Outcomes for Rare Diseases Clinical Trials - Pr. Shahram ATTARIAN Reference center for
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Outcomes for Rare Diseases
Clinical Trials
Pr. Shahram ATTARIAN
Reference center for
Neuromuscular disorders & ALS
CHU Timone
Marseille
Outcomes for Rare Diseases
Clinical Trials
• To evaluate the therapeutic efficacy of an intervention
should be considered as fundamental to the design of
trials .
• Flawed measures threaten the significance of trials that
use them and impede comparisons of the results.
• Selected outcome measures need to be clinimetrically
well evaluated.
• Which kind of Outcome in clinical trials?
– Clinical ?
– Biomarkers?
– Imaging?
– Electrophysiology?
Clinical Outcomes • Most researchers tend to magnify the deficiencies of existing measures and underestimate the effort required to develop an adequate new measure. • This proliferation impedes research, since there are significant problems in generalizing from one set finding to another. • The first step is to be aware of any existing scales. • The next step is to understand and apply criteria for judging the usefulness of particular scale. • The scale should satisfy the following clinimetric criteria : – Validity – Reliability – Responsiveness – Simplicity – Communicability
Clinical Outcomes
Clinimetric
• Validity
Technical description of the judgment that a scale looks
reasonable (expert opinion).
Content validity: Judgment whether the scale samples all
the relevant domains of the disorder.
Criterion validity: the correlation of a scale with other
measures of the disorder under study.
Clinical Outcomes
Clinimetric
• Reliability
The scale is measuring what is intended.
Internal consistency: inter item consistency
(Cronbach’s alpha)
Stability/ Reproducibility (test-retest)
Observer reliability (interrater)Charcot-Marie Tooth (CMT) Neuropathies
First description in 1886
– Peripheral Neuropathy
– Distal motor weakness
– Progressive Muscular
Atrophy
– Sensory weakness
– Cramps, pain,
– Foot deformities
Most frequent subgroup is
the CMT1A (prevalence =
1/5000)Backgrund
• Milestones for scientific knowledge on CMT1A :
– Gene mutation Identification: duplication of
PMP22 on chromosome 17
(Lupski et al, 1991)
– Animal models
(Huxley et al, 1996; Sereda et al, 1996; 2003)Passage et al, Nat Med 2004
CMT Neuropathy Scale
CMTNS (Shy et al, Neurology 2005)
1
CMTES
2
3CMTNS
• Valid
• Reproducible
• Natural history study
• 72 patients with CMT included
• « 8 years» of follow-up
• Worsening annual rate = 0.7 (2%)
Shy et al, Neurology 2008Trials
1. Burns et al, Lancet Neurol 2009 1. Dorsiflexion des pieds
1. 81 child
2. 30 mg/kg/J; duration = 1 Y
2. Micallef et al, Lancet Neurol 2009 2. CMTNS
1. 180 patients
2. 1g/J, 3g/J; duration =1 Y
3. Pareyson et al, Lancet Neurol 2011 3. CMTNS
1. 280 patients, 1.5 g/J;
2. duration = 2 Y
4. Shy et al, Jama neurology 2013 4. CMTNS
1. 120 patients, 4g/J;
2. duration = 2 Y• Multicentric double blind (Marseille, Lyon, Paris)
• N= 180 patients
• 3 groups: placebo, 1g/J et 3g/J
• Duration: 12 mo
• Outcomes
– CMTNS
– ONLS
– QMT
– 10 WT
– SF-36
– CGI
– VASResults Micallef et al, 2009 Lancet Neurology (IF = 22.6)
Outcome measures evaluation
using French trial data
• 180 patients at Baseline • Validity
• Item analysis
• Inter-item correlations
• 62 patients in placebo
• Convergent validity/criterion-
group, followed every 3 mo
related validity
during 12 mo
• Reliability
• Internal consistency/validity
• Multicentric evaluation • Responsiveness
• Reproducibility/test-retestSensibility to change of CMTNS?
N= 61
Placebo group Baseline M3 M6 M12
CMTNS 15.7 15.7 16.1 16.4
(5.6) (5.5) (5.7) (5.8)
CMTES 10.9 11.1 11.5 12.0 0.9 (3.0)
(4.8) (4.8) (4.7) ( 4.4) p=0.022Limits of CMTNS
Items 0 1 2 3 4
2-Motor symptoms legs None Trips, catches AFO on at least 1 leg or Cane, walker, Wheelchair most of
toes, slaps feet ankle support ankle surgery the time
3-Motor symptoms None Difficulty with Unable to do Can’t write or Proximal
arms buttons/zippers buttons or zippers, use keyboard arms
but can write
4-Pin sensibility Normal Reduced in fingers/toes Reduced up to Reduced up to Reduced
and may include wrist/ankle and may include above elbow/knee
elbow/knee
8- Ulnar CMAP >6 mV 4–5.9 mV 2–3.9 mV 0.1–1.9 mV Absent
(Median CMAP) (>4 mV) (2.8–3.9) (1.2–2.7) (0.1–1.1) (Absent)
9- Ulnar SNAP >9 V 6–8.9 V 3–5.9 V 0.1–2.9 V Absent
(Median SNAP) (>22V) (14–21.9) (7–13.9) (0.1–6.9) (Absent)CMTNS v2
Next therapeutic trial in CMT1a The Pleotherapy
Networking for new drugs
Nature Medicine 2011
17, 1166–1168
PXT3003 is a combination of the generic drugs baclofen, normally used to treat
spasticity, naltrexone, usually used to treat opiate and alcohol addiction, and sorbitol, a
laxative.
The trial began in December 2010, involves 80 participants and results are expected at
the end of next year.5 years Natural History
5 20
2006 (AA)
5 * 2006 (AA)
2011 (PXT)
18
2011 (PXT)
4 16
4 14
ONLS scores
3 12
Scores
3 10
2 8
2 6
1 4
1 2
0
0
ONLS total score ONLS arm score ONLS leg score
CMTNS CMTES
Comparative analysis of data collected from
AA and PXT 3003 trialsConclusion • To evaluate the therapeutic efficacy of an intervention should be considered as fundamental to the design of trials . • Flawed measures threaten the significance of trials that use them and impede comparisons of the results. • Selected outcome measures need to be clinimetrically well evaluated: – Validity – Reliability – Responsiveness – Simplicity – Communicability
J. Pouget
A. Verschueren
E. Campana-Salort
J. Franques
J. Gallard
R. Bernard
N. Lévy
JM Vallat
L. Magy J. Micallef
B. Funalot E Jouve
A. Lacour M.N. Lefebvre
O. Dubourg C Colomban
T. Stojkovic
M. Berro
PM. Gonnaud
Y. Péréon Y Adjibi
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