SlideShare uma empresa Scribd logo
1 de 34
Baixar para ler offline
Applicability of naturalistic
principles in a clinical study:
          PROMPT

      Joop C. van Oene, PhD
Clinical development rate of paramount importance



     Speeding-up approval/licensing processes is important to
      gain time to
       –   provide better care earlier
       –   reduce trial performance costs by being more efficient
       –   start rewarding long-term investments earlier
       –   leave longer profitable period (till patent expiry)
       –   exploit competitive advantage
Recruitment problems are often rate-limiting



     Recruitment rate may be slowed down by
       – Low incidence/prevalence of the disease
       –   Logistic factors related to finding patients, obtaining
           informed consent, proper investigational facilities, etc
            o tackeled by raising sponsor involvement/investment
       –   Psychologic factors related to motivational level of
            o investigators (doctors)
            o trial subjects (patients)
How motivate Doctors to participate



                               CONs
     loss of time involved in study approval and performance -
      usually financially compensated
                               PROs
     explore new treatment options for own patients
     contribute to the advancement of medical knowledge
     be recognised for that effort by colleagues and institution
     generate funds from revenues
How motivate Patients to participate



       “WHAT’S IN IT FOR ME?” will be the patient’s first question !!
                                      CONs
     loss of time (for work, education, leisure):
      usually not compensated for
     loss of money (travel costs, drink&eat):
      can be partly or fully reimbursed
                                      PROs
     explore new, alternative and potentially better treatment options
     receive (supposedly) active treatment for free
     obtain better insight/control of the disorder through tighter monitoring
      during trial as compared to standard-of-care
What are the implications for clinical study design



      Both doctors and patients want to test the new treatment
        by experiencing its therapeutic and adverse effects
         to conclude on its merits for future/continued use

     To be able to draw such conclusions they should ideally
       – Know for sure which treatment is taken -> open-label medication
       – Be allowed to adjust/optimize the dose -> flexible dosing
       – Compare to no treatment (or placebo) and, if available,
         to alternative treatment(s)
       – Compare to the effects in similar patients
Where do the regular RCTs fall short



     Randomization (treatment is imposed as is the dose)
       – neither doctor nor patient has any choice
       – may involve a low or even zero dose (placebo) leading to trial
         discontinuation for lack of efficacy
       – may involve a (too) high dose leading to trial discontinuation for
         of lack of tolerance
     Blinding (often double-blind):
       – patient and/or doctor are unaware of medication type and/or dose



  RESULT: patient and doctor are both uncertain about the interpretation
  of the trial results and the potential effectiveness of the investigational
  drug -> reduced motivation to participate or continue with the study
What does “naturalistic” mean



  [Cambridge Advanced Learner's Dictionary:]

     Naturalism
       –   (in art and literature) showing people and experiences
           as they really are, instead of suggesting that they are
           better than they really are or representing them in a
           fixed style
     Naturalistic adjective
       – showing things as they really are …
How does „naturalistic‟ work in clinical studies



     To mimick everyday clinical practice, use
       – open-label study medication with
       – flexible dosing (within specified range) at least during an early
         part of the study to
       – optimise patient-preferred dosing by finding the best balance of
         therapeutic effects and side effects

     Combination with a randomized, (double-blind), comparative phase
      is recommended to enable
        – answering scientific questions, draw solid conclusions
        – meet ethics requirements (avoid “seeding” impression)
Where to fit in the clinical development program



     Early-phase clinical studies (I-IIIa) focus on the
      investigational drug, their primary goal is to
       –   demonstrate that the drug is efficacious in the patient

     Late-phase clinical studies (IIIb-IV) focus on the
      patient, their primary goal is to
       –   find out how the patient benefits most from the drug


  Statement
  Naturalistic features fit best in late-phase clinical studies but should be
  incorporated as early as possible in the development program to raise
  predictive power of the trial results for everyday clinical practice
Will a naturalistic design facilitate recruitment



      A naturalistic study design is expected to positively
       influence the motivation of both doctors and patients
       because it will
        –   Raise doctor’s experience with handling (side) effects
            of the drug in relation to dosing
        –   Position the doctor better to treat future patients in the
            most appropriate manner
        –   Assure the patient of getting active treatment and
            achieving the most suitable dose for his/her condition
PROlonged Migraine Prevention
      with Topiramate
         (PROMPT)

           Protocol: TOPMAT-MIG-303
            EudraCT: 2005-000321-29

           running: Dec 2003 - May 2006
 primary publication: Lancet Neurol 2007;6:1054-62
PROMPT rationale



   Topiramate had been registered for the prevention of
  migraine in most European countries
    Label text did not limit the treatment duration with
  topiramate
    Various local/national guidelines, however, demanded
  revision of migraine preventive therapy after 4-6 months of
  treatment, but
   No evidence was available from clinical studies to
  support the validity of these guidelines


  PROMPT was set up to address this issue
PROMPT objectives




      Primary Objective
      – evaluate the continued efficacy (beyond 6 months) of
        topiramate in the prophylaxis of migraine



