Study to Evaluate the Safety and Concentrations of Monoclonal Antibody Against Virus That Causes COVID-19 Disease.
Condition: COVID-19 Virus Disease
MeSH terms: COVID-19; Virus Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      A Phase I dose-escalation study to test a new monoclonal antibody (called MAD0004J08) against
      severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19
      disease. The study aims to evaluate the safety and pharmacokinetics (distribution and
      elimination) of anti-SARSCoV-2 monoclonal antibody in healthy adults.

      The primary objective of the study is to evaluate the safety of anti-SARSCoV-2 monoclonal
      antibody (that is the appearance of adverse events), the pharmacokinetics (how MAD0004J08 is
      distributed and eliminated by human body), the generation of anti-drug antibodies (ADAs)
      (that is the possible production of antibodies against the drug, which could invalidate it
      efficacy) and finally the ability of MAD0004J08 to neutralize SARSCoV-2. Furthermore a blood
      sample would be used to evaluate a kit (DIESSE kit), developed by Toscana Life Sciences, able
      to detect the administered drug. This kit is not used to evaluate study paramethers.

      30 subjects, that should respect the Inclusion/Exclusion criteria, will be enrolled.

      About 12 visits will be performed during the study, study duration will be about 6 months.

      Subjects will be distributed into 3 Cohorts, each of them divided into 2 groups that would
      receive MAD0004J08 (Dose 1 = 48 mg, Dose 2 = 100 mg or Dose 3 = 400 mg) or placebo.
      Administration occurs as intramuscular injection (single injection for Cohort 1 and Cohort 2
      and, two injections for Cohort 3) .
    

Detailed description: 
      A Phase I dose-escalation study to evaluate the safety and pharmacokinetics of anti-SARSCoV-
      2 monoclonal antibody MAD0004J08 in healthy adults.

      Two Italian clinical sites are involved in the study. It is a first-in-human, single-dose,
      dose-escalation, double-blind, placebo-controlled, randomised, safety and pharmacokinetics
      study.

      Three single ascending doses (48 mg, 100 mg and 400 mg) and placebo will be administered by
      intramuscular injection to three study cohorts (10 subjects/cohort) as single doses, in the
      morning of day 1.

      There are 5 sentinel subjects for each Cohort, they will be treated one at the time at 48 h
      distance (after evaluation of any possible treatment related adverse event).

      Active treatment and placebo will be assigned within each cohort and group according to the
      study randomisation list.

      Go/No-go decision on escalation from Cohort 1 to Cohort 2 and from Cohort 2 to Cohort 3 will
      be taken after evaluation of Cohort 1/Cohort 2 safety data up to 48 h post-dose by an
      independent Data Safety Monitoring Board.

      The primary objective of the study is to evaluate the safety of three single dose levels of
      MAD0004J08 in healthy subjects.

      Secondary objectives are to evaluate the pharmacokinetics of MAD0004J08, potency in terms of
      serum neutralisation power and immunogenicity in terms of generation of anti-drug antibodies
      (ADAs) after single dose of 48 mg, 100 mg and 400 mg.

      The following procedures will be performed:

      Visit 1 - Screening Day -21 / Day -2

        -  Explanation to the subject of study aims, procedures and possible risks

        -  Informed consent signature

        -  Screening number assignment (as S001, S002, etc.)

        -  Demographic data and life style recording

        -  Medical history

        -  Previous/concomitant medications

        -  Physical examination (including body weight, height)

        -  Vital signs (blood pressure, heart rate, body temperature)

        -  12-lead Electrocardiogram (ECG)

        -  SARS-CoV-2 serology test

        -  Laboratory analyses: haematology, blood chemistry, urinalysis, serum virology,
           coagulation, ferritin

        -  Drug of abuse test

        -  Urinary pregnancy test (women)

        -  SARS-CoV-2 Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) in the 72 h before
           day 1 (could be performed on day -3 or day-2 or day -1)

