Effects of Nigella Sativa as a Treatment of Patients With Upper Respiratory Tract Infection Caused by SARS-coronavirus-2: a Prospective, Randomized, Open-label, Controlled Clinical Study
Phase: PHASE2
Conditions: COVID-19, SARS-CoV-2
Sponsor: King Abdulaziz University

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Clinical Research Protocol 
Effects of Nigella Sativa as a treatment of patients with upper respiratory 
tract infection caused by SARS-cononavirus-2: a prospective, randomized, open-label, 
controlled clinical study 
Protocol Number: 
NA 
Version Date: 
14.07.2020 
Investigational Product: 
Nigella sativa oil (CUMINMAR) 
IND Number: 
NA 
Development Phase: 
Phase II 
Sponsor: 
Self-sponsored 
King Abdulaziz University 
Jeddah, Saudi Arabia 
Funding Organization: 
NA 
Principal Investigator: 
Name: Dr Abdulrahman Koshak 
 
 
 
E-mail: aekoshak@kau.edu.sa 
 
 

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing [Dr Abdulrahman Koshak] with complete and timely information, as outlined in 
the protocol.  It is understood that all information pertaining to the study will be held 
strictly confidential and that this confidentiality requirement applies to all study staff at this 
site. Furthermore, on behalf of the study staff and myself, I agree to maintain the 
procedures required to carry out the study in accordance with accepted GCP principles and 
to abide by the terms of this protocol. 
 
Protocol Number:  NA 
 
Protocol Title:  Effects of Nigella Sativa as a treatment of patients with upper respiratory 
tract infection caused by SARS-cononavirus-2: a prospective, randomized, open-label, 
controlled clinical study 
 
Protocol Date:  14.07.2020 
 
 
 
14.07.2020 
Investigator Signature  
 
Date 
Dr Abdulrahman Koshak 
Print Name and Title 
Site # 
NA 
 
Site Name 
King Abdulaziz University Hospital 
Address 
Jeddah 21589 
 
Saudi Arabia 
 
 
 
 
Phone Number 
012-6408222 

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TABLE OF CONTENTS 
 
1 
BACKGROUND ................................................................................................................. 4 
1.1 
Overview of Non-Clinical Studies .............................................................................. 10 
1.2 
Overview of Clinical Studies ...................................................................................... 11 
2 
STUDY RATIONALE ........................................................................................................ 12 
2.1 
Risk / Benefit Assessment ........................................................................................... 12 
3 
STUDY OBJECTIVES ....................................................................................................... 13 
3.1 
Primary Objective ....................................................................................................... 13 
3.2 
Secondary Objectives .................................................................................................. 13 
4 
STUDY DESIGN ................................................................................................................. 13 
4.1 
Study Overview ........................................................................................................... 13 
5 
CRITERIA FOR EVALUATION ..................................................................................... 13 
5.1 
Primary Efficacy Endpoint .......................................................................................... 13 
5.2 
Secondary Efficacy Endpoints .................................................................................... 13 
5.3 
Safety Evaluations ....................................................................................................... 14 
5.4 
Other Evaluations (include only if applicable) ........................................................... 14 
6 
SUBJECT SELECTION .................................................................................................... 14 
6.1 
Study Population ......................................................................................................... 14 
6.2 
Inclusion Criteria ......................................................................................................... 14 
6.3 
Exclusion Criteria ....................................................................................................... 14 
7 
CONCURRENT MEDICATIONS .................................................................................... 15 
7.1 
Allowed ....................................................................................................................... 15 
7.2 
Prohibited .................................................................................................................... 15 
8 
STUDY TREATMENTS .................................................................................................... 15 
8.1 
Method of Assigning Subjects to Treatment Groups .................................................. 15 
8.2 
Blinding ....................................................................................................................... 15 
8.3 
Test and Control Formulation ..................................................................................... 15 
8.4 
Supply of Study Medication at the Site ....................................................................... 16 
8.5 
Study Medication Accountability ............................................................................... 16 
8.6 
Measures of Treatment Compliance ........................................................................... 16 
9 
STUDY PROCEDURES AND GUIDELINES ................................................................. 16 
9.1 
Clinical Assessments ................................................................................................... 16 
9.2 
Clinical Laboratory Measurements (include sections as appropriate) ........................ 17 
9.3 
Pharmacokinetic Measurements
 
