Preprint Article Version 1 This version is not peer-reviewed

COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study

Version 1 : Received: 30 June 2020 / Approved: 3 July 2020 / Online: 3 July 2020 (08:52:22 CEST)

How to cite: Scholz, M.; Derwand, R.; Zelenko, V. COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study. Preprints 2020, 2020070025 (doi: 10.20944/preprints202007.0025.v1). Scholz, M.; Derwand, R.; Zelenko, V. COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study. Preprints 2020, 2020070025 (doi: 10.20944/preprints202007.0025.v1).

Abstract

Objective: To describe outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low dose hydroxychloroquine, and azithromycin (the triple therapy) dependent on risk stratification. Design: Retrospective case series study. Setting: General practice. Participants: 141 COVID-19 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the year 2020. Main Outcome Measures: Risk-stratified treatment decision, rate of hospitalization and all-cause death. Results: Of 335 positively PCR-tested COVID-19 patients, 127 were treated with the triple therapy. 104 of 127 met the defined risk stratification criteria and were included in the analysis. In addition, 37 treated and eligible patients who were confirmed by IgG tests were included in the treatment group (total N=141). 208 of the 335 patients did not meet the risk stratification criteria and were not treated. After 4 days (median, IQR 3-6, available for N=66/141) of onset of symptoms, 141 patients (median age 58 years, IQR 40-67; 73% male) got a prescription for the triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control. 4 of 141 treated patients (2.8%) were hospitalized, which was significantly less (p<0.001) compared with 58 of 377 untreated patients (15.4%) (odds ratio 0.16, 95% CI 0.06-0.5). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated group. One patient (0.7%) died in the treatment group versus 13 patients (3.5%) in the untreated group (odds ratio 0.2, 95% CI 0.03-1.5; p=0.16). There were no cardiac side effects. Conclusions: Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset with the used triple therapy, including the combination of zinc with low dose hydroxychloroquine, was associated with significantly less hospitalizations and 5 times less all-cause deaths.

Subject Areas

SARS-CoV-2; COVID-19; outpatients; treatment; zinc; hydroxychloroquine; azithromycin

Comments (50)

