Chronic Kidney disease (CKD) is an impairment of kidney structure or function and is a growing public health concern. It is becoming increasingly common and is associated with high treatment costs and often leads to poor outcomes as CKD frequently occurs with a wide range of other conditions such as high blood pressure, diabetes, and heart disease. Advanced CKD also results in the reduction of the number of red blood cells, a condition referred to as anaemia, which can lead to adverse consequences. Roxadustat is a drug that stimulates production of hemoglobin and red blood cells. It is currently in clinical development for the treatment of anaemia resulting from CKD. Part of the drug development process is to ensure that the new drug is safe and does not lead to more adverse outcome to what is normally experienced by CKD patients. However, there is limited data on how common those adverse events are in CKD patients. Lack of understanding of baseline adverse outcomes in patients with CKD can limit the ability of dialysis organizations, government agencies and other institutions to assess quality of care; hinder patient counselling and patient education; and impair the development and delivery of innovative therapies to patients. Our proposed study aims to facilitate the development and delivery of innovative therapies to patients, by quantifying how commonly adverse events occur in the general CKD population with varying degree of severity.
Objectives
Advanced CKD is associated with anaemia which can lead to adverse consequences. Roxadustat is one of several hypoxia inducible-factor prolyl hydroxylase inhibitors (HIF PHI) in late-phase clinical development for the treatment of anaemia secondary to chronic kidney disease (Gupta and Wish, AJKD 2017). These programs are powered to assess the cardiovascular safety of HIF PHIs versus comparator. However, data on the risk of rare events is likely to be inconclusive. Our proposed study aims to facilitate the development and delivery of innovative therapies and treatment strategies, to patients, by characterising rates for events of interest, in populations with baseline CKD of varying severity.
Specific objective:
1. Describe baseline characteristics of CKD patients and stratify these by disease severity (estimated glomerular filtration rate (eGFR) stage) and dialysis status.
2. Quantify the risk of all-cause mortality and adverse events in patients with CKD after diagnosis.
3. Stratify the risk of adverse events by CKD stage and dialysis status.
Methods and analysis plan
We will study individuals with recorded diagnosis of CKD between 2004 and 2019 in CPRD linked to Hospital Episode Statistics (HES) data. For each patient, serum creatinine values will be extracted and eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. CKD will be defined using two consecutive measurements of (eGFR) < 60 mL/min/1.73m2 recorded at least 3 months apart. Information on baseline characteristics (age, gender etc.) and pre-specified adverse events (e.g. pancreatitis, cardiovascular events, tachycardia) will be extracted using both primary and secondary care data. Office of National Statistics (ONS) mortality data will be used to better ascertain deaths. Baseline characteristics will be summarised using descriptive statistics. Incidence rate will be calculated by dividing the total number of adverse events by person-years of follow-up. We will stratify these estimates by disease severity.
All-cause mortality and adverse events. We will specifically study the following adverse events:
Infection/sepsis events
Urinary tract infection events
Gastrointestinal haemorrhage events
Hypoglycemia events
Pancreatitis events
Thyroid events
Acidosis
Hyperkalemia
Rhabdomyolysis
Tachycardia events
Pneumonia and lower respiratory infection events
Hepatic events
Seizure events
Retinal events
Allergic and anaphylaxis events
Severe cutaneous adverse reactions
Pure red cell aplasia
Deep vein thrombosis
All cause mortality
Dustin Little - Chief Investigator - AstraZeneca Ltd - UK Headquarters
Alyshah Abdul Sultan - Corresponding Applicant - AstraZeneca Ltd - UK Headquarters
Glen James - Collaborator - AstraZeneca Ltd - UK Headquarters
Matthew Arnold - Collaborator - AstraZeneca Ltd - UK Headquarters
Ping Sun - Collaborator - AstraZeneca Ltd - UK Headquarters
HES Accident and Emergency;HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data;Practice Level Index of Multiple Deprivation