ACTIV-5 / Big Effect Trial (BET-C) for the Treatment of COVID-19
Condition: COVID-19
MeSH terms: COVID-19
Intervention: Danicopan; Placebo; Remdesivir
Intervention description: Danicopan is a small molecule, orally administered complement factor D (FD) inhibitor; Danicopan matching placebo tablet; Remdesivir is a single diastereomer monophosphoramidate prodrug for the intracellular delivery of a modified adenine nucleoside analog GS-441524.
Intervention MeSH terms: Remdesivir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 201.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Adults; covid-19; Multicenter; Putative; Therapeutics

Summary:

      This is a platform trial to conduct a series of randomized, double-blind, placebo-controlled
      trials using common assessments and endpoints in hospitalized adults diagnosed with COVID-19.
      BET is a proof-of-concept study with the intent of identifying promising treatments to enter
      a more definitive study. The study will be conducted in up to 70 domestic sites and 5
      international sites. The study will compare different investigational therapeutic agents to a
      common control arm and determine which have relatively large effects. In order to maintain
      the double blind, each intervention will have a matched placebo. However, the control arm
      will be shared between interventions and may include participants receiving the matched
      placebo for a different intervention.

      The goal is not to determine clear statistical significance for an intervention, but rather
      to determine which products have clinical data suggestive of efficacy and should be moved
      quickly into larger studies. Estimates produced from BET will provide an improved basis for
      designing the larger trial, in terms of sample size and endpoint selection. Products with
      little indication of efficacy will be dropped on the basis of interim evaluations. In
      addition, some interventions may be discontinued on the basis of interim futility or efficacy
      analyses.

      One or more interventions may be started at any time. The number of interventions enrolling
      are programmatic decisions and will be based on the number of sites and the pace of
      enrollment. At the time of enrollment, subjects will be randomized to receive any one of the
      active arms they are eligible for or placebo. Approximately 200 (100 treatment and 100 shared
      placebo) subjects will be assigned to each arm entering the platform and a given site will
      generally have no more than 3 interventions at once.

      The BET-C stage will evaluate the combination of remdesivir with danicopan vs remdesivir with
      a placebo. Subjects will be assessed daily while hospitalized. Once subjects are discharged
      from the hospital, they will have a study visit at Days 8, 15, 22, 29, and 60 as an
      outpatient. The Day 8, Day 22 and Day 60 visits do not have laboratory tests or collection of
      samples and may be conducted by phone. All subjects will undergo a series of efficacy and
      safety laboratory assessments. Safety laboratory tests and blood (serum, plasma and RNA)
      research samples on Day 1 (prior to study product administration) and Days 3, 5, 8, and 11
      while hospitalized. Blood research samples plus safety laboratory tests will be collected on
      Day 15 and 29 if the subject attends an in-person visit or is still hospitalized. However, if
      infection control considerations or other restrictions prevent the subject from returning to
      the clinic, Day 15 and 29 visits may be conducted by phone and only clinical data will be
      obtained.

      The primary objective is to evaluate the clinical efficacy of danicopan relative to the
      control arm in adults hospitalized with COVID-19 according to clinical status (8-point
      ordinal scale) at Day 8.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Admitted to a hospital with symptoms suggestive of COVID-19 and requires ongoing
             medical care.

          2. Subject (or legally authorized representative) provides informed consent prior to
             initiation of any study procedures.

          3. Subject (or legally authorized representative) understands and agrees to comply with
             planned study procedures.

          4. Male or non-pregnant female adult >/=18 years of age at time of enrollment.

          5. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as
             determined by polymerase chain reaction (PCR) or other commercial or public health
             assay (e.g., Nucleic Acid Amplification Test [NAAT], antigen test) in any respiratory
             specimen or saliva </=14 days prior to randomization.

          6. Illness of any duration, and requiring, just prior to randomization, supplemental
             oxygen (any flow), mechanical ventilation or extracorporeal membrane oxygenation
             (ECMO) (ordinal scale category 5, 6, or 7).*

             *If written documentation of the positive test result is not available at the time of
             enrollment (e.g., report came from other institution), the test should be repeated and
             the subject may be enrolled if positive.

          7. Women of childbearing potential and men must agree to either abstinence or use at
             least one acceptable method of contraception** from the time of screening through 30
             days after the last dose of danicopan for women and 90 days after the last dose for
             men.

             **Acceptable methods include barrier contraceptives (condoms or diaphragm) with
             spermicide, intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive
             pills, and surgical sterilization.

          8. Agrees not to participate in another blinded clinical trial (both pharmacologic and
             other types of interventions) for the treatment of COVID-19 through Day 29

        Exclusion Criteria:

          1. aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper
             limit of normal.

          2. Subjects with a low glomerular filtration rate (eGFR), specifically:

               1. Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the
                  principal investigator (PI), the potential benefit of participation outweighs the
                  potential risk of study participation.

               2. All subjects with an eGFR <15 mL/min (including hemodialysis and hemofiltration)
                  are excluded.

          3. Pregnancy or breast feeding

          4. Anticipated discharge from the hospital or transfer to another hospital which is not a
             study site within 72 hours of enrollment.

          5. Allergy to any study medication.

          6. Received five or more doses of remdesivir prior to screening.

          7. Treatment with a complement inhibitor in the prior 8 weeks.*

          8. Has active uncontrolled opportunistic infection, or uncontrolled cirrhosis.*

          9. History of infection with N. meningitidis.*

         10. Known history of hypersensitivity to danicopan or its excipients.*

         11. Has a medical condition that could, in the judgment of the investigator, limit the
             interpretation and generalizability of trial results.

         12. Positive test for influenza virus during the current illness (influenza testing is not
             required by protocol).

         13. History of liver cirrhosis.*

         14. Previous participation in an ACTIV-5/BET trial.

         15. Refuses to refrain from breastfeeding from the time of screening through 30 days after
             the last dose of danicopan.*

         16. Refuses to receive prophylactic antibiotics against meningococcal infections if the
             subject has not been vaccinated in the 3 years prior to Study Day 1.