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Abstract
Introduction Acute kidney injury (AKI) is a common complication after cardiac surgery (CS) and is associated with adverse short-term and long-term outcomes. Alpha-1-microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme binding and mitochondrial-protective mechanisms. RMC-035 is a modified, more soluble, variant of A1M and has been proposed as a novel targeted therapeutic protein to prevent CS-associated AKI (CS-AKI). RMC-035 was considered safe and generally well tolerated when evaluated in four clinical phase 1 studies.
Methods and analysis This is a phase 2, randomised, double-blind, adaptive design, parallel group clinical study that evaluates RMC-035 compared with placebo in approximately 268 cardiac surgical patients at high risk for CS-AKI. RMC-035 is administered as an intravenous infusion. In total, five doses will be given. Dosing is based on presurgery estimated glomerular filtration rate (eGFR), and will be either 1.3 or 0.65 mg/kg.
The primary study objective is to evaluate whether RMC-035 reduces the incidence of postoperative AKI, and key secondary objectives are to evaluate whether RMC-035 improves postoperative renal function compared with placebo. A blinded interim analysis with potential sample size reassessment is planned once 134 randomised subjects have completed dosing. An independent data monitoring committee will evaluate safety and efficacy data at prespecified intervals throughout the trial. The study is a global multicentre study at approximately 30 sites.
Ethics and dissemination The trial was approved by the joint ethics committee of the physician chamber Westfalen-Lippe and the University of Münster (code ‘2021-778 f-A’) and subsequently approved by the responsible ethics committees/relevant institutional review boards for the participating sites. The study is conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal.
Trial registration number NCT05126303.
- Cardiac surgery
- Acute renal failure
- Adult intensive & critical care
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The trial was designed by a group of global experts in acute kidney injury (AKI) and cardiac surgery, with input from or review by the US Food and Drug Administration and several national medicinal regulatory authorities in Europe and North America.
This trial uses an adaptive trial design while preserving data integrity based on a blinded interim analysis, allowing for reassessment of statistical assumptions, for example, AKI event rate, with the possibility to increase the number of patients to be recruited.
Trial subjects will be recruited at multiple centres in Europe and North America that are considered to reflect standard of care in cardiac surgery.
The trial is not powered to show differences in less frequently occurring longer-term outcomes such as major adverse kidney events.
Introduction
Globally, an estimated 2 million cardiovascular procedures per year are performed.1 Acute kidney injury (AKI) is considered an important determinant of mortality in patients undergoing cardiovascular surgery.2 3 Various epidemiological studies show that cardiac surgery-associated AKI (CS-AKI) occurs in up to 30% of CS patients4 and is associated with an increased morbidity as well as short-term and long-term mortality.5–8 The short-term and long-term mortality rate are 10.7% and 30%, respectively, and increase along with severity of stages.6 Heart failure, chronic hyperglycaemia, anaemia, obesity, preoperative exposure to nephrotoxic drugs or contrast media, inflammation, proteinuria, and pre-existing kidney disease were systematically reviewed and were found to be associated with an increased risk of postoperative CS-AKI.9
In clinical studies evaluating potential treatments to prevent CS-AKI in high-risk groups, event rates of AKI up to 65.5% in a high-risk population10 and 71.7% in patients with a positive biomarker test (that identifies patients at very high risk for AKI) shortly after surgery11 have been reported. Recent studies on CS-AKI showed that patient enrichment based on the combination of the complexity of surgery and comorbidities resulted in AKI rates between 28% and 34.2%.12 13
Current treatment strategies and clinical management of CS-AKI are mainly supportive, including optimal fluid management and maintenance of haemodynamic stability.14 At present, no specific therapeutic interventions are available for prevention or treatment of CS-AKI. This is an area of large unmet clinical need, where patients who develop CS-AKI are at risk for additional severe complications, including need for renal replacement therapy (RRT), development of chronic kidney disease (CKD) and mortality. Thus, a single AKI episode after CS can lead to a significant burden of comorbidities, prolonged hospital stays, poor quality of life and high long-term costs.
