Safety of oral administration of Molnupiravir for hospitalized elderly people aged 80 years old or older with Covid-19

doi:10.21203/rs.3.rs-1815198/v1

Objective: The number of elderly people with coronavirus disease 2019 (Covid-19) is increasing. In order to reduce the risk of progress of Covid-19, Molnupiravir, an oral small molecule antiviral prodrug active against severe acute respiratory syndrome coronavirus 2, was administered. The targets of administration were 29 elderly people over 80 years old (median 87 years old, range 80-100). We evaluated the efficacy and safety of treatment with Molnupiravir, which we had started oral administration within 24 hours after the onset of signs or symptoms in hospitalized elderly with at least one risk factor for Covid-19 disease confirmed in the laboratory. Molnupiravir 800 mg was administered twice daily for 5 days.

Results: There was no death within 30 days and it was effective. Adverse events occurred only in 55% of target patients within 7 days after internal administration, but only nausea was observed, no serious side effects were observed, and thus the drug could be safely administered to the elderly. Early treatment with Molnupiravir reduced the risk of death in the elderly at risk for Covid-19.

Covid-19

100 years old

Molnupiravir

Coronavirus Disease 2019 (Covid-19) Pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reports more than 530 million confirmed cases and more than 6.2 million deaths around the world [1]. In particular, elderly inpatients infected with Covid-19 in the hospital need to start treatment as soon as possible to reduce the risk of progression after the onset of symptoms, and easy-to-administer antiviral therapy is desirable. Molnupiravir is a small molecule ribonucleoside prodrug of N-hydroxycytidine (NHC), and after oral administration, NHC circulates systemically and is phosphorylated into NHC triphosphate in cells. NHC triphosphate is incorporated into the viral Ribonucleic acid (RNA) by viral RNA polymerase, and then induces viral polymerase to erroneously incorporate either guanosine or adenosine during virus replication. This results in harmful errors throughout the virus genome, ultimately making the virus non-infectious and incapable of replicating [2]. Oral molnupilavir has been found to be effective in the treatment of Covid-19 if it is initiated within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults who were at risk of progression to serious disease, without obvious safety concerns [3]. We evaluated the efficacy and safety of oral administration of Molnupiravir to the hospitalized elderly patients.

The subjects of administration were 29 elderly people over 80 years of age (median 87 years old, range 80-100) (Table 1). Polymerase chain reaction (PCR) tests were performed using the Applied Biosystems^TM QuantStudio Real-Time PCR Systems Product (Code.15731248) and Cycle Threshold (Ct) values were measured as an infectivity assessment [4]. Both nasopharyngeal swabs used for SARS-CoV-2 RNA quantification by PCR and baseline virus genotyping using next-generation sequencing were performed in the central laboratory and were collected on the first day of the patient’s fever and/or patient’s roommate’s fever. Hospitalization conditions and vital sign evaluations, clinical examinations and physical examinations were also conducted on the day. In this analysis of the pharyngeal sample, SARS-CoV-2 delta, gamma, and mu variants could not be identified. Within 24 hours after the onset of signs or symptoms, 800 mg of Molnupiravir was administered as four 200 mg capsules twice daily for 5 days [5, 6]. The follow-up observation period was 28 days during the treatment period and after the end of the treatment period, and the mortality rate was evaluated as efficacy and the adverse event incidence rate was evaluated as safety. In addition, the possibility of drug-induced liver injury was evaluated according to changes in platelet levels and liver enzymes. Target elderly patients have at least one risk factor of age> 60 years, active cancer, chronic kidney disease, chronic obstructive pulmonary disease, obesity defined by a body-mass index (the weight in kilograms divided by the square of the height in meters) ≥30, serious heart conditions (heart failure, coronary artery disease, or cardiomyopathies), diabetes mellitus, according to the guidance of Food and Drug Administration and World Health Organization (WHO). The use of dialysis estimated glomerular filtration rate of 30 ml / minute /1.73 m2 or less, pregnancy, neutropenia (neutrophil count of <500 / ml), platelet count <100,000 / microliter, monoclonal antibodies, remdesivir was excluded. Standard-of-care treatment with antipyretic agents, anti-inflammatory agents, glucocorticoids or a combination thereof was allowed.

