Prospective validation of a proteomic urine test for early and accurate prognosis of critical course complications in patients with SARS-CoV-2 infection
Organizational Data
- DRKS-ID:
- DRKS00022495
- Recruitment Status:
- Recruiting complete, study complete
- Date of registration in DRKS:
- 2020-08-25
- Last update in DRKS:
- 2023-07-04
- Registration type:
- Retrospective
Acronym/abbreviation of the study
Crit-Cov-U
URL of the study
Brief summary in lay language
The investigation of protein fragment patterns in urine (urine proteomics) is intended to predict the severity of Covid-19 disease.
Brief summary in scientific language
Three urine samples are collected from each patient or sent from home, a first urine sample at the time of the first presentation (day 0-1), a second on day 4-5 and a third on day 10-14, to determine the best time to collect the sample for prognostic purposes. A classification into moderate, severe and critical courses of disease is carried out according to the WHO classification criteria (to be found at: https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf), which also includes intensive care, ventilation and death as patient-relevant endpoints. The urine samples are collected, prepared, measured by CE-MS, evaluated and patient-specific peptide lists prepared according to established SOP specifications and in conformity with ISO standard 13485/2016. The peptide profiles of the first 250 patients at all sample times will be used to verify the 31 peptide markers associated with the severity of SARS-CoV-2 infection identified in the pilot study. The higher statistical power will also be used to search for additional peptide markers that show a correlation to the severity of SARS-CoV-2 infection. Based on the results of the statistical analysis, the COVID31 classification model established in a previous pilot study will be adapted. By classifying the first 250 patients at all sample times, the threshold value for a positive test result is determined with regard to the prediction of a critical course of disease in total cross-validation. The completion of the first phase of model optimization is documented before the model is then validated prospectively in routine operation on a further 750 patients using the predetermined threshold value for a positive test result. The final evaluation of the study will be performed using the established statistical methods Receiver Operating Characteristics and Precision Recall curves, as well as univariate and multivariate Cox regression analyses.
Health condition or problem studied
- ICD10:
- U07.9
- Healthy volunteers:
- No
Interventions, Observational Groups
- Arm 1:
- Not applicable (observational study) Patients are screened for their urinary proteome and compared whether a proteome risk score is associated with the clinical severity of Covid-19 disease
Endpoints
- Primary outcome:
- Predictive strength of a urine protein fragment pattern (proteomics) for the severity of Covid19 disease
- Secondary outcome:
- Best time-point to use the urinary proteomic test for severity prediction of Covid-19 disease
Study Design
- Purpose:
- Prognosis
- Retrospective/prospective:
- Prospective
- Study type:
- Non-interventional
- Longitudinal/cross-sectional:
- Cross-sectional study
- Study type non-interventional:
- Epidemiological study
Recruitment
- Recruitment Status:
- Recruiting complete, study complete
- Reason if recruiting stopped or withdrawn:
- No Entry
Recruitment Locations
- Recruitment countries:
-
- Austria
- France
- Germany
- Poland
- Spain
- Sweden
- Number of study centers:
- Multicenter study
- Recruitment location(s):
-
- Medical center Leipzig
Recruitment period and number of participants
- Planned study start date:
- 2020-08-01
- Actual study start date:
- 2020-08-01
- Planned study completion date:
- No Entry
- Actual Study Completion Date:
- 2021-10-31
- Target Sample Size:
- 1000
- Final Sample Size:
- 1012
Inclusion Criteria
- Sex:
- All
- Minimum Age:
- 18 Years
- Maximum Age:
- no maximum age
- Additional Inclusion Criteria:
- Covid-19 disease Ability for informed consent
Exclusion Criteria
Anuria
Addresses
Primary Sponsor
- Address:
- Medizinische Hochschule Hannover HannoverClinical Trial CenterProf. Dr. med. Heiko von der LeyenCarl-Neuberg-Str. 130625 HannoverGermany
- Telephone:
- +49 511 532 115-10
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- http://www.mh-hannover.de
- Investigator Sponsored/Initiated Trial (IST/IIT):
- Yes
Contact for Scientific Queries
- Address:
- Klinik für Infektiologie, Nephrologie, RheumatologieProf. Dr. med. Joachim BeigeDelitzscher Strasse 141 / Haus 5404129 LeipzigGermany
- Telephone:
- 0341/9092613
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- http://www.sanktgeorg.de/nephro.html
Contact for Public Queries
- Address:
- Medizinische Hochschule HannoverHannover Clinical Trial CenterProf. Dr. Heiko von der LeyenCarl-Neuberg-Str. 130625 HannoverGermany
- Telephone:
- +49 (0) 511 532 115-10
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- http://www.mh-hannover.de
Principal Investigator
- Address:
- Klinik für Infektiologie, Nephrologie, RheumatologieProf. Dr. med. Joachim BeigeDelitzscher Strasse 141 / Haus 5404129 LeipzigGermany
- Telephone:
- 0341/9092613
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- http://www.sanktgeorg.de/nephro.html
Sources of Monetary or Material Support
Public funding institutions financed by tax money/Government funding body (German Research Foundation (DFG), Federal Ministry of Education and Research (BMBF), etc.)
