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Clinical trial
Bagian Farmakologi dan ToksikologiFak. Kedokteran, Gadjah Mada University
Phase – III Clinical Trial
Randomized Controlled Trial
Ukuran sampel yang besar
Mengevaluasi obat ‘baru’ vs. control (positif/negatif)
Paling mahal dan time consuming
Obat diuji dengan metodologi yang ketat
Steps for RCT Design
1. Seleksi subyek penelitian
2. Jenis dan bentuk perlakuan
3. Randomisasi
4. Blinding
5. Pengukuran outcome
6. Analisa data
1. Appropriate to the study question2. Generalizable3. Consider the outcome of interest4. Allow adequate recruitment (study
patients you have access to)
Kriteria inklusi
1. Exclude patients with conditions that will compete with the outcomes (e.g. likely early death from cancer)
2. Contradictions to interventions3. Difficult to comply
Kriteria eksklusi
1. Seleksi subyek penelitian
• Male and female outpatients• Clinically diagnosed as CAP• Chest-X-ray: pulmonary infiltrate or consolidation• Showing at least three of the following symptom/sign:
– nonproductive cough, – new onset of purulent sputum (productive cough), or– change in the character of their sputum; – sputum culture positive for gram-positive diplococci;– body temperature of 38 7C or more at least twice within a 24 h
period; and/or – elevated leukocyte count (10x10 9 /l).
RCT: azithromycin vs. clarithromycin for adult with mild to moderate CAP
Example of exclusion criteria
• Terminal illness• Any condition that could interfere with the attendance
schedule• Patient with the followings:
1. Likely to affect gastrointestinal absorption of antimicrobial activity
2. significant hepatic disease with a serum transaminaselevel more than three times the upper limit of the normal range [serum glutamic oxalacetic transaminase (SGOT) 0.02–0.90 mM/s/; serum glutamic pryruvic transaminase(SGPT) 0.15–0.95 mM/s/l].
3. hypersensitive to azithromycin, clarithromycin, or other macrolide, cyclosporine, theophylline, astemizole, terfenadine, or antacids
TreatmentTreatment ControlControl
• Drug formulation • therapeutic class• dosage• drug administration,
frequency• duration of treatment
• standard drug (DOC)• placebo
• non fatal outcome/ disease
Treatment & Control groupTreatment & Control group
2. Jenis dan bentuk perlakuan
Sama dalam hal• bentuk• rupa• warna• rasa• bau• konsistensi• cara pemberian
Obat/intervensi
RANDOMIZATION
� Objective measures� Equal chance for treatment or control group� Both groups are balanced� To prevent bias
Simple randomization
Randompermuted block
Randompermuted block
within strata
metode
3. Randomize
RANDOMIZATION
2 treatment groups: (0-4= A; 5-9=B)
3 treatment groups: (1-3= A; 4-6= B; 7-9 = C)
4 treatment groups (1-2= A; 3-4= B; 5-6= C; 7-9=D)
Simple randomizationSimple randomization
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RANDOM LISTS
RANDOMISASI
� 2 treatment groups: AB for 0-4; BA for 5-9
� 3 treatment groups:ABC= 1; ACB= 2; BAC= 3BCA= 4; CAB= 5; CBA= 6
� 2 treatment group with block of 4 patientAABB= 1; ABAB= 2; ABBA= 3BBAA= 4; BABA= 5; BAAB= 6
Random permuted blocksRandom permuted blocks
4.BLINDING
� To prevent bias� To prevent prediction effect� Objective measures� Reducing risk of overwhelming
examination
Aims:Aims:
RCTs according to whether the investigators and participants know which intervention is being assessed
Open trials
Triple and quadruple-blind trials
Double blind trials
Single blind trials
BLINDING
Single blind Double blind Triple blind
Patient Patientdoctor/rater
PatientDoctor/raterStatistician
5. PENGUKURAN BASELINE & OUTCOME
� Measurable� Objective� Accurate� Consistent
Define potential important variables
Compare between study groups
Account for differences in study design or analysis of results
Measure baseline variables
RCT helicobacter pylori eradication in NSAID user
Outcome Measures
Easy to diagnose and observeEasy to diagnose and observe
Free of measurement or ascertainment errors
Free of measurement or ascertainment errors
Can be observed independent oftreatment assignment
Can be observed independent oftreatment assignment
Chosen before the start of data collectionChosen before the start of data collection
Clinically relevant Clinically relevant
Measurement bias� Measurement error� Recall bias� Observer bias
Sumber-sumber bias
� peneliti (misalnya interviewer bias)� subyek penelitian (recall bias)� pengukuran outcome
(measurement bias)
� Descriptives
� Survival time: early treatment vs. dead� tumor response: reduction of tumor size
� Duration of treatment vs. treatment response� Patients improvement
� Toxicity
e.g: e.g: cytostaticscytostatics
6. Analisa data
Bagaimana menyajikan data descriptive?
