Pilot Study to Evaluate the Safety, Tolerability, and Efficacy of 5-ALA-Phosphate + SFC in Subjects With COVID-19

NCT04542850 | Completed DMC

• 1 other identifier: 68 / 02-Aug-2020
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 2

Brief Summary

This is an open-label, interventional exploratory study to evaluate the safety and efficacy of 5-ALA-Phosphate + SFC in subjects with acute moderate or severe respiratory illness secondary to infection with SARS-CoV-2 virus (COVID-19) involving 40 subjects. The primary objective is to evaluate the safety of 4-week oral administration of 5-ALAPhosphate + SFC. This study is expected to last for 4 weeks and will include follow-up until day 28 in the hospital or in an outpatient setting if the subjects are discharged earlier.

Conditions

SARS-CoV 2; COVID-19

Keywords

5-ALAPhosphate + SFC; COVID-19

Outcome Measures

Primary Outcomes (1)

• The incidence of treatment emergent Adverse Events (safety and tolerability) of 5-ALA-Phospate + SFC in patients with acute moderate or severe respiratory illness secondary to infection with SARS-CoV-2 virus (COVID-19).

  To describe the incidence of treatment-emergent Adverse Events (TEAEs) of CTC Grades III and IV within four weeks following base line dose.

  28 days

Secondary Outcomes (49)

• Sum COVID-19 Modified Ordinal Scale for Clinical Improvement maximum daily score over 28 days of dosing for Moderate group and for Severe group

  28 days

• Rate of change in COVID-19 Modified Ordinal Scale for Clinical Improvement maximum daily score over 28 days of dosing for individual subjects in Moderate group and in Severe group

  28 days

• Patient and subgroup profile of COVID-19 Modified Ordinal Scale for Clinical Improvement score vs. days hospitalized

  28 days

• Overall survival

  day 14 and day 28

• Results of investigator´s assessment of patient´s oxygen therapy

  28 days

Study Arms (1)

Moderate group and Severe Group

OTHER

Moderate group and Severe group - . Both groups will be administered 5-aminolevulinic acid (5-ALA) is a natural delta amino acid widely present in nature that can be found in common food. 5-ALA combined with sodium ferrous citrate (SFC) produces the nutritional dietary supplement 5-ALA-Phosphate + SFC (5-ALA + SFC).

Dietary Supplement: 5-ALA-Phosphate + SFC (5-ALA + SFC)

Interventions

5-ALA-Phosphate + SFC (5-ALA + SFC) DIETARY_SUPPLEMENT

Moderately ill hospitalized patients will receive: 250 mg 5-ALA-Phosphate and 143.4 mg SFC (15.2 mg as Fe) two times daily (resulting in 500 mg 5-ALA-Phosphate and 286.8 mg SFC (30.4 mg as Fe) daily) for 7 days, then 250 mg 5-ALA-Phosphate and 143.4 mg SFC (15.2 mg as Fe) once daily for 21 days Severely ill hospitalized patients will receive: 250 mg 5-ALA-Phosphate and 143.4 mg SFC (15.2 mg as Fe) three times daily (resulting in 750 mg 5-ALA-Phosphate and 430.2 mg SFC (45.6 mg as Fe) daily) for 7 days, then 250 mg 5-ALA-Phosphate and 143.4 mg SFC (15.2 mg as Fe) once daily for 21 days

Moderate group and Severe Group

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent, or with a legal representative who can provide informed consent
• Aged ≥ 21 to 70 years
• Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test before beginning study dose regime
• qSOFA ≥ 1
• Currently hospitalized
• Moderate COVID-19 patients should meet any of the following criteria:
• evidence of lower respiratory disease by clinical assessment (qSOFA ≥ 1or imaging) and saturation of oxygen (SpO2) ≥94% on room air at sea level.
• Severe COVID-19 patients should meet any of the following criteria: a respiratory frequency \>30 breaths per minute, SpO2 \<94% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) \<300 mmHg, and lung infiltrates \>50% (if possible to measure). In exceptional cases the investigator can decide due to certain signs and symptoms to assign a moderate patient to the severe group although not all criteria mentioned before are fulfilled (to be documented with explanation).
• Radiographic evidence (chest X-ray or chest CT scan) of pulmonary infiltrates
• Able to swallow 5 capsules of study product at dosing time points.

