Clinical trial NCT04542850: Pilot Study to Evaluate the Safety, Tolerability, and Efficacy of 5-ALA-Phosphate + SFC in Subjects With COVID-19
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: SARS-CoV 2
COVID-19
Keywords: 5-ALAPhosphate + SFC
COVID-19
Lead sponsor: Royal College of Surgeons in Ireland - Medical University of Bahrain
Sponsor class: OTHER
Collaborators: name: Bahrain Defence Force Hospital
name: Salmaniya Medical Complex
First posted: 2020-09-09
Enrollment: 15
Sex: ALL
Minimum age (years): 21
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
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).
Primary purpose: TREATMENT

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.

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.

Eligibility 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 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

Primary outcomes:
measure: 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).
timeFrame: 28 days
Secondary outcomes:
measure: Sum COVID-19 Modified Ordinal Scale for Clinical Improvement maximum daily score over 28 days of dosing for Moderate group and for Severe group
timeFrame: 28 days
measure: 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
timeFrame: 28 days
measure: Patient and subgroup profile of COVID-19 Modified Ordinal Scale for Clinical Improvement score vs. days hospitalized
timeFrame: 28 days
measure: Overall survival
timeFrame: day 14 and day 28
measure: Results of investigator´s assessment of patient´s oxygen therapy
timeFrame: 28 days
measure: Results of mechanical ventilation settings
timeFrame: 28 days
measure: Results of duration of ventilation
timeFrame: from date of enrolment until the extubation or until last 5-ALA- Phosphate -SFC administration on day 28
measure: The time to resolution of patient´s symptoms
timeFrame: 28 days
measure: Results of patient´s oxygen saturation (respiratory parameters)
timeFrame: 28 days
measure: Length of hospitalization
timeFrame: From date of enrolment until last 5-ALA- Phosphate -SFC administration at day 28
measure: The total time in ICU
timeFrame: From date of enrolment until last 5-ALA- Phosphate -SFC administration at day 28
measure: Results of investigator´s assessment of patient´s condition using (q)SOFA score
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results of patient´s PT parameter
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results of patient´s D-Dimer parameter
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results of patient´s PTT parameter
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results of patient´s SARS-CoV-2 viral load status (efficacy)
timeFrame: day 7, 14 and 28
measure: Results of patient´s Procalcitonin level.
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results of patient´s IL-6 level
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results of patient´s Serum Ferritin level
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results of patient´s C-Reactive protein (CRP) level
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results of patient´s T helper cells (CD4/CD8) level.
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results of patient´s Bilirubin level.
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Leucocytes
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Neutrophils
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Lymphocyte
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Platelets
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Hemoglobin
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Albumin
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s AST
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s ALT
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Total bilirubin
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Blood urea nitrogen
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Serum creatinine
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Creatinine kinase
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s LDH
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Myoglobin glucose
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s aPTT
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s urine
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on hepatic function
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s renal function
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s iron parameters
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s physical examination
timeFrame: day 0, 2, 3, 5, 7, 10, 14, 21, 28
measure: Results on patient´s Co-infections
timeFrame: 28 days
measure: Results on patient´s Care Level
timeFrame: 28 days
measure: Results on patient´s Mean arterial pressure(MAP)
timeFrame: 28 days
measure: Results on patient´s heart rate (HR)
timeFrame: 28 days
measure: Results on patient´s respiratory rate (RR)
timeFrame: 28 days
measure: Results on patient´s 12-lead ECG
timeFrame: day 0, 7, 14 and 28
measure: Organ damage
timeFrame: 28 days
Other outcomes:
Locations:
city: Manama
country: Bahrain
facility: Bahrain Defense Force Royal Medical Services, Military Hospital
city: Manama
country: Bahrain
facility: Salmaniya Medical Complex
Study officials:
affiliation: Bahrain Defense Force Royal Medical Services, Military Hospital
name: Abdullah Darwish, Dr
role: PRINCIPAL_INVESTIGATOR
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