A Study to Evaluate the Efficacy of Venetoclax Monotherapy in Relapsed/Refractory Participants With Chronic Lymphocytic Leukemia (CLL)

Chronic Lymphocytic Leukemia Clinical Trial

— VENICE I  

Official title:

Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating the Efficacy of Venetoclax (ABT 199) in Relapsed/Refractory Subjects With Chronic Lymphocytic Leukemia (CLL)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02756611
• Other study ID #: M15-550
• Secondary ID: 2015-003667-11
• Status: Completed
• Phase: Phase 3
• Start date: June 22, 2016
• Est. completion date: March 11, 2022

Study information

• Verified date: April 2023
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy of venetoclax monotherapy in participants with relapsed/refractory CLL with or without the 17p deletion or TP53 mutation, including those who have received prior treatment with a B-cell receptor inhibitor.

Description:

Following the Screening period, all eligible participants initiate venetoclax on a once daily (QD) dosing schedule. To mitigate the risk for tumor lysis syndrome (TLS), dosing will start with a 5-week dose titration phase. Participants may receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator assessment), do not have unacceptable toxicity and do not meet any of the criteria for subject discontinuation. In countries where venetoclax is not commercially available, participants who continued to derive benefit after 2 years of treatment may extend their treatment for up to 2 additional years in an extended access phase. Participants in the extended access phase of this study who continue to derive benefit from venetoclax after the 2-year extension and are transferring to the venetoclax extension study, Study M19-388 (NCT03844048), may remain in Extended Access for up to 1 additional year or until the extension study is approved and initiated at the site, whichever is sooner.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 258
• Est. completion date: March 11, 2022
• Est. primary completion date: April 10, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Participant has Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2
• Participant has relapsed/refractory disease (received at least 1 prior therapy)
• Participant has diagnosis of CLL that meets published 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute Working Group

(IWCLL NCI-WG) Guidelines and:

• has an indication for treatment according to the 2008 Modified IWCLL NCI-WG criteria
• has clinically measurable disease (lymphocytosis greater than 5 × 10^9/L and/or palpable and measurable nodes by physical exam and/or organomegaly assessed by physical exam)
• In addition, participants:
• with or without 17p deletion or TP53 mutation, assessed by a local laboratory in bone marrow or peripheral blood are eligible
• may have been previously treated with a prior B-cell receptor inhibitor
• Participant must have adequate bone marrow function, coagulation profile, renal, and hepatic function, per laboratory at Screening

Exclusion Criteria:

• Participant has developed Richter's transformation or Prolymphocytic leukemia
• Participant has previously received venetoclax
• History of active malignancies other than CLL within the past 2 years prior to first

dose of venetoclax, with the exception of:

• adequately treated in situ carcinoma of the cervix uteri
• adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
• previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
• Participant has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), including autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura despite low dose corticosteroids
• Participant has undergone an allogeneic stem cell transplant
• Treatment with any of the following within five half-lives or 14 days (if half-life unknown) as applicable prior to the first dose of venetoclax, or clinically significant adverse effect(s)/toxicity(s) of the previous therapy have not resolved to < National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)

v4.03 Grade 2:

• Any anti-cancer therapy including chemotherapy, or radiotherapy;
• Investigational therapy, including targeted small molecule agents
• Participant is human immunodeficiency virus (HIV) positive
• Participant has known allergy to both xanthine oxidase inhibitors and rasburicase

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Venetoclax
Tablets for oral administration

