Efficacy of Lactococcus lactis strain plasma (LC-Plasma) in easing symptoms in patients with mild COVID-19: protocol for an exploratory, multicentre, double-blinded, randomised controlled trial (PLATEAU study)
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Abstract
The COVID-19 pandemic has been a major concern worldwide; however, easily accessible treatment options for patients with mild COVID-19 remain limited. Since the oral intake of Lactococcus lactis strain plasma (LC-Plasma) enhances both the innate and acquired immune systems through the activation of plasmacytoid dendritic cells (pDCs), we hypothesised that the oral intake of LC-Plasma could aid the relief or prevention of symptoms in patients with asymptomatic or mild COVID-19.
Methods and analysis
This is an exploratory, multicentre, double-blinded, randomised, placebo-controlled trial. This study was initiated in December 2021 and concludes in April 2023. The planned number of enrolled subjects is 100 (50 subjects×2 groups); subject enrolment will be conducted until October 2022. Patients with asymptomatic or mild COVID-19 will be enrolled and randomly assigned in a 1:1 ratio to group A (oral intake of LC-Plasma-containing capsule, 200 mg/day, for 14 days) or group B (oral intake of placebo capsule, for 14 days). The primary endpoint is the change in subjective symptoms measured by the severity score. Secondary endpoints include SARS-CoV-2 viral loads, biomarkers for pDC activation, serum SARS-CoV-2-specific antibodies, serum cytokines, interferon and interferon-inducible antiviral effectors and the proportion of subjects with emergency room visits to medical institutions or who are hospitalised.
Ethics and dissemination
The study protocol was approved by the Clinical Research Review Board of Nagasaki University, in accordance with the Clinical Trials Act of Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act, and other current legal regulations in Japan. Written informed consent will be obtained from all the participants. The results of this study will be reported in journal publications.
Trial registration number
Japan Registry of Clinical Trials (registration number: jRCTs071210097).
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SciScore for 10.1101/2022.02.13.22270913: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Study design and setting: The “efficacy of Lactococcus lactis strain PLasmA To EAse symptoms in patients with coronavirUs disease 2019 (PLATEAU) study: a multicenter, double-blinded, randomized placebo-controlled trial” was initiated in December 2021 following approval by the Clinical Research Review Board of Nagasaki University in November, 2021 (approval number: CRB20-027).
Consent: As shown in Figure 1, eligible patients will be asked to participate in this study, and informed consent will be obtained prior to registration/randomization.Sex as a biological variable not detected. Randomization Study design and setting: The “efficacy of Lactococcus lactis strain PLasmA To EAse symptoms … SciScore for 10.1101/2022.02.13.22270913: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Study design and setting: The “efficacy of Lactococcus lactis strain PLasmA To EAse symptoms in patients with coronavirUs disease 2019 (PLATEAU) study: a multicenter, double-blinded, randomized placebo-controlled trial” was initiated in December 2021 following approval by the Clinical Research Review Board of Nagasaki University in November, 2021 (approval number: CRB20-027).
Consent: As shown in Figure 1, eligible patients will be asked to participate in this study, and informed consent will be obtained prior to registration/randomization.Sex as a biological variable not detected. Randomization Study design and setting: The “efficacy of Lactococcus lactis strain PLasmA To EAse symptoms in patients with coronavirUs disease 2019 (PLATEAU) study: a multicenter, double-blinded, randomized placebo-controlled trial” was initiated in December 2021 following approval by the Clinical Research Review Board of Nagasaki University in November, 2021 (approval number: CRB20-027). Blinding All parties are blinded, including investigators, participants, the manufacturer of test capsules, core laboratories, and biostatisticians. Power Analysis Sample size calculation: The severity score was used in a case series study to estimate the patients’ subjective symptoms.[21] When the total severity score from this previous study was translated using a calculation method mentioned in the outcomes section of the present study, the total score on days 0 and 14 was 11 ± 5.3 and 1.7 ± 2.3, respectively, and the change from day 0 to day 14 was –9.3 ± 6.0. Table 2: Resources
