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Organizing Clinical research

Organizing Clinical research. Pr Christine Katlama Hopital pitié salpetriere Université pierre et marie Curie ECRECO AIX Sept 2013. Main s teps of C linical study building . 12 to 36 months. 6 months. 6 to 24 months. The clinical study players. Methodologist

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Organizing Clinical research

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  1. OrganizingClinicalresearch Pr Christine Katlama Hopital pitié salpetriere Université pierre et marie Curie ECRECO AIX Sept 2013

  2. Main steps of Clinicalstudy building 12 to 36 months 6 months 6 to 24 months

  3. The clinicalstudyplayers Methodologist statistician Co investigators Principal Investigator PI Labs Virology Immunology … Sponsor

  4. Building a clinicalstudy : step by step • Research question ; validate the adequacy and pertinence of the idea ; formulate the Objective • Choose the right study design withmethodologist; • Evaluatefaisability • Write the proposal/ study synopsis ; test for interest • Write aprotocol; submit the protocol to researchscientificauthorities or fundings • Determine the studypartners • Fundings ; call • LaunchstudySelect centers • Regulatory ; ethics • Set up the study

  5. Outline of a study • Title • Research question • Objectives • Study design • Population • End points outcomes • Studyfollow up • Statistical /mathodology issues

  6. Research question • A key issue :to solvea pertinent question • Whatis a pertinent problem? - a problemis a scientificclinical question for whichthereis no answer; itis «  Whatyouwant to know ; a lack of knowledge • Compared to whatisknown on the subject ( maybe not by you ) : the Knowledge • How to solve the problem? formulate a question : STUDY OBJECTIVE - • Transform the question in one hypothesis

  7. Background and Significance Define the rationale +++ • Whatisknown about the topic ? • Whatscientificknowledgeismissing ?Whythis question is important ? • Whatkind of answerswill the studyprovide ? • Which new scientificknowledgewillbeobtained ? • How will the results influence clinical practice or public healthpolicies ?

  8. Validif the question youask • willbestill a question within the time you finish the study • evaluate the ration COST / Interest - importance of the problem in the context - recruitmentachievable

  9. Developing the research question and study plan • A fundamentalstep • 1 or 2 pages; clarifyideas • Look for expertise ; askadvice • Study plan graduallyemerges and isevolutingthrough discussion • Primary objective : primaryresearch question • Primary end point +++ • Secondaryresearch questions ++ Enough questions to «  investment return «  but not toomany !!!! A unique design can’t do everything

  10. Study Protocol • Title • Organizing team • Context • Studyrationale • Hypothesis • Methods • Study design • Primary end point • patients selection • Followup flow chart • management of special conditions • Methods and analysis • Study surveillance • Steering – scientificcomittee • Data safety monitoring board • Study agenda inclusion and follow up periods

  11. Regulatory and Ethic issues The philosophy • A study has to bescientificallyethics • Achievable • Respect patients rights and safety • Informed consent : the master piece of the study - Whois the Sponsor ? The body responsible for the study ? - Sponsor ≠ funder - Ethicscomittee - CNIL - Drugsagency - Insurance Anyprotocol modification has to besubmitted

  12. Main steps of Clinicalstudy building 12 to 36 months 6 months 6 to 24 months

  13. StudyOperation Group • Study team - whoisgoing to do what ? ClinicianMethologistvirologyimmunology radio ? • Participatingcenters Establish the studytoolsthatwillgaranteeveracity and safety • CRF • Database • Standard operating procedures ( SOP ) • Monitoring

  14. OtherStudymembers • Steeringcommittee - Carries responsability of the study • Accept DSMB recommendations • Composition : investigators , scientificpersonnalites • Data safety monitoring board DSMB - independantfrom the study Statistician , clinicians , - Role : protection of the persons - Analyse intermediateresults ; evaluatewhether the studycanbecontinued - Can recommend to STOP a study Participatingcenters Do not look only for yourfriends • Copperativecenters • Quality of work • Quality of their files

  15. A randomized multicenter study to compare the efficacy of a monotherapy of darunavir to a triple therapy with 2 nucleosides analogues combined to darunavir/r in HIV infected patients with full viral suppression. MONOI ANRS 136

  16. MONOI Background • ART has increasedsurvival • ART cannotbestopped once inititiated • ART willbeprescribedatearlier stages of HIV disease Longer time on ART for any patient • 3 drugsregimen leads to long termtoxicity - NRTI : mitochondrial toxicity ; evenlesstoxiconesmay not besafe on very long term - Median time on NRTI in treated patients isseveralyears • Proteaseinhibitors are the only class withbothpotency and highbarrier to resistance; pilot studieswithlopinavirsuggestingthat PI mono couldbe a possible approach

