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CVO+.pdf

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Randomized clinical trial, phase 3, to evaluate the efficacy of
CVO + versus placebo for the treatment of COVID-
19.
Promo...

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1. Context and justification
2. Purpose of the trial
3. Methods
 Desing and setting of study
 Study schema
 Population:...

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3
SRAS-COV-2 infection
Context
Research stage
Retrieved june, 21,2021

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CVO+.pdf

  1. 1. Randomized clinical trial, phase 3, to evaluate the efficacy of CVO + versus placebo for the treatment of COVID- 19. Promotor Pharmalagasy PI RAKOTO Alson Olivat, Pofessor RAKOTOSAONA Rianasoambolanoro, PhD, HDR Scientifc responsible RATSIMBASOA Claude Arsène, MD,PhD,HDR Technical collaborators Ministry of Public Health WHO Madagascar INSTAT home ppt
  2. 2. 1. Context and justification 2. Purpose of the trial 3. Methods  Desing and setting of study  Study schema  Population: list inclusion criteria  Allocation to intervention  Conduct of the study  Outcomes  Statistical analysis  Adverse effect  Ethics approval  Chronogram 4. Results 2 home ppt Plan
  3. 3. 3 SRAS-COV-2 infection Context Research stage Retrieved june, 21,2021
  4. 4. 4 SRAS-COV-2 infection • Non-curative treatment without there being reasonable • Vaccine effective at preventing severe forms of diseases , not for the treatment • Madagascar (2020):  Randomized clinical trial, phase 2, to evaluate the efficacy of Artesunate IV alone or combined with vitamin C IV for the treatment of COVID-19.  CERBM ID n° : 073 MINSANP/SG/AGMED/CERBM  PACTR ID n° : PACTR20210399597082  Promoter: Malagasy governement Context « . This study demonstrates the efficacy of artesunate IV alone. Howether, this study is limited, the requested analysis was not performed because of insufficient sample. Interventions recommended for large-scale deployment .
  5. 5. 5 home ppt Assumption • Disavantages of Artesunate IV:  Injectable form,  Number of days of treatment : 7 days,  Clinical surveillance +++ BUT • Artésunate IV group alone demonstrated progressive decrease of viral load median and result becomes negative at day 14. • Viral load increases at day 21 and decreases at day 28. The increase on day 21 suggests that the duration of treatment is not sufficient. ENDEED • Assumption : Treatment duration should be prolonged and a new galenic formulation (eg oral) would be more appropriate for a better therapeutic response. Context
  6. 6. 6 home ppt Evidence base • Rapidly metabolized to DHA in the liver with involvement of cytochrome P450 • Rapid but incomplete absorbtion (low aqueous solubility) • Low and variable bioavailability by the oral administration . The use of betacyclodextrins as an excipient increases the stability and solubility and therefore the bioavailability of artemisinin. • Rapidly metabolized to DHA in the liver with involvement of cytochrome P450 • Rapid absorbtion • High biovalability Artemisinin Artesunate Context ) )