Antibodies Sentences Resources Subjects who meet any of the following exclusion criteria will be excluded from participation: 1) obese (body mass index (BMI) ≥30 kg/m2), 2) subjects with strong dyspnea, chest pain, or hemosputum, 3) previous history of COVID-19, 4) being treated or planning to be treated with neutralizing antibody drugs for SARS-CoV-2, 5) being treated with immunosuppressive agents, antirheumatic agents, corticosteroids, or immunoglobulin preparations, 6) subjects administered oral intestinal regulators, 7) taking one or more beverage or food containing LC-Plasma or yogurt that contains Lactobacillus delbrueckii subsp. bulgaricus daily, 8) who are pregnant, possibly pregnant, or breastfeeding, 9) participating in other clinical trials, 10) requiring legal representation for giving consent, or 11) with other conditions that the responsible investigator or sub-investigators deem inappropriate for study participation. BMI ) ≥30 kg/m2) , 2suggested: NoneThe observation items are as follows: 1) subjects’ background characteristics (sex, height, weight, BMI, presence or absence of onset of COVID-19, estimated infection day, onset day of COVID-19 if symptomatic, SARS-CoV-2 vaccination status (timing, number of vaccinations, vaccine type, last day of vaccination), 2) Severity of COVID-19 assessed by severity classification according to COVID-19 infectious disease treatment guidelines published by the Ministry of Health, Labor and Welfare in Japan [20] (mild: SpO2 ≥ 96%, no respiratory symptoms or only coughing without dyspnea, and without pneumonia findings, moderate I: 93% < SpO2 < 96%, with dyspnea, and with pneumonia findings, moderate II: SpO2 ≤ 93% and oxygen administration required, and severe: admission to intensive care unit or ventilator required), 3) Blood Test 1 (differential count of leukocytes (neutrophil, lymphocyte, eosinophil, monocyte, and basophil), platelet, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, blood urea nitrogen, serum creatinine, lactate dehydrogenase, C-reactive protein, ferritin, and HbA1c), 4) Blood Test 2 (pDCs activation markers (human leukocyte antigen DR and CD86), cytokines (interleukin-6 and monocyte chemoattractant protein-1), SARS-CoV-2 specific antibodies (immunoglobulin M and G), expression of interferon and interferon-inducible antiviral effector genes in PBMC, and immune cell analysis (T cells and B cells), 4) real-time polymerase chain reaction test for SARS-CoV-2 by nasopharyngeal swabs, 5) medication information, 6) vital signs (body temperature, pulse, SpO2, and frequency of breath), 7) adherence of test capsules, 8) patients’ subjective symptoms measured by the severity score [21] lactate dehydrogenase , C-reactive protein , ferritin ,suggested: NoneCD86suggested: Noneinterleukin-6suggested: NoneSARS-CoV-2suggested: NoneSecondary endpoints are as follows: 1) change or percent change in viral load of SARS-CoV-2, 2) change or percent change in biomarkers for pDC activation (HLA-DR, CD86), 3) change or percent change in SARS-CoV-2-specific antibodies (immunoglobulin G and M), 4) change or percent change in blood cytokines (IL-6, MCP-1), 5) change or percent change in IFN-or IFN-inducible antiviral effectors, and 6) proportion of subjects who visit the emergency room and are hospitalized. HLA-DR, CD86), 3suggested: NoneIL-6suggested: Noneantiviral effectors, and 6suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This study has several limitations. First, this is an exploratory study due to the lack of previous clinical evaluation of the effects of LC-Plasma intake in patients with COVID-19. The target number of enrolled patients in this study was calculated from results of a case series study estimating subjective symptoms in non-hospitalized patients with COVID-19 treated with the histamine-2 receptor antagonist famotidine.[21] Since this case series evaluated subjective symptoms in only 10 patients, the calculated mean and standard deviation of the results might not reflect the actual patients’ subjective symptoms. Second, the primary endpoint in this study is patients’ subjective symptoms as reported by subjects themselves. Therefore, biases such as responder bias, non-responder bias, and volunteer bias cannot be completely avoided. However, the effect of bias is minimized using a double-blinded study design. Third, this study will be conducted in medical institutions in Japan and will enroll only Japanese patients. These constraints could limit the generalizability of this study. Further larger-scale, international clinical trials are required in the future. Ethics and dissemination: This study and its protocol were approved by the Clinical Research Review Board of Nagasaki University (Approval No. CRB20-027) in accordance with the Clinical Trials Act of Japan. The study will be conducted in accordance with the Declaration of Helsinki, Clinical Trials Act, and other current legal...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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