  17. Research Question and hypothesis 1 In patient withsuppressedviremia and controlled HIV infection canwemaintain viral suppression with a darunavirmonotherapy , which has been shown to bepotent , with a highgeneticbarrier to resistance and with good tolerability ? 2 Whichbenefits on fat tissue distribution ? Bone ? Consequences in term of resistance in case of failure ? Pharmacokinetics and distribution of darunavir in sperm Evolution of DNA content Determinants of virologicalfailure

  18. MONOI Study team

  19. Study Design Randomisation (1:1) DRV/r (600/100 mg bid) Introduction DRV/r DRV/r (600/100 mg bid)+ 2 NRTIs W96 W-8 W48 W-10 W-4 Phase I Long-term follow-up Phase II Primary Endpoint • Multicenter open label randomized study • Main inclusion criteria • Age >18 years. • On cART (2 NRTIs + PI or NNRTI or a third NRTI) for at least 18 months . • CD4 count >200 cells/mm3 or greater. • Nadir CD4 > 50 cells/mm3 • Viral load < 400 copies/ml in the last 18 months and < 50 copies/ml at entry. • No history of PI failure • Naïve to darunavir

  20. Eligibilitycriteria • Inclusion criteria specifying population relevant to the research question - Demographiccharacteristics • Clinicalcharacteristics • Biologicalcharacteristics • Temporal characteristics +++ do not be to selective test yourcriteria

  21. Eligibilitycriteria • Exclusion criteria : specifysubsets of population thatwill not bestudiedbecause of - a highlikelihood to belost to follow up - inability to provide good data - concomittanttherapy - priormedicalhistory - highrisk of sideeffects Careful +++ do not be to restrictive ; do not include population withpotentialselectionbias

  22. MONOI Study Design 1 • Primary End Point Proportion of patients in success of therapywith HIV RNA < 400 cp • Secondary End Points • % patients with < 50cp/ml up to W96 • Genotyperesistance mutations • Evolution of CD4 • Proportion of patients withsideeffects • HIV RNA in sperm( substudy in 40 patients ). • Quantification of body fat by DEXA (substudy in 120 pts) • Bonemineraldensitywith DEXA • Primary Objective To demonstrate that -DRV/r monotherapy can maintain viral suppression in patients receiving a triple therapy with viral versus 2 NRTIs + DRV/r in patients with viral suppression ( per protocol population ) • Secondary Objectives • Treatmentsuccess up to W96 • Time to failure • Factorsassociated to failure • Resistance mutations profile • % and time to stop the strategy • Evolution of CD4 • Incidence of sideeffects • Evolution of glucidic and lipids • Evaluateevolution of viral replication in genitalcompartments • Evolution of fat distribution

  23. MONOI Study Design 2 • Non inclusion criteria • Infection par le VIH2. • Patient ayant eu un stade C (SIDA). • Nadir des CD4 ≤100/ mm3. • Antécédents d’atteintes neurologiques (méningite, encéphalites, myélites, polyradiculonévrites) liées à l’infection VIH (à n’importe quel moment de l’infection VIH, y compris la primo-infection). • Hépatite virale B chronique. • Hépatite virale C chronique nécessitant une mise au traitement spécifique. • Echec virologique défini par une charge virale > 400 cp/ml sous inhibiteur de protéase. • Survenue d’un événement opportuniste ou infectieux majeur. • Inclusion criteria • Patient >18 ans, ayant une infection VIH-1 documentée. • Sous trithérapie ≥18 mois. • CV <50 cp/ml • CD4>200/mm3depuis au moins 6 mois • CV < 400 cp/ml au cours des 18 mois précédents avec au moins 4 CV < 400 cp/ml. • Absence d’ATCD d’échec virologique sous IP( 2CV successives > 1000 cp/ml). • Nadir des CD4>100/mm3. • CV documentée avant mise sous ARV (donnée nécessaire à la randomisation). • Patient n’ayant jamais reçu du darunavir. •  HCG – et utilisation d’une contraception mécanique. • Affilié ou bénéficiaire d’un régime de sécurité sociale. • Consentement signé.