        -  Adverse event monitoring

        -  Inclusion/exclusion criteria evaluation

        -  Eligibility evaluation Visit 2 - Day -1

        -  SARS-CoV-2 qRT-PCR in the 72 h before treatment. On day -1 either test performance, or
           result check if already performed on day -3 or day -2

        -  Drug of abuse test

        -  Inclusion/exclusion criteria evaluation

        -  Check of AEs and concomitant medications

        -  Vital signs (blood pressure, heart rate, body temperature)

        -  Physical examination

        -  Eligibility evaluation Visit 3 - Day 1

        -  Urine pregnancy test (women)

        -  Inclusion/exclusion criteria evaluation, eligibility evaluation, and randomisation

        -  12-lead ECG

        -  Dispensation of 2 diaries to the subject (diary 1 to report solicited adverse events
           from day 1 to day 8, diary 2 to report all unsolicited adverse events and concomitant
           medication from day 1 to month 1)

        -  Laboratory analyses: haematology, coagulation, blood chemistry, urinalysis, SARS-CoV-2
           serology test - baseline

        -  Blood sample collection for pharmacokinetic analysis at predose (0) and 1h, 2h, 3h, 4h,
           6h, 8h, 12h post-dose

        -  Blood sample collection for ADA analysis at pre-dose (0)

        -  Blood sample collection for serum neutralising power test at pre-dose (0)

        -  Blood sample collection for DIESSE Elisa kit characterisation at pre-dose (0)

        -  Vital signs (blood pressure, heart rate, body temperature) measurement at pre-dose (0),
           2h post-dose and 12 h post-dose

        -  Investigational product administration (active or placebo according to study Cohort,
           Group and randomisation)

        -  Adverse events monitoring

        -  Injection site reactions check

        -  Concomitant medications check Visit 4 - Day 2

        -  Physical examination

        -  Vital signs (blood pressure, heart rate, body temperature) measurement at 24 h post-dose

        -  Blood sample collection for pharmacokinetic analysis at 24h post-dose

        -  Adverse events monitoring

        -  Injection site reactions check

        -  Diary 1 and diary 2 check

        -  Concomitant medications check

        -  Laboratory analyses: haematology, blood chemistry, coagulation, urinalysis, SARS-CoV-2
           serology test at 24 h post-dose

        -  12-lead ECG at 24 h post-dose Visit 5 - Day 3

        -  Vital signs (blood pressure, heart rate, body temperature) measurement at 48 h post-dose

        -  Blood sample collection for pharmacokinetic analysis at 48h post-dose

        -  Blood sample collection for serum neutralising power test at 48h post-dose

        -  Blood sample collection for DIESSE Elisa kit characterisation at 48 h post-dose

        -  Adverse events monitoring

        -  Injection site reactions check

        -  Diary 1 and diary 2 check

        -  Concomitant medications check

        -  Laboratory analyses: haematology, blood chemistry, coagulation, urinalysis, SARS-CoV-2
           serology test - at 48 h post-dose

        -  Physical examination Visits 6 / Week 1 / Day 8 and Visit 7 / Week 2 / Day 15±2

        -  Physical examination

        -  Vital signs (blood pressure, heart rate, body temperature) measurement

        -  Blood sample collection for pharmacokinetic analysis

        -  Blood sample collection for ADA analysis

        -  Blood sample collection for serum neutralising power test on day 8 only

        -  Blood sample collection for DIESSE Elisa kit characterisation on day 8 only

        -  Adverse events monitoring

        -  Concomitant medications check

        -  Laboratory analyses: haematology, blood chemistry, coagulation, urinalysis, SARS-CoV-2
           serology test

        -  Diary 1 check - day 8 only

        -  Diary 2 check - day 8 and day 15

        -  Subjects' diary 1 return - day 8 only Visit 8 Week 3 Day 22±2

        -  Physical examination

        -  Vital signs (blood pressure, heart rate, body temperature)

        -  Blood sample collection for pharmacokinetic analysis

        -  Adverse events monitoring

        -  Diary 2 check

        -  Concomitant medications check

        -  Laboratory analyses: haematology, blood chemistry, coagulation, urinalysis, SARS-CoV-2
           serology test Visit 9 - 1 month Day 30±3