You may not qualify if:

• Subject has critical symptoms of COVID19 infection as defined as: high-flow oxygen therapy (\>15 l/min delivered by nasal cannula or mask) or invasive mechanical ventilation signifying respiratory failure, septic shock, and/or multiple organ dysfunction ventilation at screening.
• Subject is nourished via a nasogastric tube
• Subject has acute or chronic type(s) of porphyria or a family history of porphyria
• Subject has demonstrated previous intolerance of 5-ALA and/or SFC by topical or oral administration (except for photosensitivity)
• Pregnant or nursing women
• Males and females of reproductive potential who have not agreed to use an
• adequate method of contraception during the study For females, adequate birth control methods will be defined as: hormonal contraceptives, intrauterine device or double barrier contraception, i.e., condom + diaphragm, condom or diaphragm + spermicidal gel or foam For males, adequate birth control methods will be defined as double barrier contraception, i.e., condom + diaphragm, condom or diaphragm + spermicidal gel or foam For females, menopause is defined as one year without menses; if in question, a folliclestimulating hormone of \>40 U/ml must be documented. Hysterectomy, bilateral oophorectomy,or bilateral tubal ligation must be documented, as applicable
• Subjects who are unable or unwilling to comply with requirements of the clinical trial
• Participation in any other clinical trial of an experimental treatment for COVID-19
• Evidence of multiorgan failure
• Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) \> 5 X upper limit of normal (ULN)
• Creatinine clearance \< 50 mL/min using the Cockcroft-Gault formula for participants ≥ 18 years of age {Cockcroft 1976}
• Any other reason that makes the subject unsuitable in the Investigator's opinion

Sponsors & Collaborators

• Royal College of Surgeons in Ireland - Medical University of Bahrain: lead
• Bahrain Defence Force Hospital: collaborator
• Salmaniya Medical Complex: collaborator

Study Sites (2)

Bahrain Defense Force Royal Medical Services, Military Hospital

Manama, Bahrain

Location

Salmaniya Medical Complex

Manama, Bahrain

Location

Related Publications (19)

• El Kalamouni C, Frumence E, Bos S, Turpin J, Nativel B, Harrabi W, Wilkinson DA, Meilhac O, Gadea G, Despres P, Krejbich-Trotot P, Viranaicken W. Subversion of the Heme Oxygenase-1 Antiviral Activity by Zika Virus. Viruses. 2018 Dec 20;11(1):2. doi: 10.3390/v11010002.

  PMID: 30577437 BACKGROUND

• Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. doi: 10.1159/000180580.

  PMID: 1244564 BACKGROUND

• Devadas K, Dhawan S. Hemin activation ameliorates HIV-1 infection via heme oxygenase-1 induction. J Immunol. 2006 Apr 1;176(7):4252-7. doi: 10.4049/jimmunol.176.7.4252.

  PMID: 16547262 BACKGROUND

• Hill-Batorski L, Halfmann P, Neumann G, Kawaoka Y. The cytoprotective enzyme heme oxygenase-1 suppresses Ebola virus replication. J Virol. 2013 Dec;87(24):13795-802. doi: 10.1128/JVI.02422-13. Epub 2013 Oct 9.

  PMID: 24109237 BACKGROUND

• Hooper PL. COVID-19 and heme oxygenase: novel insight into the disease and potential therapies. Cell Stress Chaperones. 2020 Sep;25(5):707-710. doi: 10.1007/s12192-020-01126-9. Epub 2020 Jun 4.

  PMID: 32500379 BACKGROUND

• Ibanez FJ, Farias MA, Retamal-Diaz A, Espinoza JA, Kalergis AM, Gonzalez PA. Pharmacological Induction of Heme Oxygenase-1 Impairs Nuclear Accumulation of Herpes Simplex Virus Capsids upon Infection. Front Microbiol. 2017 Oct 31;8:2108. doi: 10.3389/fmicb.2017.02108. eCollection 2017.

  PMID: 29163402 BACKGROUND

• Ito H, Nishio Y, Hara T, Sugihara H, Tanaka T, Li XK. Oral administration of 5-aminolevulinic acid induces heme oxygenase-1 expression in peripheral blood mononuclear cells of healthy human subjects in combination with ferrous iron. Eur J Pharmacol. 2018 Aug 15;833:25-33. doi: 10.1016/j.ejphar.2018.05.009. Epub 2018 May 10.

  PMID: 29753693 BACKGROUND

• Nishio Y, Fujino M, Zhao M, Ishii T, Ishizuka M, Ito H, Takahashi K, Abe F, Nakajima M, Tanaka T, Taketani S, Nagahara Y, Li XK. 5-Aminolevulinic acid combined with ferrous iron enhances the expression of heme oxygenase-1. Int Immunopharmacol. 2014 Apr;19(2):300-7. doi: 10.1016/j.intimp.2014.02.003. Epub 2014 Feb 13.

