Study to Evaluate the Efficacy and Safety of GSK3196165 Plus Methotrexate in Subjects With Active Moderate-Severe Rheumatoid Arthritis

Arthritis, Rheumatoid Clinical Trial

Official title:

A Phase IIb, Double-Blind, Placebo-Controlled, Dose-Adaptive, Study of the Efficacy and Safety of GSK3196165 in Combination With Methotrexate Therapy, in Subjects With Active Moderate-Severe Rheumatoid Arthritis Despite Treatment With Methotrexate

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02504671
• Other study ID #: 201755
• Secondary ID: 2014-003453-34
• Status: Completed
• Phase: Phase 2
• Start date: July 23, 2015
• Est. completion date: December 29, 2017

Study information

• Verified date: December 2020
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomised, Phase IIb, dose-adaptive, multicentre, double-blind, parallel group, placebo-controlled study with the primary objective to assess the efficacy of GSK3196165, in combination with methotrexate (MTX), in subjects with active moderate severe rheumatoid arthritis (RA) despite treatment with MTX. Approximately 210 subjects will be randomised into the study, following a screening period of up to four weeks. The total treatment period is up to 52 weeks, with a 12-week follow-up period after the last dose (Week 50). Subjects will be randomised (1:1:1:1:1:1) to placebo or one of five subcutaneous (SC) GSK3196165 doses, in combination with MTX (at a weekly dose between 15-25 milligram [mg]), previously received for at least 12 weeks, with a stable and tolerated dose and route of administration for >=4 weeks. Escape therapy is provided at specified timepoints in the protocol for subjects that do not achieve adequate disease improvement.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 222
• Est. completion date: December 29, 2017
• Est. primary completion date: December 22, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age >=18 years at the time of signing informed consent.

• Meets ACR/EULAR 2010 RA Classification Criteria, with disease duration of >=12 weeks.

• Swollen joint count of >=4 (66-joint count) and tender joint count of >=4 (68-joint count).

• DAS28(CRP) >=3.2.

• CRP >=5.0 milligram per litre (mg/L) at screening.

• Must have previously received MTX (15-25 mg weekly) for at least 12 weeks before screening, with no change in route of administration, with a stable and tolerated dose for >=4 weeks prior to Day 1. A stable dose of MTX >=7.5 mg/week is acceptable, if the MTX dose has been reduced for reasons of documented intolerance to MTX, e.g. hepatic or hematologic toxicity, or per local requirement.

• Weight >=45 kilogram (kg).

• Male or female subjects are eligible to participate so long as they meet and agree to abide by the contraceptive criteria.

• Diffusing capacity of the lung for carbon monoxide (DLCO) >=60% predicted; forced expiratory volume in 1 second (FEV1) >=70% predicted

• No evidence of active or latent infection with Mycobacterium tuberculosis (TB).

Exclusion Criteria:

• Pregnant or lactating women.

• History of other inflammatory rheumatological or autoimmune disorders, other than Sjögren's syndrome secondary to RA.

• History of any respiratory disease which (in the opinion of the investigator) would compromise subject safety or the ability of the subject to complete the study (e.g. significant interstitial lung disease, such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), moderate-severe asthma, bronchiectasis, previous pulmonary alveolar proteinosis [PAP]).

• Clinically-significant or unstable (in the opinion of the investigator) persistent cough or dyspnea that is unexplained.

• Significant unstable or uncontrolled acute or chronic disease which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk.

• A history of malignancy.

• Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.

• Current/previous Hepatitis B virus (HBV), Hepatitis C virus (HCV) or human immunodeficiency virus (HIV) 1 or 2 infection.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid

Intervention

Drug:
• GSK3196165
GSK3196165 is supplied as liquid and will be administered as SC injection.
• MTX
MTX will be supplied as capsule, tablet or liquid and will be administered orally or as SC injection.
• Folic acid
Folic acid will be supplied as capsule, tablet or liquid and will be administered orally.
• Placebo
Placebo is supplied as liquid as sterile 0.9% weight by volume (w/v) sodium chloride solution and will be administered as SC injection

