Summary of COVID-19 miscellaneous studies
Studies
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RCT 75 outpatients in India with mild to moderate COVID-19 showing faster viral clearance, faster time to symptom resolution, and improvement in disease progression with probenecid treatment for 5 days compared to placebo. Probenecid was well tolerated with only mild adverse events noted. There was a dose-dependent response, with probenecid 1000mg twice daily performing better than 500mg twice daily.
Jul 2023, Viruses, https://www.mdpi.com/1999-4915/15/7/1508, https://c19p.org/martin
RCT 592 hospitalized moderate COVID-19 patients in Ukraine showing improved recovery and lower progression with enisamium. The trial initially included patients with moderate COVID-19 not requiring oxygen, but a mid-trial change was made to exclude this group due to a lack of benefit, and results are reported for the patients requiring oxygen. The greatest benefit was seen in patients treated within 5 days of symptom onset.
May 2024, Advances in Respiratory Medicine, https://www.mdpi.com/2543-6031/92/3/21, https://c19p.org/holubovska
RCT 189 hospitalized COVID-19 patients showing lower mortality and faster recovery with spirulina. Spirulina treatment also resulted in greater reductions in inflammatory markers such as IL-6, TNF-a, IP-10, CRP, ESR, and ferritin. All patients received remdesivir. Spirulina contains many components including calcium spirulan, a sulfated polysaccharide shown to inhibit the replication of various enveloped viruses in vitro, and many nutrients showing benefits for COVID-19 including vitamins A, C, and D, selenium, and zinc.
Apr 2024, Frontiers in Immunology, https://www.frontiersin.org/articles/10.3389/fimmu.2024.1332425/full, https://c19p.org/aghasadeghi
RCT 77 hospitalized patients showing no significant differences with virgin coconut oil (VCO) treatment.
May 2024, Acta Medica Philippina, https://actamedicaphilippina.upm.edu.ph/index.php/acta/article/view/7498, https://c19p.org/alejandria
1,217 patient GST-HG171 early treatment RCT: 13% faster recovery (p=0.03) and 25% faster viral clearance (p<0.0001).
RCT 1,213 outpatients with mild-to-moderate COVID-19 in China showing a shorter time to sustained recovery and faster viral clearance with GST-HG171 plus ritonavir.
May 2024, eClinicalMedicine, https://www.sciencedirect.com/science/article/pii/S2589537024001615, https://c19p.org/lu5
1,323 patient azithromycin late treatment RCT: 16% lower need for oxygen therapy (p=0.69), 9% lower hospitalization (p=0.87), and 7% improved recovery (p=0.23).
RCT 1,388 outpatients in the UK showing no significant benefit with azithromycin. There was no significant difference in time to first reported recovery or risk of hospitalization or death by 28 days with azithromycin compared to usual care alone. Only 31% of participants had PCR-confirmed SARS-CoV-2 infection.
Mar 2021, The Lancet, https://www.sciencedirect.com/science/article/pii/S014067362100461X, https://c19p.org/butler4
80 patient Mito-MES prophylaxis study: 91% fewer moderate/severe cases (p=0.05), 83% fewer symptomatic cases (p<0.0001), and 60% fewer cases (p=0.0001).
Open-label non-randomized trial with 80 participants exposed to confirmed SARS-CoV-2 cases, showing lower risk of infection and milder symptoms with mitoquinone mesylate (Mito-MES) prophylaxis. 40 participants took Mito-MES 20mg daily for 14 days, starting within 5 days of exposure, while 40 did not take Mito-MES. 30% of Mito-MES participants tested positive for SARS-CoV-2 compared to 75% of controls. None of the participants who started Mito-MES within 72 hours developed infection, compared to 12 who started on days 3-5. There was no hospitalization in either group.
Mar 2024, eBioMedicine, https://www.sciencedirect.com/science/article/pii/S235239642400077X, https://c19p.org/chen17
Randomized controlled trial of 111 hospitalized COVID-19 patients in Iran showing significantly shorter hospital stay, higher oxygen saturation, and lower respiratory rate at discharge with azithromycin plus hydroxychloroquine and lopinavir/ritonavir compared to hydroxychloroquine and lopinavir/ritonavir alone. There were no significant differences in ICU admission, intubation, or mortality, although there was a trend towards lower ICU admission with azithromycin (3.6% vs. 12.7%, p = 0.07). Patients with prior cardiac disease were excluded. The study is limited by the small sample size and open-label design.
Oct 2020, Int. J. Antimicrobial Agents, https://www.sciencedirect.com/science/article/pii/S0924857920303411, https://c19p.org/sekhavati
RCT 76 hospitalized mild-to-moderate COVID-19 patients in the Philippines showing faster resolution of symptoms with virgin coconut oil (VCO) treatment, without statistical significance.
Jan 2024, J. Nutritional Science, https://www.cambridge.org/core/product/identifier/S2048679023001180/type/journal_article, https://c19p.org/angelesagdeppa
3,462 patient azithromycin late treatment study: 67% lower mortality (p=0.0001).
