Clinical trial NCT04619290: Outpatient Treatment With CoVid-19 With Prexablu
Official title: Treatment in Outpatient Patients With Covid-19 With Methylene Blue and Photodynamic
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Sars Cov 2
Keywords: COVID-19
methylene blue
photodynamic interval therapy
outpatient
Mexico
Lead sponsor: Hospital Reg. Lic. Adolfo Lopez Mateos
Sponsor class: OTHER_GOV
First posted: 2020-11-06
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single group comparison with contemporaneous conventionally treated patients.
Primary purpose: TREATMENT

Brief summary: Within the epidemic context of phase 3 in Mexico, the implementation of new treatments that have been shown to be beneficial for patients in other countries is an urgent need. Methylene blue (MB, the oxidized form, blue color) has been used in many different clinical medicine areas, ranging from malaria to orthopedics. Methylene blue absorbs energy directly from a light source and then transfers this energy to molecules of oxygen creating singlet oxygen (O2), which is the first electronic excited state of molecular oxygen (O2). Singlet oxygen is extremely electrophilic; thus, it can directly oxidize electron-rich double bonds in biological molecules and macromolecules. For this reason, methylene blue has been used as a photosensitizer in the treatment of cancer and the protection of serum from viral agents. Methylene blue can be reactivated using energy from a light source in the body until processed out through the kidneys.

Detailed description: Patients diagnosed with COVID-19 and confirmed positive with the virus by PCR will be treated with Prexablu for seven days. The administration is Sublingual 1 ml Prexablu once a day and PDT for 1 hour daily x 7 days. Days to clinical improvement to be evaluated for seven days considering temperature and other vital signs measurement, arterial oxygen saturation.

I. On day one and day seven a blood sample will be drawn to assess chemistry (including liver function tests), C reactive protein, IgG, IgM, IL-6, erythrocyte sedimentation rates like procalcitonin, ferritin levels, and the D dimer II. Daily PCR Swabs measuring cycle threshold (CT) will be collected (days 1 - 7) III. Daily 1ml Prexablu will be placed sublingual

1. Prexablu activated for 10 minutes with Low Level Light Therapy (670 nm light) before being placed sublingually.
2. Low Level Light Therapy (NocUlite device) will be placed on wrist for 50 minutes.

Eligibility criteria: Inclusion Criteria:

* Patients over 18 years of age
* Of both sexes
* Confirmed case of Covid-19 (by RT-PCR) and CT less than 32 in the E
* That they go to the ER service due to COVID symptoms, and that they voluntarily agree to participate in the study by written the informed consent
* With at least 1 of the following symptoms: fever, headache, nausea, dyspnea, myalgia, vomiting, or diarrhea
* With chest X-ray without pneumonia criteria
* With SO2\> 90
* No history of allergic reaction to methylene blue
* No history of treatment with medication with methylene blue negative interaction

Exclusion Criteria:

* Pregnancy and breastfeeding
* Preadmission anticoagulation
* Severe renal insufficiency (glomerular filtration rate \<30 mL/min/1.73m2)
* Active chronic hepatitis
* Patients with history of allergic reaction or significant sensitivity to methylene blue
* Treatment with immunosuppressive agents
* Diagnosis of cancer at any stage and of any type.
* Pregnancy and breastfeeding
* Patients who plan to become pregnant during the study period or within 6 months after the end of the study period.
* Participation in another clinical trial with an experimental drug in the last 30 days.
* Other pathologies that, in the medical opinion, contraindicate participation in the study.
* Uncompensated comorbidities