      Secondary Objectives
      – determine the preferred topiramate dose
      – evaluate the use of acute medication
PROMPT trial design



         4-8 weeks : prospective baseline [no preventive treatment]
      – 4 weeks if number of migraine days is at least 4 per month
      – 8 weeks if this number has not been reached in the first month

         6 months : open label (OL) treatment with topiramate
      – dose 50-200 mg/day determined by patient’s preference
      – individually preferred dose is fixed for month 6

   6 months : double-blind (DB) treatment with topiramate or
  placebo
      – determined by randomization (1:1)
      – same dose (number of tablets) as in month-6 of open-label treatment

         0-1 week : run-out
      – trial medication tapered off in 1 week if >100 mg/day
      – trial medication stopped immediately if <100 mg/day
PROMPT dosing


     Baseline                       Open-Label Phase                    Double-Blind Phase       Run-Out
      Phase                                                                                       Phase
                        Titration       Flexible dose   Fixed dose              Fixed dose          Taper
                                                                                                      off
                                        200 mg/d                               200 mg/d


                                        TOPIRAMATE                            TOPIRAMATE
                                  100
                             75
                        50
                   25                   50 mg/d                                50 mg/d


    No Treatment                                                              PLACEBO




     4 (8) weeks        4 weeks           18 weeks       4 weeks     1 week      25 weeks          1 week


Screening     Week 0                                           Week 26                         Week 52
            (Enrollment)                                   (Randomization)                   (Completion)
PROMPT key selection criteria




  Inclusion criteria
     •   Aged 18-80 years inclusive
     •   Meets the IHS criteria for migraine*
     •   Established history of migraine for > 1 year
     •   At least 4 monthly migraine days during the previous 3 months
     •   Capable of keeping trial records and having signed the ICF




         * Headache Classification Committee of the International Headache Society
           Cephalalgia 1988;8(Suppl 7):1-96.
PROMPT primary endpoint




      Primary efficacy parameter
      – Change in the number of migraine days during
        the last 4 weeks of the double-blind phase
        relative to
        the last 4 weeks of the open-label phase

      Hypothesis (pre-trial)
      – Difference between topiramate and placebo group is
        (at least) 1.0 migraine day per 4 weeks
PROMPT

RECRUITMENT AND TRIAL SAMPLE
PROMPT participation




            21 countries / 88 sites* / 954 subjects

            954 Screened
                136 Screen Failures = 14.3%                             [ est. 25% ]

            818 Enrolled OL phase
             259 Early Terminated = 31.6%                               [ est. 35% ]
              45 Not Randomized = 8.1%                                  [ est. 20% ]

            514 Randomized DB phase
                                  = 53.9% of Screened                    [ est. 39% ]

             * ) 1 more site with 10 subjects was disqualified and left out of the analysis




                                                                                              15
PROMPT subject recruitment
Demographic and Baseline Characteristics



 mean                                         Enrolled         Randomized
 median (range)                               N = 818            N = 514
 Age, years                                      39.8               40.1
                                              40 (18-69)         40 (18-69)

 Height, cm                                     166.0              165.8
                                            165 (140-194)      165 (140-194)

 Weight, kg                                       69.8               70.6
                                              67 (45-151)        68 (45-151)

 BMI, kg/m²                                       25.3               25.6
                                            24.5 (16.4-52.5)   24.9 (16.6-52.1)

 Gender, male/female %                          13 / 87            13 / 87

 Number of monthly migraine days at start          8.9                8.7
                                              8.0 (0.0-28)       8.0 (3.3-28)
PROMPT records in baseline/OL phase




       Migraine observations                 29,935
       Acute medication observations         28,031
       Adverse event observations            2,877
       Concomitant medication observations   1,866
       Trial medication observations         4,665
PROMPT

TOPIRAMATE DOSING
Flexible dosing of topiramate (OL phase)
 Distribution of the last daily doses (N = 818)



                   50

                   40
      % Subjects




                   30

                   20

                   10

                   0
                        12,5   25   50    75   100   125   150   175   200
                                    Topiramate dose (mg/day)
Fixed dosing of trial medication (DB phase)
 Distribution of the last daily doses


                            topiramate (N=254)        placebo (N=258)

                   50

                   40
      % Subjects




                   30

                   20

                   10

                   0
                        0   25   50    75 100 125 150 175 200
                                      Dose (mg/day)
PROMPT

    EFFICACY RESULTS
Change in monthly migraine days
PROMPT primary efficacy parameter (OL phase)
 Mean number of migraine days per 4 weeks

     intent-to-treat analysis (n=811)         completer analysis (n=559)
10     8,9                                      8,8
 8
                  5,8
 6                                                          4,8
 4
 2
 0                          ***                                         ***
-2

-4                          -3,1
                                                                        -4,0
-6
     Baseline   Month 6                      Baseline    Month 6
         migraine days    change in migraine days
                                                      *** p <0.0001 versus baseline
PROMPT time course of migraine days
  Mean number of migraine days per 4 weeks (observed cases)


