Aerosol Combination Therapy of All-trans Retinoic Acid and Isotretinoin as A Novel Treatment for Inducing Neutralizing Antibodies in COVID -19 Infected Patients Better Than Vaccine : An Innovative Treatment
试验速览
- 阶段
- 2 期
- 入组人数
- 360
- 主要终点
- lung injury score
研究概览
简要总结
Aerosol Combination therapy of All-trans retinoic acid and Isotretinoin as A novel Treatment for Inducing Neutralizing Antibodies in COVID -19 Infected Patients better than vaccine : An innovative Treatment
Mahmoud ELkazzaz(1),Tamer Haydara(2), Mohamed Abdelaal(3), Ahmed M. Kabel(4), Abedelaziz Elsayed(5) ,Yousry Abo-amer(6) ,Hesham Attia(7)
- 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 Clinical Pharmacy, Faculty of Medicine , Tanta 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.
- Study Chair ((( Dr.Tamer Hydara))), Department of Internal Medicine,Faculty of Medicine, Kafrelsheikh University, Egypt Contact: Dr.Tamer Hydara-Tel: 00201142233340 Mail: tamerhydara@yahoo.com
- Principal Investigator ((( Mahmoud Elkazzaz))), Faculty of Science, Damietta University,GOEIC,Egypt Contact:Tel: 00201090302015 Mail: mahmoudramadan2051@yahoo.com
- Study coordinator ((Prof/Dr Mohamed Abdelaal)), Department of Cardiothoracic Surgery,Faculty of Medicine, Kafrelsheikh University, Egypt Contact:Tel: 00201001422577 Mail: Malaal2@hotmail.com
Abstract
The pandemic of COVID-19 which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has infected over 20,000,000 people causing over 700,000 deaths .It has no currently approved treatments. In this clinical study we confirm that combination of isotretinoin and All trans retinoic acid can be used in the treatment of SARS-COV-2 better than vaccine according to the findings of previous studies and researches. Retenoic acid can induce neutralizing antibodies in case of corona virus (COVID-19) by restoring inhebited and exhausted T cells via inhebiting both CD13 and Angiotensin-converting enzyme-2 (ACE2). CD13 amyloid receptor which abundantly overexpressed on cell surface of lymphocyte, Dentritic cell, Macrophage, granulocytes and monocytes and is ubiquitous in respiratory tract epithelial cells, smooth muscle cells, fibroblasts, epithelial cells in the kidneys and small intestine, activated endothelial cells, and platelets In addition inhibing 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 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.Butisotretinoin was found to be the strongest down-regulator of ACE 2 receptors.and this will give hope for diabetic patients or patients with hypertension infected with COVID-19.Therefore we suggest that Retinoic Acid will help in inhabiting factors which may enhance antibody dependent enhancement (ADE), A phenomenon caused by covid-19 which expected to lead to failure of vaccination specially in case of corona virus (covid-19) as a hyper mutatated COVID-19 antigens can lead to (ADE) phenomenon in which IgG antibodies facilitate viral entry and fusion with infected cell through uptake of the virus-IgG complex via the Fc receptors and later viral fusion with antigen presenting cells like Dentric cells, macrophages and B cells via FcR , through the neonatal FcR instead of antibodies induced viral agglutination and this is known as antibody dependent enhancement (ADE)(2) ADE can hamper vaccine development, as a vaccine may cause the production of antibodies which, via ADE, worsen the disease the vaccine is designed to protect against. ADE in COVID-19 infection can be caused by high mutation rate of the gene that encodes spike (S) protein. In this clinical study we suggest that Hyper mutated spike protein ,lymphopenia, and impaired dentreic cells all these factors can help in and lead to delayed antibodies response and appearing after a period of covid -19 symptoms onset and this may be responsible for antibody dependent enhancement (ADE)
Keywords: COVID 2019 , Retinoic acid, Lymphopenia ,T Cells, Dentric cells , ADE, Vaccine
详细描述
This is a Phase 2, , randomized (1:1:1), placebo-controlled, 2-weeks, proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic effect of oral administration of potent inhibitor of neutrophil elastase(Inhaled All trans retinoic acid and inhaled isotretinoin in subjects infected with COVID -19
Unfortunately, all of the vaccinated monkeys treated with the Oxford vaccine known as ChAdOx1 nCoV-19, is undergoing human trials in Britain.became infected when challenged as judged by recovery of virus genomic RNA from nasal secretions," said Dr William Haseltine, a former Harvard Medical School professor who had a pivotal role in the development of early HIV/Aids treatments. and in general future COVID-19 vaccination which depends on inactivated viral vaccine will be restricted to healthy people with strong immunity and It will not be given to patients with History of contact with a SARS-CoV-2 infection (positive in nucleic acid test). In addition to the COVID-19 viral antigens lead to stimulate antibodies formation of IgM in acute phase and IgG type in chronic phase which is facilitate viral entry and fusion with infected cell through uptake of the virus-IgG complex via the Fc family of receptors and later viral fusion with antigen presenting cells like macrophages, B cells, monocytes via FcR family, and vascular endothelium through the neonatal Fc receptor (nFcR) instead of antibodies induced viral agglutination and this is known as antibody dependent enhancement (ADE)(2).
