Efficacy and safety of CVO PLUS CURATIF capsules, Malagasy improved traditional medication for treating COVID-19 a randomized, double-blind, placebo-controlled trial

doi:10.21203/rs.3.rs-1274428/v1

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Efficacy and safety of CVO PLUS CURATIF capsules, Malagasy improved traditional medication for treating COVID-19 a randomized, double-blind, placebo-controlled trial

https://doi.org/10.21203/rs.3.rs-1274428/v1

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Background

There is currently no validated, effective, safe treatment for severe illness caused by SARS-CoV-2. CVO PLUS CURATIF (CVO+C) is a capsule formulation of two compounds of plant origin with anti-inflammatory and antiviral activities in vitro: artemisinin and 1,8-cineole. These compounds have been repurposed for possible use as an oral treatment against COVID-19.

Methods

We performed a phase 3 randomized clinical trials on patients over the age of 18 years with SARS-CoV-2 infection confirmed by RT-PCR and mild-to-moderate symptoms. Patients were randomly assigned to receive CVO+C (3 capsules per day) or placebo for 15 days. The primary outcome was the proportion of patients testing negative for SARS-CoV-2 by RT-PCR on day 28 and an absence of severe and serious adverse events. Recovery time, and biological parameters on days 7, 14, 21 and 28 of the trial were considered as secondary outcomes. The safety outcomes considered were adverse events on treatment.

Results

In total, 1,576 individuals underwent RT-PCR screening for SARS-CoV-2 infection during the study period. Positive test results were obtained for 591 subjects, 339 of whom met the inclusion criteria for this study. The final analysis included 339 subjects: 132 from the CVO+C arm and 144 from the placebo arm. Treatment efficacy differed significantly (p=0.011) between the CVO+C arm (87.1%, 95% CI: 81.3%-92.9%, with 70.45% of patients cured by day 14) and the placebo arm (75.0%, 95% CI: 67.8% - 82.1%), with an OR of 2.25.

The median time to recovery was 14 days for the CVO+C group and 21 days for the placebo group. A total of 72 incidences of mild and moderate adverse events, 14 severe adverse events and no serious adverse events were observed in both groups.

Conclusion

CVO+C was effective for the treatment of mild-to-moderate COVID-19. None of the patients in the CVO+C arm displayed progression to the severe form of COVID-19. Liver kidney and metabolic functions were preserved in all patients.

Trial registration:

Registered at Pan African Clinical Trials Registry: (No. PACTR202103601407640, date of approval: 24/03/2021) and approved by the ethics committee of the Ministry of Public Health of Madagascar (approval No. 216 MINSANP/SG/AGMED/CERBM, 17/12/2020)

CVO+Curatif

COVID-19

artemisinin

8 cineole

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), was first detected in Wuhan, China, in 2019 [1]. On July 11, 2020, the WHO officially declared the outbreak. The disease has continued to spread worldwide with a cumulative total of more than 186 million confirmed cases globally, and at least four million deaths. [2]

Several therapeutic agents have been evaluated for use in the treatment of COVID-19, but very few have been found to have positive clinical effects. Dexamethasone has been shown to be beneficial for patients on ventilators and to reduce mortality (25.7% in the usual care group vs. 22.9% in the dexamethasone group) [3]. Remdesivir has been reported to shorten recovery time (median of 10 days in the remdesivir group vs. 15 days in placebo group) [4]. Some studies have reported treatment with hydroxychloroquine to be effective, due to a significant decrease in viral load when used in combination with azithromycin [5], or a shortening of the time until the viral RNA becomes undetectable [6]. However, mortality remains high in patients on remdesivir, and the use of hydroxychloroquine is controversial. The identification of safe and effective treatments for COVID-19 therefore remains a matter of priority.

