BAX 855 Continuation

Hemophilia A Clinical Trial

Official title:

A Phase 3b Continuation Study of the Safety and Efficacy of PEGylated Recombinant Factor VIII (PEG-rFVIII; BAX 855) in Prophylaxis of Bleeding in Previously Treated Patients With Severe Hemophilia A

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01945593
• Other study ID #: 261302
• Secondary ID: 2013-002236-24
• Status: Completed
• Phase: Phase 3
• Start date: October 15, 2013
• Est. completion date: March 2, 2018

Study information

• Verified date: April 2021
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To continue the evaluation of the safety and efficacy of BAX 855 for prophylaxis and treatment of bleeding episodes in adult and pediatric previously treated patients (PTPs) aged ≤ 75 years of age with severe hemophilia A.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 218
• Est. completion date: March 2, 2018
• Est. primary completion date: March 2, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 75 Years

Eligibility

INCLUSION CRITERIA

Participants Transitioning from Other BAX 855 Studies:

Participants transitioning from other BAX 855 studies can be provided with the continuation study informed consent form (ICF) prior to the end of study visit to review and consider participation in this continuation study. These participants will complete any additional screening assessments within 2 weeks of the previous study's end of study visit and will return to the study site within 6 (± 1) weeks of the previous study end of study visit to confirm eligibility for this continuation study.

• Participants transitioning from other BAX 855 studies who meet ALL of the following criteria are eligible for this study:

1. Participant has completed a previous BAX 855 study and is willing to immediately transition into this continuation study.

2. Participant is =75 years of age at screening of the previous BAX 855 study.

3. Participant continues to have a Karnofsky (for participants aged = 16 years) or Lansky (for participants aged < 16 years) performance score of = 60.

4. Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count = 200 cells/mm^3, as confirmed by central laboratory at screening.

5. Participant is hepatitis C virus negative (HCV-) by antibody or polymerase chain reaction (PCR) testing (if positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis.

6. If female of childbearing potential, participant presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study.

7. Participant and/or legally authorized representative is willing and able to comply with the requirements of the protocol.

• BAX 855 Naïve Participants:

BAX 855 naïve participants who are = 12 years of age can only be enrolled in this continuation study after enrollment in the phase 2/3 pivotal study is closed. BAX 855 naïve participants who are < 12 years of age can only be enrolled in this continuation study after enrollment in the pediatric previously treated patient (PTP) study is closed.

• Enrolment of BAX 855 naïve participants will only start once the sponsor has notified the study sites accordingly.

BAX 855 naïve participants who meet ALL of the following criteria are eligible for this study:

1. Participant is =75 years of age at screening.

2. Participant is naïve to BAX 855.

3. Participant has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory at screening after at least a 72-hour washout period.

4. Participant aged = 6 years has documented previous treatment with plasma-derived FVIII or rFVIII for = 150 exposure days (EDs).

5. Participant aged < 6 years has documented previous treatment with plasma-derived FVIII concentrates or rFVIII for = 50 EDs.

6. Participant is currently receiving prophylaxis or on-demand therapy with FVIII.

7. Participant has a Karnofsky (for participants aged = 16 years) or Lansky (for participants aged < 16 years) performance score of = 60.

8. Participant is HIV-; or HIV+ with stable disease and CD4+ count = 200 cells/mm^3, as confirmed by central laboratory at screening.

9. Participant is HCV- by antibody or PCR testing (if positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis.

10. If female of childbearing potential, participant presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study.

11. Participant and/or legally authorized representative is willing and able to comply with the requirements of the protocol.

EXCLUSION CRITERA

• Participants Transitioning from Other BAX 855 Studies:

Participants transitioning from other BAX 855 studies who meet ANY of the following criteria are not eligible for this study:

1. Participant had detectable factor VIII (FVIII) inhibitory antibodies (= 0.6 Bethesda unit (BU) using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening.

2. Participant has developed FVIII inhibitory antibodies (= 0.6 BU using the Nijmegen modification of the Bethesda assay as determined at central laboratory in a previous BAX 855 study).

3. Participant has acquired a hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease) in a previous BAX 855 study.

4. Participant has severe chronic hepatic dysfunction (eg, = 5 times upper limit of normal alanine aminotransferase [ALT], as confirmed by central laboratory at screening).