Retrospective 3,462 hospitalized COVID-19 patients across 13 states in Nigiera, showing lower mortality with AZ. Authors note the worse results with a combination of CQ/HCQ and AZ, compared to either alone, may be related to the side effects becoming more significant for late stage patients.
May 2023, Nigerian Medical J., https://nigerianmedjournal.org/index.php/nmj/article/view/174, https://c19p.org/yilgwanaz
Retrospective 672 COVID-19 patients in Zimbabwe, showing lower mortality with azithromycin treatment.
Mar 2023, Pan African Medical J., https://www.panafrican-med-journal.com/content/article/44/142/full, https://c19p.org/madamombeaz
azithromycin prophylaxis study: 58% lower mortality (p=0.02).
Retrospective study of 367 hematology patients with COVID-19 in Spain. Among 216 patients with very severe COVID-19, there was significantly lower mortality with azithromycin treatment. Mortality was also lower with HCQ, but without statistical significance.
Aug 2020, Experimental Hematology & Oncology, https://ehoonline.biomedcentral.com/articles/10.1186/s40164-020-00177-z, https://c19p.org/pinanaaz
azithromycin early treatment PSM study: 27% lower combined mortality/ICU admission (p=0.0005).
Independent analysis of the IHU-Mediterranean data [Brouqui] with 30,423 COVID-19 patients showing significantly lower risk of ICU admission or death with early treatment of hydroxychloroquine plus azithromycin (HCQ-AZ), and with azithromycin, both compared to no treatment.
Feb 2024, Archives of Microbiology & Immunology, https://www.fortunejournals.com/articles/an-independent-analysis-of-a-retrospective-cohort-of-30423-covid19-patients-treated-at-ihumediterranean-in-marseille-france-part-1.html, https://c19p.org/lounnas2az
RCT 90 outpatients showing potential benefit of azelastine nasal spray for reducing viral load. Patients were randomized to receive placebo, 0.02%, or 0.1% azelastine nasal spray for 11 days. The 0.1% azelastine group showed greater viral load reduction compared to placebo (p=0.007) and achieved PCR negativity earlier (48.2% vs 23.1% negative by day 11). Symptoms improved across all groups, with the 0.1% group showing slightly greater improvement (12.74 point reduction vs 11.12 for placebo) and significantly better improvement in shortness of breath on days 3-4. No significant differences were found in quality of life measures or WHO clinical progression scores.
Apr 2023, Scientific Reports, https://www.nature.com/articles/s41598-023-32546-z, https://c19p.org/klussmann
RCT 192 critically ill COVID-19 ICU patients showing reduced SOFA score, hospital stay and ICU stay with spirulina supplementation (5g/day), but no significant difference in mortality, NEWS2 score, APACHE score, NUTRIC score, or respiratory support at discharge.
Sep 2024, J. Cellular and Molecular Anesthesia, https://brieflands.com/articles/jcma-149015, https://c19p.org/shadnoush
RCT 294 low-risk subjects with mild COVID-19 showing significantly greater reduction in viral load with azelastine 0.1% nasal spray vs. placebo. There was no COVID-19 related hospitalization in either group. The reduction in viral load was significantly higher in the azelastine group at day 3, 6 and 11. Authors report that treatment was associated with significant improvement in fever (p=0.0046), weakness (p=0.0012) and hypoxia (p<0.0001) compared to placebo, however detailed results are not provided for these and other symptoms. Treatment delay from symptom onset is not specified, however the baseline viral load, lack of progression, and recovery profile are consistent with relatively late treatment among low-risk patients. Time to recovery results are not clear, with an inconsistent HR and 95% CI reported 0.32 [0.83-2.32].
Oct 2024, MDPI AG, https://www.preprints.org/manuscript/202410.2532/v1, https://c19p.org/meiser
Late stage RCT of 667 hospitalized patients with up to 14 days of symptoms at enrollment and receiving up to 4 liters per minute supplemental oxygen, not finding a significant effect after 15 days. Authors note: "the trial cannot definitively rule out either a substantial benefit of the trial drugs or a substantial harm", sample sizes are too small. The paper uses the terms mild and moderate, however all patients had serious enough disease to be hospitalized, and 14% were actually randomized in the ICU. The trial had significant protocol deviations and unusually low medication adherence. Authors note: "our aim was to exclude patients already receiving longer and potentially therapeutic doses of the study treatments" in explanation for why the study protocol was changed to exclude patients with previous use of the medications >24hrs. Analyzing these patients rather than excluding them may have revealed effectiveness with early use as shown in other studies. The..
Jul 2020, NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2019014, https://c19p.org/cavalcantiaz
Retrospective 31,260 COVID-19 cases and 125,039 matched controls, showing lower risk of COVID-19 with previous azithromycin use.
Mar 2023, Antibiotics, https://www.mdpi.com/2079-6382/12/3/587, https://c19p.org/dugot
Retrospective 15,968 COVID-19 hospitalized patients in Spain, showing lower mortality with existing use of several medications including metformin, HCQ, azithromycin, aspirin, vitamin D, vitamin C, and budesonide. Since only hospitalized patients are included, results do not reflect different probabilities of hospitalization across treatments.
