key: cord-286441-nl3kuqw3
authors: Murray, D. D.; Babiker, A. G.; Baker, J. V.; Barkauskas, C. E.; Brown, S. M.; Chang, C.; Davey, V. J.; Gelijns, A. C.; Ginde, A. A.; Grund, B.; Higgs, E.; Hudson, F.; Kan, V. K.; Lane, H. C.; Murray, T. A.; Paredes, R.; Parmar, M. K. B.; Pett, S.; Phillips, A. N.; Polizzotto, M. N.; Reilly, C.; Sandkovsky, U.; Sharma, S.; Teitelbaum, M.; Thompson, B. T.; Young, B. E.; Neaton, J. D.; Lundgren, J. D.; group, TICO study
title: Design and implementation of the multi-arm, multi-stage Therapeutics for Inpatients with COVID-19 (TICO) platform master protocol: An Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative
date: 2020-11-12
journal: nan
DOI: 10.1101/2020.11.08.20227876
sha: 
doc_id: 286441
cord_uid: nl3kuqw3

Background: The SARS-CoV-2 pandemic is a public health emergency. Safe and effective therapies are urgently needed. Methods: Therapeutics for Inpatients with COVID-19 (TICO), is a global multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. The protocol design allows multiple therapeutic agents to be evaluated in an efficient and scientifically rigorous manner, with efficiencies delivered by the MAMS design, and began by studying neutralizing monoclonal antibodies. TICO employs an agile and robust approach to futility and safety evaluation at 300 patients enrolled (Stage 1), with subsequent expansion to full sample size and an expanded target population (Stage 2) if the agent shows an acceptable safety profile and evidence of efficacy. Two ordinal outcomes applied early (Day 5) determine the efficacy signals of the investigational agents(s) and progression to Stage 2. These ordinal outcomes assess both respiratory and other organ failure events, recognizing the broad range of COVID-19 morbidity. In Stage 2, overall efficacy is assessed using the primary outcome of time to sustained recovery, assessed over 90 days. This approach to early futility assessment using an early intermediate outcome and a primary endpoint out to 90 days allows the study team to make rapid decisions on safety and potential efficacy of novel agents while ultimately focusing on patient-centered, longer-term outcomes. The implementation of TICO across a global network allows for continued enrollment despite variations in geographic epidemiology. Study Status: The TICO master protocol moved from conception to first patient enrolled in approximately 9 weeks, a testament to the expedited regulatory and ethics review, coupled with flexible and responsive study operations. The first agent to be tested using this protocol, LY-CoV-555, enrolled N=326 participants before undergoing Stage 1 futility and safety assessment. Two additional agents will enter the study in November 2020, with other agents planned. Conclusion: The TICO MAMS platform trial has been implemented efficiently across a global network of sites and several trial networks. It will generate results rapidly for multiple novel neutralizing monoclonal antibodies and other therapeutics agents.

Background: The SARS-CoV-2 pandemic is a public health emergency. Safe and effective therapies are urgently needed.

Methods: Therapeutics for Inpatients with COVID-19 (TICO), is a global multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. The protocol design allows multiple therapeutic agents to be evaluated in an efficient and scientifically rigorous manner, with efficiencies delivered by the MAMS design, and began by studying neutralizing monoclonal antibodies. TICO employs an agile and robust approach to futility and safety evaluation at 300 patients enrolled (Stage 1), with subsequent expansion to full sample size and an expanded target population (Stage 2) if the agent shows an acceptable safety profile and evidence of efficacy. Two ordinal outcomes applied early (Day 5) determine the efficacy signals of the investigational agents(s) and progression to Stage 2. These ordinal outcomes assess both respiratory and other organ failure events, recognizing the broad range of COVID-19 morbidity. In Stage 2, overall efficacy is assessed using the primary outcome of 'time to sustained recovery' assessed over 90 days. This approach to early futility assessment using an early intermediate outcome and a primary endpoint out to 90 days allows the study team to make rapid decisions on safety and potential efficacy of novel agents while ultimately focusing on patient-centered, longer-term outcomes. The implementation of TICO across a global network allows for continued enrollment despite variations in geographic epidemiology.

