Beating the Beast: Best Current Pharmacological Modalities for Treating Covid-19 Infection

Beating the Beast: Best Current
Pharmacological Modalities for
Treating Covid-19 Infection
Dr. Imad Salah Ahmed Hassan MD Immunology (UK),
MSc Infectious Diseases (UK), FACP, FRCPI
Head of Section, Medical Protocol Department,
King Abdulaziz Medical City, Riyadh,
Kingdom of Saudi Arabia

 Empower the audience with the
current “effective” therapeutic
modalities based on Systematic
Reviews of these interventions.
Aim of the Presentation: Towards ZERO Mortality!

 The Challenge of Covid-19
 Background Knowledge
 Evidence-based Interventions
 Recommendations
The Roadmap

4 April 2021
Cases
392,682
Recovered
379,816
Deaths
6,697
Deaths Rate
(Case Fatality Rate)
Approx.:1.7%
(22% lower than World
Rate)
The Challenge
of Covid-19

Covid-19 Challenge
4 April 2021
Cases
131,501,898
Recovered
105,905,371
Deaths
2,861,564
Death Rate:
(Case Fatality
Rate)
Approx. 2.2%
The Challenge
of Covid-19

Covid-19 Challenge
Non-ICU Mortality Rate
11.5%
(95% CI 7.7; 16.9, I2 =
96.7%)
ICU-Mortality Rate
40.5%
(95% CI 31.2; 50.6, I2 =
91.8%)
The Challenge
of Covid-19
COVID-19 fatality rates in hospitalized patients: systematic review and meta-analysis. Macedo A, et
al. Ann Epidemiol. 2021 Mar 2;57:14-21.

 The Evidence Pyramid
 Systematic Reviews
 Meta-analysis
 Forest Plot
 Network Meta-analysis
 GRADE Tool
Some EBM Jargon!

The Evidence Pyramid
What is
Best
Evidence?
Hierarchy
of Levels of
Evidence-
Top of
Pyramid
is best!

“…a scientific investigation that focuses on
a specific question (intervention and health
issue) and uses explicit, pre-specified
scientific methods to identify, select, assess
(critically appraise), and summarize the
findings of similar but separate studies.”
What is a Systematic Review?

Statistical methods (meta-
analysis) may or may not be
used to analyze and
summarize the results of the
included studies.
What is a Systematic Review & Meta-analysis?

Forest Plot
A graphical
summary of
the findings
of a
Systematic
Review
No effect
Study
Meta-an.

● Traditional meta-analysis:
● Is treatment A better than
treatment B?
What is a Network Meta-analysis?

● What if there are more than
10 other treatments for this
condition?
● Which one to choose?

The real clinical question
A B
C
D
E
F
Which of the six available treatments is the most effective and
safest?
Is treatment B better than treatment F?

● Networks: using indirect
comparisons
 If we know how much taller building B is to A
and how much taller is C to A, we know how
much taller is B compared to C.
 For any pair B and C, typical difference of C
over B = difference of C over A minus
difference of B over A.

● "Network meta-analysis
compares multiple interventions
simultaneously by analyzing
studies making different
comparisons in the same
analysis."
● (Source: M. Petticrew et al (2013)

● Network meta-analyses are best designed for:
• Conditions with multiple interventions
• Many combinations of direct or indirect interactions
• To answer more relevant clinical questions
● To make treatment estimates for an entire treatment network instead of
scanning each individual pair-wise comparison
• To give the "full picture" to clinicians
• Gain precision by considering all available evidence, not just (A vs. B
comparisons)
• Potential to more explicitly "rank" treatments using summary outputs
(Rankogram)

The review identified
3249 citations, and 46
randomized controlled
trials met inclusion
criteria; 27 trials
contained sufficient or
appropriate data for
inclusion in the
analysis.
Efficacy of drug treatments for generalized anxiety disorder: systematic review and meta-analysis.
Baldwin D, et al. BMJ. 2011.

In the primary probabilistic mixed
treatment meta-analyses, fluoxetine
was ranked first for response and
remission (probability of 62.9% and
60.6%, respectively) and sertraline
was ranked first for tolerability
(49.3%) etc.
Efficacy of drug treatments for generalized anxiety disorder:
systematic review and meta-analysis.Baldwin D, et al. BMJ. 2011.