Aug 2022, Virology J., https://virologyj.biomedcentral.com/articles/10.1186/s12985-023-02195-9, https://c19p.org/loucera3az
RCT 7,763 hospitalized COVID-19 patients showing no significant differences with very late (75% on oxygen at baseline) azithromycin treatment. Only 91% of treatment patients received azithromycin and 17% of control patients received azithromycin or other macrolides.
Feb 2021, The Lancet, https://www.sciencedirect.com/science/article/pii/S0140673621001495, https://c19p.org/abaleke
Retrospective study of 917,198 hospitalized COVID-19 cases covered by the Iran Health Insurance Organization over 26 months showing that antithrombotics, corticosteroids, and antivirals reduced mortality while diuretics, antibiotics, and antidiabetics increased it. Confounding makes some results very unreliable. For example, diuretics like furosemide are often used to treat fluid overload, which is more likely in ICU or advanced disease requiring aggressive fluid resuscitation. Hospitalization length has increased risk of significant confounding, for example longer hospitalization increases the chance of receiving a medication, and death may result in shorter hospitalization. Mortality results may be more reliable. Confounding by indication is likely to be significant for many medications. Authors adjustments have very limited severity information (admission type refers to ward vs. ER department on initial arrival). We can estimate the impact of confounding from typical usage..
Dec 2023, Frontiers in Public Health, https://www.frontiersin.org/articles/10.3389/fpubh.2023.1280434/full, https://c19p.org/mehriziaz
60 patient azithromycin late treatment study: 85% lower mortality (p=0.31).
RCT 60 hospitalized COVID-19 patients evaluating the efficacy and safety of adding oral N-acetylcysteine (NAC) at 600mg three times daily to standard antiviral treatment regimens. There was lower mortality for patients that received azithromycin, without statistical significance.
Nov 2023, Immunity, Inflammation and Disease, https://onlinelibrary.wiley.com/doi/10.1002/iid3.1083, https://c19p.org/atefiaz
Retrospective 723 hospitalized COVID-19 patients in Italy showing no significant difference with azithromycin treatment.
Jan 2024, BMC Infectious Diseases, https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-024-09034-4, https://c19p.org/donidaaz
Retrospective 7,158 hospitalized COVID-19 patients in the USA analyzing famotidine treatment, showing no significant difference in mortality with associated azithromycin treatment.
Feb 2021, Gastroenterology, https://www.gastrojournal.org/article/S0016-5085(20)35249-5/fulltext, https://c19p.org/yeramaneniaz
RCT 298 mild-to-moderate COVID-19 outpatients in the UK showing no significant difference in hospitalization or death with late azithromycin treatment. Treatment was delayed an average of 6 days from onset. 7 vs. 3 hospitalizations occurred by day 1 in the treatment vs. control groups in this open label trial (Figure 2).
Oct 2021, The Lancet Respiratory Medicine, https://www.sciencedirect.com/science/article/pii/S2213260021002630, https://c19p.org/hinks
397 patient azithromycin late treatment RCT: 8% higher mortality (p=0.63) and 30% improvement (p=0.08).
Small RCT comparing the addition of AZ for very late stage patients on ventilation or oxygen. One notable result is that even within this extremely late stage population, results suggest increased efficacy with the addition of AZ for patients with earlier use of AZ/HCQ, OR 0.71 [0.25-2.03] (Figure S4). Patients received 8g of HCQ over 10 days, approaching the high levels used in the RECOVERY trial (9.2g over 10 days), showing significantly more adverse events than typical trials. 50% of patients were on mechanical ventilation at baseline. More than the increase in mortality at day 29 occurred on day 0, and more than 3x the increase occurred by day 2.
Sep 2020, The Lancet, https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31862-6/fulltext, https://c19p.org/furtadoaz
Retrospective 848 ICU patients in Saudi Arabia, showing higher mortality with azithromycin in unadjusted results.
May 2023, Clinical Infection in Practice, https://www.sciencedirect.com/science/article/pii/S2590170223000122, https://c19p.org/alqadheebaz
Retrospective database analysis showing no significant differences with azithromycin use.
Dec 2020, Int. J. Infectious Diseases, https://www.sciencedirect.com/science/article/pii/S1201971220325650, https://c19p.org/huh2az
Low risk patient RCT for HCQ+AZ and HCQ vs. control, not showing any significant differences. Authors note that the results are not applicable to higher risk patients, that positive PCR may simply reflect detection of inactive (non-infectious) viral remnants, that an alternative dosage regimen may be more effective, and that medication adherence was unknown. HCQ dosing was 600mg/day for 1 week, therapeutic levels may not be reached for several days. There were no deaths or serious adverse events. Viral load was already very high at baseline.
Nov 2020, eClinicalMedicine, https://www.sciencedirect.com/science/article/pii/S2589537020303898, https://c19p.org/omraniaz
Retrospective 2,196 COVID-19 patients in Taiwan (49% mild cases, 44% moderate, 7% severe) showing significantly higher mortality with dexamethasone. Authors report that all infected patients were hospitalized at the time of the study in Taiwan.
