A Randomized, Double-blind, Placebo-controled, Phase 2a Trial Evaluating the Safety and Initial Efficacy of Resomelagon in Patients With Dengue Infection
Phase: PHASE2
Conditions: Dengue Fever
Sponsor: Federal University of Minas Gerais

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Master Protocol:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Trial Evaluating the Safety and
Efficacy of RESOMELAGON in Patients with Dengue Infection (RESOVIR-2)
Short title: Safety and efficacy of RESOMELAGON in dengue infection
Acronym: RESOVIR-2
Date and version number:
Version 3.0 dated March 12, 2025

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Index
1. SYNOPSIS
4
2. LIST OF ABBREVIATIONS
6
3. BACKGROUND AND RATIONALE
7
3010 Proposal
8
3020Pharmacodynamic evaluation
9
4. OBJECTIVES AND OUTCOMES
9
5. STUDY DESIGN
10
5010 Intervention
11
6. PATIENT IDENTIFICATION AND RECRUITMENT
11
6010 Study participants
11
6020 Inclusion criteria
11
6030 Exclusion criteria
11
7. INCLUSION AND PROCEDURES IN THE STUDY
12
7010 Virological sampling
13
7020 Recruitment
13
7030 Screening and eligibility assessment
13
7040 Informed consent
13
7050 Baseline Assessments (See Appendix 1 for detailed schedule of activities)
13
7060 Study days
14
7070 Intensive Pharmacokinetic Sampling:
15
7080 Management of patients who become ill
15
7090 Sample Handling and Retention
15
8. DISCONTINUATION/WITHDRAWAL OF PATIENTS FROM THE STUDY
16
8010 Definition of End of Study
16
9. SAFETY REPORT
16
9010 Definitions
16
9020Causality
17
9030 Procedures for recording adverse events
18
9040 Classification of laboratory abnormalities
18
9050 Procedures for reporting serious adverse events
18
9060 Data Security Monitoring Board (DSMB)
19
10. STATISTICS AND ANALYSIS
19
10010 Overview of the adaptive study design and general approach
19
10020 Bayesian hierarchical model of viral clearance
20
10030 Time variation effects
20
10040 Sample size estimation, randomization, and statistical considerations
21

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10060 Final analysis of the primary result
21
11. DATA MANAGEMENT
21
11010 Access to data
21
11020 Data Processing and Record Keeping
22
12. QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES
22
13. ETHICAL AND REGULATORY CONSIDERATIONS
22
13010 Declaration of Helsinki
22
13020 Guidelines for Good Clinical Practice
22
13030 Approvals
23
13040 Patient confidentiality
23
13050 Expenses
23
13060 Risk
23
13070 Benefits
23
13080 Communicating
23
13090 Finance
23
130100 Data ownership
23
130110 publishing policy
23
14. REFERENCES
24
15. Annex 1: Schedule of activities
26

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10 SYNOPSIS
Study Title
A phase 2, randomized, double-blind, placebo-controlled study evaluating
the safety and initial efficacy of RESOMELAGON in patients with dengue
infection (Resovir-2).
Bottom
Dengue complication follows the peak of viremia and is associated with
increased activation of the immune response. Proof-of-concept studies in
animal models of dengue infection have shown that blocking certain
aspects of the inflammatory response or administering pro-resolving
molecules is beneficial in experimental dengue. In these experiments,
administration of certain anti-inflammatory or pro-resolving molecules
decreases disease severity and aspects of the inflammatory response,
including changes in vascular permeability. We have previously shown that
treatment with RESOMELAGON decreased lung inflammation and outcome
in animal models of beta coronavirus infection (including SARS-CoV-2) and
decreased disease severity in patients with COVID-19, even in the presence
of glucocorticoid therapy. Preclinical experiments have also shown that
RESOMELAGON decreased disease severity in an animal model of dengue
infection and decreased cytokine release by human PBMC infected with
dengue virus. RESOMELAGON is safe in healthy individuals, those with
rheumatoid arthritis, and in patients with COVID-19. Further studies are
needed to evaluate the safety and efficacy of RESOMELAGON in patients
with dengue fever.
Study design
Randomized, placebo-controlled, double-blind trial
Study Patients
Adult patients with early arboviral infection
Inclusion and Exclusion
Criteria
Inclusion Criteria:
1.
Participants aged 18 to 65;
2.
The participant is able to understand the study procedures and
provide informed consent;
3.
Presents more than 36 and less than 84 hours after the onset of
symptoms;
4.
Symptoms compatible with dengue infection with a positive antigen
test or positive polymerase chain reaction test. Dengue is suspected
by a report of fever and at least 2 other signs or symptoms of the
disease, including myalgia, arthralgia, headache or conjunctivitis.
Exclusion Criteria :
1.
Have any comorbidity that is perceived as decompensated by the
investigator;
2.
The following significant laboratory abnormalities discovered at
screening would lead to participant discontinuation:
●
Hemoglobin <10g/dl
●
Platelet count <50,000/ul
●
ALT>3x ULN
●
Total bilirubin > 1.5 x ULN
●
GFR <60mls/min/1.73m2
3.
Contraindications or known hypersensitivity to RESOMELAGON;

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4.
Presents as dengue with warning signs# or severe dengue* upon
inclusion;
5.
Currently participating in another clinical drug trial;
6.
Clinical evidence of another infection that may explain the current
symptoms;
7.
Pregnant women or women actively trying to achieve pregnancy.
*Severe dengue: hemodynamic shock, severe bleeding, severe organ
dysfunctions.
#Dengue
with
warning
signs:
persistent
vomiting,
plasma
leakage
(pericardial effusion, ascites, pleural effusion), increased hematocrit for age
and sex or 10% increase in basic hematocrit, postural hypotension or
syncope, any spontaneous bleeding, severe prostration, severe abdominal
pain, Hepatomegaly (> 2cm from the rib cage)
ALT: Alanine aminotransferase; ULN: Upper limit of normal; GFR:
Glomerular filtration rate, estimated by the 2021 Chronic Kidney disease
epidemiology collaboration (CKD-EPI) formula with the serum creatinine
value, gender and age of the participant.
Planned sample size
60 Participants in each arm of the study. 120 participants in total
Planned Study Period
2 years for total trial duration and 28 days for individual patient
involvement
Interventions
RESOMELAGON 100mg PO once daily + standard treatment
Control
Placebo + standard treatment
Justification
a.
To evaluate the safety of RESOMELAGON in patients infected with
dengue fever. The drug has been studied in healthy individuals and
patients with rheumatoid arthritis and COVID-19 with favorable
safety parameters, but never in dengue fever. Therefore, safety
data are needed for future phase 3 trials.
b.
To assess trends in the efficacy of RESOMELAGON. Dengue is a
disease with inflammatory pathogenesis, but currently no drug has
been proven to be effective. A drug that is capable of reducing the
severity of the disease is needed for this infectious disease that is
prevalent both in Brazil and in other developing countries.
Objectives
Outcome
Primary security
To evaluate the safety of
RESOMELAGON in patients infected
with dengue fever
Frequency of adverse events and
comparison of hematological,
biochemical and virological
parameters.
Primary efficacy
Efficacy of RESOMELAGON in reducing
disease duration
Time to disease resolution as
defined by a composite outcome:
a. Patient afebrile for 48 hours
with or without antipyretic
medication;
b. Increasing platelet counts
of >20% of the lowest count,
or normal platelet counts if
the patient did not have
thrombocytopenia, after two
consecutive measurements
of the lowest platelet count
c. Stabilized hematocrit or
return to normal hematocrit

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for age and sex after two
consecutive measurements
d. Absence of significant
bleeding or vomiting for 48
hours.
Secondary efficacy
Efficacy of RESOMELAGON in reducing
disease severity
Incidence of dengue with warning
signs or severe dengue in study
patients
Efficacy of RESOMELAGON in reducing
plasma extravasation
Evidence of pleural effusion OR
evidence of ascites OR pericardial
effusion OR incidence of
hemoconcentration (increased
hematocrit of >10% from baseline
or elevated for age and sex)
Efficacy of RESOMELAGON in reducing
dengue hospitalization or prolonged
observation in the emergency
department, both of which represent
a burden on healthcare systems
Incidence of stays of more than 12
hours in the emergency
department or hospital admission
Tertiary
To evaluate mechanisms that may
explain the mechanism of action of
RESOMELAGON in patients infected
with dengue fever
Measurement of cytokines and
chemokines and other parameters
involved in inflammation and
resolution, leukocyte testing for
microvesicles and other laboratory
parameters considered potentially
significant.

