (Bi-weekly Means)	Salbutamol, albuterol or levalbuterol were used as rescue medication during the study in the event of a worsening of asthma symptoms. Rescue medication use was measured by the bi-weekly mean number of inhalations (puffs) per day, calculated as: total morning puffs + total evening puffs + 2*(total morning nebuliser use + total evening nebuliser use)/ total number of days with data in bi-weekly period. The change from baseline in bi-weekly mean total asthma rescue medication use at Week 52 is presented.	Baseline (Week 0) and Week 52
Secondary	Change From Baseline in Home Peak Expiratory Flow (PEF) (Morning and Evening) at Week 52	Home PEF testing was performed by the patient using an electronic, hand-held spirometer (peak flow meter) and was performed in the morning upon awakening (prior to taking their morning asthma controller) and in the evening at bedtime (prior to taking their evening asthma controller). The mean change from baseline in home PEF values at Week 52 are presented separately for morning and evening.	Baseline (Week 0) and Week 52
Secondary	Change From Baseline in Night-time Awakenings Due to Asthma Requiring Rescue Medication Use at Week 52 (Bi-weekly Means [Percentage])	The patient captured night-time awakenings (yes/no) and the use of rescue medication during these awakenings (yes/no) each morning in the Asthma Daily Diary. Night-time awakenings (percentage) was defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data. The change from baseline in bi-weekly means (percentage) night-time awakenings due to asthma requiring rescue medication use at Week 52 is presented.	Baseline (Week 0) and Week 52
Secondary	Number of Patients With =1 Asthma Exacerbation up to Week 52	The number of patients with =1 asthma exacerbation up to Week 52 is presented.	Baseline (Week 0) up to Week 52
Secondary	Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questions (WPAI+CIQ): Productivity Loss at Week 52	The WPAI+CIQ consists of questions about how asthma and asthma-related issues impact a patient's ability to work, attend classes and perform regular daily activities. The questionnaire contains 10 questions relating to the patient's experience over the previous 7 days. The WPAI+CIQ outcomes for productivity loss are presented separately for those currently employed and for those currently in school and are expressed as mean productivity loss (percentage) at Week 52, with higher numbers indicating less productivity.; Work Productivity Loss = {Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]}*100 (Absenteeism = Q2/(Q2+Q4)*100; Presenteeism = (Q5/10)*100).; Class Productivity Loss = {Q7/(Q7+Q8) + [(1-Q7/(Q7+Q8))x(Q9/10)]}*100 (Absenteeism = Q7/ (Q7+Q8)*100; Presenteeism = (Q9/10)*100).; Note: QX refers to response to question number X on WPAI+CIQ questionnaire.	At Week 52
Secondary	WPAI+CIQ: Activity Impairment at Week 52	The WPAI+CIQ consists of questions about how asthma and asthma-related issues impact a patient's ability to work, attend classes and perform regular daily activities. The questionnaire contains 10 questions relating to the patient's experience over the previous 7 days.; The WPAI+CIQ outcomes for activity impairment are presented separately for those currently employed and for those currently in school and are expressed as mean impairment percentages at Week 52, with higher numbers indicating greater impairment.; Activity impairment = (Q10/10)*100. Note: QX refers to response to question number X on WPAI+CIQ questionnaire.	At Week 52
Secondary	Asthma-related Healthcare Encounters by Type up to Week 52	Broad-based healthcare utilisation asthma-related event information was collected by the Investigator/authorised delegate at each visit. At Visit 1, healthcare resource utilisation information was collected with a 1-year recall period; subsequent visits collected information with a recall period of 'since the last scheduled visit'. Total number of times the healthcare encounter occurred was calculated across all patients for each of the following categories: Ambulance transport,; Emergency room visits,; Unscheduled outpatient visits (visit to specialist and/or visit to primary healthcare physician and/or other healthcare visit),; Home visits (home visit, physician and/or other healthcare professional),; Telephone calls (telephone calls to physician and/or nurse), and; Advanced pulmonary function test.	Baseline (Week 0) up to Week 52
Secondary	Asthma-related Healthcare Encounters by Type up to Week 52: Hospitalisations	Broad-based healthcare utilisation asthma-related event information was collected by the Investigator/authorised delegate at each visit. At Visit 1, healthcare resource utilisation information was collected with a 1-year recall period; subsequent visits collected information with a recall period of 'since the last scheduled visit'. Total number of days spent in hospital was calculated across all patients for the following healthcare encounter category: • Hospitalisations (hospitalisations, intensive care and/or general care).	Baseline (Week 0) up to Week 52
Secondary	Asthma-related Healthcare Encounters by Type up to Week 52: Spirometry	Broad-based healthcare utilisation asthma-related event information was collected by the Investigator/authorised delegate at each visit. At Visit 1, healthcare resource utilisation information was collected with a 1-year recall period; subsequent visits collected information with a recall period of 'since the last scheduled visit'. Total number of assessments was calculated across all patients for the following healthcare encounter category: • Spirometry.	Baseline (Week 0) up to Week 52
Secondary	Serum Trough Concentration (Ctrough) of Tralokinumab During the Study Period up to Week 72	To evaluate the pharmacokinetics (PK), pre-dose blood samples were collected at each visit and tralokinumab concentrations in serum were determined. Mean Ctrough concentrations are presented at each indicated visit up to Week 72.	Blood samples were collected pre-dose at Baseline (Week 0), and at Week 4, Week 8, Week 26, Week 52 and Week 72 (follow-up)
Secondary	Number of Patients Positive for Anti-drug Antibodies (ADAs)	ADA assessments performed using a tiered approach (screening, confirmatory and titering assays). Confirmed ADA positive samples were also tested for neutralising antibodies (nAb). ADA prevalence defined as proportion of study population with drug-reactive antibodies at any point in time. ADA incidence (treatment-emergent ADA) defined as sum of treatment-induced (post-baseline ADA positive only) and treatment-boosted ADA. Persistently positive defined as positive at =2 post-baseline assessments (with =16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive defined as having =1 post-baseline ADA positive assessment and not fulfilling conditions of persistently positive. Treatment-boosted ADA defined as baseline positive ADA titer boosted to a 4-fold or higher level following drug administration. In some category titles 'positive' is denoted by 'pos'.	Baseline (Week 0), Week 26, Week 56 (follow-up) and Week 72 (follow-up)