Comment 1
Received: 4 July 2020
Commenter: Bob O'Hara (Click to see Publons profile: )
The commenter has declared there is no conflict of interests.
Comment: The main problem with this work is that the demographics of the control group are not reported, so we have no idea if they are similar. This them means that we have no idea if the differences in outcomes are because of the treatment, or if they would be expected because of the demographies of the groups. A subtler point is that the reported age profile of the treatment group is impossible. Group A is aged >60 years, and almost half of the treatment group was in that group. But the IQR was reported as 40-60, so only 25% of the treatment group had an age >60. I hope this was due to excessive rounding, or a similar error that can be corrected.
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Response 1 to Comment 1
Received: 6 July 2020
Commenter: john mecomb
The commenter has declared there is no conflict of interests.
Comment: The control group would have to be people with symptoms at high risk for progression of disease. Would this not be unethical for this kind of study? I for one would not want to be in such a control group and, as a patient, if informed as such would decline. As a physician, under the current circumstances, it would violate my hippocratic oath to place people in such a control group. If this was remdesivir, this study would be on the front page of the NYT. The "control group" has to be a preponderance of the evidence at this point. It appears from this study, these medicines do no harm in the first several days of the infection. Let practicing physicians be free to judge not policicophysicians without patients.
Response 2 to Comment 1
Received: 6 July 2020
Commenter: Tom Hogan
The commenter has declared there is no conflict of interests.
Comment: [I am a random internet personality with a BA (chem) and a MA (physics). I was involved in the internet analysis of the withdrawn Lancet article on hydroxychloroquine.] This article is groundbreaking and important, if not conclusive. I expect it to be published if only to set a starting bar for outpatient studies where hydroxychloroquine / zinc / azithromycin are used to treat covid and for its method of triaging patients for treatment. It's unfortunate that we know nothing about demographics/comorbidities/disease severity of the control group. The patient numbers aren't large enough to tell us anything about potential mortality reduction for group A. However, the rate of hospitalization looks quite low for group A. This makes this study important for public health policy. It would also be helpful to break the ages for group A into (<70, 70-79, 80+). The fatality rates go from 3% for 60-69 to 10% for 70-79 to 30% for 80+ in my county and I suspect that there is similar variability everywhere. Group B seems like a throwaway as it stands. There is no evidence of SOB beyond self-reporting in group B from the reported data. At least pO2 should be reported for Group B for SOB confirmation.
Response 3 to Comment 1
Received: 6 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear Mr O'Hara, thank you very much for your comment! We went back to the respective data matrix to check the IQR for age of the total treatment group (N=141). Indeed, there is a typo in the current version of the manuscript: the IQR is 40-67 and not 40-60. We will revise this and upload a version 2 as soon as possible. Again thank you very much for informing us. Best regards, Martin Scholz
Response 4 to Comment 1
Received: 6 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear all, thank you very much for all your comments. As you have read this retrospective case series study analysed data from COVID-19 outpatients with 100 % confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a community in New York State, USA. Outcome of patients who were treated with the specific triple therapy zinc, low dose hydroxychloroquine, and azithromycin was compared to public reference data of patients in exactly the same community who were not treated with this therapy. However, for our analysis we unfortunately only had access to the outcome data of the untreated patient group (not treated with the triple therapy zinc, low dose HCQ, and azithromycin) and so we were also not able to do a risk adjustment. However, the patients in the treated group were all positively risk-stratified while the risk of the untreated group was probably lower as this group included high- and low-risk patients. Of course, this issue is mentioned (page 3) and discussed (page 15) in the paper. Again thank you very much for your feedback and support. Best regards, Martin Scholz
Response 5 to Comment 1
Received: 7 July 2020
Commenter: Dr. Chirag Shah
The commenter has declared there is no conflict of interests.
Comment: First of all congratulations for this wonderfully written article and sharing this extremely valuable evidence in these pandemic times. My question is about the rationale behind presence of at least 1 comorbidity in Group C? Would there be any data that may indicate positive evidence in symptomatic patients <60 without any co-morbidities? Thank you.
Response 6 to Comment 1
Received: 8 July 2020
Commenter: Nick Divito
The commenter has declared there is no conflict of interests.
Comment: Curious to hear your thoughts on other potentially repurposed existing drugs such as famotidine and ivermectin that have similar retrospective data but are not in the public arena? Also would like to hear your thoughts on the MATH+ protocol that some are using.
Response 7 to Comment 1
Received: 15 July 2020
Commenter: Samuel Mondy
The commenter has declared there is no conflict of interests.
Comment: Moreover to the fact that the demographics are not known for the untreated groups, the major bias in this study that the authors cannot address and deserve the withdraw of this preprint is that the treated group only group young people or old with no symptom. It is not possible according to the experimental procedure and patient selection to the authors to conclude to any effect of HCQ alone or with any conbination.
Response 8 to Comment 1
Received: 26 July 2020
Commenter: Tianchi Zhao
The commenter has declared there is no conflict of interests.
Comment: I have been following the excellent work you and Dr. Zelenko have been doing that can save lives of millions around the world. I would like to add my observation to support your conclusions. Countries that use Hydroxychloroquine for early treatment covid-19 all have very low death rate. These countries include: India, Russia, Turkey and many mid-east countries. Among them, Qatar has 109,036 people test positive, but only 164 total deaths with a fatality rate 0.15% !!! The country's hospitals are empty even though the infection rate is very high for a small country with 2.8 million population. Brazil started relatively late due to short of Hydroxychloroquine. President Trump sent 2 millions of pills to Brazil on May 31st upon the request from Brazil's Bolsonaro.
Comment 2
Received: 5 July 2020
Commenter: Brian Hollingworth
The commenter has declared there is no conflict of interests.
Comment: The paper is excellent and, as far as I, a mere engineer, am able to judge, it is well-founded, has been rigorously conducted and is clearly presented. The authors should justifiably take credit for a solid usable study, one that goes quite some way to counter the cynical efforts of a large and powerful body of self-interested persons and organisations who, in my humble opinion, have placed their own gain above the misery and tragedy of thousands of Covid-19 victims. Well done.
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Response 1 to Comment 2
Received: 6 July 2020
Commenter: Sbabo David
The commenter has declared there is no conflict of interests.
Comment: "The paper is excellent and, as far as I, a mere engineer, am able to judge, it is well-founded, has been rigorously conducted and is clearly presented."

I am sorry, but did you check the numbers?
IQR for the 141 patients: 40-60. Then a maximum of 25% of the 141 patients = 35,25 are 61 years old or older.
IQR for group A, 69 patients: 64-69. So a minimum of 75% of the 69 patients = 51,75 are 64 years old or older.

Don't you see the problem?
Response 2 to Comment 2
Received: 6 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear Mr Sbabo,

thank you very much for your comment! We went back to the respective data matrix to check the IQR for age of the total treatment group (N=141). Indeed, there is a typo in the current version of the manuscript: the IQR is 40-67 and not 40-60. We will revise this and upload a version 2 as soon as possible. Again thank you very much for informing us.