Artemisinin is the starting material for the latest antimalarial drugs (ACTs: Artemisinin Combined Therapies), which is obtained from a plant that has been used in traditional Chinese medicine for centuries: Artemisia annua L. [7]

In addition, artemisinin have been shown significant potential for cancer and antiviral therapy. [8] [9]

Artemisinin has been shown to have antiviral activity in vitro against SARS-CoV-2 in the monkey cell line Vero E6 [10], [11]. In silico studies have suggested that artemisinin interacts with the Lys353 and Lys31 binding hotspots of the SARS COV-2 spike protein [12]. It also has anti-inflammatory activities [13], [14]. The incidence of COVID-19 and COVID-19-related mortality rates have been reported to be very low in countries in which artemisinin is regularly used to treat malaria [15]. The combined antiviral and anti-inflammatory activities of artemisinin and its excellent safety profile in humans identify this drug as a potential candidate treatment for COVID-19 in patients. [14], [16]

Another molecule, 1,8-cineole, is a terpen oxide and is the major compound present in many essential oils mainly those extracted from Eucalyptus species and particularly in essential oil from leaves of Cinnamomum camphora L. grown in Madagascar. [17]–[20]. 1,8-cineole, also known as eucalyptol is often used in drug formulation for its expectorant and antitussive effects [21], [22]

1,8-cineole has been shown to inhibit the Mpro proteinase of SARS-CoV-2, which is required for the reproduction of the virus [23]. In vitro studies have highlighted the anti-inflammatory properties of 1.8-cineole, which inhibits the production of IL-1β (interleukin-1-beta) and TNF-α by acting on the NF-κB signaling pathway [24], and improves respiratory function when used to treat asthma or bronchial inflammation. [25]

CVO+C is a capsule formulation for oral administration containing Artemisia annua L. extract (150 mg artemisinin and specific flavonoid and terpenic fractions) and an essential oil from leaves of Cinnamomum camphora L. from Madagascar chemotype 1.8-cineole (7.1 mg 1,8-cineole).

To evaluate the clinical efficacy and safety of CVO+C as treatment for COVID-19, we conducted a, randomized placebo-controlled clinical trial in adult with COVID-19.

1.1 Study design

1.1.1 Study type

This study was a phase 3 randomized, double-blind clinical trial evaluating the efficacy and safety of CVO+C for the treatment of COVID-19.

1.1.2 Study site

The study was performed in the Analamanga region of Madagascar. Subjects were recruited from Voara village in Andohatapenaka, Antananarivo, Madagascar, and from three secondary healthcare centers in Antananarivo.

Follow-up was conducted at the health center of the CNARP (Centre National d’Application de Recherches Pharmaceutiques)

1.2 Patients

Subjects with positive RT-PCR test results for SARS-CoV-2 were asked to participate in the study. They were included if they met the inclusion criteria for the study: adult male or non-pregnant (checked with a pregnancy test) female patient capable of understanding the information given, providing written informed consent (including consent for the collection of oropharyngeal swabs and venous blood in accordance with the protocol), with laboratory-confirmed (RT-PCR on nasopharyngeal/throat swabs) SARS-CoV-2 infection. The illness could be of any duration, but the patients had to display infiltrates on radiological imaging (chest X ray or CT-scan) or clinical signs on examination (rales/crackles). Patients had to have a creatinine concentration ≤ 110 µmol/L, a creatinine clearance rate (EGFR) ≥ 60 mL/min /1.73 m², ASAT and ALAT levels no higher than five times the upper limit of the normal range (ULN), and TBIL levels no higher than twice the ULN. In addition, patients had to have a normal baseline ECG for inclusion in this study, and ECG results had to remain normal throughout the study.

Patients were excluded if their ALAT/ASAT levels were more than five times the ULN, if they were pregnant or breast-feeding, had severe (stage 4) chronic kidney disease or required dialysis (eGFR<30), were expected to be transferred to another non-participating hospital site within 72 hours, were allergic to any of the study drugs, had shortness of breath, known prolonged QT syndrome or were using other drugs known to prolong the QT/QTc interval. We also excluded patients with other types of viral pneumonia

1.3 Randomization and blinding

The patients were randomly assigned to double-blind treatment or placebo, in a 1:1 ratio. One of the investigators provided code following simple randomization procedures using a computer-generated randomization. The code was kept by the study pharmacist, who provided participants medication for 15 days. Patients and physicians kept blinded to the allocation.

1.4 Study medication

The patients were randomized to two arms. The patients in the treatment arm received CVO+C (Pharmalagasy, batch no. 1923-001) for oral administration, and were required to take three capsules per day for 15 days. The patients in the control arm received a placebo (Pharmalagasy, beta cyclodextrin and magnesium stearate, batch no. 1919-001) under the same conditions (3 capsules per day for 15 days) as the study treatment. The study treatment and the placebo were identical in physical appearance and taste.