Aug 2024, BMC Infectious Diseases, https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-024-09654-w, https://c19p.org/yen2dex
Retrospective 672 COVID-19 patients in Zimbabwe, showing higher mortality with dexamethasone treatment.
Mar 2023, Pan African Medical J., https://www.panafrican-med-journal.com/content/article/44/142/full, https://c19p.org/madamombedx
RCT 1,126 patients in Brazil showing no significant differences with low dose spirulina. The dose used was 7.6 times lower than the dose used by [Aghasadeghi] which shows significantly lower mortality. eFigure 1 shows 12 events in the treatment group before the first event in the placebo group. The probability of this happening is very low, ~ 0.001. One possible cause would be if some process resulted in patients expected to visit the ER soon being more likely to be placed in the treatment group. (Another possibility is treatment side effects causing ER visits, however the were fewer adverse events and fewer severe adverse events in the treatment group).
Aug 2024, The American J. Clinical Nutrition, https://www.sciencedirect.com/science/article/pii/S0002916524005884, https://c19p.org/reis13
RCT 126 hospitalized COVID-19 pneumonia patients not requiring oxygen at admission, showing no significant difference in outcomes with dexamethasone treatment.
Jul 2024, Frontiers in Medicine, https://www.frontiersin.org/articles/10.3389/fmed.2024.1385833/full, https://c19p.org/francomoreno
RCT 126 hospitalized COVID-19 pneumonia patients not requiring oxygen at admission, showing no significant difference in outcomes with dexamethasone treatment.
Jul 2024, Frontiers in Medicine, https://www.frontiersin.org/articles/10.3389/fmed.2024.1385833/full, https://c19p.org/francomorenodex
1. Martin et al., Oral Probenecid for Nonhospitalized Adults with Symptomatic Mild-to-Moderate COVID-19
75 patient probenicid early treatment RCT: 90% improved recovery (p<0.0001) and 36% faster viral clearance (p=0.0001).RCT 75 outpatients in India with mild to moderate COVID-19 showing faster viral clearance, faster time to symptom resolution, and improvement in disease progression with probenecid treatment for 5 days compared to placebo. Probenecid was well tolerated with only mild adverse events noted. There was a dose-dependent response, with probenecid 1000mg twice daily performing better than 500mg twice daily.
Jul 2023, Viruses, https://www.mdpi.com/1999-4915/15/7/1508, https://c19p.org/martin
2. Holubovska et al., RNA Polymerase Inhibitor Enisamium for Treatment of Moderate COVID-19 Patients: A Randomized, Placebo-Controlled, Multicenter, Double-Blind Phase 3 Clinical Trial
285 patient enisamium late treatment RCT: 86% lower mortality (p=0.25), 75% lower progression (p=0.03), 9% faster improvement (p=0.01), and 89% higher hospital discharge (p=0.12).RCT 592 hospitalized moderate COVID-19 patients in Ukraine showing improved recovery and lower progression with enisamium. The trial initially included patients with moderate COVID-19 not requiring oxygen, but a mid-trial change was made to exclude this group due to a lack of benefit, and results are reported for the patients requiring oxygen. The greatest benefit was seen in patients treated within 5 days of symptom onset.
May 2024, Advances in Respiratory Medicine, https://www.mdpi.com/2543-6031/92/3/21, https://c19p.org/holubovska
3. Aghasadeghi et al., Effect of high-dose Spirulina supplementation on hospitalized adults with COVID-19: a randomized controlled trial
189 patient spirulina late treatment RCT: 85% lower mortality (p=0.0002) and 75% higher hospital discharge (p=0.003).RCT 189 hospitalized COVID-19 patients showing lower mortality and faster recovery with spirulina. Spirulina treatment also resulted in greater reductions in inflammatory markers such as IL-6, TNF-a, IP-10, CRP, ESR, and ferritin. All patients received remdesivir. Spirulina contains many components including calcium spirulan, a sulfated polysaccharide shown to inhibit the replication of various enveloped viruses in vitro, and many nutrients showing benefits for COVID-19 including vitamins A, C, and D, selenium, and zinc.
Apr 2024, Frontiers in Immunology, https://www.frontiersin.org/articles/10.3389/fimmu.2024.1332425/full, https://c19p.org/aghasadeghi
4. Alejandria et al., Virgin Coconut Oil as Adjunctive Therapy for Hospitalized COVID-19 Patients in a Tertiary Referral Hospital: A Randomized Controlled Trial
77 patient VCO late treatment RCT: 86% lower mortality (p=0.12), 86% lower ventilation (p=0.12), 10% shorter hospitalization (p=0.41), and 3% faster recovery (p=0.77).RCT 77 hospitalized patients showing no significant differences with virgin coconut oil (VCO) treatment.
May 2024, Acta Medica Philippina, https://actamedicaphilippina.upm.edu.ph/index.php/acta/article/view/7498, https://c19p.org/alejandria
1,217 patient GST-HG171 early treatment RCT: 13% faster recovery (p=0.03) and 25% faster viral clearance (p<0.0001).