Locations

Country	Name	City	State
Bulgaria	GSK Investigational Site	Plovdiv
Bulgaria	GSK Investigational Site	Plovdiv
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Canada	GSK Investigational Site	Barrie
Canada	GSK Investigational Site	Brampton	Ontario
Czechia	GSK Investigational Site	Brno
Czechia	GSK Investigational Site	Bruntal
Czechia	GSK Investigational Site	Praha
Czechia	GSK Investigational Site	Praha 5
Czechia	GSK Investigational Site	Uherske Hradiste
Estonia	GSK Investigational Site	Tallinn
Estonia	GSK Investigational Site	Tallinn
Germany	GSK Investigational Site	Bad Doberan
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Kistarcsa
Hungary	GSK Investigational Site	Veszprém
Italy	GSK Investigational Site	Bologna
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Napoli
Mexico	GSK Investigational Site	Cuernavaca	Morelos
Mexico	GSK Investigational Site	Cuernavaca	Morelos
Mexico	GSK Investigational Site	Guadalajara	Jalisco
Mexico	GSK Investigational Site	Merida	Yucatán
Mexico	GSK Investigational Site	San Luis Potosí
Poland	GSK Investigational Site	Bialystok
Poland	GSK Investigational Site	Bydgoszcz
Poland	GSK Investigational Site	Bytom
Poland	GSK Investigational Site	Grodzisk Mazowiecki
Poland	GSK Investigational Site	Lodz
Poland	GSK Investigational Site	Lublin
Poland	GSK Investigational Site	Torun
Poland	GSK Investigational Site	Warszawa
Poland	GSK Investigational Site	Warszawa
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Novosibirsk
Russian Federation	GSK Investigational Site	Omsk
Russian Federation	GSK Investigational Site	Ryazan
Russian Federation	GSK Investigational Site	Saint Petersburg
Russian Federation	GSK Investigational Site	Tver
Russian Federation	GSK Investigational Site	Vladimir
Russian Federation	GSK Investigational Site	Yaroslavl
Russian Federation	GSK Investigational Site	Yaroslavl
South Africa	GSK Investigational Site	Panorama / Cape Town
South Africa	GSK Investigational Site	Pretoria	Gauteng
South Africa	GSK Investigational Site	Stellenbosch
Spain	GSK Investigational Site	Coruña
Spain	GSK Investigational Site	Madrid
Ukraine	GSK Investigational Site	Ivano-Frankivsk
Ukraine	GSK Investigational Site	Kharkiv
Ukraine	GSK Investigational Site	Kharkiv
Ukraine	GSK Investigational Site	Kryvyi Rih
Ukraine	GSK Investigational Site	Lviv
Ukraine	GSK Investigational Site	Odesa
Ukraine	GSK Investigational Site	Poltava
Ukraine	GSK Investigational Site	Sumy
Ukraine	GSK Investigational Site	Vinnytsia
Ukraine	GSK Investigational Site	Vinnytsya
Ukraine	GSK Investigational Site	Zhytomyr
United Kingdom	GSK Investigational Site	Birmingham
United Kingdom	GSK Investigational Site	Leeds

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Bulgaria,  Canada,  Czechia,  Estonia,  Germany,  Hungary,  Italy,  Mexico,  Poland,  Russian Federation,  South Africa,  Spain,  Ukraine,  United Kingdom, 

References & Publications (1)

C Buckley, J Simon Campos, V Zhdan, K Davy, D Inman, E Fisheleva, A Gupta, M Layton, N Mitchell, J Patel, R Williamson, D Saurigny, P-P Tak, C Hawkes, B Becker. A Phase IIb Dose-Ranging Randomised Study of Efficacy, Patient-Reported Outcomes and Safety of the Anti-Granulocyte Macrophage Colony-Stimulating Factor Antibody Otilimab (GSK3196165) in Patients with Rheumatoid Arthritis. Lancet Rheumatol. 2020; DOI: 10.1016/S2665-9913(20)30229-0