  7. 7. 7 Therapeutic potentiel of CVO + Antiviral : • interactions with Lys353 and Lys31 binding hotspots of SARS COV-2 spike protein. (1). • SARS COV-2 protease inhibitor (2) • Anti-SARS COV-2 in vitro (Vero E6 cells) (3) anti-inflammatory Inhibits IL-1β production. IL-6. by inhibition of the NF- κB signaling pathway. IL-10 (1) Sehailia. M. et al.. Journal of Biomolecular Structure and Dynamics 2020. 1–11. (2) Banerjee. R.; et al.. Drug Discovery Today 2020. (3) CAO. et al ACS Infectious Diseases. 2020. Vol. 6. n° 9. pp. 2524-2531 (4) KSHIRSAGAR. Suhas G. et RAO. Rammohan 2021. vol. 57. no 3. p. 217. Antiviral : • SARS inhibitor COV-2 proteinase Mpro necessary for its reproduction (6) Anti-inflammatory • Inhibits IL-1β.TNF-α production (7) • Improves respiratory function tests. anti-asthma and anti-bronchial inflammatory (6) SHARMA. Arun D. et al. Notulae Scientia Biologicae. 2020. Vol. 12. n° 3. pp. 536-545. (7) FEUILLET. Vincent et Al. Trends in Immunology. 2021. Vol. 42. n° 1. pp. 31-44. Context )
  8. 8. Composition Quantity Artemisia annua extract dosed with Artemisinin 150 mg Flavonoïd extract 3.3 mg Terpenic extract 4 mg Essential oil of Cinnamomum camphora dosed with 1.8 cineol (eucalyptol) 7.1 mg Excipients Beta cyclodextrine and magnesium stearate Qsp Pharmaceutical form : capsule 8
  9. 9. 9 CONTEXT Objective To assess the efficacy of curative CVO + in significantly reducing or completely eliminating the SARS-CoV-2 virus in Oro-pharyngeal samples Based on WHO/AFRO’s master protocol
  10. 10. 10 home ppt Methods • Study area: Analamanga region • recruitment site: Voara village. CSB 2 Antananarivo Renivohitra • Follow up : CNARP • Type of study: quasi experimental study .exposed vs unexposed CVO+ curative Placebo Random allocation sick Not sick Sick Before test Before test After test After test Effect or impact measure Not sick Subject group
  11. 11. 11 home ppt Methods • Placebo effect+++ CVO+ curative Placebo Spontaneous evolution Spontaneous evolution Pharmacological Effet Initial effect Initial effect Treatement effect Treatement effect Final state Final state Placebo effect Medical doctor Environment Patient personality Avalaibility of treatement Comprehensive treatement progam
  12. 12. 12 home ppt Methods • Treatment assignment method:  randomized  In double blind • Clinical question: P I C O Patient. population or population? Patient infected with COVID-19: moderate form. Comparaison Placebo. Outcome Significant reduction or complete elimination of SARS-CoV-2 in Oro-pharyngeal samples « End-point analysis ». Intervention CVO plus curatif. Intervention Placebo Dose 150 mg 3 times per day 3 capsules per day duration 15 days 15 days Description Artemisinine + cineol capsules like intervention without active substance
  13. 13. 13 home ppt Inclusion criteria  Participant (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.  Understands and agrees to comply with planned study procedures.  Agrees to the collection of OP swabs and venous blood per protocol.  Male or non-pregnant female (pregnancy test) adult ≥18 years of age at time of enrolment.  Laboratory-confirmed SARS-CoV-2 infection as determined by PCR at a Government approved lab. from throat/nasopharyngeal swab.  Illness of any duration, and at least one of the following:  Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), or  Clinical assessment (evidence of rales/crackles on exam) or  Requiring mechanical ventilation and/or supplemental oxygen.  Creatinine ≤ 110 µmol/L, creatinine clearance rate (EGFR) ≥ 60 ml / min / 1.73m2, AST and ALT ≤ 5 × ULN, TBIL ≤ 2 × ULN;  A Normal ECG Baseline result, which is maintained throughout the study. Methods
