A quadruple blind, randomised controlled trial of gargling agents in reducing intraoral viral load among hospitalised COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial

Khan et al., Trials, doi:10.1186/s13063-020-04634-2, GARGLES, NCT04341688, Jul 2022

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https://c19early.org/khan6hp.html

Hydrogen Peroxide

24th treatment shown to reduce risk in May 2021, now with p = 0.024 from 8 studies.

Lower risk for viral clearance.

No treatment is 100% effective. Protocols combine treatments.

6,200+ studies for 180+ treatments. c19early.org

Estimated 50 patient hydrogen peroxide early treatment RCT with results not reported over 3 years after estimated completion.

2 hydrogen peroxide RCTs have results missing long after expected1,2
The trials report an estimated total of 140 patients.

Important missing comments or errors? Let us know.

Study covers povidone-iodine and hydrogen peroxide.

1. Khan et al., A quadruple blind, randomised controlled trial of gargling agents in reducing intraoral viral load among hospitalised COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial, Trials, doi:10.1186/s13063-020-04634-2.biomedcentral.com, doi.org.

2. Xie et al., Oral Rinse to Reduced Expelled Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) During COVID-19 Infection, NCT04931004, clinicaltrials.gov/study/NCT04931004clinicaltrials.gov.

Khan et al., 31 Jul 2022, Double Blind Randomized Controlled Trial, Pakistan, trial NCT04341688 (history) (GARGLES). Contact: amjadkhan@lumhs.edu.pk.

This Paper Hydrogen Per..All

Oral Co-Supplementation of Curcumin, Quercetin, and Vitamin D3 as an Adjuvant Therapy for Mild to Moderate Symptoms of COVID-19—Results From a Pilot Open-Label, Randomized Controlled Trial

Amjad Khan, Somia Iqtadar, Sami Ullah Mumtaz, Michael Heinrich, Domingo A Pascual-Figal, Shona Livingstone, Sajid Abaidullah

Frontiers in Pharmacology, doi:10.3389/fphar.2022.898062

Background: Curcumin, quercetin, and vitamin D3 (cholecalciferol) are common natural ingredients of human nutrition and reportedly exhibit promising anti-inflammatory, immunomodulatory, broad-spectrum antiviral, and antioxidant activities. Objective: The present study aimed to investigate the possible therapeutic benefits of a single oral formulation containing supplements curcumin, quercetin, and cholecalciferol (combinedly referred to here as CQC) as an adjuvant therapy for early-stage of symptomatic coronavirus disease 2019 in a pilot open-label, randomized controlled trial conducted at

