key: cord-0319905-2mq42tv8
authors: Pajon, R.; Paila, Y.; Girard, B.; Dixon, G.; Kacena, K.; Baden, L. R.; El Sahly, H. M.; Essink, B.; Mullane, K. M.; Frank, I.; Denham, D.; Kerwin, E.; Zhao, X.; Ding, B.; Deng, W.; Tomassini, J.; Zhou, H.; Leav, B.; Schodel, F.
title: Initial Analysis of Viral Dynamics and Circulating Viral Variants During the mRNA-1273 Phase 3 COVE Trial
date: 2021-09-29
journal: nan
DOI: 10.1101/2021.09.28.21264252
sha: 8924a95f51b7ddb3269893dc5d080954fd7f1fee
doc_id: 319905
cord_uid: 2mq42tv8

This analysis assessed the impact of mRNA-1273 vaccination on the viral dynamics of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the ongoing Coronavirus Efficacy (COVE) trial. mRNA-1273 vaccination significantly reduced SARS-CoV-2 viral copy number (95% confidence interval [CI]) by 100-fold on the day of diagnosis (4.1 [3.4-4.8] versus placebo (6.2 [6.0-6.4] log10 copies/ml). Median times to undetectable viral copies were 4 days for mRNA-1273 and 7 for placebo. Vaccination also reduced the burden of disease and infection scores. Vaccine efficacies (95% CI) during the trial against SARS-CoV-2 variants circulating in the US were 82.4% (40.4%-94.8%) for Epsilon and Gamma, and 81.2% (36.1%-94.5%) for the Epsilon variants. The detection of other respiratory viruses during the trial was similar between groups. In those who became SARS-CoV-2 infected, the reduction of viral load after mRNA-1273 vaccination is potentially correlated to the risk of transmission, which has not been assessed in this study.

The mRNA-1273 vaccine, a lipid nanoparticle-encapsulated messenger RNA vaccine encoding a prefusion-stabilized spike (S) protein of the prototype Wuhan-Hu-1 virus isolate, demonstrated high efficacy in preventing symptomatic and asymptomatic severe acute respiratory syndrome (SARS-CoV-2) infections at the primary analysis (December 2020) of the ongoing Coronavirus Efficacy (COVE) phase 3 trial. 1 11, 12 The emergence of several SARS-CoV-2 variants with mutations in the S protein genes and in other regions of the genome with decreased susceptibility to neutralization by vaccine-induced antibodies has raised the possibility for increased transmission, breakthrough infections and waning efficacy with current vaccines. [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] The variants include those previously considered to be variants of concern (VOC; Alpha [B. 23 From initiation of the COVE trial (July 2020) to completion of the blinded portion of the study (data cutoff-date of March 26, 2021) , the proportions of circulating VOC and VOI were very low in the US and were predominantly of the Alpha, Beta, Epsilon and Iota lineages. In recent months, the highly transmissible Delta (B1.617.2) VOC, has become the predominant cause of SARS-CoV-2 infections in the United States. [23] [24] [25] [26] Co-infection of SARS-CoV-2 with respiratory pathogens also occurs, and can complicate the evaluation of SARS-CoV-2 infection rates as well as patient management due to the presence of non-specific symptoms unrelated to Covid-19 illness. [27] [28] [29] The aim of this study was to assess the effect of mRNA-1273 vaccination on viral copy and viral shedding, as well as the burden of disease in participants with Covid-19 by study group in the COVE ongoing trial. We also assessed the prevalence of SARS-CoV-2 viral variants and coinfecting respiratory pathogens, and the effect of vaccination on viral variants detected during the placebo-controlled phase of the study. 1 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 29, 2021. ;  https://doi.org/10.1101/2021.09.28.21264252 doi: medRxiv preprint

This is an analysis of the previously reported COVE study, a phase 3 randomized, observerblinded, placebo-controlled trial that enrolled adults in medically-stable condition at 99 US sites (clintrials.gov NCT04470427). 1, 2 Eligible participants included adults 18 years or older with no known history of SARS-CoV-2 infection, whose circumstances put them at appreciable risk for SARS-CoV-2 infection and/or high risk of severe Covid-19. Participants were randomized 1:1 to receive mRNA-1273 vaccine (100 µg) or placebo and stratified by age and Covid-19 complications risk criteria (≥18 and <65 years and not at risk, ≥18 and <65 years and at risk, and ≥65 years).