Study Status: The TICO master protocol moved from conception to first patient enrolled in approximately 9 weeks, a testament to the expedited regulatory and ethics review, coupled with flexible and responsive study operations. The first agent to be tested using this protocol, LY-CoV-555, enrolled N=326 participants before undergoing Stage 1 futility and safety assessment. Two additional agents will enter the study in November 2020, with other agents planned.

Conclusion: The TICO MAMS platform trial has been implemented efficiently across a global network of sites and several trial networks. It will generate results rapidly for multiple novel neutralizing monoclonal antibodies and other therapeutics agents.

SARS-CoV-2, COVID-19, Multi-arm Multi-stage, platform trials, neutralizing monoclonal antibody 3 

Coronavirus Disease-2019 is caused by the novel betacoronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). While frequently mild, this can cause severe illness associated with both pulmonary and extra-pulmonary morbidity and death. Risk factors for severe disease are older age, male gender [1, 2] , Afro-American, Hispanic and South Asian ethnicity, obesity, and comorbidities including diabetes mellitus and hypertension [3] . While the primary manifestation of severe COVID-19

is progressive respiratory failure, other extra-pulmonary severe sequelae, including cardiac, neurological and arterial/venous thromboembolic events, are known to occur [4] [5] [6] . As of 7 th of November, there have been >49 million cases diagnosed and >1,240,000 deaths worldwide; >500,000 cases continue to be reported daily [7] . In many countries, the current standard-of-care in hospitalized patients includes remdesivir and glucocorticoids (for those requiring supplemental oxygen) [8, 9] . However, substantial morbidity and mortality persists, and there remains an urgent need to assess emerging anti-SARS-CoV-2 agents to improve outcomes in COVID-19 inpatients.

To address this need, the U.S. National Institutes of Health (NIH) launched the Accelerating COVID-19

Therapeutic Interventions and Vaccines (ACTIV) public-private partnership [10] . The ACTIV therapeutics working group identified the need for four master protocols to evaluate investigational agents in both the ambulatory and hospital setting. ACTIV-1 investigates host-directed therapies (NCT04593940); ACTIV-2 therapeutics in the ambulatory setting (NCT04518410); ACTIV-3 therapeutics in hospitalized patients (NCT04501978), and ACTIV-4 anticoagulation strategies in the ambulatory/hospitalized/convalescent setting (NCT04498273 and NCT04505774). Three clinical trial networks, the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) [11] (which includes the U.S. Department of Veterans Affairs (VA) research network [12] ), the Cardiothoracic Surgical Trials Network (CTSN) [13] and the Prevention and Early Treatment of Acute Lung Injury network (PETAL) [14] collaborated to develop and implement the ACTIV-3 protocol (titled Therapeutics for Inpatients with COVID-19 or TICO). Together these networks work with over 300 sites across North and South America, Europe, Australia, Africa and Asia. The study design and implementation features, along with study status, through November 1, 2020, of TICO are presented here.

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The TICO protocol is part of the ACTIV public-private partnership initiative led by the NIH and supported by Operation Warp Speed (OWS) [15] , through the National Institute of Allergy and Infectious Diseases 

The Trial Oversight Committee (TOC) has been established to provide oversight for both the ACTIV-2 and ACTIV-3 initiatives and includes the trial co-chairs and representatives from OWS therapeutics and NIAID. Additional voting members include leaders from National Heart, Lung and Blood Institute (NHLBI), Biomedical Advanced Research and Development Authority (BARDA), Food and Drug Administration (FDA) and the National Center for Advancing Translational Sciences (NCATS). Agents are submitted for consideration to ACTIV through a public portal, before undergoing a systematic scientific review, and are ultimately approved by the TOC for entry into ACTIV 2 or ACTIV 3. ACTIV 2 and 3 are overseen by a shared independent DSMB which conducts frequent safety monitoring and scheduled interim reviews of efficacy and futility.

