Artificial Intelligence for Optimal Anemia Management in End-stage Renal Disease: The Anemia Control Model (ACM) Trial

Study Overview
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Brief Summary
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Fresenius Medical Care has developed a computer software programme called the Anaemia Control Management (ACM) software to assist in the anaemia management of patients with chronic kidney disease (CKD) undergoing hemodialysis. This trial is designed to assess the effectiveness of this ACM software on anaemia management in routine clinical practice. However, all ultimate decisions on therapeutic or diagnostic procedures, treatments, management of the disease, or resource utilisation will be at the discretion of the Investigator. The trial consists of a retrospective (historical) control period and a prospective (going forward) period. During the prospective period, the ACM will be used to assist the Investigators' decision making and will help the Investigators to administer a personalised intravenous (IV) iron and red blood cell stimulating agent (ESA) therapy, whereas treatment according to standard of care will be documented retrospectively for the same patients during the retrospective period of the trial. Thus, patients can serve as their own control.

Detailed Description
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Fresenius Medical Care has developed an algorithm that uses a data-driven computational intelligence model based on an artificial neural network architecture (ACM) to generate individualised ESA dose recommendations from a history of dose and response information and specific patient demographic characteristics. The ACM has been validated and complies with the European requirements for medical devices. The ACM was classified as a Class I medical device in accordance with Directive 93/42/EEC. A proof of concept trial was conducted in 3 NephroCare dialysis clinics (managed by Fresenius) in the Czech Republic, Portugal, and Spain. It could be shown that the introduction of ACM-guided therapy led to a significant decrease in median darbepoetin doses and to a significant increase in on-target haemoglobin (Hb) values along with a decrease in Hb fluctuation. Moreover, a retrospective trial conducted in NephroCare clinics in Portugal, suggested that ACM is able to reliably predict the long-term response to ESA and iron therapy in patients undergoing haemodialysis. The current trial will test the applicability of the ACM outside of Fresenius clinics in a public hospital setting in the UK. Both intravenous (IV) iron and ESA doses will be recommended by the algorithm. The effectiveness of ACM-guided therapy on several anaemia outcomes will be assessed in adult patients with End Stage Renal Disease (ESRD).This trial will be conducted at 1 main unit and 5 satellite units at King's College Hospital, London, UK, in patients with ESRD who are routinely undergoing haemodialysis. This trial is designed to assess the effectiveness of the ACM software on anaemia management in routine clinical practice. However, all ultimate decisions on therapeutic or diagnostic procedures, treatments, management of the disease, or resource utilisation will be at the discretion of the Investigator. The trial will consist of a retrospective control period and a prospective period. During the prospective period, the ACM will be used to facilitate the Investigators' decision making and will help the Investigators to administer a personalised IV iron and ESA therapy, whereas treatment according to standard of care will be documented retrospectively for the same patients during the retrospective period of the trial. Thus, patients can serve as their own control. The planned overall duration of the trial is 18 months (12 months recruitment period + 6 months until last patient last visit). The planned duration of prospective treatment for an individual patient will be 6 months. The collection of retrospective data from medical records covering a period of 6 months will take place as soon as the Informed Consent Form (ICF) is signed but at the latest at baseline. Data will be collected at designated time Points (monthly) throughout the Trial once the ICF is signed: at the latest at baseline (collection of retrospective data), at baseline (start of prospective documentation), and for the observation time points (Month 1 to Month 6). However, examinations will follow routine clinical practice at the site according to the Investigator's decision.

Official Title
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ANEMEX UK Trial: Artificial Intelligence for Optimal Anemia Management in End-stage Renal Disease: The Anemia Control Model (ACM) Trial

Conditions
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Anemia, End Stage Renal Disease