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20 LIST OF ABBREVIATIONS
ALT
Alanine aminotransferase
ADLs
Daily activities
CEP
Research Ethics Committee
CRF
Case Report Form – clinical research form
CTCAE
Common terminology criteria for adverse events
DSMB
Data Safety and Monitoring Board
EA
Adverse Event
EAG
Serious Adverse Event
EDTA
Ethylenediaminetetraacetic acid
PPE
Personal protective equipment
EV
Intravenous
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICH
International Conference on Harmonization
IM
intramuscular
BMI
Body Mass Index
WHO
World Health Organization
PD
Pharmacodynamics
IP
Principal Investigator
PK
Pharmacokinetics
POP
Standard Operating Procedure
PSI
Product Under Investigation
FROG
Adverse reaction
RAG
Serious Adverse Reaction
RT-qPCR or
qPCR
Real-time quantitative polymerase chain reaction
SAR-CoV2
Severe acute respiratory syndrome coronavirus 2
TCLE
Free and Informed Consent Form
GFR
Estimated Glomerular Filtration Rate
TNF
Tumor necrosis factor
U&E
Urea and Electrolytes

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30 BACKGROUND AND RATIONALE
The situation for the treatment of socially determined diseases caused by arboviruses, which in
Brazil mainly include Dengue, Chikungunya, Yellow Fever and Zika, is quite bleak . In fact, in 2024, we had
the worst epidemic in the country's history, with more than 16 million cases and 5 thousand deaths. Although
some preventive measures are beginning to be available for some arboviruses, there are no antivirals with
demonstrated clinical effect for these diseases. The experience with COVID-19 has clearly shown the beneficial
effect of treatment with antivirals (e.g. Paxlovid) and anti-inflammatories (e.g. Glucocorticoids) on the
evolution of the disease. In this project, we will focus on the attempt to develop a drug with the potential to
change the natural history of dengue.
Over the past two decades, Brazil has been facing constant dengue epidemics with increasing numbers
of cases of illness and death, according to data from the Ministry of Health (https://www.gov.br/saude/pt-
br/assuntos/saude-de-aaz/d/dengue). Although there is a vaccine approved a few years ago (DengVaxia) and
another approved last year (2023 – Qdenga), the use of these vaccines is not yet widespread and they are not
effective against all types of dengue. There are advances in the use of innovative vector control strategies
(such as the use of mosquitoes with the Wolbachia bacteria) (9) , but these are also not widely used in our
country or even worldwide. Finally, and of interest for the present study, there are no antiviral drugs or drugs
with another mechanism of action approved for use in patients with Dengue. In fact, there are no medications
that prevent progression to more severe conditions or that modify the course of the infection in those who
develop the most severe forms of the disease.
The inflammatory response is a complex and articulated reaction of our body to external and internal
threats, with the aim of controlling them and accelerating the recovery of normal physiological functions. In
the last 20 years, studies have emerged that have demonstrated that a protective, efficient and non-chronic
inflammatory response consists of an initial phase, characterized by the predominance of pro-inflammatory
mediators, followed by a resolution phase that ends the entire response with a return to a new state of
homeostasis. Although in the past the resolution phase of inflammation was considered a passive
phenomenon (i.e., occurring due to the absence or catabolism of pro-inflammatory mediators), it is now fully
appreciated that specific mediators, signaling pathways and mechanisms must be used to promote the
resolution phase of the inflammatory process.
When inflammation persists, it becomes "pathological" and, as such, contributes to the pathogenesis
of the vast majority of chronic diseases that affect the general population, such as arthritis, cardiovascular
diseases, diabetes, liver diseases and degenerative pathologies of the central nervous system. The chronic
inflammation phase is irreversible and causes deleterious effects on tissues and organs, affecting the general
homeostasis of the body. Since the resolution phase of inflammation is an active process, chronic inflammation
can result not only from an overload of pro-inflammatory mediators and mechanisms, but also from an
inadequate or insufficient involvement of problem-solving processes. This opens up a possibility for therapeutic
innovations since almost all anti-inflammatory drugs, with the exception of corticosteroids, act by inhibiting
the inflammatory phase and not by pro-resolution mechanisms ( https://doi.org/10.1016/j.it.2019.01.007 ).
Although most dengue virus infections are mild, approximately 5% of cases evolve with an exacerbated
inflammatory response that leads to endothelial damage and, thus, plasma leakage. This complication is known
as
severe
dengue
and
can
lead
to
hypovolemic
shock,
which
is
sometimes
fatal
( https://pmc.ncbi.nlm.nih.gov/articles/PMC9699586 ). We hypothesize that mechanisms regulating the
resolution of inflammation are altered in viral diseases such as dengue ( https://doi.org/10.1111/bph.16323
and https://doi.org/10.1111/bph.15164 ). Thus, the administration of pro-resolution molecules could be useful
to slow down or prevent dengue complications. Indeed, the potential benefits of a pro-resolving treatment
with Annexin A1 have already been described in a murine model of dengue, reducing thrombocytopenia,
vascular permeability and pro-inflammatory cytokines ( https://doi.org/10.7554/eLife.73853 ). Thus, we
established a proof of concept that the administration of pro-resolving molecules, which are also anti-
inflammatory, are beneficial in the context of dengue.
RESOMELAGON , a small molecule drug, is a “biased” agonist of melanocortin receptors 1 and 3 (MCR1
and MCR3). In the last decade, it has been demonstrated that the melanocortin system has several pro-
resolution effects. MCR agonists, mainly adrenocorticotropic hormone (ACTH) and αMSH, as well as synthetic
analogues such as the AP214 peptide, are anti-inflammatory and have organ-protective effects in several in

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vivo models. Furthermore, MCs have been shown to induce pro-resolution effects, such as phagocytosis and
efferocytosis, which gives a new aspect to MC-based therapy ( https://doi.org/10.3389/fendo.2019.00683 ).
RESOMELAGON has advantageous pharmacology by presenting a biased activation of intracellular signaling
pathways, by phosphorylation of extracellular signal-regulated kinases (ERK ½) and intracellular calcium influx
without causing cyclic AMP formation. At the functional level, RESOMELAGON modulated inflammatory
responses in experimental animals and exerted pro-resolution effects on immune cells, including promotion of
efferocytosis and inhibition of cytokine release. In more detail, the compound: 1) reduced the release of pro-
inflammatory cytokines such as IL-1β and IL-6 from stimulated macrophages in an ex vivo setting; 2) increased
the capacity of macrophages for phagocytosis and efferocytosis, which indicates a phenotypic shift from type
1 (M1) to type 2 (M2), with this phenomenon playing a central role in the pro-resolution effects of the
compound; 3) reduced cytokine release in vivo in both LPS-induced systemic inflammatory stress and peritonitis
models and 4) significantly accelerated resolution in a peritonitis model when administered therapeutically up
to 12 hours after disease induction. Furthermore, biased agonism against cAMP accumulation implied that
RESOMELAGON did not activate melanin biosynthesis. The latter is potentially a significant advantage compared
to the classical MCR (and ACTH) agonist, where the most undesirable side effect is the induction of skin
pigmentation after repeated doses. ( https://www.jimmunol.org/content/194/7/3381 )
3.1. Preclinical results of RESOMELAGON in Dengue
Using a preclinical model of dengue infection with A129 mice (deficient for the type I interferon
receptor), we evaluated the impact of therapeutic treatment with RESOMELAGON on disease progression.
Treatment was initiated 36 hours after infection with 2×10⁴ PFU of DENV-2, administered subcutaneously at a
dose of 20 mg/kg every 12 hours. Our results demonstrate that RESOMELAGON is capable of significantly
delaying the onset of clinical signs, such as weight loss, conjunctivitis, hair ruffling and reduced locomotor
activity, compared to the control groups (MOCK and vehicle). In addition, the treatment was effective in
preventing thrombocytopenia, observed by maintaining the number of platelets at levels significantly higher
than those of the untreated groups. Additionally, plasma biochemical analyses revealed that RESOMELAGON
promotes a significant reduction in the production of inflammatory mediators, such as MCPT-1 and CCL5,
known markers of mast cell activation and inflammation, respectively. These anti-inflammatory effects were
accompanied by the absence of a significant impact on plasma viral titers, as demonstrated by the quantification
of viable viruses by titration assay in Vero CCL81 cells. These findings indicate that RESOMELAGON acts as a
modulator of the inflammatory response in the preclinical model, contributing to the improvement of the
clinical picture and the preservation of platelets without directly interfering with viral replication.

