Safety and Efficacy Study of Roxadustat with compare to Placebo for treatment of Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis
Scientific Title of Study
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study
Evaluating the Safety and Efficacy of Roxadustat for the Treatment of
Anemia in Chronic Kidney Disease Patients not on Dialysis
Trial Acronym
OLYMPUS
Secondary IDs if Any
Secondary ID
Identifier
D5740C00001 Version 4.0, Date 26 September 2014
Protocol Number
NCT02174627
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)
Country Head - Site Management and Monitoring – India
Affiliation
AstraZeneca Pharma India Ltd.
Address
AstraZeneca Pharma India Ltd.
Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road
Bangalore
Bangalore KARNATAKA 560024 India
Phone
9535104975
Fax
918067748857
Email
tapankumar.shah@astrazeneca.com
Details of Contact Person Public Query
Name
Mr Tapankumar Shah
Designation
Country Head – Clinical Operations
Affiliation
AstraZeneca Pharma India Ltd.
Address
Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road
Bangalore KARNATAKA 560024 India
Phone
918067748006
Fax
918023622015
Email
Tapankumar.Shah@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB, 151 85 Södertälje, Sweden
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Södertälje, Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
Argentina Brazil Bulgaria Canada Colombia Czech Republic Democratic People's Republic of Korea Germany Hungary India Mexico Peru Philippines Poland Romania Russian Federation Slovakia Spain Taiwan Thailand Turkey Ukraine United States of America Viet Nam
B.J Govt. Medical College & Sassoon General Hospital
Department of Nephrology
B.J Govt. Medical College and Sassoon General Hospital
Jai Prakash Narayan Road, Near Pune Railway Station, Pune - 411001
Pune MAHARASHTRA
Opp. Corporation Bank, Bellapu Sobhanadri Road, Near Pushpa Hotel Centre, Vijayawada - 522002, Andhra Pradesh, India Vizianagaram ANDHRA PRADESH
9848148967
krishnamvs@yahoo.com
Dr Kalpana Mehta Head and Professor in Nephrology
Topiwala National Medical College & B. Y. L. Nair Charitable Hospital
Department of Nephrology
Topiwala National Medical College & B. Y. L. Nair Charitable Hospital Dr. A. L. Nair Road, Mumbai – 400009 Mumbai MAHARASHTRA
Ethics Committee Meditrina Institute of Medical Science, 78, Central Bazar Road, Ramdaspeth, Nagpur, Maharashtra 440010
Approved
Instituational Ethics Committee SUNRISE HOSPITALS Opp. Corporation Bank, Bellapu Sobhanadri Road, Near Pushpa Hotel Centre, Vijayawada - 522002, Andhra Pradesh, India
Approved
Institutional Ethical Committee, JSS Medical College, Mysore –570 015
Approved
Institutional Ethics Committee BJG Medical College and Sassoon General Hospitals, Pune
Approved
Institutional Ethics Committee Noble Hospital Pvt. Ltd, 153, Magarpatta City Road, Pune 411013, Maharashtra
Institutional Ethics Committee King George Hospital Visakhapatnam – 530002
Approved
Institutional Ethics Committee of Topiwala National Medical College and BYL Nair Charitable Hospital G Building Ground Floor, Dr A.L Nair Road, Mumbai Central ,Mumbai-400008
Approved
Institutional Ethics Committee Siddharatha Medical College & Govt General Hospital (IEC SMC & GGH) Near Dr.NTR Health University Gunadala, Vijayawada – 520008 Andhra Pradesh, India
Approved
Institutional Ethics Committee, Department of Pharmacology, Government Medical College and Hospital, Napur 440009
Institutional Ethics Committee, B. J. Medical College & Civil Hospital Asarwa, Ahmedabad, Gujarat 380016
Approved
Institutional Ethics Committee, Max Healthcare Super Speciality Hospital, 6th floor, 2, Press Enclave Road, Saket, New Delhi-110017
Approved
Institutional Ethics Committee, Poona Medical Research Foundation, E4 – C to E4 – F 4th Floor, Fifth Avenue, Condomonium, Dhole Patil Road, Pune 411001
(1) ICD-10 Condition: N189||Chronic kidney disease, unspecified, Male and Female patients ≥ 18 years of age with chronic kidney disease stage 3 to 5 not on dialysis and who have anemia (Hb ≤ 10 g/dL) ,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Experimental: Roxadustat
The initial study drug dose is 70 mg three times a week (TIW). The dose is subsequently adjusted to achieve and maintain Hb 11±1 g/dL and the expected treatment duration is 1-2 years.
Comparator Agent
Placebo Comparator: Placebo
Drug: Placebo
The initial study drug dose is 70 mg three times a week (TIW). The dose is subsequently adjusted to achieve and maintain Hb 11±1 g/dL and the expected treatment duration is 1-2 years.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
1. A glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, corresponding to stage 3, 4 or 5 chronic kidney disease (CKD) according to the Kidney Disease Outcomes Quality Initiative, not receiving dialysis.
2. Mean of 2 most recent central laboratory hemoglobin (Hb) values during the screening period, obtained at least 7 days apart, must be <10.0 g/dL.- Ferritin ≥50 ng/mL at randomization.
3. Transferrin saturation ≥15% at randomization.
4. Serum folate level ≥ lower limit of normal (LLN) at randomization. - Serum vitamin B12 level ≥LLN at randomization.
5. Alanine aminotransferase and aspartate aminotransferase ≤3 x upper limit of normal (ULN) and total bilirubin ≤1.5 x ULN at randomization.
