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1.
Clin Microbiol Infect ; 28(4): 602-608, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1708470

ABSTRACT

OBJECTIVE: To evaluate whether favipiravir reduces the time to viral clearance as documented by negative RT-PCR results for severe acute respiratory syndrome coronavirus 2 in mild cases of coronavirus disease 2019 (COVID-19) compared to placebo. METHODS: In this randomized, double-blinded, multicentre, and placebo-controlled trial, adults with PCR-confirmed mild COVID-19 were recruited in an outpatient setting at seven medical facilities across Saudi Arabia. Participants were randomized in a 1:1 ratio to receive either favipiravir 1800 mg by mouth twice daily on day 1 followed by 800 mg twice daily (n = 112) or a matching placebo (n = 119) for a total of 5 to 7 days. The primary outcome was the effect of favipiravir on reducing the time to viral clearance (by PCR test) within 15 days of starting the treatment compared to the placebo group. The trial included the following secondary outcomes: symptom resolution, hospitalization, intensive care unit admissions, adverse events, and 28-day mortality. RESULTS: Two hundred thirty-one patients were randomized and began the study (median age, 37 years; interquartile range (IQR): 32-44 years; 155 [67%] male), and 112 (48.5%) were assigned to the treatment group and 119 (51.5%) into the placebo group. The data and safety monitoring board recommended stopping enrolment because of futility at the interim analysis. The median time to viral clearance was 10 days (IQR: 6-12 days) in the favipiravir group and 8 days (IQR: 6-12 days) in the placebo group, with a hazard ratio of 0.87 for the favipiravir group (95% CI 0.571-1.326; p = 0.51). The median time to clinical recovery was 7 days (IQR: 4-11 days) in the favipiravir group and 7 days (IQR: 5-10 days) in the placebo group. There was no difference between the two groups in the secondary outcome of hospital admission. There were no drug-related severe adverse events. CONCLUSION: In this clinical trial, favipiravir therapy in mild COVID-19 patients did not reduce the time to viral clearance within 15 days of starting the treatment.


Subject(s)
COVID-19 , Adult , Amides/therapeutic use , COVID-19/drug therapy , Double-Blind Method , Humans , Male , Pyrazines/adverse effects , Treatment Outcome
2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-319678

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) is a global pandemic with a substantial impact on mortality, the health system and the economy 8,9 . Several observational studies reported the rate of venous and arterial thrombotic events in patients infected with COVID-19, with conflicting results . The aim of this multicentre study was to estimate the rate of thrombotic and bleeding events in hospitalized patients diagnosed with COVID-19 in Saudi Arabia. Method: multicenter study of 636 hospitalized patients with COVID-19. Result: Twelve patients were diagnosed with VTE 1.89% (95% CI, 1.18–3). The rate in the non-ICU group was 0.19% (95% CI, 0.04–0.84) compared to 10.38% (95% CI, 6.45–16.27) in the ICU group. Fourteen patients were diagnosed with an arterial event with an overall rate of 2.20% (95% CI, 1.43–3.38). The rate in the non-ICU group was 0.94% (95% CI, 0.46–0.1.93) and 8.49% (95% CI, 5.01–14.04) in the ICU group. The overall composite events rate was 2.99% (95% CI, 2.06–4.31). The composite events rate in the non-ICU group was 0.94% (95% CI, 0.46–0.1.93) and 13.21% (95% CI, 8.7–19.54) in the ICU group. Eleven patients developed bleeding with an overall rate of 1.73% (95% CI, 1.06–2.81). The bleeding rate in the non-ICU group was 0.19% (95% CI, 0.04–0.84), and 9.43% (95% CI, 5.72–15.16) in the ICU group. Of the selected risk factors, the only risk factor that predicted VTE and the composite outcome, was the baseline D-dimer. (OR 1.31, 95% CI, 1.084-1.573, p=0.005) and composite events (OR 1.32, 95% CI, 1.126-1.555, p=0.0007). Conclusion: Of 636 adults with COVID-19, the rate of VTE was similar to the rate of hospitalized patients with a similar degree of critical illness. In contrast to the risk of VTE, we found a high rate of arterial and bleeding complications in patients admitted to ICU. An elevated D-dimer at baseline could predict a thrombotic complication in the COVID-19 patients, which may assist in the identification of these patients. Given the high rate of bleeding, the current study suggests that the intensification of anticoagulation in COVID-19 patients beyond the standard of care, should be pursued with caution and is best evaluated in a randomised controlled study.