Best regards,

Martin Scholz
Response 3 to Comment 2
Received: 3 August 2020
Commenter: Brian Hollingworth
The commenter has declared there is no conflict of interests.
Comment: I did in fact spot the typo, a significant one for me as I myself am over 70 years of age. However, since this version has not been peer reviewed I had enough faith in that system to assume this would be corrected. I believe one must consider first and foremost that this is battlefield medicine, an analogy which I believe Dr. Zelenko himself has used. There will be errors here and there, as there always are, but there are lives to be saved here, a great many lives.
Comment 3
Received: 5 July 2020
Commenter: EDIGEZIR B GOMES
The commenter has declared there is no conflict of interests.
Comment: O presente artigo reforça a síntese de que a HCQ tem ação na redução da replicação viral, Seu uso no tratamento das artrites, a princípio era entendido como potencial amplificador dos efeito anti-inflamatórios dos corticoides no corpo humano. Alguns endocrinologistas, mais recentemente demonstravam conhecimento de que a droga sozinha sem associação com corticoide, agia efetivamente na redução dos efeitos inflamatórios de algumas artrites. E só mais recentemente como a pandemia do Covid-19, é que seu uso como antivirótico foi introduzido. Essa sequencia clínica, fora espelhada pelo Dr. Siddiqui, que tornou fácil o entendimento clinico das fases da doença em curso, levando de imediato a conclusão de que o tratamento das fases iniciais com HCQ, Zinc , Azitromicina e corticoides reduziam drasticamente a evolução da doença para fases mais tardias onde praticamento o sistema imunológico perderia para a tempestade citotóxica. Por outro lado, com a replicação viral reduzida pelo efeito comprovado da HCQ, problemas menores ocorreriam na troca gasosa alveolar, reduzindo a necessidade de entubação e mesmo se assim o fossem, haveria suficiente troca gasosa nos pulmões.
Desta forma quero deixa aqui meus elogios ao Ilustres colegas Scholz, M.; Derwand, R.; Zelenko, V, que tanto lutaram nessa guerra política que pela primeira vez, graças as Mídias Sociais , a Industria Farmacêutica perde sua hegemonia em impor medicações caras , e muitas vezes sem devido seguimento dos efeitos colaterais. Uma coisa nós sabemos, a HCQ tem 0 anos de uso no mundo sem nenhum relato de danos ao usuário necessitado.
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Response 1 to Comment 3
Received: 24 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Thank you for your comment. On behalf of my colleagues I hope that this treatment protocol will save the lives of many patients worldwide. Even those who cannot afford expensive treatmen regimens. "Obrigado por este comentário. Em nome dos meus colegas, espero que este protocolo de tratamento ajude muitas pessoas. Mesmo para aqueles que não podem pagar por terapia cara."
Comment 4
Received: 6 July 2020
Commenter: Jay Silverman
The commenter has declared there is no conflict of interests.
Comment: Thank you Dr. Z and the others for publishing this paper that proves that the medicine works.
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Comment 5
Received: 6 July 2020
Commenter: Del McReynolds
The commenter has declared there is no conflict of interests.
Comment: Dr Zelenko is one of hundreds and probably more like thousands of doctors who use this protocol with their patients and themselves. You doubters and your reasons for not trusting anything that could save the world from people like you wanting to put your trust in a vaccine called "WARP SPEED" is strange. The drug has been safe to use for other issues for the past 65 years which already proves is it safe and is still being used by MILLIONS today. Now it is being used off label for covid 19 with world saving success, so to use something that will probably save your life and inexpensive is a no brainer. It sure won't kill you to at least try it.
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Response 1 to Comment 5
Received: 21 July 2020
Commenter: Herbert von Kalmt
The commenter has declared there is no conflict of interests.
Comment: You do know that the dose per kilogram bodyweight is different I hope?
Comment 6
Received: 6 July 2020
Commenter: Brian K
The commenter has declared there is no conflict of interests.
Comment: I have been closely following Dr. Zelenko and researching this combination protocol since March 2020. Congratulation to Dr. Zelenko et al for the hard work and courage in conducting this study. With politically tainted bias subtracted it is becoming easier to distinguish sincere HCQ studies from tainted HCQ studies that have been creatively constructed to discredit HCQ. Many HCQ studies didn't administer the treatment early, omitted zinc, administered unsafe dosing and/or included patients with comorbidities at a higher rate in the treatment group. This study should open the door for further HCQ and zinc studies, perhaps a HCQ and zinc prophylaxis study.
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Comment 7
Received: 7 July 2020
The commenter has declared there is no conflict of interests.
Comment: I am concerned with a number of biases in the data that seem to stack the deck in favor of the treatment group:

1) The inclusion of 37 cases substantiated by an antibody test is highly problematic, as in order to receive the antibody rest, each of these patients needed to survive covid. Any additional patients that died prior to otherwise receiving an antibody test are excluded. This stacks the deck in favor of the treatment group, and absent any intervention at all, we would still expect them to fare better than the control.

2) Separate from the study itself, I feel compelled to observe that the data described in the report seems to contradict public statements by one of the authors, Dr. Zev Zelenko. The author has publicly claimed to have treated more than 1500 patients with this treatment, but only provides data on 377.

The study states that the control group is based on laboratory results of patients in the same community - how big a population were these drawn from? If these are Dr. Zelenko’s patients, where are the rest of them? Why are we presented with no results from the other patients treated with this cocktail? If these are not Dr. Zelenko’s patients, who are they?