Following issuance of the Emergency Use Authorization of mRNA-1273, the protocol was amended as a two-part phase 3 study (A and B; supplementary protocol). Part A was the observer blinded to-treatment phase which concluded when participants unblinded and consideration given those on placebo to receive mRNA-1273. Part B is the currently ongoing open-label phase. The blinded part of the trial was completed. 2 Participants will continue to be followed-up for up to two years as originally planned.

The COVE trial is conducted in accordance with the International Council for Technical

Guidance, and applicable government regulations. The central Institutional Review Board/Ethics Committee, Advarra, Inc., 6100 Merriweather Drive, Columbia, MD 21044 approved the protocol and consent forms. All participants provided written informed consent.

The trial design, efficacy assessments and study treatment have been previously described and are provided in the supplementary protocol online. 1 solicited local and systemic adverse events with onset during the 7 days following   each injection to resolution, unsolicited adverse events during 28 days following each injection, adverse events leading to discontinuation from dosing and/or study participation, medicallyattended and serious adverse events throughout the study, and severity graded as described in the protocol.

In this analysis, viral variants were sequenced and viral copy number and shedding were assessed in 799 adjudicated Covid-19 cases in the per-protocol set from the blinded portion of the study (data cut-off March 26th, 2021). Following amendment (December 23rd, 2020) of the COVE phase 3 study, the open-label phase of the trial was initiated and participants in the placebo arm started to receive the mRNA-1273 vaccine. Sequence data for viral variants and also assessment of the presence of other respiratory pathogens extended into the time-frame of the open-label part of the study.

The study population for analysis of viral load were those participants in the per-protocol population who had binding antibody (Elecsys; nucleocapsid protein [NP]) negative baseline values (baseline SARS-CoV-2 negative), and also had follow-up Elecsys-negative values at days 29 and 57 and RT-PCR-negative results at baseline, day 29, and at day 57 (only Elecsys). The analysis period was limited to the blinded portion of the study and the data cut-off date was 26-March-2021 (or earlier unblinding).

For the cohort of Covid-19 adjudicated subjects, the day 1 illness nasopharyngeal swab and the days 3, 5, 6, 9, 14, 21, and 28 of illness saliva specimens were matched to assess the qualitative and quantitative results for each. SARS-CoV-2 RT-PCR was performed as described below (Eurofins Viracor, Kansas City, MO). Conversion from cycle-threshold (Ct) time to viral copies for the quantitative RT-PCR were Log10 viral copies/mL=Ct-40.9578)/-3.3385 for swabs (day1) and

Log10 viral copies/mL=CT-41.0349)/-3.3346) for saliva (days 3, 5, 7, 9, 14, 21 and 28) . If the qualitative result was negative, the log10viral copies was assumed to be 0. A mixed model repeated measures (MMRM) analysis was performed comparing absolute and change from baseline log10 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 29, 2021. ; https://doi.org/10.1101/2021.09.28.21264252 doi: medRxiv preprint viral load between vaccinated and placebo participants from the nasopharyngeal swab day 1 of illness through saliva sample days 3, 5, 7, 9, 14, 21 , and 28 of illness. Only participants with a quantitative result in the day 1 illness nasopharyngeal swab were included in the MMRM modeling. Any MMRM result estimate under 0 copies, was truncated at 0. There was no imputation for missing data.

