key: cord-0695353-qvsaq3i2
authors: Liao, Gary; Zheng, Katina; Lalu, Manoj M.; Fergusson, Dean A.; Allan, David S.
title: A Scoping Review of Registered Clinical Trials of Cellular Therapy for COVID-19 and a Framework for Accelerated Synthesis of Trial Evidence – FAST Evidence
date: 2020-06-27
journal: Transfus Med Rev
DOI: 10.1016/j.tmrv.2020.06.001
sha: cc8a25835978e3864108eb447442dd356d315b21
doc_id: 695353
cord_uid: qvsaq3i2

Abstract The urgent need for safe and effective treatments for COVID-19 has fueled the launch of many parallel complex studies of cellular therapies with small to modest enrolment projections. By pooling data from multiple studies that are similar, we can increase the ability to achieve sufficient power to determine effectiveness more quickly through metanalysis. A scoping review of registered clinical trials using cell-based interventions for COVID-19 was conducted to identify candidate studies for metanalysis that could support an accelerated regulatory review. ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were searched April 23, 2020. Trials were included if they utilized cell or cell-derived products to treat or prevent COVID-19. Fifty-four registered cellular therapy trials were identified and included for analysis. Studies of mesenchymal stromal cells (MSCs; 41 studies; 1129 subjects projected to receive cells) and natural killer (NK) cells (5 studies; 135 projected to received cells) were observed most commonly. A subset of studies are controlled (34 studies, or 63%), including 27 studies of MSCs and 3 of NK cells. While heterogeneity in study design exists, the cumulative projected enrolment of patients from similar studies appears sufficient to allow the detection of meaningful differences in clinically important outcomes such as mortality, admission to intensive care and need for mechanical ventilation by September 2020 – sooner than any individual study could determine effectiveness. MSCs are the predominant cell type in registered trials for severe or critical COVID-19 and represent the most promising candidates for future metanalysis. Sufficient pooled sample size to detect clinically important reductions in multiple outcomes, including mortality, is anticipated by September 2020, but may require accessing supplementary data to align outcome reporting. Regulatory approval, funding and implementation by cell manufacturing partners will be accelerated by our framework for rapid metanalysis.

COVID-19 represents one of the most significant global health crises in recent times [1] .

Effective therapies are lacking, and a significant proportion of patients experience progressive dyspnea, hypoxemia and respiratory failure. The acute respiratory distress syndrome (ARDS) is the greatest contributing factor leading to the death of many patients [2] . Cellular therapies such as mesenchymal stromal cells (MSCs) have immune modulating functions that can inhibit the infiltration of inflammatory cells and/or attenuate the expression of cytokines and chemokines that induce damaging inflammation and fibrosis following infection [3, 4] . Cell-based therapies for ARDS, other lung diseases and sepsis have been investigated predominantly in pre-clinical animal models [3, 4] . Early phase clinical trials have been conducted [5] [6] [7] but no cellular therapy has been approved for the treatment of ARDS, sepsis, or cytokine release syndromes, as far as we know. Early phase studies have demonstrated safety and feasibility of treating patients who have ARDS or sepsis with MSCs but remain underpowered to establish efficacy [8] . Moreover, aspects of ARDS in COVID-19 may be distinct from other causes and effectiveness in patients with ARDS related to SARS-Cov-2 will be needed. Greater emphasis on standardized cell manufacturing methods have allowed the field of cellular therapy to mature to a stage where larger scale clinical trials are occurring, however, heterogeneity in the source of cells used to generate various cell products, various components of cell culture methods, and methods of storage and administration need to be carefully considered when pooling data for metanalysis.

