06 Completed Thesisfdfd

MGM School of Biomedical Sciences, Aurangabad.
1. Introduction:
Osteoarthritis (OA) is the most common type of arthritis and is the major cause of chronic
musculoskeletal pain and mobility disability in elderly population worldwide. Knee and hip pain are
the major causes of difficulty in walking and climbing stairs in the elderly. Treatment of OA of the
knee and hip is directed towards reducing pain, stiffness and improving mobility [17,18] As per
Osteoarthritis Research International (OARSI) guidelines topical NSAIDs are widely used as
adjunctive or alternative therapy by patients with OA knee and are recommended in 7/9 existing
[5,19- 20]
guidelines where this modality of therapy is considered . Dexketoprofen is an NSAID with
[21- 23]
analgesic, anti-inflammatory and antipyretic actions belonging to the aryl propionic acid family .
Dexketoprofen is the S(+) enantiomer of the racemic compound ketoprofen and acts on both
isoenzymes of cyclooxygenase (COX). As with other aryl propionic acid derivatives, it has been
shown that the levorotatory enantiomer (- or R) does not contribute to the efficacy of the racemic
drug, but may have influence on the safety profile of dexketoprofen. Dexketoprofen has been
developed as the tromethamine salt (dexketoprofen trometamol), a formulation with high water
solubility. Based on the efficacy and safety evidence for the oral formulation, Dexketoprofen
trometamol gel for topical application in the treatment of painful, inflammatory, degenerative or
[24, 25]
traumatic origin of the joints, tendons or muscles has been developed . The stratum corneum, the
rate limiting barrier to percutaneous absorption, is made up of keratin and ceramides which could
[24- 26]
potentially provide a chiral environment . Differential binding of enantiomers to keratin or
interactions with ceramide may give rise to differences in the permeation profiles of the enantiomers
[3, 23]
. The trometamol salt form of dexketoprofen was formulated to improve the pharmacokinetics of
the orally administered drug. The maximum concentration is greater and the time to it less, with the
trometamol salt compared with the free acid form of dexketoprofen [6, 23, 27].
The methodology most commonly used for the evaluation of pain severity and relief is the visual
analogue scale (VAS).1 It is easy to use, provides reproducible results. It is also sensitive to
treatment effects and the data derived can be analyzed using statistical techniques. The main
disadvantage of this methodology is that there is limited information to correlate these statistically
[35, 36]
significant results with clinical significance to patients in terms of reduction of their pain . The
present study was performed in patients with knee osteoarthritis comparing the efficacy and safety of
Dexketoprofen Gel and Diclofenac Gel, an NSAID widely accepted as reference therapy for
[28, 29, 32]
symptomatic treatment of osteoarthritis . The primary objective of this study was to compare
the effects of Dexketoprofen Gel with Diclofenac gel for measuring the pain relieving activity by
using a visual analogue scale (VAS), in knee osteoarthritis [31, 33, 34 ].
2. Disease and Drug review:
Page 1
2.1 Arthritis-
Arthritis is a group of conditions involving damage to the joints of the body. The major complaint
by individuals who have arthritis is joint pain. Pain is often a constant and may be localized to the
joint affected. The pain from arthritis occurs due to inflammation that occurs around the joint,
damage to the joint from disease, daily wear and tear of joint, muscle strains caused by forceful
movements against stiff, painful joints and fatigue [web1].
2.1.1 Types of arthritis
Different Types of arthritis but most common arthritis are-
 Rheumatoid arthritis: Rheumatoid arthritis is the most common serious inflammatory form
of arthritis. It affects roughly 1 per cent of the population and is the prototypical autoimmune
form of arthritis. Because it may do most of its damage in the first year, early diagnosis and
aggressive therapy is critical. Left untreated RA may shorten life expectancy by as much as
18 years [web3].
 Psoriatic arthritis: Psoriatic arthritis is a potentially serious inflammatory form of arthritis
that is often found in association with psoriasis. Because it may begin and progress
insidiously, it can cause serious problems. Early diagnosis and aggressive intervention are
recommended[web10].
 Osteoarthritis: This type of arthritis is the one people think of as being associated with
aging. osteoarthritis affects weight-bearing areas such as the spine, hips, knees, base of the
thumbs, and feet. Genetics and mechanical factors also play a big role. Research is being
done on medications that will slow down the progression of this disease [web2].
 Polymyalgia rheumatica: Polymyalgia rheumatica occurs in people after the age of 50 and
presents with severe stiffness and aching in the neck, shoulders, and hips. Because it is very
treatable, accurate diagnosis is needed. Because so many other conditions look like it, an
accurate diagnosis is not always easy[web10].
 Ankylosing spondylitis: This inflammatory form of arthritis affects the spine and the
sacroiliac joints. Since it often presents with low back pain, it is often misdiagnosed. AS is
very treatable; accurate diagnosis and agressive therapy are advisable [web10]
 Reactive arthritis: Reactive arthritis is a form of arthritis that comes on after infections... the
most common being types of infections being intestinal or genitourinary. Young adults are
often affected. Appropriate medical treatment is very effective [web10].
 Gout: This common form of arthritis is due to deposition of monosodium urate (MSU)
crystals. In addition to joints, the kidneys are a big target of this disease. Dietary changes and
medicines are very effective in treating this disorder [web5].
Page 2
 Pseudogout: This form of arthritis is also due to crystals- deposits of calcium pyrophosphate
or hydroxyapatite in most instances. Pseudogout may mimic other types of arthritis such as
gout and rheumatoid arthritis. Further, it may coexist with other types of arthritis making it
very difficult to diagnose[web10].
 Lupus: This is a common collagen vascular disorder that can be present with severe arthritis.
Other features of lupus include a skin rash, extreme photosensitivity, hair loss, kidney
problems, emotional lability, lung fibrosis and constant joint pain. [web4]
 Polymyositis This inflammatory form of muscle disease is often associated with arthritis.
Because it is a systemic condition that affects all muscles- including those that are
responsible for the functioning of the heart, lungs, etc., careful examination and appropriate
aggressive medical therapy are necessary [web10].
 Fibromyalgia Fibromyalgia is a soft tissue form of arthritis that is due to defective
neurotransmitter function in the brain. Because these neurotransmitters are responsible for
many sensory functions, patients with fibromyalgia present with bizarre symptoms. It is
imperative that other forms of arthritis be ruled out first [web10].
 Lyme disease Lyme disease occurs as a result of infection with Borrelia burgdorferi. The
organism is transmitted by a deer tick bite. Early recognition and antibiotic therapy is
effective in most cases[web10].
2.1.2 Causes of Arthritis

