Pilot Study to Evaluate the Safety, Tolerability, and Efficacy of 5-ALA-Phosphate + SFC as an Immune System Enhancer Along With Vaccination Against COVID-19

Study Overview
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Brief Summary
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This is an open-label, two arm interventional exploratory study to evaluate the safety and efficacy of 5-ALA-Phosphate-SFC during the vaccination of subjects against SARS-CoV-2 (COVID-19) virus infection to define the safety and to activate the immune system during SARS-CoV-2 vaccination. The primary objective of this study is to determine the safety of a 4 week daily oral administration of 5-ALA-Phosphate + SFC in subjects vaccinated with COVID-19 Vaccine

Detailed Description
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This is an open-label, two arm interventional exploratory study to evaluate the safety and efficacy of 5-ALA-Phosphate-SFC during the vaccination of subjects against SARS-CoV-2 (COVID-19) virus infection to define the safety and to activate the immune system during SARS-CoV-2 vaccination. Arm 1: 100 subjects that were vaccinated with the first dose of a COVID-19 Vaccine (any brand approved in Bahrain is permitted) and that will be treated with 150mg 5-ALA Phosphate/SFC for 28 days and Arm 2: 100 subjects that were vaccinated with the first dose of a COVID-19 Vaccine (any brand approved in Bahrain is permitted) only (Control) The duration of this clinical study will depend on the type of the vaccine, the subject was administered with. Primary Endpoints: All treatment emergent AEs and SAEs Grade III and IV (CTC) with reasonable possibility of causal relationship to 5-ALA-Phosphate + SFC Secondary Endpoint: Serum levels of biomarkers (CD4+/- and CD8+/- ) before and after vaccination with and without ALA/SFC administration. Total antibody level and neutralizing antibody level Exploratory Endpoints: Measurement of total IgA, IgM and IgG antibodies against SARS-CoV 2. Measurement of neutralizing antibodies against SARS-CoV-2. Safety: The following safety endpoints will be assessed: Clinical laboratory assessments (hepatic function,) All reports of AEs and SAEs Grade III and IV (CTC) with reasonable possibility of causal relationship to 5-ALA-Phosphate + SFC Efficacy: Efficacy will be assessing the immune system related T-helper cells and antibodies after SARS-CoV-2 vaccination for each subject. From day 0 onwards, all subjects keep a subject diary, which they fill out daily in order to record the dosage with the study treatment. Patients must meet the testing requirements on the day of the first vaccination (Day 0) and on the Day of the second vaccination and on Day 28 and on Follow-up visit. The food supplement 5-Aminolevulinic acid phosphate and Sodium ferrous citrate (5-ALA-Phosphate + SFC) will be administered orally daily for 4 weeks at the following TOTAL daily doses: Subjects in the vaccination + ALA/SFC arm (Arm 1) will receive: • In total 3 capsules of 50 mg 5-ALA-Phosphate and 28.68 mg SFC (3.04 mg as Fe) per day, 2 capsules in the morning and 1 capsule in the evening resulting in 150 mg 5-ALA-Phosphate and 86.04 mg SFC ( 9.12 mg as Fe) total daily dose for 28 days 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. Nishio reported 2014 that 5-aminolevulinic acid, a precursor of heme, in combination with divalent iron (SFC) is also able to induce HO-1 in vitro (Nishio 2014). This was attributed to the upregulation of heme synthesis and that 5-ALA+SFC transiently increased the intracellular heme amount through the phosphorylation of ERK / p38 and the nuclear translocation of a transcription factor Nrf2, as well as the depletion of a repressor protein BACH1 binding to the promoter site of HO-1. Similarly, Nakaso et al., 2003, Nishio et al., 2014, Ogawa et al., 2001, Saito et al., 2017 found that hemin administration promoted Nrf2 nuclear translocation and BACH1 dissociation leading to HO-1 induction. Ito found in 2018 that the combination of 5-ALA 600 mg and sodium ferrous citrate (SFC) 942 mg upregulated HO-1 in PBMC at 8 h after administration while sole administration of 5-ALA or SFC was unable to induce HO-1. HO-1 in blood myeloid and plasmacytoid dendritic cells was also upregulated by the combination of 5-ALA + SFC. In summary the versatility of the administration of 5-ALA plus iron citrate (SFC) enables the body to counteract the inflammatory reactions that the virus induces in the endothelial system and multiple organs in the event of a virus attack by increasing the formation of HO-1.

Official Title
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An Open-Label, Pilot Study to Evaluate the Safety, Tolerability, and Efficacy of 5-ALA-Phosphate + SFC as an Immune System Enhancer Along With Vaccination Against SARS-CoV-2 Virus Infection

Conditions
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SARS-COV 2, Covid19

Intervention / Treatment
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* Dietary Supplement: 5-ALA-Phosphate + SFC (5-ALA+SFC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent, or with a legal representative who can provide informed consent Aged ≥ 21 years (at all sites) Subjects that have been vaccinated with the first dose of a vaccine (any brand approved in Bahrain is permitted) to protect against COVID-19 infection Exclusion Criteria: 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. 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 Subjects who may be excluded at the Investigator's discretion

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an open-label, two arm interventional exploratory study, in which one arm will consist of 100 subjects that were vaccinated with the first dose of a COVID-19 Vaccine (any brand approved in Bahrain is permitted) and those will be treated with 150mg 5-ALA Phosphate/SFC for 28 days. The second arm will consist of 100 subjects that were vaccinated with the first dose of a COVID-19 Vaccine (any brand approved in Bahrain is permitted) only (Control). This is to determine the safety and evaluate the efficacy of 5-ALA-Phosphate-SFC during the vaccination of subjects against SARS-CoV-2 (COVID-19) virus infection and to activate the immune system during SARS-CoV-2 vaccination.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccinated with 1st dose of COVID-19 Vaccine & treated with 5-ALA Phosphate/SFC<br>100 subjects that were vaccinated with the first dose of a COVID-19 Vaccine (any brand approved in Bahrain is permitted) and that will be treated with 150mg 5-ALA Phosphate/SFC for 28 days | Dietary Supplement: 5-ALA-Phosphate + SFC (5-ALA+SFC)<br>* The food supplement 5-Aminolevulinic acid phosphate and Sodium ferrous citrate (5-ALA-Phosphate + SFC) will be administered orally daily for 28 days. The dose will be in total 3 capsules of 50 mg 5-ALA-Phosphate and 28.68 mg SFC (3.04 mg as Fe) per day, 2 capsules in the morning and 1 capsule in the evening resulting in 150 mg 5-ALA-Phosphate and 86.04 mg SFC ( 9.12 mg as Fe).<br>|
| No Intervention: Vaccinated with 1st dose of COVID-19 Vaccine<br>100 subjects that were vaccinated with the first dose of a COVID-19 Vaccine (any brand approved in Bahrain is permitted) only (Control) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety of a 4 week daily oral administration of 5-ALA + SFC in subject vaccinated with COVID-19 Vaccine | To capture the incidence of all treatment emergent AEs and SAEs Grade III and IV (CTC) with reasonable possibility of causal relationship to 5-ALA + SFC | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of 5-ALA + SFC in activating the immune system in subject vaccinated with COVID-19 Vaccine | To determine the serum levels of biomarkers (CD4+/- and CD8+/- ) before and after vaccination with and without 5-ALA + SFC administration and total antibody level and neutralizing antibody level | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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5-ALAPhosphate + SFC, COVID-19 Vaccination