Efficacy and safety of IHP Detox Tea (a

special blend of Andrographis paniculata,

Garcinia kola and Psidium guajava) for

treatment of Corona virus disease 2019

(COVID-19): a pilot randomized trial

By

DR GEORGE UCHENNA ELEJE

CO-PRINCIPAL INVESTIGATOR

PRESENTATION OVERVIEW

Research Team

Background of the Study:

Literature Review

Research Objectives:

Justification for the study:

Methodology:

Project Impacts:

Dissemination Strategies

Resources

Thank you

RESEARCH TEAM • Charles Esimone/Professor/PhD/ Pharmaceutical Microbiology and

Biotechnology [Principal Investigator].

• Joseph Ikechebelu/Professor/FWACS/Obstetrics and Gynaecology.

• George Eleje/Senior Lecturer/Consultant/FMCOG/Obstetrics & Gynaecology & Evidence-based Medicine [Co-Principal Investigator].

• Edamisan Olusoji TEMIYE - Professor/Consultant Paediatric Oncologist/Hematologist

• Department of Paediatric, Department of Paediatrics,

• College of Medicine, Lagos University Teaching Hospital [LUTH], Idi-Araba, Lagos.

• e-mail: edatemiye2000@yahoo.co.uk [Clinical Trialist/Co-Principal Investigator].

•

• .

RESEARCH TEAM

• George Chukwuma/Senior Lecturer/PhD/Virology.

• Ekwunife/Senior Lecturer/PhD/ Clinical Pharmacy.

• Festus Okoye/Professor/PhD/ Pharmaceutical and Medicinal Chemistry/Natural Product Drug Discovery.

• Kenneth Ngwoke/Reader/PhD/ Pharmaceutical and Medicinal Chemistry.

• Godwin Nchinda/Professor/PhD/Virology and Immunology.

• Henrietta Ogbunugafor/Professor/PhD/Biochemistry

BACKGROUND OF THE STUDY RESEARCH

The corona virus disease 2019 (COVID-19) has remained a major source of disaster and global catastrophe in this 21st century

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a positive sense, single-stranded RNA genome [Prajapat et al, 2020]

BACKGROUND OF THE STUDY RESEARCH

Since December 2019, COVID-19 outbreaks have occurred in China and many countries around the world, including Nigeria [Duan et al, 2020; Gao et al, 2020]

The ensuing COVID-19 has become a challenging source of morbidity and mortality across the globe.

BACKGROUND OF THE STUDY RESEARCH

Although there is a massive global rush to optimize prophylactic or therapeutic strategies, indigenous drugs have again taken a back stage.

Bioresources Development Group, Nigeria developed a novel nutriceutical IHP Detox Tea which is an optimized natural blend of Andrographis paniculata, Garcinia kola and Psidium guajava

BACKGROUND OF THE STUDY RESEARCH

Following NAFDAC approval (NAFDAC number A7-1951L) the IHP Detox Tea has been produced and marketed in Nigeria since 2016

Some components of IHP Detox tea like Andrographis paniculata have been shown to alleviate symptoms of acute respiratory tract infections in both adults and children (Xiao-Yang Hu et al., 2017

BACKGROUND OF THE STUDY RESEARCH

In addition to immunostimulatory properties and anti-cancer activities components, IHP Detox Tea have also been demonstrated to have

antiviral activities on earlier strains of coronavirus, Ebola virus, SARS-CoV and MERS-CoV (Bertoglio et al, 2016; Coon & Ernst, 2004; Kligler et al, 2006; Saxena et al, 2010; Hu et al, 2017)

Given its demonstrated ability to alleviate symptoms of acute respiratory tract infections in both children and adults we hypothesize that IHP Detox Tea could have therapeutic or prophylactic properties against SARS-CoV-2 infection

BACKGROUND OF THE STUDY RESEARCH

• In this light, we are conducting a randomized clinical trial to

• assemble data supporting the beneficial or

•deleterious effect of IHP Detox Tea •when co-administered with conventional

therapy for treatment and prevention of COVID-19

LITERATURE REVIEW

• Scientific Case for IHP Detox Tea for the Treatment of COVID -19

• IHP Detox Tea contains Andrographis, Garcinia kola seed extract and Psidium guajava leaf extract.

