Clinical Trial Dolor 2 Update
-
Upload
taufik-akbar-faried-lubis -
Category
Documents
-
view
217 -
download
0
Transcript of Clinical Trial Dolor 2 Update
-
8/3/2019 Clinical Trial Dolor 2 Update
1/54
Low Back Pain:
Treatment and New Evidence
Clinical Trial Dolor
Professor Marco Antonio Naslausky MibielliSerra dos rgos University-TeresopolisHead of Service from Clinical Hospital UniversityMaster in Medicine - Orthopaedic and Traumatology
-
8/3/2019 Clinical Trial Dolor 2 Update
2/54
Clinical Trial
DOLORDiclofenac Combined with B Vitamins in Acute
Lumbago: Rapidness of Pain ReliefCompared to Diclofenac Monotherapy(DOLOR)
-
8/3/2019 Clinical Trial Dolor 2 Update
3/54
Low Back Pain
-
8/3/2019 Clinical Trial Dolor 2 Update
4/54
Clinical Significance
Fifth most common symptom-related reasonfor all physician visits in the U.S.The lifetime prevalence in Europe is 60-80%Estimated 84% (Waddel) of adults will experience
at least one episode of LBP at some point of the lifeJust 25% of Adults do sufer from this disorder and
about one third of this patients report substantiallimitation in their activity
-
8/3/2019 Clinical Trial Dolor 2 Update
5/54
Low Back Pain
Low Back Pain (LBP) = Symptom of musculoskeletaldisorders involving the lumbar vertebrae
Progression of LBP:
Acute - subchronic - chronic - recurrent(severe acute episodes)
Mechanical Causes
Triggers
Contributing conditions
-
8/3/2019 Clinical Trial Dolor 2 Update
6/54
Spinal disc herniation
Spinal stenosis
-
8/3/2019 Clinical Trial Dolor 2 Update
7/54
FracturesImproper lifting
Sports injury
Carrying heavy briefcase or backpack
-
8/3/2019 Clinical Trial Dolor 2 Update
8/54
Poor standing posture
Poor sitting posture
-
8/3/2019 Clinical Trial Dolor 2 Update
9/54
Excess weight & Lack ofmuscle tonus
Pregnancy
-
8/3/2019 Clinical Trial Dolor 2 Update
10/54
Sleep position Stress and muscletension
-
8/3/2019 Clinical Trial Dolor 2 Update
11/54
TYPES OF PAIN
Nociceptive Pain: caused byactivity in neural pathways inresponse to potentially tissue-damaging stimuli.
Mixed Type: caused by acombination of both primaryinjury or secondary effects.
Neuropathic Pain: iniciated orcaused by primary lesion ordysfunction in the nervoussystem.
-
8/3/2019 Clinical Trial Dolor 2 Update
12/54
Nociceptive Pain
-
8/3/2019 Clinical Trial Dolor 2 Update
13/54
Neuropathic Pain component
in Low Back Pain
Presence of a lesion or disruption to primary sensoryneurons (peripheral, dorsal) due to:TraumaCompressionTumor
Ischemia
Inflammation: metabolic disturbances, degenerative disordersor cytotoxic substances
Nervous system dysfunctionHyperalgesia and allodynia due to cytokine release(NGF, TNF, NFkappaB)
-
8/3/2019 Clinical Trial Dolor 2 Update
14/54
Patients with Low Back Pain:
Targets of Drug Therapy
Rapid and efficient amelioration of pain
Restoration of mobility
Improvement of sleep
Improvement of reduced daily activities
Fitness for work
Avoidance of chronification
-
8/3/2019 Clinical Trial Dolor 2 Update
15/54
Diclofenac - Mechanisms of Actions:
Anti-inflammatory - Analgesic - Antipyretic
Inhibition of Prostaglandin Synthesis by Inhibition ofCyclooxygenases (COX)- Moderate Preference to block COX-2 !