Recombinant alpha-1-microglobulin
The investigational medicinal product (IMP), RMC-035, contains the pharmacologically active protein RMC-035, which is a recombinant and modified variant of endogenous human alpha-1-microglobulin (A1M). It has four distinct molecular mechanisms, including heme binding, reductase activity, radical scavenging and mitochondrial binding/protection.15 Employing several antioxidative mechanisms, it protects cells and tissues from various forms of cell damage caused by oxidative stress, including free radicals and reactive oxygen species.16–19
RMC-035 has been evaluated in four phase 1 clinical studies: single ascending dose and multiple ascending dose studies in healthy subjects, a renal impairment study, and a phase 1b pharmacokinetic and safety study in CS patients. Available clinical data indicate that RMC-035 is safe and generally well tolerated across study populations and support its continued development in CS-AKI.
The pharmacological characteristics of RMC-035 are appropriate for the chosen indication of CS-AKI as it targets multiple critical disease pathways of CS-AKI, including ischaemia–reperfusion injury, heme toxicity and mitochondrial dysfunction. Furthermore, RMC-035 is rapidly distributed to kidney proximal tubular cells (via glomerular filtration), resulting in high drug exposure in the cells where the primary injury occurs in AKI. It is administered as intravenous infusion with short systemic half-life, which is ideal for hospitalised patients requiring specific renal protection.
Trial objectives
This is a phase 2, randomised, placebo-controlled, double-blind, adaptive design, parallel group clinical study to evaluate the efficacy and safety of RMC-035 in subjects at high risk for AKI following open-chest CS. The study is being conducted to provide proof-of-concept efficacy data and to guide the design of a subsequent pivotal study in this patient population. Based on an integrated assessment of available non-clinical and clinical data, RMC-035 is considered to be well tolerated and is expected to provide targeted renal protection in this patient population, with the aim to prevent or ameliorate perioperative and postsurgery renal injury.
Primary objectives are to evaluate RMC-035 for the following outcomes:
Prevention of AKI (Kidney Disease Improving Global Outcomes (KDIGO)) definition20 in subjects undergoing CS with additional risk factors for developing CS-AKI.
Safety and tolerability.
Key secondary objectives are to evaluate RMC-035 for the following outcomes:
To evaluate RMC-035 for the prevention of postoperative decline (within 72 hours) in renal function.
To evaluate RMC-035 for the reduction of postoperative AKI duration.
Other secondary objectives are to evaluate RMC-035 for the following outcomes:
To evaluate RMC-035 for preserving postsurgery renal function up to day 90.
To evaluate RMC-035 for the prevention of postoperative dialysis up to day 90.
To evaluate RMC-035 for the prevention of major adverse kidney events (MAKE) at days 30 and 90, respectively.
To evaluate RMC-035 for the prevention of AKI within 72 hours (based on cystatin C and/or urine output (UO)).
To further evaluate RMC-035 for the prevention, persistence and severity of AKI within 72 hours (based on serum creatinine (SCr) and/or UO or cystatin C and/or UO)and within 7 days (based on SCr and/or UO r cystatin C and/or UO).
To evaluate RMC-035 for reducing postoperative albuminuria and proteinuria up to day 90.
To evaluate the pharmacokinetics of RMC-035.
Identification and characterisation of antidrug antibodies (ADA) developed after intravenous administration of RMC-035.
Exploratory objectives are to evaluate:
Postbaseline changes in kidney and cardiac biomarkers.
Length of postoperative stay in intensive care unit and overall hospitalisation time.
Health-related quality of life.
Methods and analysis
Patients
The target patient population is adults undergoing open-chest CS, that is, coronary artery bypass grafting and/or valve surgery and/or aorta surgery with additional predisposing risk factors for CS-AKI. Subjects planned to undergo CS will be systematically screened for eligibility. Informed consent will be obtained by study site’s principal or subinvestigators in all eligible patients before randomisation and surgery. Inclusion and exclusion criteria are described in table 1.
Inclusion and exclusion criteria
Main outcomes
Primary endpoints
Primary efficacy endpoint
Proportion of patients developing AKI within 72 hours after first dose of IMP, based on SCr and/or UO (AKI of any stage/severity according to KDIGO definition, that is, SCr ≥1.5 times baseline, or increase of SCr of ≥0.3 mg/dL (≥26.5 µmol/L), or UO <0.5 mL/kg/hour for ≥6 hours).
Primary safety endpoint
Nature, frequency and severity of treatment-emergent adverse events (TEAEs; defined as any AE which occur within 72 hours after last IMP administration).
Secondary endpoints
Key secondary endpoints
Time-corrected area under the curve (AUC) of SCr for days 1–4 (72 hours after first dose of IMP).