RCT 1,213 outpatients with mild-to-moderate COVID-19 in China showing a shorter time to sustained recovery and faster viral clearance with GST-HG171 plus ritonavir.
May 2024, eClinicalMedicine, https://www.sciencedirect.com/science/article/pii/S2589537024001615, https://c19p.org/lu5
1,323 patient azithromycin late treatment RCT: 16% lower need for oxygen therapy (p=0.69), 9% lower hospitalization (p=0.87), and 7% improved recovery (p=0.23).
RCT 1,388 outpatients in the UK showing no significant benefit with azithromycin. There was no significant difference in time to first reported recovery or risk of hospitalization or death by 28 days with azithromycin compared to usual care alone. Only 31% of participants had PCR-confirmed SARS-CoV-2 infection.
Mar 2021, The Lancet, https://www.sciencedirect.com/science/article/pii/S014067362100461X, https://c19p.org/butler4
80 patient Mito-MES prophylaxis study: 91% fewer moderate/severe cases (p=0.05), 83% fewer symptomatic cases (p<0.0001), and 60% fewer cases (p=0.0001).
Open-label non-randomized trial with 80 participants exposed to confirmed SARS-CoV-2 cases, showing lower risk of infection and milder symptoms with mitoquinone mesylate (Mito-MES) prophylaxis. 40 participants took Mito-MES 20mg daily for 14 days, starting within 5 days of exposure, while 40 did not take Mito-MES. 30% of Mito-MES participants tested positive for SARS-CoV-2 compared to 75% of controls. None of the participants who started Mito-MES within 72 hours developed infection, compared to 12 who started on days 3-5. There was no hospitalization in either group.
Mar 2024, eBioMedicine, https://www.sciencedirect.com/science/article/pii/S235239642400077X, https://c19p.org/chen17
8. Sekhavati et al., Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial
111 patient azithromycin late treatment RCT: 86% lower ventilation (p=0.12), 72% lower ICU admission (p=0.09), and 23% shorter hospitalization (p=0.02).Randomized controlled trial of 111 hospitalized COVID-19 patients in Iran showing significantly shorter hospital stay, higher oxygen saturation, and lower respiratory rate at discharge with azithromycin plus hydroxychloroquine and lopinavir/ritonavir compared to hydroxychloroquine and lopinavir/ritonavir alone. There were no significant differences in ICU admission, intubation, or mortality, although there was a trend towards lower ICU admission with azithromycin (3.6% vs. 12.7%, p = 0.07). Patients with prior cardiac disease were excluded. The study is limited by the small sample size and open-label design.
Oct 2020, Int. J. Antimicrobial Agents, https://www.sciencedirect.com/science/article/pii/S0924857920303411, https://c19p.org/sekhavati
9. Angeles-Agdeppa et al., Virgin coconut oil (VCO) supplementation relieves symptoms and inflammation among COVID-19 positive adults: a single-blind randomized trial
76 patient VCO late treatment RCT: 47% improved recovery (p=0.13).RCT 76 hospitalized mild-to-moderate COVID-19 patients in the Philippines showing faster resolution of symptoms with virgin coconut oil (VCO) treatment, without statistical significance.
Jan 2024, J. Nutritional Science, https://www.cambridge.org/core/product/identifier/S2048679023001180/type/journal_article, https://c19p.org/angelesagdeppa
3,462 patient azithromycin late treatment study: 67% lower mortality (p=0.0001).
Retrospective 3,462 hospitalized COVID-19 patients across 13 states in Nigiera, showing lower mortality with AZ. Authors note the worse results with a combination of CQ/HCQ and AZ, compared to either alone, may be related to the side effects becoming more significant for late stage patients.
May 2023, Nigerian Medical J., https://nigerianmedjournal.org/index.php/nmj/article/view/174, https://c19p.org/yilgwanaz
11. Madamombe et al., Factors associated with COVID-19 fatality among patients admitted in Mashonaland West Province, Zimbabwe 2020-2022: a secondary data analysis
672 patient azithromycin early treatment study: 40% lower mortality (p=0.03).Retrospective 672 COVID-19 patients in Zimbabwe, showing lower mortality with azithromycin treatment.
Mar 2023, Pan African Medical J., https://www.panafrican-med-journal.com/content/article/44/142/full, https://c19p.org/madamombeaz
azithromycin prophylaxis study: 58% lower mortality (p=0.02).
Retrospective study of 367 hematology patients with COVID-19 in Spain. Among 216 patients with very severe COVID-19, there was significantly lower mortality with azithromycin treatment. Mortality was also lower with HCQ, but without statistical significance.
Aug 2020, Experimental Hematology & Oncology, https://ehoonline.biomedcentral.com/articles/10.1186/s40164-020-00177-z, https://c19p.org/pinanaaz
azithromycin early treatment PSM study: 27% lower combined mortality/ICU admission (p=0.0005).
Independent analysis of the IHU-Mediterranean data [Brouqui] with 30,423 COVID-19 patients showing significantly lower risk of ICU admission or death with early treatment of hydroxychloroquine plus azithromycin (HCQ-AZ), and with azithromycin, both compared to no treatment.
