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

Double-Blind Phase Baseline

Phase

Titration Fixed dose

200 mg/d

50 mg/d 25

4 (8) weeks 4 weeks 18 weeks 4 weeks

Week 0 (Enrollment)

Week 26 (Randomization)

Screening

Flexible dose

50

75

Open-Label Phase

1 week 25 weeks

Week 52 (Completion)

PLACEBO

200 mg/d

50 mg/d

Fixed dose

1 week

Run-Out

Phase

100

Taper

off

TOPIRAMATE TOPIRAMATE

No Treatment

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

median (range) Enrolled

N = 818

Randomized

N = 514

Age, years 39.8

40 (18-69)

40.1

40 (18-69)

Height, cm 166.0

165 (140-194)

165.8

165 (140-194)

Weight, kg 69.8

67 (45-151)

70.6

68 (45-151)

BMI, kg/m² 25.3

24.5 (16.4-52.5)

25.6

24.9 (16.6-52.1)

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

Number of monthly migraine days at start 8.9

8.0 (0.0-28)

8.7

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

0

10

20

30

40

50

12,5 25 50 75 100 125 150 175 200

Topiramate dose (mg/day)

% S

ub

jec

ts

Flexible dosing of topiramate (OL phase)

Distribution of the last daily doses (N = 818)

0

10

20

30

40

50

0 25 50 75 100 125 150 175 200

Dose (mg/day)

% S

ub

jec

ts

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

Fixed dosing of trial medication (DB phase)

Distribution of the last daily doses

PROMPT

EFFICACY RESULTS

Change in monthly migraine days

*** p <0.0001 versus baseline

8,9

5,8

8,8

4,8

-3,1-4,0

-6

-4

-2

0

2

4

6

8

10

Baseline Month 6 Baseline Month 6

migraine days change in migraine days

*** ***

intent-to-treat analysis (n=811) completer analysis (n=559)

PROMPT primary efficacy parameter (OL phase) Mean number of migraine days per 4 weeks

0

1

2

3

4

5

6

7

8

9

10

0 10 20 30 40 50 60

Time (weeks)

All OL (N=811) Topiramate DB (N=253) Placebo DB (N=257)

PROMPT time course of migraine days

Mean number of migraine days per 4 weeks (observed cases)

*

* p < 0.05

OL PHASE DB PHASE

0,1

1,2

-0,4

-0,2

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

1,6

Start

DB

Week

+4

Week

+8

Week

+16

Week

+26

Last 4

weeks

topiramate placebo

**

***

PROMPT primary efficacy parameter (DB phase)

Mean change in number of migraine days per 4 weeks

*** **

** p<0.01 vs. topiramate

*** p<0.001 vs. topiramate

Primary

endpoint

6,1

4,2

5,0

3,73,0

1,9

-1,3 -1,1-2,0

-3

-2

-1

0

1

2

3

4

5

6

7

Base-

line

End-

point

Base-

line

End-

point

Base-

line

End-

point

acute medication days change in acute medication days

*** ***

any acute triptans analgesics

***

*** p <0.0001 versus start

PROMPT acute medication days (OL phase) Mean number of days per 4 weeks with acute medication intake

PROMPT change in Kg body weight versus baseline (observed cases)

OL PHASE DB PHASE

-4,5

-4

-3,5

-3

-2,5

-2

-1,5

-1

-0,5

0

0 10 20 30 40 50 60

Time (weeks)

topiramate-topiramate topiramate-placebo

*** ***

*** p < 0.001

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