Duration of AKI defined as the number of days meeting the definition of AKI (KDIGO definition) starting within 72 hours after first dose of IMP until resolution.
For other secondary endpoints and exploratory endpoints, please see table 2.
Other secondary endpoints and exploratory endpoints
Trial oversight
A scientific advisory board of experts in anaesthesiology and CS has been established by the sponsor to facilitate design of the trial, provide medical scientific leadership and make trial-specific recommendations to the sponsor. Likewise, an independent unblinded data monitoring committee (DMC) consisting of experts in AKI and a statistician will perform review of safety findings at regular intervals during the study. The working procedures of the DMC are defined in a DMC charter; their safety evaluation will be based on all available accumulated safety data. The DMC will also be responsible for recommendation on the study conduct following the interim analysis (IA) based on predefined unblinded statistical output. Communication and recommendations by the DMC will be blinded. Completeness and accuracy of the data will be monitored by a clinical research organisation, which performs regular monitoring visits.
Patient and public involvement statement
Reflecting the acute and unpredictable nature of CS-AKI, there are no specific patient advocacy groups at present; closest are organisations that represent kidney diseases after CS in general and, although they are aware of our programme, they were not specifically consulted on the design of this study.
Trial design
Overall study design
This is a phase 2, multicentre, randomised, double-blind, placebo-controlled, adaptive design, parallel group trial including patients undergoing open-chest CS. The study consists of a screening period of up to 30 days before surgery, five in-hospital visits during the anticipated postoperative hospitalisation period and two additional follow-up visits at day 30 and day 90, respectively. A study flow chart is shown in figure 1 and the schedule of study specific assessments is presented in table 3. The study reporting was assessed following Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines and is presented in the SPIRIT checklist in online supplemental material 1.
Supplemental material
Schedule of assessments—complete study protocol
Plasma pharmacokinetics (PK) sampling scheme
Plasma and urinary biomarker sampling scheme
Study flow chart. AE, adverse event; ICU, intensive care unit; SAE, serious AE.
Randomisation procedure
The trial population consists of patients at high risk for AKI and undergo CS with additional predisposing risk factors for CS-AKI (inclusion and exclusion criteria are shown in table 1). Eligible subjects will be randomised to receive either RMC-035 or placebo in a 1:1 randomisation ratio. Both region (EU vs North America) and preoperative eGFR calculated using the CKD-Epidemiology Collaboration (EPI) equation with SCr on local laboratory results (≥60 and <60 mL/min/1.73 m2) will be used as stratification factors to ensure a balanced randomisation within these groups. Randomisation will be performed by the investigators using the centralised electronic randomisation platform. Randomisation codes will be subsequently computer generated and sent to study pharmacists for IMP preparation.
IMP presentation and blinding
The investigator, study personnel and subject will be blinded to the identity of the IMP (RMC-035 or placebo). The investigational pharmacist will be responsible for the preparation of IMP for each subject and will be unblinded to the randomisation assignment. In the event of a medical emergency requiring knowledge of the treatment assigned to the subject, unblinding can be performed and the treatment code for a given randomised subject will be provided. The time, date, subject number and reason for obtaining any of these codes, and therefore, breaking the blind will be documented in the study file. The treatment code can only be requested by the investigator or other persons designated as subinvestigators. No subjects or study personnel will be made aware of the treatment given unless a medical emergency necessitates such disclosure. Both IMP and placebo will be presented in 50 mL syringes and labelled in a standardised manner. Label information includes study protocol number, subject-ID, syringe number, date and time of IMP preparation, IMP content (RMC-035 or placebo) and sponsor contact information, but no information about randomisation group. Both RMC-035 and placebo are transparent, odourless fluids that cannot be differentiated optically or by other sensations. Pharmacokinetic samples taken at the study sites and evaluated in a central laboratory of the sponsor will be used to determine systemic exposure to study drug.
IMP dosing
In total, five intravenous doses of either RMC-035 or placebo will be administered during the study. The first dose will start approximately 10 min before cardiopulmonary surgery is initiated (0 hour), and subsequent doses will be given at 6, 12, 24 and 48 hours later. IMP will be given as a continuous intravenous infusion over either 60 min (first two doses) or 30 min for subsequent doses. Due to the pharmacokinetic properties of RMC-035, the predefined dose levels (prior to surgery) are based on renal function (eGFR by CKD-EPI equation with SCr) at screening (day −1, visit 1): (1) subjects with eGFR ≥60 mL/min/1.73 m2 will receive 1.3 mg/kg (per dose) for the first and second dose, followed by 0.65 mg/kg (per dose) for the third, fourth and fifth dose; (2) subjects with eGFR >30 and <60 mL/min/1.73 m2 will receive 0.65 mg/kg (per dose) for all five doses. The trial drug is provided on top of standard of care of each centre.