            All OL (N=811)   Topiramate DB (N=253)   Placebo DB (N=257)   * p < 0.05

   10
            OL PHASE                           DB PHASE
   9
   8
   7
                                           *
   6
   5
   4
   3
   2
   1
   0
        0        10          20           30         40           50           60
                                    Time (weeks)
PROMPT primary efficacy parameter (DB phase)
 Mean change in number of migraine days per 4 weeks


                             topiramate        placebo   Primary
                     ***                                 endpoint
 1,6
 1,4
                                ***                            **
                                                               1,2
 1,2
 1,0
 0,8                                              **
 0,6
 0,4
 0,2                                                     0,1
 0,0
 -0,2   Start    Week       Week        Week    Week     Last 4
 -0,4    DB       +4         +8         +16     +26      weeks

                 ** p<0.01 vs. topiramate
                *** p<0.001 vs. topiramate
PROMPT acute medication days (OL phase)
Mean number of days per 4 weeks with acute medication intake


        any acute                triptans              analgesics

   7       6,1
   6                              5,0
   5             4,2
                                        3,7
   4                                                     3,0
   3
                                                                1,9
   2
   1
                        ***                    ***                    ***
   0
  -1
  -2                                            -1,3                    -1,1
                         -2,0
  -3
          Base- End-             Base- End-             Base- End-
           line point             line point             line point

         acute medication days     change in acute medication days
                                                       *** p <0.0001 versus start
PROMPT change in Kg body weight versus baseline
  (observed cases)


               topiramate-topiramate          topiramate-placebo

           0      10     20        30          40     50      60
      0
    -0,5
                 OL PHASE               DB PHASE
     -1
    -1,5
     -2
    -2,5
     -3                                                ***
    -3,5                                ***
     -4
    -4,5                                                           *** p < 0.001
                              Time (weeks)
PROMPT conclusions




      Efficacy
      – The primary efficacy parameter after withdrawal of
        study medication was positive, showing an increase in
        the number of migraine days with placebo versus no
        change with topiramate.


      Safety
      – Adverse events were similar to those observed in
        previous studies both in nature and in frequency of
        occurrence.
Naturalistic principle conclusions



     Attractive to investigators as treating physicians -
      “hands-on experience”
     Motivating for patients - helpful in patient recruitment
     Prerequisite to obtain insight into patient-preferred
      dosages
     Powerful in combination with double-blind, randomized
      part in order to meet both scientific standards and ethics
      requirements

Mais conteúdo relacionado

Mais procurados

Integrated aspects of rct niper feb 2009 final
Integrated aspects of rct niper feb 2009 finalIntegrated aspects of rct niper feb 2009 final
Integrated aspects of rct niper feb 2009 finalBhaswat Chakraborty
 
Artigo (acupuntura) - Efeito placebo da acupuntura
Artigo (acupuntura) - Efeito placebo da acupunturaArtigo (acupuntura) - Efeito placebo da acupuntura
Artigo (acupuntura) - Efeito placebo da acupunturaRenato Almeida
 
Theory-based interventions to promote physical activity: Lessons learned from...
Theory-based interventions to promote physical activity: Lessons learned from...Theory-based interventions to promote physical activity: Lessons learned from...
Theory-based interventions to promote physical activity: Lessons learned from...BERNARD Paquito
 
Learn-Apply Paradigm to Drug Development
Learn-Apply Paradigm to Drug DevelopmentLearn-Apply Paradigm to Drug Development
Learn-Apply Paradigm to Drug DevelopmentJogaGobburu
 
Bioavailability and bioequivalence
Bioavailability and bioequivalenceBioavailability and bioequivalence
Bioavailability and bioequivalenceNaresh Gorantla
 
Comparitive Study of the Efficacy and Tolerance of Prokinetic Drugs - Metaclo...
Comparitive Study of the Efficacy and Tolerance of Prokinetic Drugs - Metaclo...Comparitive Study of the Efficacy and Tolerance of Prokinetic Drugs - Metaclo...
Comparitive Study of the Efficacy and Tolerance of Prokinetic Drugs - Metaclo...pharmaindexing
 
How to double success rate of pediatric trials?
How to double success rate of pediatric trials?How to double success rate of pediatric trials?
How to double success rate of pediatric trials?JogaGobburu
 
Research Methodology 2
Research Methodology 2Research Methodology 2
Research Methodology 2Tamer Hifnawy
 
phase 1 clinical trial
phase 1 clinical trialphase 1 clinical trial
phase 1 clinical trialJyoti Sharma
 
Paroxetine h cl-tablets-sm-pc-taj pharmaceuticals
Paroxetine h cl-tablets-sm-pc-taj pharmaceuticalsParoxetine h cl-tablets-sm-pc-taj pharmaceuticals
Paroxetine h cl-tablets-sm-pc-taj pharmaceuticalsTajPharmaQC
 