• The extracts of these herbs as well as some of their major phytochemical constituents have shown validated antiviral, immunomodulatory and adaptogenic activities.

• These herbs have long standing ethnomedicinal use and the safety profiles of their major phytoconstituents are well validated and documented.

LITERATURE REVIEW •Andrographolide, the major component of Andrographis, showed in vitro inhibition of the growth of Ebola virus (Zaire) with EC50 activity of 10 μM which is twenty-five-fold the activity of the control Favipiravir (EC50 = 250 μM) in the Crystal violet (Plaque reduction/ Neutral red (Toxicity) assay.

LITERATURE REVIEW

• It also showed significant activity against Dengue fever virus with EC50 value of 0.56 μg/ml in the Visual (Cytopathic effect/ Toxicity) Assay and EC50 of 0.58 μg/ml in the Neutral Red (Cytopathic effect/ Toxicity) Assay (comparable to the values obtained with 6-Azauridine as the positive control EC50 = 0.32 μg/ml and 0.38 μg/ml in the respective bioassays.

• In a study against SARS Coronavirus, Andrographolide had an EC50 of 1.2 μg/ml in the Visual (cytopathic effect/toxicity) assay and 1.1 μg/ml in the Neutral Red (cytopathic effect/toxicity) assay.

LITERATURE REVIEW

• The compound exerts several immunomodulatory properties.

• In experimental models, it effectively reduce the levels of proinflammatory cytokines such as IL-1𝛽, IL-6, GMCSF, and TNF-𝛼.

• Extracts of Garcinia kola seed as well as the major phytoconstituent, Kolaviron, and Akiluvir have shown in vitro inhibitory effect against SARS Coronavirus and Ebola virus.

• Kolaviron has also shown validated potent immunomodulatory and adaptogenic activities.

LITERATURE REVIEW

• Similarly, guava flavonoid glycosides (GFGs) have shown promising activity against influenza A virus and dengue virus.

• GFGs have also shown potent immunomodulatory activities.

• The potent antiviral activities of two of the major active ingredients of the tea namely, Andrographolide and Kolaviron on SARS Corona virus were recently validated by In vitro studies carried out by NIH.

• This further lends credence to the potential application of IHP Detox Tea in management of SARS Corona virus pandemic.

LITERATURE REVIEW

• IHP Detox Tea have, thus, shown proven pharmacological efficacy in several of the conditions which supports its potential beneficial use in COVID-19 patients.

• Apart from the proven antiviral effects of the components of IHP Detox Tea, the immune boosting and adaptogenic effects of the major phytochemical constituents will definitely contribute to better prognosis of Covid-19 patients placed on the proposed therapy.

RESEARCH OBJECTIVES

Major:

To determine the efficacy and safety IHP Detox Tea, when used as adjuvants with already available conventional therapy for novel COVID-19 in Nigeria

Specific OBJECTIVES

• To determine the mean time to negative test to COVID-19 following combined IHP Detox Tea and conventional therapy for COVID-19 among COVID-19 positive patients compared with those on conventional therapy alone.

• To determine the proportion of disappearance of respiratory symptoms following combined IHP Detox Tea and conventional therapy for COVID-19 among COVID-19 positive patients compared with those on conventional therapy alone.

Specific OBJECTIVES contd:

• To determine the proportion of adverse events following combined IHP Detox Tea and conventional therapy for COVID-19 among COVID-19 positive patients compared with those on conventional therapy alone.

• To determine the proportion of discharges from hospital and deaths following combined IHP Detox Tea and conventional therapy for COVID-19 among COVID-19 positive patients compared with those on conventional therapy alone.

