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During the trial the Alpha SARS-CoV-2 variant was the dominant variant of concern, while the 252 Delta variant became more prevalent in the final time epoch (Supplement). We found no 253 relative difference in mAb treatment effects over time and no comparisons reached a pre-254 specified statistical threshold (Supplement). 255 |
In a learning healthcare system trial of mAb for Covid-19, treatment of EHR-screen eligible 258 patients increased 7.5-fold, particularly among historically and geographically underserved 259 populations. We found a 91% and 94% probability of inferiority of bamlanivimab respectively to 260 bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence 261 between bamlanivimab-etesevimab and casirivimab-imdevimab at the first pre-specified bound, 262 with regard to the odds of improvement in hospital-free days by 28 days. However, the 263 bamlanivimab and bamlanivimab-etesevimab arms were stopped early, and the identified 264 probabilities did not meet prespecified statistical triggers for trial conclusions of inferiority or 265 equivalence. 266 267 OPTIMISE-C19 is designed to continuously compare all available mAb for Covid-19 and can 268 stop mAb arms based on internal statistical triggers or external factors, such as U.S. federal 269 decisions limiting mAb availability or re-introduction of mAb into distribution networks. Had 270 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. screening of all patients within the system with a positive SARS-CoV-2 followed by direct-to-279 patient outreach phone calls, 3) paper referral form for patients without access to an in-system 280 provider, 4) community leader and existing outreach network collaboration for patient 281 engagement, 5) phone line for patients and community members to call and speak with a 282 healthcare professional, 6) providing infusions at home for patients without transportation. 283 |
The finding of potential inferiority of bamlanivimab is similar to mechanistic studies that suggest 285 a waning efficacy of bamlanivimab in the face of certain SARS-CoV-2 variants. It supports the 286 FDA decision to revoke the bamlanivimab EUA. 26 A recent observational study reached a 287 different conclusion and found similar effectiveness between bamlanivimab and casirivimab-288 imdevimab. 31 However, this study analyzed patients treated between November 2020 and 289 |
February 2021, prior to widespread emergence of variants and U.S. federal decisions to halt 290 bamlanivimab distribution. 291 292 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. where variant resistance to this mAb is < 5%, based on in vitro data of activity against the Delta 296 variant, and lack of activity against the Beta, Gamma, Delta plus, and B.1.621 variants. 31,32 The 297 similar effectiveness of bamlanivimab-etesevimab and casirivimab-imdevimab in the current 298 trial supports this decision. Also aligning with these data is a recent observational study of 165 299 patients that found no difference in hospitalization or death between bamlanivimab-etesevimab 300 and casirivimab-imdevimab in patients infected with Alpha, but worse outcomes with 301 bamlanivimab-etesevimab in patients infected with Gamma. 33 302 303 |
The strengths of this report include capture of nearly all patients infused with mAb from 49 sites 304 across a large geographic region, enhancing the generalizability of the results. In addition, an 305 advantage of the Bayesian design is that any data, including data following unplanned cessation 306 in enrollment into a trial arm, can be analyzed and quantified as posterior probabilities, which is 307 potentially more useful and is more quantitative than a frequentist conclusion of failure to reject 308 a null hypothesis possibly because of lack of power. 34 Third, the trial was embedded into usual 309 care which enhanced patient and provider engagement. 12 The trial also has limitations. First, the 310 results are presented before any prespecified internal trigger was reached. Nonetheless, to our 311 knowledge, this trial represents the largest randomized comparative effectiveness data of mAb 312 |
for Covid-19. Second, the absence of patient-level variant data limited ability to directly assess 313 comparative effectiveness relative to variant strains. Alpha was also the dominant variant during 314 the majority of the trial. Using regional data as a surrogate for variant data in the Pennsylvania 315 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint population over time, we found no difference in treatment effect over time. Third, we primarily 316 relied on UPMC EHR data to capture death and hospitalization, and patients may have accessed 317 care outside our health system after mAb treatment. We conducted direct-to patient calls and 318 national death registry queries to address this concern. Fourth, the EHR eligibility screen 319 identified most, but not all EUA risk factors, and could not identify if a patient was symptomatic. 320 321 |
