Isotretinoin in Treatment of COVID-19 (Randomized)
试验速览
- 阶段
- 3 期
- 入组人数
- 100,000
- 试验地点
- 1
- 主要终点
- lung injury score
研究概览
简要总结
Assessment the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the Treatment of COVID-19
Mahmoud ELkazzaz(1),Tamer Haydara(2), Mohamed Abdelaal(3), Abedelaziz Elsayed(4) ,Yousry Abo-amer(5), Hesham Attia(6), Quan Liu(7)' Tim Duong(8) and Heba Sahyon(9)
- Department of chemistry and biochemistry, Faculty of Science, Damietta University, Egypt.
- Department of Internal Medicine, Faculty of Medicine, Kafrelsheikh University, Egypt
- Department of Cardiothoracic Surgery, Faculty of Medicine, Kafrelsheikh University, Egypt
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tanta University, Egypt.
- Hepatology,Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Egypt
- Department of Immunology and Parasitology, Faculty of Science, Cairo University, Egypt.
- School of Life Sciences and Engineering, Foshan University, Laboratory of Emerging Infectious Disease, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
- Montefiore Health System and Albert Einstein College of Medicine, New York, United States of America.
- Chemistry Department, Faculty of Science, Kafrelsheikh University, Egypt.
- This clinical study is the first clinical study in literature (submitted on 20 April, 2020) which demonstrated that Isotretinoin will provide complete protection against COVID-19
Abstract
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths over the world, and it is still expanding. There is an urgent need for targeted and effective COVID-19 treatments which has put great pressure on researchers across the world for developing effective drugs. In this clinical study we attempt to demonstrate Isotretinoin could be an effective and promising treatment for SARS-CoV-2 based on the intracellular mechanism of SARS-CoV-2 transmission and consequences caused. Isotretinoin could strongly inhibit both inflammation and viral entry in severe acute respiratory syndrome coronavirus 2 infection via decreasing the overproduction of early response proinflammatory cytokines (interleukin-6 ) which are over expressed in COVID-19 and contributed to disease progression, poor outcomes, vascular hyper permeability and multiorgan failure in patients infected with COVID-19. It could also block the entry of COVID-19 by inhibiting androgenic factors that induce serine 2 transmembrane protease (TMPRSS2) expressions.. In addition to inhibiting of Angiotensin-converting enzyme-2 (ACE2), Angiotensin T1 protein and Angiotensin II-mediated intracellular calcium release pathway which is responsible for COVID-19 cell fusion and entry, ACE2-expressing cells are prone to SARS-CoV-2 infection as ACE2 receptor facilitates cellular viral entry and invasion. Moreover, isotretinoin is a potential repressor and inhibitor of papain-like protease (PLpro), which is a lethal protein expressed by COVID-19 genes and is an enzyme of dubiquitination which facilitates virus replication in patients with COVID-19.The genome of Middle East Respiratory Syndrome Coronavirus is recognized by melanoma differentiation-associated protein-5 (MDA5), retinoic acid inducible gene-1 (RIG-1) and endosomal toll-like receptor 3 (TLR3) as pathogen-associated molecular patterns. This recognition resulted in the formation of type-1 interferon (IFN1). As an evasion mechanism, virus synthesize proteins that hinder the production IFN1 in the pathway. 13-cis retinoic acid induced significant upregulation of toll-like receptor 3 (TLR3), mitochondrial antiviral-signaling protein (MAVS) and IFN regulatory factor 1 expression in a time-dependent. Furthermore, 13 cis Retinoic Acid (13 cis RA) could be an effective and promising treatment for SARS-CoV-2 owing to its ability to increase CD4 cells and induce mucosal IgA antibodies that are less prone to Antibody Dependent Enhancement process (ADE) and responsible for passive mucosal immunity in the respiratory tract. ADE is a phenomenon in which antiviral antibodies facilitate viral infection of target immune cells and, in some cases, make a second infection worse, such as dengue fever (dengue virus), By inducing IgA antibodies, 13 cis retinoic acid enhances mucosal immunity and is known to be a potent IgA isotype.13 Cis retinoic acid induced significant upregulation of toll-like receptor 3 an immune boosting action that may result in an immune response to dsRNA intermediate leading to the production of type I IFNs which is important to enhance the release of antiviral proteins for the protection of uninfected cells. Isotretinoin therapy has furthermore proven anti-platelet and fibrinolytic activities which may protect patients infected with covid-19 from widespread blood clots. From this point, we suggest that isotretinon will be the Immunity passport" in the context of COVID-19
详细描述
The study is a randomized interventional comparative Phase III trial. 10000 adult male and female patients with positive COVID-19 diagnosis and fulfilling the below outlined inclusion criteria will be enrolled into the study.