● GRADE (Grading of Recommendations, Assessment,
Development and Evaluations) is a transparent framework for
developing and presenting summaries of evidence and provides
a systematic approach for making clinical practice
recommendations.
● It is the most widely adopted tool for grading the quality of
evidence and for making recommendations with over 100
organizations worldwide officially endorsing GRADE.
What is a GRADE?

Table 1. GRADE certainty ratings
Certainty What it means
High
The authors have a lot of confidence that the true
effect is similar to the estimated effect
Moderate
The authors believe that the true effect is probably
close to the estimated effect
Low
The true effect might be markedly different from
the estimated effect
Very low
The true effect is probably markedly different from
the estimated effect

● Comparative efficacy and safety of
pharmacological interventions for the
treatment of COVID-19: A systematic
review and network meta-analysis.
● Kim MS, et al. PLoS Med. Impact factor:
10.500 (2019)
● Published: December 30, 2020
Covid-19 Network Meta-analysis

Inclusion Criteria:
 Pharmacological interventions
 Moderate to severe disease (Hospitalized): Mild patients who do
not require hospitalization or have self-limiting disease courses
were not eligible.
 Randomized controlled trials (RCTs)
 Confounding-adjusted observational studies.
 Age more than 18 years.

Definitions:
 Moderate-severe patients were defined as patients
hospitalized in a non-ICU setting at admission.
 A critically ill patient was defined as a patient who
received invasive mechanical ventilation or needed
intensive care in the ICU before or soon after beginning
the treatment of interest.

Definitions:
 For corticosteroids, average daily dosage of 40 mg
methylprednisolone (or equivalent) was regarded as the
standard dosage, while 1 to 2 mg/kg/day methylprednisolone
(or equivalent) was regarded as high dose.
 A total of 1 mg methylprednisolone was considered equivalent
to 0.1875 mg dexamethasone and 5 mg hydrocortisone.
40 mg Methylprednisolone= 7.5 mg Dexamethasone

Outcomes: The outcomes of interest were:
● Mortality
● Progression to severe disease (severe pneumonia, admission
to intensive care unit (ICU), and/or mechanical ventilation)
● Viral clearance rate
● Cardiac Complications: QT prolongation, fatal cardiac
complications
● Non-cardiac serious adverse events.

●Literature Search:
● PubMed, Google Scholar, MEDLINE, the Cochrane
Library, medRxiv, SSRN, WHO International Clinical
Trials Registry Platform, and ClinicalTrials.gov were
searched from the beginning of 2020 to August 24, 2020.

Literature Search:
 The initial search identified 6,209 articles.
 A total of 110 studies (40 RCTs and 70 Observational studies OS) were
included in the NWM.
 Studies from Asia (41 countries, 37.2%), Europe (28 countries, 25.4%),
North America (24 countries, 21.8%), South America (5 countries,
4.5%), and Middle East (6 countries, 5.4%), and additional 6
multinational studies (5.4%) were included in our analyses.

● Literature Search:
 47 Pharmacological Interventions
 49,569 COVID-19 patients

Mortality,
non-ICU
setting
compared
to the
control
group
Drug/No. of Studies Type of Study Magnitude of Effect GRADE
Corticosteroids RCT (OR 0.78, 95% CI
0.66 to 0.91, p = 0.002)
High
Remdesivir (4)
(RNA Polymerase Inhibitor)
RCT (OR 0.62, 95% CI 0.39 to 0.98, p =
0.041)
High
Sofosbuvir
Plus Daclatasvir (3)
RCT (OR 0.26, 95% CI 0.07 to 0.88, p =
0.030)
High
High-Dose Corticosteroid
(7)
OS (OR 0.38, 95% CI 0.24 to 0.63, p <
0.001)
Moderate
Tocilizumab
(IL6 Inhibitor)
OS (OR 0.43, 95% CI 0.30 to 0.60, p <
0.001)
Low
Convalescent
Plasma (3)
OS (OR 0.48, 95% CI 0.24 to 0.96, p =
0.038)
Low
Interferon-A2b OS (OR 0.05, 95% CI 0.01 to 0.39,
p = 0.004)
Very Low
Itolizumab OS (OR 0.10, 95% CI 0.01 to 0.92, p =
0.042)
Very Low
Anakinra
(IL-1 receptor
antagonist)
OS (OR 0.30,
95% CI 0.11 to 0.82, p = 0.019)
Very Low
Plus Tocilizumab
OS (OR 0.04, 95% CI
0.01 to 0.17, p < 0.001)
very low