The TICO protocol is designed as a Multi-arm Multi-stage (MAMS) platform master protocol that allows for multiple agents to be studied concurrently and to enter the protocol at various time-points. The master protocol contains all study details that apply across all agents, while agent specific details, including any changes to eligibility criteria, are contained within an agent-specific appendix. When a new agent enters protocol, the new agent's appendix is submitted as a protocol amendment. Trials within . 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 November 12, 2020. ; https://doi.org/10.1101/2020.11.08.20227876 doi: medRxiv preprint TICO are randomized, double blinded, placebo-controlled and phase III. Each agent will undergo an early futility and safety assessment (Stage 1) before a definitive assessment of safety and efficacy (Stage 2).

All participants will receive SOC treatment (therapies strongly recommended by national/international guidelines based on high-quality evidence, remdesivir and glucocorticoids as of November 2, 2020), as part of this protocol unless there is a specific contraindication. The Appendix pertaining to SOC will be amended as SOC advances, on the basis of data from RCTs, including results from TICO itself.

In TICO, each person randomised could potentially receive any of the active agents (vs matching placebo) for which they are eligible, factoring in the potential differences in eligibility criteria between agents (see supplemental materials for a description of the TICO randomization application). The placebo group is then "pooled" so those randomized to the placebo of one agent will be part of the control group for other agents to which the person could have been allocated. This is done such that the probability of being allocated to any one given agent is the same as the probability of being allocated to any of the placebo agents. This design means that the more agents under study at the time a participant is randomised, the greater the probability they will receive an active agent.

ACTIV leadership requested TICO focus initially on SARS-CoV-2 neutralizing monoclonal antibodies (nMABs), with expansion to other novel antiviral agents at later time-points. While individual nMABs may vary substantially in efficacy and safety profiles, certain nMABS have proven effective in previous infectious disease settings, including during the recent Ebola outbreak, where two monoclonal therapies plus standard of care (SOC) (one a single mAb, the other a two-agent cocktail) were shown to be superior to Zmapp (a triple monoclonal therapy) plus SOC [16] . nMABs have also shown efficacy in Respiratory Syncytial Virus prevention [17] and inhalational anthrax [18] . nMABs also show clinical promise for treating COVID-19 [19] [20] [21] . Existing pipelines have allowed rapid production of many nMABs, [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] most of which target the immunogenic spike protein of SARS-CoV-2 (S protein), which is necessary for binding to human ACE-2 [35] . This has resulted in a large number of promising nMAB agents. Although the primary target of these nMAB is S protein, the pharmacokinetic profiles and specific target within S protein varies considerably, and it is not clear from in vitro or animal models which of these nMABs, if any, will be clinically effective in hospitalized individuals with COVID-19.

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Given the urgent clinical need and the large number of emerging anti-SARS-CoV-2 agents to be tested, the protocol team opted for a MAMS design. MAMS designs have been used successfully in many different settings, including during the current pandemic, e.g. the UK RECOVERY study (NCT04381936) and the WHO SOLIDARITY trial (ISRCTN83971151). MAMS platforms have a number of key design advantages over traditional clinical trials and are useful for studying several candidate agents rapidly.

These advantages include the ability to share/pool placebo controls across multiple agents and the use of intermediate futility and safety assessments to focus on the most promising agents, while maintaining scientific rigor such as double blinding, placebo control, and randomization [36, 37] . These features ensure that limited resources, that are currently stretched due to the pandemic response, are not dedicated to redundant placebo arms or large-scale randomisation to ineffective agents. Furthermore, the use of a MAMS platform master protocol to study broadly similar agents allows efficiencies by avoiding overlapping or redundant work on parallel protocols while maximizing enrollment efficiencies through a stable group of enrolling sites.

Clinical site implementation is complicated by rapidly changing infection rates across geographical areas. Additionally, as infection rates and recruitment capabilities can vary even across the same country/city, clinical sites are encouraged to select a pharmacy that can serve multiple clinical sites within a close geographical vicinity, as opposed to a more traditional one-site one-pharmacy model (see Pharmacy

Options in Supplemental materials). This one pharmacy, multiple sites model is intended to ensure delivery of limited study drug (including relevant SOC) to a single location where it can be more . 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 November 12, 2020. ; https://doi.org/10.1101/2020.11.08.20227876 doi: medRxiv preprint efficiently distributed to study sites according to local recruitment capabilities. When this model is not possible, sites may use a one-site one pharmacy model.

