A Clinical Study to Evaluate the Efficacy and Safety of SIM0417 Orally Co-Administered With Ritonavir in Symptomatic Adult Participants With Mild to Moderate COVID-19

A Multicenter, Randomized, Double-blind, Phase Ⅱ/Ⅲ Clinical Study to Evaluate the Efficacy and Safety of SIM0417 Orally Co-Administered With Ritonavir in Symptomatic Adult Participants With Mild to Moderate COVID-19

This Phase Ⅱ/Ⅲ study is to evaluate whether or not there is a difference in time recovery of COVID-19 signs and symptoms through Day 29 between SIM0417/ritonavir and placebo.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Placebo; Drug: SIM0417

Detailed Description

The efficacy, safety, and tolerability of SIM0417/ritonavir compared to placebo will be investigated. The exposure to SIM0417 in this population will also be investigated.

• Study Type: Interventional
• Enrollment (Actual): 1208
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • Hefei First People's Hospital
  • Beijing
    • Beijing, Beijing, China
      • Beijing Ditan Hospital Captial Medical University
  • Chongqing
    • Chongqing, Chongqing, China
      • Chongqing Public Health Medical Center
  • Fujian
    • Xiamen, Fujian, China
      • The First Affiliated Hospital of Xiamen University
  • Guangdong
    • Guangzhou, Guangdong, China
      • GUANGZHOU EIGHTH PEOPLE'S HOSPITAL GUANGZHOU MEDICAL UNIVERSITY
    • Maoming, Guangdong, China
      • Maoming People's Hospital
    • Qingyuan, Guangdong, China
      • Qingyuan People's Hospital
    • Shenzhen, Guangdong, China
      • The Third People's Hospital of Shenzhen
    • Zhanjiang, Guangdong, China
      • Central People's Hospital of Zhanjiang
    • Zhuhai, Guangdong, China
      • The Fifth Affiliated Hospital Sun Yat-Sen University
  • Guizhou
    • Guiyang, Guizhou, China
      • Guizhou Province People's Hospital
  • Hainan
    • Haikou, Hainan, China
      • Haikou People's Hospital
    • Sanya, Hainan, China
      • Hainan Third People's Hospital
  • Heilongjiang
    • Mudanjiang, Heilongjiang, China
      • Mudanjiang Kangan Hospital
  • Hubei
    • Wuhan, Hubei, China
      • Wuhan Jinyintan Hospital
  • Hunan
    • Changsha, Hunan, China
      • The First Hospital of Changsha
  • Jiangsu
    • Nanjing, Jiangsu, China
      • The Second Hospital of Nanjing
    • Nanjing, Jiangsu, China
      • Zhongda Hospital Southeast University
    • Suzhou, Jiangsu, China
      • The Fifth People's Hospital of Suzhou
    • Taizhou, Jiangsu, China
      • Taizhou People's Hospital
    • Wuxi, Jiangsu, China
      • Wuxi No.5 People's Hospital
    • Xuzhou, Jiangsu, China
      • Xuzhou Infectious Disease Hospital
    • Yangzhou, Jiangsu, China
      • Subei People's Hospital of Jiangsu province
    • Zhenjiang, Jiangsu, China
      • The Third People's Hospital of Zhenjiang
  • Jiangxi
    • Nanchang, Jiangxi, China
      • The First Affiliated Hospital of Nanchang University
  • Liaoning
    • Shenyang, Liaoning, China
      • The Sixth People's Hospital of Shenyang
  • Shandong
    • Jinan, Shandong, China
      • Shandong Public Health Clinical Center
  • Shanghai
    • Shanghai, Shanghai, China
      • Shanghai Public Health Clinical Center
  • Sichuan
    • Chengdu, Sichuan, China
      • Public Health Clinical Center of Chengdu
    • Suining, Sichuan, China
      • Suining Central Hospital
  • Tianjin
    • Tianjin, Tianjin, China
      • Tianjin First Center Hospital
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Affliated Hangzhou XiXi Hospital Zhejiang University School of Medicine
    • Huzhou, Zhejiang, China
      • Huzhou Central Hospital
    • Ningbo, Zhejiang, China
      • HwaMei Hospital University of Chinese Academy of Sciences
    • Wenzhou, Zhejiang, China
      • Wenzhou Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Participants ≥18 years of age (or the minimum country-specific age of consent if >18) at the time of signing the informed consent/assent form.
2. Initial positive SARS-CoV-2 tested by RT-PCR or rapid antigen test within 5 days (120 h) prior to the first dose of study drug collected from any respiratory tract specimen (e.g., oropharyngeal, NP or nasal swab, or saliva).
3. Initial onset of signs/symptoms attributable to COVID-19 within 3 days prior to the day of the first dose of study drug. The onset time of symptoms was defined as the time when body temperature first rose; or the onset of any of these COVID-19 symptoms.
4. At least one of the following symptoms of COVID-19 present within 24 hours prior to the first dose of study drug and meeting severity.
5. Has mild or moderate COVID-19.
6. Participants agree to take highly effective contraceptive measures from signing the informed consent to at least 1 month after the last dose of study intervention.
7. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
8. Willing and able to provide written informed consent, or with a legal representative who can provide informed consent.