Error! Bookmark not defined. 
9.4 
Research Laboratory Measurements (include sections as appropriate)
 
Error! Bookmark not defined. 
10 EVALUATIONS BY VISIT ............................................................................................... 17 
10.1 Visit 1 (Day/Week/Month #) ...................................................................................... 17 

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10.2 Visit 2 (Day/Week/Month # include visit window)
 
Error! Bookmark not defined. 
10.3 Visit 3 (Day/Week/Month # include visit window)
 
Error! Bookmark not defined. 
10.4 Visit 4 (Day/Week/Month # include visit window)
 
Error! Bookmark not defined. 
10.5 Visit 5 (Follow-up or Day/Week/Month # include visit window)
 
Error! Bookmark not defined. 
10.6 Early Withdrawal Visit
 
Error! Bookmark not defined. 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................ 18 
11.1 Adverse Events ........................................................................................................... 18 
11.2 Serious Adverse Experiences (SAE) ........................................................................... 19 
11.3 Protocol Defined Important Medical Findings Requiring Real Time Reporting
 
Error! Bookmark not defined. 
11.4 Medical Monitoring .................................................................................................... 19 
11.5 Safety Management Plan............................................................................................. 4 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS................................... 20 
12.1 Withdrawal of Subjects ............................................................................................... 20 
12.3 Replacement of Subjects ............................................................................................. 20 
13 PROTOCOL VIOLATIONS ............................................................................................. 21 
14 DATA SAFETY MONITORING (OPTIONAL SECTION – INCLUDE WHEN 
APPROPRIATE)
 
ERROR! BOOKMARK NOT DEFINED. 
15 STATISTICAL METHODS AND CONSIDERATIONS ............................................... 21 
15.1 Data Sets Analyzed ..................................................................................................... 21 
15.2 Demographic and Baseline Characteristics ................................................................. 21 
15.3 Analysis of Primary Endpoint ..................................................................................... 21 
15.4 Analysis of Secondary Endpoints ............................................................................... 21 
15.5 Interim Analysis
 
Error! Bookmark not defined. 
15.6 Sample Size and Randomization ................................................................................. 21 
16 DATA COLLECTION, RETENTION AND MONITORING ....................................... 22 
16.1 Data Collection Instruments ........................................................................................ 22 
16.2 Data Management Procedures ..................................................................................... 22 
16.3 Data Quality Control and Reporting ........................................................................... 22 
16.4 Archival of Data .......................................................................................................... 22 
16.5 Availability and Retention of Investigational Records ............................................... 22 
16.6 Monitoring .................................................................................................................. 23 
16.7 Subject Confidentiality................................................................................................ 23 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................. 23 
17.1 Protocol Amendments ................................................................................................. 23 
17.2 Institutional Review Boards and Independent Ethics Committees ............................. 23 

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17.3 Informed Consent Form .............................................................................................. 24 
17.4 Publications ................................................................................................................. 24 
17.5 Investigator Responsibilities ....................................................................................... 24 
 

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LIST OF ABBREVIATIONS 
Add all other abbreviations referenced in the protocol and delete any not referenced in 
the protocol. 
NS 
Nigella sativa 
CRF 
case report form 
SFDA 
Saudi Food and Drug Authority 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
SAE 
serious adverse experience 

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PROTOCOL SYNOPSIS 
TITLE 
Effects of Nigella Sativa as a treatment of patients with upper 
respiratory tract infection caused by SARS-cononavirus-2: a 
prospective, randomized, open-label, controlled clinical study 
SPONSOR 
Self-sponsored 
FUNDING 
ORGANIZATION 
NA 
NUMBER OF SITES 
1 
RATIONALE 
The world is currently facing a crisis because of this potentially fatal 
COVID-19 outbreak with no proven efficacy yet of any drug therapy, 
while vaccination is not expected until 2021. Therefore, this study is 
intended to evaluate the potential efficacy for using Nigella sativa 
(NS) oil in patients with COVID-19. 
STUDY DESIGN 
Prospective, two-arm, parallel-group, randomised (1:1 allocation 
ratio), open-label, controlled, exploratory phase II clinical trial 
PRIMARY 
OBJECTIVE 
The primary objective is to assess the clinical efficacy as measured by 
the change in clinical recovery period over the 10 days treatment 
period. 
SECONDARY 
OBJECTIVES 
Assess the effect of NS on COVID-19 symptoms recovery. 
NUMBER OF 
SUBJECTS 
200 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
-Patients with mild COVID19 (defined as upper respiratory tract 
infection symptoms in the absence of clinical or radiological signs of 
pneumonia). 
-Adult (18 - 65 years old). 
-Written informed consent by the patient (or legally authorized 
representative) prior to initiation of any study procedures. 
-All patients should understand and agree to comply with planned 
study procedures. 
-Polymerase chain reaction (PCR)-confirmed infection with Severe 
Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). 
 