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Figure 1: Treatment with RESOMELAGON delays the onset of clinical signs, prevents thrombocytopenia, and
reduces
the
production
of
inflammatory
mediators
without
impacting
viral
titers
in
plasma0
A) Experimental scheme: A129 mice (deficient for type I interferon receptor) were infected with 2×10⁴ PFU of
DENV-2 subcutaneously (intraplantar). Treatment with RESOMELAGON was initiated 36 hours after infection,
at a dose of 20 mg/kg every 12 hours, subcutaneously. Euthanasia was performed 72 hours after infection for
analysis. B) Clinical score evaluating weight loss, conjunctivitis, hair erection, and reduced movement. C)
Platelet count expressed as platelets × 10³/mL of blood. DE) Quantification of MCPT-1 and CCL5 in plasma by
ELISA, with results expressed in pg/mL. F) Viable viral titers in plasma quantified by titration in permissive Vero
CCL81 cells, expressed as Log10 PFU/mL of plasma. Statistical analysis by one-way ANOVA. *p<0.05 in relation
to the MOCK group; #p<0.05 in relation to the vehicle group.
3.2 Summary of ascending dose trials
The compound was tested in a randomized, double-blind, placebo-controlled, single ascending dose study with
RESOMELAGON or placebo administered as an oral suspension. Seven healthy male volunteer groups (48 men)
and one female group of eight healthy postmenopausal women (defined by at least a two-year period of
amenorrhea and a follicle-stimulating hormone (FSH) level >30 IU/L) received a single ascending dose with
RESOMELAGON/placebo administered as an oral suspension of PSI dissolved in SyrSpend ALKA under fasting
conditions. The dose range tested in men was 15 to 800 mg. The dose tested in women was 400 mg.
Pharmacokinetic (PK) results showed that in male participants across the dose range of 50 to 800 mg,
RESOMELAGON was rapidly absorbed with a median T max (time at which C max is observed) between 1 and 4
hours. Inter-individual variability was low to moderate for C max (maximum plasma concentration) and AUCs
(area under the curve) (<36%). The median t 1/2was close to 20 h (CV% <20%). The mean Vd/F (apparent volume
of distribution) was between 556 and 784 L with CV% below 35%, and the mean CL/F (apparent total clearance)
was between 20.26 and 31.26 L/h with CV% below 50%.

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In female participants, following administration of 400 mg RESOMELAGON, C max and AUCs were slightly
increased compared to male participants. Apparent clearance was lower in the female population (17.26 L/h),
and the apparent volume of distribution was similar. However, statistically, no conclusions can be made
regarding the effect of gender.
Twenty (20) participants reported a total of 38 Treatment-Emergent Adverse Events (TEAEs). All TEAEs were
mild (27) or moderate (11) in severity. No serious adverse events were reported during the study. Twenty-two
(22) of the 38 TEAEs were considered related to study treatment: 21 of these events occurred following
administration of 200 to 800 mg of RESOMELAGON and one event occurred following administration of placebo.
The most frequent treatment-related TEAEs were gastrointestinal disorders (19 events reported by fourteen
(14) subjects): nausea (7 events), abdominal pain (5 events), vomiting (3 events), diarrhea (2 events), abdominal
distension (1 event), and dyspepsia (1 event). The frequency of these related TEAEs increased with dose.
However, the amount of vehicle in the suspension increased with dose, leading to a consistency and increased
taste of the study drug. This change in consistency and taste of the suspension may be involved in this effect.
Among the TEAEs considered unrelated, headache was reported by seven (7) subjects. Other TEAEs were
sporadic.
A total of four (4) male subjects treated with active PSI had isolated elevations in aminotransferases (no
concomitant changes in alkaline phosphatase or bilirubin were reported). Elevations, which ranged up to 1.6
times the upper normal range for alanine transaminase (ALT), were observed in one (1) subject treated with
400 mg, two (2) subjects treated with 600 mg, and one (1) subject treated with 800 mg. No elevations of
aminotransferases above the upper normal range were observed in placebo-treated subjects.
No RESOMELAGON-associated increases in QTcF (the Fridericia-corrected QT interval) or changes in any other
cardiac parameters were identified during continuous 24-hour assessment of 1000 HZ ECG Holter recording.
No treatment-related changes in vital signs were observed.
Based on the safety assessment, it can be concluded that the maximum tolerated dose (MTD) was not reached.
At the maximum administered dose (MAD), the exposure achieved was more than 10x above the expected
exposure level to achieve therapeutic efficacy. Therefore, it was decided not to further increase the dose above
800 mg.
3.2. Summary of repeated dose trials
The compound was tested in a randomized, double-blind, placebo-controlled, repeat-dose study with
RESOMELAGON or placebo administered as an oral suspension given once daily for 14 days. Three trials of 12
participants (9 active; 3 placebo) were dosed with the same formulation used in part 1 of the study. The dose
levels tested were 50 mg, 100 mg, or 200 mg with matching placebo.
Pharmacokinetic evaluation showed that C max was observed between 1 and 205 hours post-dose , regardless
of the day of administration. Steady state was reached by day 7. At steady state, C max at the 50 mg dose level
was approximately 180 ng/mL (group mean), which is expected to be the exposure level required to induce
anti-inflammatory efficacy. Dosing at the 100 mg dose level achieved C max of approximately 400 ng/mL (group
mean) at steady state, i.e. a maximum increase of approximately 2-fold compared to the 50 mg dose level.
Dosing at the 200 mg dose level identified C maxat 900 ng/mL (group mean) with the highest measured level of
1,300 ng/mL. Since the expected peak exposure required to induce therapeutic efficacy is expected to be
around 170-180 ng/ml, the exposure at the 200 mg dose levels, based on Cmax , is up to 5x and, for the highest
exposed individual, more than 7x the expected therapeutic value.
Fourteen (14) subjects reported a total of 35 Treatment-Emergent Adverse Events (TEAEs). All TEAEs were mild
(27) or moderate (8) in severity. No serious adverse events were reported during the study. Four (4) of the 35
TEAEs were considered possibly related to study treatment. All four of these events related to gastrointestinal
disorders were observed following administration of the investigational drug (two (2) in the same subject at
the 50 mg dose level (one episode of diarrhea and one episode of abdominal cramping, two (2) in the same
subject at the 200 mg dose level (one episode of nausea and one episode of vomiting). Among the TEAEs