1.5 Follow-up

The patients enrolled in the study were required to attend follow-up visits on days 7, 14, 21 and 28. At each visit, any adverse events or serious adverse events were recorded, viral load was determined (CT method for the ORF1ab and N genes of thevirus), and clinical, hematological and biological parameters (liver and kidney function) were assessed.

1.6 Outcomes

The primary outcome was the proportion of patients with complete clearance of SARS-CoV-2 virus from oropharyngeal samples on day 28 and an absence of severe and serious adverse events. The secondary outcomes were recovery time, hematological parameters (leukocytes, lymphocytes and ESR), biomarkers of liver function (ASAT and ALAT), renal function (creatinine levels) and blood sugar levels on days 7, 14, 21 and 28. Safety outcomes included adverse events occurring during treatment, serious adverse events, and premature discontinuation of treatment. Treatment was stopped early if a severe or serious adverse event occurred. The participant received the official standard of care.

1.7 Statistical analysis

1.7.1 Required sample size

Assuming a treatment efficacy of 40% for the placebo arm and 60% for the CVO+C arm, with equal numbers of patients assigned to each arm, a margin of error of 0.03, a power of 80% and an alpha risk of 5%, we would need to include 306 patients, with 153 patients per arm, to detect a significant difference between the two arms. Assuming an attrition rate of 10% due to deaths and withdrawals from the study, a total sample size of 338 patients would be required.

1.7.2 Statistical analyses

A per-protocol analysis was performed, by the endpoint analysis method. For quantitative endpoints and dichotomous qualitative endpoints measured at regular intervals, the last known values were used if the subjects were lost to follow-up. The criteria for treatment efficacy were a negative RT-PCR test for SARS-CoV-2 at the end of the study, with no adverse events or with only mild (grade 1) or moderate (grade 2) adverse events.

Regardless of the RT-PCR result at the end of the study (positive or negative), treatment was considered to have failed if the patient died, displayed serious adverse events (grade 3 or 4), was hospitalized with or without oxygenotherapy (via a mask, nasal prongs, high-flow oxygen treatment, intubation and mechanical ventilation with or without additional organ support, such as renal replacement therapy, or extracorporeal membrane oxygenation) or had been released from hospital but was unable to perform everyday activities normally.

Adverse events were considered mild (grade 1) if they were transient, required little or no treatment and did not interfere with everyday activities. They were considered moderate (grade 2) if they interfered with everyday activities, causing discomfort but no significant or permanent risk of harm to the subject, and were alleviated by additional treatment.

Two grades of serious adverse events were considered. Grade 3 severe adverse events were defined as events disrupting everyday activities or significantly affecting clinical status, generally incapacitating the subject and possibly requiring intensive treatment interventions. Grade 4 serious adverse events were defined as potentially life - threatening.

Qualitative variables are expressed as percentages or composition ratios for descriptive statistical analysis. They were analyzed with c² tests, Fisher’s exact tests and Wilcoxon Mann-Whitney tests. Quantitative variables are expressed as medians and interquartile range. Normally distributed quantitative variables were analyzed with t-tests, whereas Wilcoxon rank-sum tests were used to compare the two groups for non-normally distributed variables. All tests were one-tailed, and a p-value < 0.05 was considered significant. The odds ratio (OR) corresponding 95% confidence intervals (CI) were calculated in patients treated with CVO+C compared with placebo. The overall probability of conversion to negativity for RT-PCR tests was estimated by determining the time taken for viral RNA levels to become undetectable. This analysis was performed by the Kaplan-Meier method, with log-rank tests used for comparisons.

2.1 Patients

Between January 18, 2021, and May 4, 2021, 1,576 underwent RT-PCR tests for SARS-CoV-2. The eligibility criteria were checked for the 591 patients who tested positive. We included 339 patients, 276 of whom were included in the final analysis. There were 132 patients in the CVO+C group and 144 in the placebo group (Figure 1). Baseline characteristics of the groups are presented in Table 1. The two groups of patients presented no significant differences in terms of sociodemographic, clinical, or biological characteristics at the start of the study.

2.2 Outcomes

2.2.1 Primary outcome

Treatment success rates were significantly higher for the CVO+C group than for the control group (CVO+C: 87.1% [95% CI 81.3% - 92.9%], control: 75.0% [95% CI 67.8% – 82.1%]; p= 0.011), with an odds ratio of 2.25 [95% CI 1.19 – 4.24] (table 2).