Topiramate Tablets USP Taj Pharma SmPC
Topiramate Tablets USP Taj Pharma SmPCTopiramate Tablets USP Taj Pharma SmPC
Topiramate Tablets USP Taj Pharma SmPCTajPharmaQC
 
Ayurveda shows a way forward to drug discovery
Ayurveda shows a way  forward to drug discoveryAyurveda shows a way  forward to drug discovery
Ayurveda shows a way forward to drug discoverysaumyagulati4
 
Introduction to experimental pharmacology
Introduction to experimental pharmacologyIntroduction to experimental pharmacology
Introduction to experimental pharmacologyShaikh Abusufyan
 

Mais procurados (20)

ABE IBE PBE
ABE IBE PBEABE IBE PBE
ABE IBE PBE
 
Integrated aspects of rct niper feb 2009 final
Integrated aspects of rct niper feb 2009 finalIntegrated aspects of rct niper feb 2009 final
Integrated aspects of rct niper feb 2009 final
 
Artigo (acupuntura) - Efeito placebo da acupuntura
Artigo (acupuntura) - Efeito placebo da acupunturaArtigo (acupuntura) - Efeito placebo da acupuntura
Artigo (acupuntura) - Efeito placebo da acupuntura
 
Theory-based interventions to promote physical activity: Lessons learned from...
Theory-based interventions to promote physical activity: Lessons learned from...Theory-based interventions to promote physical activity: Lessons learned from...
Theory-based interventions to promote physical activity: Lessons learned from...
 
Pharmacometrics
PharmacometricsPharmacometrics
Pharmacometrics
 
Unblinded Monitoring Programs
Unblinded Monitoring ProgramsUnblinded Monitoring Programs
Unblinded Monitoring Programs
 
Learn-Apply Paradigm to Drug Development
Learn-Apply Paradigm to Drug DevelopmentLearn-Apply Paradigm to Drug Development
Learn-Apply Paradigm to Drug Development
 
Bioavailability and bioequivalence
Bioavailability and bioequivalenceBioavailability and bioequivalence
Bioavailability and bioequivalence
 
Comparitive Study of the Efficacy and Tolerance of Prokinetic Drugs - Metaclo...
Comparitive Study of the Efficacy and Tolerance of Prokinetic Drugs - Metaclo...Comparitive Study of the Efficacy and Tolerance of Prokinetic Drugs - Metaclo...
Comparitive Study of the Efficacy and Tolerance of Prokinetic Drugs - Metaclo...
 
Clinical trials designs
Clinical trials designsClinical trials designs
Clinical trials designs
 
EJPB Pub
EJPB PubEJPB Pub
EJPB Pub
 
How to double success rate of pediatric trials?
How to double success rate of pediatric trials?How to double success rate of pediatric trials?
How to double success rate of pediatric trials?
 
Research Methodology 2
Research Methodology 2Research Methodology 2
Research Methodology 2
 
Clinical trials
Clinical trialsClinical trials
Clinical trials
 
phase 1 clinical trial
phase 1 clinical trialphase 1 clinical trial
phase 1 clinical trial
 
Paroxetine h cl-tablets-sm-pc-taj pharmaceuticals
Paroxetine h cl-tablets-sm-pc-taj pharmaceuticalsParoxetine h cl-tablets-sm-pc-taj pharmaceuticals
Paroxetine h cl-tablets-sm-pc-taj pharmaceuticals
 
Topiramate Tablets USP Taj Pharma SmPC
Topiramate Tablets USP Taj Pharma SmPCTopiramate Tablets USP Taj Pharma SmPC
Topiramate Tablets USP Taj Pharma SmPC
 
Ayurveda shows a way forward to drug discovery
Ayurveda shows a way  forward to drug discoveryAyurveda shows a way  forward to drug discovery
Ayurveda shows a way forward to drug discovery
 
Introduction to experimental pharmacology
Introduction to experimental pharmacologyIntroduction to experimental pharmacology
Introduction to experimental pharmacology
 
Placebo and nocebo
Placebo and noceboPlacebo and nocebo
Placebo and nocebo
 

Semelhante a Joop vanoene 6thannualwien_1

Understanding Clinical Trials
Understanding Clinical TrialsUnderstanding Clinical Trials
Understanding Clinical TrialsBartsMSBlog
 
Understanding clinical trials
Understanding clinical trialsUnderstanding clinical trials
Understanding clinical trialsMS Trust
 
Clinical trials
Clinical trialsClinical trials
Clinical trialsVibha Manu
 
Field trials and clinical trials
Field trials and clinical trialsField trials and clinical trials
Field trials and clinical trialsBhoj Raj Singh
 
Clinical trials by khadga
Clinical trials by  khadgaClinical trials by  khadga
Clinical trials by khadgaKhadga Raj
 
Clinical trial phases, requirements and regulations
Clinical trial  phases, requirements and regulationsClinical trial  phases, requirements and regulations
Clinical trial phases, requirements and regulationsDr. Siddhartha Dutta
 