Locations

Country	Name	City	State
Austria	LKH-Univ. Klinikum Graz /ID# 147547	Graz
Austria	LKH Salzburg and Paracelsus /ID# 147549	Salzburg
Austria	Hanusch Krankenhaus der WGKK /ID# 147548	Wien
Belgium	UZ Leuven /ID# 147387	Leuven
Belgium	Cliniques Universitaires Saint Luc /ID# 147388	Woluwe-Saint-Lambert	Bruxelles-Capitale
Canada	Qe Ii Hsc /Id# 147460	Halifax	Nova Scotia
Canada	Juravinski Cancer Clinic /ID# 149152	Hamilton	Ontario
Canada	CHU de Quebec-Universite Laval /ID# 150299	Quebec City	Quebec
Canada	Sunnybrook Health Sciences Ctr /ID# 147462	Toronto	Ontario
Canada	BC Cancer Agency /ID# 153091	Vancouver	British Columbia
Denmark	Aarhus University Hospital /ID# 147409	Aarhus N	Midtjylland
Denmark	Herlev Hospital /ID# 150183	Herlev	Hovedstaden
Finland	Turku University Hospital /ID# 147551	Turku
France	Institut Bergonie /ID# 147482	Bordeaux
France	CHRU de Brest - Hopital Morvan /ID# 147485	Brest
France	CHU Dupuytren /ID# 147552	Limoges CEDEX 1	Franche-Comte
France	CHU de la miletrie /ID# 147484	Poitiers	Poitou-Charentes
France	clinique Sainte Anne /ID# 147556	Strasbourg
Germany	Onkologische Schwerpunktpraxis /ID# 147516	Berlin
Germany	Cent fuer Haematologie und Onk /ID# 147511	Frankfurt
Germany	OncoResearch Lerchenfeld GmbH /ID# 164044	Hamburg
Germany	Mannheimer Onkologiepraxis /ID# 147512	Mannheim
Germany	Staedt. Klinikum Schwabing /ID# 147510	Munich
Greece	General Hospital of Athens Laiko /ID# 147517	Athens	Attiki
Greece	G. Papanikolaou Hospital /ID# 147518	Thessaloniki
Ireland	Beaumont Hospital /ID# 147522	Dublin
Ireland	St. James's Hospital /ID# 147519	Dublin 8	Dublin
Israel	Galilee Medical Center /ID# 159971	Nahariya
Israel	Sheba Medical Center /ID# 147509	Ramat Gan
Israel	Tel Aviv Sourasky Medical Ctr /ID# 151624	Tel Aviv-Yafo	Tel-Aviv
Italy	A.O.U. Policlinico S.Orsola-Malpighi /ID# 147505	Bologna	Emilia-Romagna
Italy	Ospedale San Raffaele IRCCS /ID# 147504	Milan
Italy	ASST Grande Ospedale Metropolitano Niguarda /ID# 147503	Milano	Lombardia
Italy	AO Maggiore della Carita /ID# 147499	Novara
Italy	AP Romano Umberto I /ID# 147500	Rome	Lazio
Netherlands	Academisch Medisch Centrum /ID# 147494	Amsterdam	Noord-Holland
Netherlands	Albert Schweitzer Ziekenhuis /ID# 147495	Dordrecht	Zuid-Holland
Norway	Haukeland University Hospital /ID# 147382	Bergen	Hordaland
Norway	Rikshospitalet OUS HF /ID# 201812	Oslo
Portugal	IPO Lisboa FG, EPE /ID# 147385	Lisboa
Portugal	IPO Porto FG, EPE /ID# 147389	Porto
Puerto Rico	Puerto Rico Hematology Oncolog /ID# 150003	San Juan
Spain	Hospital Santa Creu i Sant Pau /ID# 151230	Barcelona
Spain	Fundacion Jimenez Diaz /ID# 151231	Madrid
Spain	Hosp Univ Puerta de Hierro /ID# 147391	Majadahonda
Spain	Hospital Clinico Univ de Salamanca /ID# 147392	Salamanca
Spain	Hosp Clin Univ de Valencia /ID# 147396	València
Sweden	Skanes Universitetssjukhus Lund /ID# 147439	Lund	Skane Lan
Sweden	Akademiska Sjukhuset /ID# 150184	Uppsala	Uppsala Lan
Switzerland	Ospedale Regional Bellinzona e /ID# 151232	Bellinzona
Switzerland	Hopitaux Universitaires de Geneve /ID# 147930	Genève	Geneve
Switzerland	University Hospital Zurich /ID# 157910	Zurich	Zuerich
Turkey	Ankara Univ Medical Faculty /ID# 147443	Ankara
Turkey	Istanbul University Istanbul Medical Faculty /ID# 156040	Istanbul
Turkey	Vehbi Koc vakfi Amerikan Hasta /ID# 147325	Istanbul
Turkey	Dokuz Eylul University /ID# 147442	Izmir
Turkey	Ondokuz mayis University Facul /ID# 147326	Samsun
United Kingdom	Blackpool Teaching Hosp NHS /ID# 149581	Blackpool
United Kingdom	Univ Hosp Bristol NHS Foundati /ID# 147647	Bristol
United Kingdom	Southampton General Hospital /ID# 147646	Southampton
United Kingdom	The Royal Wolverhampton NHS Tr /ID# 147945	Wolverhampton
United States	St. Agnes Cancer Center /ID# 149782	Baltimore	Maryland
United States	Hackensack Univ Med Ctr /ID# 151574	Hackensack	New Jersey
United States	Norton Cancer Institute /ID# 149788	Louisville	Kentucky
United States	West Virginia Univ School Med /ID# 151602	Morgantown	West Virginia
United States	Utah Cancer Specialists /ID# 151604	Salt Lake City	Utah
United States	Cancer Care Northwest /ID# 151605	Spokane	Washington

