A Study of Ravulizumab to Protect Patients with Chronic Kidney Disease (CKD) from Cardiac Surgery Associated-Acute Kidney Injury and Major Adverse Kidney Events
Scientific Title of Study
RAvulizumab to PRotect PaTients with Chronic Kidney DisEase (CKD) froM Cardiac Surgery Associated Acute Kidney Injury (CSA-AKI) and Subsequent Major Adverse Kidney Events (MAKE): A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study
Trial Acronym
ARTEMIS
Secondary IDs if Any
Secondary ID
Identifier
D928DC00001 Amendment version 1 dated 12 JUN 2023
Protocol Number
NCT05746559
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Santosh Kadam
Designation
Director, SMM BioPharmaceuticals
Affiliation
AstraZeneca Pharma India Ltd.
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road
Bangalore KARNATAKA 560045 India
Phone
9535999494
Fax
Email
santosh.kadam@astrazeneca.com
Details of Contact Person Scientific Query
Name
Dr Santosh Kadam
Designation
Director, SMM BioPharmaceuticals
Affiliation
AstraZeneca Pharma India Ltd.
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road
Bangalore KARNATAKA 560045 India
Phone
9535999494
Fax
Email
santosh.kadam@astrazeneca.com
Details of Contact Person Public Query
Name
Dr Santosh Kadam
Designation
Director, SMM BioPharmaceuticals
Affiliation
AstraZeneca Pharma India Ltd.
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road
Bangalore KARNATAKA 560045 India
Phone
9535999494
Fax
Email
santosh.kadam@astrazeneca.com
Source of Monetary or Material Support
Alexion Pharmaceuticals Inc.
121 Seaport Boulevard
Boston MA 02210
USA
Primary Sponsor
Name
Alexion Pharmaceuticals, Inc.,
Address
121 Seaport Boulevard, Boston MA 02210, USA
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AstraZeneca AB
151 85 Sodertalje, Sweden
AstraZeneca Pharma India Ltd
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road, Bangalore - 560045,
Karnataka, India
Countries of Recruitment
Argentina Australia Brazil Canada China Germany Hong Kong India Israel Italy Japan Netherlands Poland Republic of Korea Spain Taiwan Turkey United Kingdom United States of America
Participants randomized to the Placebo group will receive a single dose of placebo 1 to 7 days (ie, at least 1 calendar day) prior to CPB procedure.
Intervention
Ravulizumab
Participants randomized to the ravulizumab group will receive a single weight-based dose of ravulizumab unmit dose strength 300 gm (10mg/ml concentrated solution) 1 to 7 days (ie, at least 1 calendar day) prior to CPB procedure.
More than or equal to 30 to less than 40kg is 2700mg, More than or equal to 40 to less than 60kg is 3000mg, more than or equal to 60 to less than 100kg is 3300mg, more than or equal to 100kg is 3600mg. This is a single dose study.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
90.00 Year(s)
Gender
Both
Details
1. Greater than or equal to 18 to less than or equal to 90 years of age at the time of signing the informed consent.
2. Male or female.
3. Body weight greater than or equal 30 kg at Screening.
4. Planned non-emergent sternotomy with CPB procedure for the following surgeries
i. Multi-vessel CABG
ii. Valve replacement or repair; ascending aorta surgery permitted if combined with aortic valve replacement or repair
iii. Combined CABG and valve surgery; inclusion of single-vessel CABG when combined with valve replacement or repair is permitted.
5. Known CKD for at least 90 days with eGFR Greaterthan or equal to 20 to less than 60 mL min 1.73 m2 CKD Stage 3A, 3B, or 4 at Screening
6. At risk for postsurgical AKI as defined by a minimum STS Calculator Renal Failure Risk Score of 3 percentage assessed at time of screening.
7. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol
ExclusionCriteria
Details
1. Emergency or salvage cardiac surgery is expected at screening or randomization, as assessed by the Investigator
2. Single-vessel CABG without valve surgery is planned.
3. Off-pump surgery is planned (eg, surgery without CPB).
4. Any use of KRT or presence of AKI within 30 days of randomization (AKI defined as 1.5× increase in sCr over baseline), except transient (less than or equal to 5 days) Stage 1 AKI after iodinated contrast exposure
5. Recipient of a solid organ or bone marrow transplantation.
6. Cardiogenic shock, hemodynamic instability, use of intra-aortic balloon pump (IABP), extracorporeal membrane oxygenation, or left ventricular assist device within 72 hours of randomization.
7. Active systemic bacterial, viral, or fungal infection within 14 days prior to randomization.
8. Participants with history of human immunodeficiency virus (HIV) who are not on anti- retroviral therapy or if on therapy have a known detectable viral load within 1 year of Screening
9. Congenital immunodeficiency.
10. History of unexplained, recurrent infection.
11. Known medical or psychological condition(s), including substance abuse, or risk factor that, in the opinion of the Investigator, might interfere with the participant s full participation in the study, pose any additional risk for the participant, or confound the assessment of the participant or outcome of the study.
12. History of, or unresolved, N meningitidis infection.
13. Hypersensitivity to any ingredient contained in the study intervention, including hypersensitivity to murine proteins.
14. Current malignancy or receiving treatment for malignancy except for non-melanoma skin cancer.
15. Use of any complement inhibitors, or plasmapheresis or plasma exchange within the year prior to Screening, or planned use during the course of the study
16. Planned use of any pharmacologic agent specifically for prevention or treatment of AKI
17. Planned use of KRT, IABP, extracorporeal membrane oxygenation, or left ventricular assist device between randomization and surgery.
18. Participation in another interventional treatment study or use of any experimental therapy within 30 days before initiation of study intervention on Day 1 in this study or within 5 half lives of that IP, whichever is greater, or planned participation use during the course of the study.
19. Presence of a do-not-resuscitate order or life expectancy of less than 3 months
20. Pregnant, breastfeeding, or intending to conceive within 8 months after the dose of study intervention.
21. Participant is not willing to be vaccinated against N meningitidis or is unwilling to receive prophylactic treatment with appropriate antibiotics
Method of Generating Random Sequence
Stratified block randomization
Method of Concealment
Centralized
Blinding/Masking
Participant, Investigator and Outcome Assessor Blinded
Primary Outcome
Outcome
TimePoints
To assess the efficacy of ravulizumab in reducing risk of MAKE90 following CPB
Adult participants with CKD as defined by the inclusion and exclusion criteria
To assess the efficacy of ravulizumab in reducing risk of MAKE90 following CPB at DAY 90 post CPB.
Secondary Outcome
Outcome
TimePoints
To assess the efficacy of ravulizumab in reducing risk of AKI (based on sCr) following CPB
1) CSA-AKI free at Day 90 post CPB
2) Free of severe CSA-AKI KDIGO Stage 2 or 3 based on highest observed sCr within 7 days post CPB
3) Free of any severe AKI RIFLE Injury or Failure criteria based on highest observed sCr within Day 30 post CPB
4) Free of any severe AKI KDIGO Stage 2 or 3 based on highest observed sCr within Day 30 post CPB
5) Free of any RIFLE Failure criteria based on highest observed sCr within Day 30 post CPB
6) All cause mortality from randomization
Other Secondary Efficacy
To assess the efficacy of ravulizumab in reducing risk of MAKE, MAKE (based on sCr), AKI (based on sCr), and related outcomes
Other Secondary Efficacy
To assess the efficacy of ravulizumab in reducing risk of MAKE, MAKE (based on sCr), AKI (based on sCr), and related outcomes following CPB:
Mak and its components at Days 30, 60, and 90 post CPB
Occurrence of KRT or death by Days 30, 60, and 90 post CPB
Highest CSA-AKI stage within 3 and 7 days post CPB
CSA AKI free at Day 15, 30, and 60 post CPB
CSA AKI free at Day 15, 30, and 60 post CPB
Free of any AKI at Days 3, 7, 15, 30, 60, and 90 post CPB
Other Secondary Efficacy
To assess the efficacy of ravulizumab in reducing risk of MAKE, MAKE (based on sCr), AKI (based on sCr), and related outcomes contd..