Feb 2024, Archives of Microbiology & Immunology, https://www.fortunejournals.com/articles/an-independent-analysis-of-a-retrospective-cohort-of-30423-covid19-patients-treated-at-ihumediterranean-in-marseille-france-part-1.html, https://c19p.org/lounnas2az
14. Klussmann et al., Early intervention with azelastine nasal spray may reduce viral load in SARS-CoV-2 infected patients
61 patient azelastine early treatment RCT: 13% improved recovery (p=0.54) and 14% improved viral clearance (p=0.22).RCT 90 outpatients showing potential benefit of azelastine nasal spray for reducing viral load. Patients were randomized to receive placebo, 0.02%, or 0.1% azelastine nasal spray for 11 days. The 0.1% azelastine group showed greater viral load reduction compared to placebo (p=0.007) and achieved PCR negativity earlier (48.2% vs 23.1% negative by day 11). Symptoms improved across all groups, with the 0.1% group showing slightly greater improvement (12.74 point reduction vs 11.12 for placebo) and significantly better improvement in shortness of breath on days 3-4. No significant differences were found in quality of life measures or WHO clinical progression scores.
Apr 2023, Scientific Reports, https://www.nature.com/articles/s41598-023-32546-z, https://c19p.org/klussmann
15. Shadnoush et al., Effects of Spirulina platensis Supplementation on COVID-19 Severity in Critically Ill Patients: A Randomized Clinical Trial
126 patient spirulina ICU RCT: 3% higher mortality (p=0.93), 26% shorter ICU admission (p=0.007), 17% lower need for oxygen therapy (p=0.64), and 20% shorter hospitalization (p=0.001).RCT 192 critically ill COVID-19 ICU patients showing reduced SOFA score, hospital stay and ICU stay with spirulina supplementation (5g/day), but no significant difference in mortality, NEWS2 score, APACHE score, NUTRIC score, or respiratory support at discharge.
Sep 2024, J. Cellular and Molecular Anesthesia, https://brieflands.com/articles/jcma-149015, https://c19p.org/shadnoush
16. Meiser et al., Azelastine Nasal Spray in Non-Hospitalised Subjects with Mild COVID-19 Infection: A Randomized Placebo-Controlled, Parallel-Group, Multicentric, Phase II Clinical Trial
251 patient azelastine late treatment RCT: 13% improved recovery (p=0.42) and 6% improved viral clearance (p<0.0001).RCT 294 low-risk subjects with mild COVID-19 showing significantly greater reduction in viral load with azelastine 0.1% nasal spray vs. placebo. There was no COVID-19 related hospitalization in either group. The reduction in viral load was significantly higher in the azelastine group at day 3, 6 and 11. Authors report that treatment was associated with significant improvement in fever (p=0.0046), weakness (p=0.0012) and hypoxia (p<0.0001) compared to placebo, however detailed results are not provided for these and other symptoms. Treatment delay from symptom onset is not specified, however the baseline viral load, lack of progression, and recovery profile are consistent with relatively late treatment among low-risk patients. Time to recovery results are not clear, with an inconsistent HR and 95% CI reported 0.32 [0.83-2.32].
Oct 2024, MDPI AG, https://www.preprints.org/manuscript/202410.2532/v1, https://c19p.org/meiser
17. Cavalcanti et al., Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19
667 patient azithromycin late treatment RCT: 57% lower mortality (p=0.17), 54% higher ventilation (p=0.28), and 18% improved 7-point scale results (p=0.49).Late stage RCT of 667 hospitalized patients with up to 14 days of symptoms at enrollment and receiving up to 4 liters per minute supplemental oxygen, not finding a significant effect after 15 days. Authors note: "the trial cannot definitively rule out either a substantial benefit of the trial drugs or a substantial harm", sample sizes are too small. The paper uses the terms mild and moderate, however all patients had serious enough disease to be hospitalized, and 14% were actually randomized in the ICU. The trial had significant protocol deviations and unusually low medication adherence. Authors note: "our aim was to exclude patients already receiving longer and potentially therapeutic doses of the study treatments" in explanation for why the study protocol was changed to exclude patients with previous use of the medications >24hrs. Analyzing these patients rather than excluding them may have revealed effectiveness with early use as shown in other studies. The..
Jul 2020, NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2019014, https://c19p.org/cavalcantiaz
18. Dugot et al., The Association between Previous Antibiotic Consumption and SARS-CoV-2 Infection: A Population-Based Case-Control Study
156,299 patient azithromycin prophylaxis study: 12% fewer cases (p<0.0001).Retrospective 31,260 COVID-19 cases and 125,039 matched controls, showing lower risk of COVID-19 with previous azithromycin use.
Mar 2023, Antibiotics, https://www.mdpi.com/2079-6382/12/3/587, https://c19p.org/dugot
19. Loucera et al., Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments
15,968 patient azithromycin prophylaxis study: 15% lower mortality (p=0.005).Retrospective 15,968 COVID-19 hospitalized patients in Spain, showing lower mortality with existing use of several medications including metformin, HCQ, azithromycin, aspirin, vitamin D, vitamin C, and budesonide. Since only hospitalized patients are included, results do not reflect different probabilities of hospitalization across treatments.
