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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04542850
Recruitment Status : Not yet recruiting
First Posted : September 9, 2020
Last Update Posted : October 8, 2020
Sponsor:
Collaborator:
Bahrain Defence Force Royal Medical Services, Military Hospital
Information provided by (Responsible Party):
Royal College of Surgeons in Ireland - Medical University of Bahrain

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.


Condition or disease Intervention/treatment Phase
SARS-CoV 2 COVID-19 Dietary Supplement: 5-ALA-Phosphate + SFC (5-ALA + SFC) Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 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).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Estimated Study Start Date : November 2020
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Moderate group and Severe Group
Moderate group - not requiring assisted ventilation and Severe group - requiring assisted ventilation. 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 (not requiring assisted ventilation) 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 (requiring assisted ventilation) 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





Primary Outcome Measures :
  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). [ Time Frame: 28 days ]
    To describe the incidence of treatment-emergent Adverse Events (TEAEs) of CTC Grades III and IV within four weeks following base line dose.


Secondary Outcome Measures :
  1. Sum COVID-19 Modified Ordinal Scale for Clinical Improvement maximum daily score over 28 days of dosing for Moderate group and for Severe group [ Time Frame: 28 days ]
    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.

  2. 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 [ Time Frame: 28 days ]
    To describe patient´s condition in Moderate and Severe Group using rate of change in COVID-19 Modified Ordinal Scale for Clinical Improvement score.

  3. Patient and subgroup profile of COVID-19 Modified Ordinal Scale for Clinical Improvement score vs. days hospitalized [ Time Frame: 28 days ]
    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.

  4. Overall survival [ Time Frame: day 14 and day 28 ]
    To describe time until death from any cause

  5. Results of investigator´s assessment of patient´s oxygen therapy [ Time Frame: 28 days ]
    To describe patient´s blood oxygenation

  6. Results of mechanical ventilation settings [ Time Frame: 28 days ]
    To describe mechanical ventilation settings course during study.

  7. Results of duration of ventilation [ Time Frame: from date of enrolment until the extubation or until last 5-ALA- Phosphate -SFC administration on day 28 ]
    To describe duration of patient´s ventilation

  8. The time to resolution of patient´s symptoms [ Time Frame: 28 days ]
    To describe patient´s specific symptoms course during study.

  9. Results of patient´s oxygen saturation (respiratory parameters) [ Time Frame: 28 days ]
    To describe patient´s oxygen saturation course during study.

  10. Length of hospitalization [ Time Frame: From date of enrolment until last 5-ALA- Phosphate -SFC administration at day 28 ]
    To describe duration of hospitalization in the patient groups.

  11. The total time in ICU [ Time Frame: From date of enrolment until last 5-ALA- Phosphate -SFC administration at day 28 ]
    To describe duration of residence in ICU in the patient groups.

  12. Results of investigator´s assessment of patient´s condition using (q)SOFA score [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe patient´s (q)SOFA score course during study.

  13. Results of patient´s PT parameter [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe patient´s coagulation function course during study which by evaluating the PT value.

  14. Results of patient´s D-Dimer parameter [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe patient´s coagulation function course during study which by evaluating the D-Dimer value.

  15. Results of patient´s PTT parameter [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe patient´s coagulation function course during study which by evaluating the PTT value.

  16. Results of patient´s SARS-CoV-2 viral load status (efficacy) [ Time Frame: day 7, 14 and 28 ]
    To describe patient's SARS-CoV-2 viral load course during study.

  17. Results of patient´s Procalcitonin level. [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe infection parameter course of each patient during study by evaluating the Procalcitonin value.

  18. Results of patient´s IL-6 level [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe infection parameter course of each patient during study by evaluating the IL-6 value.

  19. Results of patient´s Serum Ferritin level [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe infection parameter course of each patient during study by evaluating the Serum ferritin value.

  20. Results of patient´s C-Reactive protein (CRP) level [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe infection parameter course of each patient during study by evaluating the C-Reactive protein (CRP) value.

  21. Results of patient´s T helper cells (CD4/CD8) level. [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe infection parameter course of each patient during study by evaluating the T helper cells (CD4/CD8) value.

  22. Results of patient´s Bilirubin level. [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe infection parameter course of each patient during study by evaluating the Bilirubin value.