Bioavailability and bioequivalence lecture
Bioavailability and bioequivalence lectureBioavailability and bioequivalence lecture
Bioavailability and bioequivalence lecturesagar joshi
 
SuYoungChoi_clinicalinvestigator_SC_Phase2_3_100516.pptx
SuYoungChoi_clinicalinvestigator_SC_Phase2_3_100516.pptxSuYoungChoi_clinicalinvestigator_SC_Phase2_3_100516.pptx
SuYoungChoi_clinicalinvestigator_SC_Phase2_3_100516.pptxGeletaGalataa
 
trial and protocol design
trial and protocol design trial and protocol design
trial and protocol design Rohit K.
 
Clinical trails overview
 Clinical trails overview Clinical trails overview
Clinical trails overviewshashi sinha
 
1 Phases of clinical trial.pptx
1 Phases of clinical trial.pptx1 Phases of clinical trial.pptx
1 Phases of clinical trial.pptxDr Abisha T
 
Drug discovery By Neelima Sharma WCC chennai,neelima.sharma60@gmail.com
Drug discovery By  Neelima Sharma WCC chennai,neelima.sharma60@gmail.comDrug discovery By  Neelima Sharma WCC chennai,neelima.sharma60@gmail.com
Drug discovery By Neelima Sharma WCC chennai,neelima.sharma60@gmail.comNeelima Sharma
 
Role of clinical trials in drug discovery &
Role of clinical trials in drug discovery &Role of clinical trials in drug discovery &
Role of clinical trials in drug discovery &Bhaswat Chakraborty
 

Semelhante a Joop vanoene 6thannualwien_1 (20)

Understanding Clinical Trials
Understanding Clinical TrialsUnderstanding Clinical Trials
Understanding Clinical Trials
 
Understanding clinical trials
Understanding clinical trialsUnderstanding clinical trials
Understanding clinical trials
 
Clinical trials
Clinical trialsClinical trials
Clinical trials
 
Field trials and clinical trials
Field trials and clinical trialsField trials and clinical trials
Field trials and clinical trials
 
Clinical trials by khadga
Clinical trials by  khadgaClinical trials by  khadga
Clinical trials by khadga
 
Clinical trial
Clinical trialClinical trial
Clinical trial
 
Clinical trial phases, requirements and regulations
Clinical trial  phases, requirements and regulationsClinical trial  phases, requirements and regulations
Clinical trial phases, requirements and regulations
 
Bioequivalence protocol 46
Bioequivalence  protocol 46Bioequivalence  protocol 46
Bioequivalence protocol 46
 
Bioavailability and bioequivalence lecture
Bioavailability and bioequivalence lectureBioavailability and bioequivalence lecture
Bioavailability and bioequivalence lecture
 
Mpharm RA 103.pdf
Mpharm RA 103.pdfMpharm RA 103.pdf
Mpharm RA 103.pdf
 
Microdosing (Phase 0) studies
Microdosing (Phase 0) studiesMicrodosing (Phase 0) studies
Microdosing (Phase 0) studies
 
SuYoungChoi_clinicalinvestigator_SC_Phase2_3_100516.pptx
SuYoungChoi_clinicalinvestigator_SC_Phase2_3_100516.pptxSuYoungChoi_clinicalinvestigator_SC_Phase2_3_100516.pptx
SuYoungChoi_clinicalinvestigator_SC_Phase2_3_100516.pptx
 
Clinical Trial phases.pptx
Clinical Trial phases.pptxClinical Trial phases.pptx
Clinical Trial phases.pptx
 
trial and protocol design
trial and protocol design trial and protocol design
trial and protocol design
 
Clinical trails overview
 Clinical trails overview Clinical trails overview
Clinical trails overview
 
1 Phases of clinical trial.pptx
1 Phases of clinical trial.pptx1 Phases of clinical trial.pptx
1 Phases of clinical trial.pptx
 
Drug discovery By Neelima Sharma WCC chennai,neelima.sharma60@gmail.com
Drug discovery By  Neelima Sharma WCC chennai,neelima.sharma60@gmail.comDrug discovery By  Neelima Sharma WCC chennai,neelima.sharma60@gmail.com
Drug discovery By Neelima Sharma WCC chennai,neelima.sharma60@gmail.com
 
Schedule y by dr.roohna
Schedule y by dr.roohnaSchedule y by dr.roohna
Schedule y by dr.roohna
 
Randomized Control Trail
Randomized Control TrailRandomized Control Trail
Randomized Control Trail
 
Role of clinical trials in drug discovery &
Role of clinical trials in drug discovery &Role of clinical trials in drug discovery &
Role of clinical trials in drug discovery &
 

Último

DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptxDNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptxMAsifAhmad
 
