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July 11, 2021

dir@icb.usp.br, comunicacao@icb.usp.br, vahan.agopyan@usp.br
cc list below

Director, Biomedical Institute at University of São Paulo

Letter of Support for Professor Paolo Marinho De Andrade Zanotto

Dean of the University of São Paulo, Prof. Vahan Agopyan and Distinguished Professors

I am writing in support of Professor Paolo Marinho De Andrade Zanotto, who has advocated for the early
treatment of Covid-19. I am confident that after a diligent and scientific review of this information
contained herein, he will be restored to his rightful position. Joining me in support of Professor Zanotto
are the medical, scientific and academic professionals whose names are appended below. This group
includes people from across the political spectrum. Party politics have no role in the science of Covid-19.
This letter is not intended to serve as support for, or opposition against, any political party or individual in
Brazil, or elsewhere.

The opposition to early treatment using, for example, hydroxychloroquine (HCQ) or ivermectin (IVM) is
largely based on severely flawed studies appearing in top journals of the peer-reviewed literature. We
have conducted detailed re-analyses of patient-level raw datasets for several of these studies. Our
findings reverse the conclusions of those studies, thereby supporting early treatment of Covid-19.

Ivermectin (IVM)
You are no doubt familiar with the ever-growing number of meta-analyses supporting the use of IVM in
Covid-19 (1,2). I will focus on just one study appearing recently in the Journal of the American Medical
Association (3) involving early treatment of Covid-19 with IVM, in Cali, Colombia. This paper, with its
erroneous conclusions, had a major negative impact on the formulation of international Covid-19
guidelines.

The authors of this study reported a number of execution flaws. Our re-analysis of the study dataset, with
calculations verified by the original authors, revealed strong evidence that switching of placebo and
active drug in subjects between patients within the same household assigned to different study arms
likely contributed to the reduced effect size seen with IVM. Because of other study execution errors, it
was possible to adjust for this effect to yield a 56% reduction (p=0.033) of C19 symptom persistence
associated with use of IVM. You can access our results here: https://osf.io/bvznd/ (4).

Hydroxychloroquine (HCQ)
The politicization of this drug around the world has no place in the rational evaluation of evidence
concerning its use. The opposition to the use of HCQ is largely based on a collection of three severely
flawed studies from the University of Minnesota (UMN). The question of early treatment of C19 is closely
related to pre- and post-exposure prophylaxis, as reflected in a number of meta-analyses.(5).
Accordingly, we summarize our findings here. Under a registered protocol, we prospectively conducted
re-analyses of patient-level raw datasets for these studies. We have summarized our findings in a letter to
the NIH, available at: https://osf.io/7trh4/.
Post-exposure Prophylaxis
In the first of these studies, published in the New England Journal of Medicine (NEJM) (6). the effect of
HCQ on early post-exposure prophylaxis (PEP) was examined. This study is of extreme significance as it
was the only prophylaxis RCT cited by FDA in its revocation of the Emergency Use Authorization for HCQ
in June 2020 (7). Along with the other studies I shall discuss, these studies have been the cornerstone of
NIH guidelines and global public policy on this topic.

Our detailed re-analysis of the raw dataset revealed that the authors failed to consider the actual times
taken to ship study drug to participants. This is crucial to consider in any effort to rapidly pre-empt the
development of Covid-19. We asked for and received shipping time data from the authors, and found that
not only did over 50% of subjects receive drug later than the assumed one day after enrollment, but re-
stratification of data yielded a 42% (p=0.044) reduction in development of C19, associated with early
(<= 3 days) receipt of drug after high or moderate risk exposure to C19. Our findings are described here
(8). To date, the original authors have failed to correct this and other critical flaws. They have feebly
criticized our analysis,(9) as we discuss.(8) They have attempted to cite two similarly designed studies
(10,11) to support their claim of inefficacy of HCQ. They ignored their own (12) pharmacokinetic modelling
which suggested that the loading and maintenance doses used in these studies were unlikely to be
effective. We address these and other flaws, including the inappropriate use of a folate placebo (8). We
have confirmed other re-analyses of this study from distinguished colleagues in Brazil (13) and Argentina
(14) that revealed other evidence of HCQ’s efficacy.