An exploratory analysis of burden of disease (BOD) due to Covid-19 was performed in the PP set based on adjudicated cases in participants who were SARS-CoV-2-naîve by serology and PCR at randomization and had available post-baseline data. A BOD score was based on post-SARS-CoV- BOD score and the number and percentage of participants with each level of BOD score was provided by treatment group. To assess disease burden in participants with Covid-19, a summary of BOD was provided in participants with Covid-19, (ie, participants with BOD score of zero were excluded from the analysis) and for assessment of the impact of baseline risk of severe disease on the vaccine effect regarding disease severity, a summary of BOD was provided by randomization strata (ie, ≥65 years; <65 years at risk; and <65 years not at risk). A proportional means model, including treatment group as fixed effect and stratified with stratification factor at randomization, was used to assess the vaccine effect on BOD. The VE for the BOD score was estimated as 1-the ratio of means as estimated by the proportional means model and reported with 95% CIs.

An exploratory analysis of burden of infection (BOI) was performed in the PP set based on asymptomatic infections and adjudicated Covid-19 cases in participants who were SARS-CoV-2 infection negative at baseline and had available post-baseline data. As with the BOD, a BOI score was defined to assess the severity of symptoms ( . A proportional means model, including treatment group as fixed effect and stratified with stratification factor at randomization, was used to assess the vaccine effect on BOI. The VE for BOI was estimated as 1the ratio of mean BOI scores and reported with 95% CIs.

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The copyright holder for this this version posted September 29, 2021. ; https://doi.org/10.1101/2021.09.28.21264252 doi: medRxiv preprint Sequencing of the SARS-CoV-2 spike gene was attempted from all available SARS-CoV-2 RT-PCR positive nasopharyngeal samples (n=832) collected between July 2020 through May 2021 from participants in the blinded portion of the COVE trial. This corresponded to 791 participants, (n=720 placebo and n=71 mRNA-1273). For 41 participants, more than one sample was sequenced within the illness period. The analysis of these cases is ongoing and will be included in additional analyses/reporting at a later date. Sequencing data was generated using three different approaches in two different laboratories.

Viral RNA from nasal swabs was extracted using the NucliSENS® easyMag® extraction kit.

Extracted RNA was used as template in a Qiagen One-Step Reverse Transcription-PCR (RT-PCR) reaction for cDNA synthesis using SARS-CoV-2 S gene Conventional RT-PCR primer mixes. The Agilent 2200 or 4200 TapeStation in conjunction with D5000 ScreenTapes, D5000 reagents, and the TapeStation Analysis software was used to assess post-amplified and purified PCR reactions for the presence, size, and concentration of any products generated. Library preparation was performed using Illumina Nextera XT Library Prep Kit. The Agilent 2200 or 4200 TapeStation in conjunction with D5000 ScreenTapes, D5000 reagents and the TapeStation Analysis software was used to assess purified libraries for presence, average fragment size, and concentration of the fragment distributions generated. Analysis of next generation sequencing data for the SARS-CoV-2 S gene NGS assay was done using Qiagen CLC Genomics Workbench v20.0.1 using NC_045512.2 as the reference strain. The custom workflow in CLC Genomics Workbench processed the sequencing data as follows: paired fastq files were imported, primer sequences were trimmed from 5'-ends of reads, reads were mapped to the full SARS-CoV-2 reference genome (NC_045512.2), single nucleotide and insertion/deletion variants relative to reference were called and annotated, and a consensus sequence of the spike gene (bases 21615 to 25436) was generated. The analysis workflow reported annotated variant tables, spike gene coverage tables, and spike-gene consensus sequences.