Permanent discontinuation of IMP
Local laboratory results will be used for clinical care and real time evaluation of AKI for purposes of IMP discontinuation. Subjects who meet any of the following IMP discontinuation criteria during the treatment period will be discontinued from IMP and continue study participation and procedures and follow-up as per the schedule of assessment until the end of the study visit: (1) development of stage ≥2 AKI, according to KDIGO definition, (2) need for RRT, (3) need for percutaneous or surgical mechanical circulatory support or extracorporeal membrane oxygenator, (4) reporting of a grade 3 (per Common Terminology Criteria for Adverse Events) or higher AE of Injection-site reaction (ISR) or Infusion-related reaction (IRR), and which is considered to be an immune-mediated reaction
The IMP will be discontinued in case of any of the following abnormal liver chemistry tests in blood: (1) alanine aminotransferase (ALT) > 3× upper limit of normal (ULN) combined with total bilirubin >2 × ULN in the same sample, (2) ALT >3 × ULN if associated with symptoms (new or worsening) believed to be related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia), (3) ALT >3 × ULN if confirmed in a second sample within 24 hours and in the second sample international normalised ratio is increased to >1.5 × ULN, (4) ALT >8 × ULN in any individual sample during the treatment period. All liver chemistry abnormalities as summarised above need to be followed up regularly (at least every 24 hours) until values have returned to baseline or are considered stable. If IMP is discontinued, the subject will remain in the study to be evaluated until the end of the study visit (as much as possible) or complete the end of the study visit assessments.
Planned sample size and IA
A minimum of 268 and a maximum of 348 patients are planned to be randomised at approximately 30 sites predominantly across Europe and North America. The final number of patients randomised will depend on the results of the IA.
There will be one IA during the trial which will be conducted once 50% of the planned randomised subjects have completed visit 6 (days 5–9). Sample size may be increased to a maximum of 348 randomised subject but will not be decreased. The study may be stopped at the IA for futility or safety reasons. Study eligibility criteria may also be modified.
Safety reporting
Safety is followed up until last study visit at day 90. Serious AEs (SAEs) will be reported to the sponsor and other stakeholders as per regulatory requirements (eg, competent authorities and/or IRBs/CECs, when applicable). Non-SAEs will only be reported up to day 30 TEAEs are defined as AEs, which occur after the initial IMP administration through 72 hours after last IMP administration. Safety reporting will be managed by a clinical research organisation in compliance with regulatory requirements of each region of the study.
Statistical considerations
For the primary endpoint, KDIGO AKI (serum creatinine and UO) within 72 hours after first dose of IMP, RMC-035 has been assumed to lead to a 30% relative risk reduction versus placebo. The event rate in the placebo group has been assumed to be 50%.21 A sample size of 268 subjects randomised leads to a test power of 80% to show statistically significant results at a two-sided significance level (alpha) of 0.10.
The primary endpoint will be analysed by the Cochran-Mantel-Haenszel estimate of the common relative risk (RMC-035 vs placebo) across the four stratification groups formed by region and preoperative eGFR (≥60 and <60 mL/min/1.73 m2). In addition, the proportion of subjects with AKI within 72 hours after first dose of IMP and its 90% CI will be calculated for each treatment group. The hypotheses to be tested are as follows: (1) Null hypothesis: the proportion of subjects developing AKI within 72 hours after first dose of IMP is the same for the RMC-035 and the placebo treatment groups (pRMC-035=pplacebo), (2) Alternative hypothesis: the proportion of subjects developing AKI within 72 hours after first dose of IMP is different for the RMC-035 and the placebo treatment groups (pRMC-035 ≠ pplacebo).
All secondary endpoints have a supplementary character and will be reported with no strict control of the type I error. Secondary continuous efficacy endpoints that are measures of renal function will be analysed using robust regression of log-transformed values having sequentially imputed any missing data using multiple imputation. A sensitivity analysis will be performed using a mixed model for repeated measurements (MMRM) if data are approximately normally distributed.