  14. 14. 14 home ppt Exclusion criteria Participants with the following conditions will be excluded from the study:  ALT/AST > 5 times the upper limit of normal.  Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR < 30)  Pregnancy or breast feeding.  Anticipated transfer to another hospital which is not a study site within 72 hours.  Allergy to any study medication  Shortness of breath  Known prolonged QT syndrome  Use of concomitant medications that prolong the QT/QTc interval  Subject with other viral pneumonia  Participants with allergies to artemisinin containing products  History of allergic reactions to any investigational medical product ingredient  Participants who in the opinion of the investigators after assessing all relevant parameters are unsuitable for the study. Methods
  15. 15. 15 Conduct of the study Pre- inclusion Day 0 Day 7 Day 14 Day 21 Day 28 Consent x inclusions/exclusion criteria x x Medical history x Physical check-up x x x x x Vital signs x x x x x Laboratory analysis x x x x x x Concomitant treatments x x x x x Adverse events x x x x Randomization x Methods
  16. 16. 16 Endpoint • Primary endpoint: Significant reduction or complete clearance of SARS-CoV-2 virus in the OP samples on Day 28 and absence of serious adverse events.« endpoint analysis » • Secondary endpoint: Recovery time, time to clinical improvement, duration of hospitalization, date and cause of death (if applicable), grade 3 and 4 adverse events, SAEs, white cell count, hemoglobin, platelets, creatinine, glucose, total bilirubin, ALT, and AST on days 7,14, 21 and 28. Methods
  17. 17. 17 Data collection tools • Monitoring: RCF • Data Management  Data centralization: encrypted server  Computerization - Data entry: • Analysis of biological data in collaboration with : Confidentiality clause ++++ Methods
  18. 18. 18 Statistical considerations • Sample size calculation  Level of confidentiality : 95%  Level of Confidentiality = 95%  Error of Margin = 0.03  Ratio N2/N1=1  N = 397,942  Treatment efficacy hypothesis : Superior efficacy for the CVO+ arm  For Placebo arm with standard care=40%  For CVO+ arm=60%  N=306 with 153 patient per group  Addition of 10% for deaths and withdrawals brings total sample size to 338. Methods
  19. 19. 19 Statistical considerations • Frequency of statistical analyses: no intermediate analyses • Analysis strategies  Intent-to-treat analysis  Consideration of protocol deviations  Consideration of missing data • Statistical methods and software used: • Analysis plan and statistical analysis in collaboration with • Description of inclusions and follow-ups • Characteristics of the patients included in the analysis • Description of the analysis methods for the primary and secondary Methods
  20. 20. 20 Tolerance • Definitions of an adverse event (AE) and a serious adverse event (SAE) • Fatality; A life-threatening AE; • Hospitalization or extension of an existing hospitalization; • Persistent or significant disability or substantial impairment of the ability to carry out normal life functions; • Birth defect/congenital malformation; • Significant medical events that may not result in death but life-threatening. when based on appropriate medical judgment • Follow-up of Adverse Events Methods
  21. 21. 21 Ethical and regulatory considerations • Respect for good clinical practices • Submission to the Ethics Committee :  CERBM ID n°: 216 MINSANP/SG/AGMED/CERBM  PACTR ID n°: PACTR 20210601407640 • Informed consent: voluntary participation. right to withdraw at any time during the study • Data confidentiality: anonymity. data security • Storage of biological materials: at the laboratory level • Storage of research documents: CNARP • No compensation to subjects Methods