Upon TapeStation D5000 assessment and subsequent analysis of data using the TapeStation Analysis software, if the viral load was insufficient to obtain a correct band for the SARS-CoV-2 S gene targets (S1 (1026bp), S2 (893bp), S3 (1178), and S4 (1264bp), these results were considered negative. Positive results for the RT-PCR reactions were identified by 1) the presence of a band at the appropriate size for the SARS-CoV-2 S gene PCR products (S1 (1026bp), S2 (893bp), S3

(1178), and S4 (1264bp) relative to the D5000 ladder and 2) a peak table reporting a concentration for the specific bands for the sample. SARS-CoV-2 S gene NGS runs using MiSeq v2 chemistry . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 29, 2021. ; https://doi.org/10.1101/2021.09.28.21264252 doi: medRxiv preprint reagents running paired-end 2 x 151 reads must exhibit the following criteria: Cluster densities approximating 600 -1,200K/mm2; >80% of bases called exhibit Q-scores ≥30. Individual library sequence quality metrics were assessed by referencing the sequencing quality reports generated by analysis through the Qiagen CLC workbench program. For SARS-CoV-2 S gene NGS runs, up to 24 libraries can be sequenced on a single flow cell and the number of reads displayed in the trim summary section of the trim report should be ≥50,000 reads for each amplicon (prior to the reads being trimmed). Ninety-five percent of nucleotide positions between 21615-25436 should have a coverage of 100X. SARS-CoV-2 whole virus was used as a positive control. The LOD with all replicates for all 4 (S1-S4) amplicons was 6,667 copies/mL.

Viral RNA from nasal swabs stored in UTM is extracted using the Kingfisher Flex platform. 

Viral RNA from nasal swabs is extracted using the Kingfisher Flex platform and GSD NovaPrime® RNA extraction kit. Extracted RNA is used as template in a one-step RT-PCR for cDNA synthesis. Each cDNA is subjected to amplification using ARTIC SARS-CoV-2 Primer Pools. These primer pools were designed to amplify approximately 90 amplicons each with each amplicon averaging ~400bp. Mapping these amplicons to a reference sequence illustrates the 'tiled' approach used for primer design resulting in coverage of the entire SARS-CoV-2 genome.

Purification of the ARTIC PCR reactions was performed manually with Beckman-Coulter SPRIselect magnetic beads. The concentration of amplified amplicons in each sample was quantified using the Qubit FLEX fluorometer. Preparation of libraries was performed using the NEBNext Ultra II FS library prep kit in conjunction with the BRAVO liquid handling platform.

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The copyright holder for this this version posted September 29, 2021. ; https://doi.org/10.1101/2021.09.28.21264252 doi: medRxiv preprint Automated purification of the library reactions was performed using the Agilent BRAVO liquid handler and Beckman-Coulter SPRIselect magnetic beads. The fragment size distribution of the final pooled library was confirmed using the Agilent TapeStation 4200 or ThermoFisher BioAnalyzer 2100 DNA fragment analyzer prior to preparation for sequencing. Pooled libraries were denatured and sequenced on the NextSEQ 500 or 550 instrument using a NextSEQ Mid Output 500/550 flow cell and reagents running a 2x150 cycle paired-end sequencing protocol. A Twist SARS-CoV2 RNA positive control was processed in parallel with each verification run for positive control of the RT-PCR, ARTIC PCR amplification, and library preparation. The LoD for SARS-CoV2 WGS was determined to be 100 copies/ARTIC PCR assay reaction.

SARS-CoV2 variants in the study population were assessed based on amino acid mutations in the spike protein relative to the reference strain (spike mutations). For each of the three sequencing datasets, (spike-gene sequencing from Eurofins Viracor; spike-gene sequencing from Monogram Biosciences (LabCorp, South San Francisco, CA), and whole genome sequencing from Eurofins Viracor), spike protein amino acid mutations were acquired directly from the sequencing service provider. For each specimen, a single spike haplotype was designated as the ordered set of spike mutations. The same analysis was performed for the global SARS-CoV-2 genomic database available from the Global Initiative on Sharing All Influenza Data (GISAID). 25, 30 Pango Lineages 31 30 were inferred for the clinical specimens in two ways. First, they were inferred from the lineage annotations of matching spike haplotypes included in the GISAID database. In cases when a single spike haplotype was associated with more than one Pango Lineage in GISAID, the dominant lineage was used. In addition, Pango Lineages were inferred based on the presence of core backbone mutations from CDC variants in a specimen's spike haplotype. 23 To assess the relative prevalence of select lineages, the full clinical dataset and full GISAID dataset were subset to include only records annotated with the selected lineages. Prevalence for each selected lineages was then computed as the percentage of total records for a given month within each data subset.