5. Participant has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening.

6. Participant experienced a life-threatening or gastrointestinal bleeding episode within 3 months prior to study entry.

7. Participant is scheduled to use other PEGylated drugs during study participation.

8. Participant is planning to take part in any other clinical study during the course of the continuation study, with the exception of any other parallel BAX 855 study.

9. Participant has medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance.

10. Participant is a family member or employee of the investigator.

• BAX 855 Naïve Participants:

BAX 855 naïve participants who meet ANY of the following criteria are not eligible for this study:

1. Participant has detectable FVIII inhibitory antibodies (= 0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening.

2. Participant has history of FVIII inhibitory antibodies (= 0.6 BU using the Nijmegen modification of the Bethesda assay or the Bethesda assay) at any time prior to screening.

3. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).

4. Participant has known hypersensitivity towards mouse or hamster proteins, polyethylene glycol (PEG), or Tween 80.

5. Participant has severe chronic hepatic dysfunction eg, = 5 times upper limit of normal ALT, as confirmed by central laboratory at screening).

6. Participant has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening.

7. Participant experienced a life-threatening or gastrointestinal bleeding episode within 3 months prior to study entry.

8. Participant has current or recent (< 30 days) use of other PEGylated drugs prior to study participation or scheduled use of such drugs during study participation.

9. Participant has participated in another clinical study involving an IP other than BAX 855 or device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an investigational product (IP) or investigational device during the course of this study.

10. Participant has medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance.

11. Participant is a family member or employee of the investigator.

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Biological:
• BAX855
Antihemophilic Factor (Recombinant), PEGylated