3.
Blood ; 136(Supplement 1):42-43, 2020.
Article in English | PMC | ID: covidwho-1338981

ABSTRACT

IntroductionCoronavirus disease (COVID-19) pandemic has started to affect Saudi Arabia in the beginning of March 2020 and is expected to cause significant morbidity to many patients, especially to elderly, who might require intensive care unit (ICU) support to survive as its lethality increases with the increasing age. Recent publications suggested the benefit of utilizing convalescent plasma from recovered donors as a therapeutic approach in treating COVID-19 patients. Convalescent plasma could provide our first-line defense for people with COVID-19, especially those who are older and at a much higher risk for complications., therefore, we developed a national protocol to investigate the safety, benefit and applicability at larger scale and at different health care facilities in Saudi Arabia (KSA).ObjectivesPrimary endpoints are1. ICU (or designated area for critical patients) length of stay2. Safety of convalescent plasma>Secondary endpoints included:1. 30 days mortality2. Number of days on mechanical ventilation3. Days to clinical recoveryMethodEligible convalescent plasma donors will be invited to participate in trial. The arrangement for plasmapheresis will start after obtaining donor informed consent. The collected plasma will be treated with pathogen reduction system. The convalescent plasma units will be labelled, stored and shipped as per the standard transfusion medicine protocols. It will be used only for eligible patients' "recipients" as per the following eligibility criteria:1. Inclusion criteria:- Confirmed case of SARS-CoV-2 infection with POSITIVE rRT PCR test-18 or older-Must have been requiring ICU care or severe or immediately life-threatening care (any one of the following):1. Patient requiring ICU care/admission.2. Severe disease is defined as:a. Dyspneab. Respiratory frequency ≥ 30/minc. Blood oxygen saturation ≤ 93%d. Partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300, and/or Lung infiltrates >50% within 24 to 48 hours3. Life-threatening disease is defined as:a. Respiratory failureb. Septic shock, and/orc.Multiple organ dysfunction or failureExclusion criteria:1. Negative or non-conclusive test COVID-19 rRT PCR test2. Mild symptoms3. Hospitalization not requiring ICU care/admissionEligible Patients will be infused with the convalescent plasma (200-400 ml / treatment dose)at least once & if possible, daily, for up to 5 sessions. Other supportive and therapeutic measures should continue according to the locally approved protocols with due diligence.Sample size was calculated with 80% power and 5% level of significance based on the recently published data to detect statistical difference in the study outcome. Therefore, we plan to recruit total of 575 patients.Convalescent plasma Recipient Group: 115 patients (recipients) who have COVID 19 as per the inclusion criteria.Comparative control Group: 460 Patients who are eitherCOVID 19 historical control or only consent for sharing their clinical and laboratory dataMatching for age, gender, Hypertension, Diabetes and intubation status were done based on the propensity score. Continuous variables will be presented as the median and interquartile range (IQR). Statistical software SPSS 24.0 will be used. Demographic, Clinical, imaging and laboratory information of all enrolled patients will be retrieved from the hospital electronic/paper records system to be used for the outcomes analysis.Results22 sites across KSA that participated in the study. Tertiary, secondary, academic and non-academic centers participated (real world data). There were no unusual safety issues related to convalescent plasma infusion since all mortalities in the plasma group were not related to plasma infusion which represent similar finding from other the published international reports. Keeping in-mind that our data is still maturing, 30 survival probability in the plasma group was 69% compared to 56% in the comparative group (p value = 0.066) (figure-1). This benefit to seem to be more noticeable in the COVID-19 cases who did not meet he criteria for life-threatening disease (figure-2).ConclusionOur study supports the safety of convalescent plasma in treating COVID-19 patients. Patients who are in the category of life-threating/end organs failure do not seem to benefit. There might be a benefit in the other subgroups.