Aug 2022, Virology J., https://virologyj.biomedcentral.com/articles/10.1186/s12985-023-02195-9, https://c19p.org/loucera3az
20. Abaleke et al., Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
7,763 patient azithromycin late treatment RCT: 3% lower mortality (p=0.5), 8% lower ventilation (p=0.29), and 9% higher hospital discharge.RCT 7,763 hospitalized COVID-19 patients showing no significant differences with very late (75% on oxygen at baseline) azithromycin treatment. Only 91% of treatment patients received azithromycin and 17% of control patients received azithromycin or other macrolides.
Feb 2021, The Lancet, https://www.sciencedirect.com/science/article/pii/S0140673621001495, https://c19p.org/abaleke
21. Mehrizi et al., Drug prescription patterns and their association with mortality and hospitalization duration in COVID-19 patients: insights from big data
917,198 patient azithromycin late treatment study: 32% lower mortality (p<0.0001).Retrospective study of 917,198 hospitalized COVID-19 cases covered by the Iran Health Insurance Organization over 26 months showing that antithrombotics, corticosteroids, and antivirals reduced mortality while diuretics, antibiotics, and antidiabetics increased it. Confounding makes some results very unreliable. For example, diuretics like furosemide are often used to treat fluid overload, which is more likely in ICU or advanced disease requiring aggressive fluid resuscitation. Hospitalization length has increased risk of significant confounding, for example longer hospitalization increases the chance of receiving a medication, and death may result in shorter hospitalization. Mortality results may be more reliable. Confounding by indication is likely to be significant for many medications. Authors adjustments have very limited severity information (admission type refers to ward vs. ER department on initial arrival). We can estimate the impact of confounding from typical usage..
Dec 2023, Frontiers in Public Health, https://www.frontiersin.org/articles/10.3389/fpubh.2023.1280434/full, https://c19p.org/mehriziaz
60 patient azithromycin late treatment study: 85% lower mortality (p=0.31).
RCT 60 hospitalized COVID-19 patients evaluating the efficacy and safety of adding oral N-acetylcysteine (NAC) at 600mg three times daily to standard antiviral treatment regimens. There was lower mortality for patients that received azithromycin, without statistical significance.
Nov 2023, Immunity, Inflammation and Disease, https://onlinelibrary.wiley.com/doi/10.1002/iid3.1083, https://c19p.org/atefiaz
23. Donida et al., First COVID-19 wave in the province of Bergamo, Italy: epidemiological and clinical characteristics, outcome and management of the first hospitalized patients
723 patient azithromycin late treatment study: 7% lower mortality (p=0.79).Retrospective 723 hospitalized COVID-19 patients in Italy showing no significant difference with azithromycin treatment.
Jan 2024, BMC Infectious Diseases, https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-024-09034-4, https://c19p.org/donidaaz
24. Yeramaneni et al., Famotidine Use Is Not Associated With 30-day Mortality: A Coarsened Exact Match Study in 7158 Hospitalized Patients With Coronavirus Disease 2019 From a Large Healthcare System
7,158 patient azithromycin late treatment study: 7% lower mortality (p=0.84).Retrospective 7,158 hospitalized COVID-19 patients in the USA analyzing famotidine treatment, showing no significant difference in mortality with associated azithromycin treatment.
Feb 2021, Gastroenterology, https://www.gastrojournal.org/article/S0016-5085(20)35249-5/fulltext, https://c19p.org/yeramaneniaz
25. Hinks et al., Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial
298 patient azithromycin late treatment RCT: 1% lower combined mortality/hospitalization (p=0.99) and 80% lower progression (p=0.24).RCT 298 mild-to-moderate COVID-19 outpatients in the UK showing no significant difference in hospitalization or death with late azithromycin treatment. Treatment was delayed an average of 6 days from onset. 7 vs. 3 hospitalizations occurred by day 1 in the treatment vs. control groups in this open label trial (Figure 2).
Oct 2021, The Lancet Respiratory Medicine, https://www.sciencedirect.com/science/article/pii/S2213260021002630, https://c19p.org/hinks
397 patient azithromycin late treatment RCT: 8% higher mortality (p=0.63) and 30% improvement (p=0.08).
Small RCT comparing the addition of AZ for very late stage patients on ventilation or oxygen. One notable result is that even within this extremely late stage population, results suggest increased efficacy with the addition of AZ for patients with earlier use of AZ/HCQ, OR 0.71 [0.25-2.03] (Figure S4). Patients received 8g of HCQ over 10 days, approaching the high levels used in the RECOVERY trial (9.2g over 10 days), showing significantly more adverse events than typical trials. 50% of patients were on mechanical ventilation at baseline. More than the increase in mortality at day 29 occurred on day 0, and more than 3x the increase occurred by day 2.
Sep 2020, The Lancet, https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31862-6/fulltext, https://c19p.org/furtadoaz
27. AlQadheeb et al., Impact of common comorbidities on antimicrobial consumption and mortality amongst critically ill COVID-19 patients: A retrospective two center study in Saudi Arabia
848 patient azithromycin ICU study: 22% higher mortality (p=0.08).Retrospective 848 ICU patients in Saudi Arabia, showing higher mortality with azithromycin in unadjusted results.