Some of the risk Factors that can cause arthritis, which are following
 Genetics-
Exactly how much heredity or genetics contributes to the cause of arthritis is not well
understood. However, there are likely genetic variations that can contribute to the cause of
arthritis.
 Age
Cartilage becomes more brittle with age and has less of a capacity to repair itself. As people
grow older they are more likely to develop arthritis.
 Weight
because joint damage is partly dependent on the load the joint has to support, excess body
weight lead to arthritis. This is especially true of the hips and knees that can be worn quickly
in heavier patients.
 Previous Injury
Joint damage can cause irregularities in the normal smooth joint surface. Previous major
Page 3
injuries can be part of the cause of arthritis. An example of an injury leading to arthritis is a
tibial plateau facture. Where the broken area of bone enters the cartilage of the knee joint.
 Occupational Hazards
Workers in some specific occupations seem to have a higher risk of developing arthritis than
other jobs. These are primarily high demand jobs such as assembly line workers and heavy
construction.
 Some High-Level Sports
it is difficult to determine how much sports participation contributes to development of
arthritis. Certainly, sports participation can lead to joint injury and subsequent arthritis.
However, the benefits of activity likely outweigh any risk of arthritis.
 Illness or Infection
People who experience a joint infection (septic joint), multiple episodes of gout, or other
medical conditions, can develop arthritis of the joint [web5].
2.2 Dexketoprofen:
2.2.1 Introduction
Dexketoprofen is a water-soluble salt of the dextrorotatory enantiomer of the nonsteroidal anti-
inflammatory drug (NSAID) ketoprofen. Racemic ketoprofen is used as an analgesic and an anti-
inflammatory agent, and is one of the most potent in vitro inhibitors of prostaglandin synthesis.
This effect is due to the (S)-(+)-enantiomer (dexketoprofen), while the (R)-(-)-enantiomer is devoid
of such activity [16].
2.2.2 Chemistry
Pharmacotherapeutic group: propionic acid derivatives.
The structural formula is represented below:
Scientific Name-[2s]-2-[3-benzoyl] phenyl] propanoic acid
Page 4
Dexketoprofen trometamol is the tromethamine salt of S-(+)-2-(3- benzoylphenyl)propionic acid,

an analgesic, antiinflammatory and antipyretic drug, which belongs to the non-steroidal anti-
inflammatory group of drugs (M01AE).
2.2.3 The mechanism of action
The mechanism of action of non-steroidal antiinflammatory drugs is related to the reduction of

prostaglandin synthesis by the inhibition of cyclooxygenase pathway. Specifically, there is an
inhibition of the transformation of arachidonic acid into cyclic endoperoxides, PGG 2 and PGH2,
which produce prostaglandins PGE1, PGE2, PGF2α and PGD2 and also prostacyclin PGI2 and
thromboxanes (TxA2 and TxB2). Furthermore, the inhibition of the synthesis of prostaglandins
could affect other inflammation mediators such as kinins, causing an indirect action which would
be additional to the direct action. Dexketoprofen has been demonstrated to be an inhibitor for COX-
1 and COX-2 activities in experimental animals and humans. Clinical studies performed on several
pain models demonstrated effective analgesic activity of dexketoprofen trometamol. The onset of
the analgesic activity was obtained in some studies at 30 minutes post-administration. The analgesic
effect persists for 4 to 6 hours.[web1]
2.2.4 Pharmacokinetic
After administration of dexketoprofen trometamol to humans, the Cmax is reached at 30 min (range
15 to 60 min). The distribution half-life and elimination half-life values of dexketoprofen
trometamol are 0.35 and 1.65 hours, respectively. As with other drugs with a high plasma protein
binding (99%), its volume of distribution has a mean value below 0.25 l/kg. The main elimination
route for dexketoprofen is glucuronide conjugation followed by renal excretion. After
administration of dexketoprofen trometamol only the S-(+) enantiomer is obtained in urine,
demonstrating that no conversion to the R-(-) enantiomer occurs in humans. In multiple-dose
pharmacokinetic studies, it was observed that the AUC after the last administration is not different
from that obtained following a single dose, indicating that no drug accumulation occurs. When
administered concomitantly with food, the AUC does not change, however the Cmax of
dexketoprofen trometamol decreases and its absorption rate is delayed (increased tmax) [1].
2.2.5 Pre-clinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and
immunopharmacology. The chronic toxicity studies carried out in mice and monkeys gave a No
Page 5
Observed Adverse Effect Level (NOAEL) of 3 mg/kg/day. The main adverse effect observed at
high doses was gastrointestinal erosions and ulcers that developed dose-dependently [web1].
2.2.6 Drug Interaction
The following interactions apply to non-steroidal antiinflammatory drugs (NSAIDs) in general
Inadvisable combinations: Other NSAIDs, including high doses of salicylates ( 3 g/day):

administration of several NSAIDs together may increase the risk of gastrointestinal ulcers and
bleeding, via a synergistic effect.
– Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see
section 4.4) due to the high plasma protein binding of dexketoprofen and the inhibition of
platelet function and damage to the gastroduodenal mucosa. If the combination cannot be
avoided, close clinical observation and monitoring of laboratory values should be carried
out.
– Heparins: increased risk of haemorrhage (due to the inhibition of platelet function and
damage to the gastroduodenal mucosa). If the combination cannot be avoided, close clinical
observation and monitoring of laboratory values should be carried out.
– Corticosteroids: there is an increased risk of gastrointestinal ulceration or bleeding.
– Lithium (described with several NSAIDs): NSAIDs increase blood lithium levels, which
may reach toxic values (decreased renal excretion of lithium). This parameter therefore
requires monitoring during the initiation, adjustment and withdrawal of treatment with
dexketoprofen.
– Methotrexate, used at high doses of 15 mg/week or more: increased haematological toxicity

of methotrexate via a decrease in its renal clearance by antiinflammatory agents in general.
– Hydantoines and sulphonamides: the toxic effects of these substances may be increased.
Combinations requiring precautions
– Diuretics, ACE inhibitors and angiotensin II receptor antagonists: Dexketoprofen may

reduce the effect of diuretics and antihypertensive drugs. In some patients with
compromised renal function (e. g. dehydrated patients or elderly patients with compromised
renal function), In case of combined prescription of dexketoprofen and a diuretic, it is
Page 6
essential to ensure that the patient is adequately hydrated and to monitor renal function at
the start of the treatment.
– Methotrexate, used at low doses, less than 15 mg/week: increased haematological toxicity
of methotrexate via a decrease in its renal clearance by antiinflammatory agents in general.
– Pentoxyfilline: increased risk of bleeding. Increase clinical monitoring and check bleeding
time more often.
– Zidovudine: risk of increased red cell line toxicity via action on reticulocytes, with severe
anaemia occurring one week after the NSAID is started. Check CBC and reticulocyte count
one to two weeks after starting treatment with the NSAID.
– Sulfonylureas: NSAIDs can increase the hypoglycaemic effect of sulfonylureas by

displacement from plasma protein binding sites[web1].
2.2.7 Pregnancy and Lactation
Dexketoprofen tablet are contraindicated during pregnancy and lactation
2.2.8 Contraindications
– Patients hypersensitive to dexketoprofen, to any other NSAID, or to any of the excipients
of the product.
– Patients in whom substances with a similar action (e.g. aspirin, or other NSAIDs)
precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria
or angioneurotic oedema.
– Patients with active or suspected peptic ulcer/haemorrhage or history of recurrent peptic
ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding) or
chronic dyspepsia.
– Patients with Crohn's disease or ulcerative colitis, history of bronchial asthma & Patients
with severe heart failure[web1].
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2.2.9 Adverse Reaction:

SYSTEM ORGAN Common (1- Uncommon (0.1- Rare (0.01-0.1%) Very rare / Isolated reports
CLASS 10%) 1%) ( < 0.01%)
Blood and lymphatic Neutropenia
system disorders hrombocytopenia
Immune system disorders Anaphylactic reaction,
including anaphylactic shock
Metabolism and nutrition Anorexia
disorders
Psychiatric disorders Insomnia, anxiety
Nervous system disorders Headache, Paraesthesia, syncope
dizziness,
somnolence
Eye disorders Blurred vision

Ear and labyrinth Vertigo Tinnitus
disorders
Cardiac disorders Palpitations Tachycardia
Vascular disorders Flushing Hypertension Hypotension
Respiratory, thoracic and Bradypnoea Bronchospasm, dyspnoea
mediastinal disorders
Gastrointestinal disorders Nausea and/or Gastritis, Peptic ulcer, peptic Pancreatitis
vomiting, constipation, dry ulcer haemorrhage or
abdominal pain, mouth, flatulence peptic ulcer perforation
diarrhoea,
dyspepsia.
Hepatobiliary disorders Hepatocellular damage
Skin and subcutaneous Rash Urticaria, acne, Stevens Johnson syndrome,
tissue disorders sweating increased toxic epidermal necrolysis
(Lyell's syndrome),
angioneurotic oedema, facial
oedema, photosensitivity
reactions, pruritus
Musculoskeletal and Back pain
connective tissue disorders
Renal and urinary Polyuria Nephritis or nephrotic
disorders syndrome
Reproductive system and Menstrual disorder,
breast disorders > prostatic disorder
Page 8
General disorders and Fatigue, pain, Peripheral oedema

administration site asthenia, rigors,
conditions malaise
2.3 Diclofenac Sodium:

2.3.1Introduction
Diclofenac sodium is a white to slightly yellow crystalline powder. It is freely soluble in methanol,
soluble in ethanol, sparingly soluble in water, slightly soluble in acetone, and partially insoluble.
Diclofenac sodium has a molecular weight of 318.13.

The structural formula is represented below:
Structure of diclofenac Sodium
The chemical name for Diclofenac sodium is:

Sodium [o-(2,6-dichloranilino) phenyl] acetate [6].
2.3.2 Pharmacology
Diclofenac has pharmacologic action similar to those of other prototypical NSAIAs. The drug
exhibits anti-inflammatory, analgesic, and antipyretic activity. The exact mechanisms have not been
clearly established, but many of the action appear to be associated principally with the inhibition of
prostaglandins synthesis. Diclofenac inhibits the synthesis of prostaglandins in body tissues by
inhibiting cyclooxgenase; at least 2 isoenzymes, cyclooxygenase-2 (COX-1) and -2 (COX-2) (also
referred to as prostaglandin G/H synthase-1[PGHS-1] and [PGHS-2], respectively), have been
identified that catalyze the formation of prostaglandins in the arachidonic acid pathway [4].
2.3.3 Pharmacodynamic
The pharmacodynamic effect is thought to reduce prostaglandin E 2 (PGE2) synthesis. PGE2 has been
shown to inhibit polymorphonuclear leukocytes function by reducing chemotaxis, superoxides
production, and protease production; natural killer cell cytotoxicity; and mitogen-induced lymphocytes
proliferation. NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity through
Page 9
inhibition of COX-2 isoenzyme; COX-1 presumbly is responsible for the drugs unwanted effect on GI
mucosa and platelet aggregation [4].
2.3.5 Pharmacokinetics
 Absorption
Diclofenac Sodium undergo extensive first-pass metabolism in the liver, with only about 50-60% of a
dose of Diclofenac Sodium reaching systemic circulation as unchanged drug. When dosage forms
containing Diclofenac are applied topically it is absorbed into the epidermis. Patients with actopic
dermatitis and other dermatitis have found to be responding approximately 10% systemic absorption of
Diclofenac from normal epidermis of the hands, arms or face after seven days, with four times daily
application. Scientists have also confirmed that systemic absorption of Diclofenac at 0.5g in patients
treated topically with Solaraze® on the face, forehead, hands, forearm, and scalp is much lower than
that occurring after oral daily dosing of Diclofenac Sodium [5-7].
 Distribution
Distribution of Diclofenac into human body tissues and fluids has not been fully characterized.
Following IV administration of Diclofenac in rats, the drug is widely distributed, achieving highest
concentrations in bile, liver, blood, heart, lungs, and kidneys and lower concentrations in adrenals,
thyroid glands, salivary glands, pancreas, spleen, muscles, brain, and spinal cord. Diclofenac binds
tightly to serum albumin. The volume of distribution of Diclofenac following oral administration is
approximately 550 mL/kg[5-7].
 Metabolism
Metabolism of Diclofenac following topical administration is thought to be similar to that after oral
administration. The small amounts of Diclofenac and its metabolites appearing in the plasma
[5-7]
following topical administration makes the quantification of specific metabolites imprecise
 Elimination
The exact metabolic fate of Diclofenac has not been fully elucidated, but the drug is rapidly and
extensively metabolized in the liver. Diclofenac undergoes extensive hydroxylation and subsequent
conjugation with glucuronic acid, taurine amide, sulfuric acid, and other biogenic ligands.
Conjugation of unchanged drug also may occur. Diclofenac and its metabolites are excreted mainly in
the urine after oral dosing. Systemic clearance of Diclofenac from plasma is 263±56 mL/min
Page 10
(mean±SD). The terminal plasma half-life is 1-2 hours. Four of the metabolites also have short
terminal half-lives of 1-3 hours [5-7].
2.3.6 Drug Interactions:
As Diclofenac is highly protein bound, it could be displaced from the binding site, or it theoretically
could displace from binding site, other protein-bound drugs. In-vitro studies suggest that Diclofenac
only minimally displace from protein binding site other highly protein –bound drugs (e.g.,
prednisolone, salicylates, tolbutamide, warfarin), although Diclofenac may be displaced from binding
sites by high doses of ionized protein-bound drugs (e.g., salicyates) [4,7]. The Diclofenac Sodium is
about to interact with prescription and nonprescription/herbal products, especially of: anti-platelet
drugs (e.g., clopidogrel), "blood thinners" (e.g., warfarin, heparin, enoxaparin), cidofovir,
corticosteroids (e.g., prednisone), cyclosporine, desmopressin, digoxin, high blood pressure
medications (e.g., ACE inhibitors such as lisinopril, beta blockers such as atenolol), lithium,
methotrexate, pemetrexed, probenecid, other products applied to skin on the treated area, SSRI
antidepressants (e.g., fluoxetine, sertraline), tenofovir, "water pills" (diuretics such as
hydrochlorothiazide, furosemide, triamterene) [5,6].
2.3.7 Adverse Reactions:

– Rash, scaling, dry skin or itching may occur at application site. If any of these effects persist
or worsen, discontinue the drug.
– Unlikely but serious side effects may occur: eye redness/itching, stomach/abdominal pain,
headache, shortness of breath, muscle pain, swelling at application site.
– Rare but very serious side effects occur: dark urine, yellowing eyes/skin, change in the
amount of urine, easy bruising/bleeding, unexplained stiff neck, signs of infection (e.g.,
fever, persistent sore throat), persistent/severe headache, swelling hands/feet,
sudden/unexplained weight gain, vision changes, hearing changes (e.g., ringing in the ears),
mental/mood changes (e.g., depression), fast/pounding heartbeat, fainting.
– Rare but very serious adverse effect may occur, stop using this medication and seek
immediate medical attention: black/bloody stools, persistent stomach/abdominal pain, vomit
that looks like coffee grounds, chest pain, sudden vision changes, and weakness on one side
of the body, slurred speech.
– A very serious allergic reaction to this drug is rare. However, seek immediate medical
attention if you notice any symptoms of a serious allergic reaction, including: rash, itching,
swelling, severe dizziness, trouble breathing [4,5,7].
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2.3.8 Precautions and Contraindications:

– Diclofenac Sodium should be used with caution in patients with active gastrointestinal
ulceration or bleeding and severe renal or hepatic impairments.
– It should not be applied to open skin wounds, infections, or exfoliative dermatitis.
– It should not be allowed to come in contact with the eyes.
– Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic
epidermal necrolysis) can occur in patients receiving Diclofenac. These serious skin reactions
may occur without warning; patients should be advised to consult their clinician if skin rash
and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.
– Diclofenac should be discontinued at the first appearance of rash or any other sign of
hypersensitivity.
– When Diclofenac Sodium is used in fixed combination with misoprostol, the cautions,
precautions, and contraindications associated with misoprostol must be considered in addition
to those associated with Diclofenac[ 5,6].
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3 Aim and objectives:

Aim
To compare the safety and efficacy of two topical formulations in the patients with knee
osteoarthritis by using VAS score.
Objectives
To evaluate
- The Safety of topical Dexketoprofen gel in patients with knee osteoarthritis.
- Efficacy of topical Dexketoprofen gel with diclofenac gel in patients with knee
osteoarthritis by using VAS.
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4 Experimental Procedures
4.1 Study title

“Comparative Clinical Study of two topical formulations in the patients with knee osteoarthritis
by using VAS score”.
4.2 Study Plan: flow chart

Study plan is prepared on the basis of the study timeline, patient recruitment rate. The study plan
for project was as follows:
Patient information and informed consent
Screening
Thorough clinical history and examination
Include the patients as per the checklist of inclusion and exclusion criteria
Enrollment and Assigning the serial number
Randomize the patient to either ‘Test’ or ‘Control’ group
Baseline assessment of VAS
Topical application of a gel thrice a day for total of 2 weeks
Assessment of VAS scores at the end of 2 weeks
Record adverse events, if any, throughout the study period &

Inform the serious adverse events within 24 hours to the sponsor.
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4.3 Ethical Considerations:

 Institutional Review Board (IRB)
The study was approved by the IRB, Kotbagi Hospital, Aundh, Pune after reviewing the
following documents:
– Protocol and CRF.
– Study synopsis
– Serious adverse event reporting form
– Patient diary card
– Patient information sheet and Informed Consent form in English and their translated
version in Marathi & Hindi language.
– Investigator’s Brochure
– Investigator’s consent and current updated CVs.
 Ethical Conduct of the study:

It is confirmed and insisted by monitoring that the clinical study was conducted
according to the ethical principles that have their origins in the Declaration of Helsinki.
 Regulatory
Approval from local regulatory authority was taken prior to initiating the trial.
 Patient Information and Consent
Consent of patient is obtained at the screening and the necessary information was
provided along with consent form. Informed consent form is again obtained for the
enrolled subjects.
4.4 Study design:

This will be a multicentre, randomized, comparative, clinical study to assess the efficacy and safety
of topical Dexketoprofen gel (1.25%) compared to Diclofenac gel (1%) in patients of knee
osteoarthritis. A total of 20 male or female patients in the age group of 40-65 years with
osteoarthritis attending the outpatient departments of respective centers will be enrolled. After
written consent and randomization, the patients will be prescribed either Dexketoprofen gel or
Diclofenac gel for topical application for 2 weeks. Patients will be evaluated by Visual Analogue
Scale (VAS).
Page 15
4.5 Dosage regimen and Study duration

The first 50 patients in each group will apply 2 gm of test / reference gel TID locally. Later on dose
escalation will be done if clinically required. The dosage will be increased to 4 gm of test / reference
gel TID in next 50 patients in each group if clinically required. Patients will apply the medication
locally thrice daily for 2 weeks.
Rescue Medication: Paracetamol tablets 650 mg tablet every 6 hours, if required (Not more than 4
tablets in 24 hours).
4.6 Selection of subject
 Inclusion Criteria
– Male or female patients between 40 – 65 years
– Patients diagnosed to have knee osteoarthritis.
– Willing to give written informed consent and willing to comply with the
trial protocol.
– Patients not on any anti-inflammatory or other therapy known to affect
the study outcome.
 Exclusion Criteria
– Patients with known hypersensitivity to the study medications and / or
history of any drug allergy or intolerance to NSAIDs.
– Patients with the history of or evidence of any cardiac, renal, hepatic,
neurologic or any other major medical or psychiatric illness.
– Any contraindication to use of NSAIDs.
– Women who are pregnant, lactating, of child beating potential who are
not practicing effective methods of contraception.
– Any condition that, in the opinion of the investigator, does not justify
the patients’ inclusion in the study.
– Drug addiction or alcoholism
– Current participation or participation within the previous three month
in other clinical trials.
Page 16
4.7 Treatments administered

Dexketoprofen Gel (1.25%) is topically applied on the knee about 2g TID for two week in the
treatment of knee osteoarthritis for patients which are selected to Group A. Diclofenac Gel (1%) is
topically applied on the knee at the same amount and for same period as Dexketoprofen Gel for
patients which are selected for Group B. Dose may be escalated to 4g TID at the discretion of
investigator or if clinically required.
 Rescue Medication: Paracetamol tablets 650 mg tablet every 6 hours, if required (Not
more than 4 tablets in 24 hours).
4.8 Method of assigning patients to treatment groups

This is a randomized clinical study and patients will be prescribed either Dexketoprofen gel or
Diclofenac gel for topical application as per a computer generated randomization chart. The
randomization was carried by sponsor. Thereafter, patient enrollment to study carried out and will
receive the treatment according to randomization sheet.
4.9 Sample Size determination

Total 20 patients were enrolled to achieve sample size of 20 (10 in each group). No subject will be
kept standby because there was very less chance of patient withdrawing from the study. Sample
size determination was done at the discretion of investigator-sponsor.
4.10 Dose Selection

Dose escalation was done from the previous human trials. Patients in each group will apply 2g of test
/ reference gel TID locally. Later on dose escalation will be done if clinically required. The dosage
will be increased to 4 g of test / reference gel TID if clinically required. Patients will apply the
medication locally thrice daily for 2 weeks.
4.11 Efficacy and safety variables

 Primary Efficacy variables
Primary efficacy variable is responder rate. The patients with at least 20%
improvement in pain intensity difference (PID) will be termed as responders.
 Secondary Efficacy Variables
– Improvement in average VAS scores.
Page 17
– Improvement in patients and physicians global assessment of arthritis.