  24. Flow chartPatient agenda • Define patient visits , blood test , other exams • A protocolisalmostalways more time consuming and potentiallyunpleasantthan standard procedure : more visits , more bood tests, blindedpills , other tests • DO onlyverynecessary tests and visits • A lot of pedagogynecessary : tole of clinicalresearch team • The objective is not only to recruit put to keep the patients in the study

  25. MONOI Substudies • Can a monotherapy control viral replication in compartments • associated to transmission ? • Can a NRTI sparingstrategy have a benefit on fat tissue and bone composition? Sperme DEXA Scan L’évaluation de la CV dans le compartiment génital masculin ( 40 patients) • L’évolution de la répartition des graisses • ( 120 patients) • Prélèvement de sperme, avant la prise de darunavir/r • J0, S48, S96 et en cas de sortie d’étude • Technique d’absorptiometrie biphotonique à rayons X (DXA). • J0, S48, S96 et en cas de sortie d’étude Analyse centralisée à Pitié dans le laboratoire de virologie Analyse centralisée à Cochin Dr S.KOLTA

  26. MONOI Statistics How many patients to include ? Considérations statistiques A total of 220 patients needed to takeintoconsideration the non evaluable patients • Change in the studytreatment failure • Viral load data missing  failure échec except if surrounded by two values <50 copies/ml

  27. Specific management in case of virologicfailure CV > 400 copies/ml Echec confirmé par le 2ème prélèvement Réalisation d’un Génotype de résistance Si CV< 400 cp/ml Poursuite de la stratégie Groupe monothérapie Groupe trithérapie Sans attendre les résultats du génotype et même si pas de mutations induites par les IP Choix laissé à l’investigateur Réintroduction des 2 INTI initiaux + darunavir/r Après résultat du génotype Réadaptation des ARV si besoin

  28. Specific management in case of intolerance Intolérance au darunavir/r Si EI (grade 1 ou 2) Si (grade 3/4) Traitement symptomatique Pas de modification de posologie du TMC 114/r Evaluation des symptômes dans un délai de 15j Fosamprénavir/r Atazanavir/r Lopinavir/r Arrêt du darunavir Intolérance aux INTI Choix d’une autre molécule de la même classe thérapeutique / l’investigateur

  29. Recruitment /Participatingcenters Tourcoing 15 Centres en province 18 Centres à Paris et en Ile de France 1 en Martinique 7/6 Paris/IdF Strasbourg Rennes Nancy 146/135 3/2 Martinique 6/5 1/1 Tours Belfort 3/3 1/1 Fort de France Besançon 7/7 Lyon 2/2 Bordeaux 3/3 6/4 Grenoble 7/7 Nice Marseille 4/4 Montpellier 3/1 Toulouse 7/3 Toulon 11/5 1/0 Nbr Patients pré inclus (S-10) / Nbr Patients Inclus (J0)

  30. MONOI Recruitmentfollow up / 218 patients pré-inclus (S-10 et S-8) 178 patients inclus Estimation Haute (prévisions) : 273 Patients 12 march 2008 Date de début des pré-inclusions : 05/03/07 Date de première inclusion (premier JO) : 14/05/2007

  31. MONOI Recruitmentfollow up / Dynamique des Inclusions au 12 mars 2008 Date de début des pré-inclusions : 05/03/07 Date de la première inclusion (premier JO) : 14/05/2007

  32. Recruitment : a key issue • 1 Recruitment must ensure to recruit a samplethatrepresentsthe target population • Recruitment must ensureenoughsubjectsto meet the sample size requirement • Population has to befollowedalong the entireduration of the study Caution : do not push toomuchrecruitmentwithany patients … if theyquit the studyyouloose !!! • Select carefully the participatingcenters • Support of patient providers and organizations

  33. Previsional agenda • 26 visites S-10 supplémentaires prévues jusqu’au 15 avril 2008, compte tenu des échecs d’inclusions (15 à ce jour), le chiffre de 220 patients devrait être atteint • Derniers JO devraient être effectués 30/06/2008 • Derniers S48 seront effectués au 01/06/2008

  34. MONOI Amendment n°1 • Amendement n°1 du 11 mai 2007 • Ayant reçu l’avis favorable du CPP Ile de France VI le 28/05/2007 et l’autorisation de l’AFSSAPS le 23/01/2007 • Modifications des critères d’inclusion : • 1.Suppression de : “Charge viraledocumentéeavantmise sous traitementantirétroviral, (donnéenécessaireà la randomisation)” • 2. Modification : “ Nadir CD4 > 100 / mm3 " en “ Nadir CD4 > 50 / mm3 " • 3. Suppression du critère de non inclusion : • “Patient ayanteu un évènementclassant SIDA”