This is an interesting read, but in the public interest, the authors should publish results from the entirety of the patient population treated by Dr. Zelenko.
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Response 1 to Comment 7
Received: 7 July 2020
Commenter: Baruch Wilks
The commenter has declared there is no conflict of interests.
Comment: I agree that it would have been nice to have the full data set to look at but this is standard practice in a lot of studies. Unfortunately there is no way to know what the numbers would have been like if they added more data points. That is why reputation is so important and why it is very hard to extrapolate from studies. You can only look at what you are given and make conclusions based on that data set. I also would have liked a bigger patient population with more subsections but they decided to use this one. Since this is really only an introductory study into the use of zinc and hydroxycloroquine and not conclusive enough to say it is a good treatment I feel that it is fine though.
Response 2 to Comment 7
Received: 7 July 2020
Commenter: Grant Klappstein
The commenter has declared there is no conflict of interests.
Comment: "As of today, my team has tested approximately 200 people from this community for Covid-19, and 65 per cent of the results have been positive. If extrapolated to the entire community, that means more than 20,000 people are infected at the present time. Of this group, I estimate that there are 1500 patients who are in the high-risk category (i.e. >60, immunocompromised, comorbidities, etc)."
Read more at: https://www.vanguardngr.com/2020/03/coronavirus-new-york-doctor-successfully-treats-patients-with-drug-cocktail/

So that is a quote from Zelenko's published letter of late March 2020. Depending how you interpret the word "patients" in the context of his sentence it is possible, although unlikely, that the 1500 refers to patients treated but not confirmed for Covid. Or, more likely, that they were potential patients based on the rate of infection in the general population. In either case I am sure you would not argue Zelenko should include untested patients and/or non patients.

If my memory is right, Zelenko started with claims of 5 or 600 treated patients but later revealed that many of the original treated cohort had not been confirmed for Covid infections, they were putative based on symptoms. He then indicated he was going to get some help from researchers to refine the claims according to general research protocols. This paper appears to be the result of that, I expect the 377 was what was left over when "putative+actual" covid infections were trimmed to "actual".

For a summary of covid 19 trials I found the site clinicaltrials.gov which is from the US National Library of Medicine. I did a search of trials using the following terms, "hydroxychloroquine" and "covid-19" considering "active", "recruiting" or "not yet recruiting". This search yielded 189 studies from around the world, and provides, if perhaps not full accounting, at least a valid sample of ongoing research. When I added "zinc" to the search there were 9 results. In one of those 9 the zinc was mentioned only in the title of the trial, in the other 8 zinc was mentioned in the "interventions' column which lists the drugs and dietary supplements. This result suggests that 9 of 189 are testing HCQ plus zinc and the remainder omit zinc.

Of course if the details of these trials were examined one by one, more using zinc might surface, not listed in interventions nor the title. However it probably gives some sort of reasonable estimate of the ratio of zinc+HCQ trials vs HCQ without zinc, ie about 5%. Since many of these trials are in response to the early anecdotal findings that zinc plus HCQ was a valid treatment, worthy of further testing, it is disappointing that so many of the trials do not include zinc. I am not sure what to make of this exactly but I do share a certain uneasiness about motivations as expressed by comment 6, above.
Response 3 to Comment 7
Received: 7 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear anonymous,

Thank you very much for your comments and questions. Please find enclosed our responses:

Question number 1:
This retrospective case series study analyzed data only from COVID-19 outpatients with a laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a community in New York State, USA. During the peak of the pandemic the responsible primary care physician diagnosed many patients often first clinically during the early course of the disease and initiated treatment with the described triple therapy zinc, low dose hydroxychloroquine, and azithromycin as soon as possible. Most of these patients were already tested for SARS-CoV-2 but did not have a final test result yet. Some others were not able to get a PCR test and the infection was confirmed by IgG tests later. However, in accordance with the study protocol all patients with a positive test result were included in the retrospective analysis at a defined point of time. This included also one deceased patient. The SARS-CoV-2 infection of this patient was also finally confirmed after initiation of treatment and after hospitalization. All patients with a laboratory confirmed COVID-19 diagnosis, who were positively risk stratified, and who were treated with the triple therapy were included in the detailed analysis.
For the analysis of the untreated patient group of the public reference (not of the respective practice and not treated with the triple therapy zinc, low dose HCQ, and azithromycin) unfortunately only the outcome data was available and so also a risk adjustment was not possible. However, the patients in the treated group were all positively risk-stratified while the risk of the untreated group was probably lower as this group included high- and low-risk patients. Of course, this issue is mentioned (page 3) and discussed (page 15) in the paper.

Question number 2:
At the point of closing the database 372 positively tested patients of the respective practice were included and 377 positively tested but untreated COVID 19 patients (not treated with te triple therapy, public reference, s. figure 1). Of course, after this time the pandemic has been still ongoing and more patients have been obviously treated but these were not included in this analysis and report anymore.
During the pandemic many jurisdictions in the United States, like states, counties and even cities released data about COVID-19 cases including outcomes (even based on respective zip codes). This was also the case for the respective community. As described in the study approval section on page 9 this analysis was conducted with de-identified patient data, according to the USA Health Insurance Portability and Accountability Act (HIPAA), Safe Harbor and so it is not allowed to report exact dates or more detailed information about the respective community etc. in the publication.

All data available at the time of analysis is included in this publication.
We agree that it would be very interesting to do an additional analysis of more available patient data at a later point of time.