The TICO primary objective is to determine whether investigational agents are safe and efficacious compared with placebo when given with established standard of care (SOC) among an estimated 1000 individuals. The primary efficacy endpoint is time to sustained recovery through day 90, which is achieved when a participant is discharged from hospitalization to home and remains at home for 14 days. This patient-centered endpoint was chosen because of the extended duration of health impairment associated with COVID-19 [3, 38, 39] . The longer follow-up to capture this endpoint (compared to the common 28 days [8, 9] ) will provide a more accurate assessment of the capacity of a therapeutic agent to speed recovery from COVID-19.

Sustained recovery is defined as 14 continuous days at home, where home is defined as the type or level of residence where the participant lived prior to their SARS-CoV-2 infection. This approach avoids categorizing patients as recovered if they continue to have care needs beyond their pre-morbid state despite discharge from an acute care facility, or if they are re-admitted to hospital shortly after initial discharge. A participant's 'home' is classified at enrolment (see supplemental materials for classification of types of residences) and a participant's current location, and consecutive days spent at that location, is collected during follow-up (see full protocol for complete details). A complete description of the operationalization of this endpoint is beyond the scope of this manuscript and will be the subject of a follow-up manuscript.

While individual agents can enter the study concurrently and/or independently (Figure 1) , each agent undergoes two-stage testing: an early futility and safety evaluation (Stage 1) when 300 patients (150 with active agent, 150 with placebo) have Day 5 data, followed by a full efficacy and safety assessment (Stage 2) among 1000 patients (500 with active agent, 500 with placebo; the Stage 1 patients are included in the total sample size). Eligibility criteria ( Table 1) will expand across the two-stage enrollment, with less sick (i.e. without severe end-organ disease) enrolled in Stage 1, whereas in Stage 2 those with end-organ disease can also be enrolled (although Stage 2 does not restrict the recruitment of those without end-organ disease). The target population is narrower in Stage 1 in order to expedite . 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 November 12, 2020. ; https://doi.org/10.1101/2020.11.08.20227876 doi: medRxiv preprint identification of any early signals of safety and efficacy as patients with end organ dysfunction would not be likely to recover in a 5-day interval and safety would be more challenging to assess. Participants included in Stage 1 contribute to the total sample size needed for stage 2. Study procedures for data collection and primary endpoint ascertainment do not change between Stage 1 and Stage 2, and all patients recruited as part of Stage 1 are also included in the final efficacy assessment at the end of Stage 2.

Three key considerations drove the outcome selection for the Stage 1 futility and safety assessment: capacity to quickly assess for potential efficacy and safety, hypothesized high correlation with the primary endpoint of time to sustained recovery, and capacity to capture both pulmonary and nonpulmonary events among participants. Use of the primary endpoint for early futility and safety assessments was deemed impracticable, as it requires substantial follow-up time for ascertainment.

Intermediate assessments must thus be made at much earlier time points, using surrogates for the ultimate primary endpoint. Given these design considerations, the study assesses two ordinal outcomes at day 5 to determine whether an agent will proceed to Stage 2 (Error! Reference source not found.).

The Pulmonary outcome is a 7-category outcome largely based on the degree of respiratory failure, adapted from a similar outcome used in the ACTT-1 study [9] and an initial WHO master protocol [40] . In unpublished analyses of ACTT-1 data and review of the literature on COVID-19 prognostication, the probability that this intermediate outcome correlated with time to recovery (essentially discharge by 28 days) was very high. Analyses also suggested that day 5 would be provide good prognostication of recovery. A second ordinal outcome, called the Pulmonary-plus (Pulmonary+) outcome, adds extrapulmonary conditions to the pulmonary outcome that cover a range of organ dysfunction associated with COVID-19. For each of the two outcomes, the highest category that applies on day 5 will be used.

Agents that fail to meet a relatively modest bar for potential efficacy or that exhibit concerning safety signals will not proceed to full efficacy assessment in Stage 2.