Exclusion Criteria:

1. Urgent or expected need for nasal high-flow oxygen therapy or positive pressure ventilation, invasive mechanical ventilation or Extracorporeal membrane oxygenation(ECMO).
2. Known medical history of active liver disease (other than nonalcoholic hepatic steatosis), including acute or chronic active hepatitis B or C infection, primary biliary cirrhosis, Child-Pugh Class B or C, or acute liver failure.
3. Receiving dialysis or have known moderate to severe renal impairment (ie, eGFR <45 mL/min/1.73 m2 within 6 months of the screening visit, using the serum creatinine-based CKD-EPI formula).
4. Compromised immune system (including patients receiving long-term immunosuppressant therapy, or those with progressed or relapsed cancer or human immunodeficiency virus [HIV] infection).
5. Moderate to severe congestive heart failure (New York Heart Association class III or IV) within 6 months prior to Screening, recent (within the past 6 months prior to Screening) cerebrovascular accident, myocardial infarction, coronary artery stenting, or uncontrolled hypertension (defined as documented systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg).
6. Acute episode of chronic respiratory diseases, including bronchial asthma, chronic obstructive pulmonary disease.
7. Suspected or confirmed concurrent active systemic infection other than COVID-19 (eg, co-infected with influenza) that may interfere with the evaluation of response to the study intervention.
8. Any comorbidity requiring surgery within 14 days prior to study entry, or that is considered life-threatening within 30 days prior to study entry, as determined by the investigator.
9. Has hypersensitivity or other contraindication to any of the components of the study interventions.
10. Other medical or psychiatric conditions including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
11. Clinical signs indicative of severe systemic illness with COVID-19, such as respiratory rate ≥30 per minute, heart rate ≥125 per minute, oxygen saturation (SpO2) of ≤93% on room air or the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) <300 obtained at rest within 24 hours prior to randomization.
12. Treatment with antivirals against SARS-CoV-2 within 14 days prior to the first dose of randomization.
13. Current or expected use of any medications or substances that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations may be associated with serious and/or life-threatening events during study treatment and for 4 days after the last dose of study drug (refer to Appendix 6).
14. Concomitant use of any medications or substances that are strong inducers of CYP3A4 are prohibited within 21 days prior to randomization and during study treatment (refer to Appendix 6).
15. Has received (within the past 30 days or 5 × drug half-life prior to randomization, which is longer) or is expected to receive COVID-19 monoclonal antibody or convalescent COVID-19 plasma during study treatment.
16. Systemic glucocorticoid therapy (prednisone ≥ 20 mg/day or equivalent doses of other steroids) for at least 14 consecutive days within 30 days prior to randomization.
17. Has received any SARS-CoV-2 vaccine within 3 months prior to randomization.
18. Participating in another interventional clinical study with an investigational compound or device, including those for COVID-19.
19. Previous administration with any investigational drug or vaccine within 30 days (or as determined by the local requirement) or 5 half-lives (whichever is longer) prior to randomization.
20. Known prior participation in this trial or other trial involving SIM0417.

21. Women who are breastfeeding or have a positive pregnancy test in the pre-dose examinations. The following female patients who have documentation of either a or b below do not need to undergo a pregnancy test in the pre-dose examinations:

    1. Postmenopausal women (defined as cessation of regular menstrual periods for 12 months or more, and confirmed by a follicle-stimulating hormone test if <60 years old)
    2. Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or tubal ligation

22. 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.