Best regards,

Martin Scholz & Roland Derwand
Response 4 to Comment 7
Received: 9 July 2020
Commenter: samuel gluck
The commenter has declared there is no conflict of interests.
Comment: this study report would benefit from some easy to read color coded charts, the institutional bias against trump and anything he supports leads to think publication will not be easy. hope i'm wrong. regarding the number of patients treated dr. zz has stated that he did not prescribe the protocol to all the patients he saw only to those over certain age or with other medical conditions etc. that would make them more vulnerable . the way i read it only 377 were treated . this should be clearer.
Comment 8
Received: 7 July 2020
Commenter: Jeffrey LeRoux
The commenter has declared there is no conflict of interests.
Comment: A very

A very interesting study. I would love to see a better designed study. There is not enough details in this prepublication study to reach any other conclusion. I would love to see the details about classification and data about the comparability of the groups. The age difference noted above is a big problem.
More research needed.
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Response 1 to Comment 8
Received: 7 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear Mr LeRoux,

Thank you very much for your comments. As explained above there is a typo in version 1 of the manuscript: the IQR of the age of the total treatment group (N = 141) is 40-67 and not 40-60. We currently work on a revised version and will upload it soon.
In this retrospective analysis outcome of patients who were treated with the specific triple therapy zinc, low dose hydroxychloroquine, and azithromycin was compared to public reference data of patients in exactly the same community who were not treated with this therapy. For our analysis we unfortunately only had access to the outcome data of the untreated patient group (not treated with the triple therapy zinc, low dose HCQ, and azithromycin) and so we were also not able to do a risk adjustment. However, the patients in the treated group were all positively risk-stratified while the risk of the untreated group was probably lower as this group included high- and low-risk patients. Of course, this issue is mentioned (page 3) and discussed (page 15) in the paper.

To our knowledge this is still the only COVID-19 outpatient risk stratification and treatment study and so we agree that more research is needed. Responsible experts and stakeholders should ensure a common effort to continue to close this gap by designing studies specifically for primary care setting. Based on the observed magnitude of the reported results associated with the use of the triple therapy zinc, low dose HCQ, and azithromycin and based on other available data, we propose to amend ongoing studies with HCQ to include combination with zinc.

Best regards,

Martin Scholz & Roland Derwand
Comment 9
Received: 7 July 2020
Commenter: Roger Burrows
The commenter has declared there is no conflict of interests.
Comment: I am a retired engineer, and I am at a loss as to why the study does not headline every news outlet today. Maybe it plays as old, tired news? My Dad's explanation "It is always about the money. Unless they say it is not about the money, and then it is really all about the money"?
I have questions about the participants in the study. Maybe this is in the depth of the study but not clear to me from the extract.
335 candidates -- COVID-19 patients, not yet hospitalized when the selection for treatment was done.
127 treated with the protocol. How were these selected out of the 335 candidates? Some criteria? Randomly?
104 included in the analysis. Why were 23 treated patients excluded from analysis? That is a lot out of such a small sample size. I think hardly any would be found to have contraindications after the treatment was done. I assume all 23 didn't just die due to unrelated somethings. Maybe they got well and were just not seen on follow-up?

37 patients added to the treatment group with positive serum tests. Were these 37 out of the original 208 unselected candidates? Why were these patients added? It could be humanitarian reasons, I think.
141 treated patients included in the analysis.

Thank you and congratulations of your continued high-value contribution.
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Comment 10
Received: 8 July 2020
Commenter: Dr. Chirag Shah
The commenter has declared there is no conflict of interests.
Comment: First of all congratulations for this wonderfully written article and sharing this extremely valuable evidence in these pandemic times. My question is about the rationale behind presence of at least 1 comorbidity in Group C? Would there be any data that may indicate positive evidence in symptomatic patients <60 without any co-morbidities? Thank you.
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Comment 11
Received: 10 July 2020
Commenter: Elsa Schieder, PhD
The commenter has declared there is no conflict of interests.
Comment: Dr Zelenko, I am so grateful for all you have done: first, doing the research to see what might help your patients; then putting together 2 treatments to create your protocol; then keeping a record of the outcome; then reaching out in a hundred different ways (interviews, letters including to Pres Trump), and on to this, with 2 world-class experts, to prove to the most science-centered that the protocol worked. Plus you have established a Crowd Protocol.
Congratulations,
And once again, much gratitude,
Elsa
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Comment 12
Received: 13 July 2020
Commenter: Pierre Hendricks MD
The commenter has declared there is no conflict of interests.
Comment: The criticism of Dr. Zelenko’s original claim was that he treated many patients with HCQ+zinc+zpack who would not be expected to be hospitalized or die of COVID-19. This appears to be a response to that criticism by selecting a group of his patients who might not be expected to do well. Those patients did very well. However my criticism is that the paper left the impression that the untreated group were the stratified patients who did not meet the conditions of >60, SOB, or a comorbidity. They were not. This is a major weakness. How does the author know that these other COVID-19 patients did not receive the same medications or that these controls had a higher percentage of high risk attributes. I am disappointed as I touted the use of HCQ/zinc/Zpack based on this article and my incorrect assumptions of it. It would have been better to have eliminated the “control” group and let his results stand on their own.
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Response 1 to Comment 12
Received: 28 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear Dr. Hendricks (comment 12): Thank you for your comment. The untreated patients who presented in the practice of Dr. Zelenko were indeed the patient group comprising patients at low risk of severe disease progression (according to the risk stratification approach described in the Method section) and thus were risk-stratified to the non-treatment group. This group differs from the control group from the same community without triple treatment protocol but with comparable risk distribution (according to groups A, B, C) to develop severe disease progression. We hope that we understood your comment correctly.
Martin Scholz and Roland Derwand
Comment 13
Received: 13 July 2020
Commenter: Robert Mankin
The commenter has declared there is no conflict of interests.
Comment: A very important study.