Treatment failure

Treatment failure was observed in 53 patients, but there were no deaths during the study period. Treatment failure was virological in 39 patients: 11 patients from the CVO+C group and 28 patients from the placebo group. No cases of biological treatment failure were reported. Clinical treatment failure was reported in 14 patients who experienced severe adverse event and stopped treatment early (6 patients in the CVO+C group and 8 patients in the placebo group).

Secondary outcomes

The percentages of patients for whom SARS-CoV-2 was undetectable on days 7, 14, 21, and 28 differed significantly (p<0.0001, log-rank test) between the CVO+C group (42.42%, 70,45%, 76.52%, and 89.39%, respectively) and the control group (27.08%, 39.85%, 40.97%, 56.94%, and 77.78%, respectively) (figure2). Median recovery time was 14 days for the CVO+C group and 21 days for the control group.

Leukocyte and lymphocyte levels were normal throughout the study in most patients and there was no clear difference between the groups. Median ESR was above normal values in both groups, and appeared to be slightly higher in the control group.

In general, aminotransferase levels increased at D7, gradually decreasing thereafter to reach normal values by D28. A similar pattern of change in aminotransferase levels was observed in both groups. Blood sugar and creatinine levels were normal in most patients, with no marked differences between groups. (Table 3)

Drug safety

Adverse events

Safety analysis

A total of 72 incidences of mild and moderate adverse events, 14 severe adverse events and no serious adverse events were observed in both groups. Some patients experienced more than one adverse event (range: 1 to 4). Generally, the frequency was higher among placebo recipients than among CVO+C recipients (29,1% vs. 22.7%), with similar frequencies of severe adverse events (5.6% vs. 4.6%),

The percentages of patients experiencing adverse events on days 7, 14, 21, and 28 were 12.9%, 5.3%, 1.5% and 3.0%, respectively, for the CVO+C group, and 9.7%, 7.6%, 8.3%, and 3.5%, respectively, for the placebo group.

The mild and moderate adverse events observed included somatic, pulmonary, neurological, muscular, digestive and cutaneous events. Digestive adverse events were the most frequently reported (30 incidences, 12 in CVO+C and in placebo)

Adverse events resolved progressively after the end of treatment.

Severe adverse events led to the discontinuation of treatment. Severe asthenia was reported in two participants in CVO+C group. Dyspnoea was reported in four participants with 2 in CVO+C group and 2 in control group. Cardiac disturbance was reported with three participants in the control group. Digestive severe adverse events were reported in three patients with 1 placebo and 2 in CVO+C group. And two patients in placebo group progressed in severe form. None of the patients in the CVO+C group presented progression to the severe form of COVID-19.

Treatment for 15 days with CVO+C capsules resulted in a significantly higher rate of treatment success, and a shorter time to undetectable levels of SARS-CoV-2 than were observed for the placebo. No serious (grade 3 or 4) adverse reactions were observed. No laboratory abnormalities suggestive of drug-related systemic or organ-specific toxicity were observed in the CVO+C group. The CVO+C capsules were therefore considered to have a satisfactory safety profile. None of the patients treated with CVO+C displayed progression to severe COVID-19.

The clinical manifestations of confirmed COVID-19 are highly variable, ranging from asymptomatic infection to severe respiratory distress, and some patients have a high risk of death [26]. No specific treatment for SARS-CoV-2 infection has yet been available. Patient management is therefore based essentially on the treatment of symptoms and supportive care [27].

In patients progressing to severe COVID-19, clinical deterioration results largely from a cytokine release syndrome (CRS) [28], [29] induced by several pro-inflammatory cytokines, including interleukin-6 (IL6), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) [30], [31].

Many studies have described the anti-inflammatory and immunomodulatory effects of artemisinin and its derivatives, which, by inhibiting the pro-inflammatory nuclear factor kappa B (NF-κB) signalling pathway, decrease TNF-α and IL-6 levels and attenuate signalling via the Smad2/3-dependent TGF-β pathway. [32]–[34]

Studies in vitro and ex vivo have also shown 1.8-cineole to have immunomodulatory properties, reducing the release of pro-inflammatory cytokines from monocytes and macrophages. [25], [35]

The tea version of CVO (Covid Organics) was first introduced in Madagascar at the onset of the Covid-19 outbreak [36]. Perter Seeberger’s research team at German based Max Planck Institute showed in vitro efficacy of Covid Organics against SARS CoV-2 with an EC₅₀ of 7.73% and a selectivity index of 5.28 [37]. This first step led to the development of CVO+C formulations. Compared to the initial tea-based version of CVO, CVO+C is based on standardized formulations of Artemisinin and 1,8-cineole with much higher percentages of active compounds.