  PMID: 24530569 BACKGROUND

• Ogawa K, Sun J, Taketani S, Nakajima O, Nishitani C, Sassa S, Hayashi N, Yamamoto M, Shibahara S, Fujita H, Igarashi K. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. EMBO J. 2001 Jun 1;20(11):2835-43. doi: 10.1093/emboj/20.11.2835.

  PMID: 11387216 BACKGROUND

• Protzer U, Seyfried S, Quasdorff M, Sass G, Svorcova M, Webb D, Bohne F, Hosel M, Schirmacher P, Tiegs G. Antiviral activity and hepatoprotection by heme oxygenase-1 in hepatitis B virus infection. Gastroenterology. 2007 Oct;133(4):1156-65. doi: 10.1053/j.gastro.2007.07.021. Epub 2007 Jul 25.

  PMID: 17919491 BACKGROUND

• Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev. 2006 Apr;86(2):583-650. doi: 10.1152/physrev.00011.2005.

  PMID: 16601269 BACKGROUND

• Saito K, Fujiwara T, Ota U, Hatta S, Ichikawa S, Kobayashi M, Okitsu Y, Fukuhara N, Onishi Y, Ishizuka M, Tanaka T, Harigae H. Dynamics of absorption, metabolism, and excretion of 5-aminolevulinic acid in human intestinal Caco-2 cells. Biochem Biophys Rep. 2017 Jul 13;11:105-111. doi: 10.1016/j.bbrep.2017.07.006. eCollection 2017 Sep.

  PMID: 28955775 BACKGROUND

• Schmidt WN, Mathahs MM, Zhu Z. Heme and HO-1 Inhibition of HCV, HBV, and HIV. Front Pharmacol. 2012 Oct 4;3:129. doi: 10.3389/fphar.2012.00129. eCollection 2012.

  PMID: 23060790 BACKGROUND

• Tseng CK, Lin CK, Wu YH, Chen YH, Chen WC, Young KC, Lee JC. Human heme oxygenase 1 is a potential host cell factor against dengue virus replication. Sci Rep. 2016 Aug 24;6:32176. doi: 10.1038/srep32176.

  PMID: 27553177 BACKGROUND

• Zhong M, Wang H, Ma L, Yan H, Wu S, Gu Z, Li Y. DMO-CAP inhibits influenza virus replication by activating heme oxygenase-1-mediated IFN response. Virol J. 2019 Feb 20;16(1):21. doi: 10.1186/s12985-019-1125-9.

  PMID: 30786886 BACKGROUND

• Brooks A., Study 8259980 5-ALA/SFC: A Phase I, Double-Blind, Placebo-Controlled, Single and Multiple Oral Dose, Safety, Tolerability and Pharmacokinetic Study in Healthy Caucasian and Japanese Subjects, Covance: Leeds and London, UK (2013)

  BACKGROUND

• Investigator's Brochure, SBI Pharmaceuticals Internal Document: 5-Aminolevulinic Acid (5-ALA)Phosphate Version 1.0. July, 2020

  BACKGROUND

• Matsumoto C., Study ALA-01 "Bioequivalence study of test foods A, B, and C - Based on the PlasmaConcentration of 5-Aminolevulinic Acid." Kaiyu Clinic: Tokyo Japan (2010)

  BACKGROUND

• World Health Organization (WHO) R&D Blueprint: Novel Coronavirus COVID-19 Therapuetic Trial Synopsis. Draft dated February 18, 2020. Accesssed online 09Jul20 at https://www.who.int/blueprint/priority-diseases/key-action/COVID- 19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf

  BACKGROUND

MeSH Terms

Conditions

COVID-19

Interventions

Sodium Glutamate

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Glutamic Acid; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Officials

• Abdullah Darwish, Dr

  Bahrain Defense Force Royal Medical Services, Military Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is an open label pilot study involving 40 patients with COVID-19 disease. Patients that are hospitalized due to confirmed SARS-CoV-2 infection will be assigned to two groups according o their severity grade (moderate or severe).

Study Record Dates

• First Submitted: August 16, 2020
• First Posted: September 9, 2020
• Study Start: November 15, 2020
• Primary Completion: August 31, 2021
• Study Completion: October 28, 2021
• Last Updated: February 9, 2022

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR, ANALYTIC CODE
• Time Frame: Data will be collected in the case report form to allow for cross referencing to check validity. Study documents (paper) will be retained in a secure (kept locked when not in use) location during and after the trial has finished. All essential documents including source documents will be retained for a period of 5 years after study completion (last patient, last study point).
• Access Criteria: Study documents (paper) will be retained in a secure (kept locked when not in use) location during and after the trial has finished.

Locations

BA (2)