6. Body weight 45 to 160 kg.
ExclusionCriteria
Details
1. Any erythropoietin analogue treatment within 6 weeks of randomization.
2. New York Heart Association Class III or IV congestive heart failure at enrollment- Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
3. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune liver disease, cirrhosis or fibrosis of the liver).
4. Known hereditary hematologic disease such as thalassemia, sickle cell anemia, a history of pure red cell aplasia or other known causes for anemia other than CKD.
5. Known and untreated retinal vein occlusion or known and untreated proliferative diabetic retinopathy (risk for retinal vein thrombosis).
6. Diagnosis or suspicion (e.g. complex kidney cyst of Bosniak Category II F, III or IV) of renal cell carcinoma on renal ultrasound (or other imaging procedure e.g. computerized tomography scan or magnetic resonance imaging conducted at screening or within 12 weeks prior to randomization.
7. Systolic blood pressure (BP) ≥160 mmHg or diastolic BP ≥95 mmHg, within 2 weeks prior to randomization. Patients may be rescreened once BP controlled.
8. History of prostate cancer, breast cancer or any other malignancy, except the following: cancers determined to be cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.
9. Positive for any of the following: human immunodeficiency virus, hepatitis B surface antigen or anti-hepatitis C virus antibody.
10. Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis or inflammatory bowel disease that is determined to be the principal cause of anemia.
11. Known hemosiderosis, hemochromatosis or hypercoagulable condition.
12. Any prior organ transplant or a scheduled organ transplantation date.
13. Any red blood cell transfusion during the screening period.
14. Any current condition leading to active significant blood loss.
15. Any treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor.
16. Has received another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment within at least 1 month of the first administration of investigation product in this study. (Note: patients consented and screened, but not randomized in this study or a previous study are not excluded).
17. History of alcohol or drug abuse within 2 years prior to randomization.
18. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence.
19. Pregnant or breastfeeding females.
20. Known allergy to the investigational product or any of its ingredients.
21. Any medical condition, including active, clinically significant infection, that in the opinion of the investigator or Sponsor may pose a safety risk to a patient in this study, which may confound safety or efficacy assessment or may interfere with study participation.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Double Blind Double Dummy
Primary Outcome
Outcome
TimePoints
Major adverse cardiovascular (CV) events (MACE): Time to first occurrence of all-cause mortality, non-fatal myocardial infarction or non-fatal stroke
The number from randomization to the first occurrence of any of the components of the primary composite endpoints.
Major adverse cardiovascular (CV) events (MACE): Time to first occurrence of all-cause mortality, non-fatal myocardial infarction or non-fatal stroke
The number from randomization to the first occurrence of any of the components of the primary composite endpoints.
Secondary Outcome
Outcome
TimePoints
Mean change in hemoglobin (Hb) from baseline to the end of treatment period (event-driven, anticipate 1-2 years)
Baseline to end of study (event-driven, anticipate 1-2 years)
Mean value of all Hb measurements
From week 28 until the end of study will be used.
Proportion of total time of Hb measurements within the interval of 11±1 g/dL
From week 28 until end of study (event-driven, anticipate 1-2 years)
Proportion of total time of Hb values within the interval 11±1 g/dL
From week 28 until end of treatment visit
MACE: Time to first occurrence of all-cause mortality, non-fatal myocardial infarction (MI) or non-fatal stroke, heart failure requiring hospitalization or unstable angina leading to hospitalization
The number from randomization to the first occurrence of any of the components of the primary composite endpoints.
From randomization (week 0) to end of study (event-driven, anticipate 1-2 years)
Change in estimated glomerular filtration rate (eGFR) from baseline to the end of treatment period (event-driven, anticipate 1-2 years)
From baseline to end of study (event-driven, anticipate 1-2 years)
Changes in anemia symptoms and four disease-specific Health Related Quality of Life (HRQoL) domains as measured by the Functional Assessment of Cancer Therapy-Anemia (FACT-An)
Measured at visit randomization (week 0), week 12, 28 and 52
Changes in generic HRQoL as measured by the Short Form 36 (SF-36) (vers 2, standard)
Measured at visit randomization (week 0), week 12, 28 and 52
Changes in self-reported health status as measured by the EuroQol Health Utility Index-5-dimensional-5-level (EQ-5D-5L) and Patients Global Impression of Change (PGIC).
At baseline, week 12, 28 and 52
Adverse events (AEs), serious adverse events (SAEs) and changes in vital signs, electrocardiogram (ECG) and laboratory values. Measured from first screening visit to end of study (event-driven, anticipate 1-2 years)
From the first screening visit to the end of the study (event-driven, anticipate 1-2 years)
Target Sample Size
Total Sample Size="2600" Sample Size from India="200" Final Enrollment numbers achieved (Total)= "2781" Final Enrollment numbers achieved (India)="205"
The present randomized double-blind placebo-controlled study objective is to assess the cardiovascular safety and efficacy of Roxadustat in patients with stage 3, 4, or 5 CKD who are anemic and not on dialysis.
Patients will be randomized (1:1) to double-blind treatment with roxadustat or placebo, TIW and titrated to achieve and maintain Hb 11±1 g/dL. Treatment duration is variable for individual patients (estimated treatment duration 1 to 2 years). A study end date will be declared and common closeout will occur when the target number of CV events has been accrued.