The target patients who had quantifiable RNAs in the nasopharyngeal sample took Molnupiravir orally for 5 days according to the standard protocol. Fever of 38 degrees was observed once (group A), twice (group B), and three or more (groups C) 10 days after oral administration (Figure 1).

There were no significant differences in the Ct values of the A group, the B group, and the C group. However, there were differences in symptoms during and after oral administration (Table 2). No deaths were observed during the observation period. No exacerbation of the risk factor was observed in patients with at least one risk factor. Compared to before administration, there was no myelosuppression such as such as thrombocytopenia during the observation period, and no hepatic dysfunction or renal dysfunction was observed. No significant changes in blood pressure or pulse were observed.

Patients in A group had a fever of 38 degrees or higher and then reduced to 36 degrees or lower and have not had a fever since then. Nausea and anaphylaxis were observed in 1 patient each within 14 days after the start of oral administration. Two patients were disturbed loudly, one had hypoglycemic symptoms, and one tube-fed patient required sputum aspiration for 12 days, but it improved with the use of antiemetics and antihistamines. Two patients with tube feeding have resumed rehabilitation without any accident. Each is a separate patient.

Patients in B Group had a fever of 38 degrees or higher and then decreased to 36 degrees or lower, but had only one fever of 38 degrees or higher during 10 days. No fever occurred since the administration of acetaminophen. During oral administration, one developed nausea and another developed vomiting. It improved with the use of antiemetics. In the 14 days after the start, a large amount of sputum was discharged by 2 people, and suction was required. One of them is a vomiting patient. Aspiration was suspected. Two had poor eating, and one had nausea. In addition to these patients, one patient had SaO2 (Saturation artery Oxygen) of 90% or less and required oxygen administration (0.5-1 L / min). No increase in white blood cells (WBC) or C-reactive protein (CRP) was observed. X-ray examination and computerized tomography (CT) scan examination could not be performed due to the spread of infection. After that, one tube feeding patient could eat without fever and resumed rehabilitation without accident.

Patients in C group had a fever of 38 degrees or higher and then decreased to 36 degrees or lower but had a fever of 38 degrees or higher twice or more in 10 days. No fever occurred since the administration of acetaminophen. However, symptoms were noted in seven patients who did not have a fever. 1. During the oral administration, one person had feeling dizzy, but no numbness, paralysis, nystagmus, or pupil abnormalities were observed in the extremities and the condition improved without medication. 2. During the oral administration, one person had headaches, but improved with the use of acetaminophen. CT scan had no abnormalities. 3. One diarrhea were observed after the oral administration but improved without antidiarrheal or relieve intestinal ailments. 4. One of the two diarrhea patients, during administration, felt nausea, drained a large amount of sputum, and was given oxygen. This patient became inedible and improved with one week-long infusion and was then able to feed orally. 5. Patient with chronic obstructive pulmonary disease discharged more sputum after infection, was given oxygen. After dosing, nausea and vomiting were observed, but improved with the use of antiemetics. However, developed an eating disorder, and received nutrition from a nasogastric tube. 6. Patient with chronic interstitial pneumonia had a large discharge of sputum during the oral administration and was given oxygen. This patient then vomited and developed an eating disorder and was fed from a nasogastric tube. 7. One patient had melena during oral administration, but there is a possibility of colorectal cancer, and a colonoscopic examination is planned.

In the 14 days after the start, a large amount of sputum was discharged from 3 patients, and suction was required. Two of them were vomiting patients. Aspiration was suspected. These two patients became inedible due to difficulty swallowing and underwent tube feeding management. At the same time, swallowing training was conducted, and as a result, the patient was able to eat. Oxygen was administered (1-3 L / min) to 3 patients who had SaO2 of 87% or less. Two of them were patients who required sputum aspiration. The two patients had elevated WBC and CRP, had a history of sepsis, suspected bacterial pneumonia, added a loxoprofen antipyretic, and administered meropenem antibiotics to improve. One of them ended the oxygen administration, another continued to receive oxygen due to a history of brainstem infarction. One had a history of interstitial pneumonia, which was improved by steroid administration for 3 days, and the oxygen dose was reduced (0.5-1 L / min). They had SaO2 of 95% or more. If it worsens, we plan to manage the ventilator considering the need for endotracheal intubation. Rehabilitation has been resumed except for the 3 patients.