Primary outcomes:
measure: Change form baseline in Arterial oxygen saturation
timeFrame: up to 7 days
measure: Days to clinical improvement
timeFrame: up to 7 days
Secondary outcomes:
measure: Change Form Baseline in C reactive protein at 7 days
timeFrame: up to 7 days
measure: Change Form Baseline in IL-1β
timeFrame: up to 7 days
measure: Change Form Baseline in Erythrocyte sedimentation rate like procalcitonin
timeFrame: up to 7 days
measure: Change Form Baseline in Ferritin levels
timeFrame: up to 7 days
measure: Change Form Baseline in D dimer
timeFrame: up to 7 days
Other outcomes:
Locations:
city: Mexico City
country: Mexico
facility: Hospital Regional Lic Adolfo Lopez Mateos
state: Ciudad De Mexico CDMX (Mexico City)
Study officials:
References:
citation: Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Apr 7;323(13):1239-1242. doi: 10.1001/jama.2020.2648. No abstract available.
citation: Ji W, Wang W, Zhao X, Zai J, Li X. Cross-species transmission of the newly identified coronavirus 2019-nCoV. J Med Virol. 2020 Apr;92(4):433-440. doi: 10.1002/jmv.25682.
citation: Baud D, Qi X, Nielsen-Saines K, Musso D, Pomar L, Favre G. Real estimates of mortality following COVID-19 infection. Lancet Infect Dis. 2020 Jul;20(7):773. doi: 10.1016/S1473-3099(20)30195-X. Epub 2020 Mar 12. No abstract available.
citation: Backer JA, Klinkenberg D, Wallinga J. Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020. Euro Surveill. 2020 Feb;25(5):2000062. doi: 10.2807/1560-7917.ES.2020.25.5.2000062.
citation: Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020 May 12;323(18):1843-1844. doi: 10.1001/jama.2020.3786.
citation: Oz M, Lorke DE, Hasan M, Petroianu GA. Cellular and molecular actions of Methylene Blue in the nervous system. Med Res Rev. 2011 Jan;31(1):93-117. doi: 10.1002/med.20177.
citation: Bradberry SM. Occupational methaemoglobinaemia. Mechanisms of production, features, diagnosis and management including the use of methylene blue. Toxicol Rev. 2003;22(1):13-27. doi: 10.2165/00139709-200322010-00003.
citation: Barbosa P, Peters TM. The effects of vital dyes on living organisms with special reference to methylene blue and neutral red. Histochem J. 1971 Jan;3(1):71-93. doi: 10.1007/BF01686508. No abstract available.
citation: Wainwright M, Crossley KB. Methylene Blue--a therapeutic dye for all seasons? J Chemother. 2002 Oct;14(5):431-43. doi: 10.1179/joc.2002.14.5.431.
citation: Lee SK, Mills A. Novel photochemistry of leuco-Methylene Blue. Chem Commun (Camb). 2003 Sep 21;(18):2366-7. doi: 10.1039/b307228b.
citation: Khan S, Alam F, Azam A, Khan AU. Gold nanoparticles enhance methylene blue-induced photodynamic therapy: a novel therapeutic approach to inhibit Candida albicans biofilm. Int J Nanomedicine. 2012;7:3245-57. doi: 10.2147/IJN.S31219. Epub 2012 Jun 29.
citation: Wainwright M. Methylene blue derivatives--suitable photoantimicrobials for blood product disinfection? Int J Antimicrob Agents. 2000 Dec;16(4):381-94. doi: 10.1016/s0924-8579(00)00207-7.
citation: Tardivo JP, Del Giglio A, de Oliveira CS, Gabrielli DS, Junqueira HC, Tada DB, Severino D, de Fatima Turchiello R, Baptista MS. Methylene blue in photodynamic therapy: From basic mechanisms to clinical applications. Photodiagnosis Photodyn Ther. 2005 Sep;2(3):175-91. doi: 10.1016/S1572-1000(05)00097-9. Epub 2005 Nov 21.
citation: Tuite EM, Kelly JM. Photochemical interactions of methylene blue and analogues with DNA and other biological substrates. J Photochem Photobiol B. 1993 Dec;21(2-3):103-24. doi: 10.1016/1011-1344(93)80173-7.