The anti-inflammatory and immunomodulatory activities of artemisinin and 1.8-cineole may have contributed to the faster recovery of patients in the CVO+C group. Treatments reducing the release or activity of pro-inflammatory mediators might also be able to prevent or reverse the cytokine storm, thereby improving the condition of patients who would otherwise progress to severe COVID-19, but this remains to be demonstrated for CVO+C. Mild, moderate and severe adverse events occurred in this study are similar to the symptoms and the signs of the Covid-19. Digestive symptoms were reported as the third symptom after fever and cough [38]–[40]. Asthenia and dyspnoea are cited among the specific signs to the Covid-19 in hospitalized patients. [41]. Nevertheless, for ethical reasons and for the security of the patients, treatment of the 14 participants who developed severe adverse events was stopped.

These adverse events may be unrelated to the treatment but this remains to be confirmed with a larger scale study.

Our findings indicate that CVO+C capsules are safe and could be recommended for patients with mild-to-moderate COVID-19. However, this study has several limitations.

The main limitation was the poor knowledge about the disease. The study was conducted a year into the pandemic. Despite efforts and scientific advances, the state of the medical knowledge of the COVID-19 still limited. [42], [43]

In addition, we recruited 339 participants but we lost more than expected (18.58%) and 276 were included to the final analysis (instead of 306) and because of the urgent circumstances in which the study was done, we ended the study.

Furthermore, the study was facing a lack of funding. We had planned to perform CT scan, variant searches and immunological studies for more comprehension of the primary outcomes.

In summary, the efficacy of CVO+C for the treatment of non-severe COVID-19 was 87.1% [CI: 95%: 81.3% - 92.9%] and 70.45% of the patients were cured by day 14. None of the patients treated with CVO+C progressed to the severe form and all patients had preserved liver, kidney and metabolic functions. In light of the efficacy and safety profiles of CVO+C capsules in this study, this treatment could be considered for patients with mild-to-moderate COVID-19.

Ethics approval and consent to participate

This trial is registered with the Pan African Clinical Trials Registry (No. PACTR202103601407640, date of approval: 24/03/2021) and was approved by the ethics committee of the Ministry of Public Health of Madagascar (approval no. 216 MINSANP/SG/AGMED/CERBM, 17/12/2020). The trial was conducted in accordance with the Declaration of Helsinki and all methods were performed in accordance with the relevant guidelines and regulations.

Informed consent was obtained from the subjects studied for all tests and treatments.

Consent for publication

All authors have agreed to the submission of this manuscript for publication.

Availability of data and materials

The data are available from the Centre National d’ Application de Recherches Pharmaceutiques.

Competing interests

The authors declare that they have no other conflict of interest.

Funding

This work was supported by Pharmalagasy, the Ministry of Health, Ministry of High-Level Education and Scientific Research and the World Health Organization (WHO).

Authors' contributions

R.R, O.R,Ar.Rat have made major contributions in writing the manuscript

S.M, An.R, Ar.Rav, F.M analyzed and interpreted the patient data

M.A, E.R, Fe.R performed the biological examination,

Ra.R, Z.R, Riv.R, Ar.Rat supervised and revised the article

Acknowledgments

We thank the World Health Organization (WHO) for logistics and technical advices and Bionexx who along with Pharmalagasy and CNARP developed the CVO+ C formulation.

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Table1

Socio-demographic and clinical characteristics of the patients at baseline

Variables	Placebo	CVO+ C	p-value
Age (years) median (IQR)	34.3 (27.3 – 43.2)	34.4 (28.8 – 42.0)	0.9^a
Sex
Male	76 (52.8)	79 (59.9)	0.2^b
Female	68 (47.2)	53 (40.1)	0.2^b
Sex-ratio	1.1	1.4
General signs
FR med (IQR)	19 (18 - 22)	19 (18 – 22)	0.4^a
FC med (IQR)	78 (70 – 89)	78 (69 – 87)	0.6^a
TAS med (IQR)	110 (100 – 120)	110 (100 – 120)	0.3^c
TAD med (IQR)	70 (60 – 80)	70 (60 – 80)	0.2^c
*Clinical signs*
Dyspnea	8 (5.6)	10 (7.6)	0.4^b
Fever	29 (20.1)	31 (23.5)	0.5^b
Cough	70 (48.6)	50 (37.9)	0.07^b
Asthenia	67 (46.5)	53 (40.1)	0.2^b
Aching	42 (29.8)	41 (31.0)	0.7^b
Odynophagia	9 (6.2)	5 (3.8)	0.3^b
Chest pain	21 (14.6)	25 (18.9)	0.3^b
Diarrhea	12 (8.3)	14 (10.6)	0.5^b
Agueusia	37 (25.7)	21 (15.9)	0.04^b
Anosmia	59 (40.9)	43 (32.6)	0.1^b