TICO has been designed to facilitate rapid and rigorous assessment of novel therapeutic agents. In this setting detailed data collection and extensive safety monitoring are priorities (see the protocol for full details on data collection). The specific safety collection schedule in TICO was designed in close consultation with the FDA (Supplemental Table 1 ) and targets infusion related reactions along with . 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 copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.08.20227876 doi: medRxiv preprint frequent assessments of AEs and serious adverse events (SAEs). To review this data, the DSMB conducts regular reviews throughout both Stage 1 and Stage 2, including, but not limited to, an initial safety review for the first 30 participants enrolled, the formal Stage 1 futility and safety assessment at 300 participants and once enrolment to an agent is complete.

In addition to the statistical analysis plan for the master protocol, agent-specific analysis plans may be developed. These will be finalized by blinded statisticians prior to the planned unblinding for a specific treatment comparison. Investigational agents are compared to concurrent controls by intention-totreat. Detailed descriptions of sample size calculations, as well as planned analyses and justification for these analyses are given in supplemental materials and the protocol. A summary is provided below.

Assessment of safety data will occur at regular DSMB reviews throughout both Stage 1 and Stage 2.

Primary safety outcome is the proportion of participants who died, experienced SAEs, or new grade 3 or 4 AEs within the first 5 days. Proportions will be compared between the randomized treatment groups using Mantel-Haenszel tests, stratified by study pharmacy (see supplemental materials for description of TICO pharmacy options). Important secondary safety outcomes include time to the composite safety outcome through day 28, its components (including mortality), and infusion reactions that occurred during and within 2 hours after infusion. Additional safety outcomes are collected, and efficacy outcomes (including time to sustained recovery and the Pulmonary and Pulmonary+ outcomes as well as end organ disease and serious infection to monitor for the theoretical risk of antibody dependent enhancement) are included in the assessment of potential harm.

The planned sample size for each investigational agent and the concurrently randomized pooled placebo arm in Stage 1 is 300 patients (1:1 randomization; i.e., 150 patients per group). The evaluation of the intermediate efficacy outcomes for Stage 1, the Pulmonary and Pulmonary+ ordinal outcomes, will use proportional odds models and the estimated summary odds ratio (OR) to compare the investigational agent versus placebo. Guidelines for the DSMB recommend advancing the investigational agent to Stage 2, if the agent is superior to placebo in a 1-sided test with a significance level of 0.3 for one or both ordinal outcomes. The sample size of 300 is sufficient to detect an OR of 1.60 or greater with 95% power. We chose the relatively high type 1 error rate of 0.30 in the Stage 1 assessment , based on . 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 copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.08.20227876 doi: medRxiv preprint previous work in MAMS cancer trials [41] [42] [43] , to avoid premature declarations of futility for potentially promising agents while preserving our capacity to suspend enrolment to a non-promising agent. For agents that advanced to Stage 2, additional futility analyses in Stage 2 will protect against randomizing too many patients to an investigational agent which is unlikely to be effective. Models will be stratified by the baseline categories of the ordinal outcomes, and by study pharmacy.

The final sample size for the definitive efficacy analysis will be event driven. With the planned follow-up of 90 days, sample size was estimated at 1,000 patients (i.e. 500 in each group) to obtain 843 sustained recovery outcomes. All participants randomized to an agent/placebo (i.e. regardless of whether this was in Stage 1 or 2) will be included in the definitive efficacy analysis. All efficacy analyses will utilize twosided tests with a 5% significance level. The investigational agent will be compared to placebo for time to sustained recovery (primary endpoint), using Gray's test with rho=0 [44] , cumulative incidence functions will be estimated using the Aalen-Johansen estimator [45] , and the recovery rate ratio (RRR) will be estimated using the the Fine-Gray method [46, 47] These methods are the competing-risk analogues of the log-rank test, Kaplan-Meier estimates, and Cox proportional hazards models, taking into account the competing risk of death. Models will be stratified by disease severity at entry and study pharmacy. Consistent with standard practice, there will be no adjustment for the number of other agents being tested in TICO trials.