May 2023, Clinical Infection in Practice, https://www.sciencedirect.com/science/article/pii/S2590170223000122, https://c19p.org/alqadheebaz
28. Huh et al., Association of prescribed medications with the risk of COVID-19 infection and severity among adults in South Korea
44,046 patient azithromycin prophylaxis study: 54% higher progression (p=0.33) and 42% fewer cases (p=0.1).Retrospective database analysis showing no significant differences with azithromycin use.
Dec 2020, Int. J. Infectious Diseases, https://www.sciencedirect.com/science/article/pii/S1201971220325650, https://c19p.org/huh2az
29. Omrani et al., Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19
304 patient azithromycin early treatment RCT: 33% higher hospitalization (p=1), 67% lower progression (p=0.62), 100% worse recovery (p=0.5), and 4% worse viral clearance (p=0.63).Low risk patient RCT for HCQ+AZ and HCQ vs. control, not showing any significant differences. Authors note that the results are not applicable to higher risk patients, that positive PCR may simply reflect detection of inactive (non-infectious) viral remnants, that an alternative dosage regimen may be more effective, and that medication adherence was unknown. HCQ dosing was 600mg/day for 1 week, therapeutic levels may not be reached for several days. There were no deaths or serious adverse events. Viral load was already very high at baseline.
Nov 2020, eClinicalMedicine, https://www.sciencedirect.com/science/article/pii/S2589537020303898, https://c19p.org/omraniaz
30. Yen et al., Predictors for cause-specific and timing of deaths in patients with COVID-19: a cohort study in Taiwan
2,196 patient dexamethasone early treatment study: 103% higher mortality (p=0.0002).Retrospective 2,196 COVID-19 patients in Taiwan (49% mild cases, 44% moderate, 7% severe) showing significantly higher mortality with dexamethasone. Authors report that all infected patients were hospitalized at the time of the study in Taiwan.
Aug 2024, BMC Infectious Diseases, https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-024-09654-w, https://c19p.org/yen2dex
31. Madamombe et al., Factors associated with COVID-19 fatality among patients admitted in Mashonaland West Province, Zimbabwe 2020-2022: a secondary data analysis
672 patient dexamethasone early treatment study: 130% higher mortality (p<0.0001).Retrospective 672 COVID-19 patients in Zimbabwe, showing higher mortality with dexamethasone treatment.
Mar 2023, Pan African Medical J., https://www.panafrican-med-journal.com/content/article/44/142/full, https://c19p.org/madamombedx
32. Reis et al., Effect of spirulina on risk of hospitalization among patients with COVID-19: the TOGETHER randomized trial
1,126 patient spirulina early treatment RCT: 21% higher progression (p=0.29).RCT 1,126 patients in Brazil showing no significant differences with low dose spirulina. The dose used was 7.6 times lower than the dose used by [Aghasadeghi] which shows significantly lower mortality. eFigure 1 shows 12 events in the treatment group before the first event in the placebo group. The probability of this happening is very low, ~ 0.001. One possible cause would be if some process resulted in patients expected to visit the ER soon being more likely to be placed in the treatment group. (Another possibility is treatment side effects causing ER visits, however the were fewer adverse events and fewer severe adverse events in the treatment group).
Aug 2024, The American J. Clinical Nutrition, https://www.sciencedirect.com/science/article/pii/S0002916524005884, https://c19p.org/reis13
33. Franco-Moreno et al., Effect of early administration of dexamethasone in patients with COVID-19 pneumonia without acute hypoxemic respiratory failure and risk of development of acute respiratory distress syndrome: EARLY-DEX COVID-19 trial
126 patient dexamethasone late treatment RCT: 134% higher ventilation (p=0.41), 217% higher ICU admission (p=0.46), 17% higher ARDS (p=0.81), and 3% shorter hospitalization (p=0.88).RCT 126 hospitalized COVID-19 pneumonia patients not requiring oxygen at admission, showing no significant difference in outcomes with dexamethasone treatment.
Jul 2024, Frontiers in Medicine, https://www.frontiersin.org/articles/10.3389/fmed.2024.1385833/full, https://c19p.org/francomoreno
34. Franco-Moreno et al., Effect of early administration of dexamethasone in patients with COVID-19 pneumonia without acute hypoxemic respiratory failure and risk of development of acute respiratory distress syndrome: EARLY-DEX COVID-19 trial
126 patient dexamethasone late treatment RCT: 134% higher ventilation (p=0.41), 217% higher ICU admission (p=0.46), 17% higher ARDS (p=0.81), and 3% shorter hospitalization (p=0.88).RCT 126 hospitalized COVID-19 pneumonia patients not requiring oxygen at admission, showing no significant difference in outcomes with dexamethasone treatment.
Jul 2024, Frontiers in Medicine, https://www.frontiersin.org/articles/10.3389/fmed.2024.1385833/full, https://c19p.org/francomorenodex
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