Inhibition of Lipoxygenase Pathways
- Reducing Formation of Leukotriens
Inhibition of Phospholipase A2
Blockade of Voltage-dependent Sodium Channels
Blockade of Acid-sensing Ion Channels (ASICs)
Modulation of Potassium Channels
-
8/3/2019 Clinical Trial Dolor 2 Update
16/54
Mechanisms of NSAIDs Action Brune 2007
-
8/3/2019 Clinical Trial Dolor 2 Update
17/54
Diclofenac - Kinetics
Increased concentrations of Diclofenac in targetareas
Lower protein binding of Diclofenac Enhanced drug-diffusion into intracellular Space
in therapeutic areas Fast decline of concentrations in compartmentscausing
side effects (CV, GI, Kidney)
-
8/3/2019 Clinical Trial Dolor 2 Update
18/54
Concentration of Diclofenac in Plasma and
Synovial Fluid over Time
-
8/3/2019 Clinical Trial Dolor 2 Update
19/54
Diclofenac versus Placebo in LBP patients:
Assessment of 50% pain reduction McQuay 1997
-
8/3/2019 Clinical Trial Dolor 2 Update
20/54
Characteristics of B-Vitamins B1 and B6
B-Vitamins counterract nerve damage by various mechanisms Vitamin B1
formation of Acetylcholine
transmission of impulses from nerves to muscles regeneration of the nervous system after strain
reduction of hyperexcitability lessening of Na currents alterations in injured neurons suppressing thermal hyperalgesia
Vitamin B6
modulates GABA release from pre-synaptic cells influences biosynthesis of neurotransmitters
serotonin, epinephrine, GABA Vitamins B1 and B6 activate cGMP involved in the inhibition ofthermal hyperalgesia
-
8/3/2019 Clinical Trial Dolor 2 Update
21/54
Characteristics of B-Vitamin B12
Vitamin B12 biosynthesis of neurotransmitters (EGF) methionine (myelin) synthesis)
Vitamin B12 deficiency increased production of TNF-alpha, IL-1, IL-6, NFB, NGF
a noxious role in the progression of neuropathya deficiency can be normalised by Vitamin B12 treatment
-
8/3/2019 Clinical Trial Dolor 2 Update
22/54
Improvement of Cold and Warm Sensation in
Patients with Diabetic Polyneuropathy
Cold sensation dotted: Placebo
Janka 1991
continuous : Vitamins B1, 6, 12
treatment 18 weeksWarm sensation
less means better
-
8/3/2019 Clinical Trial Dolor 2 Update
23/54
Percentage of Axons of N. saphenus
10 Days after Cold Damage
70
% 60
50
40
30
20
10
0Regenerating Degenerating not assigned
B Vitamins
Control
Axons covered with myelin sheaths
-
8/3/2019 Clinical Trial Dolor 2 Update
24/54
Writhing-test in Rats: Number of Pain RelatedSymptoms
Vehicle Diclofenac Diclofenac
+B-Vit
Rocha e cols. 2004
-
8/3/2019 Clinical Trial Dolor 2 Update
25/54
Clinical Trial DOLOR
Participating Professors from:
UNIFESO Universidade Federal do Rio de Janeiro (UFRJ)
Universidade Estadual do Rio de Janeiro (UERJ) Instituto Nacional de Traumatologia e Ortopedia (INTO) Centro Ortopdico Traumatolgico Sociedade Brasileira de Ortopedia e Traumatologia
Instituto de Ps-Graduao Mdica Carlos Chagas
(ICC)
-
8/3/2019 Clinical Trial Dolor 2 Update
26/54
DOLOR - Primary Study Objective
Percentage of patients with pain reduction:
VAS < 20 mm
Patients satisfaction
after 3 days of treatment allowing them to terminate the study
Comparison of treatment groups:
DB: Fixed combination of diclofenac + vitamins B1, B6, B12
versusD: Diclofenac monotherapy
-
8/3/2019 Clinical Trial Dolor 2 Update
27/54
-
8/3/2019 Clinical Trial Dolor 2 Update
28/54
Visual-Analog Pain Scale (VAS)
No Pain Most Severe Pain
-
8/3/2019 Clinical Trial Dolor 2 Update
29/54
PATIENT FUNCTIONALITY
QUESTIONNAIRE (PFQ)
Due to my back pain
I do not sleep well
I have to lie down more often
It is difficult for me to get up from my bed or a chair
I can stand only for a short while
I can walk up stairs only slowly
It is difficult for me to wash or dry off my whole body
It is difficult for me to put on my clothes
I can only walk short distances I try to avoid picking things up from the floor
I have to changemy posture more often
I cannot carry heavy things
I have to ask other people for assistance
1 oint was iven for each es answer
-
8/3/2019 Clinical Trial Dolor 2 Update
30/54
DOLOR
Subject Characteristics
Inclusion criteria
acute episode of
low back pain < 3 days
non-hospitalized, 18 years of age VAS between 20
and 80 mm
Exclusion criteria
Hypersensitivity to test products
Pregnancy or lactation
Acute disc damage Need of surgical treatment
Intake of other analgesics
Physical treatment
Blood coagulation diseases Gastric or intestinal ulcers
Asthma or acute rhinitis
Pathologic laboratory values
-
8/3/2019 Clinical Trial Dolor 2 Update
31/54
DOLOR: Study Course
Visit 1: Pre-treatment
- screening, randomization
- baseline evaluations
- study medication distribution Visit 2*: after 3 days of treatment
Visit 3*: after 5 days of treatment Visit 4: after 7 days of treatment
*Patients with sufficient pain reduction at Visits 2 and 3 mayterminate the study
-
8/3/2019 Clinical Trial Dolor 2 Update
32/54
DOLOR:
Efficacy and Tolerability Evaluations
Findings on admission
Medical history
Complete physical
evaluation Visual-analog pain scale
VAS (0-100 mm)
Patient functionalityquestionnaire (PFQ)
Motility evaluations (FFD)
Laboratory tests.
