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
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
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