For specific viral variants with a sufficient number of variant cases during the blinded phase of the study, the competing risk method was used to estimate the vaccine efficacy of mRNA-1273, specifically, Fine and Gray's (FG) sub-distribution hazard model was used. COVID-19 cases of specific variant were considered as cases, and COVID-19 cases of variants other than that of interest were considered as competing events in this analysis.

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Participants with symptoms of a respiratory illness were advised to contact the clinical site within 72 hours of onset. Such visit defined the day 1 illness date and triggered SARS-CoV-2 molecular testing via a nasopharyngeal swab that included testing for additional respiratory pathogens (Biofire RP2) and a 28-day follow-up period with periodic sampling (SARS-CoV-2 RT-PCR) also at days 3, 5, 7, 9, 14, 21 and 28 using saliva samples.

Respiratory pathogens were detected using the BioFire Respiratory Panel RP, a diagnostic multiplexed nucleic acid test intended for the simultaneous qualitative detection and differentiation of nucleic acids from 20 viral and bacterial respiratory organisms. The disposable closed system pouch was run on the Filmarray® Torch system which lyses samples, extracts, and purifies all nucleic acids, and performs nested multiplex PCR. Endpoint melting curve data was used to detect target-specific amplicons and analyze data to generate a result for each analyte. Nasopharyngeal Only participants with a quantitative result available at the day 1 illness nasopharyngeal swab were included in the MMRM analysis. A total of 36 participants in the mRNA-1273 and 595 in the placebo groups were included in the MMRM analysis of viral copy number. On illness visit day 1, the median number of viral copies/ml (log 10) were 6.7 for the placebo group and 3.4 for the mRNA-1273 group (Table S2 ). The MRMM analysis showed that from day 1 of illness through day 9, the number of viral copies detected in the placebo arm were significantly higher (p<0.001) than those in the mRNA-1273 arm (Figure 2A and Table S3 ). The difference (95% confidence interval) between the mRNA-1273 and placebo arms showed over a 100-fold reduction in viral copies/ml (log10) at day 1 (4. and Table S4 ). Similarly, in age cohorts of participants 18 to <65 and ≥65 years of age, a 150-fold reduction in viral copy number at day 1 illness was observed for mRNA versus placebo . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 29, 2021. ; https://doi.org/10.1101/2021.09.28.21264252 doi: medRxiv preprint ( Figure S2 ). The median times to undetectable viral copies (lower limit of quantitation <2.85 log10 viral copies/ml) were 4 days for mRNA-1273 and 7 days for placebo ( Figure S3 ).

Exploratory analyses of BOD and BOI were performed in the COVE trial to assess the effect of vaccination on the severity and symptoms of Covid-19 (Table S5) (Table   S9 ). Overall, 18 (2.3%) of the adjudicated cases starting after randomization were attributed to Epsilon, Gamma and Zeta variants in the placebo group and 3 (5.4%) in the mRNA-1273 group (Tables 1 and S9 as the total number of such cases were >10, and also against the formerly designated VOC and VOI given the interest in these variants. 23, 25 For Epsilon variants first detected in California, the VEs . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