Early Treatment of Covid-19

A second UMN paper (15) examined the early treatment of C19 with HCQ. This has also been the
cornerstone of NIH guidelines on early treatment with HCQ. Because this study was a companion to the
PEP/NEJM study described above, it shared the same flaws related to the non-consideration of actual
shipping times. Despite numerous requests, the authors have refused to provide actual shipping time
data that would resolve whether or not correct time stratification would improve on the 20% (p=0.21)
reduction in symptom persistence reported in their paper. Further, the raw dataset, even versions
provided to colleagues recently, contain obvious data errors and are missing substantial amounts of data.
The authors have refused to correct this situation or to provide explanations as to other dataset
anomalies. Taken together, this landmark study cannot be relied upon to draw any conclusions as to
HCQ’s inefficacy. The study has also been criticized by distinguished colleagues in Brazil (16). As is the
case for post-exposure prophylaxis, two similarly conducted studies (17,18) employed loading or
maintenance doses far too low for efficacy, according to the pharmacokinetic modelling (12) of the UMN
group.

Another severely flawed early treatment study involving HCQ was reported in JAMA recently (19). We
posted our comments to the online forum on JAMA. The study conclusions about the inefficacy of HCQ
were overreaching and unjustified given the small number outcome events, early termination, and several
other reasons. The small effect reported is unsurprising with 84% of subjects delaying treatment more than
5 days from symptom onset, using a HCQ dose reported to be inadequate by the UMN PK modelling (12).
The paper states that the placebo was talc. The protocol specifies ascorbate, which cannot be assumed to
be inert.(20) Subjects were permitted to take additional, undocumented, ascorbate. The protocol states that
study drugs differed in appearance and that blinding was not feasible. Participants from the same household
could be assigned to different regimes, with the possibility of cluster effects, drug sharing or switching. This
is supported by the high rate of (unspecified) adverse events in the placebo group (20.9%) compared with
the HCQ (22.2%) and lopinavir-ritonovir (39.7%) groups. This high AE rate also suggests ex-protocol use
of HCQ or other drugs such as IVM, available OTC for part of the study period (ictq.com.br/assuntos-
regulatorios/1855-exigencia-de-receita-para-ivermectina-pode-cair). Blood samples were not taken to
examine compliance or ex-protocol drug use. There remains in this highly compromised, confounded and
underpowered study abortus, a 24% reduction signal (RR 0.76) in hospitalization associated with HCQ,
close to the 27.5% effect target (90% power) specified by protocol (contradicted by the paper’s 37.5% effect
size, 80% power).
Pre-exposure prophylaxis
Another cornerstone of public (e.g. NIH) policy or guidelines regarding prevention or early treatment, is
the UMN study on pre-exposure prophylaxis. This study assessed the ability of HCQ given once or twice
a week, to prevent C19 (21).

This study is severely flawed for several reasons, primarily that the placebo groups were inappropriately
pooled for the once and twice weekly dose arms, thereby masking 30-50% dose, gender and age
dependent reductions in C19 associated with HCQ. Significantly, the authors failed to explain why the
once weekly dose was used, when their own pharmacokinetic modelling (12) suggested that it would be
ineffective. They also did not explain why they ignored their own conclusions in that same modeling
study, of using a 3x/week dosing schedule. A full discussion of this study is given in our letter to NIH
(https://osf.io/7trh4/). Other criticisms of this study have been voiced, again from distinguished Brazilian
colleagues (22).

Another study (23) reported in JAMA was terminated early, with only 132 subjects. The authors noted
that: “Our study was likely established with insufficient power” (added emphasis). Accordingly, we place
little to no weight on this study with 4/64 and 4/61 subjects in the two treatment arms developing
infections. Its value is extremely limited.

Fluvoxamine (FLV)
There are studies emerging with other drugs for the early treatment of Covid-19, which must be noted. In
particular, representative of other drugs in its pharmacological class, is fluvoxamine (24,25).

Other drugs and agents

This is not intended as an exclusive list of drugs effective for early or ambulatory treatment of Covid-19.
There are a growing number of reports, e.g. (26), about the successful use of other agents, alone or in
various combinations. These agents include, doxycycline, zinc, proxalutamide, vitamins C and D.

Safety
No one, even the authors of the flawed HCQ studies (27), is seriously doubting the safety of these drugs
for early treatment of C19.

CONCLUSION
Taken together, proper consideration of these key flawed studies supports the early treatment of C19 with
HCQ and IVM, along with emerging evidence for FLV.

In addition to the specific flaws described, many of the flawed studies were terminated early, used
inappropriate placebos and were overly optimistic in estimating an effect size in their power calculation.