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  Denmark,  Finland,  France,  Germany,  Greece,  Ireland,  Israel,  Italy,  Netherlands,  Norway,  Portugal,  Puerto Rico,  Spain,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Final Analysis	Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria.; CR required all of the following: Peripheral blood lymphocytes < 4000/µL; Absence of lymphadenopathy by physical examination and computed tomography scan; No hepatomegaly or splenomegaly by physical examination; Absence of disease or constitutional symptoms (unexplained fevers > 38°C, drenching night sweats, > 10% weight loss in last 6 months); Blood counts above the following: Neutrophils > 1500/µL; Platelets > 100,000/µL; Hemoglobin > 110 g/L; Bone marrow at least normocellular for age, < 30% lymphocytes.; CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.	From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Other	Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Final Analysis	Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria.; CR required all of the following: Peripheral blood lymphocytes < 4000/µL; Absence of lymphadenopathy by physical examination and computed tomography scan; No hepatomegaly or splenomegaly by physical examination; Absence of disease or constitutional symptoms (unexplained fevers > 38°C, drenching night sweats, > 10% weight loss in last 6 months); Blood counts above the following: Neutrophils > 1500/µL; Platelets > 100,000/µL; Hemoglobin > 110 g/L; Bone marrow at least normocellular for age, < 30% lymphocytes; CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.	From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Other	Overall Response Rate (ORR) - Final Analysis	Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 modified IWCLL NCI-WG criteria assessed by the investigator.; CR and CRi are defined above. nPR is defined as for CR but bone marrow nodules could be identified histologically.; For PR at least 2 of the following must be met: 50% decrease in peripheral blood lymphocyte count from the Baseline value; 50% reduction in lymphadenopathy; 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy); In addition at least 1 of the following criteria must be met: Neutrophils > 1,500/µL or = 50% improvement over Baseline; Platelets > 100,000/µL or = 50% improvement over Baseline; Hemoglobin > 11.0 g/dL or = 50% improvement over Baseline without transfusions or exogenous growth factors.; PR must have been confirmed at least 7 weeks later.	From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Other	Duration of Overall Response (DOR) - Final Analysis	Duration of response was defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) was objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding the data were censored at the date of the last available disease assessment prior to the data cutoff date.	From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Other	Time to Progression (TTP) - Final Analysis	Time to progression was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.	From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Other	Progression-Free Survival (PFS) - Final Analysis	Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.	From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Other	Overall Survival (OS) - Final Analysis	Overall survival (time to death) was defined as the time from the first dose date of venetoclax to the date of death. If a participant had not died the data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.	From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Other	Minimal Residual Disease (MRD) Negativity Rate - Primary Analysis	The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (< 10-4) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Other	Minimal Residual Disease (MRD) Negativity Rate - Final Analysis	The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (< 10-4) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.	From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Primary	Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Primary Analysis	Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria.; CR required all of the following: Peripheral blood lymphocytes < 4000/µL; Absence of lymphadenopathy by physical examination and computed tomography scan; No hepatomegaly or splenomegaly by physical examination; Absence of disease or constitutional symptoms (unexplained fevers > 38°C, drenching night sweats, > 10% weight loss in last 6 months); Blood counts above the following: Neutrophils > 1500/µL; Platelets > 100,000/µL; Hemoglobin > 110 g/L; Bone marrow at least normocellular for age, < 30% lymphocytes.; CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Secondary	Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Primary Analysis	Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria.; CR required all of the following: Peripheral