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Who Achieved Disease Activity Score for 28 Different Joints With C-reactive Protein Value (DAS28{CRP}) Remission (DAS28 <2.6) at Week 24	DAS28 is a modification of the original DAS and is based on a count of 28 swollen and tender joints and is used to evaluate a participant's response to treatment. DAS 28 CRP utilizing joint scores from the following 28 joints: elbows, shoulders, elbow, wrists, metacarpal- phalangeal I-V, proximal interphalangeal I-V and knees and is calculated using the following formula: DAS28 (CRP) = 0.56*v(TJC28) +0.28*v(SJC28)+0.014*GH+0.36*ln(CRP+1)+0.96. Where TJC - Tender joint Count, SJC= Swollen Joint Count, (GH=participant assessment of disease activity using a 100 millimeter [mm] visual analogue scale with 0 = best, 100 = worst) and CRP= C reactive Protein (in [milligrams/liter] mg/L). It ranges between 0.96 and 8.61. High score (worse outcome) and low scores (better outcome). ITT population comprised of all participants who were randomized to treatment and who received at least one dose of study treatment (GSK3196165 or placebo).	Week 24
Secondary	Change From Baseline in DAS28(CRP) at Week 12	DAS28 is a modification of the original DAS and is based on a count of 28 swollen and tender joints and is used to evaluate a participant's response to treatment. DAS 28 CRP utilizing joint scores from the following 28 joints: elbows, shoulders, elbow, wrists, metacarpal- phalangeal I-V, proximal interphalangeal I-V and knees and is calculated using the following formula: DAS28 (CRP) = 0.56*v(TJC28) +0.28*v(SJC28)+0.014*GH+0.36*ln(CRP+1)+0.96. Where TJC - Tender joint Count, SJC= Swollen Joint Count, (GH=participant global assessment of disease activity (PtGA) using a 100 mm visual analogue scale with 0 = best, 100 = worst) and CRP= C reactive Protein (in mg/L). It ranges between 0.96 and 8.61. High score (worse outcome) and low scores (better outcome). Baseline was defined as the last available assessment prior to the start of study treatment. Change from Baseline was calculated by subtracting the post dose visit value from the Baseline value.	Baseline and Week 12
Secondary	Percentage of Participants Who Achieved DAS28(CRP) Remission (DAS28 <2.6) at All Time Points	DAS28(CRP) remission is defined as a DAS28 score of <2.6 points. The DAS index combines information relating to the number of swollen and tender joints. The DAS28 is a modification of the original DAS and is based on a count of 28 swollen and tender joints and is used to evaluate a participant's response to treatment. DAS 28 CRP utilizing joint scores from the following 28 joints: elbows, shoulders, elbow, wrists, metacarpal- phalangeal I-V, proximal interphalangeal I-V and knees and is calculated using the following formula: DAS28 (CRP) = 0.56*v(TJC28) +0.28*v(SJC28)+0.014*GH+0.36*ln(CRP+1)+0.96. Where TJC - Tender joint Count, SJC= Swollen Joint Count, (GH=participant assessment of disease activity using a 100 mm visual analogue scale with 0 = best, 100 = worst) and CRP= C reactive Protein (in mg/L). It ranges between 0.96 and 8.61. High score (worse outcome) and low scores (better outcome).	Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up)
Secondary	Change From Baseline in DAS28(CRP) at All Assessment Time Points	DAS28 is a modification of the original DAS and is based on a count of 28 swollen and tender joints and is used to evaluate a participant's response to treatment. DAS 28 CRP utilizing joint scores from the following 28 joints: elbows, shoulders, elbow, wrists, metacarpal- phalangeal I-V, proximal interphalangeal I-V and knees and is calculated using the following formula: DAS28 (CRP) = 0.56*v(TJC28) +0.28*v(SJC28)+0.014*GH+0.36*ln(CRP+1)+0.96. Where TJC - Tender joint Count, SJC= Swollen Joint Count, (GH=participant assessment of disease activity using a 100 mm visual analogue scale with 0 = best, 100 = worst) and CRP= C reactive Protein (in mg/L). It ranges between 0.96 and 8.61. High score (worse outcome) and low scores (better outcome). Baseline was defined as the last available assessment prior to the start of study treatment. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline.	Baseline and Weeks 1, 2, 4, 6, 8, 12, 16, 20 and 24