  22. 22. 22 Chronogram • Approval request CERBM : December 2020 • Start of recruitment: January 18, 2021 • End of inclusion: May 4, 2021 (N=339) • End of data entry: June 7, 2021 • Data cleaning, analysis: Beginning of June 2021 • Data validation by the scientific committee: June 21, 2021 • Final report CERBM : June 22, 2021 Methods
  23. 23. 23 Méthodes Results
  24. 24. 24 Flowshart of the study Méthodes PCR Tests 1 576 included 339 Placebo 157 Placebo 144 withdrew 3 Lost to follow-up 8 CURATIVE CVO+ 161 CURATIVE CVO+ 132 withdrew 8 Lost to follow-up 6 Incomplete information at D0 21 Withdrew consent 252 PCR-negatives 985 Assessed for eligibility N=591 Randomized N=318 Analyzed N=276 57.3% Results
  25. 25. 25 Méthodes • Baseline characteristics of patients variables Placebo CVO+ CURATIVE p-value Age median (IQR) 34.3 (27.3 – 43.2) 34.4 (28.8 – 42.0) 0.9a gender Male 76 (52.8) 79 (59.9) 0.2b Female 68 (47.2) 53 (40.1) Sex-ratio 1.1 1.4 Signes généraux FR med (IQR) 19 (18 - 22) 19 (18 – 22) 0.4a FC med (IQR) 78 (70 – 89) 78 (69 – 87) 0.6a TAS med (IQR) 110 (100 – 120) 110 (100 – 120) 0.3c TAD med (IQR) 70 (60 – 80) 70 (60 – 80) 0.2c Results a: Wilcoxon test (Mann-Whitney) b: Chi2 test c: Student test Patients features
  26. 26. 26 Patients features Méthodes variables Placebo n (%) CVO+ CURATIF n (%) p-valuea Dyspnea 8 (5.6) 10 (7.6) 0.4 fever 29 (20.1) 31 (23.5) 0.5 cough 70 (48.6) 50 (37.9) 0.07 Asthenia 67 (46.5) 53 (40.1) 0.2 Aching 42 (29.8) 41 (31.0) 0.7 Odynophagia 9 (6.2) 5 (3.8) 0.3 Chest pain 21 (14.6) 25 (18.9) 0.3 Diarrhea 12 (8.3) 14 (10.6) 0.5 Agueusia 37 (25.7) 21 (15.9) 0.04 Anosmia 59 (40.9) 43 (32.6) 0.1 Résultats a: Chi2 test • Initial vital signs (D0)
  27. 27. 27 Méthodes variables Placebo Median (IQR) CVO+ CURATIVE Median (IQR) p-valuea Référence values Hematology Leukocytes 3.0 (2.1 – 3.7) 3.1 (1.6 – 3.9) 0.9 2.0 – 7.5 g/L Lymphocyte 1.8 (1.5 – 2.3) 1.8 (1.3 – 2.3) 0.6 1.0 – 4.8 g/L ESR 21 (10 – 33) 12 (4.5 – 28.5) 0.2 <10 mm Liver function AST 40 (32 – 52) 41 (35 – 52) 0.4 < 40 U/L ALT 24.5 (17 – 41) 25 (16 – 35) 0.8 < 40 U/L Renal function Creatinine levels 71 (63 – 81) 90.5 (83.5 – 101.5) 78 (69 – 89) 94 (82 – 106) 0.06 0.4 Female 44-105 µmol/L Male 53-115 µmol/L blood sugar levels 5.1 (4.7 – 5.9) 5.1 (4.6 – 5.5) 0.2 4.10 – 5.90 mmol/L Résultats a: Wilcoxon test (Mann-Whitney) Patients features • Initial laboratory data
  28. 28. 28 Therapeutic efficacy Méthodes • Therapeutic efficacy « End-point analysis » group Success Failure Total p-value* n (%) 95% CI n (%) N (%) Placebo 108 (75.0) 67.8 – 82.1 36 (25.0) 144 (100.0) 0.011 CVO+ CURATIVE 115 (87.1) 81.3 - 92.9 17 (12.9) 132 (100.0) Global 223 (80.8) 77.1 – 86.2 53 (19.2) 276 (100.0) * chi2 test Significant difference between Placebo and CVO+ CURATIVE, with p= 0.011 and with RR 2.25, the chance of recovery is 2.25 times higher with CVO+ CURATIVE versus Placebo Relative Risk [CI à 95% ] = 2.25 [1.19 – 4.24] , p=0.001 Results