Okinawa Prefecture is located in the southernmost part of Japan and is known as a prefecture with longevity over 90 years old [7]. At this stage, the number of Covid-19 infected people per 100,000 people is the worst among the prefectures in Japan. There are many healthy elderly people in Okinawa prefecture, but there are also many elderly people who are being treated in hospital. This hospital is a rehabilitation facility for the elderly, and it is required to maintain good health and return to home by rehabilitation. This time, 30 nosocomial infections occurred in 60 wards. It was necessary to reduce the risk of infection death, to the elderly in the same ward, and to return them to early rehabilitation. Focusing on elderly patients who are most likely to require antiviral treatment, a more rapid evaluation of the therapeutic effect of oral Molnupiravir in the elderly was needed. In addition, due to the explosive pandemic, detention at the core hospital could not keep up, and transfer and treatment requests were restricted, so in-hospital treatment was indispensable.

Certainly vaccination is effective. In A group, more than 1 year ago, 4 out of 13 patients were vaccinated 3 or more times, and 2 patients were vaccinated twice. In B group, 2 out of 9 patients were vaccinated 3 times or more, 1 patient was vaccinated twice, and in C group, 1 patient was vaccinated twice. All of them have passed without any serious symptoms after infection and after oral administration. By the way, the patient who was vaccinated within 3 months was a 90-year-old female patient who was hospitalized in the same ward, but was not infected even while hospitalized in the same room as the infected person.

Now, data from elderly people infected with Covid-19 during hospitalization show that Molnupiravir, which started within 24 hours after the onset of symptoms, reduces the risk of inpatients of any cause or death by day 28. It was also shown that Molnupiravir can be safely administered to patients aged 90 to 100 years. The clinical symptoms after oral administration shown in Table 2 cannot be determined to be a side effect of Molnupiravir, however, in patients with a history of disuse syndrome with cancer and/or interstitial pneumonia, wavy fever was observed, and thus caution is required for observation and treatment after oral administration.

Also, thanks to the medication, it was possible to prevent infection of other patients in the ward. Furthermore, at present, this ward accepts infected patients from other wards in the hospital as an infected ward that can be rehabilitated, but the administration of Molnupiravir not only improved the patient himself but also the infection to patients in the same ward could be avoided. Oral administration of Molnupiravir in the elderly aged 80 years and older is effective and is considered to be a potentially significant improvement in outcome because it can prevent patient-to-patient and patient-to-medical personnel transmission.

The sample size was small and, thus, not sufficient to provide solid evidence. Thus, these findings are preliminary and should be supplemented by further studies on a larger number of subjects.

Covid-19: coronavirus disease 2019

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

NHC: N-hydroxycytidine

RNA: ribonucleic acid

PCR: polymerase chain reaction

Ct: Cycle threshold

SaO2: Saturation artery oxygen

WBC: white blood cells

CRP: C-reactive protein

CT: computerized tomography

Ethics approval and consent to participate

Molnupiravir has been distributed with the approval from the Ministry of Health, Labor and Welfare of Japan. The medication was approved by the in-hospital clinical trial review committee, ethics committee, and regulatory authorities in accordance with the medical guidelines of the Ministry of Health, Labor and Welfare in Japan. The study was conducted according to the guidelines of the Declaration of Helsinki, and it was registered and approved by the Institutional Review Board of Daido Central Hospital (protocol code number: No.35, May 2022). Written informed consent was obtained from all patients and their families. If serious side effects are observed during oral administration, the administration should be stopped immediately. An independent data monitoring committee advised to stop recruiting new participants in the test early. Safety monitoring was performed by the Data Monitoring Committee. Data were collected by the investigators and attending physicians, analyzed by statisticians of the Fukushima Medical University, and interpreted by the authors. Data on adverse events were collected until the end of the follow-up observation period, and they were approved from all patients and their families for their storage, analysis, utilization, and publication of the data. The authors guarantee the accuracy and integrity of the data and the fidelity of the test protocol. In accordance with the Personal Protection Law, no patient name or family name will be published, and the subject patients will not be tracked or specified from this article.

Consent for publication

Not applicable.

Availability of data and materials

The data collected for this study may be available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

There was no sponsor.

