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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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SARS-CoV 2, COVID-19

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 to 70 years Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test before beginning study dose regime qSOFA ≥ 1 Currently hospitalized 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). Radiographic evidence (chest X-ray or chest CT scan) of pulmonary infiltrates Able to swallow 5 capsules of study product at dosing time points. Exclusion Criteria: 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. Subject is nourished via a nasogastric tube 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 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 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 Evidence of multiorgan failure Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 X upper limit of normal (ULN) Creatinine clearance < 50 mL/min using the Cockcroft-Gault formula for participants ≥ 18 years of age {Cockcroft 1976} Any other reason that makes the subject unsuitable in the Investigator's opinion

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Moderate group and Severe Group<br>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)<br>* 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<br>|

What is the study measuring?
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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 | 

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