    For subjects who have conditional ECG at screening only:

23. Clinically relevant or significant electrocardiographic abnormalities (e.g., second-degree type II AV block, left bundle branch block, etc.), including electrocardiographic QT interval corrected for heart rate using Fridericia 's correction formula (QTcF = QT/(RR0.33)) > 450 ms (males) or > 470 ms (females).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo (tablet)
Experimental: SIM-0417; orally administrated SIM0417+ ritonavir	Drug: SIM0417; dose of 750 mg SIM0417 with 100 mg ritonavir.; Other Names: Simnotrelvir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to sustained recovery of 11 COVID-19 symptoms	The time from the start of treatment to the time when 11 COVID-19 symptoms get scores of 0 (absence or return to the status before the onset) for two consecutive days.(Participant-completed study diary (COVID-19 symptoms and signs, and global impression questions))	Baseline through Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to sustained alleviation of 11 COVID-19 symptoms	The time from the start of treatment to the time when 11 COVID-19 symptoms get scores of 0 (absence or return to the status before the onset) or 1 (mild) for two consecutive days.	Baseline through Day 29
Viral load	Changes of viral load compared to the baseline.	Baseline through Day 14
Time to sustained recovery of 5 COVID-19 symptoms	The time from the start of treatment to the time when 5 COVID-19 symptoms get scores of 0 (absence or return to the status before the onset) or 1 (mild) for two consecutive days.	Baseline through Day 29
Time to sustained alleviation of 7 COVID-19 symptoms	The time from the start of treatment to the time when 7 COVID-19 symptoms get scores of 0 (absence or return to the status before the onset) or 1 (mild) for two consecutive days.	Baseline through Day 29
SARS-CoV-2 RNA	Proportion of participants with SARS-CoV-2 RNA below the threshold.	Baseline through Day 14
Severe COVID-19 disease	Incidence of disease progression by COVID-19 severity.	Baseline through Day 29
Hospitalization or death	Proportion of participants with hospitalization or death from any cause.	Baseline through Day 29
ICU stay	Proportion of participants admitted into ICU.	Baseline through Day 29
Requiring supplemental oxygen	Proportion of participants requiring supplemental oxygen (low-flow nasal cannula, simple face mask).	Baseline through Day 29
Requiring mechanical ventilation/ECMO	Proportion of participants requiring mechanical ventilation/ECMO.	Baseline through Day 29
Death (all cause)	Proportion of participants with death (all cause).	Baseline through Week 12
WHO clinical progression scale score	Change from baseline in WHO clinical progression scale score.	Baseline through Day 29
Time to sustained recovery of each targeted COVID-19 symptom	The time from the start of treatment to the time when each targeted COVID-19 symptom gets scores of 0 (absence or return to the status before the onset) for two consecutive days.	Baseline through Day 29
Proportion of sustained recovery of COVID-19 symptoms	Proportion of patients whose symptoms has been sustainedly recovered.	Baseline through Day 29
Severity of COVID-19 symptoms	Severity of each COVID-19 symptom.	Baseline through Day 29
Composite symptom score	Change from baseline in composite symptom score.	Baseline through Day 29
Treatment-Related Adverse Events (TEAEs)	Incidence of Treatment-Related Adverse Events (TEAEs).	Baseline through Day 29
Serious Adverse Events (SAEs)	Incidence of Serious Adverse Events (SAEs) Assessed.	Baseline through Week 12
The plasma concentration of SIM0417	The trough concentrations of SIM0417.	Baseline through Day 5

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health Economic Outcome	Change from baseline in EuroQol 5 Dimension 5 Level (EQ-5D-5L) index score at applicable timepoint; The EQ-5D-5L index score comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems.	Baseline through week 12
Time to cessation of SARS-CoV-2 viral shedding (Viral load assessment)	The length of time from the start of treatment to first time when the virus RNA is below the defined threshold.	Baseline through Day 29
Hospital and ICU stay	Number of days in hospital and ICU stay in participants with COVID-19 related hospitalization.	Baseline through Week 12
COVID-19 related medical visits	Number of COVID-19 related medical visits other than hospitalization.	Baseline through Day 29
WHO clinical progression scale	Proportion of participants at each clinical status as assessed by WHO clinical progression scale.	Baseline through Day 29
Resolution of fever	Time to resolution of fever (Defined as the time between the initiation of the study treatment and the resolution of fever).	Baseline through Day 29
Global Impression Questions	Time to self-reported return to usual (pre-COVID-19) health status (Global Impression Questions, section 8.1.1).	Baseline through Day 29
viral variants	Explore the prevalence of viral variants.	Baseline through Day 29
drug-resistance mutation	Explore the clinical drug-resistance mutation.	Baseline through Day 29

Collaborators and Investigators

• Sponsor: Jiangsu Simcere Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Chen Wang, China-Japan Friendship Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2022
• Primary Completion (Actual): January 23, 2023
• Study Completion (Actual): March 21, 2023

Study Registration Dates

• First Submitted: August 12, 2022
• First Submitted That Met QC Criteria: August 17, 2022
• First Posted (Actual): August 18, 2022

Study Record Updates

• Last Update Posted (Estimate): May 8, 2023
• Last Update Submitted That Met QC Criteria: May 4, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Mild to Moderate COVID-19
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: SIM0417-301

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No