4.
BMJ Open ; 11(4): e047495, 2021 04 14.
Article in English | MEDLINE | ID: covidwho-1186293

ABSTRACT

INTRODUCTION: A novel coronavirus, designated SARS-CoV-2, caused an international outbreak of a respiratory illness, termed COVID-19 in December 2019. There is a lack of specific therapeutic agents based on evidence for this novel coronavirus infection; however, several medications have been evaluated as a potential therapy. Therapy is required to treat symptomatic patients and decrease the virus carriage duration to limit the communitytransmission. METHODS AND ANALYSIS: We hypothesise that patients with mild COVID-19 treated with favipiravir will have a shorter duration of time to virus clearance than the control group. The primary outcome is to evaluate the effect of favipiravir on the timing of the PCR test conversion from positive to negative within 15 days after starting the medicine.Adults (>18 years, men or nonpregnant women, diagnosed with mild COVID-19 within 5 days of disease onset) are being recruited by physicians participating from the Ministry of National Guard Health Affairs and the Ministry of Health ethics committee approved primary healthcare centres. This double-blind, randomised trial comprises three significant parts: screening, treatment and a follow-up period. The treating physician and patients are blinded. Eligible participants are randomised in a 1:1 ratio to either the therapy group (favipiravir) or a control group (placebo) with 1800 mg by mouth two times per day for the first day, followed by 800 mg two times per day for 4-7 days. Serial nasopharyngeal/oropharyngeal swab samples are obtained on day 1 (5 days before therapy). On day5±1 day, 10±1 day, 15±2 days, extra nasopharyngeal/oropharyngeal PCR COVID-19 samples are requested.The primary analysis population for evaluating both the efficacy and safety outcomes will be a modified intention to treat population. Anticipating a 10% dropout rate, we expect to recruit 288 subjects per arm. The results assume that the hazard ratio is constant throughout the study and that the Cox proportional hazard regression is used to analyse the data. ETHICS AND DISSEMINATION: The study was approved by the King Abdullah International Medical Research Centre Institutional Review Board (28 April 2020) and the Ministry of Health Institutional Review Board (1 July 2020). Protocol details and any amendments will be reported to https://clinicaltrials.gov/ct2/show/NCT04464408. The results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: National Clinical Trial Registry (NCT04464408).


Subject(s)
Amides/therapeutic use , COVID-19/drug therapy , Pyrazines/therapeutic use , Adult , Female , Humans , Male , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Treatment Outcome
5.
Genomics ; 113(4): 1733-1741, 2021 07.
Article in English | MEDLINE | ID: covidwho-1171554

ABSTRACT

Interferon-induced membrane proteins (IFITM) 3 gene variants are known risk factor for severe viral diseases. We examined whether IFITM3 variant may underlie the heterogeneous clinical outcomes of SARS-CoV-2 infection-induced COVID-19 in large Arab population. We genotyped 880 Saudi patients; 93.8% were PCR-confirmed SARS-CoV-2 infection, encompassing most COVID-19 phenotypes. Mortality at 90 days was 9.1%. IFITM3-SNP, rs12252-G allele was associated with hospital admission (OR = 1.65 [95% CI; 1.01-2.70], P = 0.04]) and mortality (OR = 2.2 [95% CI; 1.16-4.20], P = 0.01). Patients less than 60 years old had a lower survival probability if they harbor this allele (log-rank test P = 0.002). Plasma levels of IFNγ were significantly lower in a subset of patients with AG/GG genotypes than patients with AA genotype (P = 0.00016). Early identification of these individuals at higher risk of death may inform precision public health response.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease , Membrane Proteins/genetics , RNA-Binding Proteins/genetics , SARS-CoV-2/genetics , Adult , Aged , Aged, 80 and over , COVID-19/mortality , COVID-19/virology , Female , Genetic Association Studies , Genotype , Humans , Interferons/genetics , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , SARS-CoV-2/pathogenicity
6.
Int J Infect Dis ; 105: 448-451, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1103971