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Fremantle Hospital	Fremantle	Western Australia
Australia	The Alfred Hospital	Melbourne	Victoria
Austria	Landes-Frauen-und Kinderklinik Linz	Linz
Austria	Universitatsklinik fur Innere Medizin I	Vienna
Bulgaria	UMHAT "Sv. Georgi", EAD	Plovdiv
Bulgaria	SHAT of Oncohaematology Diseases	Sofia
Bulgaria	MHAT 'Sv. Marina', EAD	Varna
Czechia	Fakultni nemocnice Brno	Brno
Czechia	Fakultni nemocnice Olomouc	Olomouc
Czechia	Fakultni nemocnice v Motole	Praha 5
Germany	Vivantes Klinikum im Friedrichshain - Landsberger Allee	Berlin
Germany	Gerinnungszentrum Rhein-Ruhr	Duisburg	Nordrhein Westfalen
Germany	Universitaetsklinikum Hamburg-Eppendorf	Hamburg
Germany	Werlhof-Institut GmbH	Hannover	Niedersachsen
Hong Kong	Prince of Wales Hospital	Shatin
Israel	Rambam Health Care Campus	Haifa
Israel	Chaim Sheba Medical Center	Ramat-Gan
Japan	Hiroshima University Hospital	Hiroshima-shi	Hiroshima-Ken
Japan	Nara Medical University Hospital	Kashihara-shi	Nara-Ken
Japan	St. Marianna University School of Medicine Hospital	Kawasaki-shi	Kanagawa-Ken
Japan	University of Occupational and Environmental Health Hospital	Kitakyushu-shi	Fukuoka-Ken
Japan	Nagoya University Hospital	Nagoya-shi	Aichi-Ken
Japan	Tokyo Medical University Hospital	Shinjuku-ku	Tokyo-To
Japan	Ogikubo Hospital	Suginami City	Tokyo
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Eulji University Hospital	Daejeon
Korea, Republic of	Chonnam National University Hwasun Hospital	Hwasun-gun	Jeollanam-do
Korea, Republic of	Kyung Hee University Hospital at Gangdong	Seoul
Korea, Republic of	Ulsan University Hospital	Ulsan
Lithuania	Children's Hospital, Affiliate of Vilnius University Hospital Santariskiu Klinikos	Vilnius
Lithuania	Vilnius University Hospital Santariskiu Clinics, Public Institution	Vilnius
Malaysia	Hospital Ampang	Ampang	Selangor
Malaysia	Penang General Hospital	George Town	Penang
Malaysia	Pusat Darah Negara	Kuala Lumpur
Malaysia	Hospital Umum Sarawak	Kuching	Sarawak
Malaysia	Hospital Pulau Pinang	Pulau Pinang
Malaysia	Hospital Sibu	Sibu	Sarawak
Netherlands	Academisch Medisch Centrum	Amsterdam
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Wojewodzki Szpital Specjalistyczny im.M.Kopernika w Lodzi	Lodz
Romania	Sanador SRL	Bucuresti
Russian Federation	LLC "Alba Dent"	Kirov
Russian Federation	Regional Clinical Hospital	Krasnoyarsk
Spain	Complejo Hospitalario Universitario A Coruña	A Coruña	La Coruña
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Regional Universitario de Malaga	Malaga	Málaga
Spain	Hospital Universitari Son Espases	Palma de Mallorca	Baleares
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Sweden	Sjukhusapoteket Malmo	Malmo
Sweden	Karolinska	Stockholm
Switzerland	Universitaetsspital Zuerich	Zuerich
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	Tri-Service General Hospital	Taipei
Turkey	Ankara University Medical Faculty	Ankara
Turkey	Akdeniz University Faculty of Medicine	Antalya
Turkey	Istanbul University Cerrahpasa Medical Faculty	Istanbul
Ukraine	SI V.K.Gusak Emergency and Reconstructive Surgery Institute of NAMSU	Donetsk
Ukraine	SI Institute of Blood Pathology and Transfusion Medicine of NAMSU	Lviv
United Kingdom	Birmingham Children's Hospital	Birmingham	West Midlands
United Kingdom	Bristol Royal Hospital for Children	Bristol	Avon
United Kingdom	Leicester Royal Infirmary	Leicester	Leicestershire
United Kingdom	Great Ormond Street Hospital for Children	London	Greater London
United Kingdom	Royal Free Hospital	London	Greater London
United Kingdom	St Thomas' Hospital	London	Greater London
United Kingdom	Royal Manchester Children's Hospital	Manchester	Greater Manchester
United Kingdom	The Churchill Hospital	Oxford
United Kingdom	Southampton General Hospital	Southampton	Hampshire
United States	University of Colorado	Aurora	Colorado
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Palmetto Health Richland	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida College of Medicine	Gainesville	Florida
United States	Penn State Hershey Cancer Center	Hershey	Pennsylvania
United States	Children's Mercy Hospitals & Clinics	Kansas City	Missouri
United States	University of Kentucky Medical Center	Lexington	Kentucky
United States	University of Louisville	Louisville	Kentucky
United States	North Shore-Long Island Jewish Health System	New Hyde Park	New York
United States	Tulane University School of Medicine	New Orleans	Louisiana
United States	New York - Presbyterian/Weill Cornell Medical Center	New York	New York
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	Bleeding and Clotting Disorders Institute	Peoria	Illinois
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	University of Utah	Salt Lake City	Utah
United States	Puget Sound Blood Group	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Baxalta now part of Shire	Baxalta Innovations GmbH, now part of Shire