Secondary	Time to First DAS28(CRP) Remission	The DAS index combines information relating to the number of swollen and tender joints. The DAS28 is a modification of the original DAS and is based on a count of 28 swollen and tender joints and is used to evaluate a participant's response to treatment. DAS 28 CRP utilizing joint scores from the following 28 joints: elbows, shoulders, elbow, wrists, metacarpal- phalangeal I-V, proximal interphalangeal I-V and knees and is calculated using the following formula: DAS28 (CRP) = 0.56*v(TJC28) +0.28*v(SJC28)+0.014*GH+0.36*ln(CRP+1)+0.96. Where TJC - Tender joint Count, SJC= Swollen Joint Count, (GH=participant assessment of disease activity using a 100 mm visual analogue scale with 0 = best, 100 = worst) and CRP= C reactive Protein (in mg/L). It ranges between 0.96 and 8.61. High score (worse outcome) and low scores (better outcome). Median time, to remission has been presented.	Up to Week 62
Secondary	Percentage of Participants Achieving Categorical DAS28(CRP) Response (Moderate/Good [European League Against Rheumatism] EULAR Response) at All Assessment Time Points	DAS28(CRP) scores were categorized using EULAR response criteria. Response at a given time point was defined based on the combination of current DAS28 score and the improvement in the current DAS28 score relative to Baseline. The definition of no response, moderate response and good response was as follows: Current DAS28 <=3.2 and DAS28 decrease from Baseline (>1.2=good response), (>0.6 to <=1.2 = moderate response) and (<=0.6 =no response). Current DAS28 >3.2 to <=5.1 and DAS28 decrease from Baseline value (>1.2 =moderate response), (>0.6 to <=1.2 = moderate response) and (<=0.6 =no response). Current DAS28 >5.1 and DAS28 decrease from Baseline value (>1.2=moderate response), (>0.6 to <=1.2 = no response) and (<=0.6 =no response). If the post-Baseline DAS28(CRP) score was missing, then the corresponding EULAR category was set to missing.	Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up)
Secondary	Percentage of Participants With American College of Rheumatology's (ACR) 20/50/70 Response Rates at All Assessment Time Points	The ACR definition for calculating improvement in rheumatoid arthritis is calculated as a 20% improvement (ACR20) in both tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR-core set measures: participant and physician global assessments, participant's assessment of arthritis pain, disability, and an acute-phase reactant (i.e. CRP value). Similarly, ACR50 and ACR70 were calculated with the respective percent improvement. The specific components of the ACR assessments are as follows: Tender/Painful Joint count 68 (TJC68), Swollen Joint Count 66 (SJC66), Participant's Assessment of Arthritis Pain, Participant's Global Assessment of Arthritis Disease Activity, Physician's Global Assessment of Arthritis, CRP (mg/L) and Health Assessment Questionnaire - Disability Index (HAQ-DI). For all visits, if any of the component scores were missing, then those scores were considered as not having met the criteria for improvement.	Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up)
Secondary	Percentage of Participants With Index-based ACR/EULAR Remission Rates at All Assessment Time Points	Index-based remission was achieved if the following requirement was met: SDAI <= 3.3. If the SDAI value was missing at an individual assessment point, Index-based remission for that assessment was set to missing.	Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up)
Secondary	Percentage of Participants With Boolean-based ACR/EULAR Remission Rates at All Assessment Time Points	Boolean-based remission was achieved if all of the following requirements were met at the same time: TJC68 <= 1,SJC66 <= 1,CRP <= 1mg/dL, PtGA <= 10. If one of the components was missing at an individual assessment point, Boolean-based remission for that assessment was set to missing.	Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up)
Secondary	Percentage of Participants in Clinical Disease Activity Index (CDAI) Remission	CDAI combines information relating to the number of swollen and tender joints, in addition to a measure of general health from both the participants and the physician. CDAI utilizing joint scores from the following 28 joints: elbows, shoulders, elbow, wrists, metacarpal- phalangeal I-V, proximal interphalangeal I-V and knees and is calculated using the following formula: CDAI =TJC28 + SJC28 + GH + GP Where TJC - Tender joint Count, SJC= Swollen Joint Count, (GH=participant assessment of disease activity and GP=physician assessment of disease activity using a 10 cm visual analogue scale with 0 = best, 100 = worst). It ranges between 0 and 76. High score indicates worse outcome, low score indicates better outcome. Remission was achieved for a non-missing CDAI value <=2.8.	Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up)