Given the urgency and magnitude of the health challenge posed by COVID-19, health research funding agencies around the world and the biomedical cell manufacturing industry are rapidly pivoting to address COVID-19 and are dedicating significant efforts and funds towards studies for the treatment of COVID-19. Identifying registered studies of cell-based therapy for COVID-19 will identify a network of investigators, allow for the creation of a compendium of actively recruiting registered studies and will allow for the rapid pooling of data that emerges Journal Pre-proof J o u r n a l P r e -p r o o f 5 from similar studies to accelerate the assessment of efficacy and also adverse event rates associated with these therapies. Studies are too small in size to determine efficacy on their own without metanalysis and obtaining supplemental data from investigators will be essential to align outcome measures that are consistent and objective as many studies plan to report surrogate markers of efficacy such as biomarker responses. A framework for accelerated synthesis of trial evidence, or FAST Evidence, will be needed to rapidly identify studies that share sufficient homogeneity, obtain the required supplemental data and facilitate a planned metanalysis in realtime to provide the required knowledge synthesis that could allow timely approval and delivery of effective cellular therapies to treat COVID-19.

J o u r n a l P r e -p r o o f 6

The registry of clinical trials at clinicaltrials.gov and the WHO International Clinical Trials Registry Platform using the COVID-19 registry of trials were searched on April 23, 2020. The registers were searched for trials of cellular therapy of COVID-19 using the following search strategy (for www.clinicaltrials.gov): (COVID OR "COVID-19" OR "2019-nCoV" OR "novel coronavirus" OR Coronavirus OR "SARS-COV-2" OR SARS) AND (cell OR stem cell OR MSC OR cell therapy OR exosome OR vesicle OR "conditioned media"); and for the WHO registry of COVID-19 studies (www.who.int/ictrp/en/): Cell OR stem cell OR MSC OR exosome OR vesicle OR conditioned media.

Registered clinical studies were included for analysis if they utilized a cell or cell-derived product for interventional purposes to treat or prevent infection of SARS-CoV-2 and its associated disease COVID-19. Registered studies were not included if they did not administer a cell or cellderived product for interventional purposes to treat or prevent infection of SARS-CoV-2, and if the study was listed as withdrawn or cancelled. Registered studies were reviewed by two individuals independently for assessment of inclusion and exclusion criteria.

For each included record, the following data (if available): were extracted by two individuals independently Trial ID, registry and date of registration, recruiting status, phase, title, planned start date, anticipated primary completion (data collection complete), anticipated study completion, inclusion and exclusion criteria, disease severity, age range of eligible study participants, anticipated number of subjects to be enrolled in both the intervention and control groups (if any), whether randomization is planned, cell type and source, dosage, manufacturing method, whether any cell-derived products are to be given, route of administration, primary and secondary outcomes, country of origin of primary or lead investigator.

We described the characteristics of all included trials. In order to estimate the required sample size to determine efficacy for a 2, 5, 7.5 and 10% absolute reduction in mortality, we assumed an alpha error of 5% and used a power calculation of 80% and assumed enrolment of subjects in the intervention group was 1:1 compared to control groups. Statistical modelling was done by comparing proportions of two independent groups using a calculator to determine sample size 

A total of 169 records were identified from Clinicaltrials.gov and 142 records from the WHO International Clinical Trials Registry Platform [10] . After removing duplicates, 288 records were reviewed. There were 13 studies that were withdrawn or cancelled, leaving 275 for determination of eligibility. After reviewing the records in detail, 221 were excluded (220 did not treat patients with a cellular product and 1 trial was for compassionate use only and not a clinical trial). A total of 54 studies were included in our review (see Figure 1 ). Study characteristics are summarized in Table 1 (see Table A The most common cell type described in the planned studies was MSCs (41 studies, 76%), including 3 studies that will administer MSC-derived extracellular vesicles or "exosomes", with a total of 1129 enrolled subjects projected to receive cells or cell-derived products (see Table A .2. for details). Amongst MSC studies, 27 (51%) describe a control group for comparison, with a combined projected enrollment of 801 patients to be treated with MSCs or MSC-derived products in a 1:1 (22 studies), 1:2 (4 studies), or 2:1 (1 study) ratio of controls to those in the intervention group. Controls were placebo (9 studies) or saline (7 studies) in a combined total of 16 studies that have a cumulative total projected enrolment of 429 subjects in the intervention arms. The remaining studies describe a control group that will receive conventional therapy, standard of care, or was unspecified. With regards to potential risk of bias, we noted that while randomization was described in 61% of studies, the method of randomization was not described for 39% of registered trials (see Table A .3.). Allocation concealment and blinding of assessors was described in 11% and 24% of the registered protocols.