Exclusion Criteria: 
-Patients with pneumonia or severe illness requiring admission to 
intensive care unit. 
-Asymptomatic patients. 

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-Severe chronic kidney disease (i.e. estimated glomerular filtration 
rate [eGFR] < 30 mL/min) or end stage renal disease requiring 
dialysis 
-Severe chronic liver disease (Alanine transaminase [AlT] or 
Aspartate transaminase [AST] > 5 times the upper limit of normal). 
-Pregnancy or breast feeding. 
-Anticipated transfer within 72 hours to another hospital that is not a 
study site. 
-Allergy to the study medication. 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
SFDA-licensed Marnys CUMINMAR Nigella sativa oil 500mg 
softgel capsules in oral twice daily dose for 10 days 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
NA 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 14 days 
Screening:  up to 7 days 
Treatment:  10 days 
Follow-up:  14 days 
The total duration of the study is expected to be 12 months 
CONCOMMITANT 
MEDICATIONS 
Allowed: Any medication with no interaction with NS 
Prohibited: ANTICOAGULANT/ANTIPLATELET DRUGS, CNS 
DEPRESSANTS, CYCLOSPORINE, IMMUNOSUPPRESSANTS 
 
EFFICACY 
EVALUATIONS 
Clinical monitoring for 14 days 
PRIMARY ENDPOINT 
Proportion of patients who clinically recovered (defined as 3 days of 
no symptoms) within 14 days after date of onset of symptoms. 
SECONDARY 
ENDPOINTS 
- 
Improvement of Clinical Parameters: 
o Time to full clinical recovery 
o Time to progression to pneumonia or hypoxia 
o Duration of illness 
o Discharge to home 
o Normalization of chest radiograph. 
o Rate of complications: ICU admission, noninvasive ventilator, 
superadded infection 

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o Death. 
- 
Normalization of Routine Laboratory Tests: 
o Complete Blood Count (CBC) 
o Erythrocyte sedimentation rate (ESR) 
o C-reactive protein 
o D-dimer 
o Liver function test 
o Renal function test 
o Lactate Dehydrogenase (LDH), 
o Immunoglobulins (IgA, IgE, IgG, IgM), 
o Compliments (c3, c4), 
o Chest X-ray, CT scan 
o COVID-19 PCR 
o Immune phenotype (CD3 T Cell, CD4 T Cell, CD8 T Cell, CD19 B 
Cell, CD20 B Cell, NK Cell). 
OTHER 
EVALUATIONS 
Inflammatory cytokines (IL-1β, IL-1Ra, IL-2, IL-6, IL-10, INF-alpha, 
INF-gamma, Eotaxin, RANTES & TNF-α). 
SAFETY 
EVALUATIONS 
Incidence of adverse events from the investigational drug or transfer 
to ICU 
 
PLANNED INTERIM 
ANALYSES  
When approximately 50% of patients have completed the study, an 
interim analysis for safety will be conducted by an independent data 
monitoring committee. Serious adverse events will be monitored by 
the research team on an ongoing basis throughout the study. 
STATISTICS 
Primary Analysis Plan 
After 10 days of intervention, the Proportion of patients who clinically 
recovered on day 14 will be compared with control group. Student t 
test will be used to compare means of both groups. 
Rationale for Number 
of Subjects 
To achieve a power of 80% and a two-tailed p-value of <0.05 of an 
assumed 40% difference between the proportion of patients with 
clinical cure among the NS group in comparison with the control 
group, a total of at least 200 patients assigned randomly into the two 
arms (ie 100 patients per arm) will be needed to be included in the 
study as calculated using G*Power version 3.1.9.2 (Heinrich-Heine-
University Düsseldorf, Düsseldorf, Germany). 
 