Mortality,
ICU
setting
compared
to the
control
group
Drug/No. of
Studies
Type of Study Magnitude of Effect GRADE
Corticosteroid RCT (OR 0.54, 95% CI
0.40 to 0.73,p <
0.001)
High
High-Dose IVIG OS (OR 0.13, 95% CI
0.03 to 0.49, p =
0.003)
low
Ivermectin OS (OR 0.15, 95% CI
0.04 to 0.57, p =
0.005)
very low
Tocilizumab (6)
(monoclonal IL-6
receptor antibody)
OS (OR 0.62, 95% CI
0.42 to 0.90, p =
0.012)
very low

Progression
to severe
disease
(progress to
severe
pneumonia
or
admission
to ICU)
Drug/No. of Studies Type of Study Magnitude of Effect GRADE
High-Dose
Corticosteroid (2)
RCT (OR 0.23, 95% CI 0.06 to
0.86, p = 0.032)
High
Remdesivir (3) RCT (OR 0.29, 95% CI 0.17 to
0.50, p < 0.001)
High
Remdesivir OS (OR 0.28, 95% CI 0.16 to
0.50, p < 0.001)
High
(5)
OS (OR 0.11, 95% CI 0.06 to
0.19, p < 0.001)
Moderate
Corticosteroid (2) OS (OR 0.51, 95% CI 0.35 to
0.76, p < 0.001)
Moderate
Tocilizumab (4)
(monoclonal IL-6 receptor
antibody)
OS (OR 0.39, 95% CI 0.24 to
0.62, p < 0.001)
Low
Convalescent
Plasma (2)
OS (OR
0.53, 95% CI 0.28 to 0.98,
p = 0.043)
Low
Baricitinib
(Janus kinase JAK
inhibitor)
OS (OR 0.02, 95% CI 0.00 to
0.32, p = 0.006)
Very Low
Anakinra
(IL-1 receptor
antagonist)
OS (OR 0.22, 95% CI 0.09 to
0.56, p = 0.002)
Very Low

Viral
clearance
rate
(negative
conversion
rate within
14 days)*
Drug/No. of
Studies
Type of
Study
Magnitude
of Effect
GRADE
Convalescent
Plasma
RCT (OR 11.39,
95% CI 3.91 to
33.18, p <
0.001)
Low
No active drug was associated with improved viral clearance rate
within 14 days in mixed studies.

● The combination of hydroxychloroquine and azithromycin was
shown to be associated with increased QT prolongation
incidence (OR 2.01, 95% CI 1.26 to 3.20, p = 0.003) and fatal
cardiac complications in cardiac-impaired populations (OR
2.23, 95% CI 1.24 to 4.00, p = 0.007).
● No drug was significantly associated with increased non-
cardiac serious adverse events compared to standard care.

For moderate and severe patients hospitalized in non-ICU
settings:
● Corticosteroids, Tocilizumab, Anakinra, Remdesivir, and
Convalescent Plasma were associated with reduced risk of
progression to severe pneumonia, admission to ICU, and/or
mechanical ventilation.
● Corticosteroids and Remdesivir further showed survival benefit
compared to standard care.
Covid-19 Network Meta-analysis: Conclusions

For ICU-based critically ill patients:
● Corticosteroids reduced mortality from RCT evidence.
● High-dose IVIG, Ivermectin, and Tocilizumab may be
associated with reduced mortality when including
observational data.
● Hydroxychloroquine, was not shown to reduce mortality
rate or prevent progression to severe disease.
Covid-19 Network Meta-analysis : Conclusions

● Anti-inflammatory drugs are more effective in
the hospital setting compared to antivirals
(except for Remdesivir, ?Convalescent Plasma):
Management of hyper-reactivity of the
host immune response is advantageous
over targeting viral replication itself!
Covid-19 Network Meta-analysis: Conclusions

What is Missing!