- Address:
- Bundesministerium für GesundheitRochusstraße 153123 BonnGermany
- Telephone:
- 030 18441-0
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
Ethics Committee
Address Ethics Committee
- Address:
- Sächsische Landesärztekammer EthikkommissionSchützenhöhe 1601099 DresdenGermany
- Telephone:
- +49-351-8267333
- Fax:
- +40-351-8267332
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
Vote of leading Ethics Committee
- Vote of leading Ethics Committee
- Date of ethics committee application:
- 2020-07-08
- Ethics committee number:
- EK-BR-88/20-1
- Vote of the Ethics Committee:
- Approved
- Date of the vote:
- 2020-07-29
Further identification numbers
- Other primary registry ID:
- No Entry
- EudraCT Number:
- No Entry
IPD - Individual Participant Data
- Do you plan to make participant-related data (IPD) available to other researchers in an anonymized form?:
- No
- IPD Sharing Plan:
- N.a.
Study protocol and other study documents
- Study protocols:
- Beige et al. 2020
- Study abstract:
- Background The SARS-CoV-2 pandemic is a worldwide challenge. The CRIT-CoV-U pilot study generated a urinary proteomic biomarker consisting of 50 peptides (COV50), which predicted death and disease progression from SARS-CoV-2. After the interim analysis presented for the German Government, here, we aimed to analyse the full dataset to consolidate the findings and propose potential clinical applications of this biomarker. Methods CRIT-CoV-U was a prospective multicentre cohort study. In eight European countries (Austria, France, Germany, Greece, North Macedonia, Poland, Spain, and Sweden), 1012 adults with PCR-confirmed COVID-19 were followed up for death and progression along the 8-point WHO scale. Capillary electrophoresis coupled with mass spectrometry was used for urinary proteomic profiling. Statistical methods included logistic regression and receiver operating characteristic curve analysis with a comparison of the area under curve (AUC) between nested models. Hospitalisation costs were derived from the care facility corresponding with the Markov chain probability of reaching WHO scores ranging from 3 to 8 and flat-rate hospitalisation costs adjusted for the gross per capita domestic product of each country. Findings From June 30 to Nov 19, 2020, 228 participants were recruited, and from April 30, 2020, to April 14, 2021, 784 participants were recruited, resulting in a total of 1012 participants. The entry WHO scores were 1–3 in 445 (44%) participants, 4–5 in 529 (52%) participants, and 6 in 38 (4%) participants; and of all participants, 119 died and 271 had disease progression. The odds ratio (OR) associated with COV50 in all 1012 participants for death was 2·44 (95% CI 2·05–2·92) unadjusted and 1·67 (1·34–2·07) when adjusted for sex, age, BMI, comorbidities, and baseline WHO score; and for disease progression, the OR was 1·79 (1·60–2·01) when unadjusted and 1·63 (1·41–1·91) when adjusted (p<0·0001 for all). The predictive accuracy of the optimised COV50 thresholds was 74·4% (71·6–77·1%) for mortality (threshold 0·47) and 67·4% (64·4–70·3%) for disease progression (threshold 0·04). When adjusted for covariables and the baseline WHO score, these thresholds improved AUCs from 0·835 to 0·853 (p=0·033) for death and from 0·697 to 0·730 (p=0·0008) for progression. Of 196 participants who received ambulatory care, 194 (99%) did not reach the 0·04 threshold. The cost reductions associated with 1 day less