        -  Physical examination

        -  Vital signs (blood pressure, heart rate, body temperature) measurement

        -  Blood sample collection for pharmacokinetic analysis

        -  Blood sample collection for ADA analysis

        -  Blood sample collection for serum neutralising power test

        -  Blood sample collection for DIESSE Elisa kit characterisation

        -  Adverse events monitoring

        -  Diary 2 check

        -  Concomitant medications check

        -  Laboratory analyses: haematology, blood chemistry, coagulation, urinalysis, SARS-CoV-2
           serology test

        -  Urine pregnancy test (women)

        -  Subjects' diary 2 return Visit 10 - 2 months Day 60±4

        -  Physical examination

        -  Vital signs (blood pressure, heart rate, body temperature) measurement

        -  Blood sample collection for pharmacokinetic analysis

        -  Adverse events monitoring

        -  Concomitant medications check

        -  Laboratory analyses: haematology, blood chemistry, coagulation, urinalysis, SARS-CoV-2
           serology test

        -  Urine pregnancy test (women) Visit 11 - 4 months Day 120±4 days

        -  Physical examination

        -  Vital signs (blood pressure, heart rate, body temperature) measurement

        -  Blood sample collection for pharmacokinetic analysis

        -  Blood sample collection for ADA

        -  Blood sample collection for serum neutralising power test

        -  Blood sample collection for DIESSE Elisa kit characterisation

        -  Adverse events monitoring

        -  Concomitant medications check

        -  Laboratory analyses: haematology, blood chemistry, coagulation, urinalysis, SARS-CoV-2
           serology test

        -  Urine pregnancy test (women) Visit 12 - 6 months Final visit Day 180±7 days

        -  Physical examination (including body weight)

        -  Vital signs (blood pressure, heart rate, body temperature) measurement

        -  Blood sample collection for pharmacokinetic analysis

        -  Blood sample collection for ADA

        -  Blood sample collection for serum neutralising power test

        -  Blood sample collection for DIESSE Elisa kit characterisation

        -  Adverse events monitoring

        -  Concomitant medications check

        -  Laboratory analyses: haematology, blood chemistry, urinalysis, coagulation, SARS-CoV-2
           serology test

        -  12-lead ECG The data documented in this trial and the measured clinical parameters will
           be presented using classic descriptive statistics for quantitative variables and
           frequencies for qualitative variables.

      A Statistical Analysis Plan will be prepared by CROSS Research S.A. Biometry Unit, approved
      by the Sponsor and finalised before database lock.

      Safety, serum neutralising power, immunogenicity and demography data will be analysed by
      CROSS Research Biometry Unit using SAS® version 9.3 (TS1M1) or higher (the actual version
      will be stated in the final report).

      Adverse events and serious adverse events (including clinically significant laboratory
      parameters, vital signs, ECG results and adverse reactions at the injection sites) will be
      listed by treatment. Number and percentage of subjects with adverse events and serious
      adverse events will be summarised.

      Serum MAD0004J08 concentrations and pharmacokinetic parameters will be analysed using Phoenix
      WinNonlin® validated version 6.3 or higher (Pharsight Corporation) and SAS® version 9.3 for
      Windows® or higher. Pharmacokinetics data will be listed and summarised by descriptive
      statistics. Individual and mean concentration curves will also be generated. ADA
      concentrations will be summarised by descriptive statistics. Number and percentage of
      ADA-positive subjects will be listed and summarised by assessment time and overall. Serum
      neutralising power results will be listed by subject and assessment time-point and summarised
      by descriptive statistics.
    

Intervention name(s): MAD0004J08; Placebo
Intervention type(s): Biological; Other
Intervention description(s): Human mAb 100 mg / 2.5 mL solution for injection; Placebo matching to MAD0004J08 2.5 mL solution for injection
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: COVID-19 Pandemic; SARS-CoV-2 Infection; SARS-CoV-2 Monoclonal Antibody