  29. 29. 29 Méthodes • Therapeutic efficacy per follow-up day Results N Placebo n (%) CVO+ CURATIF n (%) p-value* Risk difference Recover Total recover Total M-H; [95% CI] D7 253 84 (65.1) 129 82 (66.1) 124 0.865 -0.01 [-0.12; 0.10] D14 255 95 (73.6) 129 116 (92.1) 126 <0.001 -0.18 [-0.27 ; -0.09] D21 233 94 (77.7) 121 99 (88.4) 112 0.030 -0.10 [-0.20; -0.01] D28 227 94 (79.6) 118 98 (89.9) 109 0.033 - 0.10 [-0.19 ; -0.01] At D14 there were 18 more times ( p<0.001) successes in the CVO plus curative group versus the placebo group ... Therapeutic efficacy
  30. 30. 30 Survival analysis Méthodes • Kaplan-Meier estimator N Median Placebo 144 21 CVO+ CURATIF 132 14 Global 276 14 • Recovery time Results CVO+ CURATIVE: rapid recovery rate compared to placebo; 70.45% of patients recovered by day 14
  31. 31. 31 Serious adverse events • Therapeutic faliure : withdrew by medical decision Withdrew by medical decision YES n (%) No n (%) Total Placebo 8 (5.6) 136 (94.4) 144 (100) CVO+ CURATIF 6 (4.6) 126 (95.4) 132 (100) Global 14 (5.1) 262 (94.9) 276 (100) • incessant vomiting at D4 • onset of dyspnea at day 3 • introduction of other treatment and azythromycin at day 9 • prescription of dexamethasone at D3 because of increased clinical signs • discontinuation of treatment for cardiac complications • discontinuation of treatment for dyspnea at D7 • Occurrence of severe form at D6 of treatment • Occurrence of cardiac complications • discontinuation of treatment at D9 because of BBC) Results Fisher test, p-value= 0.7 • Hospitalized at D3 because 25% of the lungs were affected. • Hospitalized at D4 at CTC Alarobia for dyspnea • Hospitalized at D2 at CHU Anosiala for asthenia • Hospitalized at D2 at CHU Anosiala for dyspnea • Less hospitalization in CVO+ CURATIVE arm • No significant difference between the 2 groups • No deaths during the trial
  32. 32. 32 Clinical tolerance Méthodes • Proportion of Adverse Events Results 0 2 4 6 8 10 12 14 16 18 Placebo CVO+ curatif Placebo CVO+ curatif Placebo CVO+ curatif Placebo CVO+ curatif D7 D14 D21 D28 Somatic Pulmonary Neurological Muscular Digestive Cutaneous Cardiac Deterioration of general condition
  33. 33. 33 Méthodes • Adverse events at D7 AE Placebo n (%) CVO+ CURATIVE n (%) Total n (%) DGC 1 (0,7) 1 (0,4) Cardiac 1 (0,8) 1 (0,4) Cutaneous 3 (2,1) 3 (1,1) Digestive 5 (3,5) 9 (6,8) 14 (5,1) Muscular Neurological 5 (3,5) 7 (5,3) 12 (4,3) Pulmonary Somatic Total AE 14 (9,7) 17 (12,9) 31 (11,2) N 144 (100) 132 (100) 276 (100) • vomiting • Epigastralgia • Pruritus and hives • tingling of the hands • dizziness • agueusia • nausea + vomiting + abdominal pain asthenia (GDC) • pruritic skin rash • diarrhea • fluid diarrhea • GERD • tinnitus • headache • abdominal pain • Bitter sensation in the mouth • Precordialgia Results Clinical tolerance
  34. 34. 34 Méthodes • Adverse events at D14 AE Placebo n (%) CVO+ CURATIF n (%) Total n (%) DGC Cardiac Cutaneous 5 (3,5) 3 (2,3) 8 (2,9) Digestive 6 (4,2) 1 (0,8) 7 (2,5) Muscular Neurological 2 (1,5) 12 (4,3) Pulmonary Somatic 1 (0,8) 1 (0,4) Total AE 11 (7,6) 7 (5,3) 18 (6,5) N 144 (100) 132 (100) 276 (100) • Insomnia in the 2nd half of the night • pruritus of the face • feeling of heat for about 2 hours a day relief after taking water • nausea • pruritus • GERD • pruritus of the throat • perineal pruritus • epigastralgia • Hair loss • Headache • thirst Results Clinical tolerance