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1 
BACKGROUND 
The clinical disease termed COVID-19 is caused by a novel betacorona virus, now named 
SARS-CoV-2. The most common symptoms being reported are fever, cough or chest 
tightness, and dyspnoea. Most cases are reported to experience a mild illness course (1). 
Thirty-two per cent required intensive care unit (ICU) admission for respiratory support 
(1). Laboratory features in this case series commonly included leukopenia, lymphopenia 
and raised aspartate aminotransferase (1). An epidemiological study of 99 cases of 2019 
novel coronavirus pneumonia in Wuhan, China. found an overall mortality rate of 11% 
with 23% of patients requiring ICU admission (1). Currently, the World Health 
Organization (WHO) upgraded the status of the COVID-19 outbreak from epidemic to 
pandemic. In Saudi Arabia, the number of cases of infection with COVID-19 continues to 
be markedly increasing over the last couple of weeks (2). 
Given no specific proven antiviral therapy or vaccination available for COVID-19, the 
Nigella sativa (NS) seed oil is suggested as a potential supplement due to its known 
immunostimulant and antiviral activities in previous published studies (3,4). Fortunately, 
NS oil is available as an oral softgel capsules in commercial pharmacies in Saudi Arabia 
and licensed by the Saudi Food and Drug Authority (SFDA). 
NS (known as Black seed) in Latin language or “Habatulbarakah” in Arabic language, is a 
well-known food supplement and medicinal plant in the Arabic and Islamic culture. It is 
used as a food spice and it has plenty of medical claims that originate from different 
historical backgrounds. The seeds of NS contain several active compounds that have been 
isolated, identified and reported, most importantly thymoquinone. 
In the literature, NS showed several pharmacological activities including anti-
inflammatory, anti-viral, and immunostimulatory activities (3,4). 
1.1 
Overview of Non-Clinical Studies 
Regarding antiviral activity, NS oil was found to suppress viral load of Murine 
cytomegalovirus (MCNV) in infected mice to undetectable level in the liver and spleen in 
10 days’ intraperitoneal administration (5). This was possibly due to the increase in number 
and function of T cells and increased production of interferon-gamma. In addition, a review 
article discussed the potential antiviral activities of NS on different viruses including avian 
influenza (H9N2) in animal models. Interestingly, an in-vitro study showed the virus load 
decreased significantly when NS extract was added to the CoV infected cells and increased 
Interleukin-8 secretion (6). 
Regarding immunostimulant activity, NS oil was found to exhibit nonspecific 
immunostimulant effect and able to induce cellular immune response as increasing 
lymphocytes pathogenesis and macrophage activities percent and macrophage index. It was 
found that it enhances T cells, natural killer cell activity and both interleukin-IB (IL-IB) 
and interleukine-3 (IL-3). Based on animal study, treatment with NS oil increased the 
phagocytic activity and phagocytic index of peritoneal macrophages and lymphocyte count 
in peripheral blood in diabetic hamsters (3). NS also reversed the  Immunosuppression 
induced by lead and calcium in animal study. Based on laboratory study, a melanin extract 
from NS may induce the expression of three cytokines (TNF-alpha "Tumor necrosis factor 