Isotretinoin(13cis RA) may be able to inhibit COVID 2019 entry via down regulation of ACE2 , AT1 protein and Ang II-mediated intracellular calcium release rather than inhibition of interleukin-6 (IL-6) and this is discussed as follow :
The COVID-19 pandemic caused by SARS-COV-2 has infected over 2,000,000 people causing over 150,000 deaths. A key host cellular protein required for the virus entry is angiotensin-converting enzyme 2 (ACE2) whose expression has been demonstrated in many tissues including alveolar epithelial type II cells in lungs, oral mucosa ,intestine, heart, kidney, endothelium and skin. ACE2-expressing cells can act as home cells and are prone to SARS-CoV-2 infection as ACE2 receptor facilitates cellular viral entry and replication. A study demonestrated that patients with hypertension and diabetes mellitus may be at higher risk of SARS-CoV-2 infection, as these patients are often treated with ACE inhibitors (ACEIs) or angiotensin II type-I receptor blockers (ARBs), which have been previously suggested to increase ACE2 expression. In another study by Sinha et al who analyzed a publicly available Connectivity Map (CMAP) dataset of pre/post transcriptomic profiles for drug treatment in cell lines for over 20,000 small molecules, isotretinoin was the strongest down-regulator of ACE 2 receptors. On the other hand, they found 6 drugs in CMAP that are currently being investigated in clinical trials for treating COVID-19 (chloroquine, thalidomide, methylprednisolone, losartan, lopinavir and ritonavir, from clinicaltrials.gov), none of which was found to significantly alter ACE2 expression (P>0.1) Moreover, another study demonstrated that isotretinoin is a potential papain like protease (PLpro) inhibitor which is a protein encoded by SARS-CoV-2 genes and considered one of the proteins that should be targeted in COVID-19 treatment by performing target-based virtual ligand screening.
Previous studies on the related severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV FP FP have shown that calcium (Ca2+) plays an important role for fusogenic activity via a Ca2+ binding pocket with conserved glutamic acid (E) and aspartic acid (D) residuesdemonstrated that intracellular Ca2+ enhances MERS-CoV WT PPs infection by approximately two-fold and that E891 is a crucial residue for Ca2+interaction. Electron spin resonance revealed that this enhancement could be attributed to Ca2+ increasing MERS-CoV FP fusion-relevant membrane ordering. Intriguingly, isothermal calorimetry titration showed that MERS-CoV FP binds one Ca2+, as opposed to SARS-CoV FP which binds to two Ca2+ ion.