Stages
Pre-clinical Phase: Post-exposure, viral
replication phase
Average duration (Incubation): 5 days, 1-14 days.
Clinical Phase:
Covid-19
infection is a
“Phasic
Disease”: Close
Monitoring and
Stage-Specific
interventions
are mandatory!
Stage 1
• Viral Infection +/-Interstitial Pneumonia-1st 5-7 days (Hospital admission
usually day 7 onward!).
Stage 2
• Hyper-inflammation: Following 5-10 Days i.e. second week.
(Immunopathology)/ARDS, Cytokine Storm etc.
Stage 3
•Hypercoagulability: Second-third week on-wards.
Stage 4
•Post-Covid-19 Syndrome (Long COVID).

Incubation
Period
Pre-clinical
(Replication)
Viral Infection
Hyper-
inflammation
Coagulopathy
Post-Covid-19
Syndrome
Community
Community/
General Ward
General ward ICU
Hospital or
Community
Asymptomatic
RT-PCR +VE or
-VE
Flu symptoms
+/- Pneumonia
RT-PCR +VE
High CRP &
other
Inflammatory
Markers e.g.
IL-6
Progressive
Pneumonitis
Desaturation
High or
Increasing d-
Dimer
+ve Doppler,
CTPA
Multiorgan
Failure
Residual Organ
Dysfunction
Pre-clinical Phase Stage 1 Stage 2 Stage 3 Stage 4

Three Drugs:
 Anticoagulants
 Vitamin D
 Doxycycline
 + More on Ivermectin
Covid-19 Missed Drugs in the Network Meta-analysis

In 33 studies (n = 4009 inpatients):
VTE incidence was 9% overall, and
21% (95%CI 14-28%, I2 = 87.6%) for ICU patients.
Screening and absence of anticoagulation were
associated with a higher VTE incidence.
High prevalence of thromboprophylaxis failure
among COVID-19 patients admitted to intensive
care units.
Proximal deep vein thrombosis and pulmonary embolism in COVID-19 patients: a systematic review and meta-analysis.
Longchamp G, et al. Thromb J. 2021 Mar 9;19(1):15. doi: 10.1186/s12959-021-00266-x.

Anticoagulation
for COVID-19
Thirty-five observational studies were included.
The pooled incidence rates of total venous
thromboembolism (N = 4,685) were: no prophylaxis
41.9%, standard-dose prophylaxis 19.8% , intermediate-
dose prophylaxis 11.9% and therapeutic-dose
anticoagulants 10.5%.
Conclusion:
Thrombosis rates were lower in hospitalized COVID-19
patients who received pharmacologic thromboprophylaxis.
Thrombosis and bleeding rates for patients receiving
intermediate-dose thromboprophylaxis or therapeutic
anticoagulation were similar to those who received
standard-dose pharmacologic thromboprophylaxis.
Pharmacologic Thromboprophylaxis and Thrombosis in Hospitalized Patients with COVID-19: A Pooled Analysis. Patell
R, et al. JI.Thromb Haemost. 2021 Jan;121(1):76-85. doi: 10.1055/s-0040-1721664.

Anticoagulation
for COVID-19
Variable/inconsistent Guidelines
Recommendations

Anticoagulation
for COVID-19
Intermediate-dose anticoagulation, aspirin, and in-hospital
mortality in COVID-19: a propensity score-matched analysis.
Meizlish ML, et AI. medRxiv. 2021 Jan
15:2021.01.12.21249577.
Interpretation:
In this propensity score-matched, observational
study of COVID-19, intermediate-dose
anticoagulation and aspirin were each
associated with a lower cumulative incidence of
in-hospital death.

Anticoagulation
for COVID-19
Therapeutic versus prophylactic anticoagulation for severe
COVID-19: A randomized phase II clinical trial (HESACOVID).
Lemos ACB et al. Thromb Res. 2020 Dec;196:359-366. doi:
10.1016/j.thromres.2020.09.026.
Conclusion: Therapeutic enoxaparin
improves gas exchange and
decreases the need for mechanical
ventilation in severe COVID-19.

