Phase-3 Randomized Controlled Trials on Exclusion of Participants With Kidney Disease in COVID-19 (2020)

Severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019 (COVID-19), has a range of presentations and outcomes from asymptomatic carriage to acute respiratory distress syndrome and death.1Harapan H. Itoh N. Yufika A. et al.Coronavirus disease 2019 (COVID-19): A literature review.J Infect Public Health. 2020; 13: 667-673Crossref PubMed Scopus (971) Google Scholar The incidence of acute kidney injury (AKI) is high among patients with COVID-19.2Hirsch J.S. Ng J.H. Ross D.W. et al.Acute kidney injury in patients hospitalized with COVID-19.Kidney Int. 2020; 98: 209-218Abstract Full Text Full Text PDF PubMed Scopus (1020) Google Scholar,3Batlle D. Soler M.J. Sparks M.A. et al.Acute kidney injury in COVID-19: emerging evidence of a distinct pathophysiology.J Am Soc Nephrol. 2020; 31: 1380-1383Crossref PubMed Scopus (413) Google Scholar Moreover, patients with chronic kidney disease (CKD), who make up more than 10% of the global population,4Coresh J. Update on the burden of CKD.J Am Soc Nephrol. 2017; 28: 1020Crossref PubMed Scopus (122) Google Scholar are at high risk for severe COVID-19.5Henry B.M. Lippi G. Chronic kidney disease is associated with severe coronavirus disease 2019 (COVID-19) infection.Int Urol Nephrol. 2020; 52: 1193-1194Crossref PubMed Scopus (399) Google Scholar Patients with end-stage renal disease who make frequent visits to in-center hemodialysis facilities are at high risk for exposure to and infection with severe acute respiratory syndrome coronavirus 2 and are at high risk of developing disease once exposed because of their older average age and multiple comorbidities.6Ikizler T.A. COVID-19 and dialysis units: what do we know now and what should we do?.Am J Kidney Dis. 2020; 76: 1-3Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar Remarkably, nearly 250 phase-3 randomized controlled trials have been planned to identify safe and effective interventions to prevent or treat COVID-19. To inform practitioners and researchers whether and how findings from these trials can be applied to patients with kidney disease (AKI, CKD, or end-stage renal disease), we conducted a systematic review of registered trials and quantified the proportion of potential subjects with kidney disease who are excluded from enrollment. Variables predicting trials with exclusion criteria regarding kidney disease were also explored using multiple logistic regression (Supplementary Methods). A total of 248 trials were identified, of which 55 trials did not meet the inclusion criteria (13 trials were for unrelated topics, 4 trials were nonrandomized single-arm interventions, and 38 trials included fewer than 100 participants). Of the remaining 193 trials (representing 258,794 participants), 83 trials (43.0%) (representing 149,294 participants [57.7%]) excluded patients with kidney disease. Criteria to exclude patients with kidney disease included abnormal estimated glomerular filtration rate (eGFR) or renal replacement therapy (n = 57 trials), abnormal serum creatinine (n = 6 trials), history of kidney stone (n = 1 trial), history of nephrotic syndrome (n = 1 trial), or renal impairment, not further specified (n = 18 trials). The eGFR thresholds provided as exclusion cutoffs are summarized in Figure 1. The exclusion of patients with kidney disease occurred across the spectra of trials with varying sample sizes, funding sources, and outpatient/inpatient settings (Table 1). Details on the exclusion criteria thresholds applied to each trial for each intervention are shown in Table 2. The corresponding appropriate thresholds at which each intervention was contraindicated are represented in Supplementary Table S1. It appears that exclusion criteria regarding kidney disease are generally applied regardless of number of enrollments (100–499, 500–999, >1,000), participant settings (outpatient, inpatient, health