In addition to the planned analysis of the primary endpoint, additional secondary outcomes are assessed. Key secondary outcomes are mortality, and a composite outcome that combines time to sustained recovery and time to death, comparing treatment groups using a win-ratio statistic. Our intention is to measure as key secondary outcomes endpoints used in other COVID-19 trials in order to facilitate comparison of results of TICO studies to other trials. A full list of secondary outcomes and analysis plan for these can be found in the protocol.

A timeline of TICO protocol development and implementation can be found in Figure 2 . To expedite the FDA Investigational Drug Application (IND) process, the FDA was engaged very early and reviewed TICO at key stages of protocol development. The time taken from first meeting to FDA 'safe to proceed' (not licensure) approval was 8 weeks, and the first participant was enrolled approximately one week later.

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The first study agent to gain approval for study within the framework of this master protocol was LY-CoV-555, a neutralizing monoclonal antibody discovered by Abcellera Biologics, Inc. in collaboration with NIAID's Vaccine Research Center (VRC) and developed by Lilly Research Laboratories, Eli Lilly and Company, in partnership with AbCellera Biologics, Inc. Regulatory approval for study of this agent has been received in the U.S., Denmark, U.K., Spain and Singapore. Between August 5 and October 13, 2020, 326 participants were enrolled. On the 26 th of October Ly-CoV-555 underwent Stage 1 futility and safety assessment. The result of this assessment will be the subject of a separate report. Two agents (both nMABs) will be submitted for regulatory approval in November 2020, with additional agents expected subsequently. The number of clinical sites and countries that will participate in the study of additional agents will expand substantially, facilitating rapid assessment of both planned and future agents. A full list of clinical sites that have agreed to participate in TICO (so far 193 sites from 27 countries, with more expected) can be found in Supplemental Table 3 .

The TICO master protocol responds to the urgent need to accelerate the development of safe, efficacious, novel therapeutics for hospitalized SARS-CoV-2 patients. Through a successful collaboration of clinical trial networks, TICO has been successfully designed and implemented globally. TICO is an efficient, flexible, rigorous MAMS platform master protocol that allows for concurrent safety and efficacy evaluation of multiple therapeutic agents, allowing for the entry of agents at different times.

Furthermore, the two-stages of this protocol allow for the rapid selection of only the most promising agents (using intermediate outcomes to test for early futility and safety) for full evaluation using a clinically relevant primary endpoint, while the thorough safety data collection and frequent DSMB review means that safety is not compromised in the interest of speed. The study is currently underway in multiple countries and can respond to fluctuations in infection and recruitment rates across geographical areas. Finally, the provision of remdesivir (unless contraindicated), as well as the flexibility to incorporate new SOC in the future, ensures that any agent in this study is evaluated for efficacy in combination with the most current SOC. The unique design and implementation features of this protocol may inform future protocol design during the COVID-19 pandemic and in infectious diseases/acute respiratory failure research more broadly.

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The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.08.20227876 doi: medRxiv preprint Figure 1 Agent entry and progression through the two-stages of the TICO study. The TICO study allows for multiple agents to be studied concurrently and for agents to enter the study at different time-points. In the scenario presented in figure 2 , Agent A is the only agent that is available for randomisation at the beginning of the study. Later, Agent B and Agent C enter the study, and new participants are able to be randomized across three agents (and corresponding placebo). Agent A completes recruitment to Stage 1 and, after DSMB review, is approved to continue into Stage 2. Agent B and Agent C both complete Stage 1, however, only Agent B continues into Stage 2, while Agent C does not receive DSMB approval to proceed and randomisation to this agent ceases. In Stage 2 the target population is expanded to include those with end-organ disease (although this does not restrict the recruitment of those without end-organ disease). Agent A and Agent B progress through Stage 2 and both undergo a final DSMB review of safety and efficacy (using the primary endpoint) when recruitment is complete.

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The authors would like to thank the large number individuals across all the contributing trials networks, government agencies, local clinical sites, lab staff, pharmacists, logistics personnel and regulatory bodies who contributed to the design and implementation of the TICO protocol.