Given the emergence of vaccine-resistant variants as well as a growing concern as to vaccine safety, the
use of early treatment strategies remains a critical necessity in fighting the Covid-19 pandemic. Too many
studies have been under-powered and draw conclusions subject to Type II errors.

A full risk-benefit analysis must factor in the medical and economic costs in setting of acceptable values
for Type I (false positive) and Type II errors (false negative rates) (28,29). Given the safety profile and the
low monetary cost of these drugs, the medical and economic cost of a false positive result is so low such
that an acceptable alpha value should be much higher than the traditional 0.05 threshold. Conversely, the
cost of a false negative, i.e. rejecting a drug that possesses efficacy, is extremely high.
We certainly do not have all the answers, but there appears to be no justification for the continued
opposition to early treatment of Covid-19, especially in younger subjects.

Since the publication of the PEP/NEJM study on June 4 2020, there have been over 3.6 million deaths
worldwide according to WHO. In Brazil alone there have been nearly 500,000 (half a million) deaths since
then. How many of these might have been saved by early treatment or prophylaxis with HCQ, IVM or
FLV?

These issues must be fully and fairly debated and not subject to censorship, demonization, or pressure
on scientists such as Professor Zanotto to conform with a particular view.
I am available to answer any questions you may have. I am also available to provide video evidence for
Professor Zanotto by Zoom in your deliberations which I trust will be conducted according to the highest
standards of transparency, academic integrity and fairness.

Respectfully

David Wiseman PhD, MRPharmS

President, Synechion, Inc.
972 931 5596 | 469 939 5596 cell
Google Scholar: scholar.google.com/citations?hl=en&user=XGvjyC8AAAAJ
Orcid: orcid.org/0000-0002-8367-6158
Research Gate: researchgate.net/profile/David_Wiseman
Web of Science: AAT-2147-2021

Cc

André Fini Terçarolli <andre@advpimentel.com.br>,

Bruno Franchi Theophilo <brunoftheophilo@yahoo.com.br>,
Bruno Theófilo <bftheophilo@gmail.com>,
Carlos Taborda <taborda@usp.br>,
Edison Durigon <eldurigo@usp.br>,
Francisco Nobrega <francisco.nobrega@gmail.com>,
Gustavo Amarante-Mendes <gpam@usp.br>,
Jorge Kalil <jkalil@usp.br>,
Luis Carlos de Souza Ferreira <lcsf@usp.br>,
Maurício Pazini Brandão <pazinibrandao@gmail.com>,
Osmar Serraglio <osmar@osmarserraglio.com>,
Paolo Zanotto <pzanotto@usp.br>,
Patricia Gama <patgama@usp.br>,
Paulo Saldiva <pepino@usp.br>,
Péricles Prade <pericles2@pradeprade.adv.br>,
Regina Scivoletto <rscivole.rs@gmail.com>,
Secretaria ICB <icbsedir@icb.usp.br>,
Wothan Tavares <wtavares@usp.br>,
This letter has been endorsed by (alphabetical order):

The endorsements below represent those of the individuals listed and not necessarily those of their
respective institutions.