For the key secondary AUC endpoint, the geometric least square means of the time-corrected AUC of SCr for days 1–4 will be obtained for each, RMC-035 and placebo, by transforming the model estimates back to the original scale.
Supportive analyses of renal function will be performed on cystatin C levels (and corresponding eGFR values assessed by CKD-EPI equations with either SCr, cystatin C or both) and cumulative AUC values up to each timepoint. Secondary binary efficacy endpoints will be analysed using the same approach as specified above for the primary endpoint.
Further details on the IA and the control of the type I error will be provided in the DMC Charter and the statistical analysis plan (SAP).
Safety endpoints
Safety analyses will be conducted on the safety analysis set, which includes all randomised subjects who received at least 1 dose of IMP. To characterise the safety profile, the number and percentage of subjects with TEAEs and AEs per dose group will be tabulated. Descriptive statistics will be provided for laboratory tests (haematology, biochemistry, urinalysis) and vital signs (pulse rate, respiratory rate and blood pressure) by visit and for the changes from baseline to each visit split by treatment group. In addition, the development of ADAs after intravenous administration of RMC-035 will be investigated and characterised.
Pharmacokinetics
Descriptive statistics will be presented for plasma concentrations by scheduled sample time. Specific pharmacokinetic parameters will be presented separately. Summaries will be provided by dose group, age group and by renal function prior to surgery.
Sensitivity analyses and secondary endpoints
Secondary continuous efficacy endpoints that are measures of renal function will be analysed using robust regression of log-transformed values having sequentially imputed any missing data using multiple imputation. A sensitivity analysis will be performed using a MMRM if data are approximately normally distributed. The relative difference (RMC-035 vs placebo) and its 90% CI will also be reported.
Supportive analyses of renal function will be performed by using cystatin C levels (and corresponding eGFR values assessed by CKD-EPI equations with either SCr, cystatin C or both) and cumulative AUC values up to each time point.
Secondary binary efficacy endpoints will be analysed using the same approach as specified above for the primary endpoint.
Additional sensitivity analyses of the primary and secondary endpoints, and evaluation of exploratory endpoints, will be detailed in the SAP.
Ethics and dissemination
This trial will be conducted in accordance with the protocol and consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organisations of Medical Sciences International Ethical Guidelines; applicable International Conference on Harmonisation Good Clinical Practice Guidelines; and applicable laws and regulations. The protocol, substantial protocol amendments, ICF, IB and other relevant documents (eg, any other written information regarding this trial to be provided to the patient or the patient’s legal representative) are approved by the Ethics Committee of the Physicians Chamber Westfalen-Lippe and the University of Münster in Germany (file number 2021-778 f-A), as well as the relevant ethics committees or institutional review boards at all participating sites.
Informed consent will be given by patients before any study relevant procedure is performed. Patients will be assigned a unique patient identification number. Any patient records or datasets that are transferred to the Sponsor will contain this identifier only; patient names and any information which would make the patient identifiable will not be transferred. All laboratory specimens, evaluation forms, reports and other records will be identified in a manner designed to maintain patient confidentiality.
Irrespective of whether the trial is completed or prematurely terminated, the sponsor will ensure that the trial results will be posted on publicly available clinical trial registries in accordance with their requirements. In addition, results will be presented at international congresses and published in peer-reviewed journals. Participant-level access to data will not be granted to the public.
Conclusions
The ongoing phase 2 (AKITA) study is specifically designed to answer the primary research question whether the investigational drug RMC-035 can reduce the occurrence of CS-AKI within 3 days after open CS. Study results will also provide pertinent information on other clinically relevant endpoints, such as the severity, duration and persistence of AKI, changes in postoperative renal function and MAKE, and will significantly expand the current knowledge of the safety profile of RMC-035. Finally, biomarker analysis may improve the understanding of its mechanism of action, shed light on relevant disease pathways in CS-AKI and facilitate the design of future clinical trials of RMC-035.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @thilo_vg
Contributors AZ, CDM, TEL and RR codrafted the manuscript. NS-F, JB, FW, AM, CDB, JLK, AB, DTE, BdV, NN, MT, AL, ML, TvG and CR participated in trial protocol design, reviewed and edited the manuscript.
Funding This work was supported by Guard Therapeutics.
Competing interests AZ received advisory board consultancy and travel reimbursements from Guard Therapeutics. TEL is employed by Guard Therapeutics.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.