care workers, and not specified), locations (North America, South America, Africa, Asia/Australia, Europe, and multiple locations), and funding sources (academic/government, industry, and not specified), as none of these factors were significantly different across various exclusion criteria regarding kidney disease, as shown in Supplementary Table S2. Moreover, none of these factors significantly predict whether or not trials have exclusion criteria regarding kidney disease. (Supplementary Table S3)Table 1Characteristics of COVID-19 trialsCharacteristicsTrials, nParticipants, nPercentage of trials with exclusion of kidney disease, n (%)Percentage of participants with exclusion of kidney disease, n (%)Total193258,79483 (43)149,294 (58)Number of enrollments 100–49910227,18237 (37)9,987 (37) 500–9993522,63618 (51)11,942 (52) >100056208,97628 (50)127,365 (61)Participant settings Outpatient3853,34117 (45)27,866 (52) Inpatient11294,58946 (41)36,650 (38) Health care workers26104,51614 (54)82,640 (79) Not specified176,3486 (35)2,138 (35)Sites Single center9577,12037 (39)28,903 (37) Multicenter77167,06738 (49)114,688 (69) Not specified2114,6078 (38)5,703 (39)Location North America5863,27327 (47)41,331 (65) South America119,1932 (18)1,750 (19) Africa196,8589 (47)3,368 (51) Asia/Australia1425,0504 (29)2,402 (10) Europe7764,43632 (42)28,159 (44) Multiple locations1489,9849 (64)72,284 (80)Funding sources Academic grant/government139161,17459 (43)76,358 (48) Industry4589,33919 (42)70,096 (78) Not specified98,2815 (56)2,840 (34)Type of interventions Humanized monoclonal antibody vs placebo/standard of care144,2302 (14)410 (10) Hydroxychloroquine/chloroquine vs placebo/standard of care3353,08520 (61)41,229 (78) Vaccine vs. placebo921,0782 (22)1,380 (7) Convalescent plasma/ immunoglobulin vs placebo/standard of care124,3871 (8)138 (3) Hyperbaric oxygen/ozone therapy vs standard of care35080 (0)0 (0) Favipiravir vs placebo/standard of care22001 (50)100 (50) Lopinavir/ritonavir vs. placebo/standard of care11,2200 (0)0 (0) Remdesivir vs placebo/standard of care38,4003 (100)8,400 (100) Supplements/Herbs vs. placebo/standard of care138,3064 (31)1,910 (23) Multiple medication comparisons57126,51732 (56)83,865 (66) Other medicationsaOther medications include azoximer bromide, amiodarone, almitrine, ABX464, aviptadil, anakinra, azithromycin, budesonide, bactek-R, ciclesonide, colchicine, doxycycline, dalargin, DAS181, dornase alfa inhalation solution, dociparstat, dapagliflozin, escin, IMU-838, IFX-1, imatinib, ifenprodil, lenzilumab, nitazoxanide, nafamostat mesylate, naproxen, pacritinib, ruxolitinib, remestemcel-L, symbicort rapihaler, steroid, and VPM1002. vs. placebo/standard of care4630,86318 (39)11,862 (37)a Other medications include azoximer bromide, amiodarone, almitrine, ABX464, aviptadil, anakinra, azithromycin, budesonide, bactek-R, ciclesonide, colchicine, doxycycline, dalargin, DAS181, dornase alfa inhalation solution, dociparstat, dapagliflozin, escin, IMU-838, IFX-1, imatinib, ifenprodil, lenzilumab, nitazoxanide, nafamostat mesylate, naproxen, pacritinib, ruxolitinib, remestemcel-L, symbicort rapihaler, steroid, and VPM1002. Open table in a new tab Table 2Number of trials (number of enrollments) with each exclusion criterion regarding kidney disease for each interventionInterventionNo exclusion for kidney diseaseThreshold GFR <15Threshold GFR 15–30Threshold GFR 30–60Renal impairment, not further specifiedOther criteriaaOther criteria include history of nephrotic syndrome (0.2%), history of kidney stone (0.3%) and various serum creatinine cutoffs (2.1%).Humanized monoclonal antibody vs. placebo/standard of care12 (3,820)02 (410)000Hydroxychloroquine/chloroquine vs. placebo/standard of care13 (11,856)3 (5,260)12 (15,220)02 (16,739)3 (4,010)Vaccine vs. placebo7 (19,698)0002 (1,380)0Convalescent plasma/ immunoglobulin vs. placebo/standard of care11 (4,249)00001 (138)Hyperbaric oxygen/ozone