Intervention / Treatment
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* Device: Anemia Control Model (ACM)
* Drug: IV iron
* Drug: Erythropoiesis-Stimulating Agent (ESA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 19 to 90 years On haemodialysis for the past 18 months prior to baseline Treatment with IV iron sucrose during the past 6 months according to the respective Summary of Product Characteristics (SmPC) Treatment with epoetin beta during the past 6 months according to the respective SmPC Regular Hb measurements and at least 5 (standard of care, approximately monthly) Hb measurements during the past 6 months Ferritin measurements during the past 6 months (at least 2 measurements) Signed informed consent Exclusion Criteria: Life expectancy <6 months One or more Hb measurements <8 g/dl during the control period Living-donor transplant scheduled within the next 6 months Scheduled for switch to peritoneal dialysis or home haemodialysis Blood transfusion during the past 9 months Pregnancy or breast feeding Active infection Current malignancy or haematological disorder Previous severe hypersensitivity reaction to IV iron sucrose Serious allergic reactions to darbepoetin alfa or epoetin alfa/beta/zeta, respectively Current treatment with PEGylated erythropoietin Surgery in the past 6 months Surgery scheduled within the next 6 months Participation in a clinical trial in the past 7 months

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: The trial will consist of a retrospective control period and a prospective period. During the prospective period, the ACM will be used to facilitate the Investigators' decision making and will help the Investigators to administer a personalised IV iron and ESA therapy, whereas treatment according to standard of care will be documented retrospectively for the same patients during the retrospective (historical) period of the trial. Thus, patients can serve as their own control.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anemia Control Model IV iron and ESA<br>Anemia Control Model (ACM) algorithm to recommend monthly IV and ESA dose over a 6 month period IV iron: given monthly as required - dosing recommendation by ACM over 6 a month period Erythropoiesis-Stimulating Agent (ESA): given monthly as required - dosing recommendation by ACM over 6 a month period | Device: Anemia Control Model (ACM)<br>* The ACM is mainly composed of 2 sub-Systems - predictor model which, depending on the input data, forecasts the response to anaemia drug therapy for a specific patient. The predictor model is implemented as a feed-forward artificial neural network. The ACM is an algorithm that extracts the optimal policy to achieve the established clinical outcome for anaemia management using the predictor model.<br>Drug: IV iron<br>* IV iron given monthly as required - dose determined by the ACM and as agreed by the investigator<br>* Other names: iron sucrose;Drug: Erythropoiesis-Stimulating Agent (ESA)<br>* ESA given monthly as required over 6 months - dose determined by the ACM and as agreed by the investigator<br>* Other names: epoetin beta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the proportion of patients with haemoglobin within the target range as compared to the historical control period (non-inferiority testing) | The proportion of patients with at least 5 (standard of care, approximately monthly) Hb measurements and with 80% of these measurements within the target range of 10 to 12 g/dl from Month -6 to Month -1 will be compared with the proportion of patients with at least 5 measurements and with 80% of these measurements within target range of 10 to 12 g/dl from Month 1 to Month 6 (non-inferiority testing). | Month -6 to Month -1 compared with Month +1 to Month +6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the proportion of patients with haemoglobin within the target range as compared to historical control period (superiority testing) | The proportion of patients with at least 5 (standard of care, approximately monthly) Hb measurements and with 80% of these measurements within the Hb target range of 10 to 12 g/dl from Month -6 to Month -1 will be compared with the proportion of patients with at least 5 measurements and with 80% of these measurements within target range of 10 to 12 g/dl from Month 1 to Month 6 (superiority testing). | Month -6 to Month -1 compared with Month +1 to Month +6 | 
| Change in haemoglobin fluctuations as compared to historical control period | The Hb fluctuation in patients with at least 5 (standard of care, approximately monthly) Hb measurements from Month -6 to Month -1 and from Month 1 to Month 6 as measured by Hb, Coefficient of Variation (CV), and Standard Deviation (SD) from Month -6 to Month -1 period versus Month 1 to Month 6. | Month -6 to Month -1 compared with Month +1 to Month +6 | 
| Change in cumulative ESA dose as compared to historical control period | Cumulative ESA dose from Month -6 to Month -1 versus cumulative ESA dose from Month 1 to Month 6. | Month -6 to Month -1 compared with Month +1 to Month +6 | 
| Change in cumulative IV iron dose as compared to historical control period | Cumulative IV iron dose from Month -6 to Month -1 versus cumulative IV iron dose from Month +1 to Month +6. | Month -6 to Month -1 compared with Month +1 to Month +6 |