  23. Results on patient´s Leucocytes [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Leucocytes value

  24. Results on patient´s Neutrophils [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Neutrophils value

  25. Results on patient´s Lymphocyte [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Lymphocyte value

  26. Results on patient´s Platelets [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Platelets value

  27. Results on patient´s Hemoglobin [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Hemoglobin value

  28. Results on patient´s Albumin [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Albumin value

  29. Results on patient´s AST [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating AST value

  30. Results on patient´s ALT [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating ALT value

  31. Results on patient´s Total bilirubin [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Total bilirubin value

  32. Results on patient´s Blood urea nitrogen [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Blood urea nitrogen value

  33. Results on patient´s Serum creatinine [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Serum creatinine value

  34. Results on patient´s Creatinine kinase [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Creatinine kinase value

  35. Results on patient´s LDH [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating LDH value

  36. Results on patient´s Myoglobin glucose [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating Myoglobin glucose value

  37. Results on patient´s aPTT [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating aPTT value

  38. Results on patient´s urine [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating urinalysis (urine test strip)

  39. Results on hepatic function [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating hepatic function

  40. Results on patient´s renal function [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating renal function

  41. Results on patient´s iron parameters [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe laboratory assessments course during study by evaluating iron parameters

  42. Results on patient´s physical examination [ Time Frame: day 0, 2, 3, 5, 7, 10, 14, 21, 28 ]
    To describe patient´s conditions course during study using physical examination which include General Appearance, ENT, Respiratory, Cardiovascular, Musculoskeletal, Skin and Neurological.

  43. Results on patient´s Co-infections [ Time Frame: 28 days ]
    To describe patient's Co-infections course during study.

  44. Results on patient´s Care Level [ Time Frame: 28 days ]
    To describe patient´s care level course during study.

  45. Results on patient´s Mean arterial pressure(MAP) [ Time Frame: 28 days ]
    To describe patient´s vital signs course during study by evaluating Mean arterial pressure(MAP)

  46. Results on patient´s heart rate (HR) [ Time Frame: 28 days ]
    To describe patient´s vital signs course during study by evaluating heart rate (HR)

  47. Results on patient´s respiratory rate (RR) [ Time Frame: 28 days ]
    To describe patient´s vital signs course during study by evaluating respiratory rate (RR)

  48. Results on patient´s 12-lead ECG [ Time Frame: day 0, 7, 14 and 28 ]
    To describe patient´s 12-lead ECG result course during study.

  49. Organ damage [ Time Frame: 28 days ]
    To describe patient´s organ damage status during the study



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Willing and able to provide written informed consent, or with a legal representative who can provide informed consent.
  2. Aged ≥ 21 years (at all sites).
  3. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test ≤ 4 days before beginning dose regime.
  4. qSOFA ≥ 1
  5. Currently hospitalized
  6. Peripheral capillary oxygen saturation (SpO2) > 94% for moderate patients and < 94% for severe patients or requiring supplemental oxygen at screening.
  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. If patient will be nourished via a nasogastric tube, nasogastric administration of 5-ALA-Phosphate + SFC will be allowed.

Exclusion Criteria:

  1. Subject has acute or chronic type(s) of porphyria or a family history of porphyria.
  2. Subject has demonstrated previous intolerance of 5-ALAPhosphate and/or SFC by topical or oral administration (except for photosensitivity).
  3. Pregnant or nursing women.
  4. Males and females of reproductive potential who have not agreed to use an acceptable method of contraception during the study.
  5. Subjects who are unable or unwilling to comply with requirements of the clinical trial.
  6. Participation in any other clinical trial of an experimental treatment for COVID-19.
  7. Evidence of multiorgan failure.
  8. Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 X upper limit of normal (ULN).
  9. Creatinine clearance < 50 mL/min using the Cockcroft- Gault formula for participants ≥ 18 years of age {Cockcroft1976}.
  10. Subjects who may be excluded at the Investigator's discretion.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04542850


Contacts
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Contact: Abdulla Darwish, Dr 39666023 abdulla.darwish@bdfmedical.org
Contact: Mariam Murad, Dr 33981813 mmurad@rcsi.com

Locations
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Bahrain
Bahrain Defense Force Royal Medical Services, Military Hospital
Manama, Bahrain
Contact: Abdulla Darwish, Dr    39666023    abdulla.darwish@bdfmedical.org   
Sub-Investigator: Abdulrahman Hasan Almadani, Dr         
Sub-Investigator: Jalal Abdullah Al-Kahn, Dr         
Sponsors and Collaborators
Royal College of Surgeons in Ireland - Medical University of Bahrain
Bahrain Defence Force Royal Medical Services, Military Hospital
Investigators
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Principal Investigator: Abdullah Darwish, Dr Bahrain Defense Force Royal Medical Services, Military Hospital
Publications:
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

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Responsible Party: Royal College of Surgeons in Ireland - Medical University of Bahrain
ClinicalTrials.gov Identifier: NCT04542850    
Other Study ID Numbers: 68 / 02-Aug-2020
First Posted: September 9, 2020    Key Record Dates
Last Update Posted: October 8, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Royal College of Surgeons in Ireland - Medical University of Bahrain:
5-ALAPhosphate + SFC
COVID-19