ABSTRACT

The 11th KAIMRC Annual Research Forum Themed "COVID-19 Vaccine: Global Challenges and Prospects Forum" discussed COVID19 Vaccines. The Forum was a vital event as it provided a hub for leading COVID-19 vaccine scientists, regulators, developers, and distributors to learn about COVID-19 vaccines in development, make decisions about the best vaccines to use, and develop appropriate plans for global distribution and pricing. The COVID-19: Global Efforts for Development, Clinical Trials and Distribution Symposium brought together leading scientists, clinicians, pharma, decision makers, academic institutions and businesses to present and discuss the vaccines that are being currently developed for the COVID19. This event was held to shed light on these vaccines as many are at the late stage of Phase III clinical trials and ready to be marketed. This follows the confusion that few vaccines were produced and pushed into phase III without sharing all the necessary data preventing the scientific and clinical community to judge its efficacy and safety. This event allowed a discussion into the challenges in the distribution, pricing and accessibility of the vaccines. Moreover, the symposium discussed the importance to invest in Biotech-Pharma to combat and overcome any future health crisis. The discussion focused on Saudi Arabia leading initiatives as front runner in the field among G20 members.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , COVID-19 Vaccines/economics , Costs and Cost Analysis , Delivery of Health Care , Drug Development , Health Services Accessibility , Humans , Practice Guidelines as Topic , SARS-CoV-2 , Saudi Arabia
7.
Saudi J Med Med Sci ; 9(1): 16-23, 2021.
Article in English | MEDLINE | ID: covidwho-1027809

ABSTRACT

OBJECTIVE: To present the interim findings from a national study investigating the safety and efficacy of convalescent plasma (CP) containing detectable IgG antibodies as a treatment strategy for severe coronavirus disease 2019 (COVID-19). TRIAL DESIGN AND PARTICIPANTS: An open label, two-arm, phase-II clinical trial conducted across 22 hospitals from Saudi Arabia. The intervention group included 40 adults (aged ≥18 years) with confirmed severe COVID-19 and the control group included 124 patients matched using propensity score for age, gender, intubation status, and history of diabetes and/or hypertension. Intervention group included those (a) with severe symptoms (dyspnea; respiratory rate, ≥30/min; SpO2, ≤93%, PaO2/FiO2 ratio, <300; and/or lung infiltrates >50% within 24-48 h), (b) requiring intensive care unit (ICU) care or (c) experiencing life-threatening conditions. The control group included confirmed severe COVID-19 patients of similar characteristics who did not consent for CP infusion or were not able to receive CP due to its nonavailability. INTERVENTIONS: The intervention group participants were infused 300 ml (200-400 ml/treatment dose) CP at least once, and if required, daily for up to 5 sessions, along with receiving the best standard of care. The control group only received the best standard of care. OUTCOMES: The primary endpoints were safety and ICU length of stay (LOS). The secondary endpoints included 30-day mortality, days on mechanical ventilation and days to clinical recovery. RESULTS: CP transfusion did not result in any adverse effects. There was no difference in the ICU LOS (median 8 days in both groups). The mortality risk was lower in the CP group: 13% absolute risk reduction (P = 0.147), hazard ratio (95% confidence interval): 0.554 (0.299-1.027; P = 0.061) by log-rank test. There was no significant difference in the days on mechanical ventilation and days to clinical recovery. CONCLUSION: CP containing detectable antibodies is a safe strategy and may result in a decrease in mortality in patients with severe COVID-19. The results of the completed trial with a larger study sample would provide more clarity if this difference in mortality is significant. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04347681; Saudi Clinical Trials Registry No.: 20041102.