Angiotensin II increases the intracellular calcium activity in podocytes of the intact glomerulus. The L-type Ca2+ channel blocker nicardipine did not influence the Ang II-mediated [Ca2+] increase and it has been postulated that SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity, skewing the ACE/ACE2 balance to a state of heightened angiotensin II activity leading to pulmonary vasoconstriction and inflammatory and oxidative organ damage, which increases the risk for acute lung injury (ALI). AngII via AT1 receptors upregulates many proinflammatory genes, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6).30 but 13cis RA specifically down-regulated the AT1 protein in a dose- and time-dependent manner. Down-regulation of the AT1 expression leads to reduced AngII-mediated intracellular calcium release Similarly with receptor down-regulation, Treatment with 13cRA resulted in a significant reduction in AT1 mRNA .13cRA has a glucose- and RAR/RXR independent mechanism for transcriptional inhibition of AT1,
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult SARI patients with 2019-ncov infection confirmed by PCR; Absolute value of lymphocytes <
- •6x 109/L; Severe respiratory failure within 48 hours and requires admission to ICU. (severe respiratory failure was defined as PaO2/FiO2 < 200 mmHg and was supported by positive pressure mechanical ventilation (including non-invasive and invasive mechanical ventilation, PEEP>=5cmH2O))
排除标准
- •Age < 18 Pregnant Allergic to experimental drugs and patients have the following conditions:
- •Hypercholesterolemia
- •Hypertriglyceridemia
- •Liver disease
- •Renal disease
- •Sjögren syndrome
- •Depressive disorder
- •Body mass index less than 18 points or higher than 25 points
- •Contraindications for hormonal contraception or intrauterine device.
- •Autoimmune diseases A history of organ, bone marrow or hematopoietic stem cell transplantation
- •Patients receiving anti-hcv treatment
- •Permanent blindness in one eye
- •History of iritis, endophthalmitis, scleral inflammation or retinitis 15-90 days of retinal detachment or eye surgery
- •16-The competent physician considered it inappropriate to participate in the study
- •-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
- •Safety and promising features of isotretinoin in tne era of COVID 2019 according Principal Investigator Protocol:
- •This medication have the feature of Aerosolized Drug Delivery to increase its efficacy beside Oral administration, Which makes it distinct from other medication in which should dose be only given orally. A study demonstrated that treating with 13 cis retinoic acid aerosolized via inhalation rout did not cause any damage in lung cells.
- •Repeated high doses of 13 cis retinoic by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lung.
- •Inhaled isotretinoin might provide sufficient drug to the target cells for efficacy while avoiding systemic toxicity.
- •A study demonstrated that 13 cis retinoic is used in treating Emphysema (emphysema is a lung condition that causes shortness of breath)
- •RA has been reported to induce formation of new alveoli and returns elastic recoil in the lung to approximately normal values in animal models of emphysema.
- •Strong expectation of complete COVID -19 blockade from cell entry and infection depending on strong ethics, researches and references.
- •Availability of our compounds.
- •Ease of application.
- •Expectation of COVID -19 treating by isotretinoin via more than one distinct mechanism.
- •Expectation of High induction of anti- inflammatory T cells and significant inhibition of IL-6 at low concentrations of isotretinoin.
- •Controlling Accompanying cytokine storm.
- •No interactions with Egyptian protocol drugs were found.
- •(13- cis -Retinoic acid ) can be given in the form of aerosol to avoid these systemic side effects. A clinical trial conducted on 148 subject from 5 university hospitals to evaluate the possibility of retinoids in the treatment of emphysema. The patients, were randomized to receive 13-cis retinoic acid (1 mg/kg/day, daily or ATRA at either low dose (1 mg/kg/day for 4 days/wk) or high dose (2 mg/kg/day for 4 days/wk), placebo for six months, followed by a three-month crossover phase. then, they were observed for an additional nine months before the final evaluation. In the trial, retinoids(13 cis retinoic acid ) were proven to be safe as the drug-related AEs were generally mild[188]. A study reported that the application of aerosolized RA system led to a rise of RA levels in lung, but not plasma. or liver. In lung concentration and levels of retinol, retinyl palmitate and retinyl stearate also showed to be unchanged [189] A study on rabbits demonstrated that 13 cis retinoic acid can be given in the form of aerosol without serious side effects In this study repeated elevated doses of 13 cis retinoic acid by inhalation caused moderate loss of body weight, but microscopic examination of ten tissues including oesophagus and lung did not found any significant inhalation-induced injury or damage therefore aerosolized 13 cis retinoic acid might provide sufficient therapy to the target cells in lung for efficacy while avoiding systemic toxicity © 2000 Cancer Research Campaign[190]
研究组 & 干预措施
13 cis retinoic acid doses orally plus the standard therapy
Arm 1: infected patients will receive the standard therapy for COVID-19 (Paracetamol 500 mg /6h, Hydroxychloroquine 500 mg/ 12h, Oseltamivir 150 mg /12 h for 5 days, Azithromycin 1 gm first day then 500 mg/day for 1st line or Clarithromycin 500 mg/12 h for 7-14 days, Ascorbic acid 500 mg/12 h and Cyanocobalamin IV once daily plus Lopinavir 400mg/Ritonavir 100 mg caps 2 capsules twice daily in severe cases) and after three days of the standard therapy the infected patients will receive 13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days combined with the standard therapy . All subjects were encouraged to complete the full course of treatment and common side effects were explained. Side effects and compliance will be documented.