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considered unrelated, nine (9) subjects reported headache, seven (7) treated with investigational drug and two
(2) treated with placebo. Other TEAEs were sporadic.
Some mean changes and individual abnormalities were observed in laboratory parameters, vital signs and ECG
parameters. Most of these changes and abnormalities were limited and considered not clinically significant.
Evaluation of QTcF from a continuous 1000 Hz Holter ECG recording performed on day 14 and compared to day
1 (baseline) is still ongoing based on the exposure/response statistical analysis. No clinically significant
individual QTcF values were observed at any time point in this study on the repeated standard 12-lead safety
ECG.
A total of five (5) participants, all enrolled in Cohort 3 (200 mg), three (3) active-treated and two (2) placebo-
treated, had isolated elevations in aminotransferases (no concomitant changes in alkaline phosphatase or
bilirubin were reported). The elevations were more pronounced in the active-treated subjects, where
elevations reached up to 3.6x and 2.9x above the upper normal value for ALT. Upon completion of the study,
all values returned to normal.
Based on the safety assessment, it can be concluded that the MTD was not reached. At the maximum
administered dose (MAD), the exposure was 5x above what would be expected to be the exposure level to
achieve therapeutic efficacy. Therefore, it was decided not to further escalate the dose above 200 mg per day.
Consequently, RESOMELAGON has an excellent safety profile, allowing its administration in patients at doses
of 50 mg or 100 mg for four weeks. Additional information about RESOMELAGON, including its physicochemical
properties and the results of nonclinical in vitro and in vivo pharmacology, pharmacokinetic and toxicology
studies, is presented in the Investigator's Brochure.
3.3. Phase 2 clinical trial in COVID-19
A phase 2, double-blind, placebo-controlled clinical trial was conducted with 60 participants to evaluate the
safety and efficacy of RESOMELAGON (100 mg/day) for the treatment of COVID-19, an infectious disease also
with a significant pro-inflammatory pathogenesis. In this study, RESOMELAGON was shown to be safe, with no
significant increase in adverse events compared to the control group, with only a tendency for the occurrence
of gastrointestinal events. There were also no significant laboratory abnormalities. Although preliminary, a 2-
day reduction in the time to respiratory recovery was also demonstrated, with a time of 6 (IQR 4.12) days in the
placebo group and 4 (IQR 3.7) in the treatment group (p=0.017). A reduction in hospital stay from 7 (IQR 5, 14)
in the placebo group to 6 (IQR 4, 8) in the RESOMELAGON group was also observed (p=0.038)
( https://doi.org/10.1111/bph.17322 ).
3.4. Phase 2a Clinical Study in 105 Patients with RA
In the Phase 2a study, RESOMELAGON was administered as an oral suspension once daily for four weeks as an
add-on to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who were MTX-naïve and had
high disease activity (Clinical Disease Activity Index (CDAI) >22 at baseline). The study included 105 patients
randomized in a 2:1 ratio to active drug versus placebo in a two-arm design.
●
Part A : Two groups received active drug (50 mg and 100 mg) versus placebo.
●
Part B : Participants received active drug/placebo according to one of three study schedules:
1.
50 mg active drug/placebo
2.
100 mg active drug/placebo
3.
Either 50 mg or 100 mg of active drug versus placebo.
None of the participants in the active treatment groups had abnormal or clinically significant changes
in vital signs during study participation. The incidence of adverse events (AEs) was slightly higher in the
RESOMELAGON groups compared with placebo, primarily due to nausea, constipation, and headache. AEs in
the RESOMELAGON-treated groups were predominantly mild, and no serious cases were reported. No signs of

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immunosuppression were identified in any of the three treatment groups. There were no significant differences
in liver enzyme abnormalities between the RESOMELAGON 50 mg and placebo groups. No increases in liver
enzymes were observed in participants treated with RESOMELAGON 100 mg. Assessment of the 12-lead ECG
performed at each visit did not identify clinically significant abnormal changes. In addition, based on assessment
of the RR interval, PR interval, QRS duration, QT interval, and QTcF interval, no treatment-related changes were
identified in any of the three groups. There were no reports of serious adverse events (SAEs) or deaths during
the study.
3.5. Phase 2a Clinical Study in 122 Patients with RA
This was a multicenter, randomized, double-blind, placebo-controlled, two-part study of once-daily
RESOMELAGON. The study population consisted of participants with highly active RA (CDAI >22) and inadequate
response to DMARD therapy (DMARD-IR), but without elevated CRP at baseline. The first part of the study (Part
A) was intended to assess the preliminary safety and efficacy of 4 weeks of treatment with 60 mg, 80 mg, and
100 mg of RESOMELAGON once daily, with approximately 30 participants per group (1:1:1:1). A total of 122
participants were enrolled and 113 (92.6%) completed the study. The results of Part A indicated that
RESOMELAGON was safe and well tolerated.
3.6. Phase 2b Clinical Study in 127 Patients with RA
This was a multicenter, randomized, double-blind, placebo-controlled, 12-week study of once-daily
RESOMELAGON. The study population consisted of newly diagnosed patients with highly active RA (CDAI >22)
without elevated CRP at baseline. The primary objective was to evaluate the safety and efficacy of 12 weeks of
treatment with 100 mg RESOMELAGON once daily. A total of 127 participants were enrolled in the study, and
114 (89.9%) completed the study.
Overall, RESOMELAGON was well tolerated; similar rates of treatment-emergent adverse events
(TEAEs) were observed between treatment groups (44.4% and 42.2%). Overall, treatment-related TEAEs were
reported in 11.1% of the RESOMELAGON group versus 6.3% of the placebo group. Treatment-related TEAEs
included upper respiratory tract infections (6.3% vs 6.3%), upper abdominal pain (6.3% vs 3.1%), nausea (6.3%
vs 3.1%), headache (0% vs 9.4%), and vomiting (6.3% vs 0%) (incidence rates listed for RESOMELAGON vs
placebo, respectively).
No clinically significant abnormal observations were noted in changes from baseline in mean, median,
or maximum/minimum values in safety parameters (chemistry/hematology), vital signs, physical examinations,
or ECG. Some changes from normal to abnormal were noted in categorical laboratory parameters, and a few
individual values were reported as TEAEs (none considered drug-related).
Consequently, the study showed no sign of RESOMELAGON-associated effects on liver or kidney
function, nor did it indicate RESOMELAGON-induced suppression of the immune system.
4. OBJECTIVES AND OUTCOMES
Objectives
Outcomes
Time of
outcome
assessment
Primary
security
To evaluate the safety of
RESOMELAGON in patients
infected with dengue fever
Frequency of adverse events and
comparison of hematological, biochemical
and virological parameters.
Days 0- 28
Primary
efficacy
Efficacy of RESOMELAGON in
reducing disease duration
Time to disease resolution as defined by a
composite outcome:
a. Patient afebrile for 48 hours with or
without antipyretic medication;
b. Increasing platelet counts of >20% of the
lowest count, or normal platelet counts if
the patient did not have
thrombocytopenia, after two consecutive
measurements of the lowest platelet
count
c. Stabilized hematocrit or return to normal
hematocrit for age and sex after two
consecutive measurements
Days 0-14

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d. Absence of significant bleeding or
vomiting for 48 hours.
Secondary
Efficacy
Efficacy of RESOMELAGON in
reducing disease severity
Incidence of dengue with warning signs or
severe dengue in study patients
Days 0-14
Efficacy of RESOMELAGON in
reducing plasma extravasation
Evidence of pleural effusion OR evidence of
ascites OR pericardial effusion OR incidence
of hemoconcentration (increased hematocrit
of >10% from baseline or elevated for age
and sex)
Days 0-14
Efficacy of RESOMELAGON in
reducing dengue
hospitalization or prolonged
observation in the emergency
department, both of which
represent a burden on
healthcare systems
Incidence of stays of more than 12 hours in
the emergency department or hospital
admission
Days 0-14
Tertiary
To evaluate mechanisms that
may explain the mechanism of
action of RESOMELAGON in
patients infected with dengue
fever
Measurement of cytokines and chemokines
and other parameters involved in
inflammation and resolution, leukocyte
testing for microvesicles and other
laboratory parameters considered
potentially significant.
Days 0-14
50 STUDY DESIGN
This study is a randomized, double-blind, placebo-controlled, multicenter, repeated-dose clinical trial
of RESOMELAGON in patients with acute dengue infection.
5010 Intervention
●
RESOMELAGON 100mg orally once a day
●
Placebo
The investigational product (ISP) will be administered for 5 days. The first dose will be administered at
enrollment and then daily in the morning on an empty stomach (1 hour before breakfast).
Note: All study participants will also receive supportive treatment from the local health system, for
example, antipyretics and analgesics, according to the judgment of the attending physician.
60 PATIENT IDENTIFICATION AND RECRUITMENT
6010 Study participants
Adult patients with symptomatic acute arboviral syndrome with less than 72 hours of
symptoms and DENV infection confirmed by antigen or polymerase chain reaction.
6020 Inclusion criteria

