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Submitted by: Quintiles 2021-02-18 08:25:12 Last Updated by: Principe, Jeverly Ann S 2021-02-18 18:58:21


A Phase II Study of M5049 in COVID-19 Pneumonia (ANEMONE)

PHRR210218-003364

MS200569-0026

2020-CT0580

A Phase II, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of M5049 in Hospitalized Participants with COVID-19 Pneumonia

In this study, M5049 taken for 14 days will be evaluated in participants who are hospitalized with moderate to severe COVID-19 pneumonia but not on mechanical ventilation. The exploratory Phase II study will evaluate if M5049 inhibition of the host inflammatory response targets, a potential mechanism of virus-associated cytokine storm in COVID-19. Treatment of COVID-19 pneumonia after the immediate host innate and early adaptive immune responses (hospitalization on average occurring 10 days after infectious exposure) could potentially halt progression to severe immunopathology without compromising viral clearance

Regime Classification Priority
2017 - 2022 Research to enhance and extend healthy lives Access to essential medical products, vaccines and technologies
Start Date Duration in Months Target Completion Date Actual Completion Date
2021-02-26 15 2022-05-26 0000-00-00

Ongoing

Institution Classification Region LTO #
Merck Healthcare KGaA Private Business Germany NA
Institution Classification Region LTO #
IQVIA RDS Philippines, Inc. Private Business NCR LTO-3000005977146
Institution Region
Merck Healthcare KGaA Germany
Name E-Mail Institution and Institution Address
Marissa Laureta marissa.laureta@iqvia.com IQVIA RDS Philippines Inc., Unit A, 7th Floor, 8 Rockwell Bldg. Hidalgo Drive, Rockwell Center, Makati City 1210 Philippines
Name E-Mail Institution and Institution Address
Elizabeth Adams, MD elizabeth.adams@emdserono.com Merck KGaA, Darmstadt, Germany
Name Expertise Affiliation
Arnold Germar, MD Infectious Disease Veterans Memorial Medical Center
Camilo C. Roa Jr., MD Pulmonologist Manila Doctors Hospital
Daisy Tagarda,MD Pulmonologist University of Santo Tomas Hospital
Gelza Mae A. Zabat, MD Infectious Disease St. Luke's Medcal Center Quezon City
Joel M. Santiaguel, MD Infectious Disease Quirino Memorial Medical Center
Lawrence Raymond, MD Infectious Disease Lung Center of the Philippines
Ma. Bella R. Siasoco, MD Infectious Disease East Avenue Medical Center
Rontgene M. Solante, MD Infectious Disease ManilaMed - Medical Center Manila
Project Location Institutional Ethics Review Board
Veterans Memorial Medical Center Veterans Memorial Medical Center Ethics Review Committee
Manila Doctors Hospital Manila Doctors Hospital Institutional Review Board
University of Santo Tomas Hospital University of Santo Tomas Hospital Institutional Review Board
St. Luke's Medcal Center Quezon City N/A
Quirino Memorial Medical Center Quirino Memorial Medical Center Hospital Ethics Committee
Lung Center of the Philippines Lung Center of the Philippines Ethics Review Committee
East Avenue Medical Center East Avenue Medical Center (Ethics Review Committee)
ManilaMed - Medical Center Manila N/A

COVID 19 Pneumonia treatment

To assess the safety of M5049 compared to placebo.

To assess the proportion of participants free of respiratory support in M5049 compared to placebo participants.

To assess the safety of M5049 compared to placebo.

To evaluate clinical deterioration with M5049 compared to placebo.

To evaluate the change in clinical status with M5049 compared to placebo.

To assess the PK of M5049.

To evaluate the change in clinical status with M5049 compared to placebo.

To assess normalization of oxygenation status with M5049 compared to placebo in participants who are alive and not on mechanical ventilation.

To evaluate the numbers of deaths with M5049 compared to placebo.

To evaluate clinical deterioration with M5049 compared to placebo.

To assess the length of stay in the ICU with M5049 compared to placebo.

To assess the length of hospital stay with M5049 compared to placebo.

To assess the proportion of participants free of respiratory support in M5049 compared to placebo participants.

To evaluate modulation of biomarkers of COVID-19 inflammation with M5049 compared to placebo.

To evaluate modulation of select biomarkers with M5049 compared to placebo.

To evaluate occurrence of relapse with M5049 compared to placebo.

To assess occurrence of re-hospitalizations due to COVID-19 disease complications.