therapy vs. standard of care3 (508)00000Favipiravir vs. placebo/standard of care1 (100)01 (100)000Lopinavir/ritonavir vs. placebo/standard of care1 (1,220)00000Remdesivir vs. placebo/standard of care001 (800)2 (7,600)00Supplements/Herbs vs. placebo/standard of care9 (6,396)001 (450)2 (760)1 (800)Multiple medication comparisons25 (42,652)3 (2,550)18 (16,015)4 (1,910)6 (62,490)1 (900)Other medicationsbOther medications include azoximer bromide, amiodarone, almitrine, ABX464, aviptadil, anakinra, azithromycin, budesonide, bactek-R, ciclesonide, colchicine, doxycycline, dalargin, DAS181, dornase alfa inhalation solution, dociparstat, dapagliflozin, escin, IMU-838, IFX-1, imatinib, ifenprodil, lenzilumab, nitazoxanide, nafamostat mesylate, naproxen, pacritinib, ruxolitinib, remestemcel-L, symbicort rapihaler, steroid, and VPM1002. vs. placebo/standard of care28 (19,001)1 (500)8 (8,454)1 (120)6 (1,832)2 (956)a Other criteria include history of nephrotic syndrome (0.2%), history of kidney stone (0.3%) and various serum creatinine cutoffs (2.1%).b Other medications include azoximer bromide, amiodarone, almitrine, ABX464, aviptadil, anakinra, azithromycin, budesonide, bactek-R, ciclesonide, colchicine, doxycycline, dalargin, DAS181, dornase alfa inhalation solution, dociparstat, dapagliflozin, escin, IMU-838, IFX-1, imatinib, ifenprodil, lenzilumab, nitazoxanide, nafamostat mesylate, naproxen, pacritinib, ruxolitinib, remestemcel-L, symbicort rapihaler, steroid, and VPM1002. Open table in a new tab Almost all studies of humanized monoclonal antibodies, such as tocilizumab or sarilumab, convalescent plasma, and nonpharmacologic treatment, such as hyperbaric oxygen therapy, in which renal clearance is minimal or irrelevant, included participants with kidney disease. However, 2 trials (14%) with 410 participants (10%) among humanized monoclonal antibody trials excluded patients with kidney impairment. On the contrary, most bacille Calmette-Guerin vaccine trials did not exclude patients with kidney disease. Nonetheless, 2 trials (22%) with 1380 participants (7%) excluded patients with CKD or dialysis patients. The rationale for excluding patients with kidney impairment among bacille Calmette-Guerin vaccination trials might be explained by the fact that patients with renal impairment were considered as immunocompromised hosts. They might be at risk of disseminated or severe tuberculosis infection. However, according to the manufacturer's labeling, there is no contraindication or dose adjustment for this particular population. By contrast, more than 50% of studies of small molecule antivirals, such as remdesivir or favipiravir, and antimalarials, such as hydroxychloroquine or chloroquine, excluded such participants. Regarding hydroxychloroquine/chloroquine, 20 trials (61%) with 41,229 participants (78%) excluded patients with renal impairment although there is no requirement for dose adjustment for short-term use including treating patients with COVID-19. All remdesivir trials excluded participants with kidney disease (2 trials excluded participants with eGFR <50 ml/min per 1.73 m2 and 1 trial excluded participants with eGFR <30 ml/min per 1.73 m2), as discussed in Adamsick et al.7Adamsick M.L. Gandhi R.G. Bidell M.R. et al.Remdesivir in patients with acute or chronic kidney disease and COVID-19.J Am Soc Nephrol. 2020; 31: 1384-1386Crossref PubMed Scopus (132) Google Scholar Although there is a contraindication among patients with eGFR <30 ml/min per 1.73 m2, some trials excluded participants at eGFR 50 ml/min per 1.73 m2. Interestingly, some trials excluded patients with renal diagnoses not further specified kidney function. One trial excluded patients with a history of kidney stones, as the experimental arm was vitamin C supplementation, which is associated with higher risk of kidney stones. Another trial excluded patients with a history of nephrotic syndrome, because the proposed intervention was