Anticoagulation
for COVID-19
Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane
Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION
Randomized Clinical Trial. JAMA. 2021 Mar 18. doi: 10.1001/jama.2021.4152.
Results of the INSPIRATION randomized clinical
trial including 562 patients do not support
routine empirical use of intermediate-dose
prophylactic anticoagulation in unselected
patients with COVID-19 admitted to the ICU
(INSPIRATION investigators, 18 March 2021)

FACT
 Results:
Four hundred twelve patients were included in the study. Age 41-66
years. After adjusting for 8 confounding variables, aspirin use was
independently associated with decreased risk of mechanical
ventilation (adjusted HR 0.56, 95% CI 0.37-0.85, p=0.007), ICU
admission (adjusted HR 0.57, 95% CI 0.38-0.85, p=0.005), and in-
hospital mortality (adjusted HR 0.53, 95% CI 0.31-0.90, p=0.02). There
were no differences in major bleeding (p=0.69) or overt thrombosis
(p=0.82) between aspirin users and non-aspirin users.
 Conclusions:
Aspirin use may be associated with improved outcomes in
hospitalized COVID-19 patients.
Aspirin use is associated with decreased mechanical ventilation, ICU admission, and in-hospital mortality in hospitalized patients
with COVID-19. JH Chow, AK Khanna, S Kethireddy… - Anesthesia & …, 2020 - journals.lww.com
Aspirin & Covid-
19 Infection:
Evidence

FACT  Results:
Among COVID-19 positive Veterans (average age
58 years), preexisting aspirin prescription was
associated with a statistically and clinically
significant decrease in overall mortality at 14-
days (OR 0.38, 95% CI 0.32-0.46) and at 30-days
(OR 0.38, 95% CI 0.33-0.45), cutting the odds of
mortality by more than half.
Association of mortality and aspirin prescription for COVID-19 patients at the Veterans
Health Administration. Osborne TF, et al. PLoS One. 2021 Feb 11;16(2):e0246825.
Aspirin & Covid-
19 Infection:
Evidence

FACT  232 Participants, 42-77 years old.
After propensity score-matched (PSM) case-
control analyses 24 pairs of patients were
enrolled and followed up for 2 months.
Both 30-day and 60-day mortality in the aspirin
group were significantly lower than that in the
non-aspirin group (P = .021 and P = .030,
respectively).
Effect of low-dose aspirin on mortality and viral duration of the
hospitalized adults with COVID-19. Liu Q, et al . Medicine (Baltimore).
2021 Feb 12;100(6):e24544.
Aspirin & Covid-
19 Infection:
Evidence

NICE guideline Published: 17 December 2020 www.nice.org.uk/guidance/ng187
1.2 Do not offer a vitamin D supplement to people solely to prevent COVID-19,
except as part of a clinical trial.
1.3 Do not offer a vitamin D supplement to people solely to treat COVID-19, except
as part of a clinical trial.
National Institute of Health NIH: There are insufficient data to recommend either for or against the use of vitamin D
for the prevention or treatment of COVID-19.

Vitamin D and
Covid-19
Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and
meta-analysis of 43 observational studies. Petrelli F, Luciani A, et al. J Steroid Biochem Mol Biol.
2021 Mar 25:105883. doi: 10.1016/j.jsbmb.2021.105883.
We assessed the association between
vitamin D and risk, severity, and mortality
for COVID-19 infection, through a review of
43 observational studies.
Reduced vitamin D values resulted in a
higher infection risk, mortality and
severity COVID-19 infection.
Supplementation may be considered as
preventive and therapeutic measure.

Facts  activation by immune cells and enhancement of immune
function
 reducing the survival and replication of viruses- (Increased
production of Cathelicidins)
 reducing risk of inflammatory cytokine production,
 increasing angiotensin-converting enzyme 2 concentrations,
and
 maintaining endothelial integrity.
 Vitamin D has been shown to reduce IL-6 Level (a prognostic
marker for severity and death in Covid-19 infection) in non-
Covid-19 patients both in the ward as well as in ICU settings.
Vitamin D &
Covid-19
Infection:
Rationale for
use for
Prevention.

The “intriguing” similarity between Corvid-19 Pathophysiology & Vitamin D Deficiency Pathogenic Effects!