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1.
Participants aged 18 to 65;
2.
The participant is able to understand the study procedures and provide informed consent ;
3.
Presents more than 36 and less than 84 hours after the onset of symptoms;
4.
Symptoms compatible with dengue infection with a positive antigen test or positive polymerase chain
reaction test. Dengue is suspected by a report of fever and at least 2 other signs or symptoms of the
disease, including myalgia, arthralgia, headache or conjunctivitis .
603 Exclusion criteria
1.
Have any comorbidity that is perceived as decompensated by the investigator;
2.
The following significant laboratory abnormalities discovered at screening would lead to participant
discontinuation:
●
Hemoglobin <10g/dl
●
Platelet count <50,000/Ul
●
ALT>3x ULN
●
Total bilirubin > 1.5 x ULN
●
GFR <60mls/min/1.73m2
3.
Contraindications or known hypersensitivity to RESOMELAGON;
4.
Presents as dengue with warning signs# or severe dengue* upon inclusion;
5.
Currently participating in another clinical drug trial;
6.
Clinical evidence of another infection that may explain the current symptoms;
7.
Pregnant women or women actively trying to achieve pregnancy.
*Severe dengue: hemodynamic shock, severe bleeding, severe organ dysfunctions.
#Dengue with warning signs: persistent vomiting, plasma leakage (pericardial effusion, ascites, pleural effusion),
increased hematocrit for age and sex or 10% increase in basic hematocrit, postural hypotension or syncope,
any spontaneous bleeding, severe prostration, severe abdominal pain, Hepatomegaly (> 2cm from the rib cage)
ALT: Alanine aminotransferase; ULN: Upper limit of normal; GFR: Glomerular filtration rate, estimated by the
2021 Chronic Kidney disease epidemiology collaboration (CKD-EPI) formula with the serum creatinine value,
gender and age of the participant.
70 INCLUSION AND PROCEDURES IN THE STUDY
Patients with a suspected diagnosis of acute arbovirus disease who come from primary care units or
emergency care units will be informed of the study and the possibility of undergoing diagnostic testing. Dengue
fever is suspected by reporting fever and at least 2 other signs or symptoms of the disease, including myalgia,
arthralgia, headache, or conjunctivitis. Patients who can be included will be offered the NS1 rapid test and RT-
PCR test for the diagnosis of dengue fever, if these tests have not already been performed. A rapid test for
COVID-19 may be performed to exclude individuals with this disease, if the attending physician deems it
necessary. The RT-PCR test is expected to be available within 24 hours of obtaining the blood sample.
Recruitment may occur at any time up to 84 hours after the onset of symptoms, but inclusion and randomization
must occur between 36 and 84 hours after the reported onset of symptoms. Patients with a positive RT-PCR or
NS1 test for dengue will be included in the study after written informed consent.
After enrollment, all recruited patients will be visited at their home or place of residence, or will be
seen at the referring Clinical Research Unit. All staff will wear appropriate personal protective equipment (PPE)
in accordance with local health system guidelines. For home visits, a trained member of staff will collect a blood
sample.
During the initial visit, participants will be asked about their symptoms and medical history. The patient
will undergo a physical examination and blood samples for routine hematology and biochemistry and other
baseline investigations. After enrollment in the study, the patient will be randomized to one of the study arms.
A blood sample will be obtained using a standard operating procedure (SOP) before you receive your
first dose of study medication. The first dose of RESOMELAGON or placebo will be administered under
observation in the clinical research unit. For subsequent doses, blood collection and medication administration
will be performed during daily visits (at home or at the clinical research unit) under the supervision of study
staff.

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7010 Virological sampling
Serial blood samples will be collected according to the sampling schedule by trained study personnel
following an established standard operating procedure (SOP). Daily sampling will be performed by study
personnel at the participant\s home or at the study site. Samples will be kept cool and subsequently stored at
-80 C as detailed in the SOP. Transportation times will be recorded, as well as the time for plasma to be frozen
at -80 C. Viral genomes from blood samples will be quantified by RT-qPCR. Patient measurements over time
will be used to estimate the rate of viral clearance.
All dengue-positive samples will be typed to determine the effect of subtype on viral load and response
to treatment. This will be done using whole genome sequencing technology or specific PCRs to determine
subvariants.
7020 Recruitment
Potential patients with symptoms suggestive of acute arboviral disease will be invited to participate in
the study. Dengue fever is suspected by reporting fever and at least 2 other signs or symptoms of the disease,
including myalgia, arthralgia, headache or conjunctivitis. Leaflets will be distributed at primary health care units
and/or emergency care centers informing about the study. We will also publicize the study through social
media. Participants can contact the research group for more information about the study. All procedures and
follow-up of participants will take place at the reference Clinical Research Units where the study is taking place.
If the patient has a compatible clinical picture, but less than 36 hours after the onset of symptoms, he or she
may be recruited for later inclusion after 36 hours of symptoms.
7030 Screening and eligibility assessment
Eligibility assessment will occur at the time of screening. If, based on the inclusion and exclusion criteria,
the patient is eligible and willing to complete the full study, he or she will be enrolled in the study after obtaining
informed consent.
7040 Informed consent
Written versions of the participant information and informed consent form (ICF) will be presented to
patients detailing the exact nature of the study; what it will involve for the patient; the implications and
restrictions of the protocol; and the known side effects of the drugs being evaluated and any risks involved in
their participation. It will be clearly stated that the patient is free to withdraw from the study at any time for
any reason, without prejudice to their future care and without obligation to provide a reason for withdrawal.
The patient will have all the time necessary to consider the information, and will have the opportunity
to question the investigator or other independent parties to decide whether they will participate.
Informed consent will then be documented in two copies signed and dated by the patient and the
person who provided and obtained informed consent. The person obtaining consent must be appropriately
qualified and experienced and must have been authorized to do so by the site PI. One copy of the informed
consent signed and dated by the participant and the researcher who obtained consent will be given to the
patient and the other copy will be kept on file at the study site.
7050 Baseline Assessments ( See Appendix 1 for detailed schedule of activities )
A physical examination, vital signs, oxygen saturation, symptom review, and basic demographic data
will be recorded. If there is no medical reason for exclusion, the participant will be enrolled, randomized, and
receive the first dose of the drug for which he or she is randomly assigned. A total of 40 mL of venous blood will
be collected at this time for specific study-related assessments. The participant may be discontinued before
the next dose if laboratory abnormalities result in a contraindication. If a complete blood count and
biochemistry were obtained within 36 hours of study enrollment, the results may be used to determine whether
there is a contraindication to participation in the study.
Baseline laboratory tests:
●
Blood sample for
o
Blood count and differential count (Reference laboratory of the participating
Clinical Research Unit);

