ARTEMIS: A Phase 3 Study of Ravulizumab to Protect Patients with Chronic Kidney Disease (CKD) from Cardiac Surgery Associated Acute Kidney Injury (CSA-AKI) and Major Adverse Kidney Events (MAKE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alexion Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

16 Jun 2023 → 30 Apr 2026

Decision date (initial)

2024-11-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2022-501802-36-00

ClinicalTrials.gov

NCT05746559

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis

To assess the efficacy of ravulizumab in reducing risk of MAKE90
following CPB

Secondary objectives 7

1. To assess the efficacy of ravulizumab in reducing risk of AKI (based on sCr) following CPB
2. To assess the efficacy of ravulizumab in reducing risk of MAKE (based on sCysC), MAKE (based on sCr), AKI (based on sCr), and related outcomes following CPB
3. To assess the effect of ravulizumab on health resource utilization in participants with CKD undergoing non-emergent CPB
4. To assess the effect of ravulizumab on quality of life in participants with CKD undergoing non-emergent CPB
5. To evaluate PK and PD of ravulizumab in participants with CKD undergoing non-emergent CPB
6. To evaluate safety of ravulizumab IV in participants with CKD undergoing non-emergent CPB
7. To evaluate the immunogenicity of ravulizumab IV in participants with CKD undergoing non-emergent CPB

Conditions and MedDRA coding

Prevention of cardiac surgery associated acute kidney injury

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, Pharmaceuticals And Medical Devices Agency, European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Alexion has a public commitment to allow requests for access to study data and will be supplying a protocol, CSR and plain language summaries.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. ≥ 18 to ≤ 90 years of age at the time of signing the informed consent.
2. Male or female; Female participants of childbearing potential and male participants must follow protocol-specified contraception guidance.
3. Body weight ≥ 30 kg at Screening.
4. Planned non-emergent cardiac surgery requiring CPB for the following procedures: Multi-vessel CABG; Valve replacement or repair; ascending aorta surgery permitted if combined with aortic valve replacement/repair; Combined CABG and valve surgery; inclusion of single-vessel CABG when combined with valve replacement/repair is permitted
5. Known or apparent CKD (by history, diagnostic results, or reasonable medical assessment made by the Investigator and recorded in the medical record) and eGFR ≥ 20 to < 60 mL/min/1.73 m2 using CKD-EPI equation by sCr or sCysC measurement, obtained by local or central laboratory during the 28 days prior to randomization
6. At risk for postsurgical kidney events as defined by a minimum STS Calculator Renal Failure Risk Score of ≥ 2.8% 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 (ICF) and in this protocol.

Exclusion criteria 22

1. Emergency or salvage cardiac surgery is expected at screening or randomization, as assessed by the Investigator
2. History of unexplained, recurrent infection.
3. 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.
4. History of, or unresolved, N meningitidis infection
5. Hypersensitivity to any ingredient contained in the study intervention, including hypersensitivity to murine proteins.
6. Current malignancy (excluding local or regional prostate cancer or non-melanoma skin cancer, or indolent disease not being treated) or receiving treatment for malignancy
7. 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.
8. Planned use of any pharmacologic agent specifically for prevention or treatment of AKI.
9. Anticipated use of KRT, extracorporeal membrane oxygenation, or temporary cardiac support devices including left ventricular assist device between randomization and surgery. Elective or pre-emptive insertion of temporary cardiac support devices (including IABP) in the absence of cardiogenic shock or hemodynamic instability.
10. 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 investigational product (IP), whichever is greater, or planned participation/use during the course of the study.
11. Presence of a do-not-resuscitate order or life expectancy of < 3 months.
12. Single-vessel CABG without valve surgery is planned.
13. Pregnant, breastfeeding, or intending to conceive within 8 months after the dose of study intervention.
14. Participant is not willing to be vaccinated against N meningitidis or is unwilling to receive prophylactic treatment with appropriate antibiotics, if needed
15. Off-pump surgery is planned (eg, surgery without CPB).
16. Any use of KRT or presence of AKI within 30 days prior to randomization (AKI defined as 1.5x increase in sCr over baseline), except transient (≤ 5 days) Stage 1 AKI after iodinated contrast exposure. Presence of AKI must be assessed within 72 hours prior to randomization.
17. Recipient of a solid organ or bone marrow transplantation.
18. Cardiogenic shock or hemodynamic instability, including use of intra-aortic balloon pump (IABP) or other temporary cardiac output support device, extracorporeal membrane oxygenation (ECMO), or left ventricular assist device within 72 hours prior to randomization.
19. Active systemic bacterial, viral, or fungal infection within 14 days prior to randomization.
20. 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 prior to Screening.
21. Congenital immunodeficiency.
22. Use of IVIg (eg, as acute therapy) within 4 weeks prior to dosing.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. MAKE90 defined as meeting at least 1 of the following criteria: o Decrease from baseline in eGFR (CKD-EPI formula using sCysC) of ≥ 25% at Day 90 post CPB, or o Initiation of KRT through Day 90 post CPB, or o Death from any cause through Day 90 post CPB

Secondary endpoints 18

1. 1) Occurrence of CSA-AKI without recovery at Day 90 post CPB
2. 2) Occurrence of severe CSA-AKI (KDIGO Stage 2 or 3) from randomization to Day 7 post CPB
3. 3) Occurrence of severe AKI (KDIGO Stage 2 or 3) from randomization to Day 30 post CPB
4. 6) Length of post-operative ICU stay
5. 4) Occurrence of KRT or death from randomization to Day 90 post CPB
6. 5) All-cause mortality from randomization to Day 90 post CPB
7. MAKE and its components at Days 30, 60 and 90 post CPB (excluding MAKE90 based on sCysC)
8. Occurrence of KRT or death by Days 30 and 60 Post CPB
9. Highest CSA-AKI stage within 3 and 7 days post CPB
10. Occurrence of CSA-AKI without recovery at Day 15, 30 and 60 post CPB
11. Occurrence of AKI at Days 3, 7, 15, 30, 60, and 90 post CPB
12. 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
13. • Length of post-operative hospital stay • Number of days on ventilator through Day 30 and Day 90 post CPB; • Hospital readmission rate (all-cause or AKI-related) through Day 30 and Day 90 post CPB; • Days on KRT through Day 30 and Day 90 post CPB
14. Change from baseline in KDQOL-36™ 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
15. Serum concentrations of ravulizumab; Absolute values, change from baseline and percent change from baseline in serum free C5 concentrations
16. • TEAEs and TESAEs; • Change from baseline in laboratory parameters at scheduled visits
17. ADA status, ADA response categories, and titer at Day 90 post CPB
18. Occurrence of post-operative Renal Failure (STS metric based on RIFLE Failure creatinine criteria)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alexion Pharmaceuticals Inc.

Sponsor organisation

Alexion Pharmaceuticals Inc.

Address

121 Seaport Boulevard

City

Boston

Postcode

02210-2050

Country

United States

Scientific contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Public contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Locations

8 EU/EEA countries · 49 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 100 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

16 submissions — initial application plus substantial / non-substantial modifications