Many Phase III Trials of COVID-19 Therapies Exclude Patients with Kidney Disease

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Chronic kidney disease (CKD) is now well established to be a risk factor for severe COVID-19. This is a particular concern for patients with end-stage renal disease (ESRD), who must visit hemodialysis facilities frequently. Recent research also indicates that COVID-19 is associated with high risk of acute kidney injury (AKI).

Sagar U. Nigwekar, MD, MMSc, an assistant in Medicine in the Nephrology Division at Massachusetts General Hospital, and colleagues have found that 43% of clinical trials of COVID-19 therapies excluded patients with kidney disease. In a research letter published in Kidney International Reports, they urge that future COVID-19 trials include patients with ESRD, as recommended by the Kidney Health Initiative and the U.S. Food and Drug Administration.

Scope of the Problem

In a systematic review, the researchers identified 193 phase III randomized, controlled trials that had at least 100 participants. Eighty-three of those trials (43%)—representing 149,294 participants—excluded patients with kidney disease.

Patient Exclusion

Patients with kidney disease who were excluded from the studies met various criteria across trials that varied in sample size, outpatient/inpatient settings and funding sources.

The reasons for exclusion were:

• Abnormal estimated glomerular filtration rate (eGFR) or undergoing renal replacement therapy (n=57 trials)
• Abnormal serum creatinine (n=6)
• History of kidney stone (n=1)
• History of nephrotic syndrome (n=1)
• Renal impairment not further specified (n=18)

Serum creatinine is a weak measure of renal function and might not accurately represent underlying kidney disease. Excluding patients on the basis of renal impairment not further specified might lead to exclusion of patients with only mild kidney disease.

Researchers reported the following results:

• Remdesivir—3 of 3 trials (100%) excluded patients with kidney disease
• Hydroxychloroquine/chloroquine—20 of 33 (61%)
• Multiple medications—32 of 57 (56%)
• Favipiravir—1 of 2 (50%)
• Supplement/herb—4 of 13 (31%)
• Bacille Calmette-Guérin vaccine—2 of 9 (22%)
• Monoclonal antibody—2 of 14 (14%)
• Convalescent plasma/immunoglobulin—1 of 12 (8%)
• Hyperbaric oxygen/ozone therapy—0 of 3 (0%)
• Lopinavir/ritonavir—0 of 1 (0%)
• Other medications—18 of 46 (39%)

A Better Approach to Trials

Exclusions were rational in some instances. For example, the trial that excluded patients with kidney stones was investigating vitamin C supplementation. However, most of the therapies examined are not contraindicated in patients with renal impairment patients.

In future trials, dose adjustment based on eGFR should be incorporated where necessary. Otherwise, decisions about the care of patients with CKD will be less likely to be evidence-driven, exposing some patients to excess risks and in other cases depriving them of an effective intervention.

Protocols for future studies should provide a scientific rationale for excluding patients with kidney disease. Reports of the results should clarify whether abnormal renal function during the trial was secondary to AKI, CKD or AKI superimposed on CKD.

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