With regards to MSC manufacturing, the starting cell source for MSC growth was placental tissue (18 studies, including umbilical cord or Wharton's jelly), adipose tissue in 7 J o u r n a l P r e -p r o o f 9 studies, bone marrow (1 study) and unspecified or other in the remaining trials (15 studies) (see Table A .2.) . Amongst studies with a placebo or saline control group, umbilical cord is the stated source for MSC expansion in 8 studies (50%). Additional manufacturing details such as conformance to recommendations by the International Society for Cellular Therapy for MSC characterization [11] , use of xenogeneic products such as animal serum during cell culture, passage number and storage conditions of cells administered to patients and whether release criteria such as cell viability, product potency, or other criteria were used was generally unavailable from the information provided at registration. Amongst the controlled studies of MSCs, however, the severity of disease of patients to be enrolled was moderate to critical, with most analyzing severe cases [12, 13] . We then estimated the required sample size required for different levels of significant reduction in key outcomes that could be determined through pooling of data from similar studies (See Table 2 ). Reported mortality rates for patients with severe COVID-19 are approximately 10 -20% [14] [15] [16] and for critical disease, the reported mortality rates are 40 -60% [14, [16] [17] [18] [19] [20] . For clinically meaningful absolute reductions of 2 -10% in mortality and other dichotomous outcomes, such as rates of intensive care unit (ICU) admission and need for mechanical ventilation, a cumulative sample size of 74 to 9493 subjects would be required for the intervention and control arms, depending on the outcome rate in the control arm (see Table 2 ).

Based on the projected date of completion of registered controlled trials of MSC studies (see 

The number of newly registered cell-based studies to treat severe/critical COVID-19 is significant with many launching in early 2020 and many expected to complete data collection before or soon after the end of 2020. Many of the actively recruiting trials are studying the use of MSCs and enough are planning randomization with placebo or saline control groups that will make metanalysis of similar studies feasible. The characterization and manufacturing details are lacking from the limited information available for most trials, but it is likely with efforts to standardize MSC characterization [11] and with more widespread use of similar manufacturing methods that this aspect of the study design may represent sufficient homogeneity to allow for pooling of data for metanalysis. However, aspects of manufacturing MSCs that can impact cell function such as the manufacturing site, age of the donor, source of cells (whether umbilical cord, bone marrow or adipose tissue), and the extent of in-vitro expansion, amongst other variables may be anticipated as sources of heterogeneity [21, 22] . Furthermore, storage conditions and release criteria prior to administration are also important, including cell viability and potency assays that can vary dramatically between published studies [21, 23] . If these aforementioned factors are adequately reported upon publication of the results of these identified trials, it may be possible to account for these confounding factors with subgroup analyses.

The clinical aspects of study designs appear largely similar, including the definition of disease severity, ages and sex of eligible study participants, and while many studies report similar clinical outcomes such as mortality and rates of admission to ICU and the need for mechanical ventilation, this data may need to be requested from investigators of some studies to facilitate a framework for knowledge synthesis that relies of alignment of reported outcomes.

Other surrogate markers of clinical response including radiographic responses, reverse transcriptase polymerase chain reaction results of virus levels, and measurement of J o u r n a l P r e -p r o o f inflammatory markers may be harder to combine depending on the timeframe for measuring these outcomes and specifics of the methods that will be used. A framework for sharing and obtaining supplemental data from studies on aligned outcomes will assist greatly with efforts to pool data and perform meaningful metanalysis. While blinding is not described for all studies, the use of objective outcomes may help to limit assessor bias. Moreover, randomization of subjects is described for many studies with a planned control group which limits allocation bias. Use of placebo or saline treatment instead of conventional or standard therapy as a control group will be important to control for the concomitant administration of other experimental therapies to these patients. Pooling data will increase power of these similar studies and allow for earlier understanding of efficacy. If efficacious, regulatory bodies in affected countries could move more quickly to approve the class of MSC-based therapy, notwithstanding specific review of individual products regarding details related to production, storage, release of product and treatment parameters. It is important to acknowledge that some regulatory bodies, including the Food and Drug It is possible that studies will not accrue patients at the rate anticipated. The incidence of severe COVID-19 disease will be difficult to predict in the months ahead, especially since many studies are centered in China where the disease has slowed significantly in recent weeks [24] .