Pending

Clinical Trial

MS200569-0026

20201211102944

2021-01-19

0000-00-00

36

Unspecified

Unspecified

26 Feb 2021

Inclusion Criteria

Participants are eligible to be included in the study only if all the following criteria apply during the 48-hour study Screening Period:

Informed Consent: 1. Participant (or legally authorized representative) provides signed informed consent prior to the initiation of any study assessments for participation in the study.

Age 2. Are ≥ 18 to ≤ 75 years of age, at the time of signing the informed consent.

Type of Participant and Disease Characteristics 3. Has laboratory-confirmed SARS-CoV-2 infection as determined by nucleic acid amplification test, polymerase chain reaction, antigen test, or other commercial or public health assay (based on locally accepted guidelines) in a sample collected < 10 days prior to randomization.

4. Documentation of chest imaging consistent with COVID-19 pneumonia (as per locally accepted guidelines). If chest imaging is not available during Screening, please discuss with Medical Monitor or designee regarding evidence of probable COVID-19 pneumonia for study participant eligibility.

5. Not on mechanical ventilation (invasive or noninvasive), or ventilation, or ECMO, nor (based on medical judgement of admitting physician) anticipated to be in the next 24 hours.

6. An SpO2 < 94% in room air AND able to maintain a PaO2/FiO2 ≥ 150 with a maximum FiO2 0.4. These readings may be obtained after exertion by the participant. Note: if participant is on chronic low O2 therapy (≤ 2 L), assess their current baseline O2 requirements for eligibility.

7. Requiring hospitalization (i.e., in the process of hospital admission or already admitted).

Birth Control based on Sex at Birth 8. a. Female Participants:  Not a woman of childbearing potential (See Appendix 2). OR  If a woman of childbearing potential: o Is using a depot contraceptive or extended cycle oral contraceptive from before the first dose of the study intervention(s). o Agree not to become pregnant or donate eggs (ova, oocytes) for reproduction for a full 60 days. o Use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year) as described in Appendix 2 for the duration of the study (a full 60 days), either with:  A daily use hormonal contraception from before the first dose of the study intervention(s), OR  Uses a barrier method during the length of the study (a full 60 days).

b. Male Participants:  Agree to refrain from donating sperm for at least 90 days. PLUS, either  Abstain from intercourse with a woman of childbearing potential. OR  Use a male condom for at least 90 days:st, polymerase chain reaction, antigen test, or other commercial or public health assay (based on locally accepted guidelines) in a sample collected < 10 days prior to randomization. When having sexual intercourse with a woman of childbearing potential, who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year (see Appendix 2), since a condom may break or leak.

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions 1. Any condition that could interfere with the study objectives, conduct or evaluation in the opinion of the Investigator or Sponsor or designee.

2. If pregnant (by positive high-sensitivity pregnancy test) or breastfeeding.

3. Clinically significant (i.e., active) cardiovascular disease: cerebrovascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina pectoris, congestive heart failure (New York Heart Association Classification Class ≥ III), or serious cardiac arrhythmia requiring medication (including corrected QT interval prolongation of > 470 ms and/or pacemaker) or prior diagnosis of congenital long QT syndrome. Note: documented, longstanding Left Bundle Branch Block (LBBB) resulting in a long QTc using Fridericia’s formula, is not exclusionary if corrected by the QTc-LBBB {[QT – (0.7 × QRS – 50)]/square root RR} or JTc (QTc – QRS duration) formula.

4. History of uncontrolled illness (in the opinion of the Investigator) prior to SARS-CoV-2 infection, within the 3 months prior to Screening, including but not limited to: a. Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg or lower), or b. Uncontrolled active infection, or c. Significantly uncontrolled diabetes mellitus or any diabetes that has resulted in severe end organ damage, or d. Uncontrolled or severe asthma or other chronic obstructive pulmonary disease. Note: uncontrolled asthma/chronic obstructive pulmonary disease is defined as more than 1 exacerbation in the previous 12 months that required an emergency room visit or hospitalization. Note: chronic low O2 (≤ 2 L) therapy is allowed as long as the participant meets the criteria outlined in Inclusion Criterion 6.

5. History of epilepsy, other neurological disorder associated with seizures (e.g., cerebrovascular accident/stroke, acute brain infection, traumatic brain injury, progressive brain disease, congenital brain disease), or currently active and uncontrolled neuropsychiatric condition (in the opinion of the Investigator) including depression or current suicidal ideation.