Generative AI in Health Care a scoping review and a persoanl experience.
Generative AI in Health Care a scoping review and a persoanl experience.Generative AI in Health Care a scoping review and a persoanl experience.
Generative AI in Health Care a scoping review and a persoanl experience.Vaikunthan Rajaratnam
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...Shubhanshu Gaurav
 
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdfSGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdfHongBiThi1
 
Red Blood Cells_anemia & polycythemia.pdf
Red Blood Cells_anemia & polycythemia.pdfRed Blood Cells_anemia & polycythemia.pdf
Red Blood Cells_anemia & polycythemia.pdfMedicoseAcademics
 
Using Data Visualization in Public Health Communications
Using Data Visualization in Public Health CommunicationsUsing Data Visualization in Public Health Communications
Using Data Visualization in Public Health Communicationskatiequigley33
 
Male Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondMale Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondSujoy Dasgupta
 
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdfHongBiThi1
 
Neurological history taking (2024) .
Neurological  history  taking  (2024)  .Neurological  history  taking  (2024)  .
Neurological history taking (2024) .Mohamed Rizk Khodair
 
AUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsAUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsMedicoseAcademics
 
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptxANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptxWINCY THIRUMURUGAN
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets barmohitRahangdale
 
High-Performance Thin-Layer Chromatography (HPTLC)
High-Performance Thin-Layer Chromatography (HPTLC)High-Performance Thin-Layer Chromatography (HPTLC)
High-Performance Thin-Layer Chromatography (HPTLC)kishan singh tomar
 
ayurvedic formulations herbal drug technologyppt
ayurvedic formulations herbal drug technologypptayurvedic formulations herbal drug technologyppt
ayurvedic formulations herbal drug technologypptPradnya Wadekar
 
How to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyHow to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyZurück zum Ursprung
 
CPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentCPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentsaileshpanda05
 
historyofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusanguhistoryofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusangu Medical University
 
Basic structure of hair and hair growth cycle.pptx
Basic structure of hair and hair growth cycle.pptxBasic structure of hair and hair growth cycle.pptx
Basic structure of hair and hair growth cycle.pptxkomalt2001
 
EXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung functionEXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung functionkrishnareddy157915
 
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.aarjukhadka22
 

Último (20)

DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptxDNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
 
Generative AI in Health Care a scoping review and a persoanl experience.
Generative AI in Health Care a scoping review and a persoanl experience.Generative AI in Health Care a scoping review and a persoanl experience.
Generative AI in Health Care a scoping review and a persoanl experience.
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
 
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdfSGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
 
Red Blood Cells_anemia & polycythemia.pdf
Red Blood Cells_anemia & polycythemia.pdfRed Blood Cells_anemia & polycythemia.pdf
Red Blood Cells_anemia & polycythemia.pdf
 
Using Data Visualization in Public Health Communications
Using Data Visualization in Public Health CommunicationsUsing Data Visualization in Public Health Communications
Using Data Visualization in Public Health Communications
 
Male Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondMale Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and Beyond
 
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
 
Neurological history taking (2024) .
Neurological  history  taking  (2024)  .Neurological  history  taking  (2024)  .
Neurological history taking (2024) .
 
AUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsAUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functions
 
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptxANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets bar
 
High-Performance Thin-Layer Chromatography (HPTLC)
High-Performance Thin-Layer Chromatography (HPTLC)High-Performance Thin-Layer Chromatography (HPTLC)
High-Performance Thin-Layer Chromatography (HPTLC)
 
ayurvedic formulations herbal drug technologyppt
ayurvedic formulations herbal drug technologypptayurvedic formulations herbal drug technologyppt
ayurvedic formulations herbal drug technologyppt
 
How to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyHow to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturally
 
CPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentCPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing student
 
historyofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusanguhistoryofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusangu
 
Basic structure of hair and hair growth cycle.pptx
Basic structure of hair and hair growth cycle.pptxBasic structure of hair and hair growth cycle.pptx
Basic structure of hair and hair growth cycle.pptx
 
EXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung functionEXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung function
 