Specific OBJECTIVES contd:

• To determine the Proportion of Changes and Differences if any in Biochemical and Haematological [Immunological] Changes at the Baseline and Study Conclusion of the different Clinical Study Arm Groups following combined IHP Detox Tea and Conventional Therapy for COVID-19 among COVID-19 positive patients compared with those on Conventional Therapy alone.

JUSTIFICATION FOR THE TRIAL

• Intercedd Health Product (IHP) Detox Tea (a validated marketed nutraceutical) and registered by NAFDAC (NAFDAC number A7-1951L) could serve as an effective standalone or an adjuvant in the current treatment of COVID-19

• The reason is that published reports have suggested a seemingly high efficacy of the major components of the IHP Detox tea in alleviating the symptoms of acute respiratory tract infections in both adults and children

JUSTIFICATION FOR THE TRIAL • However little is known about the role of IHP Detox

tea when used as a standalone or co-administered with the currently conventional therapy for treatment of COVID-19

• To our knowledge, there is no prior randomized trial on the effectiveness of IHP Detox Tea when co-administered with currently used therapy for treatment or prophylaxis of COVID-19

HYPOTHESIS

•The hypothesis is that combination regimen consisting of IHP Detox tea and conventional care for COVID-19 might be more efficacious than conventional care alone

OUTCOME MEASURES

•PRIMARY

•The Mean Time to Negative test to COVID-19.

•Profiles of immune determinants including inflammatory cytokines /chemokines and SARS-Cov-2 specific antibody responses in plasma

SECONDARY OUTCOMES

• Proportion of Patients with persisting Respiratory Symptoms [Cough, Expectoration, Nasal Discharge, Headache, Fever, Sore Throat, Earache, Malaise/Fatigue and Sleep Disturbance] at 2[Two and 4[Four] weeks of the Active Study Period of Product Use and Therapy in both Study Arms.

• Incidence of any Adverse Events - Serious or Minimal such as Diarrhea, Nausea, Vomiting, Colitis, Respiratory Distress, Apnea and Death following commencement and throughout Active Study Period of Product Use and Therapy in both Study Arms.

SECONDARY OUTCOMES

• Mean Levels of Renal Function Parameters of the Serum Electrolytes, Urea and Creatinine at Baseline, 2[Two and 4[Four] weeks [Conclusion] of the Active Study Period of Product Use and Therapy in both Study Arms.

• Mean Levels of Liver Function Parameters [AST, ALT and ALP] and Lipid Profiles at Baseline, 2[Two and 4[Four] weeks [Conclusion] of the Active Study Period of Product Use and Therapy in both Study Arms.

• Proportion of Patients Discharged from hospital or deaths at 2 weeks and 4 weeks of the Active Study Period of Product Use and Therapy in both Study Arms

NAFDAC IHP DETOX TEA TRIAL APPROVAL

•TRIAL HAS BEEN APPROVED BY NAFDAC

•APPROVAL NUMBER: NAFDAC/DER/IHP DETOX/CT&D/2020/VOL 1

•APPROVAL DATE: 17/08/2020

METHODOLOGY

• Study setting

• This will be a Pilot Randomized Trial to be conducted among patients being managed for COVID-19 in 1[One] or more of the Nigeria Centre for Disease Control [NCDC] COVID-19 Isolation sites in Nigeria.

•

• Study design

• This will be a pilot randomized clinical trial.

METHODS

• Study population

• The Participants will comprise Adult Patients aged 18-60 years with Clinical and Laboratory diagnosis of the COVID-19 Disease and who will be given Written Informed Consent before Recruitment.

• This Study Population MUST meets the STUDY INCLUSION CRITERIA.

• The patients will be recruited at the Isolation Centers and LUTH.

• Inclusion criteria

• Adult patients with confirmed clinical and laboratory diagnosis of COVID-19 and with normal liver and renal function markers or profiles will be included.