6. History of interstitial lung disease prior to Screening or current thrombosis or embolism present during Screening.

7. History of a primary immunodeficiency, organ transplant, splenectomy or functional asplenia.

8. History of the following prior to Screening: a. Human immunodeficiency virus infection. b. Untreated hepatitis C (i.e., if hepatitis C antibody positive, hepatitis C DNA is detectable). c. Untreated hepatitis B (positive for hepatitis B surface antigen or if hepatitis core antibody positive, hepatitis B DNA is detectable). d. Recurrent herpes zoster (two or more episodes within a 10-year period). e. Known active tuberculosis (TB) or untreated latent TB infection. Note: laboratory confirmation of inactive infection status is not required for study eligibility.

9. History of malignancy (hematologic or solid tumor) that is not currently under control or in remission prior to Screening.

10. History of known alcohol or drug abuse in the 3 months prior to Screening as per Investigator opinion. Prior/Concomitant Therapy

11. Known hypersensitivity to any study treatment, component, or placebo.

12. Daily use of the following medications associated with serotonin syndrome within 14 days prior to randomization: a. Antidepressants: selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, St. John’s wort. Exception: fluoxetine within 8 weeks prior to randomization. b. Analgesics: tramadol, fentanyl (i.e., intermittent use as needed prior to randomization is allowed). c. Long-acting anti-emetics e.g., palonosetron, dolasetron. Short-acting anti-emetics, e.g, ondansetron, potentially associated with serotonin syndrome may be prescribed on an as needed basis. If short-acting antiemetics require around the clock administration for more than 1 day, please contact your Medical Monitor or designee to ensure safety of the study participant. Short-acting anti-emetics should not be administered within 3 hours of study treatment. d. Linezolid, tryptophan, buspirone, tedizolid.

13. The initiation, use or change in therapies within 14 days prior to randomization: a. Use of raloxifene, tamoxifen, estradiol, clozapine, chlorpromazine (strong aldehyde oxidase inhibitors).b. Use of corticosteroids exceeding 40 mg daily prednisone equivalent (e.g., dexamethasone 6 mg). Use of 40 mg daily prednisone equivalent (e.g., dexamethasone 6 mg) for more than 10 days during the study. c. Any vaccination included but not limited to subunit or inactivated vaccines. d. Use of Chinese herbal/non-herbal medications (e.g., tripterygium, total glucosides of peony, etc.). e. Use of plasmapheresis.

14. The initiation, or use of therapies within 1 month prior to randomization: a. Vaccination with live or live attenuated virus vaccine. b. Use of any medication considered to have immunomodulating and/or immunosuppressant properties including but not limited to the following: antimalarials, (e.g., chloroquine, hydroxychloroquine, mefloquine), leflunomide, methotrexate, 6-mercaptopurine, sulfasalazine, mycophenolate mofetil or sodium, azathioprine, cyclophosphamide, dapsone, retinoids, abatacept, anifrolumab, thalidomide, lenalidomide, anti-TNFα agents, systemic calcineurin inhibitors (e.g., cyclosporine, tacrolimus) (although topical use of calcineurin inhibitors are allowed), Bruton’s tyrosine kinase inhibitors, other small molecules such as tofacitinib (i.e., Janus kinase/signal transducers, activators of transcription pathway inhibitors), IL-1 and IL-6 pathway inhibitors, TNFα pathway inhibitors, IL-12/IL-23 pathway inhibitors, (e.g., ustekinumab), or other disease modifying, immunosuppressive or immunomodulatory therapies not otherwise specified in protocol. c. Use of B cell depleting/modulating therapy such as anti-CD20 agents including but not limited to rituximab, ocrelizumab, ofatumumab, obinutuzumab, ocaratuzumab, veltuzumab, or biosimilars thereof, belimumab, or dual or other anti-B Lymphocyte Stimulator/a proliferation inducing ligand neutralizing therapies (e.g., RCT 18).

15. Concurrent interventional clinical study participation prior to study randomization through Day 28. After Day 28, approval to participate must be requested from the Sponsor when there exists the intent of participation in a concurrent study.

Diagnostic Assessments 16. Clinically significant or predefined abnormalities in laboratory tests (serum chemistries: aspartate aminotransferase [AST], alanine aminotransferase [ALT] or alkaline phosphatase level > 5.0 × upper limit of normal [ULN]), or hematologic test (hemoglobin < 5.0 mmol/L [9 g/dL], white blood cells < 1.5 × 109/L, absolute neutrophil count < 750/mm3, platelets < 50 × 109/L) at Screening.

17. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation: eGFR = 175 × (serum creatinine in mg/dL)–1.154 × (age in years)–0.203 × 0.742 (if female) × 1.212 (if race is black) 

Interventional

M5049

M5049 is a quinoline-based oral small molecule inhibitor of TLR7 and TLR8 which has been shown to specifically inhibit the activity of various TLR7/8 ligands, such as ssRNAs, certain GU-rich microRNAs, and small molecule receptor agonists in a wide range of in vitro assays. M5049 inhibited ex vivo cytokine production (IL-6, TNFα, and IFNα) in human peripheral blood mononuclear cells (PBMCs) and whole blood, as well as TLR8-mediated NETosis in human primary neutrophils.

M5049 is a white to yellow solid powder, formulated as immediate release film-coated tablet for oral administration. Tablets of 2 strengths with 10 mg and 25 mg of M5049, and in color and size matching placebo tablets will be used in the study. M5049 film-coated tablets and corresponding placebo tablets are yellowish to yellow, round biconvex with no embossing. M5049 will be packaged and labeled per applicable regulatory requirements and Good Manufacturing Practice (GMP) Guidelines.

None

Randomized

Double Blind

This is a 2-part, Phase II double-blind, randomized, placebo-controlled study to evaluate the safety of and clinical response to M5049 tablets taken orally twice daily for 14 days in participants initially hospitalized because of moderate to severe COVID-19 pneumonia. Participants will be randomized 1:1:1 to receive M5049 50 mg, M5049 100 mg, or placebo twice daily. Part A and Part B of this exploratory study will each consist of an up to 48-hour Screening Period, a 14-day treatment period within a 28-day inpatient and/or outpatient Surveillance period, and then a 32-day inpatient and/or outpatient Safety Follow-up Period. Study participants should be provided the local standard/supportive care but cannot be on antimalarial (chloroquine-related) medications or other immunomodulating drugs (except for corticosteroids – see eligibility and coadministrations specifications). Participants on RECOVERY Trial dexamethasone dosing equivalent of corticosteroids and initiated on antiviral therapy and/or convalescent plasma for treatment of COVID-19 may be eligible for enrollment.

Parallel

Coronavirus disease 2019 (COVID-19) is a new pandemic disease characterized by pulmonary inflammation from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a single-stranded ribonucleic acid (ssRNA) virus related to both SARS-CoV-1, which caused severe acute respiratory syndrome (SARS) disease in 2002/03, and Middle East respiratory syndrome coronavirus. While antiviral therapies to treat the COVID-19 are urgently needed, treatments for severe disease with excessive pulmonary inflammation are also critical to reduce COVID-19 complications leading to increased mortality and to decrease the burden of the rapidly evolving pandemic on the health care system (Feldmann 2020). Given that the immunopathology in reaction to SARS-CoV-2 infection is contributing to the high rate of morbidity and mortality, host-directed immunomodulatory approaches are also being evaluated (Mehta 2020, Stebbing 2020).

In this exploratory Phase II study, a 14-day course of M5049, a potent, selective toll-like receptor (TLR) 7/8 antagonist will be evaluated. The optimal timing of M5049 dosing is hypothesized to be after the participant’s initial antiviral response (so as to not interfere with initial host control or clearance of the virus) and when increasing pulmonary inflammation is signaling an overly amplified host inflammatory response. Treatment of COVID-19 pneumonia after the immediate host innate and early adaptive immune responses could potentially halt progression to severe immunopathology without compromising viral clearance (Siddiqui 2020).

The safety and clinical response to orally-administered M5049 will be evaluated for 14 days in participants with moderated to severe COVID-19 pneumonia who are maintained on local standard of care and hospitalized without the need for mechanical ventilation. The 2-part study is a randomized, double-blind, placebo-controlled design. The study design and participant safety monitoring are based on M5049 data obtained from the first-in-human (FIH) Phase I single ascending dose and 14-day multiple ascending dose healthy volunteer study, nonclinical evaluations of M5049, and the timing of other anti-inflammatory agents for treatment of COVID-19 pneumonia. M5049 demonstrates dose-proportional pharmacokinetics (PK), has a half-life of approximately 7 to 11 hours, and is mainly metabolized by aldehyde oxidase, not the common cytochrome P450 enzymes.

The small molecule, M5049, is a dual TLR7/8 antagonist shown to specifically inhibit the activity of various TLR7/8 ligands such as ssRNA, certain GU-rich micro ribonucleic acid (RNA), and small molecule receptor agonists. TLR7/8 is expressed in the endosomes of cells with innate immune function, where activation by ssRNA viruses (e.g., SARS-CoV-2) stimulates secretion of Type I interferons (IFNs) and proinflammatory cytokines (interleukin [IL] 6, tumor necrosis factor alpha [TNFα], and others), cellular maturation and activation of other host immune mechanisms (Chow 2018, Li 2013).

Phase II

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