Findings during the study
Complete physical evaluation
Motility evaluations
VAS and PFQ evaluations Laboratory tests
Adverse event monitoring
-
8/3/2019 Clinical Trial Dolor 2 Update
33/54
Correlation VAS (cm) vs. PFQ Sum
at study begin
-
8/3/2019 Clinical Trial Dolor 2 Update
34/54
DOLOR - Primary study objective
Results after 3 days of treatment - Visit 2
Group DB Group Dn = 187 n = 185
Study completed n % n %
Due to clinical success 87 46.5 55 29.7
Due to insufficient 10 5.3 10 5.4efficacy
Due to side effects 3 1.6 0
Study continued (n) 87 120
success rate: 16.8%; OR: 2.1
Chi2 = 12.06; p = 0.0005
-
8/3/2019 Clinical Trial Dolor 2 Update
35/54
DOLOR - Primary study objective
after 3 days of treatment (V2)140
120
100
80
60
40
20
Group DB
0 Clinical Insufficient Side Study
success efficacy effects continued
Study completed p> 0.0005 NNT 5.95
Group D
-
8/3/2019 Clinical Trial Dolor 2 Update
36/54
DOLOR: Clinical Results After 5 Days
(Visit 3)
Group DB n= Group D n= 12087
n / % Patients n % n %
Study completed 71 82 52 43due to success
Study continued 16 18 68 57
Chi2: 29,07 p > 0.0001 OR: 5.6 NNT = 2.6
-
8/3/2019 Clinical Trial Dolor 2 Update
37/54
DOLOR
Result after 5 days of treatment - Visit 3
70
60
50
40
30
20
10
0 Group DB
Clinical success Study Group D
continued
Study completed p> 0.0001 NNT 2.6
-
8/3/2019 Clinical Trial Dolor 2 Update
38/54
DOLOR - Visual Analog Scale
Visit 1 vs Visit 2
-
8/3/2019 Clinical Trial Dolor 2 Update
39/54
DOLOR - Patients with Changes in VAS
between Visit 1 and Visit 2
Group DB Group D
n % n %
Impaired < 0 11 5.9 10 5.4No change = 0 - 20 58 31.0 94 50.8
Improved > 20 - 40 87 46.5 55 29.8
Improved > 40 - 60 30 16.1 23 12.4
Improved > 60 1 0.5 3 1.6
Improved: 63.1% vs. 43,8% p = 0,001 OR = 2,5
-
8/3/2019 Clinical Trial Dolor 2 Update
40/54
DOLOR: Patients Functionality
Questionaire
DB D DB D
-
8/3/2019 Clinical Trial Dolor 2 Update
41/54
DOLOR- Patient Functionality Questionnaire
Patients (%) with Improvement at Visit 2
60
50
40
30
20
10
0sleeping getting up climbing
stairs
Group DB > Group D (p < 0.05)
washing walking
Group DB n = 187Group D n = 185
-
8/3/2019 Clinical Trial Dolor 2 Update
42/54
DOLOR - Patients with Changes in PFQ
Sum between Visit 1 and Visit 2
PFQ Sum Group DB Group D
n % n %
Impaired > 0 11 5.9 14 7.6
No change = 0 29 15.5 39 21.1
Improved > 0 - 3 33 17.6 49 26.5
Improved > 3 - 6 51 27.3 45 24.3
Improved > 6 - 9 44 23.5 26 14.0Improved > 9 - 12 19 6.5 12 6.5
p = 0.0034 OR = 1.5
-
8/3/2019 Clinical Trial Dolor 2 Update
43/54
DOLOR: Finger-to-Floor Distance
mm: Group DB Group Dmean SD n = 187 n = 185
Beforetreatment 19.6 6 21.2 6 p = 0.05Day 2 13.7 7 16.6 7 p = 0.001
n = 87 n = 120
Day 3 9.9 6 12.9 5 p = 0.001
-
8/3/2019 Clinical Trial Dolor 2 Update
44/54
DOLOR - Finger-to-Floor-Distance
Difference between Visit 1 & Visit 2
50
40
30
20
10
0worsened no improved > 0
change :
Group DB > Group D: p < 0,05
> 5 > 10 > 15 mm
DB (n = 187)D (n=185)
-