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alpha", IL-6 and VEGF "Vascular endothelial growth factor") that enhance 
immunogenicity (3). 
Moreover, NS has also been shown to modulate the immune system by altering levels of 
inflammatory mediators (7). Also, due to other activities of NS such as anti-inflammatory, 
analgesic, antipyretic and bronchodilatation it may be beneficial to minimize the symptoms 
in COVID-19 patients (8,9,10). 
1.2 
Overview of Clinical Studies 
In a clinical study, 30 patients with hepatitis C virus (HCV) infection, who were not 
eligible for IFN- α/ribavirin therapy showed significant improvement in HCV viral load 
(16.67% became seronegative and 50% showing significant decrement) after NS course 
given over 3 months (4). In addition, according to a case report conducted by Onifade et 
al., after treatment with 10 mL of black seed twice daily for 6 months, a complete regaining 
and seroreversion of a 46-year-old HIV positive patient was evidenced (4). 
References 
1. Lake MA. What we know so far: COVID-19 current clinical knowledge and research. 
Clin Med [Internet]. 2020 Mar 5 [cited 2020 Mar 27];20(2):124–7. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/32139372 
2. Control TSC for DP and. Publications [Internet]. [cited 2020 Mar 27]. Available from: 
https://covid19.cdc.gov.sa/professionals-health-workers/publications/ 
3. Ahmad A, Husain A, Mujeeb M, Khan SA, Najmi AK, Siddique NA, et al. A review on 
therapeutic potential of Nigella sativa: A miracle herb. Asian Pac J Trop Biomed 
[Internet]. 2013 May [cited 2013 Mar 20];3(5):337–52. Available from: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3642442&tool=pmcentrez&re
ndertype=abstract 
4. Molla S, Abul M, Azad K, Azam A, Hasib A, Monayem Hossain M, et al. A REVIEW ON 
ANTIVIRAL EFFECTS OF NIGELLA SATIVA L. pharmacologyonline [Internet]. 2019 
[cited 2020 Mar 18];2:47–53. 
Available from: http://pharmacologyonline.silae.it 
5. Yimer EM, Tuem KB, Karim A, Ur-Rehman N, Anwar F. Nigella sativa L. (Black 
Cumin): A Promising Natural Remedy for Wide Range of Illnesses. Evid Based 
Complement Alternat Med [Internet]. 2019 [cited 2020 Mar 18];2019:1528635. Available 
from: http://www.ncbi.nlm.nih.gov/pubmed/31214267 
6. Ulasli M, Gurses SA, Bayraktar R, Yumrutas O, Oztuzcu S, Igci M, et al. The effects of 
Nigella sativa (Ns), Anthemis hyalina (Ah) and Citrus sinensis (Cs) extracts on the 
replication of coronavirus and the expression of TRP genes family. Mol Biol Rep. 
2014;41(3):1703–11. 
7. Islam T. Nigellalogy: A Review on Nigella Sativa. MOJ Bioequivalence Bioavailab. 
2017 Sep 25;3(6). 
8. Koshak A, Wei L, Koshak E, Wali S, Alamoudi O, Demerdash A, et al. 
Immunomodulatory effects of Nigella sativa oil supplementation in patients with asthma: 

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an RCT. In: The UCL Institute of Immunity and Transplantation Annual Immunology 
Symposium with Pears Lecture. Royal Free Campus, University College London, London, 
UK: The UCL Institute of Immunity and Transplantation; 2016. 
9. Mady WH, Mady WH, Arafa A, Hussein AS, Aly MM, Madbouly HM. Nigella Sativa Oil 
as an Immunostimulant Adjuvant in H5 Based DNA Vaccine of H5N1 Avian Influenza 
Virus Based DNA Vaccine Highly Pathogenic Avian Influenza Virus H5N1 Nigella Sativa 
Oil Adjuvant Cell Mediated Immune Response Protective Efficacy Of H5 DNA Vaccine. 
Glob Vet. 2013;10(6):663–8. 
10. Al-Ghamdi MS. The anti-inflammatory, analgesic and antipyretic activity of Nigella 
sativa. J Ethnopharmacol. 2001 Jun 1;76(1):45–8. 
11. Gilani AH, Aziz N, Khurram IM, Chaudhary KS, Iqbal A. Bronchodilator, spasmolytic 
and calcium antagonist activities of Nigella sativa seeds (Kalonji): A traditional herbal 
product with multiple medicinal uses. J Pak Med Assoc [Internet]. 2001 Mar [cited 2016 
Sep 11];51(3):115–20. Available from: 
http://jpma.org.pk/full_article_text.php?article_id=2562 
12. Boskabady MH, Keyhanmanesh R, Khamneh S, Ebrahimi MA. The effect of Nigella 
sativa extract on tracheal responsiveness and lung inflammation in ovalbumin-sensitized 
guinea pigs. Clinics [Internet]. 2011 [cited 2014 May 28];66(5):879–87. Available from: 
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807- 
59322011000500027&lng=en&nrm=iso&tlng=en 
13. Koshak A, Wei L, Koshak E, Wali S, Alamoudi O, Demerdash A, et al. Nigella sativa 
Supplementation Improves Asthma Control and Biomarkers: A Randomized, Double-Blind, 
Placebo-Controlled Trial. Phyther Res [Internet]. 2017 Jan 17 [cited 2017 Feb 1]; 
Available from: http://doi.wiley.com/10.1002/ptr.5761 
2 
STUDY RATIONALE 
Today in the era of evidence-based medicine, it is hard to accept those traditional medical claims of medicinal 
plants without valid scientific experiments. Yet, it is important to rational the uses of these plants based on 
clinical evidence. Moreover, the world is currently facing a crisis because of this potentially fatal COVID-19 
outbreak with no proven efficacy yet of any drug therapy, while vaccination is not expected until 2021. 
Therefore, this study is intended to evaluate the potential efficacy for using NS in patients with COVID-19 
2.1 
Risk / Benefit Assessment 
Potential benefits to individual participant: Anti-inflammatory and immunodulatory effects 
to enhance the recovery from COVID-19 
Herbal product quality and safety: The Black Seed capsules (Cuminmar) are manufactured 
according to high standards of herbal product manufacturing facility and under GMP 
guidelines by Marnys Company. This product is licensed in Saudi Arabia under the local 
regulations (Saudi Food and Drug Authority) ensuring the quality and safety of drugs and 
sold in Saudi community pharmacies.  
Investigators and Patient Safety: All procedures including patient diagnosis, primary and 
secondary endpoints measurements will be carried by specialist fully qualified medical 
doctors pharmacist inside King Abdulaziz university’s hospital. 