STUDY DOSING IMAPCT
RCT1
(Non-
hospitalized)
60,000 IU PO DAILY FOR 6 days Earlier clearance of the virus.
Significant decrease in
fibrinogen. Non-significant
decrease in CRP and d-
dimer.
RCT2
(Hospitalized)
Calcifediol PO (0.532 mg Stat
then -0.266 mg on Days 3,7 and
then weekly)
Reduced ICU admission 2%
vs. 50%. Non-significant
decrease in CRP, Ferritin and
d-dimer.
OS3
(Hospitalized)
Booster Therapy
(20,000-50,000 IU weekly pre-
admission)
Reduced Risk of Mortality
OS4
(Hospitalized)
Booster Therapy
(50,000-100,000 IU every1-3
months pre-admission)
Less severe COVID-19 and
better survival.
1 Postgrad Med J . 2020 Nov 12
2 J Steroid Biochem Mol Biol 2020 Oct;203:105751.
3 Nutrients. 2020 Dec 11;12(12):E3799.
4 Nutrients. 2020 Nov 2;12(11):3377.

Effect of a Single High Dose of Vitamin D3 on
Hospital Length of Stay in Patients With
Moderate to Severe COVID-19: A Randomized
Clinical Trial. jama.2020
Conclusions and relevance: Among moderately to
severely ill hospitalized (average 10.3 days post-
disease onset) patients with COVID-19, a single high
dose of vitamin D3 (200,000 IU), compared with
placebo, did not significantly reduce hospital
length of stay, mortality, ICU admission or
mechanical ventilation.
The findings do not support the use of a high dose
of vitamin D3 for treatment of moderate to severe
COVID-19.

Vitamin D is
effective for
COVID-19: real-
time meta
analysis of 40
studies
Covid Analysis,
Dec 17, 2020
(Version 14, Jan
21, 2021)
https://vdmeta.c
om/

Facts  Doxycycline is well known to inhibit metalloproteinases
(MMPs), in particular MMP-9, which is likely required
for initial viral entry into the cell.
 Doxycycline inhibits interleukin (IL)-6, with both IL-6
and MMPs key regulators of the ‘cytokine storm’ often
associated with severe viral pneumonitis.
 Doxycycline is an established ionophore, helping
transport zinc intracellularly, with increased cellular
concentrations of zinc shown in vitro to inhibit
coronavirus replication.
Doxycycline &
Covid-19
Infection:
Potential
Benefit-Antiviral
& Anti-
inflammatory
Effects!

 Doxycycline treatment of high-risk COVID-19-positive patients with
comorbid pulmonary disease. PA Yates, SA Newman, LJ Oshry… - Therapeutic
…, 2020 - journals.sagepub.com
 Clinical outcomes of early treatment with doxycycline for 89 high-risk COVID-
19 patients in long-term care facilities in New York. MM Alam, S Mahmud,
MM Rahman, JA Simpson… - Cureus, 2020 - ncbi.nlm.nih.gov
 A case series of 100 COVID-19 positive patients treated with combination of
ivermectin and doxycycline. MT Alam, R Murshed, E Bhiuyan, S Saber… -
Journal of Bangladesh …, 2020 - banglajol.info
 A novel approach to managing COVID-19 patients; results of lopinavir plus
doxycycline cohort. Y Cag, S Icten, B Isik-Goren, NB Baysal… - European
Journal of …, 2020 – Springer
Doxycycline &
Covid-19
Infection:
Publications
with Positive
outcomes.

A total of 798 eligible participants were randomized to
doxycycline (200 mg on the first day followed by 100 mg a
day for 6 days) within the first 14-days of onset of COVID-19
and compared with 994 participants randomized to usual
care.
Per protocol, randomization into the doxycycline arm was
stopped for futility due to small probability (0.044) of a
clinically meaningful benefit (recover more quickly at home, or
prevent the need for hospital admission) compared to usual
care at an interim analysis.
Doxycycline &
Covid-19
Infection:
UK Principle Trial.
https://www.principletrial.org/n
ews/azithromycin-and-
doxycycline-are-not-generally-
effective-treatments-for-covid-
19-shows-principle-trial

Facts
Based on the interim incomplete data, both the
estimated clinical benefit in the time to recovery
(less than 1 day benefit) and hospitalization rate
(less than 2% benefit) is small for doxycycline.
Final results to be published. 25 January 2021
Doxycycline &
Covid-19
Infection:
UK Principle Trial.
https://www.principletrial.org/news/
azithromycin-and-doxycycline-are-not-
generally-effective-treatments-for-
covid-19-shows-principle-trial
There is no beneficial effect in patients aged over
50 years who are treated with Doxycycline or
Azithromycin antibiotics at home in the early stages
of COVID-19.
The PRINCIPLE trial did not look at the effects of
these drugs in patients who were already admitted
to hospital with COVID-19.