In non-hospitalized patients with mild to moderate Covid-19, bamlanivimab, compared to 323 bamlanivimab-etesevimab and casirivimab-imdevimab, resulted in 91% and 94% probabilities of 324 inferiority with regards to odds of improvement in hospital-free days within 28 days. There was 325 an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-326 imdevimab at an odds ratio bound of 0.25. However, the trial was unblinded early to these mAb 327 due to federal distribution decisions, and no mAb met prespecified criteria for statistical 328 inferiority or equivalence. 329 330 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint * IQR, interquartile range; mAb, monoclonal antibodies; SD, standard deviation. 480 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. Due to pharmacy logistics, 5 patients who received bamlanivimab-etesevimab had been 497 randomly assigned to casirivimab-imdevimab, and 7 patients who received casirivimab-498 imdevimab had been randomly assigned to bamlanivimab-etesevimab. All infused patients who 499 received bamlanivimab monotherapy had been randomly assigned to bamlanivimab 500 monotherapy. The FDA mAb policies changed over time, resulting in varying mAb availability 501 and EUA eligibility criteria over time (Supplement). 502 503 504 505 506 507 508 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. strategy to address many of these problems by gaining economies of scale from a common 581 platform, which allows for broad enrollment but retaining the ability to examine for 582 heterogeneity of treatment effects between defined subgroups. A REMAP focuses 583 predominantly on the evaluation of treatment options for the disease of interest that are 584 variations within the spectrum of standard care (although testing of novel or experimental 585 therapies is not precluded) and does so by embedding the trial within routine healthcare 586 delivery. In this regard, the REMAP seeks to replace random variation in treatment with 587 randomized variation in treatment allowing causal inference to be generated about the 588 comparative effectiveness of different existing treatment options. The use of response 589 adaptive randomization (RAR), which allows the allocation ratios to change over time based 590 on accruing outcomes data, maximises the chance of good outcomes for trial participants. The 591 embedding of such a platform within the day-to-day activities facilitates the translation of 592 outcomes to clinical practice as a "self-learning" system. As such, it also functions as an 593 embedded and automated continuous quality-improvement program. A final advantage of a 594 REMAP for optimizing monoclonal antibody treatment outcomes is the ability to rapidly 595 adapt to generate evidence if as new interventions emerge, avoiding the inevitable delays 596 associated with conventional trials. 597 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint A REMAP applies novel and innovative trial adaptive design and statistical methods to 598 evaluate a range of treatment options as efficiently as possible. The broad objective of a 599 REMAP is, over time, to determine and continuously update the optimal set of treatments for 600 the disease of interest. The set of treatments that may be tested within a REMAP comprise the 601 set of all treatments that are used currently or may be developed in the future and used or 602 considered for use in patients. The design maximizes the efficiency with which available 603 sample size is applied to evaluate treatment options as rapidly as possible. A REMAP has the 604 capacity to identify differential treatment effects in defined sub-groups (termed strata), These design features are: 618 |
• frequent adaptive analyses using Bayesian statistical methods 619 |
• response adaptive randomization 620 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint • evaluation of differential treatment effects in pre-specified sub-groups (strata) 621 |
• evaluation of specified intervention-intervention interactions 622 |
• testing of multiple interventions in parallel and, subsequently, in series 623 |
This creates a 'perpetual trial' with no pre-defined sample size, the objective of which is to 624 define and continuously update best treatment over the lifetime of the REMAP. The design 625 aspects, including the risk of type I and type II errors, are optimized prior to the 626 interventions with respect to the primary endpoint. Every participant will be assigned an 638 intervention. Inference in this REMAP is determined by analyses using pre-specified 639 statistical models that incorporate time periods, age, and disease severity to adjust for 640 heterogeneity of enrolled participants that might influence risk of death. These models 641 incorporate variables that represent each intervention assigned to participants. The efficacy of 642 each intervention is modeled as possibly varying in the different stratum in the REMAP. 643 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint Whenever a model hits a predefined threshold for any of superiority, inferiority, or 644 equivalence for an intervention with respect to the primary endpoint, this is termed a 645 statistical trigger. At any given adaptive analysis, a statistical trigger may be reached for all 646 participants or for one or more strata, further described in the statistical analysis plan 647 (Protocol Appendix, page 26) . 648 649 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Start incorporating bamlanivimabetesevimab into most sites. There was a 1-week delay to use etesevimab at six sites due to low initial supply. |