@M. Scholz: How does your study compare to the recent Boulware NEJM study which found no PEP effect of HCQ regarding Covid onset in persons exposed to a confirmed patient? https://www.nejm.org/doi/full/10.1056/NEJMoa2016638

Some differences I note: 1) Boulware didn't use zinc; 2) hospitalization was very low in both groups (0.2%), i.e. these were clearly not high-risk patients.

Do you expect HCQ or Zinc + HCQ to prevent symptom onset, or only prevent hospitalization?
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Response 1 to Comment 13
Received: 15 July 2020
Commenter: Prof U.K. Bhadra
The commenter has declared there is no conflict of interests.
Comment: Important and necessary article.

HCQ+Zn prophylaxis can't prevent infection because infection is acquired due to behavior, but the combination does prevent moderate and severe disease.
Response 2 to Comment 13
Received: 28 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear Dr. Mankin (comment 13): Thank you for your comment. Indeed, the Boulware NEJM study did not combine zinc with HCQ. The risk stratification by Dr. Zelenko enabled more specific selection of patients receiving the triple therapy. The prophylactic effects of HCQ plus zinc have to be evaluated systematically. There is currently some anecdotic evidence about prophylactic benefits. However, we have to wait for more evidence.
Martin Scholz and Roland Derwand
Comment 14
Received: 15 July 2020
Commenter: Paul Rivas MD
The commenter has declared there is no conflict of interests.
Comment: The primary mandate is ," First DO NO Harm". At the early onset of covid 19 there are few , if any, alternatives. There is now a fair degree of " smoke" circulating among doctors that HCQ with zinc may offer some real benefits prophylactically. The real question has been, does the drug prolong the qt interval and therefore lead to a serious, and perhaps life-threatening ventricular arrhythmia. Two studies are now showing that the drug appears safe when given early in the course. To me, that's the main takeaway from this study.
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Response 1 to Comment 14
Received: 28 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear Dr. Rivas (comment 14):
Thank you for your comment. Indeed, this is one of the main takeaways from this study aside from the finding that this treatment can save lives and avoid hospitalization. In addition, please read comment 5 above which relates to the safety of HCQ and the references 62-67, cited in our discussion section, page 16-17.
Martin Scholz and Roland Derwand
Comment 15
Received: 16 July 2020
Commenter: LS
Commenter's Conflict of Interests: I am totally not charging patients in any way for an in-house cocktail three drug combination and then trying to publish
Comment: I haven’t been able to find where the public reference data for the comparison comes from. If it is public, why isn’t the source provided? How do the authors know what people not seen by Dr Zelenko were treated with?

“In accordance with available public reference data, 712 confirmed SARS-CoV-2 PCR positively tested COVID-19 patients were reported for the respective community”

“Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control”

And from a comment by Martin Scholz

“For the analysis of the untreated patient group of the public reference (not of the respective practice and not treated with the triple therapy zinc, low dose HCQ, and azithromycin) unfortunately only the outcome data was available and so also a risk adjustment was not possible”

So, on the one hand, only outcome data is available, and on the other hand these people are included because they were not treated with HCQ/AZ/Zn. I don’t think these people can be both these things.
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Response 1 to Comment 15
Received: 28 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear LS (comment 15):
Thank you for your comment. The triple therapy used by Dr. Zelenko was designed based on public scientific evidence for a synergistic effect of zinc and HCQ. All three compounds, zinc, HCQ and azithromycin are safe and known to have antimicrobial effects. The treatment approach described was a logic and necessary approach to save lives in the outpatient setting and to avoid hospitalization and reduce mortality. One could say that it is unethical to not treat early with antiviral regimens, for example with this triple approach in the outpatient setting, and let the patients undergo disease progression, hospitalization, and intensive care. Due to HIPAA and safe harbor regulations, we were not allowed to provide more details about the source of the public data. Prospective controlled studies have to confirm our findings in the near future.
Martin Scholz and Roland Derwand
Response 2 to Comment 15
Received: 29 July 2020
Commenter: LS
The commenter has declared there is no conflict of interests.
Comment: Thank you for taking the time to respond.

Due to HIPAA and safe harbor regulations, we were not allowed to provide more details about the source of the public data.

If it is public data I struggle to understand what HIPAA and safe harbour regulation problems there could be. Please could you explain. The only way I understand “public data” is this is data available to the public.

