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    Summary
    EudraCT Number:2020-003367-26
    Sponsor's Protocol Code Number:MK4482-001
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-10-01
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2020-003367-26
    A.3Full title of the trial
    A Phase 2/3, Randomized, Placebo-Controlled, Double-Blind Clinical Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MK-4482 in Hospitalized Adults with COVID-19
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MK-4482 Ph 2/3 Study in Hospitalized Participants with COVID-19
    A.3.2Name or abbreviated title of the trial where available
    MK-4482 Ph 2/3 Study in Hospitalized Adults with COVID-19
    A.4.1Sponsor's protocol code numberMK4482-001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04575584
    A.5.4Other Identifiers
    Name:INDNumber:147734
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMK-4482
    D.3.2Product code MK-4482
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPGastroenteral use
    Oral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMK-4482
    D.3.9.1CAS number 2349386-89-4
    D.3.9.2Current sponsor codeMK-4482
    D.3.9.3Other descriptive name[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl 2-methylpropanoate
    D.3.9.4EV Substance CodeSUB208141
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    COVID-19
    E.1.1.1Medical condition in easily understood language
    COVID-19
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.0
    E.1.2Level LLT
    E.1.2Classification code 10084382
    E.1.2Term Coronavirus disease 2019
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To evaluate the efficacy of MK-4482 compared to placebo as assessed by the rate of sustained recovery from randomization through Day 29.
    2. To evaluate the safety and tolerability of MK-4482 compared to placebo.
    E.2.2Secondary objectives of the trial
    1. To evaluate the efficacy of MK-4482 compared to placebo as assessed by the percentage of participants who die through Day 29.
    2. To evaluate the efficacy of MK-4482 compared to placebo as assessed by the odds of a more favorable response on selected ordinal outcome scales at Day 3, End of Treatment (EOT), Day 10, Day 15, and Day 29.
    3. To evaluate the efficacy of MK-4482 compared to placebo as assessed by the odds of a more favorable response in the clinical risk of mortality category from the National Early Warning Score at EOT.
    4. To evaluate the efficacy of MK-4482 compared to placebo as assessed by the odds of a more favorable response on the World Health Organization (WHO) 11-point ordinal scale on Day 3, EOT, Day 10, Day 15, and Day 29.

    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Peripheral Blood Mononuclear Cells (PBMC) PK Sub study
    E.3Principal inclusion criteria
    1. Has documentation of PCR-confirmed SARS-CoV-2 infection with sample collection ≤ 10 days prior to randomization.
    2. Had initial onset of signs/symptoms attributable to COVID-19 for ≤10 days prior to the day of randomization and ≥1 sign/symptom attributable to COVID-19 present at randomization.
    3. Requires medical care in the hospital for ongoing clinical manifestations of COVID-19 (not just for public health or quarantine purposes).
    4. Has mild, moderate, or severe COVID-19.
    5. Is willing and able to take oral medication.
    6. Is male or female, ≥18 years of age, at the time of providing informed consent.
    7. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of study intervention:
    - Refrain from donating sperm
    PLUS either:
    - Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
    OR
    - Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below:
    Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
    - Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    - Is not a WOCBP
    OR
    - Is a WOCBP and using a contraceptive method that is highly effective (a low user dependency method OR a user dependent method in combination with barrier method), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), for 28 days from the start of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
    - A WOCBP must have a negative highly sensitive pregnancy test (serum test is required) within 24 hours before the first dose of study intervention.
    - The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
    - Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    - Given the elevated risk of venous thrombotic events in patients hospitalized with COVID-19, estrogen-containing contraceptives must not be started to fulfill the contraceptive requirement of this study at any time during participant’s hospitalization. If contraceptives are interrupted as standard of care management of COVID-19 patients and resumed at a later time point, such as at hospital discharge, then abstinence must be practiced for the defined period of back-up contraception per the contraceptive product labeling. After this
    period, contraceptive use must adhere to Protocol.
    9. Participant (or legally acceptable representative) has provided documented informed consent for the study.
    E.4Principal exclusion criteria
    1. Has critical COVID-19 with any of the following:
    - Respiratory failure defined based on resource utilization requiring at least one of the following:
    Endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5), noninvasive positive pressure ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation)
    - Shock (defined by systolic blood pressure <90 mm Hg, or diastolic blood pressure <60 mm Hg or requiring vasopressors)
    - Multi-organ dysfunction/failure
    2. Is on dialysis or has reduced eGFR <30 mL/min/1.73m2 by the MDRD equation
    3. Has any of the following conditions:
    - HIV with a recent viral load >50 copies/mL or CD4 <200 cell/mm³
    - Chemotherapy required within 6 weeks before randomization
    - A neutrophilic granulocyte absolute count <500/mm3
    - Autologous or allogeneic hematopoietic stem cell transplant recipient
    4. Has a history of HBV or HCV infection with any of the following:
    - Cirrhosis
    - End-stage liver disease
    - Hepatocellular carcinoma
    - AST and / or ALT >3X upper limit normal at screening
    5. Has a platelet count <100,000/μL or received a platelet transfusion in the 5 days prior to randomization.
    6. Has a history of acute pancreatitis within 3 months prior to randomization or a history of chronic pancreatitis.
    7. Has a baseline heart rate of < 50 beats per minute at rest.
    8. Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator.
    9. Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments including but not limited to:
    - Participants who are not expected to survive longer than 48 hours after randomization, or
    - Participants who are expected to require mechanical ventilation within 48 hours after randomization, or
    - Participants with a recent history of mechanical ventilation, or
    - Participants with conditions that could limit gastrointestinal absorption of capsule contents.
    10. Is taking or is anticipated to require any prohibited therapies as outlined in the Protocol.
    11. Is unwilling to abstain from participating in another interventional clinical trial through Day 29 with an investigational compound or device, including those for COVID-19 therapeutics.
    12. Is anticipated to require transfer to a non-study hospital within 72 hours.
    13. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study.
    E.5 End points
    E.5.1Primary end point(s)
    1. Time-to-sustained recovery
    2. Percentage of participants with an adverse event (AE)
    3. Percentage of participants who discontinued study intervention due to an AE
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to 29 Days
    2. Up to 7 Months
    3. Up to 6 Days
    E.5.2Secondary end point(s)
    1. Percentage of participants with all-cause mortality
    2. Pulmonary score on a scale
    3. Pulmonary+ score on a scale
    4. National Early Warning Score on a scale
    5. WHO 11-point outcomes score on a scale


    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to 29 Days
    2. Up to 29 Days
    3. Up to 29 Days
    4. End of Treatment (EOT) (Up to 6 Days)
    5. Up to 29 Days

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Brazil
    Chile
    Colombia
    Israel
    Japan
    Korea, Republic of
    Mexico
    Philippines
    Russian Federation
    South Africa
    Ukraine
    United States
    France
    Italy
    Poland
    Spain
    Sweden
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months12
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 845
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 455
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 250
    F.4.2.2In the whole clinical trial 1300
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-10-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-08-11
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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