 Safety Variables
Reporting of adverse events are the safety variable.
 Adverse Events (Clinical )
Any drug related adverse event will be evaluated by the investigator and
recorded in the CRF
 Serious Adverse Events
Any serious adverse reaction would be recorded and informed immediately

to the sponsor within 24 hours. Details of the AE (nature, severity, action
taken and outcome) should be filled in the SAE form provided.
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5 Analytical Procedure:
5.1 Pain
It's clear that pain is understood by anyone and that everyone feels it a bit differently. Overall, pain is an
unpleasant sensation that occurs in varying degrees of severity and is a consequence of a number of
processes. In order to manage pain, doctors discern its intensity and frequency and the circumstance from
which it springs.
5.2 Types of pain:
 Nociceptive (Tissue) Pain
Nociceptive pain results from tissue damage. Intact neurons dutifully report damage, and pain is
experienced. Nociceptive pain can be subdivided into somatic and visceral (gut) pain. Nociceptive pain
can be experienced as sharp, dull, or aching. There may be radiation of the pain, especially visceral pain,
but it will not be in a direct nerve distribution. For example, gallbladder pain can radiate to the scapula.
Nociceptive pain is generally responsive to NSAIDs (nonsteroidal anti-inflammatory drugs) and opioids.
Conditions associated with inflammation, bone pain, and joint disease are particularly responsive to
NSAIDs[web8].
 Neuropathic (Nerve) Pain
Neuropathic pain may occur when there is either damage to or dysfunction of nerves in the peripheral or
central nervous system. Faulty signals are sent to the brain and experienced as pain. Neuropathic pain can
be either peripheral (outside the central nervous system) or central in origin. Examples of neuropathic
pain include diabetic neuropathy, trigeminal neuralgia, postherpetic zoster pain (peripheral pains), and the
thalamic pain syndrome (a central pain). Neuropathic pain frequently coexists with nociceptive pain.
Examples include trauma that damages tissue and nerves, burns (that burn skin as well as nerve endings),
and external nerve compression. Examples of the latter include tumor nerve compression and sciatica
from herniated discs pressing on nerves. Neuropathic pain is often described as having a burning or
electrical quality. It may feel like a shock or lightning bolt. Sometimes stimuli that usually do not cause
pain, such as light touch, may elicit a paroxysm of pain. A light stroke of the cheek that results in the
sudden pain of trigeminal neuralgia is an example of this type of pain. Sometimes patients do not describe
the sensation as being "painful" but rather as feeling unpleasantly strange or tingly, like an arm feels when
it wakes up from "going to sleep." This is called a dysesthesia. Diabetic neuropathy commonly results in
Page 19
this type of sensation. Neuropathic pain in the peripheral nervous system frequently follows a nerve
distribution. This distribution may replicate a particular nerve, as in sciatic pain or trigeminal neuralgia,
or may represent the distribution of terminal nerve endings, as in the stocking-glove distribution of
peripheral neuropathies. Neuropathic pain is relatively resistant to NSAIDs and opioids, although they
may be helpful in certain cases. The other major classes of medications useful for neuropathic pain,
tricyclic antidepressants, anticonvulsants, and sodium channel blockers [web8].
5.3 Pain Rating Scales:
There is extensive pain in knee osteoarthritis. Major emphasis is given on the management of pain by
using various drugs i.e. symptomatic treatment. In knee osteoarthritis, management of pain is important
but there arise a problem to measure pain. To measure the pain, various kinds of the rating scales are
developed by universities and scientists. These rating scales are as follows:
 Visual Analogue Scale [VAS]

 Numerical Rating Scale [NRS]
 Faces Rating Scale [FRS]
 Behavioural Rating Scale [BRS]
 Functional Activity Score [FAS]
 WOMAC Scale
Visual analogue scale [VAS]

Instruct the patient to point to the position on the line to indicate how much pain they are currently
feeling. The far left end indicates ‘No pain’ and the far right end indicates ‘Worst pain ever.
Figure-
0 10 20 30 40 50 60 70 80 90 100
Page 20
6 Statistical Theory:
Statistical analysis is done according to the protocol. According to ICH E3 guideline statistical analysis
should be incorporated as listings and tables. These tables need to be shown according to the guideline.
The statistical analysis part is generally placed at the end in tables and figures section or may be
incorporated in the report. But report has to be written as like all the information including statistical and
clinical as one. The data generated during study is more and need to use statistical software. There are
number of statistical software are available for the analysis e.g. SPSS, SAS, STATA, MiniTab, etc. The
statistical tests in this thesis are carried out by using SAS software (version 9.0). For the statistical
analysis we have used as per protocol set. According to protocol, subjects showing PID less than 20% are
excluded from the analysis. Only one patient fails to show PID greater than or equal to 20% so his data
set has removed from efficacy analysis but used in safety and demographic analysis.
The SAS codes needed for the analyses were used from books and internet. Complete analysis has done
according to the codes used in pharmaceutical industry and tried at best level for analysis. Following are
important statistics & tests are used during the analysis:
 Summary Statistics: mean, max, min, N,
 Inferential Statistics: t-test, Fisher’s Exact Test
Fisher's exact test is a statistical significance test used in the analysis of contingency tables where
sample sizes are small.
A t-test is a statistical hypothesis test in which the test statistic follows a Student's t distribution if the null
hypothesis is supported. It is most commonly applied when the test statistic would follow a normal
distribution if the value of a scaling term in the test statistic were known
Graph showing difference after two weeks for efficacy variables (i.e. VAS score) are drawn by using SAS
software. The graphs are drawn using pscolor target device in SAS.
Summary listings are prepared for the following variables:
 Demographic variables- height, weight, age etc.
 VAS score
 Safety variable- Number of AE
T-test is carried out for efficacy variables
 VAS score
These listings are generated from the data generated in the study:
Page 21
6.1 Listing and Summary Table for Demographic Variable:

6.1.1 Demographic Parameters Listing:
Subject
Subject s Treatmen Age Weight Height
ID Initials t (years) (Kg) (cm)
1 MRB A 57 60 145
2 MPP A 55 69 148
3 MJL B 42 67 .
4 SMS B 54 69 .
5 PBR B 50 70 .
6 RNG A 50 78 .
7 MRB B 56 72 .
8 BJR B 48 55 .
9 MMP A 55 56 .
10 AIS A 50 72 .
11 MHP A 55 72 .
12 MSH A 49 58 149
13 AAJ B 46 73 150
14 SBK B 64 70 158
15 SMJ B 44 60 146
16 KGJ A 56 63 148
17 SAD B 55 72 170
18 SKS B 43 56 160
19 ADJ A 44 66 155
20 BGH A 43 68 157
* Patient 3 to 11 Height was not detected due to its absences.
Page 22
6.1.2 Demographic Summary of Parameters:
Dexket
oprofe Diclofena Overal
n c l P-
(N=10) (N=10) (N=20) value*
Age (years)0.4698
N 10 10 20 .
Mean 51.4 50.2 50.8 .
Standard 5.02 7.00 5.96 .
Deviation
Minimum 43.0 42.0 42.0 .
Maximum 57.0 64.0 64.0 .
Weight (kg)0.8197
N 10 10 20 .
Mean 66.2 66.4 66.3 .
Standard 6.97 6.82 6.71 .
Deviation
Minimum 56.0 55.0 55.0 .
Maximum 78.0 73.0 78.0 .
Height (cm)0.1699
N 6 5 11 .
Mean 150.3 156.8 153.3 .
Standard 4.63 9.34 7.55 .
Deviation
Minimum 145.0 146.0 145.0 .
Maximum 157.0 170.0 170.0 .
Page 23
6.2 Listing and Summary for efficacy Variable:

6.2.1 Listing for Efficacy Variables:
Subject Physicians
Subject VAS VAS 2 Global Global
Number Baseline weeks after Assessment Assessment
1 60 30 2 3
2 60 40 1 2
3 70 50 1 1
4 50 40 3 3
5 70 50 2 2
6 50 20 3 3
7 80 70 1 1
8 50 30 2 2
9 70 30 2 2
10 80 50 2 1
11 50 20 2 2
12 70 30 3 3
13 50 20 2 2
14 70 40 2 2
15 70 50 1 1
16 60 30 2 3
17 80 60 2 1
18 50 20 2 2
19 80 50 2 2
20 60 40 2 2
* Subject ID = 7 (Treatment given Diclofenac Gel) was excluded from the efficacy analysis because PID (pain intensity
difference) after two weeks is less than 20 %. As per the protocol such subject were termed as non-responder and should be
excluded from the efficacy analysis.
Page 24
6.1.2 Summary Statistics for efficacy variables:
Summary Statistics for efficacy variables

Dexket Diclofena Overal
o c l P-
(N=10) (N=9) (N=19) value*
VAS (0-100) 0.7665
N 10 9 19 .
Mean 64.0 62.2 63.2 .
Standard Deviation 10.75 12.02 11.08 .
Minimum 50.0 50.0 50.0 .
Maximum 80.0 80.0 80.0 .
6.3 Listing and Summary for safety (AE) variable

6.3.1 Listing for Adverse Events:
Subject Relatedness: Severity / Intensity : Body Preferred

Numbe 1=not,2=Possibl 1=mild, System of Term for
r Treatment y, 3=Probably 2=moderate,3=severe Event Event
7 B 2 1 Skin Redness
Disorder
Disorder
Disorder
20 A 2 1 Skin Redness
Disorder
6.3.2 Summary Table for Adverse Events:
Page 25
---------------------------------------------------------------------
Body System
Preferred Term Dexketo Diclofenac Overall
Severity N= 10 N= 10 N= 20
6.4 T- --------------------------------------------------------------------- test Results:

for efficacy Any Event 1 (10%) 3 (30%) 4 (20%) variable
For Mild 1 (10%) 3 (30%) 4 (20%) VAS Score
change variable:
Skin Disorder 1 (10%) 3 (30%) 4 (20%)
T-Tests
Mild 1 (10%) 3 (30%) 4 (20%)
Variable
Redness Method
1 (10%) Variances
3 (30%) 4 (20%) DF t Value Pr > |t|
Mild 1 (10%) 3 (30%) 4 (20%)
Vaschg Pooled Equal 17 2.54 0.0212
---------------------------------------------------------------------
Vaschg Satterthwaite Unequal
--------------------------------------------------------------------- 16. 2.54 0.0213
8
Equality of Variances
Variable Method Num DF Den DF F Value Pr > F

Vaschg Folded F 9 8 1.00 1.0000
6.5 Fisher (F) test for safety Variable

Safety Results [Fisher's Exact Test]
The FREQ Procedure
Page 26
Table of GRP by RESP

GRP RESP
Frequency
Row Pct YES _NO Total
1 1 9 10
10.00 90.00
2 3 7 10
30.00 70.00
Total 4 16 20
Statistics for Table of GRP by RESP
Statistic DF Value Prob
Chi-Square 1 1.2500 0.2636
Likelihood Ratio Chi- 1 1.2972 0.2547
Square
Continuity Adj. Chi- 1 0.3125 0.5762
Square
Mantel-Haenszel Chi- 1 1.1875 0.2758
Square
Phi Coefficient -0.2500
Contingency Coefficient 0.2425
Cramer's V -0.2500
WARNING: 50% of the cells have expected counts less
than 5. Chi-Square may not be a valid test.
Fisher's Exact Test

Cell (1,1) Frequency (F) 1
Left-sided Pr <= F 0.2910
Right-sided Pr >= F 0.9567
Table Probability (P) 0.2477