AKI Progression on Days 15, 30, 60, and 90 post CPB for those experiencing CSA-AKI within 7 days post CPB:
- Complete recovery
- Partial recovery
- Improvement
- Stable
- Worsening
Healthcare Resource Utilization
To assess the effect of ravulizumab on health resource utilization in participants with CKD undergoing non-emergent CPB:
Length of index hospital and ICU stay
Number of ventilator-free days through Day 30 and Day 90 post CPB
Hospital readmission rate (all-cause or AKI-related) through Day 30 and Day 90 post CPB
Health-related QoL
To assess the effect of ravulizumab on quality of life in participants with CKD undergoing non-emergent CPB.
Change from baseline in KDQOL-36â„¢ at Days 30, 60, and 90 post CPB
Change from baseline in EQ-5D-5L at Days 30, 60, and 90 post CPB
Change from baseline in FACIT-Fatigue at Days 30, 60, and 90 post CPB
PK and PD
To evaluate PK and PD of ravulizumab in participants with CKD undergoing non-emergent CPB
Serum concentrations of ravulizumab
Absolute values, change from baseline and percent change from baseline in serum free C5 concentrations
Safety:
To evaluate safety of ravulizumab IV in participants with CKD undergoing non-emergent CPB
Incidence of TEAEs and TESAEs
Change from baseline in laboratory parameters at scheduled visits
Immunogenicity
To evaluate the immunogenicity of ravulizumab IV in participants with CKD undergoing non-emergent CPB
ADA incidence, ADA response categories, and titer at Day 90 post CPB
Exploratory
To assess biomarkers at baseline and change in response to treatment
Biomarker assessments may include, but are not limited to, complement pathway activation (eg, plasma and urine soluble C5b-9), renal injury (eg, urine NGAL) and endothelial damage (eg, plasma TM)
To assess the efficacy of ravulizumab in reducing risk of CSA-AKI based on sCysC
AKI within 7 days post CPB based on sCysC:
- Highest AKI stage by KDIGO criteria
- Free of severe AKI (KDIGO Stage 2 or 3)
Target Sample Size
Total Sample Size="736" Sample Size from India="30" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Phase of Trial
Phase 3
Date of First Enrollment (India)
25/06/2024
Date of Study Completion (India)
Applicable only for Completed/Terminated trials
Date of First Enrollment (Global)
02/03/2023
Date of Study Completion (Global)
Applicable only for Completed/Terminated trials
Estimated Duration of Trial
Years="1" Months="8" Days="0"
Recruitment Status of Trial (Global)
Open to Recruitment
Recruitment Status of Trial (India)
Not Yet Recruiting
Publication Details
N/A
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study of ravulizumab in adult participants with CKD and stable cardiac disease undergoing non-emergent sternotomy with CPB for coronary artery bypass graft (CABG), valve replacement or repair, or combined procedure, to reduce the risk of post-operative AKI and subsequent MAKE at 90 days after surgery. Participants considered at risk for AKI after CPB have estimated glomerular filtration rate (eGFR) ≥ 20 to < 60 mL/min/1.73 m2 with minimum Society of Thoracic Surgeons (STS) Calculator Renal Failure Risk Score of 2.8%.
The study consists of a Screening Period of up to 28 days with Randomization and Dosing within 1 to 7 days prior to surgery with CPB, a 90-day Primary Evaluation Period post CPB, and a Survival Follow-up including assessment of KRT status at 365 days post CPB.