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o
Biochemistry (urea creatinine, liver function tests and albumin) (Reference
laboratory of the participating Clinical Research Unit);
o
Cytokines, IL-6, soluble TNR1 and TNF2 receptors and chemokines CXCL8 and
CCL2 (Central analysis at CT Terapias UFMG);
o
RT-PCR and detection of the NS1 virus (Central analysis at CT Terapias UFMG);
o
“Buffy-Coat” will be obtained to study the response of circulating leukocytes
to infection.
o
Dengue serology (IgG, antibody responses) to assess previous exposure to
dengue (Central analysis at CT Terapias UFMG);
Note: The evaluations of Cytokines, including IL-6, soluble TNR1 and TNF2 receptors, and the chemokines CXCL8
and CCL2 are important markers found in the plasma and serum of dengue patients and mark the intensity of
the inflammatory response. For these analyses, we will use commercial Elisa kits (DuoSet from RND systems)
following the manufacturer's instructions.
7060 Study days
706010 Day 1
After inclusion, the participant will be randomized to one of the study arms ( RESOMELAGON or
placebo) using envelopes previously drawn and defined by the study statistician. Randomization ratios will be
uniform for participants (1:1). Only the designated study team (unblinded team) will be allowed to access the
envelopes for patient allocation.
For participants randomized to RESOMELAGON or placebo, the first dose of treatment (hour 0) will be
supervised by study staff. The participant will then be observed for a minimum of 1 hour in the Clinical Research
Unit before being discharged home.
706020 Days 2 to 7, day 10 and day 14 *
During these days, a sample of up to 40 ml of venous blood will be obtained, if there is no contraindication.
The following variables will be evaluated daily:
●
Eligibility check and treatment assessment (administration of medications taken will be observed by
study personnel and the time recorded (days 2-5).
●
Axillary temperature recorded twice daily by study staff or participant (information collected in a diary
and reviewed daily by study staff) only through day 7.
●
Study staff complete a brief symptom checklist every day
●
Assessment of Adverse Events (AEs) and Concomitant Medications (CM).
●
Blood sample collected for biochemical laboratory tests (urea, creatinine and liver function) and
complete blood count according to the schedule (appendix 1).
●
Blood samples collected to assess cytokine levels , leukocyte testing (buffy-coat), RT-PCR and NS1,
according to the schedule (appendix 1).
* See Appendix 1 for detailed schedule of activities.
706030 Day 2 8 (1 month) assessment
The following variables will be assessed on days 28 (1 month ± 4 days) by telephone contact :
●
Study staff complete a brief symptom checklist ;
●
The participant will be asked about EAs and MCs;
●
Participation in the study will be completed.
7070 Management of patients who become ill
During the study, although it is unlikely since we are recruiting patients at low risk of developing more
severe disease, the patient may deteriorate clinically or may develop a new intercurrent illness or potentially
a side effect related to the study medication. Any patient who develops difficulty with activities of daily living
or worsening of their symptoms will be referred to the project team physicians for further evaluation. Clinical
deterioration in this study may be due to several factors, including progression of dengue disease, development
of complications such as shock, adverse drug reactions, among others. Therefore, a full clinical assessment will

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be performed by the study physician. Based on this assessment, they may be referred to an emergency
department, re-examined the following day, or asked to update the research team frequently by cell phone
about their well-being.
If a patient is referred to an emergency care unit, a clinical assessment will be performed by the
attending physician and a diagnosis will be made. The decision to discontinue the study drug will depend on
this diagnosis and will be made between the unit staff and the study PI.
Emergency care unit physicians will be responsible for patient care, but the research team will continue
to monitor patients' progress in the hospital. Treatment for dengue severe enough to warrant hospitalization
will follow national guidelines.
Blood samples will be tested for complete blood count and biochemistry (urea, creatinine, and liver
function tests) to assess for drug-related adverse effects or abnormalities that may require dose adjustment or
discontinuation of therapeutic or clinical intervention. These tests are also important for clinical follow-up of
the study participant. The responsibility for evaluating and acting on the results of the blood tests will lie with
the study team. They will use their clinical judgment in evaluating the participant, making further tests, and
referring the participant to the study. At any time during the study, additional laboratory tests may be
performed on the participant if clinically indicated by the research team based on symptoms or previous
laboratory abnormalities.
7080 Sample Handling and Retention
Samples will be transferred to designated testing facilities where they will be tested in accordance with
best practice laboratory measures and safety procedures.
Blood samples for virus detection will be processed using validated quantitative real-time polymerase
chain reaction (qPCR) to detect dengue, according to the study SOP. The kit to be used is a commercially
available kit (Biomol ZDC kit) distributed by IBMP (Instituto de Biologia Molecular do Paraná, FIOCRUZ). Samples
will be retained in accordance with local ethical regulations and approvals. Consenting patients may withdraw
their consent until the study is completed. To do so, participants must make a written request, sign and date it.
Unless requested, samples collected prior to the withdrawal date will be retained for study analysis.
Some of the remaining blood samples will be stored and may be used for further studies related to
susceptibility or response to dengue infection and treatments . Blood samples will be labeled with a unique
number and initials, but not with the patient's name. Any additional tests beyond those indicated in this study
will be performed only after obtaining permission from the ethics committee and applying a new ICF if deemed
necessary.
80 DISCONTINUATION/WITHDRAWAL OF PATIENTS FROM THE STUDY
Participants may choose to stop treatment and/or study assessments, but may remain under study
follow-up. Participants may also withdraw their consent, meaning they wish to withdraw from the study
completely. In the case of withdrawal from treatment and active follow-up, the following options for a phased
withdrawal from the study would apply:
a) Patients withdraw from the study but allow data and samples obtained up to the point of withdrawal
to be retained for use in study analysis. No further data or samples would be collected after withdrawal,
b) Patients withdraw from active follow-up and further communication, but allow study staff to
continue to access their medical records and any relevant hospital data that are recorded as part of
routine standard of care; i.e. CT scans, blood results and disease progression data, etc.
c) Patients withdraw, but do not allow the collected data and samples to be used.
In addition, the Investigator may discontinue a participant from experimental treatment at any time if the
Investigator considers it necessary for any reason, including, but not limited to:
●
Pregnancy;
●
Ineligibility (arising during the study or retrospectively having been overlooked in screening);
●
Significant deviation from protocol;
●
Significant non-compliance with the treatment regimen or study requirements;
●
An adverse event that requires discontinuation of study drug or results in the inability to continue to
comply with study procedures;

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●
Disease progression that requires discontinuation of study medication or results in the inability to
continue to comply with study procedures.
The reason for discontinuation and/or withdrawal will be recorded on the Case Report Form. The
participant will be monitored by the study clinical team until the final outcome of the reason for
discontinuation, whether due to illness and/or pregnancy.
qPCR data from participants withdrawn from the study will still be analyzed if at least three distinct time
points are available for estimation of a clearance slope. The sample size is adaptable, so there is no need to
replace withdrawn patients.
Consenting participants may withdraw their consent up until the conclusion of the study. Unless requested,
data and samples collected prior to the withdrawal date will be retained in the study database and analysis.
8010 Definition of End of Study
The end of the study is the date of the 28-day follow-up visit of the last enrolled patient.
90 SAFETY REPORT
9010 Definitions
Adverse
Event
(AE)
Any adverse medical occurrence in a patient to whom the investigational product has been
administered, including occurrences that are not necessarily caused by or related to that
product.
Adverse
Reaction
(AR)
An undesirable and unintended response in a patient to an investigational drug that is related
to any dose administered to that patient.
The phrase "response to an investigational drug" means that a causal relationship between an
investigational drug and an AE is at least a reasonable possibility, i.e., the relationship cannot
be ruled out.
All cases judged by the qualified medical professional to have a reasonable suspicion of a causal
relationship with the study drug qualify as adverse reactions.
Serious
Adverse
Event
(SAE)
A serious adverse event is any untoward medical occurrence that:
●
results in death;
●
is a threat to life;
●
requires hospital admission or extension of existing hospitalization;
●
results in persistent or significant impairment/disability;
●
consists of a congenital anomaly or birth defect.
Other 'major medical events' may also be considered serious if they endanger the patient or
require an intervention to prevent one of the above consequences.
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the
patient was at risk of death at the time of the event; it does not refer to an event that
hypothetically could have caused death if it were more serious.
Hospitalization is defined as a formal, unplanned admission, even if the admission is a
precautionary measure for continued observation. The patient must be admitted for at least
one night; a short stay of several hours to receive treatment is not considered hospitalization. If
a patient is admitted overnight or longer for social/economic or isolation reasons and is clinically
stable, this does not constitute an SAE. Other examples of visits to a hospital facility that are not
considered hospitalization include: emergency room visits, outpatient surgery, pre-planned or
elective procedures for a pre-existing condition (provided that the condition did not worsen
during the trial treatment or anticipated due to worsening symptoms), and for the purposes of
this study, being admitted for influenza isolation.
Serious
Adverse
An adverse event that is serious and, in the opinion of the reporting investigator, is reasonably
likely to be due to one of the study treatments, based on the information provided.