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint disease, cystic fibrosis, and pulmonary hypertension) • Sickle cell disease • Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies) • Having a medical-related technological dependence (e.g., tracheostomy, gastrostomy, or positive pressure ventilation [not related to COVID-19]) |
Sotrovimab is a new mAb treatment. |
Casirivimab 600mg and imdevimab 600 mg |
Casirivimab-imdevimab dose decreased from 2400mg to 1200mg. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint |
This trial protocol has been provided by the authors to give readers additional information about 690 their work. |
Protocol for: A learning health system randomized trial of monoclonal antibodies for Covid-19 |
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. • References …………………………………………………………………31 711 712 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. While COVID-19 vaccination will reduce COVID-19-related morbidity and mortality, the learned 771 immune response may vary between individuals. This means interventions such as monoclonal 772 antibodies (mAB) will still be needed to prevent progression of COVID-19 illness. Monoclonal 773 antibodies seek to mimic or enhance the natural immune system response against a pathogen and 774 are often used in the care of patients with cancer or infection. 775 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint For viral infections, mABs are created by exposing a white blood cell to a particular viral protein, 776 which is then cloned to mass produce antibodies to target that virus. For SARS-CoV-2, the virus 777 that causes COVID-19, IgG1 mABs target the spike protein of SARS-CoV-2 and block viral 778 attachment and entry into cells. Despite the EUAs, the clinical use of mABs is low due in part to lack of patient access, 804 complexities in drug allocation, and lack of knowledge among providers are contributing factors. 805 |
Further, the comparative effectiveness of different mABs is unknown and not yet directly studied. 806 |
The National Academies of Sciences, Engineering, and Medicine recently called for expanded 807 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint access and clinical use of mABs, noting it is "critical to collect data and evaluate whether they are 808 working as predicted". 809 |
This evaluation seeks to expand access to mABs at UPMC and determine their relative effects 810 versus each other, starting with those governed by EUAs. The primary objective is to evaluate the clinical and biological effect of multiple monoclonal 817 |
The primary hypothesis is clinical and biological effect will vary between mABs, by SARS-CoV-819 2 variants, and patient characteristics. 820 |
METRICS 821 822 |
The primary evaluation metric is total hospital free days (HFD) at 28 days after mAB receipt 823 calculated as 28 minus the number of days during the index stay minus the number of days 824 readmitted during the 28 days after treatment. Death within 28 days is recorded as -1 HFD. 825 |
Secondary evaluation metrics include: 826 |
• All-cause and all-location mortality at 28 and 90 days 827 |
• Emergency department visits at 28 days 828 |
• Organ-support free days at day 28 829 |
• Where feasible: 830 |
• SARS-CoV-2 nasopharyngeal and plasma viral loads among participants from baseline and 831 longitudinally through day 28 832 |
• SARS-CoV-2 antibody titers, antibody neutralization, and other immune responses at 833 baseline and longitudinally through day 28 834 |
• Detection of SARS-CoV-2 variants through next-generation sequencing at baseline and 835 longitudinally through day 28 836 |
• Determining the duration of SAR-CoV-2 infectivity and non-culture surrogates for SARS-837 |
CoV-2 infectivity among patients with persistent nasopharyngeal swab viral shedding 838 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint |
We will conduct a pragmatic evaluation of participants with COVID-19 illness under existing 841 UPMC processes for the clinical care of COVID-19 positive patients, including EUA requirements 842 for mAB administration. A patient who presents to a UPMC facility and tests positive for COVID-843 19 will, as per current common care, be offered monoclonal antibodies. Data that are already 844 collected according to UPMC procedures and EUA requirements are used for analysis. 845 846 9. |
POPULATION 847 848 |
We will evaluate patients that present to UPMC Emergency Departments, urgent care sites, 849 |
infusions centers and other facilities that can or do provide mABs for COVID-19. As of February 850 24, 2021, there are 3 EUAs, with common inclusion and exclusion criteria, and we will evaluate 851 patients that meet these criteria. As other antibodies become available, we will modify this 852 evaluation submission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. As per the current EUA criteria, the following are excluded: 884 |