ETHICS STATEMENT The study was approved by the Institutional Review Board (IRB) of King Edward Medical University, Lahore, with approval No. 785/RC/KEMU. The patients/participants provided their written informed consent to participate in this study. AUTHOR CONTRIBUTIONS AK contributed to the study design, data interpretation, writing of the manuscript, and literature search; SI, SM, and SA contributed to the study design, data collection, data interpretation, and literature search; DP-F and MH critically reviewed and edited the manuscript; and SL helped in data analysis and revision of the manuscript. All authors approved the final manuscript. Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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DOI record: { "DOI": "10.1186/s13063-020-04634-2", "ISSN": [ "1745-6215" ], "URL": "http://dx.doi.org/10.1186/s13063-020-04634-2", "abstract": "Abstract\nObjectives\n1- To compare the effectiveness of 1% Hydrogen peroxide, 0.2% Povidone-Iodine, 2% hypertonic saline and a novel solution Neem extract (Azardirachta indica) in reducing intra-oral viral load in COVID-19 positive patients.\n2- To determine the salivary cytokine profiles of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL- 17 among COVID-19 patients subjected to 1% Hydrogen peroxide, 0.2% Povidone-Iodine, 2% hypertonic saline or Neem extract (Azardirachta indica) based gargles.\n\nTrial design\nThis will be a parallel group, quadruple blind-randomised controlled pilot trial with an add on laboratory based study.\n\nParticipants\nA non-probability, purposive sampling technique will be followed to identify participants for this study.\nThe clinical trial will be carried out at the Aga Khan University Hospital (AKUH), Karachi, Pakistan. The viral PCR tests will be done at main AKUH clinical laboratories whereas the immunological tests (cytokine analysis) will be done at the Juma research laboratory of AKUH.\nThe inclusion criteria are laboratory-confirmed COVID-19 positive patients, male or female, in the age range of 18-65 years, with mild to moderate disease, already admitted to the AKUH. Subjects with low Glasgow coma score, with a history of radiotherapy or chemotherapy, who are more than 7 days past the onset of COVID- 19 symptoms, or intubated or edentulous patients will be excluded. Patients who are being treated with any form of oral or parenteral antiviral therapy will be excluded, as well as patients with known pre-existing chronic mucosal lesions such as lichen planus.\n\nIntervention and comparator\nGroup A (n=10) patients on 10 ml gargle and nasal lavage using 0.2% Povidone-Iodine (Betadiene® by Aviro Health Inc./ Pyodine® by Brooks Pharma Inc.) for 20-30 seconds, thrice daily for 6 days. Group B (n=10) patients will be subjected to 10 ml gargle and nasal lavage using 1% Hydrogen peroxide (HP® by Karachi Chemicals Products Inc./ ActiveOxy® by Boumatic Inc.) for 20-30 seconds, thrice daily for 6 days. Group C will comprised of (n=10) subjects on 10ml gargle and nasal lavage using Neem extract solution (Azardirachta indica) formulated by Karachi University (chemistry department laboratories) for 20-30 seconds, thrice daily for 6 days. Group D (n=10) patients will use 2% hypertonic saline (Plabottle® by Otsuka Inc.) gargle and nasal lavage for a similar time period. Group E (n=10) will serve as positive controls. These will be given simple distilled water gargles and nasal lavage for 20-30 seconds, thrice daily for six days. For nasal lavage, a special douche syringe will be provided to each participant. Its use will be thoroughly explained by the data collection officer. After each use, the patient is asked not to eat, drink, or rinse their mouth for the next 30 minutes.\n\nMain outcomes\nThe primary outcome is the reduction in the intra-oral viral load confirmed with real time quantitative PCR.\n\nRandomisation\nThe assignment to the study group/ allocation will be done using the sealed envelope method under the supervision of Clinical Trial Unit (CTU) of Aga Khan University, Karachi, Pakistan. The patients will be randomised to their respective study group (1:1:1:1:1 allocation ratio) immediately after the eligibility assessment and consent administration is done.\n\nBlinding (masking)\nThe study will be quadruple-blinded. Patients, intervention provider, outcome assessor and the data collection officer will be blinded. The groups will be labelled as A, B, C, D or E. The codes of the intervention will be kept in lock & key at the CTU and will only be revealed at the end of study or if the study is terminated prematurely.\n\nNumbers to be randomised (sample size)\nAs there is no prior work on this research question, so no assumptions for the sample size calculation could be made. The present study will serve as a pilot trial. We intend to study 50 patients in five study groups with 10 patients in each study group. For details, please refer to Fig. 1 for details.\n\nTrial Status\nProtocol version is 7.0, approved by the department and institutional ethics committees and clinical trial unit of the university hospital. Recruitment is planned to start as soon as the funding is sanctioned. The total duration of the study is expected to be 6 months i.e. August 2020-January 2021.\n\nTrial registration\nThis study protocol was registered at www.clinicaltrials.gov on 10 April 2020 NCT04341688.\n\nFull protocol\nThe full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).\n\n", "alternative-id": [ "4634" ], "article-number": "785", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "20 July 2020" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "26 July 2020" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "14 September 2020" }, { "group": { "label": "Ethics approval and consent to participate", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "The study protocol has been approved by the ethics review committee of the Aga Khan University, Karachi Pakistan. Approved on 16<sup>th</sup> July 2020. Reference # 2020-4926-11376. The authors certify that this trial has received ethical approval from the appropriate ethical committee as described above. Informed consent will be obtained in Urdu language (or in English for those who are well versed with the latter), where the harms and benefits of the gargles and nasal lavage will be explained along with the method of their use in a simple language. In addition to the clinical trial, this consent will also entail the use of biological specimens for the laboratory testing and analysis. The details are stated in the Urdu and English consent forms. The signed consent forms will be retained for the record purpose." }, { "group": { "label": "Consent for publication", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "Not applicable." }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 3, "value": "The authors declare that they have no competing interests." } ], "author": [ { "ORCID": "http://orcid.org/0000-0002-5650-6268", "affiliation": [], "authenticated-orcid": false, "family": "Khan", "given": "Farhan Raza", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0002-6934-6945", "affiliation": [], "authenticated-orcid": false, "family": "Kazmi", "given": "Syed Murtaza Raza", "sequence": "additional" }, { "affiliation": [], "family": "Iqbal", "given": "Najeeha Talat", "sequence": "additional" }, { "affiliation": [], "family": "Iqbal", "given": "Junaid", "sequence": "additional" }, { "affiliation": [], "family": "Ali", "given": "Syed Tariq", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-3911-1632", "affiliation": [], "authenticated-orcid": false, "family": "Abbas", "given": "Syed Akbar", "sequence": "additional" } ], "container-title": "Trials", "container-title-short": "Trials", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2020, 9, 14 ] ], "date-time": "2020-09-14T10:02:59Z", "timestamp": 1600077779000 }, "deposited": { "date-parts": [ [ 2021, 9, 14 ] ], "date-time": "2021-09-14T00:02:06Z", "timestamp": 1631577726000 }, "indexed": { "date-parts": [ [ 2023, 8, 19 ] ], "date-time": "2023-08-19T01:34:27Z", "timestamp": 1692408867704 }, "is-referenced-by-count": 13, "issue": "1", "issued": { "date-parts": [ [ 2020, 9, 14 ] ] }, "journal-issue": { "issue": "1", "published-print": { "date-parts": [ [ 2020, 12 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2020, 9, 14 ] ], "date-time": "2020-09-14T00:00:00Z", "timestamp": 1600041600000 } }, { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2020, 9, 14 ] ], "date-time": "2020-09-14T00:00:00Z", "timestamp": 1600041600000 } } ], "link": [ { "URL": "https://link.springer.com/content/pdf/10.1186/s13063-020-04634-2.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/article/10.1186/s13063-020-04634-2/fulltext.html", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/content/pdf/10.1186/s13063-020-04634-2.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1186", "published": { "date-parts": [ [ 2020, 9, 14 ] ] }, "published-online": { "date-parts": [ [ 2020, 9, 14 ] ] }, "published-print": { "date-parts": [ [ 2020, 12 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04634-2" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "Pharmacology (medical)", "Medicine (miscellaneous)" ], "subtitle": [], "title": "A quadruple blind, randomised controlled trial of gargling agents in reducing intraoral viral load among hospitalised COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial", "type": "journal-article", "update-policy": "http://dx.doi.org/10.1007/springer_crossmark_policy", "volume": "21" }

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