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Bulgaria,  Czechia,  Germany,  Hong Kong,  Israel,  Japan,  Korea, Republic of,  Lithuania,  Malaysia,  Netherlands,  Poland,  Romania,  Russian Federation,  Spain,  Sweden,  Switzerland,  Taiwan,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Inhibitory Antibodies to Factor VIII (FVIII)	Inhibitory antibodies to Factor VIII were measured by the Nijmegen modification of the Bethesda assay. Inhibitors had to be confirmed by 2 separate assessments within a 2 to 4 week period from the central laboratory.	Baseline through end of study (53 months)
Primary	Annualized Bleed Rate (ABR) - Spontaneous Bleeds	The ABR was assessed based upon each individual bleeding episode. A bleeding episode was defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. The ABR of spontaneous bleeds was reported separately for twice weekly, PK-t R, each of the every 5 days and every 7 days treatment regimens at the time of bleed.	Baseline through end of study (53 months)
Secondary	Total Annualized Bleed Rate (ABR)	The ABR was assessed based upon each individual bleeding episode. A bleeding episode was defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. Bleeding occurring at multiple locations related to the same injury (e.g., knee and ankle bleed following a fall) was counted as a single bleeding episode. Total annualized bleed rate (spontaneous and traumatic bleeding episodes) was reported.	Baseline through end of study (53 months)
Secondary	Overall Hemostatic Efficacy Rating of BAX 855 for Treatment of Breakthrough Bleeding Episodes	The participant or caregiver rated the overall treatment response at 24 (+/- 2) hours after the initiation of treatment using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.	Baseline through end of study (53 months)
Secondary	BAX 855 Infusions Needed to Treat Bleeding Episodes	The BAX 855 infusions to treat each bleeding episode was determined by the participant, the participant's caregiver, and/or investigator, and was based upon the participant's response to treatment. A bleeding episode was defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII.	Baseline through end of study (53 months)
Secondary	Total Time Intervals Between Bleeding Episodes	The time interval between bleeding episodes was calculated based upon the date and time reported for each bleeding episode. A bleeding episode was defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII.	Baseline through end of study (53 months)
Secondary	Average Dose of BAX 855 Per Prophylactic Infusion	The average dose of BAX 855 per prophylactic infusion was reported.	Baseline through end of study (53 months)
Secondary	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom (eg, rash, pain, discomfort, fever, dizziness, etc.), disease (eg, peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of an investigational product (IP), whether or not considered causally related to the IP. A serious adverse event (SAE) was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/resulted in death; was life-threatening; required inpatient hospitalization or resulted in prolongation of an existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; was a medically important event.	Baseline through end of study (53 months)
Secondary	Change From Baseline in Body Temperature	Change in body temperature at pre-infusion and post-infusion at end of the study was reported. In the below table, FDR refers to fixed dose regimen, PK-tR refers to PK tailored regimen at the time of sampling.	Baseline, end of study (53 months)
Secondary	Change From Baseline in Pulse Rate	Change in pulse rate at pre-infusion and post-infusion at end of the study was reported. In the below table, FDR refers to fixed dose regimen, PK-tR refers to PK tailored regimen at the time of sampling.	Baseline, end of study (53 months)
Secondary	Change From Baseline in Respiratory Rate	Change in respiratory rate at pre-infusion and post-infusion at end of the study was reported. In the below table, FDR refers to fixed dose regimen, PK-tR refers to PK tailored regimen at the time of sampling.	Baseline, end of study (53 months)
Secondary	Change From Baseline in Blood Pressure	Change in systolic and diastolic blood pressure at pre-infusion and post-infusion at end of the study were reported. In the below table, FDR refers to fixed dose regimen, PK-tR refers to PK tailored regimen at the time of sampling, SBP refers to systolic blood pressure, DBP refers to diastolic blood pressure.	Baseline, end of study (53 months)
Secondary	Number of Participants With Shifts in Clinical Chemistry Laboratory Assessments.	The number of participants with clinically significant shifts from "normal" "abnormal clinically significant (CS)" and "abnormal not clinically significant (abnormal NCS)" at baseline to "normal" "abnormal clinically significant (CS) and abnormal clinically significant (NCS)" at completion were reported. In the below table, FDR refers to fixed dose regimen at the time of sampling, AlA refers to alanine aminotransferase, AP refers to alkaline phosphatase, AsA refers to aspartate aminotransferase.	Baseline through end of study (53 months)