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
 

Joop vanoene 6thannualwien_1

  • 1. Applicability of naturalistic principles in a clinical study: PROMPT Joop C. van Oene, PhD
  • 2. Clinical development rate of paramount importance  Speeding-up approval/licensing processes is important to gain time to – provide better care earlier – reduce trial performance costs by being more efficient – start rewarding long-term investments earlier – leave longer profitable period (till patent expiry) – exploit competitive advantage
  • 3. Recruitment problems are often rate-limiting  Recruitment rate may be slowed down by – Low incidence/prevalence of the disease – Logistic factors related to finding patients, obtaining informed consent, proper investigational facilities, etc o tackeled by raising sponsor involvement/investment – Psychologic factors related to motivational level of o investigators (doctors) o trial subjects (patients)
  • 4. How motivate Doctors to participate CONs  loss of time involved in study approval and performance - usually financially compensated PROs  explore new treatment options for own patients  contribute to the advancement of medical knowledge  be recognised for that effort by colleagues and institution  generate funds from revenues
  • 5. How motivate Patients to participate “WHAT’S IN IT FOR ME?” will be the patient’s first question !! CONs  loss of time (for work, education, leisure): usually not compensated for  loss of money (travel costs, drink&eat): can be partly or fully reimbursed PROs  explore new, alternative and potentially better treatment options  receive (supposedly) active treatment for free  obtain better insight/control of the disorder through tighter monitoring during trial as compared to standard-of-care
  • 6. What are the implications for clinical study design Both doctors and patients want to test the new treatment by experiencing its therapeutic and adverse effects to conclude on its merits for future/continued use  To be able to draw such conclusions they should ideally – Know for sure which treatment is taken -> open-label medication – Be allowed to adjust/optimize the dose -> flexible dosing – Compare to no treatment (or placebo) and, if available, to alternative treatment(s) – Compare to the effects in similar patients
  • 7. Where do the regular RCTs fall short  Randomization (treatment is imposed as is the dose) – neither doctor nor patient has any choice – may involve a low or even zero dose (placebo) leading to trial discontinuation for lack of efficacy – may involve a (too) high dose leading to trial discontinuation for of lack of tolerance  Blinding (often double-blind): – patient and/or doctor are unaware of medication type and/or dose RESULT: patient and doctor are both uncertain about the interpretation of the trial results and the potential effectiveness of the investigational drug -> reduced motivation to participate or continue with the study
  • 8. What does “naturalistic” mean [Cambridge Advanced Learner's Dictionary:]  Naturalism – (in art and literature) showing people and experiences as they really are, instead of suggesting that they are better than they really are or representing them in a fixed style  Naturalistic adjective – showing things as they really are …
  • 9. How does „naturalistic‟ work in clinical studies  To mimick everyday clinical practice, use – open-label study medication with – flexible dosing (within specified range) at least during an early part of the study to – optimise patient-preferred dosing by finding the best balance of therapeutic effects and side effects  Combination with a randomized, (double-blind), comparative phase is recommended to enable – answering scientific questions, draw solid conclusions – meet ethics requirements (avoid “seeding” impression)
  • 10. Where to fit in the clinical development program  Early-phase clinical studies (I-IIIa) focus on the investigational drug, their primary goal is to – demonstrate that the drug is efficacious in the patient  Late-phase clinical studies (IIIb-IV) focus on the patient, their primary goal is to – find out how the patient benefits most from the drug Statement Naturalistic features fit best in late-phase clinical studies but should be incorporated as early as possible in the development program to raise predictive power of the trial results for everyday clinical practice
  • 11. Will a naturalistic design facilitate recruitment  A naturalistic study design is expected to positively influence the motivation of both doctors and patients because it will – Raise doctor’s experience with handling (side) effects of the drug in relation to dosing – Position the doctor better to treat future patients in the most appropriate manner – Assure the patient of getting active treatment and achieving the most suitable dose for his/her condition
  • 12. PROlonged Migraine Prevention with Topiramate (PROMPT) Protocol: TOPMAT-MIG-303 EudraCT: 2005-000321-29 running: Dec 2003 - May 2006 primary publication: Lancet Neurol 2007;6:1054-62
  • 13. PROMPT rationale  Topiramate had been registered for the prevention of migraine in most European countries  Label text did not limit the treatment duration with topiramate  Various local/national guidelines, however, demanded revision of migraine preventive therapy after 4-6 months of treatment, but  No evidence was available from clinical studies to support the validity of these guidelines PROMPT was set up to address this issue