^a: Wilcoxon test (Mann-Whitney) ; ^b: Chi²test ; ^c: Student’s test

Table 2

Treatment efficacy

Group	Success		Failure	Total	p-value*
Group	n (%)	95% CI	n (%)	N (%)	p-value*
Placebo	108 (75.0)	67.8 – 82.1	36 (25.0)	144 (100.0)	0.011
CVO+C	115 (87.1)	81.3 - 92.9	17 (12.9)	132 (100.0)	0.011
Total	223 (80.8)	77.1 – 86.2	53 (19.2)	276 (100.0)

Table 3

Change in hematology, biochemical markers of liver and renal functions over time

	Placebo					CVO+C
Biological Parameters	D0	D7	D14	D21	D28	D0	D7	D14	D21	D28
Hematology
Leukocytes (g/L)
Mean ± SD	3.5 ± 3.9	3.0 ± 1.3	2.7 ± 1.2	2.8 ± 1.2	2.8 ± 1.4	3.0 ±1.3	3.5 ± 1.6	3.2 ± 1.6	3.3 ± 2.7	3.0 ± 1.5
Median	3.1	2.8	2.6	2.6	2.5	3.1	3.2	2.7	2.8	2.7
Q1 – Q3	2.1 – 3.7	2.0 – 3.8	2.0 – 3.3	2.1 – 3.3	1.8 – 3.5	1.7 – 3.9	2.2 – 5.1	2.0 – 3.9	1.9 – 3.7	1.9 – 3.7
Reference Range	2.0 – 7.5	2.0 – 7.5	2.0 – 7.5	2.0 – 7.5	2.0 – 7.5	2.0 – 7.5	2.0 – 7.5	2.0 – 7.5	2.0 – 7.5	2.0 – 7.5
Lymphocytes (g/L)
Mean ± SD	1.9 ± 0.5	1.6 ± 0.5	1.8 ± 0.7	1.8 ± 0.4	1.6 ± 0.4	1.9 ± 0.6	1.8 ± 0.6	1.8 ± 0.7	1.7 ± 0.6	1.9 ± 0.5
Median	1.8	1.5	1.6	1.7	1.6	1.9	1.6	1.6	1.6	1.8
Q1 – Q3	1.5 – 2.3	1.1 – 2.0	1.5 – 1.8	1.5 – 2.0	1.4 – 1.9	1.3 – 2.4	1.4 – 2.3	1.3 – 2.1	1.3 – 2.0	1.6 – 2.0
Reference Range	1.0 – 4.8	1.0 – 4.8	1.0 – 4.8	1.0 – 4.8	1.0 – 4.8	1.0 – 4.8	1.0 – 4.8	1.0 – 4.8	1.0 – 4.8	1.0 – 4.8
Erythrocyte sedimentation (mm)
Mean ± SD	27.2 ± 26.1	22.5 ± 19.5	19.1 ± 18.1	27.0 ± 25.6	28.6 ± 27.3	23.0 ± 23.4	15.8 ± 13.0	19.8 ± 20.8	17.2 ± 15.1	20.6 ± 30.5
Median	21	18	13.5	20	24	12	10	11.5	13.5	11
Q1 – Q3	10 – 33	10 – 27	6 – 28	10 – 33	10 – 38	4.5 – 28.5	8 – 20	5.5 – 29	5 – 25	5 – 23
Reference Range	<10	<10	<10	<10	<10	<10	<10	<10	<10	<10
Hepatic function
Aspartate aminotransferase (U/L)
Mean ± SD	44.6 ± 18.6	41.9 ± 17.0	40.1 ± 14.1	38.6 ± 14.1	39.9 ± 14.9	44.3 ± 15.7	42.6 ± 17.6	45.9 ± 22.1	44.9 ± 18.9	39.6 ± 13.7
Median	40	41	38	35	35	41	40	42.5	42	37
Q1 – Q3	32 – 52	31 – 50	31 – 47.5	30 – 44	31 – 45	35 – 51	33 – 50	34 – 50	35 – 50	31 – 45
Reference Range	<40	<40	<40	<40	<40	<40	<40	<40	<40	<40
Alanine aminotransferase (U/L)
Mean ± SD	31.5 ± 24.9	32.7 ± 27.3	32.1 ± 27.8	27.6 ± 20.8	26.4 ± 19.1	30.7 ± 28.4	27.6 ± 15.5	32.1 ± 23.9	26.3 ± 18.1	22.9 ± 18.1
Median	23.5	25	22	20.5	20	24	24	24	21	17