8/3/2019 Clinical Trial Dolor 2 Update
45/54
Correlation of Finger-Floor-Distance and
VAS-Values after 3 Days of Treatment
-
8/3/2019 Clinical Trial Dolor 2 Update
46/54
DOLOR - Number of Patients with AEsVisit 2 Visit 3 Visit 4
Patients with AEs in Group DB D DB D DB Dn = 19 20 14 12 3 12
AEs (n)
GI-symptoms 8 9 2 10 2 8
CNS-symptoms 7 1 5 5 1 2
Glossitis 1
GOT/GPT elevation 6 3 7
Glucose elevation 2 1
Decreased PPT 1 3
Palate alteration 1 1
Hypertension 1 4
Urticaria, skin eruption 1 1 3
Increased BSR 1
Tinitus 1
Insomnia 1
Fatigue 1
Dry mouth 1
Depression 1
GI-symptoms: Dyspesia, Flatulence, Pyrosis nocturna, Diarrhea, ConstipationCNS-symptoms: Nauseaa, Vertigo, Headache
-
8/3/2019 Clinical Trial Dolor 2 Update
47/54
DOLOR: Number of Patients with Adverse
Events
Group DB Group D
AE = 1 AE > 2 AE = 1 AE > 2
n n n n
Visit 2 12 7 15 5
Visit 3 11 3 9 3
Visit 4 1 1 10 2
Total 24 11 34 10
-
8/3/2019 Clinical Trial Dolor 2 Update
48/54
Low Back Pain - Conclusions
The symptoms most patients are suffering appear to be
related to functional pathology, psycho-social factors and
environmental components
Pain may be of nociceptive and neuropathic origin
Drug treatment should be multi-modal
Short term administration of Diclofenac is a potent choice
for treatment of LBP relief
Vitamins B1, B6, B12 provide various effectscounteracting nerve damage and extent nociceptive pain
treatment by Diclofenac with potent activity against
neuropathic pain
-
8/3/2019 Clinical Trial Dolor 2 Update
49/54
Study Publication
DOLOR study paper published in Current MedicalResearch & Opinion (November 2009)
A MEDLINE-indexed, peer-reviewed, internationaljournal publishing original research on new and existingdrugs and therapies5-Year ISI Impact Factor (2008): 2.866
Ranked 27/107 in the Medicine, General & Internalcategory in the 2008 ISI Journal Citation Reports and32/82 in the Medicine, Research & Experimental
category.
-
8/3/2019 Clinical Trial Dolor 2 Update
50/54
Evolution of Back Pain
-
8/3/2019 Clinical Trial Dolor 2 Update
51/54
Monocentric Clinical Trial: Patients with
Acute Lumbago Lettko 1987
Clinical results after 7 days
Diclofenac Group D150mg/day + B-Vit 150 mg/dayn = 99 n = 96
n / % of patients n % n %
Study terminateddue to success 19 19.2 7 7.3
Study continued 80 80.8 89 92.7
p = 0.01
-
8/3/2019 Clinical Trial Dolor 2 Update
52/54
Monocentric Clinical Trial
Patients with Acute Lumbago
Clinical results after 3 days
Diclofenac75mg/day +B-Vit
n = 52
Kuhlwein & Koch 1991
Diclofenac75mg/day
n = 52n % n %
Patients - study successfullyterminated 18 35 6 11
Study discontinued due to failure
4 8 10 19p = 0.01
-
8/3/2019 Clinical Trial Dolor 2 Update
53/54
Multicenter Clinical Trial
Patients with Acute Lumbago Brueggeman et al 1990
Clinical results after 3 days
Diclofenac Group D150 mg/day + 150 mg/day
Vit. B1, B6, B12n = 184 n = 192
n % n %
Pain Improvedfrom heavy to mild 53 28.8 48 25
/none
p > 0.049
-
8/3/2019 Clinical Trial Dolor 2 Update
54/54
THANK YOU
M