Secondary	Change From Baseline in SDAI at All Assessment Time Points	SDAI combines information relating to the number of swollen and tender joints, in addition to a measure of general health from both the participants and the physician and acute phase reactants. The SDAI utilizing joint scores from the following 28 joints: elbows, shoulders, elbow, wrists, metacarpal-phalangeal I-V, proximal interphalangeal I-V and knees. It is calculated using the following formula: SDAI = TJC28 + SJC28 + GH + GP + CRP Where TJC - Tender joint Count, SJC= Swollen Joint Count, (GH=participant assessment, GP= physician assessment of disease activity using a 10 centimetre [cm] visual analogue scale [VAS] with 0 = best, 10 = worst), and CRP= C reactive Protein (in mg/L). It ranges between 0.1 and 86. High score indicates worse outcome, low score indicates better outcome. Baseline was defined as the last available assessment prior to the start of study treatment. Change from Baseline was calculated by subtracting the post dose visit value from the Baseline value.	Baseline and Weeks 1, 2, 4, 6, 8, 12, 16, 20 and 24
Secondary	Change From Baseline in CDAI at All Assessment Time Points	CDAI combines information relating to the number of swollen and tender joints, in addition to a measure of general health from both the participants and the physician. CDAI utilizing joint scores from the following 28 joints: elbows, shoulders, elbow, wrists, metacarpal- phalangeal I-V, proximal interphalangeal I-V and knees and is calculated using the following formula: CDAI =TJC28 + SJC28 + GH + GP Where TJC - Tender joint Count, SJC= Swollen Joint Count, (GH=participant assessment of disease activity and GP=physician assessment of disease activity using a 10 cm visual analogue scale with 0 = best, 100 = worst). It ranges between 0 and 76. High score indicates worse outcome, low score indicates better outcome. Baseline was defined as the last available assessment prior to the start of study treatment. Change from Baseline was calculated by subtracting the post dose visit value from the Baseline value.	Baseline and Weeks 1, 2, 4, 6, 8, 12, 16, 20 and 24
Secondary	Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at All Assessment Time Points	HAQ-DI is 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in eight functional areas;dressing and grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Each functional area contains at least two questions. For each question, there is a four level response set that is scored from 0 (without any difficulty) to 3 (unable to do). If aids or devices or physical assistance are used for a specific functional area and the maximum response of this functional area is 0 or 1 the according value is increased to a score of 2. HAQ-DI is only calculated if there are at least 6 functional area scores available. The average of these non-missing functional area scores defines the continuous HAQ-DI score ranging from 0 to 3. Baseline was defined as the last available assessment prior to the start of study treatment. Change from Baseline was calculated by subtracting the post dose visit value from the Baseline value.	Baseline and Weeks 1, 2, 4, 6, 8, 12, 16, 20 and 24
Secondary	Change From Baseline in Pain Score at All Assessment Time Points	Participants assessed the severity of their current arthritis pain using a 100 unit visual analog scale (VAS) by placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which corresponds to the magnitude of their pain. Baseline was defined as the last available assessment prior to the start of study treatment. Change from Baseline was calculated by subtracting the post dose visit value from the Baseline value.	Baseline and Weeks 1, 2, 4, 6, 8, 12, 16, 20 and Week 24
Secondary	Change From Baseline in Physical and Mental Component Scores (PCS, MCS) and in Domain Scores of Short Form 36 (SF-36) at All Assessment Time Points	SF-36 is a generic health survey containing 36 questions covering 8 domains of health. SF-36 yields an 8-scale profile of functional health and well-being scores as well as PCS and MCS health summary scores. The version 2, 1-week recall questionnaire was used. Recoding, calculations and standardization were done as per the User's manual of SF-36. Domain scores were only calculated if less than half of the item scores were missing. All raw domain scores were transformed on a 0-100 scale (transformed domain scores) and then standardized into norm-based scores using Z-score. Following the transformation of the 8 domain scores into z-scores, the MCS and PCS were aggregated (AGG) using weights as PCS/MCS = 50 + (AGG_PHYS *10/AGG_MENT *10). High score (worse outcome) and low score (better outcome). Baseline was defined as the last available assessment prior to the start of study treatment. Change from Baseline was calculated by subtracting the post dose visit value from the Baseline value.	Baseline and Weeks 4, 12, 24