Two-sided Pr <= P 0.5820
Sample Size = 20
6.6 Graphs:
For VAS score change:
Page 27
7 Result:
Page 28
During the analysis of the study data generated from study are shown that drug Dexketoprofen gel is
more efficacious and equally safe as that of diclofenac sodium. The results generated are needed to be
written as following in clinical study report according to guidelines. The results are described in more
details for the regulatory submissions which explain each and every statistical tests and reason for its
use as well as its disadvantages should be described. Complete data sets were analyzed for the safety
and demographic characteristics whereas per protocol data set was analyzed for the efficacy variables.
According to protocol, data of only responder subjects must be analyzed for the efficacy. Patient
having more than or equal to 20% PID (pain intensity difference) were used for analysis of efficacy
variables such VAS change. There was no significant different between the two groups for
demographic characteristics such as age, weight and height. Group A (Dexketoprofen Gel) have age
(years) 51.4 ± 5.02, weight (kg) 66.2 ± 6.97 and height (cm) 150.3 ± 4.63 whereas Group B have age
(years) 50.2 ± 7.00, weight (kg) 66.4 ± 6.82 and height (cm) 156.8 ± 9.34. Wilcoxon test conducted
for the variables age, weight and height does not show any significant difference between two
treatments for demographic characteristics. Analysis of efficacy variables shown that Dexketoprofen
Gel was more efficacious for management of pain in knee osteoarthritis as compared to the
Diclofenac Gel. For Dexketoprofen Gel, VAS score change or Pain intensity difference after two
weeks of treatment was 30.00 ± 6.67 (N=10) vs. 22.22 ± 6.67 (N=9) for Diclofenac Gel. The
unpaired t-test shown ‘p’ value 0.0212 for PID or VAS score change which is significant and show
that Dexketoprofen was efficacious than Diclofenac. Though there was significant difference between
two treatments for the total WOMAC score, it fails to show difference at Patient’s global assessment
for the Dexketoprofen Gel was 2.1 ± 0.568 whereas for Diclofenac Gel was 1.889 ± 0.601 and
physicians global assessment was 2.3 ± 0.671 for Dexketoprofen gel and 1.778 ± 0.667 for
Diclofenac Gel [1, 13].
There was only one common adverse event occurs due to study medication which mild redness. There
were 10% adverse events of mild redness in test group (Dexketoprofen Gel) against 30% in control
group (Diclofenac Gel). Mild redness was considered to be possible adverse event with that of study
medications. Summary report of adverse event was given in statistical analysis section of this thesis.
Fisher’s exact test was used for the analysis of safety data. In this adverse events reported by the
subjects during the study period were analyzed. Analysis shown that there was no significant
difference between two treatments (p value for Fisher’s exact test = 0.2910). This shows that both
products were equally safe and well tolerable by the study patients.
8 Conclusions:
Page 29
Analysis of efficacy variables shown that Dexketoprofen Gel was more efficacious for management
of pain in knee osteoarthritis as compared to the Diclofenac Gel. For Dexketoprofen Gel, VAS score
change or Pain intensity difference after two weeks of treatment was 30.00 ± 6.67 (N=10) vs. 22.22 ±
6.67 (N=9) for Diclofenac Gel. The unpaired t-test shown ‘p’ value 0.0212 for PID or VAS score
change which is significant and show that Dexketoprofen was efficacious than Diclofenac. Though
there was significant difference between two treatments for the total WOMAC score, it fails to show
difference at Patient’s global assessment for the Dexketoprofen Gel was 2.1 ± 0.568 whereas for
Diclofenac Gel was 1.889 ± 0.601 and physicians global assessment was 2.3 ± 0.671 for
Dexketoprofen gel and 1.778 ± 0.667 for Diclofenac Gel.
Study has shown that both drugs (Dexketoprofen Gel & Diclofenac Gel) were equally safe and well
tolerated by study subjects. Fisher’s exact test was used for the analysis of safety data. In this adverse
events reported by the subjects during the study period were analyzed. Analysis shown that there was
no significant difference between two treatments (p value for Fisher’s exact test = 0.2910). Mild
redness was seen at knee and it was the only adverse event shown by the study subjects (N=20). In
test group one subject shown adverse event whereas three subjects shown adverse event. Thus 10%
adverse events were shown by subjects receiving Dexketoprofen Gel vs. 30% adverse event were
shown by subjects receiving Diclofenac Gel.
9 Discussion
Page 30
The most common chronic joint disease throughout the world is osteoarthritis, which is associated
with degeneration of the joint. The prevalence of osteoarthritis of the knee is up to 44% and is
dependent on increasing age and female gender. Current guidelines for the treatment of osteoarthritis
recommend pharmacological therapy, including non-steroidal anti-inflammatory drugs (NSAIDs) for
moderate-to-severe osteoarthritis symptoms, if non-pharmacological interventions fail. NSAIDs are
among the most widely prescribed and used classes of drugs worldwide. Despite their clinical
benefits in the management of osteoarthritis and rheumatoid arthritis, NSAIDs have considerable side
effects, mostly affecting the upper gastrointestinal system, which limit their use. All NSAIDs appear
to inhibit prostaglandin synthesis by blocking cyclooxygenase (COX) activity. However, there are
some important differences between COX isoforms. COX-1 is present in the stomach and kidneys of
heath people, mediating the production of prostaglandin, which may protect the stomach and kidneys.
The larger, cytokine-induced COX-2 enzyme is induced in the joints of people with inflammatory
[7, 8, 9]
arthritis, mediating the production of prostaglandin that may cause or aggravate inflammation .
Dexketoprofen is an NSAID with analgesic, anti-inflammatory and antipyretic actions belonging to
the 2 – aryl propionic acid family. Dexketoprofen has been developed as the tromethamine salt
(dexketoprofen), a formulation with high water solubility. Based on the efficacy and safety evidence
for the oral formulation, Dexketoprofen gel for topical application in the treatment of painful,
inflammatory, degenerative or traumatic origin of the joints, tendons or muscles has been developed
[8, 10]
. For the efficacy assessment, pain intensity on VAS scale was used. Pain intensity as measures
on VAS reduced significantly in both the groups (p<0.05). The patient’s and physician’s global
assessment of the arthritics condition also improved significantly (p<0.0001) after therapy in both the
groups. Analysis of efficacy variables shown that Dexketoprofen Gel was more efficacious for
management of pain in knee osteoarthritis as compared to the Diclofenac Gel. For Dexketoprofen
Gel, VAS score change or Pain intensity difference after two weeks of treatment was 30.00 ± 6.67
(N=10) vs. 22.22 ± 6.67 (N=9) for Diclofenac Gel. The unpaired t-test shown „p‟ value 0.0212 for
PID or VAS score change which is significant and thus Dexketoprofen was efficacious than
Diclofenac.
Study has shown that both drugs (Dexketoprofen Gel & Diclofenac Gel) were equally safe and well
tolerated by study subjects. Fisher’s exact test was used for the analysis of safety data. In this adverse
events reported by the subjects during the study period were analyzed. Analysis shown that there was
no significant difference between two treatments (p value for Fisher’s exact test = 0.2910). Mild
redness was seen at knee (area of application) and it was the only adverse event shown by the study
subjects (N=4 out N=20). In test group one subject shown adverse event whereas three subjects
Page 31
shown adverse event. Thus 10% adverse events were shown by subjects receiving Dexketoprofen Gel
vs. 30% adverse event were shown by subjects receiving Diclofenac Gel.
Page 32
10 References:
1. J.L. Marenco, M. Pérez, F.J. Navarro et al., A Multicenter, Randomized, Double-Blind Study to
Compare the Efficacy and Tolerability of Dexketoprofen Trometamol versus Diclofenac in the
Symptomatic Treatment of Knee Osteoarthritis. Clinical Drug Invest. 2000; 19: 1-4.
2. P Leman, Y Kapadia, J Herington. Randomized controlled trial of the onset of analgesic efficacy
of dexketoprofen and diclofenac in lower limb injury. Emerg Med J, 2003; 20: 511–513.
3. O'Brien WM. Pharmacology of nonsteroidal anti- inflammatory drugs. Am J Med. 1983; 10:32-9.
4. Todd PA, Sorkin EM. Diclofenac sodium: a reappraisal of its pharmacodynamic and
pharmacokinetic properties, therapeutic efficacy. Drugs. 1988; 35:244-85.
5. Brogden RN, Heel RC, Pakes GE et al. Diclofenac sodium: a review of its pharmacological
properties and therapeutic use in rheumatic diseases and pain of varying origin. Drugs. 1980;
20:24-48.
6. Novartis. Voltaren® (diclofenac sodium enteric-coated tablets) prescribing information. East
Hanover, NJ; 2006 Jan.
7. Todd PA, Sorkin EM. Diclofenac sodium: a reappraisal of its pharmacodynamic and
pharmacokinetic properties, therapeutic efficacy. Drugs. 1988; 35:244-85.
8. Fowler PD., Voltarol: diclofenac sodium. Clin Rheum Dis. 1979; 5:427-64
9. Kawaguchi H. &Nuki G., “Background to outlines of the OASRI treatment guidelines”, ORASI,
2008; 16; 137-162.
10. Barbanoj M., Antoijoan R. &Gich J., “Clinical Pharmacokinetics of Dexketoprofen” Biomed
Central Ltd.; 2001; 40; 245-262.
11. Iohom G., Walsh M., Higgins G., &Shorte G., “Effect of perioperative administration od
dexketoprofen on opioids requirements & inflammatory response” British Journal of Anesthesia;
2002; 520-526.
12. Marenco J. & et.al., “A Multicenter, Randomized, Double-Blind Study to Compare the Efficacy
and Tolerability of Dexketoprofen Trometamol versus Diclofenac in the Symptomatic Treatment
of Knee Osteoarthritis”, Clin Drug Invest.; 2008; 19; 224-230.
13. Jack Shostak, “SAS programming in the pharmaceutical industry”, SAS Press; AUG 2005; 126-
197.
14. ICH E6 (R1) Expert Working Group. Guideline for Good Clinical Practice: ICH Harmonized
Tripartite Guideline, 1996.
15. ICH E3 Expert Working Group. Structure and Content of Clinical Study Reports: ICH
Harmonized Tripartite Guideline, 1995.
16. Moore R. & Borden J., “ The systemic review of dexketoprofen in acute and chronic pain” BMJ
Page 33
1998; 316; 333-338.