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Reactions
(SAD)
NB: To avoid confusion or misunderstanding about the difference between the terms SAE and “serious” grade
3 AE, the following clarification note is provided: “Serious” is often used to describe the intensity of a specific
event, which may be of relatively minor medical significance. SAE is the regulatory definition provided above.
Any pregnancy that occurs during the clinical trial and the outcome of the pregnancy should be
recorded and monitored for congenital abnormalities or birth defects, in which case it would fall within the
definition of SAE.
9020 Causality
The relationship of each adverse event to the study drug must be determined by a medically qualified
individual according to the following definitions:
Definitely related:
There is clear evidence to suggest a causal relationship and other possible
contributing factors can be ruled out.
Probably related:
There is evidence to suggest a causal relationship and the influence of other
factors is unlikely.
Possibly related:
There is some evidence to suggest a causal relationship (e.g. because the event
occurs within a reasonable time after administration of the study drug).
However, the influence of other factors may have contributed to the event (e.g.
the patient's clinical condition, other concomitant treatments).
It is unlikely to be related:
There is little evidence to suggest that there is a causal relationship (e.g., the
event did not occur within a reasonable time after administration of the study
drug) or another reasonable explanation for the event (e.g., the patient's clinical
condition, other concomitant treatment).
Unrelated:
There is no evidence of any causal relationship.
9030 Procedures for recording adverse events
A symptom checklist will be performed daily between D2 and D7 , on D10 and D14 with a final follow-
up assessment on D28 to assist in the identification of adverse events. The severity of adverse events will be
assessed following the Common Terminology Criteria for Adverse Events (CTCAE) v5.0:
1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = fatal.
AEs occurring in participants since inclusion and during participation in the study that are observed by
the investigator or reported by the patient with intensity grade 3 (severe) or higher will be recorded in the CRF,
whether or not attributed to the study drug.
The following information will be recorded: description, start date and end date, severity, assessment
of relationship to study drug, other suspected drug or device, and action taken. Follow-up information should
be provided as needed.
AEs considered related to the study drug, as judged by a qualified medical investigator, will be followed
until resolution or the event is considered stable. All such cases will be appropriately reported and discussed
with the company that produces the PSI.

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It will be up to the investigator's clinical judgment to decide whether or not an AE is of sufficient severity
to require removal of the patient from treatment. A patient may also voluntarily withdraw from treatment
because of what he or she perceives as an intolerable AE. If any of these occur, the patient must undergo a final
study evaluation and receive appropriate care under medical supervision until symptoms resolve or the
condition becomes stable. Abnormalities that are not clinically significant will not be graded or recorded on the
CRF.
9040 Classification of laboratory abnormalities
Abnormal laboratory findings detected during the study or present at baseline and worsening after
taking study medication will be reported as AEs or SAEs. If considered abnormal, the values will be graded
according to CTCAE v5.0. AEs of severity grade 3 or higher or SAEs will be recorded on the CRF and will be
followed until they are grade 2 or lower, return to baseline, or considered permanent. For laboratory results
that are not available on CTCAE v5.0, the site investigator must determine whether or not the laboratory
abnormality is clinically significant. If the site investigator believes that a laboratory abnormality is clinically
significant, it should be reported as an adverse event and a grade should be assigned to the best of one\s ability.
Abnormalities that are not clinically significant will not be graded or recorded on the CRF.
9050 Procedures for reporting serious adverse events
All SAEs detected by the site investigator must be reported to the DSMB within 24 hours of becoming
aware of the SAE.
Further follow-up reports should be submitted, if necessary, until the SAE resolves, is considered
stable/permanent, or results in death. A final status should be determined for any ongoing SAEs at the study
end date.
The site PI must also report SAEs to the local ethics committee and regulatory authority in accordance
with local requirements.
9060 Data Security Monitoring Board (DSMB)
An independent Data Safety Monitoring Board (DSMB) will be established, consisting of qualified
volunteers with the necessary knowledge of clinical trials. The DSMB will receive summary reports of the study
as defined by the charter or by ad hoc request, prior to each meeting. All data reviewed by the DSMB will be
strictly confidential. A DSMB charter will outline its responsibilities and how it will operate.
An interim report will be prepared by the Statistician for the pre-specified interim analysis. In case of
safety concerns, additional information or formal interim analyses may be requested by the DSMB.
The DSMB will formally meet at the following times:
●
after the first 30 patients were included in the study
●
At additional time points as directed by the DSMB after its review, if deemed necessary
All DSMB recommendations will be communicated. The PI will be responsible for submitting written DSMB
summary reports with applicable recommendations to the local ethics committee and other applicable groups.
100 STATISTICS AND ANALYSIS
10010 Sample size estimation and randomization
The main objective of the present study is to characterize the safety and efficacy of RESOMELAGON
versus the placebo arm in patients with dengue, mainly in reducing the duration of the disease.
The sample size estimate was calculated by a power analysis using data from the literature regarding
the mean time until resolution of symptoms and laboratory abnormalities caused by the disease
( https://doi.org/10.1371/journal.pntd.0001309 ): Time until resolution of fever in the placebo group of 136
h and variation of approximately 20% (5.6±1.1 days), time until resolution of thrombocytopenia (6.5±1.4) and
hemoconcentration (7.0±1.7). Considering that hemoconcentration is a less frequent event, the sample size
can be estimated by evaluating only the resolution of fever and thrombocytopenia. Considering also an effect
size of 1 day in reducing the duration of the disease, power of 80%, alpha of 5% and loss of 10%, we arrive at a
sample size of 120 (60 who will receive RESOMELAGON and 60 who will receive the placebo).