Authors' contributions

Study concept and design: KG. Study supervision: KG, KS. Acquisition, analysis, or interpretation of data: KG, KS. Drafting of the manuscript: KG. Critical revision of the manuscript for intellectual content: KG, KK, ST. All authors have read and approved the final manuscript.

Acknowledgements

The authors would also like to thank the Okinawan patients for their participation in this study. This study was part of the Okinawa–Fukushima Obesity Project.

Author information

Authors and Affiliations

Daido Central Hospital, Naha, Okinawa

Kenji Gonda and Kouichi Suzuki

Department of Gastrointestinal Tract Surgery, Fukushima Medical University, Fukushima

Kenji Gonda and Koji Kono

Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima

Kenji Gonda and Kouichi Suzuki

Department of Drug Research for Astatine-221 Targeted Alfa Therapy, Fukushima Medical University, Fukushima

Kenji Gonda and Seiichi Takenoshita

WHO Coronavirus (COVID-19) Dashboard https://covid19.who.int
Merck and Ridgeback’s Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study. https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/
Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022;386(6):509-520.
Thermo Fisher Scientific Inc. QuantStudio 5 qPCR System https://www.fishersci.se/shop/products/quantstudio-5-qpcr-system-1/15731248
COVID-19: developing drugs and biological products for treatment or prevention: guidance for industry. Silver Spring, MD: Food and Drug Administration, May 2020 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/covid-19-developing-drugs-and-biological-products-treatment-or-prevention
WHO COVID-19 case definitions. Geneva: World Health Organization, December 16, 2020 https://apps.who.int/iris/rest/bitstreams/1322790/retrieve
Amos Duo. Why do Okinawans live longer: The Secret To Long Life. 2021. https://therealrealreviews.com/why-do-okinawans-live-longer-the-secret-to-long-life/

Table 1. Clinical Characteristics of the Patients

Characteristic	Molnupiravir (N=29)
Female - no. (%)	12 (41)
Male - no. (%)	17 (59)
Age group - no. (%)
80-90 yr	23 (79)
91 < yr	6 (21)
Median age (range) - yr	87 (80-100)
Risk factors for severe illness from Covid-19 - no. (%)
At least one risk factor	25 (86)
Obesity	8 (28)
Age > 60 yr	25 (86)
Diabetes mellitus	5 (17)
Serious heart condition	13 (45)
Chronic kidney disease	4 (14)
Chronic obstructive pulmonary disease	5 (17)
Active cancer ¹	4 (14)
Others
bone fracture	13 (45)
artificial joint replacement	5 (17)
cerebral infarction、encephalorrhagia	10 (34)
tube feeding	6 (21)
disuse atrophy	21 (72)
Vaccination ²	11 (38)
Ct value	21 (72)

1 colon cancer, prostate cancer, lung cancer, lymphoma

2 More than one year has passed before the onset after vaccination

Table 2. Incidence of Events

n=29	<5d¹	< 7d	< 14d	< 21d	< 28d	Actual number of patients
A (n=13)
nausea	0	1	0	0	0	1
anaphylaxis	0	1	0	0	0	1 facial rash
disturbance	1	1	0	0	0	2 disturbing
IGT	1	0	0	0	0	1 hypoglycemia
sputum	1	1	1	0	0	1 sputum suction
B (n=9)
nausea	1	0	0	0	0	1
vomiting	1	0	0	0	0	1
massive sputum	2	1	0	0	0	2 sputum suction
anorexia	1	2	1	0	0	2 eating disorder
hypoxia	1	1	0	0	0	1 oxygen administration
C (n=7)
feeling dizzy	1	0	0	0	0	1
headaches	1	0	0	0	0	1
diarrhea	1	1	0	0	0	2 diarrhea
nausea	1	1	0	0	0	2 nausea
vomiting	0	2	0	0	0	2 vomiting
massive sputum	3	3	3	1	0	3 sputum suction
inedia	0	3	2	2	2	2 tube feeding management
hypoxia	3	3	3	2	2	3 oxygen administration
melena	1	0	0	0	0	1

1 d: days

2 IGT: impaired glucose tolerance

No competing interests reported.

Safety of oral administration of Molnupiravir for hospitalized elderly people aged 80 years old or older with Covid-19

Status:

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Abstract

Figures

Introduction

Methods

Results

Discussion

Limitations

List Of Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

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