I have found data down to the the county level. Dr Zelenko’s practice is based in Monroe, Orange County, NY

https://ocnygis.maps.arcgis.com/apps/opsdashboard/index.html#/21de1fb5ce0c480f95dc0cf2b8b83b71
You say in response to another comment below The control group was chosen in a very conservative manner

I note that although the public data shows positive cases in Monroe, Orange County NY there is no information about deaths or hospitalisations. As of 22nd July 2020 OC dashboard states there have been 11,006 positive cases and 489 deaths in Orange County as a whole. The control group is much smaller than the available data for the county. Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control.

Either the data is public and publicly available, or it isn’t publicly available. Either way, where does it come from?

Also, how was the control group chosen? The preprint doesn’t say. What was the conservative manner?

Prospective controlled studies have to confirm our findings in the near future. ok, but why would it be unethical not to use this treatment if there aren’t controlled studies that confirm your findings?



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Response 3 to Comment 15
Received: 29 July 2020
Commenter: James L
The commenter has declared there is no conflict of interests.
Comment: "So, on the one hand, only outcome data is available, and on the other hand these people are included because they were not treated with HCQ/AZ/Zn. I don’t think these people can be both these things."

This is the biggest issue with the study. We do NOT know what treatment the "public reference data" group received. For all we know they could have gotten HCT/AZT/Zn as well. Dr. Zelenko was not the only doctor prescribing HCT/AZT/ZN at this time.

All the authors have is outcome data for patients NOT in Dr. Zelenko's clinic.
Comment 16
Received: 19 July 2020
Commenter: David Maddison
The commenter has declared there is no conflict of interests.
Comment: Here is a new video on mechanisms by which C-19 infects cells. It is hypothesised that a new route to infection also exists. Interestingly, they mention azithromycin as a possible treatment. This is actually part of the Zelenko protocol. While it is an antibiotic it also has the ability to block C-19 from entering cells via the CD147 spike protein. This may explain its efficacy in the protocol, apart from its role in treating secondary infection.

https://youtu.be/MUnTb3_mwTY
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Comment 17
Received: 23 July 2020
Commenter: Thomas Hesselink, MD
The commenter has declared there is no conflict of interests.
Comment: I very much appreciate that you have tabulated the data you have.
Many criticize the lack of controls and the lack of high numbers
of subjects. As people came to you and you selected the more ill
for treatment, and they almost all got markedly improved in 5 days.
That is terrifically valuable data and only needs repetition to certify
stronger statistics. Thank you for demonstrating the concept of zinc
as the real antiviral agent, (the RNA replicase inhibitor) and HCQS
as the ionophore (the transfer agent). The research using HCQS alone
is silly, like serving an empty package. The research using zinc alone
would be weak, as it would take too long to penetrate the infected cells.
The critics are unreasonably devoted to ignoring this important combination.
What I would love to see in future studies is to test RBC zinc levels in a
population of nasal swab positive PCR test subjects and follow them.
I hypothesize that the zinc deficient are the ones that go on to progress
to more severe respiratory distress cases. The zinc sufficient would never
get sick enough to need the Zelenko protocol as their ACE2 bearing cells
are already preloaded with the inhibitor.
I would also like to see studies using other ionophores such as picolinate,
or carnosinate tested clinically, so that we have more options beyond
total dependence on HCQS, which is often in short supply.
doctorhesselink.mysite.com/ResRef.htm
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Comment 18
Received: 23 July 2020
Commenter: Ken Madden, M.D., Ph.D.
The commenter has declared there is no conflict of interests.
Comment: Unfortunately, the lack of information on the comparison population greatly weakens any statements regarding efficacy of the proposed treatment. There are many potential reasons for differences in hospitalizations and mortality between treated patients and an unmatched retrospective comparison group. The treated patients all evidently presented to a Family Physician office. If other patients in the community were presenting to Emergency Rooms or Urgent Care, one would naturally expect sicker patients and a higher percentage of admissions. Others have pointed out the potential higher ages within the comparison group, which would certainly slant that group toward worse outcomes. Other differences in risk factors between groups could do this as well.