• John H Abeles MD. Retired from practice. Boca Raton, FL., USA.
• Paul E. Alexander, MSc, MHSc, PhD. Evidence-Based Medicine, Clinical epidemiologist, Former
WHO-PAHO and US HHS.
• Assoc Prof. Marina Bucar Barjud MD, PhD, MSc. Internal Medicine. University CEU San Pablo,
Spain.
• Marsha Y. Blakeslee D.O. Internal Medicine- private practice, Severna Park, MD, USA.
• Dr. Ira Bernstein, BSc, MD, CCFP,FCFP. Lecturer, Dept. Family & Community Medicine,
University of Toronto, Canada.
• Mark Anderson Caldeira, MSc, Univali, Itajai, Brasil,
• Carrie S. Cannon, MD, MS, Orlando, FL USA.
• Francisco Cardoso, MD, Infectious Disease Specialist. Expert Honorum in biosafety at OEA.
Brazil.
• Gustavo Carvalho MD, PhD, MSc, MBA, Associate Professor of Surgery, University of
Pernambuco, Recife, Brazil.
• Prof. Hector Carvallo. Medical Doctor, Former Professor of internal Medicine, Buenos Aires
University, Maimonides University. Former Director Ezeiza Hospital. Editor in Chief Research &
Applied Medicine (OAJ), Argentina.
• Marcio da Costa. PhD Sociology, Full Professor Federal University of Rio de Janeiro, Rio de
Janeiro, Brazil.
• Dr. Agnaldo Dos Santos, Occupational Physician, Brazilian Medical Association, CRMSC 6919,
RQE 479, Chapecó SC. Brazil.
• Russell Gonnering, MD, MMM, FACS, CPHQ, Clinical Professor of Ophthalmology, Medical
College of Wisconsin, Elm Grove, WI. USA.
• Joel S. Hirshhorn, PhD. Medical Researcher, Chevy Chase, MD, USA.
• Parvez Dara MD, FACP, MBA. Medical Hematologist and Oncologist. Toms River, NJ, USA.
• Mary L Davenport, MD, MS, FACOG. Womens’ Health. El Sobrante, CA, USA
• Gabriel Demarchi Filler, History graduate (UNESP - São Paulo State University), São Paulo,
Brazil.
• Francisco G. Emmerich, PhD Physics, Vitória-ES, Brazil
• Ondrej Halgas, PhD. Department of Biochemistry, University of Toronto, Canada.
• Steven Hatfill MBChB, MS. MS. M.Med, Adjunct Assistant Professor, George Washington
University, Washington DC., USA.
• Michael M. Jacobs, MD, MPH, USN (ret). Complex Primary Care Medicine, VA Joint Ambulatory
Care Center, Pensacola, FL, USA.
• Joseph Ladapo MD. Associate professor of medicine, David Geffen School of Medicine,
University of California, Los Angeles, CA, USA.
• Ben Marble, MD. Founder, MyFreeDoctor.com. Santa Rosa Beach, FL, USA.
• Leisha Martin, PhD. Chief Executive Officer. LEI NanoTech, LLC, Santa Fe, NM, USA.
• Ana Maria Mihalcea, MD, PhD. President, Owner AM Medical LLC. Internal Medicine/ Integrative
Health. Services. Yelm, WA, USA.
• Meryl Nass, MD, Private Practice, Ellsworth, ME, USA.
• Marco Otávio Rocha Couto MD, Dermatologist UFMG - UnB, Brazil.
• Claudia N. Paiva, PhD, Associate Professor of Immunology, Universidade Federal do Rio de
Janeiro, Brazil.
• Lorenzo Ridolfi, PhD Computer Science, PUC-Rio, São Paulo, Brazil.
• Prof. Harvey A. Risch, MD, PhD, Professor of Epidemiology, Yale School of Public Health, New
Haven, CT, USA.
• Paula Schmitt, Brazilian journalist, MA, American University of Beirut
• Prof. Dr Andrea G. Stramezzi MD DDS PhD. Volunteer Covid-19 Physician for Italian Ministry of
Health. Milan, Italy.
• Carol Taccetta MD, FCAP. Pathologist. Thousand Oaks, CA, USA.
• Prof. HC Tenenbaum DDS, Dip. Perio., PhD, FRCD(C). Professor of Periodontology and
Professor of Laboratory Medicine and Pathobiology, University of Toronto. Professor of
Periodontology, Tel Aviv University, Israel.
• Brian Tyson, MD. Family Medicine. All Valley Urgent Care, El Centro, CA, USA.
Brief Background and Conflict Statement

My degree was in Pharmacy with First Class Honors in Pharmacology (U Manchester). My PhD (U
Manchester) and postdoctoral work (Northwestern U) was in Experimental Pathology and Cell Biology.

My work has focused on adhesions and fibrosis, women’s health and pain. I was one of only 60 Research
Fellows at Johnson & Johnson where I headed up the adhesions research program. Since 1996, my
company Synechion has provided R&D services for medical companies including pre-clinical and clinical
studies for product development, FDA submission or peer-reviewed publication.

I have been a reviewer for Cochrane and various journals. I founded the International Adhesions Society,
for patient advocacy and research, described Complex Abdominal and Pelvic Pain Syndrome (CAPPS) and
co-founded the world’s first clinic for its treatment. I pioneered the use of a device for pelvic and abdominal
pain and related conditions. I have conducted large, patient-based studies to support public policy initiatives
related to informed consent, opioid use and pain, presented to FDA, CDC, NIH or AHRQ.
Since spring 2020, my work has been devoted almost entirely to Covid-19. I am also the President of
KevMed, LLC., which focusses on products for the treatment of pain. This document has not been solicited
by any other company.

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