FDA-Last Updated: February 11, 2021
There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or
against the use of Ivermectin for the treatment of COVID-19.
EMA-22/03/202 & IDSA advise against use of Ivermectin for the prevention or treatment of COVID-19 outside
randomized clinical trials.
FRONT LINE COVID-19 CRITICAL CARE ALLIANCE (FLCCC), WASHINGTON (PRWEB) MARCH 18, 2021- FLCCC Alliance
Convenes Global Panel that Warns World Governments of the Consequences of Not Deploying Ivermectin for
COVID-19.

Ivermectin is
effective for
COVID-19: real-
time meta
analysis of 35
studies
Covid Analysis,
Nov 26, 2020
(Version 22, Jan
21, 2021)
https://ivmmeta.
com/

The association between the use of ivermectin and mortality in patients with COVID-19: a meta-analysis. Kow CS,
Merchant HA, Mustafa ZU, Hasan SS. Pharmacol Rep. 2021 Mar 29:1-7. doi: 10.1007/s43440-021-00245-z.
Results: Six randomized controlled trials
were included in this analysis with a
total of 658 patients who were
randomized to receive Ivermectin and
597 patients randomized in the control
group who did not receive Ivermectin.
Conclusion: We observed a preliminary
beneficial effect on mortality associated
with Ivermectin use in patients with COVID-
19. The estimated effect of Ivermectin
indicated mortality benefits (pooled odds
ratio = 0.21; 95% confidence interval 0.11-
0.42, n = 1255).

Moderate certainty
evidence suggests
that Ivermectin
prophylaxis among
health care workers
and COVID-19
contacts probably
reduces the risk of
COVID-19 infection by
about 88% (4 studies,
851 participants; RR
0.12, 95% CI 0.08 to
0.18; 4.3% vs 34.5%
contracted COVID-19).

Ward or ICU
Ivermectin (a core medication)
Upon admission to hospital and/or ICU 0.3 mg/kg per dose — daily for 5 days (Take with or
after a meal)
Early Outpatient Treatment Protocol
Ivermectin 0.2 mg/kg per dose – one dose daily for minimum of 2 days, continue daily
until recovered (max 5 days)

Incubation
Period
Pre-clinical
(Replication)
Viral Infection
Hyper-
inflammation
Coagulopathy
Post-Covid-19
Syndrome
Immuno-
stimulants
e.g.
Vitamin D
Zinc
Vitamin C
Black Seed
Honey
Antivirals
*Vitamin D
*Remdesivir
(non-ICU)
*Interferons
(IFN-α2b,
intramuscular or
nebulized)
*Convalescent
Plasma
*Sofosbuvir
Plus Daclatasvir
*Monoclonals
(non-
hospitalized)
*Ivermectin
*Doxycycline
Anti-
inflammatory
e.g.
*Steroids
*Vitamin D
*Tocilizumab
*Anakinra
(IL-1 Inhibitor)
*Baricitinib
(JAK Inhibitor)
Anticoagulants
e.g.
*Aspirin
*Heparins
Supportive
Pre-clinical Phase Stage 1 Stage 2 Stage 3 Stage 4
Text in pink-
need for more
evidence.

Healthy or
Incubation
Period
Pre-clinical
(Replication)
Community
(Symptomatic)
Ward ICU
Post-Covid-19
Syndrome
Immuno-
stimulants
e.g.
*Vitamin D
*Ivermectin
Zinc
Vitamin C
Black Seed
Honey
Antivirals
*Vitamin D
*Monoclonals
*Doxycycline
*Ivermectin
*Steroids1
*Remdesivir
*Vitamin D
*Interferon-A2b
*Tocilizumab
*Convalescent
Plasma
*Anakinra
(IL-1 Inhibitor)
*Baricitinib
(JAK Inhibitor)
*Prophylactic
Heparin
*Aspirin2
*Ivermectin
*Doxycycline
*Steroids
*Anticoagulants
e.g.
Heparins
(Therapeutic)
*Tocilizumab
*Ivermectin
Supportive
Text in pink-
need for more
evidence.
1 Only for hypoxic patients, 2 For those above 45 years old