Such criticisms do not diminish the possibility of benefit of the proposed treatment, which this report argues is a relatively safe one. However, it should not be considered substantial evidence of such.
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Response 1 to Comment 18
Received: 28 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear Dr. Madden:
Thank you for your comment. Of course, the findings have to be confirmed in a prospective controlled study because risk adjustment was not possible. However, even without the inclusion of the control group the findings are of high magnitude. The control group was chosen in a very conservative manner. If one follows the COVID-19 morbidity and mortality figures reported by CDC or other public sites the magnitude of the triple therapy effects approached by Zelenko seem to be much more important for the management of the pandemic.
Martin Scholz and Roland Derwand
Comment 19
Received: 28 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear Dr. Shah (response 5 to comment 1 and comment 10),
The rationale behind presence of at least 1 comorbidity in group C is base on reference 35 in the paper. “(CDC) CoDCaP. People Who Are at Higher Risk for Severe Illness 2020 [Available from: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.htmlaccessed 2020/05/23 2020]”. Syptomatic patients <60 years without any co-morbidity were not treated in this study according to the risk stratification approach described in the Methods section.
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Comment 20
Received: 28 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear Dr. Divito (response 6 to comment 1),
All potential repurposed drugs with sufficient evidence to be beneficial in treating COVID-19 patients should be considered. The MATH+ protocol is a strategy for hospitalized patients. The COVID-19 hyperinflammation ought to be limited as soon as possible. This is one of the key messages of our paper: Patients have to be treated early prior to the development of a cytokine storm which is extremely difficult to cure. When patients are admitted to the hospital it might be too late. However, in these cases the MATH+ protocol seems to be a feasible approach.
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Comment 21
Received: 28 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment: Dear Dr. Burrows (comment 9):
Thank you for your comment. The authors would like to refer to Figure 1 which explains the selection and exclusion procedure and our response to comment 7.
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Comment 22
Received: 30 July 2020
Commenter: Charles Dearborn
The commenter has declared there is no conflict of interests.
Comment: Let me just say while you people do your blind study with the proper control group... Yeh, yeh... If I get COVID I'll take Zinc HCQ and antibiotic and exercise my right to try as a patient before I will take anything else. Anyone coming out against this publically should be laughed out of the medical field because you all know it works... And have known since 2005 per the NIH.
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Response 1 to Comment 22
Received: 3 August 2020
Commenter: Scott Foster
The commenter has declared there is no conflict of interests.
Comment: I agree 100%. I'd like to add that HCQ is not the only ionophore that would allow zinc to enter the cell and inhibited replication of the virus. Quercetin is a safe, over the counter alternative that many doctors support use of and that are using themselves. See YouTube video MedCram 59.
Comment 23
Received: 30 July 2020
Commenter: Lee Smith
The commenter has declared there is no conflict of interests.
Comment: The treatment population are patients who presented to their family doctor with mild symptoms. The paper presents this as a strength, as the 'first outpatient study,' which fair enough. It also means that these were almost certainly patients who were less sick than average at presentation. This needs to be clearly reflected in the control group.

There is no control group. There is a comparison group, selected ad hoc after the fact, from some source of data for patients in the same community. We don't know the severity at presentation, or the treatment history, of that comparison group. The paper seems to indicate that neither do the authors. That isn't a controlled study, it's a case series with a seemingly random comparison grafted on after the fact.

We have no idea what the data source for the comparison group is. Literally, none. The authors say it's publicly available community data, but they refuse to name the data source. We have no idea of the characteristics of patients in the control group. None, nada, zilch. All we know is how many there were, how many were hospitalised, and how many died. As one of the comments already points out, we don't even know whether some of the 'controls' might have also gotten the triple therapy.

The authors cite HIPAA to say they can't disclose the data source for the control group. This is confusing. If it's public data, it's public data. Cite the public data source. If it's not public data, that statement is at best misleading. One cannot simply say 'this data came from somewhere, but I can't tell you where,' and expect it to be taken as science.

In the comments, authors respond to this criticism by saying they selected the controls very conservatively. Which means they selected control patients from that undisclosed data source. They don't disclose the selection criteria. We have no idea how they selected the controls from the data source that they also won't disclose. They won't tell us. That's not science.

Given all this, it's entirely possible the 'control group' were patients presenting at the OR with severe disease, who received triple therapy and were hospitalized and died. A reader evaluating your data simply has no way to know.

They make a great deal throughout the paper that treated patients have a much lower death rate than controls. It's one of the major claims of the paper. We have no idea what the control group is, so we don't know if the difference is relevant. But more, that difference is not even statistically significant. The stats show that there is no significant difference in death rates.

Unless I missed something, the authors disclose this in only one sentence, and in one data table, where they show that for mortality, p=0.16, without flagging it as not significant. In fact, they attempt to excuse it, by saying in effect that the lack of significance is caused because they don't know enough about patients in the comparison group. That doesn't save the claim. Rather the opposite, in fact.

It's a case series, not a "case series study." The inclusion of the comparison group in this form is worse than useless, it's actively misleading. If HCQ in any treatment regime actually works, which seems increasingly unlikely based on randomized trials, this paper does a disservice to advancing our knowledge of that fact.
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Response 1 to Comment 23
Received: 31 July 2020
Commenter: Gary B.
The commenter has declared there is no conflict of interests.
Comment: As someone who has followed Dr. Zelenko and his tx approach for some months, well before his restrospective was released, I can tell you (having also read every one of his hipaa redacted patient records), I had high hopes for this study. I do firmly believe that Dr. Zelenko observed statistically better outcomes in his treated patients than typical CFR data as presented by the CDC and NY hospitals were showing at the time. Of course we're a back to anecdotal evidence. This study is a step in the right direction as it does make an attempt to categorize his patients into subgroups and compare them with a control. That said, Lee Smith makes several very valid points. We need to know much more about the control group to understand and appreciate the significance of the results. I am hoping the study author(s) can clarify and provide a revision that includes this information.

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