blood lymphocytes < 4000/µL; Absence of lymphadenopathy by physical examination and computed tomography scan; No hepatomegaly or splenomegaly by physical examination; Absence of disease or constitutional symptoms (unexplained fevers > 38°C, drenching night sweats, > 10% weight loss in last 6 months); Blood counts above the following: Neutrophils > 1500/µL; Platelets > 100,000/µL; Hemoglobin > 110 g/L; Bone marrow at least normocellular for age, < 30% lymphocytes; CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Secondary	Overall Response Rate (ORR) - Primary Analysis	Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 modified IWCLL NCI-WG criteria assessed by the investigator.; CR and CRi are defined above. nPR is defined as for CR but bone marrow nodules could be identified histologically.; For PR at least 2 of the following must be met: 50% decrease in peripheral blood lymphocyte count from the Baseline value; 50% reduction in lymphadenopathy; 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy); In addition at least 1 of the following criteria must be met: Neutrophils > 1,500/µL or = 50% improvement over Baseline; Platelets > 100,000/µL or = 50% improvement over Baseline; Hemoglobin > 11.0 g/dL or = 50% improvement over Baseline without transfusions or exogenous growth factors.; PR must have been confirmed at least 7 weeks later.	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Secondary	Duration of Overall Response (DOR) - Primary Analysis	Duration of response was defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) was objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding the data were censored at the date of the last available disease assessment prior to the data cutoff date.	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Secondary	Time to Progression (TTP) - Primary Analysis	Time to progression was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Secondary	Progression-Free Survival (PFS) - Primary Analysis	Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Secondary	Overall Survival (OS) - Primary Analysis	Overall survival (time to death) was defined as the time from the first dose date of venetoclax to the date of death. If a participant had not died the data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.	From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Secondary	Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu)	The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess health-related quality of life (HRQoL) and leukemia-specific symptoms using a core set of questions (Functional Assessment of Cancer Therapy-General; FACT-G), and a cancer site-specific leukemia subscale. Questions are scored on a scale from 0 (not at all) to 4 (very much).; FACT-G consists of 27 general items divided into 4 primary HRQoL domains: Physical Well-being (PWB; 7 items; score range 0-28), Social/Family Well-being (SWB; 7 items; score range 0-28), Emotional Well-being (EWB; 6 items; score range 0-24), Functional Well-being (FWB; 7 items; score range 0-28). The leukemia subscale consists of 17 items (score range 0-68) that assess patient concerns relating to leukemia. Three summary scales were calculated: FACT-Trial Outcome Index composed of the PWB, FWB, and leukemia subscale (score range 0-124); FACT-G (score range 0-108) and the FACT-Leu Total (range 0-176). Higher scores reflect better HRQoL.	Baseline and Weeks 48 and 108
Secondary	Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue)	The FACIT-Fatigue questionnaire measures fatigue and its effect on functioning and daily activities. The FACIT-Fatigue includes 13 items answered on a 5-point rating scale based on a 7-day recall period. Scores range from 0 to 52, with lower scores reflecting greater fatigue.	Baseline and Weeks 48 and 108
Secondary	Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Health Index Score	The EQ-5D-5L is a generic measure of health status consisting of two parts: a descriptive system consisting of 5 items and a visual analog scale (VAS).; The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The participant is asked to rate each dimension on 5 levels of severity (1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, 5: extreme problems).; The scores for the 5 dimensions are used to compute a single health utility index score representing the general health status of the individual. The health index score ranges from zero (defined as a health state equivalent to being dead) to 1 (full health).	Baseline and Weeks 48 and 108
Secondary	Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Visual Analog Scale Score	The EQ-5D-5L is a generic measure of health status consisting of two parts, a descriptive system consisting of 5 items and a visual analog scale (VAS).; The VAS assesses the participant's self-rated overall health on a scale from 0 (worst health imaginable) to 100 (best health imaginable).	Baseline and Weeks 48 and 108