citation: Eickmann M, Gravemann U, Handke W, Tolksdorf F, Reichenberg S, Muller TH, Seltsam A. Inactivation of Ebola virus and Middle East respiratory syndrome coronavirus in platelet concentrates and plasma by ultraviolet C light and methylene blue plus visible light, respectively. Transfusion. 2018 Sep;58(9):2202-2207. doi: 10.1111/trf.14652. Epub 2018 May 6.
citation: Chatterjee GC, Noltmann EA. Dye-sensitized photooxidation as a tool for the elucidation of critical amino acid residues in phosphoglucose isomerase. Eur J Biochem. 1967 Jul;2(1):9-18. doi: 10.1111/j.1432-1033.1967.tb00098.x. No abstract available.
citation: Triesscheijn M, Baas P, Schellens JH, Stewart FA. Photodynamic therapy in oncology. Oncologist. 2006 Oct;11(9):1034-44. doi: 10.1634/theoncologist.11-9-1034.
citation: Faddy HM, Fryk JJ, Hall RA, Young PR, Reichenberg S, Tolksdorf F, Sumian C, Gravemann U, Seltsam A, Marks DC. Inactivation of yellow fever virus in plasma after treatment with methylene blue and visible light and in platelet concentrates following treatment with ultraviolet C light. Transfusion. 2019 Jul;59(7):2223-2227. doi: 10.1111/trf.15332. Epub 2019 May 3.
citation: Fryk JJ, Marks DC, Hobson-Peters J, Watterson D, Hall RA, Young PR, Reichenberg S, Tolksdorf F, Sumian C, Gravemann U, Seltsam A, Faddy HM. Reduction of Zika virus infectivity in platelet concentrates after treatment with ultraviolet C light and in plasma after treatment with methylene blue and visible light. Transfusion. 2017 Nov;57(11):2677-2682. doi: 10.1111/trf.14256. Epub 2017 Jul 17.
citation: Eickmann M, Gravemann U, Handke W, Tolksdorf F, Reichenberg S, Muller TH, Seltsam A. Inactivation of three emerging viruses - severe acute respiratory syndrome coronavirus, Crimean-Congo haemorrhagic fever virus and Nipah virus - in platelet concentrates by ultraviolet C light and in plasma by methylene blue plus visible light. Vox Sang. 2020 Apr;115(3):146-151. doi: 10.1111/vox.12888. Epub 2020 Jan 12.
citation: Ziv G, Heavner JE. Permeability of the blood-milk barrier to methylene blue in cows and goats. J Vet Pharmacol Ther. 1984 Mar;7(1):55-9. doi: 10.1111/j.1365-2885.1984.tb00879.x.
citation: Albert M, Lessin MS, Gilchrist BF. Methylene blue: dangerous dye for neonates. J Pediatr Surg. 2003 Aug;38(8):1244-5. doi: 10.1016/s0022-3468(03)00278-1.
citation: Sills MR, Zinkham WH. Methylene blue-induced Heinz body hemolytic anemia. Arch Pediatr Adolesc Med. 1994 Mar;148(3):306-10. doi: 10.1001/archpedi.1994.02170030076017.
citation: McFadyen I. The dangers of intra-amniotic methylene blue. Br J Obstet Gynaecol. 1992 Feb;99(2):89-90. doi: 10.1111/j.1471-0528.1992.tb14458.x. No abstract available.
citation: Dolk H. Methylene blue and atresia or stenosis of ileum and jejunum. EUROCAT Working Group. Lancet. 1991 Oct 19;338(8773):1021-2. doi: 10.1016/0140-6736(91)91885-x. No abstract available.
citation: van der Pol JG, Wolf H, Boer K, Treffers PE, Leschot NJ, Hey HA, Vos A. Jejunal atresia related to the use of methylene blue in genetic amniocentesis in twins. Br J Obstet Gynaecol. 1992 Feb;99(2):141-3. doi: 10.1111/j.1471-0528.1992.tb14473.x.
citation: Iyengar B, Lal SK. Methylene blue and organised differentiation in the chick embryo. Acta Anat (Basel). 1985;123(4):220-3. doi: 10.1159/000146005.
citation: Tiboni GM, Lamonaca D. Transplacental exposure to methylene blue initiates teratogenesis in the mouse: preliminary evidence for a mechanistic implication of cyclic GMP pathway disruption. Teratology. 2001 Oct;64(4):213-20. doi: 10.1002/tera.1066.