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

COVID-19 Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04542850
• Other study ID #: 68 / 02-Aug-2020
• Status: Completed
• Phase: N/A
• Start date: November 15, 2020
• Est. completion date: October 28, 2021

Study information

• Verified date: August 2021
• Source: Royal College of Surgeons in Ireland - Medical University of Bahrain
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: October 28, 2021
• Est. primary completion date: August 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• COVID-19
• SARS-CoV 2

Intervention

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

Locations

Country	Name	City	State
Bahrain	Bahrain Defense Force Royal Medical Services, Military Hospital	Manama
Bahrain	Salmaniya Medical Complex	Manama

Sponsors (3)

Lead Sponsor	Collaborator
Royal College of Surgeons in Ireland - Medical University of Bahrain	Bahrain Defence Force Hospital, Salmaniya Medical Complex

Country where clinical trial is conducted

Bahrain, 

References & Publications (19)

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)

Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. — View Citation

Devadas K, Dhawan S. Hemin activation ameliorates HIV-1 infection via heme oxygenase-1 induction. J Immunol. 2006 Apr 1;176(7):4252-7. — View Citation

El Kalamouni C, Frumence E, Bos S, Turpin J, Nativel B, Harrabi W, Wilkinson DA, Meilhac O, Gadea G, Desprès P, Krejbich-Trotot P, Viranaïcken W. Subversion of the Heme Oxygenase-1 Antiviral Activity by Zika Virus. Viruses. 2018 Dec 20;11(1). pii: E2. doi: 10.3390/v11010002. — View Citation

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. — View Citation

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. Review. Erratum in: Cell Stress Chaperones. 2020 Jun 29;:. — View Citation

Ibáñez FJ, Farías MA, Retamal-Díaz A, Espinoza JA, Kalergis AM, González 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. — View Citation

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

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. — View Citation

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)

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. — View Citation

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. — View Citation

Protzer U, Seyfried S, Quasdorff M, Sass G, Svorcova M, Webb D, Bohne F, Hösel 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. Epub 2007 Jul 25. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Overall survival	To describe time until death from any cause	day 14 and day 28
Secondary	Results of investigator´s assessment of patient´s oxygen therapy	To describe patient´s blood oxygenation	28 days
Secondary	Results of mechanical ventilation settings	To describe mechanical ventilation settings course during study.	28 days
Secondary	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
Secondary	The time to resolution of patient´s symptoms	To describe patient´s specific symptoms course during study.	28 days
Secondary	Results of patient´s oxygen saturation (respiratory parameters)	To describe patient´s oxygen saturation course during study.	28 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Results on patient´s Co-infections	To describe patient's Co-infections course during study.	28 days
Secondary	Results on patient´s Care Level	To describe patient´s care level course during study.	28 days
Secondary	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
Secondary	Results on patient´s heart rate (HR)	To describe patient´s vital signs course during study by evaluating heart rate (HR)	28 days
Secondary	Results on patient´s respiratory rate (RR)	To describe patient´s vital signs course during study by evaluating respiratory rate (RR)	28 days
Secondary	Results on patient´s 12-lead ECG	To describe patient´s 12-lead ECG result course during study.	day 0, 7, 14 and 28
Secondary	Organ damage	To describe patient´s organ damage status during the study	28 days