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

An Open-Label, Pilot Study to Evaluate the Safety, Tolerability, and Efficacy of 5-Aminolevulinic Acid Phosphate and Sodium Ferrous Citrate (5-ALA-Phosphate + SFC) in Subjects With SARS-CoV-2 Infection (COVID-19)

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.

Study Overview

• Status: Completed
• Conditions: COVID-19; SARS-CoV 2
• Intervention / Treatment: Dietary supplement: 5-ALA-Phosphate + SFC (5-ALA + SFC)

Detailed Description

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).

Heme is critical for appropriate oxygen binding and delivery to remote site and without the heme contained within the hemoglobin tetramer, multicellular organisms would be unable to survive. Furthermore HO-1 degrades heme into biliverdin, carbon monoxide (CO), and iron, and biliverdin is immediately reduced and turned into bilirubin by biliverdin reductase. Biliverdin/bilirubin and CO both have anti-oxidative functions and they regulate important biological processes like inflammation, apoptosis, cell proliferation, fibrosis, and angiogenesis. Therefore, HO-1 is deemed to be a promising drug target (Ryter 2006). HO-1 is a major anti-inflammatory enzyme and a key regulator that induces immune tolerance. 5-ALA-Phosphate + SFC increases heme metabolism and HO-1 via enhancement of porphyrin biology and utilizes the HO-1 for endothelial pacification strategy.

The primary endpoints of this study is- all treatment emergent AEs and SAEs Grade III and IV (CTC) with reasonable possibility of causal relationship to 5-ALA-Phosphate + SFC. 40 subjects with symptoms requiring hospitalization will be enrolled in thestudy, with 20 subjects enrolled in each group below:

Group 1: 20 Moderately ill hospitalized subjects not requiring assisted ventilation Group 2: 20 Severely ill hospitalized subjects requiring assisted ventilation

The duration of this clinical study will be 4 weeks, and follow-up will be performed until Day 28 in hospital, or in an outpatient setting if subjects improve and are discharged home or to alternative care facility.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Bahrain
  • Manama, Bahrain
    • Bahrain Defense Force Royal Medical Services, Military Hospital
  • Manama, Bahrain
    • Salmaniya Medical Complex

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Willing and able to provide written informed consent, or with a legal representative who can provide informed consent
2. Aged ≥ 21 to 70 years
3. Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test before beginning study dose regime
4. qSOFA ≥ 1
5. Currently hospitalized

6. 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).

7. Radiographic evidence (chest X-ray or chest CT scan) of pulmonary infiltrates
8. Able to swallow 5 capsules of study product at dosing time points.

Exclusion Criteria:

1. 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.
2. Subject is nourished via a nasogastric tube
3. Subject has acute or chronic type(s) of porphyria or a family history of porphyria
4. Subject has demonstrated previous intolerance of 5-ALA and/or SFC by topical or oral administration (except for photosensitivity)
5. Pregnant or nursing women
6. Males and females of reproductive potential who have not agreed to use an
7. 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
8. Subjects who are unable or unwilling to comply with requirements of the clinical trial
9. Participation in any other clinical trial of an experimental treatment for COVID-19
10. Evidence of multiorgan failure
11. Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 X upper limit of normal (ULN)
12. Creatinine clearance < 50 mL/min using the Cockcroft-Gault formula for participants ≥ 18 years of age {Cockcroft 1976}
13. Any other reason that makes the subject unsuitable in the Investigator's opinion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Moderate group and Severe Group; 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); 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sum COVID-19 Modified Ordinal Scale for Clinical Improvement maximum daily score over 28 days of dosing for Moderate group and for Severe group	To describe patient's condition in Moderate and Severe group using average, median, minimum and maximum in COVID-19 Modified Ordinal Scale for Clinical Improvement score.	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	To describe patient´s condition in Moderate and Severe Group using rate of change in COVID-19 Modified Ordinal Scale for Clinical Improvement score.	28 days
Patient and subgroup profile of COVID-19 Modified Ordinal Scale for Clinical Improvement score vs. days hospitalized	To describe patient´s condition in Moderate and Severe Group using patient and subgroup profile of COVID-19 Modified Ordinal Scale for Clinical Improvement score vs. days hospitalized.	28 days
Overall survival	To describe time until death from any cause	day 14 and day 28
Results of investigator´s assessment of patient´s oxygen therapy	To describe patient´s blood oxygenation	28 days
Results of mechanical ventilation settings	To describe mechanical ventilation settings course during study.	28 days
Results of duration of ventilation	To describe duration of patient´s ventilation	from date of enrolment until the extubation or until last 5-ALA- Phosphate -SFC administration on day 28
The time to resolution of patient´s symptoms	To describe patient´s specific symptoms course during study.	28 days
Results of patient´s oxygen saturation (respiratory parameters)	To describe patient´s oxygen saturation course during study.	28 days
Length of hospitalization	To describe duration of hospitalization in the patient groups.	From date of enrolment until last 5-ALA- Phosphate -SFC administration at day 28
The total time in ICU	To describe duration of residence in ICU in the patient groups.	From date of enrolment until last 5-ALA- Phosphate -SFC administration at day 28
Results of investigator´s assessment of patient´s condition using (q)SOFA score	To describe patient´s (q)SOFA score course during study.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results of patient´s PT parameter	To describe patient´s coagulation function course during study which by evaluating the PT value.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results of patient´s D-Dimer parameter	To describe patient´s coagulation function course during study which by evaluating the D-Dimer value.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results of patient´s PTT parameter	To describe patient´s coagulation function course during study which by evaluating the PTT value.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results of patient´s SARS-CoV-2 viral load status (efficacy)	To describe patient's SARS-CoV-2 viral load course during study.	day 7, 14 and 28
Results of patient´s Procalcitonin level.	To describe infection parameter course of each patient during study by evaluating the Procalcitonin value.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results of patient´s IL-6 level	To describe infection parameter course of each patient during study by evaluating the IL-6 value.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results of patient´s Serum Ferritin level	To describe infection parameter course of each patient during study by evaluating the Serum ferritin value.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results of patient´s C-Reactive protein (CRP) level	To describe infection parameter course of each patient during study by evaluating the C-Reactive protein (CRP) value.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results of patient´s T helper cells (CD4/CD8) level.	To describe infection parameter course of each patient during study by evaluating the T helper cells (CD4/CD8) value.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results of patient´s Bilirubin level.	To describe infection parameter course of each patient during study by evaluating the Bilirubin value.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Leucocytes	To describe laboratory assessments course during study by evaluating Leucocytes value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Neutrophils	To describe laboratory assessments course during study by evaluating Neutrophils value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Lymphocyte	To describe laboratory assessments course during study by evaluating Lymphocyte value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Platelets	To describe laboratory assessments course during study by evaluating Platelets value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Hemoglobin	To describe laboratory assessments course during study by evaluating Hemoglobin value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Albumin	To describe laboratory assessments course during study by evaluating Albumin value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s AST	To describe laboratory assessments course during study by evaluating AST value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s ALT	To describe laboratory assessments course during study by evaluating ALT value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Total bilirubin	To describe laboratory assessments course during study by evaluating Total bilirubin value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Blood urea nitrogen	To describe laboratory assessments course during study by evaluating Blood urea nitrogen value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Serum creatinine	To describe laboratory assessments course during study by evaluating Serum creatinine value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Creatinine kinase	To describe laboratory assessments course during study by evaluating Creatinine kinase value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s LDH	To describe laboratory assessments course during study by evaluating LDH value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Myoglobin glucose	To describe laboratory assessments course during study by evaluating Myoglobin glucose value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s aPTT	To describe laboratory assessments course during study by evaluating aPTT value	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s urine	To describe laboratory assessments course during study by evaluating urinalysis (urine test strip)	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on hepatic function	To describe laboratory assessments course during study by evaluating hepatic function	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s renal function	To describe laboratory assessments course during study by evaluating renal function	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s iron parameters	To describe laboratory assessments course during study by evaluating iron parameters	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s physical examination	To describe patient´s conditions course during study using physical examination which include General Appearance, ENT, Respiratory, Cardiovascular, Musculoskeletal, Skin and Neurological.	day 0, 2, 3, 5, 7, 10, 14, 21, 28
Results on patient´s Co-infections	To describe patient's Co-infections course during study.	28 days
Results on patient´s Care Level	To describe patient´s care level course during study.	28 days
Results on patient´s Mean arterial pressure(MAP)	To describe patient´s vital signs course during study by evaluating Mean arterial pressure(MAP)	28 days
Results on patient´s heart rate (HR)	To describe patient´s vital signs course during study by evaluating heart rate (HR)	28 days
Results on patient´s respiratory rate (RR)	To describe patient´s vital signs course during study by evaluating respiratory rate (RR)	28 days
Results on patient´s 12-lead ECG	To describe patient´s 12-lead ECG result course during study.	day 0, 7, 14 and 28
Organ damage	To describe patient´s organ damage status during the study	28 days

Collaborators and Investigators

• Sponsor: Royal College of Surgeons in Ireland - Medical University of Bahrain
• Collaborators: Bahrain Defence Force Hospital; Salmaniya Medical Complex
• Investigators: Principal Investigator: Abdullah Darwish, Dr, Bahrain Defense Force Royal Medical Services, Military Hospital

Publications and helpful links

General Publications

• Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. doi: 10.1159/000180580.
• 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.
• 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.
• 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.
• 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. Erratum In: Cell Stress Chaperones. 2020 Jun 29;:
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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)
• Investigator's Brochure, SBI Pharmaceuticals Internal Document: 5-Aminolevulinic Acid (5-ALA)Phosphate Version 1.0. July, 2020
• 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)
• 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

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2020
• Primary Completion (Actual): August 31, 2021
• Study Completion (Actual): October 28, 2021

Study Registration Dates

• First Submitted: August 16, 2020
• First Submitted That Met QC Criteria: September 6, 2020
• First Posted (Actual): September 9, 2020

Study Record Updates

• Last Update Posted (Actual): February 9, 2022
• Last Update Submitted That Met QC Criteria: February 8, 2022
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; 5-ALAPhosphate + SFC
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 68 / 02-Aug-2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Monitoring, audits, and REC review will be permitted and provide direct access to source data and documents. The Lead PI and the researchers assigned by him will have access to the stored data/specimens. Only the Lead PI and the researchers assigned working on this study will be eligible to obtain the data/specimens from the participants during data collection.

IPD Sharing 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).

• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No