Healthy or
Incubation
Period
Pre-clinical
(Replication)
Community
(Symptomatic)
Ward ICU
Post-Covid-19
Syndrome
Immuno-
stimulants
e.g.
*Vitamin D
*Ivermectin
Zinc
Vitamin C
Black Seed
Honey
Antivirals
*Vitamin D
*Doxycycline
*Ivermectin
*Vitamin D
*Prophylactic
Heparin
*Steroids1
*Remdesivir
*Tocilizumab
*Aspirin2
*Doxycycline
*Ivermectin
*Steroids
*Anticoagulants
e.g.
Heparins
(Therapeutic)
*Tocilizumab
*Doxycycline
*Ivermectin
Supportive
Text in pink-
need for more
evidence.
1 Only for hypoxic patients, 2 For those above 45 years old

Conclusions
Network Meta-analysis is a useful tool for identifying and
ranking effective pharmacological interventions.
01
Management of Covid-19 should be Stage-specific
(Precision Medicine) BOTH preventatively and
therapeutically guided by the clinical picture and
biomarkers.
02
Antivirals are best for pre-hospital patients i.e. mild
disease.
03
Anti-inflammatory/Anti-cytokine therapy improves
outcome in hospitalized patients.
04

Multifaceted combination therapy is needed to improve
prognosis in high-risk or hospitalized patients.
05 Current evidence-based pharmacological therapies
should help significantly reduce mortality especially in
hospitalized patients.
06
07 Tools to implement current evidence at the bedside are
urgently needed.
Conclusions

Comparative efficacy and safety of
pharmacological interventions for the
treatment of COVID-19: A systematic review
and network meta-analysis. Kim MS, et
al. PLoS Med. 2020. PMID: 33378357 Free
PMC article.

For all:
a. a. Self-isolation/Masking/Hand Hygiene
etc.
b. b. Immunostimulants:
c. Vitamin C-500-1000 mg daily
d. Vitamin D 50,000 units weekly
e. Zinc (Elemental) 50 mg Daily
f. Black Seed (Nigella sativa)-1-2 grams twice
Daily
g. Honey
h. Plenty of fluids/fresh fruits.
Always consult
with your
doctor before
self-treatment.

For those with moderate or severe symptoms:
bad/worsening cough, shortness of breath or are above 40
years of age or have significant other diseases like obesity,
hypertension, heart disease, lung disease etc. start:
1. Doxycycline 100 mg twice daily after food (avoid milk/milk-products) for 7-
10 days. Not suitable for pregnant women/breast feeding.
2. Daily high dose vitamin D (50,000 units/day) for 6 days if previously not on
vitamin D. Check calcium level during treatment.
3. Heparin 5000 units 8 hourly or Enoxaparin 1 mg (100 iu)/kg once per day if
hospitalized.
4. Aspirin 75-100 mg Once per day (discuss with your doctor first) with
Omeprazole 20 mg per day (to protect the stomach) if above 45 years old.
5. Ivermectin 0.2mg/kg per day for 2-5 days.
6. Dexamethasone 6 mg orally once per day or Prednisolone 40 mg once per
day if oxygen is below 90% (discuss with your doctor first) with Omeprazole 20
mg per day (to protect the stomach). May need to increase diabetes
medications e.g. insulin. Reduce salt intake and increase fruits.
Always consult
with your
doctor before
self-treatment.

Important Tests: Repeat every 2-3 days if not
improving to monitor progress:
• Complete blood count
• Kidney function
• Liver function
• CRP
• D-Dimer
• Chest X-ray (if significant or worsening respiratory
symptoms)
Home monitoring:
• Temperature (Use Acetaminophen/Panadol 1000 mg
every 6-8 hours as needed for fever, muscle pains,
headaches etc.
• Blood pressure (Hospital referral if reading is below
90/60)
• Pulse oximetry (Hospital referral/need for Oxygen &
Cortisone therapy if reading is below 88%).
Always consult
with your
doctor before
self-treatment.

Beating the Beast: Best Current Pharmacological Modalities for Treating Covid-19 Infection

Beating the Beast: Best Current Pharmacological Modalities for Treating Covid-19 Infection

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