METHODS

• Exclusion criteria

• Pregnant, lactating and breastfeeding women.

• Patients with serious ailments of heart, liver, kidney or brain.

• Chronic medical disorders including HIV/AIDS, Cancers, etc.

• Subjects who have any allergy or were allergic to any of the medication to be used.

METHODS

• Randomization and Allocation Sequence

• Eligible patient for the Study, will be randomized into 2[Two] Groups using the Simple [Block] Randomization with a Randomization Table to be created by a Computer Software.

• Allocation Sequences and Codes will be concealed from the person allocating the Study Participants to the 2[Two] Intervention Arms.

• Blinding of participants, Personnel and Outcome assessors

• The participants, personnel and outcome assessors will not be blinded.

METHODS • Study Procedure/Drug Administration

• Patients with a Clinical and Laboratory Diagnosis of COVID-19 Disease seen in Isolation Centers and managed for Symptoms or Signs of COVID-19 will be screened consecutively.

• All Participants will also undergo Routine Medical Examination including Pulse Rate; Body Weight; Blood Pressure determination and general examination to ascertain the presence of and severity of the COVID-19 Disease.

• Only patients with confirmed Clinical and Laboratory Diagnosis of COVID-19 will be randomized.

•

METHODS

• Eligible patients will be sequentially allocated using an Opaque Sealed Envelope to receive either IHP Detox Tea [One Teabag to be soaked in 100mls of warm water 12 hourly] in combination with Conventional Therapy or and Conventional Therapy alone.

•Drugs administration will be given for 4[Four] weeks. Nurses will do the Drugs dispensing while the Clinical Trialists will do the Drug auditing weekly to ensure compliance with Protocol

METHODS

• Intervention Therapy

• Standard doses of IHP Detox Tea (Two teabags to be soaked in 100mls of warm water 12 hourly) will be administered in conjunction with currently evaluated conventional therapy for COVID-19 12-hourly for 4 weeks in

• [a]Patients with COVID-19 positive with symptoms and

• [b] Patients with COVID-19 positive without symptoms [asymptomatic]

METHODS

•Control Therapy

•Conventional therapy for COVID-19 12-hourly for 4 weeks.

METHODS • Study Participants Care and Monitoring

• The Total Clinical Study Trial duration is expected to last for 4[Four] - 6[Six] months to take into consideration the PERIOD for Study Participant Recruitment and Follow-up.

• All the participants will be followed up.

• During each Follow-up Weekly Visit, participants will be assessed for level of compliance.

METHODS

• Study Participants Care and Monitoring

• All Side Effects and Adverse Events will be recorded by the Clinical Trialists/Care Givers in the Study Patients’ [Participants’] Case Report Folders [CRF] during the Active Study Period of 4[Four] weeks when they are on the Study Medications.

• Those Study Patients’ [Participants’] still on admission after the Active Study Period of 4[Four] weeks at the Isolation Centre will be continually monitored for any Side Effects and Adverse Events by the Clinical Trialists/Care Givers until they are discharged or death.

METHODS

• Study Participants Care and Monitoring

• However those Study Participants [Patients] who complete the Study and are discharged after the Active Study Period of 4[Four] weeks will be monitored by the Clinical Trialists/Care Givers for the next 6[Six] - 8[Eight] weeks for any Side Effects and Adverse Events by giving • them the standardized Side Effects and Adverse Events Reportorial Forms to

be filled out and returned during their Mandatory fortnightly Medical Check-up follow-up after being discharged

METHODS

• Study Participants Care and Monitoring

• During this Mandatory fortnightly Medical Check-up by the Clinical Trialists/Care Givers, the Study Participants [Patients] will be explicitly asked about such Side Effects and Adverse Events as recorded in their standardized Side Effects and Adverse Events Reportorial Forms and treatment instituted if required.