8.
JMIR Res Protoc ; 9(10): e23543, 2020 Oct 02.
Article in English | MEDLINE | ID: covidwho-863017

ABSTRACT

BACKGROUND: The COVID-19 pandemic is expected to cause significant morbidity and mortality. The development of an effective vaccine will take several months to become available, and its affordability is unpredictable. Transfusion of convalescent plasma (CP) may provide passive immunity. Based on initial data from China, a group of hematologists, infectious disease specialists, and intensivists drafted this protocol in March 2020. OBJECTIVE: The aim of this study is to test the feasibility, safety, and efficacy of CP in treating patients with COVID-19 across Saudi Arabia. METHODS: Eligible patients with COVID-19 will be recruited for CP infusion according to the inclusion criteria. As COVID-19 has proven to be a moving target as far as its management is concerned, we will use current definitions according to the Ministry of Health (MOH) guidelines for diagnosis, treatment, and recovery. All CP recipients will receive supportive management including all available recommended therapies according to the available MOH guidelines. Eligible CP donors will be patients with COVID-19 who have fully recovered from their disease according to MOH recovery criteria as detailed in the inclusion criteria. CP donors have to qualify as blood donors according to MOH regulations except for the history of COVID-19 in the recent past. We will also test the CP donors for the presence of SARS-CoV-2 antibodies by a rapid test, and aliquots will be archived for future antibody titration. Due to the perceived benefit of CP, randomization was not considered. However, we will compare the outcome of the cohort treated with CP with those who did not receive CP due to a lack of consent or lack of availability. In this national collaborative study, there is a likelihood of not finding exactly matched control group patients. Hence, we plan to perform a propensity score matching of the CP recipients with the comparator group patients for the major characteristics. We plan to collect demographic, clinical, and laboratory characteristics of both groups and compare the outcomes. A total sample size of 575 patients, 115 CP recipients and 460 matched controls (1:4 ratio), will be sufficient to detect a clinically important hospital stay and 30-day mortality difference between the two groups with 80% power and a 5% level of significance. RESULTS: At present, patient recruitment is still ongoing, and the interim analysis of the first 40 patients will be shared soon. CONCLUSIONS: In this paper, we present a protocol for a national collaborative multicenter phase II study in Saudi Arabia for assessing the feasibility, safety, and potential efficacy of CP in treating patients with severe COVID-19. We plan to publish an interim report of the first 40 CP recipients and their matched comparators soon. TRIAL REGISTRATION: ClinicalTrials.gov NCT04347681; https://clinicaltrials.gov/ct2/show/NCT04347681. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/23543.

9.
J Infect Public Health ; 13(10): 1544-1550, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-633894

ABSTRACT

BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV) has continued to cause sporadic outbreaks of severe respiratory tract infection over the last 8 years. METHODS: Complete genome sequencing using next-generation sequencing was performed for MERS-CoV isolates from cases that occurred in Riyadh between 2015 and 2019. Phylogenetic analysis and molecular mutational analysis were carried out to investigate disease severity. RESULTS: A total of eight MERS-CoV isolates were subjected to complete genome sequencing. Phylogenetic analysis resulted in the assembly of 7/8 sequences within lineage 3 and one sequence within lineage 4 showing complex genomic recombination. The isolates contained a variety of unique amino acid substitutions in ORF1ab (41), the N protein (10), the S protein (9) and ORF4b (5). CONCLUSION: Our study shows that MERS-CoV is evolving. The emergence of new variants carries the potential for increased virulence and could impose a challenge to the global health system. We recommend the sequencing every new MERS-CoV isolate to observe the changes in the virus and relate them to clinical outcomes.


Subject(s)
Coronavirus Infections/virology , Middle East Respiratory Syndrome Coronavirus/genetics , Mutation , RNA, Viral/analysis , Adult , Aged , Amino Acids/genetics , Coronavirus Nucleocapsid Proteins , Female , Humans , Male , Middle Aged , Nucleocapsid Proteins/genetics , Phylogeny , Saudi Arabia , Virulence/genetics , Whole Genome Sequencing
10.
Clin Lymphoma Myeloma Leuk ; 21(1): e66-e75, 2021 01.
Article in English | MEDLINE | ID: covidwho-718689

ABSTRACT

Histiocytic disorders are an exceptionally rare group of diseases with diverse manifestations and a paucity of approved treatments, thereby leading to various challenges in their diagnosis and management. With the discovery of novel molecular targets and the incorporation of targeted agents in the management of various adult histiocytic disorders, their management has become increasingly complex. In an attempt to improve the understanding of the clinical features and management of common adult histiocytic disorders (Langerhans cell histiocytosis, Erdheim-Chester disease, Rosai-Dorfman disease, and hemophagocytic lymphohistiocytosis), we created this document based on existing literature and expert opinion.


Subject(s)
Erdheim-Chester Disease/drug therapy , Histiocytosis, Langerhans-Cell/drug therapy , Histiocytosis, Sinus/drug therapy , Lymphohistiocytosis, Hemophagocytic/drug therapy , Adult , Drug Therapy, Combination , Erdheim-Chester Disease/diagnosis , Histiocytosis, Langerhans-Cell/diagnosis , Histiocytosis, Sinus/diagnosis , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Treatment Outcome
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