  35. MONOI Amendment n°2 • Amendement n°2 du 15 novembre 2007 • Ayant reçu l’avis favorable du CPP Ile de France VI le 10/12/2007 et l ‘autorisation de l’AFSSAPS le 7/01/2008 • Possibilité de modifier la posologie de darunavir à S48 : • Protocole initial : « 6.2 Médicament de l’essai. • Le darunavir : le traitement comportera l’administration du darunavir à raison de 2 comprimés dosés à 300mg matin et soir, au cours d’un repas, associés au ritonavir (Norvir®) capsule molle à 100 mg à raison de 1 capsule x 2/j. » • Suite à l’amendement :« 6.2 Médicaments de l’essai • Le darunavir : Pendant les 48 premières semaines de l’essai, le traitement comportera l’administration du darunavir à raison de deux comprimés dosés à 300 mg matin et soir, au cours d’un repas, associés au ritonavir (Norvir®) capsule molle à 100 mg à raison de 1 capsule x 2/j.  • Puis de la 48ème à la 96ème semaine de l’essai, l’administration du darunavir sera faite en monoprise à raison de deux comprimés dosés à 400mg le matin au cours d’un repas associés à 1 capsule molle à 100 mg de ritonavir (Norvir®).Les patients qui refuseraient l’administration en monoprise, pourront rester en deux prises à raison de deux comprimés de darunavir dosés à 300mg associés à 1 capsule molle à 100 mg de ritonavir (Norvir®) le matin et le soir au cours d’un repas »

  36. Suivi virologique des patients

  37. MONOI Réponse virologique

  38. A randomized multicenter study to compare the efficacy of a monotherapy of darunavir to a triple therapy with 2 nucleosides analogues combined to darunavir/r in HIV infected patients with full viral suppression. MONOI ANRS 136 C Katlama Valantin MA, M . Algarte-Genin, Duvivier C, Lambert-Niclot S, Girard PM, Molina JM, Hosten B, Pakianather S, Peytavin G, Marcelin AG, Flandre P. IAS Conference, Cape Town, South Africa, July 2009 Abstract …-LB.

  39. MONOI Study Design 2 • Primary objective To demonstrate non-inferiority of DRV/r monotheray versus 2 NRTIs + DRV/r in patients with viral suppression ( per protocol population ) • Primary endpoint : virological success until W48 Virological failure is defined as • 2 consecutive HIV-1 RNA > 400 copies/ml within 2 weeks • Any ART modification or study withdrawal • Study power Power = 80% Non-inferioritymargin of 10% ( 90% CI ) assumingsuccessrates in botharms at W48 of 90% • ITT population All patients receivingdrugat D0 (ITT exposed) • Per protocol (PP) populationexcluded Patients whowithdrew (n=6) or discontinuedRxwithout VF or SAE (n=10) Patients whodid not fulfill the inclusion criteria (n=5)

  40. Patients Disposition Screening N=242 Withdrawal n=16 Randomisation N =226 Withdrawal n=1 ITT population N=225 DRV/r +2 NRTIs n=113 DRV/r n=112 Withdrawal n=3 Withdrawal n=3 Completed W48 N=110 Completed W48 N=109

  41. Patient Characteristics

  42. DRV/r DRV/r + NRTIs MONOI PrimaryEndpoint W48

  43. MONOI Reasons for failure

  44. Virological Failures in DRV/r arm • HIV RNA and DRV PK data at time of failure pt # 1 : W8 2722 cp/mlLow C24h 1120 ng/ml pt # 2 : W24 411cp/ml Adequate C24h 3480 ng/ml pt # 3 : W32 484.569 cp/mlTreatment discontinuation • No new DRV resistance mutations in the 3 patients • In all 3 patients, intensification with 2 NRTIs added to DRV/r, led to HIV RNA <50 copies/ml

  45. Proportion of patients with HIV RNA < 50 copies /ml : ITT population 92.0% 86.6% % Patients with HIV RNA < 50 cp/ml

  46. MONOI Serious Adverse events Infections 1 0 Psychiatric events CNS disorders 1 3* Cardiovascular 2 1 Cancer 0 3 Lipodystrophy 0 1 Surgery 6 3 1 GI disorders 0 Hepatic transaminases increase 1 1 1 0 CPK 2 2 *one HIV encephalitis and one neurological symptoms possibly related to HIV, both possibly related to study treatments HIV RNA CSF:580 cp/ml and 330 cp/ml

  47. MONOI : virologicoutcomes W96 • Pas d’apparition de mutation de résistance au darunavir • Chez les patients en monothérapie, retour à l’indétectabilité après reprise des INRT • Chez les patients en arrêt de traitement, succès de la reprise du traitement antiVIH (CV<50 copies/ml) Lambert-Niclot S, Flandre P, Valantin MA et al. Resistant minority species are rarely observed in patients on darunavir/ritonavir monotherapy. J Antimicrob Chemother. 2012 Mar 5. [Epub ahead of print]

  48. Factorsassociated to virologicblips • Variation similaire entre les deux bras du l’ADN VIH entre J0 et S96: • 0.35 log cp/106 cellules (monothérapie) vs 0.51 log cp/106 cellules (trithérapie) Lambert-Niclot S, Flandre P, Valantin MA et al. Factors associated with virological failure in HIV-1-infected patients receiving darunavir/ritonavir monotherapy. J Infect Dis. 2011 Oct 15;204(8):1211-6.

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