Bagaimana menyajikan data descriptive?
�Prosentase�Mean, SD, SEM�Proporsi�RR (relative risk)
Bentuk penyajian
0
20
40
60
80
100
1st Qtr 2nd Qtr 3rd Qtr
EastWestNorth
1st Qtr2nd Qtr3rd Qtr4th Qtr
0
20
40
60
80
100
1st Qtr 2nd Qtr 3rd Qtr 4th Qtr
EastWestNorth
Deskripsi0
20
40
60
80
100
120
140
160
180
1st Qtr 2nd Qtr 3rd Qtr 4th Qtr
NorthWestEast
Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study
Lancet1998; 352: 1016–21
RisikoRisiko relatifrelatif (RR = Relative Risk)(RR = Relative Risk)
PenyakitPenyakit
+ + --
+ a b+ a b
-- c dc dEksposurEksposur
aa------------a + ba + b
RR = RR = ----------------------------cc
------------c + dc + d
RR = (a/RR = (a/a+ba+b) ) –– ((c/c+dc/c+d))
Risiko relatif (RR = Relative Risk)
Stroke
+ -
+ 10 90 = 100
- 20 80 = 100BPLD
AR = (a/a+b) – (c/c+d)
RR untuk elective SC : 0.24 (95% CI: 0.11 - 0.48)RR untuk non-elective SC : 0.30 (95% CI: 0.25 - 0.35)
Antibiotika profilaksi pada SC mencegah endometritis
95% Confidence interval
� RR = 2,45; 95% CI (1,85:2,92)
� RR = 1,85; 95% CI (0,95-2,25)
The estimate of the treatment effect?
95% Confidence interval
Risiko Odds (OR = Odds Ratio)
Penyakit
+ -
+ a b
- c dEksposur
a------0 + b
RR = --------------c
------0 + d
OR = ad/bc
Relative Risk Reduction
RRR = (|CER – EER|/CER)
CER : Control Event Rate (tanpa terapi dimaksud/plasebo)EER : Experimental Event Rate (dengan terapi dimaksud)
The effect of fosinopril on cardiovascular events in population with hypertension
100 patients RCT 50 placebo and 50 fosinoprilAfter 5 years 20 in placebo group and 10 in fosinopril group had CVECER (placebo, %) ?EER (fosinopril, %) ?RRR (CER-EER/CER) ?ARR (|CER-EER|) ?NNT (1/ARR) ?
100 patients RCT 50 placebo and 50 fosinoprilAfter 5 years 20 in placebo group and 10 in fosinopril group had CVECER (placebo, %) ?EER (fosinopril, %) ?RRR (CER-EER/CER) ?ARR (|CER-EER|) ?NNT (1/ARR) ?
CER = control event rateEER = experimental event rateRRR = relative risk reductionARR = absolute risk reductionNNT = number needed to treat
Event rate= cardiovascular events
CER (plasebo) 40%EER (fosinopril) 20%CER (plasebo) 40%EER (fosinopril) 20%
Table 5.4 EBM-Sacket
NNT (1/ARR)NNT (1/ARR)
RRR (CER-EER/CER) RRR (CER-EER/CER)
ARR (|CER-EER|) ARR (|CER-EER|)
(40% - 20%)/40% = 50%(40% - 20%)/40% = 50%
40% - 20% = 20 %40% - 20% = 20 %
1/20% = 51/20% = 5
The effect of fosinopril on cardiovascular events in population with hypertension
0 1 2 3 4 5 6
Tramadol 75mg
Parasetamol 650 mg
Parasetamol 1000 mg
Aspirin 650 mg
Parasetamol 650 mg + kodein 60 mg
Morfin 10 mg IM
Ibuprofen 400 mg
Ketorolak 10 mg
Naproksen 440 mg
Diklofenak 50 mg
Number Needed to Treat (NNT)
Efikasi berbagai AINS berdasarkan nilaiNNT (Number Needed to Treat)
• Confounding occurs when two factors are associated with each other and effect of one is confused with or distorted by the effect of the other
• A confounder is a variable which is associated with the exposure, and independent of that exposure is a risk factor of the disease
ConfoundingConfoundingConfounding
To be a confounding factor, two conditions must be met:
Be associated with exposure- without being the consequence of exposure
Be associated with outcome- independently of exposure (not an intermediary)
ConfoundingConfoundingConfounding
Exposure Outcome
Third variable
ConfoundingConfounding
Coffee CHD
Smoking
Smoking is correlated with coffee drinking and a risk factor even for those
who do not drink coffee
TERIMA KASIH