clinical trial dolor 2 update

8/3/2019 Clinical Trial Dolor 2 Update

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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


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Clinical Trial

DOLORDiclofenac Combined with B Vitamins in Acute

Lumbago: Rapidness of Pain ReliefCompared to Diclofenac Monotherapy(DOLOR)


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Low Back Pain


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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


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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


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Spinal disc herniation

Spinal stenosis


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FracturesImproper lifting

Sports injury

Carrying heavy briefcase or backpack


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Poor standing posture

Poor sitting posture


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Excess weight & Lack ofmuscle tonus

Pregnancy


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Sleep position Stress and muscletension


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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.


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Nociceptive Pain


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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)


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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


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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


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Mechanisms of NSAIDs Action Brune 2007


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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)


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Concentration of Diclofenac in Plasma and

Synovial Fluid over Time


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Diclofenac versus Placebo in LBP patients:

Assessment of 50% pain reduction McQuay 1997


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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


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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


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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


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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


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Writhing-test in Rats: Number of Pain RelatedSymptoms

Vehicle Diclofenac Diclofenac

+B-Vit

Rocha e cols. 2004


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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)


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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


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Visual-Analog Pain Scale (VAS)

No Pain Most Severe Pain


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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


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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


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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


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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


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Correlation VAS (cm) vs. PFQ Sum

at study begin


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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


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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


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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


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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


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DOLOR - Visual Analog Scale

Visit 1 vs Visit 2


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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


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DOLOR: Patients Functionality

Questionaire

DB D DB D


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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


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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


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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


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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)


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Correlation of Finger-Floor-Distance and

VAS-Values after 3 Days of Treatment


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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


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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


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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


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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.


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Evolution of Back Pain


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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


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Monocentric Clinical Trial

Patients with Acute Lumbago


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


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Multicenter Clinical Trial

Patients with Acute Lumbago Brueggeman et al 1990


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


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THANK YOU

M

clinical trial dolor 2 update

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