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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to assess the clinical efficacy as measured by the change in 
clinical recovery period over the 10 days treatment period. 
3.2 
Secondary Objectives 
Assess the effect of NS on COVID-19 symptoms recovery. 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a single center, open-label, controlled, randomized, phase II clinical trial.  200 of 
subjects are planned.  Each subject will be administered a single dose (500 mg) of study 
drug twice daily for 10 days. Subjects will be assigned to the treatments in random order.  
Evaluations will be taken daily for evaulationg symptoms imrovpment.  
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be entered into the study.  
The following treatment regimens will be used: 
• 
Experimental treatment NS at the following dose 500 mg twice daily  
• 
Comparator – Standard care for COVID-19 
Total duration of subject participation will be 14 days. Total duration of the study is 
expected to be 12 months. 
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
Proportion of patients who clinically recovered (defined as 3 days of no symptoms) within 
14 days after date of onset of symptoms. 
5.2 
Secondary Efficacy Endpoints 
- 
Improvement of Clinical Parameters: 
o Time to full clinical recovery 
o Time to progression to pneumonia or hypoxia 
o Duration of illness 
o Discharge to home 
o Normalization of chest radiograph. 
o Rate of complications: ICU admission, noninvasive ventilator, superadded infection 
o Death. 
- 
Normalization of Routine Laboratory Tests: 
o Complete Blood Count (CBC) 

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o Erythrocyte sedimentation rate (ESR) 
o C-reactive protein 
o D-dimer 
o Liver function test 
o Renal function test 
o Lactate Dehydrogenase (LDH), 
o Immunoglobulins (IgA, IgE, IgG, IgM), 
o Compliments (c3, c4), 
o Chest X-ray, CT scan 
o COVID-19 PCR 
o Immune phenotype (CD3 T Cell, CD4 T Cell, CD8 T Cell, CD19 B Cell, CD20 B Cell, 
NK Cell) 
- 
Additional: 
o Inflammatory cytokines (IL-1β, IL-1Ra, IL-2, IL-6, IL-10, INF-alpha, INF-gamma, 
Eotaxin, RANTES & TNF-α). 
5.3 
Safety Evaluations 
Incidence of adverse events from the investigational drug or transfer to ICU 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with a diagnosis of mild to moderate COVID-19 who meet the inclusion and 
exclusion criteria will be eligible for participation in this study.   
6.2 
Inclusion Criteria 
-Patients with mild COVID19 (defined as upper respiratory tract infection symptoms in the 
absence of clinical or radiological signs of pneumonia). 
-Adult (18 - 65 years old). 
-Written informed consent by the patient (or legally authorized representative) prior to 
initiation of any study procedures. 
-All patients should understand and agree to comply with planned study procedures. 
-Polymerase chain reaction (PCR)-confirmed infection with Severe Acute Respiratory 
Syndrome Coronavirus-2 (SARS-CoV-2). 
6.3 
Exclusion Criteria 
-Patients with pneumonia or severe illness requiring admission to intensive care unit. 
-Asymptomatic patients. 
-Severe chronic kidney disease (i.e. estimated glomerular filtration rate [eGFR] < 30 
mL/min) or end stage renal disease requiring dialysis 