The presence of viral and bacterial respiratory pathogens was detected during August 2020 to June Studies have shown that higher viral load assessed by Ct values (lower Ct values) and/or converted to copies/ml (as assessed in this study), is related to severe COVID-19 and mortality. [3] [4] [5] [6] [7] [8] [9] [10] Covid-19 vaccination has been shown to attenuate viral load and the duration of viral shedding and illness. 11, 12 In our study, the findings that mRNA-1273 elicited a highly significant reduction in both viral load on the day of Covid-19 illness diagnosis and persistence of viral RNA in saliva samples indicative of viral shedding up to day 9, are relevant as potential surrogates for the transmissibility of the SARS-CoV-2 virus. 4, 6, 10 In line with these findings and the efficacy results reported at the end of the blinded part of the COVE trial, 1,2 mRNA-1273 reduced the symptoms and severity of disease and infection as reflected by the lower BOD and BOI scores seen in vaccine recipients, and is consistent with recent studies showing that vaccination is highly effective in preventing severe Covid-19, asymptomatic infection and Covid-19-related hospitalizations and deaths. [32] [33] [34] [35] Although the transmission dynamics of Covid-19 are still under study, the estimated 10to 100-fold reductions in viral load, with statistically significant reductions in copies through day 9, may provide a significant reduction in Covid-19 disease spread, even in vaccine breakthrough cases.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 19, [23] [24] [25] 36 Infection with SARS-CoV-2 causes a broad range of symptoms from asymptomatic or mild symptoms to severe illness including and death; however, co-infections with respiratory pathogens can also contribute to these symptoms, complicating diagnosis and patient management. [27] [28] [29] The finding that the majority of symptomatic respiratory cases were caused by SARS-CoV-2 infection indicating that the case ascertainment between the 2 groups was unbiased, and also not impacted by . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 29, 2021. ; https://doi.org/10.1101/2021.09.28.21264252 doi: medRxiv preprint mRNA-1273 vaccination. The observations of high efficacy combined with a reduced viral load in breakthrough cases and reduced burden of disease and infections demonstrate that immunization with mRNA-1273 does not lead to vaccine enhanced respiratory disease, a theoretical concern at the onset of the Covid vaccine development. 1, 2 There are several limitations to consider. First, it should be noted that the analyses presented here are based upon an initial evaluation of data that will continue to accrue over time and will be subject to future updates. Although the BOD and BOI results were statistically significant over the entire PP set, the results were driven by the overall high vaccine efficacy and a numerically dominant prevalence of mild-to-moderate disease, including asymptomatic infections for BOI. With increased follow-up times and inevitably acquired disease in participants, the proportions of BOD and BOI may change. A prespecified, proportional means model was used for the analysis, to allow direct comparison across different periods of follow-up, minimizing these effects. The sequence data also come with known caveats, some demonstrated through this work.

For example, the fact that the vaccine has a marked effect on lowering SARS-CoV-2 viral loads hampered our efforts to generate an unbiased sequence data set. Even though sequencing efforts were performed in a blinded manner and the team was unaware of participant treatment assignments, the success rates in obtaining good quality sequences from samples of vaccine breakthrough cases was 50% or less, while it was over 80% for placebo-originated samples.

Although this is a clear, unavoidable bias in the available sequence data, it does not affect the overall assessment of the biological effect of vaccination on viral load. While a highly-aggressive variant capable of causing both a higher number of cases and viral loads among vaccine recipients was not previously seen, the emergence of the delta variant may yield samples that can be more readily sequenced and hence, a resulting detection bias in its favor. 37, 38 Finally, we must also recognize that the small sample size of variants detected limits the assessment and interpretation of VE against emerging variants. A further limitation is that the treatment groups in the original 1:1 randomized blinded and placebo-controlled trial had evolved, as an increasing number of placebo recipients either crossed over to be immunized or left the study to seek vaccination outside of the study.

In summary, this analysis of the viral load and the circulating viral variants in the mRNA-1273 phase 3 COVE trial during the placebo-controlled phase suggests that vaccination with mRNA-1273 vaccine leads to a significant reduction of the SARS-CoV-2 viral load and shedding period, and associated BOD and BOI. mRNA-1273 vaccine showed high efficacy and continues to have a marked effect in reducing symptomatic Covid-19 cases among vaccine recipients. The . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 29, 2021. ; https://doi.org/10.1101/2021.09.28.21264252 doi: medRxiv preprint

As the trial is ongoing, access to patient-level data and supporting clinical documents with qualified external researchers may be available upon request and subject to review once the trial is complete. Table 1. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

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