• Any Study Participant [Patient] found to be developing Complications such as worsening of the Symptoms from the Study will be given appropriate Treatment during the Active Study Period of 4[Four] weeks .

METHODS

• Sample size determination

• This is a pilot study.

• Therefore, no sample size calculation will be made.

• The authors plan to recruit 90 participants (ie 30 participants from each the 3 arms).

• Sampling Approach

• Simple random sampling method will be.

METHODS

• Statistical Analysis

• Interim Analysis of the Study generated Data which will be stored in each of Study Patient’s [Participant’s] Case Report Folder [CFR] will be planned.

• Data will thereafter checked for Quality and Consistency. Data will be analysed using the Statistical Software - SPSS version 23, IBM Company USA.

• When possible, Subgroup analysis will also be done.

• A p value ≤ 0.05 will be considered to be significant.

PROJECT IMPACTS

Problems the Project will solve:

1. It will provide in-country data on COVID-19

2. Contribute to the elimination of COVID-19

4. Produce policy brief that is required to develop a national strategy for the prevention and control of COVID-19

5. Provide care, improve quality of life of and reduce deaths among PRERSONS SUFFERING FROM COVID-19

PROJECT DISSEMINATION STRATEGIES

FMST – the commissioning organizations

2. Health Service providers

3.Patients and the public

4. State and Federal Ministries of Health

5.Publications (peer review journals and local university newsletter)

CONCLUSION

• IHP DETOX TEA IS PROMISING

Resources

• Bertoglio JC, Baumgartner M, Palma R, Ciampi E, Carcamo C, Cáceres DD, Acosta-Jamett G, Hancke JL, Burgos RA. Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study. BMC Neurol. 2016 May 23;16:77. doi: 10.1186/s12883-016-0595-2. PMID: 27215274; PMCID: PMC4877819.

• Coon JT, Ernst E. Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med. 2004 Apr;70(4):293-8. doi: 10.1055/s-2004-818938. PMID: 15095142.

Resources

• Kligler B, Ulbricht C, Basch E, Kirkwood CD, Abrams TR, Miranda M, Singh Khalsa KP, Giles M, Boon H, Woods J (2006). Andrographis paniculata for the treatment of upper respiratory infection: a systematic review by the natural standard research collaboration. Explore (NY);2(1):25-9. doi: 10.1016/j.explore.2005.08.008. PMID: 16781605

Resources

Prajapat M, Sarma P, Shekhar N, et al (2020). Drug targets for corona virus: A systematic review. Indian J Pharmacol.;52(1):56–65. doi:10.4103/ijp.IJP_115_20.

• Oyenihi, O. R., Brooks, N. L., Oguntibeju O. O., (2015). Effects of kolaviron on hepatic oxidative stress in streptozotocin induced diabetes. BMC Complement Altern Med, 15: 236.

• Panraksa P, Ramphan S, Khongwichit S, Smith DR. 2017. Activity of andrographolide against dengue virus, Antiviral Res. 139: 69–78.

Resources

• Kligler B, Ulbricht C, Basch E, Kirkwood CD, Abrams TR, Miranda M, Singh Khalsa KP, Giles M, Boon H, Woods J (2006). Andrographis paniculata for the treatment of upper respiratory infection: a systematic review by the natural standard research collaboration. Explore (NY);2(1):25-9. doi: 10.1016/j.explore.2005.08.008. PMID: 16781605.

• Saxena RC, Singh R, Kumar P, Yadav SC, Negi MP, Saxena VS, Joshua AJ, Vijayabalaji V, Goudar KS, Venkateshwarlu K, Amit A (2010). A randomized double blind placebo controlled clinical evaluation of extract of Andrographis paniculata (KalmCold) in patients with uncomplicated upper respiratory tract infection. Phytomedicine. 2010 Mar;17(3-4):178-85. doi: 10.1016/j.phymed.2009.12.001. Epub 2010 Jan 25. PMID: 20092985.

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