Secondary	Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue at All Assessment Time Points	The FACIT-fatigue questionnaire is a participant reported measure developed to assess fatigue consisting of 13 statements regarding feeling fatigue using a numeric rating scale ranging from 0 to 4. For only two of the items (i.e. Answer 5 [An5] and An7) a higher value represents a lower fatigue; 11 of the item scores (i.e. HI7, HI12, An1, An2, An3, An4, An8, An12, An14, An15, An16) have to be reversed by subtracting the captured value from 4 (0 is turned to a 4; 1 into 3; 3 into 1; 4 into 0). After performing the reversals the sum of the non-missing individual items were multiplied by 13 and divided by the number of the non-missing individual items. The final score ranges from 0 to 52 with higher values representing a lower fatigue (i.e. a better quality of life). Baseline was defined as the last available assessment prior to the start of study treatment. Change from Baseline was calculated by subtracting the post dose visit value from the Baseline value.	Baseline and Weeks 4, 12, 24
Secondary	Change From Baseline in Brief Fatigue Inventory (BFI) Question 3 at All Assessment Time Points	BFI is a self-reported instrument consisting of nine questions which correlate well with quality-of-life measures. For this study, Question 3 only was used which asked about fatigue severity at its worst in the last 24 hours. A discrete 11 unit numeric reporting scale was used where 0 =No fatigue, and 10=As bad as you can imagine. Baseline was defined as the last available assessment prior to the start of study treatment. Change from Baseline was calculated by subtracting the post dose visit value from the Baseline value.	Baseline and Weeks 4, 12, 24
Secondary	Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs)	An AE is any untoward medical occurrence in a participant or clinical investigation participants, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is associated with liver injury and impaired liver function or any other situations as per Medical or Scientific judgment. Overall AEs and SAEs for the entire study duration until follow-up have been presented.	Up to 62 weeks
Secondary	Number of Participants With Serious Infections	An AE is any untoward medical occurrence in a participant or clinical investigation participants, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Serious infections were categorized as AE of special interest. The number of participants with overall serious infections have been presented.	Up to 62 weeks
Secondary	Number of Participants With Opportunistic Infections	An AE is any untoward medical occurrence in a participant or clinical investigation participants, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Opportunistic infections were categorized as AE of special interest. The number of participants with overall opportunistic infections have been presented.	Up to 62 weeks
Secondary	Number of Participants With Pulmonary Events	Pulmonary assessments were performed to determine the number of participants with pulmonary events including persistent cough, persistent dyspnea, and persistent Diffusing capacity of the lung for carbon monoxide (DLCO). Persistent is defined as any event with duration >=15 days. Baseline was defined as the last available assessment prior to the start of study treatment. The number of participants experiencing pulmonary events have been reported.	Up to 62 weeks
Secondary	Number of Participants With Worst-case Post-Baseline Results for Pulse Oximetry	Oxygen saturation measures the capacity of blood to transport oxygen to other parts of the body. Oxygen binds to hemoglobin in red blood cells when moving through the lungs. A pulse oximeter uses two frequencies of light (red and infrared) to determine the percentage of hemoglobin in the blood that is saturated with oxygen, that is called as blood oxygen saturation. Baseline was defined as the last available assessment prior to the start of study treatment. The number of participants with blood oxygen level < 80%, 80% to <90% and >=90% have been reported.	Up to 62 weeks