  35. 35. 35 Méthodes • Adverse events at D14 AE Placebo n (%) CVO+ CURATIVE n (%) Total n (%) DGC Cardiac Cutaneous 2 (1,4) 2 (0,7) Digestive 3 (2,1) 1 (0,8) 4 (1,4) Muscular 2 (1,4) 2 (0,7) Neurological 3 (2,1) 3 (1,1) Pulmonary 2 (1,4) 1 (0,8) 3 (1,1) Somatic Total 12 (8,3) 2 (1,5) 14 (5,1) N 144 (100) 132 (100) 276 (100) • Short nocturnal dyspnea • Permanent dizziness • nocturnal chest pain • facial pruritus • paresthesia of the extremities of the upper limbs • cramp and muscular contracture in the hands and feet (trousseau’s sign) • pain in the right arm • vertigo • pain in the left breast like burning, exacerbated by touch • Epigastralgia • GERD • Diarrhea • transient chest pain Results Clinical tolerance
  36. 36. 36 Méthodes • Adverse events at D28 AE Placebo n (%) CVO+ CURATIVE n (%) Total n (%) DGC Cardiac Cutaneous 1 (0,7) 1 (0,4) Digestive 4 (2,8) 1 (0,8) 5 (1,8) Muscular 1 (0,8) 1 (0,4) Neurological 1 (0,8) 1 (0,4) Pulmonary 1 (0,8) 1 (0,4) Somatic Total 5 (3,5) 4 (3,0) 9 (3,3) N 144 (100) 132 (100) 276 (100) • chest pain with discontinuous compression • vertigo for half a day • sudden internal lumbago • pruritus of the face • Sore throat • liquid diarrhea for 2 days • Epigastralgia • dry throat • paresthesia of the left hemisphere • tinnitus Results Clinical tolerance
  37. 37. 37 Evolution of biological parameters Méthodes • Hematology: evolution of Leukocytes and Lymphocytes Results Leukocytes Lymphocytes Reference values : 2.0 – 7.5 g/L Reference values : 1.0 – 4.8 g/L
  38. 38. 38 Méthodes • Hematology: evolution of the ESR levels Results ESR Reference values : <10 mm Evolution of biological parameters
  39. 39. 39 Méthodes • Liver function: evolution of AST and ALT levels Results AST ALT Reference values : <40 U/L Evolution of biological parameters
  40. 40. 40 Méthodes • Renal function: evolution of creatinine levels Results Male Female Reference values : 53-115 µmol/L Reference values : 44-105 µmol/L Evolution of biological parameters
  41. 41. 41 Méthodes • Evolution of blood sugar levels Results Blood sugar levels Reference values : 4.10 – 5.90 mmol/L Evolution of biological parameters
  42. 42. • Efficacy of CVO PLUS CURATIVE in the treatment of non severe Covid-19 patient is 87.1% (CI : 95%: 81.3% - 92.9%) and 70.45% of them were cured by day 14. • No patient treated with CVO PLUS CURATIVE progressed to the severe form • All patients had preserved liver, kidney and metabolic functions. 42 Conclusion Méthodes
  43. 43. • Ratsimbasoa Arsène : Faculty of Medicine University of Fianarantsoa • Tehindrazanarivelo Alain Djacoba : World Health Organization • Razafindrabe Falihery : World Health Organization • Rakotoarivelo Rivo : Faculty of Medicine University of Fianarantsoa • Randriamanantany Zely : Faculty of Medicine University of Fianarantsoa • Rakoto Fanomezantsoa : Military Hospital • Rapelanoro Rabenja : Faculty of Medicine University of Antananarivo 43 Scientific review comitee Team
  44. 44. • Rakoto Alson Olivat : Faculty of Medicine University of Antananarivo • Rakotosaona Rianasoambolanoro : Centre National d’Application de Recherches Pharmaceutiques 44 Principal investigators Team
  45. 45. • Ravelo Arsène : Institut National de la Statistique • Mioramalala Sedera : Centre National d’Application de Recherches Pharmaceutiques • Franchard Thierry : World Health Organization • Mavuto Mukaka : Centre for Tropical Medicine and Global Health, Oxford, UK 45 Data analysis Team
  46. 46. Co-investigateurs: MIORAMALALA Sedera RAKOTONDRANDRIANA Antsa MAMINIAINA Fridolin RAKOTOARISOA Malala Arinomenjanahary RANDRIANARIVO Emmanuel RAZAFIMANDIMBY Dominique RAHANTAMALALA Mirana 46 investigators Team
  47. 47. Thank you! 47

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