  • 14. PROMPT objectives  Primary Objective – evaluate the continued efficacy (beyond 6 months) of topiramate in the prophylaxis of migraine  Secondary Objectives – determine the preferred topiramate dose – evaluate the use of acute medication
  • 15. PROMPT trial design  4-8 weeks : prospective baseline [no preventive treatment] – 4 weeks if number of migraine days is at least 4 per month – 8 weeks if this number has not been reached in the first month  6 months : open label (OL) treatment with topiramate – dose 50-200 mg/day determined by patient’s preference – individually preferred dose is fixed for month 6  6 months : double-blind (DB) treatment with topiramate or placebo – determined by randomization (1:1) – same dose (number of tablets) as in month-6 of open-label treatment  0-1 week : run-out – trial medication tapered off in 1 week if >100 mg/day – trial medication stopped immediately if <100 mg/day
  • 16. PROMPT dosing Baseline Open-Label Phase Double-Blind Phase Run-Out Phase Phase Titration Flexible dose Fixed dose Fixed dose Taper off 200 mg/d 200 mg/d TOPIRAMATE TOPIRAMATE 100 75 50 25 50 mg/d 50 mg/d No Treatment PLACEBO 4 (8) weeks 4 weeks 18 weeks 4 weeks 1 week 25 weeks 1 week Screening Week 0 Week 26 Week 52 (Enrollment) (Randomization) (Completion)
  • 17. PROMPT key selection criteria Inclusion criteria • Aged 18-80 years inclusive • Meets the IHS criteria for migraine* • Established history of migraine for > 1 year • At least 4 monthly migraine days during the previous 3 months • Capable of keeping trial records and having signed the ICF * Headache Classification Committee of the International Headache Society Cephalalgia 1988;8(Suppl 7):1-96.
  • 18. PROMPT primary endpoint  Primary efficacy parameter – Change in the number of migraine days during the last 4 weeks of the double-blind phase relative to the last 4 weeks of the open-label phase  Hypothesis (pre-trial) – Difference between topiramate and placebo group is (at least) 1.0 migraine day per 4 weeks
  • 20. PROMPT participation  21 countries / 88 sites* / 954 subjects  954 Screened  136 Screen Failures = 14.3% [ est. 25% ]  818 Enrolled OL phase 259 Early Terminated = 31.6% [ est. 35% ]  45 Not Randomized = 8.1% [ est. 20% ]  514 Randomized DB phase = 53.9% of Screened [ est. 39% ] * ) 1 more site with 10 subjects was disqualified and left out of the analysis 15
  • 22. Demographic and Baseline Characteristics mean Enrolled Randomized median (range) N = 818 N = 514 Age, years 39.8 40.1 40 (18-69) 40 (18-69) Height, cm 166.0 165.8 165 (140-194) 165 (140-194) Weight, kg 69.8 70.6 67 (45-151) 68 (45-151) BMI, kg/m² 25.3 25.6 24.5 (16.4-52.5) 24.9 (16.6-52.1) Gender, male/female % 13 / 87 13 / 87 Number of monthly migraine days at start 8.9 8.7 8.0 (0.0-28) 8.0 (3.3-28)
  • 23. PROMPT records in baseline/OL phase  Migraine observations 29,935  Acute medication observations 28,031  Adverse event observations 2,877  Concomitant medication observations 1,866  Trial medication observations 4,665
  • 25. Flexible dosing of topiramate (OL phase) Distribution of the last daily doses (N = 818) 50 40 % Subjects 30 20 10 0 12,5 25 50 75 100 125 150 175 200 Topiramate dose (mg/day)
  • 26. Fixed dosing of trial medication (DB phase) Distribution of the last daily doses topiramate (N=254) placebo (N=258) 50 40 % Subjects 30 20 10 0 0 25 50 75 100 125 150 175 200 Dose (mg/day)
  • 27. PROMPT EFFICACY RESULTS Change in monthly migraine days
  • 28. PROMPT primary efficacy parameter (OL phase) Mean number of migraine days per 4 weeks intent-to-treat analysis (n=811) completer analysis (n=559) 10 8,9 8,8 8 5,8 6 4,8 4 2 0 *** *** -2 -4 -3,1 -4,0 -6 Baseline Month 6 Baseline Month 6 migraine days change in migraine days *** p <0.0001 versus baseline
  • 29. PROMPT time course of migraine days Mean number of migraine days per 4 weeks (observed cases) All OL (N=811) Topiramate DB (N=253) Placebo DB (N=257) * p < 0.05 10 OL PHASE DB PHASE 9 8 7 * 6 5 4 3 2 1 0 0 10 20 30 40 50 60 Time (weeks)
  • 30. PROMPT primary efficacy parameter (DB phase) Mean change in number of migraine days per 4 weeks topiramate placebo Primary *** endpoint 1,6 1,4 *** ** 1,2 1,2 1,0 0,8 ** 0,6 0,4 0,2 0,1 0,0 -0,2 Start Week Week Week Week Last 4 -0,4 DB +4 +8 +16 +26 weeks ** p<0.01 vs. topiramate *** p<0.001 vs. topiramate
  • 31. PROMPT acute medication days (OL phase) Mean number of days per 4 weeks with acute medication intake any acute triptans analgesics 7 6,1 6 5,0 5 4,2 3,7 4 3,0 3 1,9 2 1 *** *** *** 0 -1 -2 -1,3 -1,1 -2,0 -3 Base- End- Base- End- Base- End- line point line point line point acute medication days change in acute medication days *** p <0.0001 versus start
  • 32. PROMPT change in Kg body weight versus baseline (observed cases) topiramate-topiramate topiramate-placebo 0 10 20 30 40 50 60 0 -0,5 OL PHASE DB PHASE -1 -1,5 -2 -2,5 -3 *** -3,5 *** -4 -4,5 *** p < 0.001 Time (weeks)
  • 33. PROMPT conclusions  Efficacy – The primary efficacy parameter after withdrawal of study medication was positive, showing an increase in the number of migraine days with placebo versus no change with topiramate.  Safety – Adverse events were similar to those observed in previous studies both in nature and in frequency of occurrence.
  • 34. Naturalistic principle conclusions  Attractive to investigators as treating physicians - “hands-on experience”  Motivating for patients - helpful in patient recruitment  Prerequisite to obtain insight into patient-preferred dosages  Powerful in combination with double-blind, randomized part in order to meet both scientific standards and ethics requirements