Secondary	Number of Participants With Shifts in Hematology Laboratory Assessments	The number of participants with clinically significant shifts from "normal" "abnormal clinically significant (CS)" and "abnormal not clinically significant (abnormal NCS)" at baseline to "normal" "abnormal clinically significant (CS) and abnormal clinically significant (NCS)" at completion were reported. In the below table, FDR refers to fixed dose regimen, PK-tR refers to PK tailored regimen at the time of sampling, Leu refers to leukocytes, MCV refers to mean corpuscular volume, Lym/Leu refers to lymphocytes/leukocytes.	Baseline through end of study (53 months)
Secondary	Number of Participants With Shifts in Lipid Panel Assessments	The number of participants with clinically significant shifts from "normal" "abnormal clinically significant (CS)" and "abnormal not clinically significant (abnormal NCS)" at baseline to "normal" "abnormal clinically significant (CS) and abnormal clinically significant (NCS)" at completion were reported.. In the below table, HDL refers to high density lipoprotein, LDL refers to low density lipoprotein, VLDL refers to very low density lipoprotein.	Baseline through end of study (53 months)
Secondary	Number of Participants With Binding Antibodies	Binding antibodies (IgG and IgM) against FVIII, polyethylene glycol (PEG) and PEGylated FVIII (PEG-FVIII) were analyzed using enzyme-linked immunosorbent assay (ELISA).	Baseline through end of study (53 months)
Secondary	Number of Participants With Anti-Chinese Hamster Ovary (CHO) Antibodies	Testing for binding of anti-CHO protein antibodies was performed on citrate-anti-coagulated plasma using an ELISA employing polyclonal antihuman IgG antibodies.	Baseline through end of study (53 months)
Secondary	Change From Baseline in Bleed Severity	Hemophilia symptom (haemo-SYM) questionnaire has two subscales: pain and bleed. It was used to asses the bleed severity for participants >=18 years of age as: severity of spontaneous bleeding in my joints (unrelated to injury or activity), spontaneous bleeding in my muscles (unrelated to injury or activity), prolonged bleeding after injury in spite of treatment, intense pain because of bleeding event, joint pain due to active bleed and bleeding during personal hygiene routine, blood in my urine, nose bleeds and assigned a score of 0=Absent, 1=very mild, 2=mild, 3=moderate, 4=severe and 5=very severe. The score was determined as (mean score/5)*100 where mean score is the mean of the available results in the particular subscale. Higher scores on the Haemo-SYM indicate more severe symptoms. Therefore, negative change scores indicate that symptoms have improved. Here 'n' refers to the number of participants evaluable for this endpoint.	Baseline, end of study (53 months)
Secondary	Change From Baseline in Pain Severity	Hemophilia symptom (haemo-SYM) questionnaire has two subscales: pain and bleed. It was used to asses the pain severity for participants >=18 years of age as: pain because of swelling in my joints, climbing stairs, upon waking in the morning, active arthritis; constant pain, in my muscles, that needs medication; joint sensitivity to weather conditions; reduced range of joint movement, joint deformity, sleep disturbance because of pain or bleeds, blood in my urine, nose bleeds and assigned a score of 0=Absent, 1=very mild, 2=mild, 3=moderate, 4=severe and 5=very severe. The score was determined as (mean score/5)*100 where mean score is the mean of the available results in the particular subscale. Higher scores on the Haemo-SYM indicate more severe symptoms. Therefore, negative change scores indicate that symptoms have improved. Here 'n' refers to the number of participants evaluable for this endpoint.	Baseline, end of study (53 months)
Secondary	Change From Baseline in Patient Reported Outcomes: Health-related Quality of Life (HRQoL): Short Form-36 (SF-36)	HRQoL in participants aged >=14 years was measured using the SF-36 questionnaire. The questionnaire was divided into 8 domains and scored as: physical functioning (1=yes, limited a lot to 3=no, not limited at all), role-physical (1=all of the time to 5=none of the time), bodily pain (1=very severe to 6=none), general health (1=poor to 5=excellent), vitality (1=none of the time to 5=all of the time), social functioning (1=all of the time: to 5=none of the time), role emotional (1=all of the time to 5=none of the time) and mental health (1=all of the time to 5=none of the time). The score for each domain is then to be transformed to a 0-100 range as [(actual raw score-lowest possible raw score)/possible raw score range]*100. Positive change scores indicate improved HRQoL. in the below table 'FDR' indicates fixed dose regimen, 'PK-tr' indicates pharmacokinetically tailored regimen and 'n' refers to the number of participants evaluable for this endpoint.	Baseline, end of study (53 months)
Secondary	Change From Baseline in Patient Reported Outcomes: Health-related Quality of Life (HRQoL): Pediatrics Quality of Life (PedsQL) Questionnaire	HRQoL in participants aged <14 years was measured using the PedsQL. It capture data for the following domains: physical functioning, emotional functioning, social functioning, school functioning, psychosocial functioning, physical health and a total score. Each question of the PedsQL was scored as Never: 100, almost never: 75, sometimes: 50, often: 25, almost always: 0. The mean of the individual question scores was calculated. Lower scores on the PedsQL indicating worse HRQoL. Here, FDR refers to fixed dose regimen, PK-t R refers to PK-tailored regimen. Here 'n' refers to the number of participants evaluable for this endpoint. Here 'n' refers to the number of participants evaluable for this endpoint.	Baseline, end of study (53 months)