There are various hypotheses on how ADE happens and there is a likelihood that more than one mechanism exists. In one such pathway, some cells of the immune system lack the usual receptors on their surfaces that the virus uses to gain entry, but they have Fc receptors that bind to one end of antibodies. The virus binds to the antigen-binding site at the other end, and in this way gains entry to and infects the immune cell. Dengue virus can use this mechanism to infect human macrophages, if there was a preceding infection with a different strain of the virus, causing a normally mild viral infection to become life-threatening.(3) An ongoing question in the COVID-19 pandemic is whether-and if so, to what extent-COVID-19 receives ADE from prior infection with other coronaviruses.
ADE can hamper vaccine development: ADE can hamper vaccine development, as a vaccine may cause the production of antibodies which, via ADE, worsen the disease the vaccine is designed to protect against. Vaccine candidates for Dengue virus and feline infectious peritonitis virus (a cat coronavirus) had to be stopped because they elicited ADE.(4)
ADE in coronavirus infection can be caused by high mutation rate of the gene that encodes spike (S) protein. A thorough analysis of amino acid variability in SARS-CoV-2 virus proteins, that included the S-protein, revealed that least conservative amino acids are in most exposed fragments of S-protein including receptor binding domain (RBD).(5) Delayed antibodies response and secretion after covid -19 symptoms onset is responsible for antibody dependent enhancement (ADE)
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
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
- •The competent physician considered it inappropriate to participate in the study
- •HIV infection or other immunodeficiency or with an absolute neutrophil count ≤1.0 × 109/L
- •Abnormal liver biochemistry (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase) >1.5 × upper limit of normal or total bilirubin > upper limit of normal (unless Gilbert's disease with normal conjugated bilirubin)
- •Any of the following laboratory abnormalities are present at baseline:
- •Platelet count <150×109/L
- •Serum albumin ≤ 3.5 g/dL
- •CPK ≥ ULN.
- •Significant liver fibrosis as evidenced by Fibrosis-4 (FIB-4) score >3.25
- •History of hypersensitivity to retinoic acid or any of its excipients or the class of neutrophil elastase inhibitors Known hypersensitivity to medications used in the study procedures (e.g. midazolam, fentanyl, and lidocaine for bronchoscopy)
研究组 & 干预措施
Aerosolized 13 cis retinoic acid
COVID 19 infected patients will receive one dose daily of Aerosolized 13 cis retinoic acid in gradual 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)
All trans retinoic acid
COVID 19 infected patients will receive one dose daily of Aerosolized All trans retinoic acid in gradual doses increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled All trans retinoic acid therapy for 14 days
干预措施: Aerosolized All trans retinoic acid (Drug)
Placebo Comparator
4 Placebo tablets twice daily by mouth for 2 weeks
干预措施: Placebo (Other)
结局指标
主要结局
lung injury score
时间窗: at 7 days
Proportion of lung injury score decreased or increased after treatment
次要结局
- The immune correlates of protection against future exposure to SARS-CoV-2(within 14 days)
- Occurrence of adverse event related to immunoglobulins(at day 14)
- Ventilation free days(at 14 days)
- Total duration of mechanical ventilation, ventilatory weaning and curarisation(at day 7 and 14)
- ACE2 expression in patients with COVID-19 infection(at day 7 and 14)
- Serum levels of CRP, ESR ,IL-1,IL-6,TNF and Type I interferon(at day 7 and 14 after randimization)
- d-dimers(within 14 days)
- Serum level of COVID19 RNA(at day 7 and 14)
- Immunological profile(within 14 days)
- Absolute lymphocyte counts(at day 7 and 14 after randimization)
- IgG, IgA and IgM against COVID-19(at day 7 and 14)
- All cause mortality rate [(at day 7 and 14)
- ICU free days(at 14 days)
研究者
Mahmoud Ramadan mohamed Elkazzaz
Principal Investigator
Damietta University