discontinuation of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, which should not be discontinued among patients with nephrotic syndrome. Their rationales appear to be appropriate. Most interventions, including humanized monoclonal antibodies, hydroxychloroquine/chloroquine, lopinavir/ritonavir, convalescent plasma, vaccination, and hyperbaric oxygen, are not contraindicated in patients with renal impairment; however, renal dose for these interventions might be required. Many ongoing trials use strict criteria excluding patients with renal impairment without considering dose adjustment. This leads to loss of potential patients who might benefit from these interventions. The exclusion of patients with kidney disease, as highlighted in this report, will limit the generalizability of results of these trials to the kidney disease population. Patients with severe kidney disease, including those requiring renal replacement therapy, are the most vulnerable patient groups to COVID-19 that nephrology practitioners encounter. The exclusion of these patients means that clinical decisions regarding their care will be less likely to be evidence-driven, exposing patients in some cases to excess risks and in some cases, depriving them of an effective intervention. Scientific rationale (lack of efficacy, safety concern, or other) should be provided for future trials that exclude patients with kidney disease. Several studies exclude patients on the basis of weak measures of renal function. Some used serum creatinine rather than eGFR as the cutoff criteria, which might not be an accurate representation of underlying kidney disease. Moreover, 18 trials (9%) excluded patients on the basis of renal impairment not further specified, which might lead to the exclusion of patients with mild kidney disease. We believe that eGFR should be used to be consistent with other trials, to more accurately reflect kidney function. and to renally adjust medication doses. Furthermore, future studies should record and clarify whether abnormal renal function is secondary to AKI, CKD, or AKI superimposed on CKD. In conclusion, more than 40% of COVID-19 trials excluded patients with kidney disease. Because patients with kidney disease are at high risk of COVID-19 exposure, infection, and severe disease, and because COVID-19 itself leads to AKI, future trials should include patients with kidney disease (AKI, CKD, or end-stage renal disease), as suggested by the Kidney Health Initiative and the US Food and Drug Administration.8U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). COVID-19: Developing Drugs and Biological Products for Treatment or Prevention Guidance for Industry. Published May 2020. Rockville, MD: Food and Drug Administration.Google Scholar,9Kidney Health Initiative. Making the Case for Change: Including People with Kidney Diseases in COVID-19 Trials. Washington, DC: American Society of Nephrology; 2020.Google Scholar eGFR rather than serum creatinine should be used to assess kidney function and to adjust doses of renally cleared interventions. Focusing on the efficacy and safety of various potential interventions for COVID-19 among the kidney disease population is of critical importance. MES has participated in scientific advisory boards for Gilead in the area of Viral Hepatitis. All the other authors declared no competing interests. SUN is supported by the American Heart Association (15FTF25980003) and by the National Institute of Diabetes and Digestive and Kidney Diseases (1U01DK123818). The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Heart Association or the National Institutes of Health. Download .pdf (.11 MB) Help with pdf files Supplementary File (PDF) Supplementary Methods. Table S1. Recommendations for dosing in adults with renal impairment. Table S2. Number of trials with each exclusion criterion regarding kidney disease. Table S3. Predictors for exclusion criteria regarding kidney disease.