The approach outlined in this proposed framework reduces bias as it would include all published data as soon as available, from studies that share sufficient similarity to be pooled and using criteria that are established in advance and registered on public registers. We have already registered a planned metanalysis of MSC trials on PROSPERO, an international register of planned metanalyses (protocol CRD42020181751; https://www.crd.york.ac.uk/prospero/ ) that will be conducted and reported in accordance with PRISMA guidelines [10] . As more study results become available, the metanalysis would be updated to refine initial estimates regarding efficacy and to confirm rates of adverse events. Additional new trials are anticipated from new regions of the global research community which will expand the international reach of this proposed framework. It is also likely that some trials will be conducted and published that were never registered. This occurs more commonly with trials that are privately funded. While the lack of registration in advance may introduce potential bias in the reporting, results of trials that are not registered will also be considered for inclusion in our metanalysis. We are aware of a few significant trials that are planned or ongoing that would fall in this category [25] [26] [27] [28] . Additionally, our search criteria for this scoping review was limited to trials registered on or after December 1, 2019, we may have missed previously registered or ongoing cell-therapy trials for the treatment of ARDS that are now enrolling a COVID-19 specific cohort. Our meta-analysis strategy will expand the search restriction in order to capture those trials we may have missed.

In conclusion, our scoping review of registered clinical trials of cellular therapy for COVID-19 highlights an opportunity to perform rapid metanalysis from placebo-controlled randomized controlled trials using MSCs which could be expanded to other cell types, to treat severe and critical cases. Sufficient power to detect important improvements in outcomes is anticipated by performing metanalysis before the end of 2020. Accessing supplemental data from published studies on aligned and consistent objective outcomes will further accelerate knowledge synthesis efforts. Regulatory bodies should prepare for assessing pooled data using such a framework to evaluate possible applications for specific cellular therapies in this unique context.

No conflicts of interest to disclose.

We acknowledge the important contribution from the many patients, families and donors that participate in clinical research in cellular therapy. We also acknowledge the climate of global cooperation in this challenging time that will be required to propel research efforts towards clinical treatments for more patients. GL, KZ and DSA designed the project, contributed to data acquisition and analysis and contributed to writing of the manuscript. ML and DF contributed to data analysis and writing of the manuscript. All authors approved the final version of the manuscript and all persons who made substantial contributions to the manuscript are listed as authors.

J o u r n a l P r e -p r o o f Table 2 . Required sample size needed to determine a significant absolute reduction in the proportion of study subjects experiencing a dichotomous outcome in the intervention group compared with a control group.

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13-19), need for ICU admission (10 -20% of hospitalized patients), or for the need for mechanical ventilation among patients admitted to the ICU (20-80%). Type I error = 0.05, Type II error = 0.2; two tailed comparison of proportions in independent groups

MSC, Mesenchymal stem cell; NK cells, natural killer cells; aAPC, artificial antigen presenting cell; a Other includes Cytotoxic T-Lymphocytes, CAStem, Cellular Stromal Vascular Fraction (cSVF) or unknown; b Other: Spain, UK, Jordan, Brazil, France, Denmark, Columbia, c Three studies used exosomes; d One study used extracellular vesicles e One study used conditioned media; All patient numbers are based on projected enrolment; Some studies used more than one cell type/derivedproduct. If the study did not specify the sampling ratio, a 1:1 ratio was assumed per arm.