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-Severe chronic liver disease (Alanine transaminase [AlT] or Aspartate transaminase [AST] 
> 5 times the upper limit of normal). 
-Pregnancy or breast feeding. 
-Anticipated transfer within 72 hours to another hospital that is not a study site. 
-Allergy to the study medication. 
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies. 
7.1 
Allowed Medications and Treatments 
Standard therapy for COVID-19 is allowed except for treatments noted in the exclusion 
criteria described above and as noted in the prohibited medications section below.   
Prohibited Medications and Treatments: ANTICOAGULANT/ANTIPLATELET DRUGS, 
CNS DEPRESSANTS, CYCLOSPORINE, IMMUNOSUPPRESSANTS 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Up to 200 eligible patients will be randomly assigned to treatment or control groups in a 
1:1 ratio using a computer-generated randomization scheme developed by 
http://www.randomization.com. 
8.2 
Blinding 
NA 
8.3 
Formulation of Test and Control Products 
SFDA-licensed Marnys CUMINMAR Nigella sativa oil 500mg softgel oral capsules. 
No control product will be used. 
 
8.3.1 
Packaging and Labeling 
Packaging: Study drug is supplied in cartons containing 3 strips of 20 single dose each.  
Each patient will receive 1 strip (20 single dose).  
Labeling example: Each strip study drug will be labeled with the required SFDA statement, 
the protocol number, a treatment number, the name of the sponsors, and directions for 
patient use and storage. 
8.4 
Supply of Study Drug at the Site 
The Sponsor will ship Study Drug to the investigational sites.  The initial study drug 
shipment will be shipped after site activation (i.e., all required regulatory documentation 

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has been received by the Sponsor and a contract has been executed). Subsequent study drug 
shipments will be made after site request for resupply. 
8.4.1 
Dosage/Dosage Regimen 
Nigella sativa oil 500mg softgel capsules in oral twice daily dose for 10 days 
8.4.2 
Dispensing 
The investigator will dispense the drug at the participation site 
8.4.3 
Administration Instructions  
Take 1 capsule with plenty glass of water. 
8.5 
Supply of Study Drug at the Site 
the study drug will be delivered from the supplier to the investigational site.   
8.5.1 
Storage 
Study drug should be stored by the study site at controlled room temperature, 15 to 25ºC in a 
dry place away from light. If the temperature of study drug storage in the clinic/pharmacy 
exceeds or falls below this range, this should be reported to the Sponsor or designee and 
captured as a deviation. Subjects will be instructed to store the medication in original 
packaging at room temperature according to the instructions outlined on the Drug 
Administration Instructions. 
8.6 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by the investigator.   
8.7 
Measures of Treatment Compliance 
Subjects will be monitored on daily bases during the study period for their study drug 
intake and any adverse events. 
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, informed consent will be taken by the 
subject or subject’s legal representative.  If appropriate, assent must also be obtained prior 
to conducting any study-related activities. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening and at Study Days and at early termination when applicable.  Dose, 

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route, unit frequency of administration, and indication for administration and dates of 
medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Screening. 
9.1.4 
Physical Examination 
A complete physical examination will be performed by either the physician of the research 
team at study site. Qualified staff (MD, NP, RN, and PA) may complete the abbreviated 
physical exam at all other visits.  New abnormal physical exam findings must be 
documented and will be followed by a physician or other qualified staff. 
9.1.5 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation to 
study drug will be recorded on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements 
NA 
10 EVALUATIONS BY VISIT 
10.1 Visit 1 (Day 1) 
1. 
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent. 
2. 
Assign the subject a unique screening number. 
3. 
Record demographics data. 
4. 
Record medical history, diagnosis date. 
5. 
Record concomitant medications. 
6. 
Randomize subject,  
7. 
Dispense study drug,  
8. 
Initiate subject diary in CRF. 
10.2 14 days monitoring 
1. 
Record patients’ symptoms 
2. 
Record any Adverse Experiences and dosing compliance. 
3. 
Concomitant medications review. 

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11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with 
the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to study 
drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including laboratory 
abnormalities judged to be clinically significant. The modified criteria can be found in the 
study manual.  If the experience is not covered in the modified criteria, the guidelines 
shown in Table 1 below should be used to grade severity.  It should be pointed out that the 
term “severe” is a measure of intensity and that a severe AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 

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Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to prevent 
one of the outcomes listed.  
 