干预措施: Drug Isotretinoin (13 cis retinoic acid ) capsules+standard treatment (Drug)
Aerosolized 13 cis retinoic acid plus the standard therapy
Arm 2: infected patients will receive the standard therapy for COVID-19 (Paracetamol 500 mg /6h, Hydroxychloroquine 500 mg/ 12h, Oseltamivir 150 mg /12 h for 5 days, Azithromycin 1 gm first day then 500 mg/day for 1st line or Clarithromycin 500 mg/12 h for 7-14 days, Ascorbic acid 500 mg/12 h and Cyanocobalamin IV once daily plus Lopinavir 400mg/Ritonavir 100 mg caps 2 capsules twice daily in severe cases) and after three days of the standard therapy the infected patients will receive Aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days
干预措施: Isotretinoin(Aerosolized 13 cis retinoic acid) +standard treatment (Drug)
13 cis retinoic acid doses orally
Infected patients will receive 13 cis retinoic acid (0.5 mg/kg/day in 2 divided doses orally for 14 days
干预措施: Isotretinoin (13 cis retinoic acid ) capsules (Drug)
Aerosolized 13 cis retinoic acid
The infected patients will receive Aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days
干预措施: Aerosolized 13 cis retinoic acid (Drug)
The standard therapy
Arm 3:infected patients will receive the standard therapy for COVID-19 for 14 days
干预措施: Standard treatment (Drug)
结局指标
主要结局
lung injury score
时间窗: at 7and 14 days
Proportion of lung injury score decreased or increased after treatment
次要结局
- Thrombin time (TT)(at day 7 and 14)
- Dihydrotestosterone(DHT) levels changes over time(at day 7 and 14)
- Serum levels of IL-6,TNF,TLR3,CRP, ESR and Type I interferon(at day 7 and 14 after randimization)
- Absolute lymphocyte counts (CD4,CD8 and CD25+FOXP3+ Regulatory T)(at day 7 and 14 after randimization)
- Serum level of COVID19 RNA(at day 7 and 14)
- All cause mortality rate(at day 7 and 14)
- d-dimers(at 3-5days)
- Ventilation free days(at 14 days)
- ICU free days(at 14 days)
- Time to first negative SARS-CoV-2 PCR in NP swap(within 14 days)
- Angiotensin 1-7 (Ang 1-7) changes over time(at day 7 and 14)
- Angiotensin 1-5 (Ang 1-5) changes over time(at day 7 and 14)
- Renin changes over time(at day 7 and 14)
- Aldosterone changes over time(at day 7 and 14)
- Angiotensin-converting enzyme II (ACE2) changes over time(at day 7 and 14)
- Angiotensin II (Ang II) changes over time(at day 7 and 14)
- Sequential organ failure assessment score(SOFA score) over time(at day 7 and 14)
- Transe membrane protease ,serine II (TMPRSS2) changes over time(at day 7 and 14)
- Frequency of adverse events and severe adverse events(14 days)
- Cholesterol levels changes over time(at day 7 and 14)
- Testosterone levels changes over time(at day 7 and 14)
- Melanoma differentiation-associated protein-5, retinoic acid inducible gene-1 (RIG-1)(at day 7 and 14)
- IgA antibodies(at day 7 and 14)
研究者
Mahmoud Ramadan mohamed Elkazzaz
Sponser Investigator
Kafrelsheikh University