Q1 – Q3	17 – 39	17 – 37	14 – 40	13.5 – 35.5	14 – 31	16 – 32	16 – 34	18 – 38	17 – 29	14 – 26
Reference Range	<40	<40	<40	<40	<40	<40	<40	<40	<40	<40
Kydney function
Creatininemia for man (µmol/L)
Mean ± SD	93.9 ± 15.1	92.1 ± 15.1	91.9 ± 16.6	91.0 ± 14.9	90.4 ± 13.8	97.3 ± 21.1	93.8 ± 13.7	92.0 ± 16.0	88.5 ± 11.8	92.1 ± 12.7
Median	90	92	90	89	92	97	93	91	87	91
Q1 – Q3	85 – 103	79.5 – 103	82 – 99	82 – 100	82.5 – 100	82.5 – 107.5	85 – 103	80 – 101	80 – 98	82 – 100
Reference Range	53 – 115	53 – 115	53 – 115	53 – 115	53 – 115	53 – 115	53 – 115	53 – 115	53 – 115	53 – 115
Creatininemia for woman (µmol/L)
Mean ± SD	74.4 ± 16.1	75.6 ± 14.1	74.8 ± 15.7	72.9 ± 12.0	74.5 ± 12.4	78.3 ± 13.1	73.9 ± 15.5	73.9 ± 15.5	72.7 ± 12.3	71.6 ± 10.6
Median	70.5	75	72	72.5	72.5	78	79.5	69	69.5	67
Q1 – Q3	63 – 80.5	65 – 86	64 – 81	64 – 80	65 – 83	69 – 89	67 – 87.5	62 – 82	64 – 78	64 – 77
Reference Range	44 – 105	44 – 105	44 – 105	44 – 105	44 – 105	44 – 105	44 – 105	44 – 105	44 – 105	44 – 105
Glycemia (mmol/L)
Mean ± SD	5.1 ± 0.8	5.4 ± 0.9	5.2 ± 1.0	5.3 ± 0.9	5.1 ± 1.0	4.9 ± 0.8	5.1 ± 0.9	5.4 ± 0.9	5.4 ± 0.8	5.2 ± 0.8
Median	5.1	5.2	5.2	5.1	5.1	4.9	5.2	5.3	5.3	5.1
Q1 – Q3	4.6 – 5.6	4.7 – 5.9	4.7 – 5.8	4.7 – 5.5	4.5 – 5.4	4.5 – 5.4	4.6 – 5.7	4.9 – 5.8	4.9 – 5.8	4.8 – 5.5
Reference Range	4.10 – 5.90	4.10 – 5.90	4.10 – 5.90	4.10 – 5.90	4.10 – 5.90	4.10 – 5.90	4.10 – 5.90	4.10 – 5.90	4.10 – 5.90	4.10 – 5.90

No competing interests reported.

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Efficacy and safety of CVO PLUS CURATIF capsules, Malagasy improved traditional medication for treating COVID-19 a randomized, double-blind, placebo-controlled trial

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Abstract

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Background

Methods

1.1 Study design

1.1.1 Study type

1.1.2 Study site

1.2 Patients

1.3 Randomization and blinding

1.4 Study medication

1.5 Follow-up

1.6 Outcomes

1.7 Statistical analysis

1.7.1 Required sample size

1.7.2 Statistical analyses

Results

2.1 Patients

2.2 Outcomes

2.2.1 Primary outcome

Treatment failure

Secondary outcomes

Drug safety

Adverse events

Safety analysis

Discussion

Conclusion

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Competing interests

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