11.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
SFDA Guidelines.  The collection period for all SAEs will begin after informed consent is 
obtained and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
11.3 Medical Monitoring 
Dr Abdulrahman Koshak should be contacted directly at these numbers to report medical 
concerns or questions regarding safety. 

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Phone: +966 543292333 
   
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  The 
following is a list of possible reasons for study treatment discontinuation:  
• 
Subject withdrawal of consent (or assent) 
• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment 
• 
Protocol violation requiring discontinuation of study treatment 
• 
Lost to follow-up 
• 
Sponsor request for early termination of study 
• 
Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the medical research team until the abnormal parameter or 
symptom has resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents Refer to Section 10 for early termination procedures. 
12.3 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  As noted above, subjects who discontinue study treatment 
early (i.e., they withdraw prior to Visit 1) should have an early discontinuation visit. Refer 
to Section 10 for early termination procedures.  Subjects who withdraw after Visit 1 should 

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be encouraged to come in for a final visit (and the procedures to be followed would include 
those for their next scheduled visit).   
12.4 
Replacement of Subjects 
Subjects who withdraw from the study treatment will be replaced.   
 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
• 
Failure to meet inclusion/exclusion criteria 
• 
Use of a prohibited concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Sponsor will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
14 STATISTICAL METHODS AND CONSIDERATIONS 
14.1 Data Sets Analyzed 
All dosed subjects will be included in data analysis 
14.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized by dose level: 
gender, age, height and weight.   
14.3 Analysis of Primary Endpoint 
Student t test will be used for significance analysis. 
14.4 Analysis of Secondary Endpoints 
Student t test will be used for significance analysis. 
14.5 Sample Size and Randomization 
 
To achieve a power of 80% and a two-tailed p-value of <0.05 of an assumed 40% 
difference between the proportion of patients with clinical cure among the NS group in 
comparison with the control group, a total of at least 200 patients assigned randomly into 
the two arms (ie 100 patients per arm) will be needed to be included in the study as 

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calculated using G*Power version 3.1.9.2 (Heinrich-Heine-University Düsseldorf, 
Düsseldorf, Germany). 
 
15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with the 
study drug.   
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific paper CRF when the information corresponding to 
that visit is available.  Subjects will not be identified by name in the study database or on 
any study documents to be collected by the Sponsor (or designee), but will be identified by 
a subject number. 
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study. 
15.2 Data Management Procedures 
The data will be entered into a validated database.  The investigator will be responsible for 
data processing, in accordance with procedural documentation. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting SFDA guidelines for the handling and analysis of data for 
clinical trials. 
15.3 Data Quality Control and Reporting 
NA 
15.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
15.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., 
SFDA) inspectors upon request.  A file for each subject must be maintained that includes 
the CRF.  The Investigator must ensure the reliability and availability of source documents 
from which the information on the CRF was derived. 

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All study documents (copies of CRFs) must be kept secured for a period of two years 
following marketing of the investigational product or for two years after centers have been 
notified that the IND has been discontinued.  There may be other circumstances for which 
the Sponsor is required to maintain study records and, therefore, the Sponsor should be 
contacted prior to removing study records for any reason. 
15.6 Monitoring 
NA 
15.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and subject 
initials will identify all study subjects on CRFs and other documentation submitted to the 
Sponsor.  Additional subject confidentiality issues (if applicable) are covered in the 
Clinical Study Agreement. 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of 
Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the SFDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act of 
1996, EU Data Protection Directive 95/46/EC). 
16.1 Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor.  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 
eliminate immediate safety hazards to patients.  A protocol amendment intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days. 
16.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of King 
Abdulaziz University Hospital.  Serious adverse experiences regardless of causality will be 
reported to the IRB/IEC in accordance with the standard operating procedures and policies 
of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress of 
the study.  The Investigator will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 

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will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  This approval must refer to the study by exact protocol title 
and number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
16.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form and submit to the IRB/IEC.  The 
consent form generated by the Investigator must be acceptable to the Sponsor and be 
approved by the IRB/IEC.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will 
also comply with local regulations. The Investigator will send an IRB/IEC-approved copy 
of the Informed Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, verbal informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to 
inquire about details of the study.  If appropriate and required by the local IRB/IEC, assent 
from the subject will also be obtained. 
16.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
16.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 

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1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally, conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to include 
amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312