MP0420 for Inpatients With COVID-19 (An ACTIV-3/TICO Treatment Trial)

This is a treatment trial of the ACTIV-3/TICO master protocol (NCT04501978) to evaluate the safety and efficacy of MP0420 in hospitalized patients infected with COVID-19.

This is a randomized, blinded, controlled sub-study of MP0420 plus current SOC against placebo plus current SOC. The placebo arm may be shared across other sub-studies of the ACTIV-3/TICO master protocol. When more than one drug is being tested at the same time, participants will be randomly allocated to treatments or placebo.

Randomization will be stratified by study site pharmacy and disease severity. There are 2 disease severity strata: participants without organ failure (severity stratum 1) and participants with organ failure (severity stratum 2).

An independent Data and Safety Monitoring Board (DSMB) will regularly review interim analyses and summarize safety and efficacy outcomes. The pace of enrollment with be initially restricted, and there will be an early review of safety data by the DSMB. At the outset of the trial, only participants in disease severity stratum 1 will be enrolled. This will continue until approximately 300 participants are enrolled and followed for 5 days. The exact number will vary according to the speed of enrollment and the timing of DSMB meetings. Prior to expanding enrollment to also include patients in disease severity stratum 2, safety will be evaluated and a pre-specified futility assessment by the DSMB will be carried out using 2 ordinal outcomes assessed at Day 5.

If MP0420 passes the futility assessment, enrollment of participants will be expanded, seamlessly and without any data unblinding, to include participants in disease severity stratum 2 as well as those in disease severity stratum 1. Future interim analyses will be based on the primary endpoint of sustained recovery and will use pre-specified guidelines to determine early evidence of benefit, harm, or futility for the investigational agent. Participants will be followed for 18 months following randomization.

This trial will be conducted in several hundred clinical sites. Participating sites are affiliated with networks funded by the United States National Institutes of Health (NIH) and the US Department of Veterans Affairs.

• MP0420 (Drug), also known as ensovibep: MP0420 is a multi-valent DARPin® molecule (designed ankyrin repeat protein), consisting of 5 DARPin® domains.
• Placebo (Drug): Commercially available 0.9% sodium chloride solution
• Remdesivir (Biological), also known as Veklury: Antiviral agent

Primary outcomes

• Number of Participants With Sustained Recovery [Through Day 90]: Sustained recovery defined as being discharged from the index hospitalization, followed by being alive and home for 14 consecutive days prior to Day 90.
• Number of Participants With an Ordinal Outcome on Day 5 [Status on Day 5]: Ordinal outcome with 7 mutually exclusive categories

Secondary outcomes

• Number of Participants Who Died From All Causes [Through Day 90]: All-cause mortality
• Number of Participants With a Safety Outcome Through Day 5 [Through Day 5]: Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 5
• Number of Participants With a Safety Outcome Through Day 28 [Through Day 28]: Death, SAE, clinical organ failure, serious infections, or Grade 3 or 4 event through Day 28
• Number of Participants With a Safety Outcome Through Day 90 [Through Day 90]: Death, SAE, clinical organ failure, serious infections through Day 90

Sex: All, ages: 18 Years to any

Inclusion Criteria: Refer to the master protocol (NCT04501978)

Exclusion Criteria: Refer to the master protocol (NCT04501978)

Additional Exclusion Criteria:

1. Pregnant women
2. Nursing mothers
3. Women of child-bearing potential who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with men or practice appropriate contraception through 11 weeks after receiving MP0420/placebo
4. Men who are unwilling to acknowledge the strong advice to abstain from sexual intercourse with women of child-bearing potential or to use barrier contraception through 11 weeks after receiving MP0420/placebo.

Participant flow

Outcome results

• Number of Participants With Sustained Recovery (Primary), Count of participants, Participants: MP0420 Plus SOC 203; Placebo Plus SOC 190
• Number of Participants With an Ordinal Outcome on Day 5 (Primary), Count of participants, Participants: MP0420 Plus SOC 1; Placebo Plus SOC 3
• Number of Participants Who Died From All Causes (Secondary), Count of participants, Participants: MP0420 Plus SOC 30; Placebo Plus SOC 35
• Number of Participants With a Safety Outcome Through Day 5 (Secondary), Count of participants, Participants: MP0420 Plus SOC 61; Placebo Plus SOC 70
• Number of Participants With a Safety Outcome Through Day 28 (Secondary), Count of participants, Participants: MP0420 Plus SOC 85; Placebo Plus SOC 97
• Number of Participants With a Safety Outcome Through Day 90 (Secondary), Count of participants, Participants: MP0420 Plus SOC 78; Placebo Plus SOC 70

Adverse events

Time frame: 90 Days

Serious adverse events by term

Other adverse events by term

44 more terms not shown.

5 more sites not listed.

• Results publication: ACTIV-3/TICO Study Group; Barkauskas C, Mylonakis E, Poulakou G, Young BE, Vock DM, Siegel L, Engen N, Grandits G, Mosaly NR, Vekstein AM, Rogers R, Shehadeh F, Kaczynski M, Mylona EK, Syrigos KN, Rapti V, Lye DC, Hui DS, Leither L, Knowlton KU, Jain MK, Marines-Price R, Osuji A, Overcash JS, Kalomenidis I, Barmparessou Z, Waters M, Zepeda K, Chen P, Torbati S, Kiweewa F, Sebudde N, Almasri E, Hughes A, Bhagani SR, Rodger A, Sandkovsky U, Gottlieb RL, Nnakelu E, Trautner B, Menon V, Lutaakome J, Matthay M, Robinson P, Protopapas K, Koulouris N, Kimuli I, Baduashvili A, Braun DL, Gunthard HF, Ramachandruni S, Kidega R, Kim K, Hatlen TJ, Phillips AN, Murray DD, Jensen TO, Padilla ML, Accardi EX, Shaw-Saliba K, Dewar RL, Teitelbaum M, Natarajan V, Laverdure S, Highbarger HC, Rehman MT, Vogel S, Vallee D, Crew P, Atri N, Schechner AJ, Pett S, Hudson F, Badrock J, Touloumi G, Brown SM, Self WH, North CM, Ginde AA, Chang CC, Kelleher A, Nagy-Agren S, Vasudeva S, Looney D, Nguyen HH, Sanchez A, Weintrob AC, Grund B, Sharma S, Reilly CS, Paredes R, Bednarska A, Gerry NP, Babiker AG, Davey VJ, Gelijns AC, Higgs ES, Kan V, Matthews G, Thompson BT, Legenne P, Chandra R, Lane HC, Neaton JD, Lundgren JD. Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19 : A Randomized Controlled Trial. Ann Intern Med. 2022 Sep;175(9):1266-1274. doi: 10.7326/M22-1503. Epub 2022 Aug 9. PMID 35939810

• Study Protocol: Trial H5 Protocol (PDF, 2021-04-09)
• Study Protocol: Master Protocol (PDF, 2021-08-17)
• Statistical Analysis Plan (PDF, 2022-02-23)
• Informed Consent Form (PDF, 2021-05-05)

• Jens Lundgren, Prof., Principal investigator, INSIGHT Copenhagen International Coordinating Centre, Rigshospitalet, University of Copenhagen
• James Neaton, Prof., Study chair, INSIGHT Statistical and Data Management Center, University of Minnesota