• Are hospitalized for the treatment of COVID-19 885 |
• Require oxygen therapy for the treatment of COVID-19 886 |
• Require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic 887 oxygen therapy due to underlying non-COVID-19 related comorbidity 888 |
• Have a known hypersensitivity to any antibody ingredient 889 |
Patients will receive COVID-19 mABs governed by FDA EUAs, when their treating physician 892 orders a mAB and they meet EUA criteria. Currently and under our examination, the treating 893 physician do not choose a specific mAB product. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Bamlanivimab is a human immunoglobulin G-1 (IgG1 variant) monoclonal antibody consisting of The EUAs require that healthcare facilities and providers report therapeutic information and 933 utilization data through HHS Protect, Teletracking, or National Healthcare Safety Network as 934 directed by the US Department of Health and Human Services. 935 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. |
The copyright holder for this preprint this version posted September 9, 2021. ; https://doi.org/10.1101/2021.09.03.21262551 doi: medRxiv preprint |
We will collect data including baseline demographics and underlying conditions, results of SARS-936 COV-2 PCR or antibody testing, and initial care including mAB infusion completion. We will 937 collect post-randomization healthcare encounters, including hospitalization, emergency 938 department visits, ICU care, and other measures of healthcare utilization. We will use an electronic 939 health record data collection process to augment existing UPMC data collection processes as 940 |
All data will be handled and secured as per University of Pittsburgh and UPMC data guidelines. 942 |
There will be no research activities involving direct interaction with subjects performed as part of 943 this evaluation. 944 |
In addition to the primary and secondary outcome data referenced in this submission, data collected 945 will include the below areas. All data will be abstracted directly from the electronic health record 946 and handled anonymously. 947 |
• Which mAB was administered, including date, time, and infusion completion as well as 948 the location of the infusion 949 Antibodies will be administered as per the EUAs and UPMC Pharmacy and Therapeutics policies. 965 |
Providers will explain mAB risks and benefits and provide the EUA Fact Sheets for Patients, 966 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The COVID-19 mABs are currently routinely used at UPMC. Once any order for mAB infusion 971 is approved by the UPMC system oversight group, the pharmacy provides whichever EUA-972 governed mAB is available under a therapeutic interchange approach. Ordering physicians review 973 with the patient the EUA Fact Sheet for each mAB and explain that the patient could receive any 974 of the mABs governed by FDA EUAs. 975 |
If demand for mAB exceeds supply, UPMC has a lottery system to allot who receives the therapy 976 once requested by a physician. 977 |
Our current proposal is a UPMC system quality improvement initiative, embracing and extending 978 the current lottery system and therapeutic interchange policy for EUA-governed mABs for 979 COVID-19 as follows: 980 |
a. If scarcity present and lottery system allow provision, proceed. 982 2. The Pharmacy fills order with one of the EUA-governed COVID-19 mABs using an embedded 983 assignment system akin to current mAb provision. This system will allow a comparative 984 effectiveness evaluation of the multiple mABs by effectively ensuring random allocation. 985 |
3. The Physician can agree to the assigned mAB or can request a specific mAB. 986 |
It is the treating physician's choice to accept the assigned mAB or not, and therefore patient 987 consent for the mAB assignment is not required. Patients will be told which mAB they are 988 receiving, along with an EUA Fact Sheet, as per EUA requirements. Predefined strata will include patients discharged home after infusion, patients admitted to hospital 996 after infusion, prior vaccination, and if known, presence of virus variants of concern at baseline 997 and presence of neutralizing antibodies to SARS-CoV-2 at baseline. 998 All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. • Are hospitalized for the treatment of COVID-19 • Require oxygen therapy for the treatment of COVID-19 • Require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity • Have a known hypersensitivity to any antibody ingredient Primary evaluation metric Total hospital free days at 28 days |
All rights reserved. No reuse allowed without permission. |
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. While COVID-19 vaccination will reduce COVID-19-related morbidity and mortality, the learned 1109 immune response may vary between individuals. This means interventions such as monoclonal 1110 antibodies (mAB) will still be needed to prevent progression of COVID-19 illness. Monoclonal 1111 antibodies seek to mimic or enhance the natural immune system response against a pathogen and 1112 are often used in the care of patients with cancer or infection. 1113 All rights reserved. No reuse allowed without permission. |