hospitalisation per 1000 participants were million Euro (M€) 0·887 (5–95% percentile interval 0·730–1·039) in participants at a low risk (COV50 <0·04) and M€2·098 (1·839-2·365) in participants at a high risk (COV50 ≥0·04). Interpretation The urinary proteomic COV50 marker might be predictive of adverse COVID-19 outcomes. Even in people with mild-to-moderate PCR-confirmed infections (WHO scores 1–4), the 0·04 COV50 threshold justifies earlier drug treatment, thereby potentially reducing the number of days in hospital and associated costs
- Other study documents:
- No Entry
- Background literature:
- No Entry
- Related DRKS studies:
- No Entry
Publication of study results
- Planned publication:
- Ab Anfang 2021
- Publikationen/Studienergebnisse:
- Staessen JA, Wendt R, Yu YL, Kalbitz S, Thijs L, Siwy J, Raad J, Metzger J, Neuhaus B, Papkalla A, von der Leyen H, Mebazaa A, Dudoignon E, Spasovski G, Milenkova M, Canevska-Taneska A, Salgueira Lazo M, Psichogiou M, Rajzer MW, Fuławka Ł, Dzitkowska-Zabielska M, Weiss G, Feldt T, Stegemann M, Normark J, Zoufaly A, Schmiedel S, Seilmaier M, Rumpf B, Banasik M, Krajewska M, Catanese L, Rupprecht HD, Czerwieńska B, Peters B, Nilsson Å, Rothfuss K, Lübbert C, Mischak H, Beige J; CRIT-CoV-U investigators. Predictive performance and clinical application of COV50, a urinary proteomic biomarker in early COVID-19 infection: a prospective multicentre cohort study. Lancet Digit Health. 2022 Oct;4(10):e727-e737. doi: 10.1016/S2589-7500(22)00150-9. Epub 2022 Aug 31. Erratum in: Lancet Digit Health. 2023 Feb;5(2):e58. PMID: 36057526; PMCID: PMC9432869.
- Wendt R, Thijs L, Kalbitz S, Mischak H, Siwy J, Raad J, Metzger J, Neuhaus B, Leyen HV, Dudoignon E, Mebazaa A, Spasovski G, Milenkova M, Canevska-Talevska A, Czerwieńska B, Wiecek A, Peters B, Nilsson Å, Schwab M, Rothfuss K, Lübbert C, Staessen JA, Beige J; CRIT-COV-U investigators. A urinary peptidomic profile predicts outcome in SARS-CoV-2-infected patients. EClinicalMedicine. 2021 Jun;36:100883. doi: 10.1016/j.eclinm.2021.100883. Epub 2021 May 3. PMID: 33969282; PMCID: PMC8092440.
- Latosinska A, Siwy J, Cherney DZ, Perkins BA, Mischak H, Beige J. SGLT2-Inhibition reverts urinary peptide changes associated with severe COVID-19: An in-silico proof-of-principle of proteomics-based drug repurposing. Proteomics. 2021 Oct;21(20):e2100160. doi: 10.1002/pmic.202100160. Epub 2021 Sep 15. PMID: 34477316; PMCID: PMC8646299.
- Wendt R, Lingitz MT, Laggner M, Mildner M, Traxler D, Graf A, Krotka P, Moser B, Hoetzenecker K, Kalbitz S, Lübbert C, Beige J, Ankersmit HJ. Clinical Relevance of Elevated Soluble ST2, HSP27 and 20S Proteasome at Hospital Admission in Patients with COVID-19. Biology (Basel). 2021 Nov 15;10(11):1186. doi: 10.3390/biology10111186. PMID: 34827178; PMCID: PMC8615143.
- Siwy J, Wendt R, Albalat A, He T, Mischak H, Mullen W, Latosinska A, Lübbert C, Kalbitz S, Mebazaa A, Peters B, Stegmayr B, Spasovski G, Wiech T, Staessen JA, Wolf J, Beige J. CD99 and polymeric immunoglobulin receptor peptides deregulation in critical COVID-19: A potential link to molecular pathophysiology? Proteomics. 2021 Oct;21(20):e2100133. doi: 10.1002/pmic.202100133. Epub 2021 Aug 21. PMID: 34383378; PMCID: PMC8420529.
- Date of first publication of study results:
- 2021-05-03
- DRKS entry published for the first time with results:
- 2023-07-04
Basic reporting
- Basic Reporting / Results tables:
- No Entry
- Brief summary of results:
- No Entry