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Participant randomization will be performed using a centralized system in which only authorized individuals
will have access to the application to allocate patients to the placebo or RESOMELAGON group. The webapp
will be password protected . All randomization activities will be tracked in the webapp and assigned a
timestamp along with the patient\s anonymized study code, age and sex.
10020 Statistical analysis overview
To assess the efficacy of Resomelagon administration on the primary outcome (time to disease
resolution) of patients included in the study, Poisson or negative binomial models will be adjusted considering
the existence of right censoring and data dispersion.
For safety analyses and secondary outcomes, the results will be tabulated comparing the treatment
with the placebo group. Integer or continuous variables will be expressed as mean and standard deviation or
median and interquartile range. Categorical variables will be presented with absolute and relative
frequencies. The normality of variables will be tested with the Shapiro-Wilk test, while equality of variance
will be analyzed with the F or Bartlett test. Differences in mean or median will be assessed by Wilcoxon,
Kruskal-Wallis, t-test or analysis of variance, considering the number of groups and assumptions of each test.
Associations between categorical variables will be tested by Fisher's exact test or Pearson's chi-square test.
Pearson's or Spearman's correlation coefficients will be estimated to explore the existence of linear
associations between continuous or integer variables. Linear and generalized linear models will be used for
multivariate structures, and data with temporal or spatial relationships will be explored with random effects
models or generalized estimating equations. Estimates of time until the occurrence of an event will be made
using Cox models or equivalent non-parametric models. The significance level will be 5%.
110 DATA MANAGEMENT
11010 Access to data
Direct access will be granted to authorized representatives, local ethics committees and regulatory
authorities, and any host institution for monitoring and/or auditing of the study to ensure regulatory
compliance. Outcome data and treatment assignment data will be made available for real-time analysis.
11020 Data Processing and Record Keeping
Clinical trial data will be recorded on CRFs developed for the trial and entered into a password-
protected database by the local trial PI, research nurse, or designee. The trial database will be built on
RedCap, a clinical data management system that complies with ICH GCP and FDA regulation, Title 21 of the
Code of Federal Regulations Part 11. It will be hosted on a secure server with restricted access. The trial
database will include internal quality checks to identify data that appears inconsistent, incomplete, or
inaccurate.
Measures will be taken to ensure that potentially harmful information is not disclosed to patients.
Paper records (e.g., patient identification information for follow-up purposes, screening records, and signed
informed consent forms) will be kept in locked cabinets; electronic data will only be accessible to personnel
with user accounts and passwords. The database contains an audit trail that keeps track of changes to data and
user activity in the database. All electronic data will be stored on secure servers that are backed up daily, with
off-site storage weekly.
On-site patient records will, taking into account site capacity, be stored in binders in a secure, limited-
access room. Records will be retained for at least five years after study completion or in accordance with local
site regulations. The study database will be retained indefinitely.
120 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES
The study will be conducted in accordance with relevant regulations and standard operating
procedures.
The study will be conducted in accordance with this protocol, the International Conference on
Harmonization (ICH) Guidelines for Good Clinical Practice (GCP) and any applicable regulatory requirements.
Monitoring will be performed locally and supervised with the assistance of the MORU Clinical Trials Support

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Group (CTSG) according to a pre-specified risk-based monitoring plan to ensure compliance with the study
protocol and applicable guidelines and regulations. Biological samples will be processed and stored in
accordance with the Research Site SOPs.
Data validation will be performed to identify errors or discrepancies and thus ensure the integrity,
validity and accuracy of the data.
130 ETHICAL AND REGULATORY CONSIDERATIONS
This study will be conducted in patients who are unlikely to develop serious illness. The drugs being
investigated may benefit the patient; that is, they may shorten the duration of symptoms or reduce their
severity, but they are unlikely to have a significant adverse effect on the patient's illness and subsequent health.
Funds will be set aside to cover hospital costs in the unlikely event of an adverse drug reaction. All assistance
will be provided to the participant should any health problems arise as a result of their participation in the study
for as long as necessary.
Women who are pregnant, actively trying to become pregnant, or breastfeeding will not be allowed to
participate in this study, as it is not known whether any of the treatments tested will have additional benefits
that outweigh any risks associated with pregnancy/breastfeeding. If pregnancy occurs after enrollment in the
study, the participant will be discontinued and followed until the pregnancy is complete.
13010 Declaration of Helsinki
The Investigator will ensure that this study is conducted in accordance with the current revision of the
Declaration of Helsinki.
13020 Guidelines for Good Clinical Practice
The Investigator will ensure that this study is conducted in accordance with relevant regulations and
Good Clinical Practice (ICH GCP).
13030 Approvals
The protocol, informed consent form, participant information sheet and any proposed publicity
material will be submitted to local ethics committees for written approval. The Investigator will submit and,
where necessary, obtain approval from the above parties for all changes to the original approved documents.
13040 Patient confidentiality
The study team will ensure that patient anonymity is maintained. Patients will be identified only by a
patient identification number in all study documents and in any electronic databases. All documents will be
stored securely and accessible only by study staff and authorized personnel. The study will comply with the
General Data Protection Law (LGPD), which requires that personal data not be kept as identifiable data for
longer than is necessary for the purposes in question.
13050 Expenses
Patients and their companions will have their expenses, such as food and transportation, arising from
their participation in the study reimbursed by the study, in accordance with current ethical regulations.
13060 Risk
Resomelagon is well tolerated and safe, and has been tested in normal subjects, patients with
rheumatoid arthritis, and patients with moderate COVID-19. The most common side effects include those
associated with the gastrointestinal tract, including nausea, vomiting, and diarrhea, and are mostly mild.
These are generally mild and resolve without the need for medical intervention. Risks associated with blood
withdrawal during the study include local discomfort, occasional bleeding or bruising at the needle puncture
site, and very rarely, infection.
Regarding pregnancy, Resomelagon should not be used during pregnancy and its use is not recommended for
women who may become pregnant and who are not using effective contraception. Pregnancy tests will be
performed on all participants who may become pregnant before the start of the study and at all scheduled

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visits. Women should avoid becoming pregnant throughout treatment and for up to 4 weeks after stopping the
medication.
Another risk related to the study concerns data confidentiality. The study team will ensure that the anonymity
of participants is maintained. Participants will be identified only by a participant identification number in all
study documents and in any electronic databases, with the exception of the CRF, where the participant's initials
may be added. The name and any other details
Identifying data will NOT be included in any electronic study data files. All documents will be stored securely
and only accessible by the study team, the Human Research Ethics Committee and any external study
auditors. All documents will be stored securely and only accessible by the study team and authorised
personnel. The study will comply with the Data Protection Act 2018, which requires that personal data should
not be kept as identifiable data for longer than is necessary for the purposes in question.
13070 Benefits
There may be early resolution of symptoms in those randomized to certain active treatment arms, but
benefit is not guaranteed. Since these are drugs already in use for other indications, no harm is expected from
their use. Although an individual patient may not personally benefit, this study should help future dengue
patients by identifying treatments that have the best antiviral effect early in the course of the disease.
Participants will be reimbursed for costs associated with travel to the study site and meals.
13080 Communicating
The PI must submit a Semiannual Progress Report to the local IRB on the anniversary of the study
approval date. In addition, the PI must submit a final study report to the local IRB.
13090 Finance
130901 Financing
The project will be financed with the researcher's own resources received by the INCT project on
Dengue and host-microorganism interactions.
130100 Data ownership
The data generated in this study belongs to the study group as a whole. The final database will be
shared between the site PI and key members of the research team.
The database may be shared with researchers not directly involved in this study after publication of the main
article. Authorship criteria will be consistent with international guidelines ( http://www.icmje.org/#author ).
130110 Publication policy
Investigators will be involved in reviewing draft manuscripts, abstracts, press releases, and any other
publications arising from the study. Authorship will be determined according to the guidelines of the
International Committee of Medical Journal Editors (ICMJE), and other contributors will be acknowledged.
Study results will be summarized in layman's terms, both in English and in the language(s) commonly spoken
at the study sites, and disseminated to key stakeholders, user communities, and patients.

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Appendices
150 Annex 1: Schedule of activities
Triag
1
2
3
4
5
6
7
10
14
28
NS1 or qPCR
(Tracking)
+
Clinical Evaluation
+
Consent
+
Inclusion in the study
+
Clinical and
demographic history
+
Vital parameters
(temp, HR, RR, BP).
Weight and height
(day 1)
+
+
+
+
+
+
+
Symptom
assessment
+
+
+
+
+
+
+
+
+
Adverse events and
medications
+
+
+
+
+
+
+
+
+
Laboratory routine*
+
+
+
+
+
+
+
+
+
Cytokines
+
+
+
+
+
+
+
+
+
Buffy coat
(Leukocytes)
+
+
+
+
+
Viral load (RT-PCR)
+
+
+
+
+
+
+
+
+
NS1 ELISA
+
+
+
+
+
+
+
+
+
PSI Administration
+
+
+
+
+
Telephone contact
+
*At inclusion and on days 3, 5, 7, 10, 14, liver function tests, albumin, urea, creatinine and ß-HCG will be
performed on days 1, 2 and 14 if necessary. For the CBC with platelet count, tests will be performed daily or
until the primary efficacy endpoint is reached.