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SARS-COV 2NCT04854876

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

A study testing 5-ALA-Phosphate + SFC (5-ALA+SFC) in people with SARS-COV 2 and Covid19, run by Royal College of Surgeons in Ireland - Medical University of Bahrain.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 21 years and olderHealthy volunteers can take part
Conditions the study is for
SARS-COV 2, Covid19
What is being tested?
5-ALA-Phosphate + SFC (5-ALA+SFC)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
15 Aug 2021to 30 Aug 2021
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 years and older
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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

About this study

Official title: 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

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

Read the detailed description

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:

  1. Measurement of total IgA, IgM and IgG antibodies against SARS-CoV 2.
  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.

Conditions
SARS-COV 2, Covid19
Being tested
5-ALA-Phosphate + SFC (5-ALA+SFC)
Keywords
5-ALAPhosphate + SFC, COVID-19 Vaccination
Medical subject headings
COVID-19

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 5-ALA-Phosphate + SFC (5-ALA+SFC)Dietary supplement

    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).

Study groups in NCT04854876
Study groupRoleWhat they receive
Vaccinated with 1st dose of COVID-19 Vaccine & treated with 5-ALA Phosphate/SFCExperimental100 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
Receives: Dietary Supplement: 5-ALA-Phosphate + SFC (5-ALA+SFC)
Vaccinated with 1st dose of COVID-19 VaccineNo intervention100 subjects that were vaccinated with the first dose of a COVID-19 Vaccine (any brand approved in Bahrain is permitted) only (Control)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: 28 days

Secondary outcomes (1)

  1. 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

    Measured: 28 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Apr 2021
  2. Study start15 Aug 2021
  3. Primary completion30 Aug 2021
  4. Study completion30 Aug 2021

Why it stopped: The food supplement/health product registration needs to be undertaken with NHRA- Pharmaceutical Product Regulations Department

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
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)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04854876
Sponsor's protocol ID
BDF/R&REC/2021-566
Status last verified
Sep 2021
First submitted
21 Apr 2021
Last updated
22 Sep 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Ahmed R, Gray D. Immunological memory and protective immunity: understanding their relation. Science. 1996 Apr 5;272(5258):54-60. doi: 10.1126/science.272.5258.54.

    PubMed 8600537

  • 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)

  • Cao WC, Liu W, Zhang PH, Zhang F, Richardus JH. Disappearance of antibodies to SARS-associated coronavirus after recovery. N Engl J Med. 2007 Sep 13;357(11):1162-3. doi: 10.1056/NEJMc070348. No abstract available.

    PubMed 17855683

  • Channappanavar R, Fett C, Zhao J, Meyerholz DK, Perlman S. Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection. J Virol. 2014 Oct;88(19):11034-44. doi: 10.1128/JVI.01505-14. Epub 2014 Jul 23.

    PubMed 25056892

  • Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, Rawlings SA, Sutherland A, Premkumar L, Jadi RS, Marrama D, de Silva AM, Frazier A, Carlin AF, Greenbaum JA, Peters B, Krammer F, Smith DM, Crotty S, Sette A. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell. 2020 Jun 25;181(7):1489-1501.e15. doi: 10.1016/j.cell.2020.05.015. Epub 2020 May 20.

    PubMed 32473127

  • Hu X. 5-Aminolevulinic acid with sodium ferrous citrate enhance the antitumor effects of PD-L1 blockade in mouse melanoma model7th International ALA and Prophyrin Symposium (IAPS7) in Sapporo 2019.

  • Ibarrondo FJ, Fulcher JA, Goodman-Meza D, Elliott J, Hofmann C, Hausner MA, Ferbas KG, Tobin NH, Aldrovandi GM, Yang OO. Rapid Decay of Anti-SARS-CoV-2 Antibodies in Persons with Mild Covid-19. N Engl J Med. 2020 Sep 10;383(11):1085-1087. doi: 10.1056/NEJMc2025179. Epub 2020 Jul 21. No abstract available.

    PubMed 32706954

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

  • Krammer F. SARS-CoV-2 vaccines in development. Nature. 2020 Oct;586(7830):516-527. doi: 10.1038/s41586-020-2798-3. Epub 2020 Sep 23.

    PubMed 32967006

  • Kreer C, Zehner M, Weber T, Ercanoglu MS, Gieselmann L, Rohde C, Halwe S, Korenkov M, Schommers P, Vanshylla K, Di Cristanziano V, Janicki H, Brinker R, Ashurov A, Krahling V, Kupke A, Cohen-Dvashi H, Koch M, Eckert JM, Lederer S, Pfeifer N, Wolf T, Vehreschild MJGT, Wendtner C, Diskin R, Gruell H, Becker S, Klein F. Longitudinal Isolation of Potent Near-Germline SARS-CoV-2-Neutralizing Antibodies from COVID-19 Patients. Cell. 2020 Aug 20;182(4):843-854.e12. doi: 10.1016/j.cell.2020.06.044. Epub 2020 Jul 13.

    PubMed 32673567

  • Le Bert N, Tan AT, Kunasegaran K, Tham CYL, Hafezi M, Chia A, Chng MHY, Lin M, Tan N, Linster M, Chia WN, Chen MI, Wang LF, Ooi EE, Kalimuddin S, Tambyah PA, Low JG, Tan YJ, Bertoletti A. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature. 2020 Aug;584(7821):457-462. doi: 10.1038/s41586-020-2550-z. Epub 2020 Jul 15.

    PubMed 32668444

  • Le TT, Cramer JP, Chen R, Mayhew S. Evolution of the COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020 Oct;19(10):667-668. doi: 10.1038/d41573-020-00151-8. No abstract available.

    PubMed 32887942

  • Long QX, Tang XJ, Shi QL, Li Q, Deng HJ, Yuan J, Hu JL, Xu W, Zhang Y, Lv FJ, Su K, Zhang F, Gong J, Wu B, Liu XM, Li JJ, Qiu JF, Chen J, Huang AL. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020 Aug;26(8):1200-1204. doi: 10.1038/s41591-020-0965-6. Epub 2020 Jun 18.

    PubMed 32555424

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

  • Ng OW, Chia A, Tan AT, Jadi RS, Leong HN, Bertoletti A, Tan YJ. Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection. Vaccine. 2016 Apr 12;34(17):2008-14. doi: 10.1016/j.vaccine.2016.02.063. Epub 2016 Mar 5.

    PubMed 26954467

Questions about this trial

What is this clinical trial studying?

A study testing 5-ALA-Phosphate + SFC (5-ALA+SFC) in people with SARS-COV 2 and Covid19, run by Royal College of Surgeons in Ireland - Medical University of Bahrain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 22 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

To determine the safety of a 4 week daily oral administration of 5-ALA + SFC in subject vaccinated with COVID-19 Vaccine (time frame: 28 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04854876, which also lists 28 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2021.

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