17. Beltrán J, Martín Mola E, Figueroa M, et al. Comparison of dexketoprofen trometamol and
ketoprofen in the treatment of osteoarthritis of the knee. J Clin Pharmacol 1998; 38 Suppl. 18: 74-
80
18. Ezcurdia M, Cartejoso FJ, Lanzón R, et al. Comparison of the efficacy and tolerability of
dexketoprofen and ketoprofen in the treatment of primary dysmenorrhea. J Clin Pharmacol 1998;
38 Suppl. 18: 65-73
19. 19. Gay C, Planas E, Donado M, et al. Analgesic effect of lowdoses of dexketoprofen in the
dental pain model: a randomised, double-blind, placebo-controlled study. Clin Drug Invest 1996;
11: 320-30
20. McGurk M, Robinson P, Rajayogeswaran V, et al. Clinical comparison of dexketoprofen

trometamol, ketoprofen, and placebo in postoperative dental pain. J Clin Pharmacol 1998; 38
Suppl. 18: 46-54
21. Swedberg JA. Osteoarthritis. Am Fam Physician 1992; 45: 557-68
22. Al Arfag A, Davis P. Osteoarthritis: current drug treatment regimens. Drugs 1991; 41 (2): 193-
201
23. Mauleón D, Artigas R, Garcia ML, et al. Preclinical and clinical development of dexketoprofen.
Drugs 1996; 52 Suppl. 5: 24-46
80.
38 Suppl. 18: 65-73.
26. Gay C, Planas E, Donado M, et al. Analgesic effect of lowdoses of dexketoprofen in the dental
pain model: a randomised, double-blind, placebo-controlled study. Clin Drug Invest 1996; 11:
320-30.
Suppl. 18: 46-54.
28. McCormack K, Urquhart E. Correlation between nonsteroidal anti-inflammatory drug efficacy in
a clinical pain model and the dissociation of their anti-inflammatory and analgesic properties in
animal models. Clin Drug Invest 1995; 9: 88-97.
Page 34
29. Al Arfag A, Davis P. Osteoarthritis: current drug treatment regimens. Drugs 1991; 41 (2): 193-
201.
80.
38 Suppl. 18: 65-73.
32. Gay C, Planas E, Donado M, et al. Analgesic effect of lowdoses of dexketoprofen in the dental
pain model: a randomised, double-blind, placebo-controlled study. Clin Drug Invest 1996; 11:
320-30.
Suppl. 18: 46-54.
34. Bagán JV, López Arranz JS, Valencia E, et al. Clinical comparison of dexketoprofen trometamol
and dipyrone in postoperative dental pain. J Clin Pharmacol 1998; 38 Suppl. 18: 55-64
35. Wallerstein SL. Scaling clinical pain and pain relief. In: Bromm B, ed. Pain measurement in man:
neurophysiological correlates of pain. New York: Elsevier, 1984.
36. Todd KH. Clinical versus statistical significance in the assessment of pain relied. Ann Emerg Med
1996;27:439–41.
Website-
1. http://www.epgonline.org/viewdrug.cfm/letter/K/language/lg0001/drugId/DR000424/drugN
ame/KERAL.
2. http://arthritis.about.com/od/painmanage/ss/painqa_2.htm.
3. http://www.health.state.ny.us/diseases/conditions/arthritis .
4. Rheumatoid Arthritis: Differential Diagnoses & Workup Emedicine Portal.
5. http://www.netdoctor.co.uk/diseases/facts/arthritis.htm.
6. Severe Arthritis Disease Facts.
7. http://www.orthop.washington.edu/uw/kneearthritis/tabID__3376/ItemID__296/Articles/De
fault.aspx.
8. http://www.mayoclinic.com/health/psoriatic-arthritis/DS00476.
9. http://www.mywhatever.com/cifwriter/library/70/4922.html.
10. http://www.arthritis-treatment-and-relief.com/types-of-arthritis.htm.
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MGM School of Biomedical Sciences, Aurangabad.

2.1.2 Causes of Arthritis

Scientific Name-[2s]-2-[3-benzoyl] phenyl] propanoic acid

Dexketoprofen trometamol is the tromethamine salt of S-(+)-2-(3- benzoylphenyl)propionic acid,

2.2.3 The mechanism of action

The mechanism of action of non-steroidal antiinflammatory drugs is related to the reduction of

2.2.5 Pre-clinical safety data

2.2.6 Drug Interaction

The following interactions apply to non-steroidal antiinflammatory drugs (NSAIDs) in general

Inadvisable combinations: Other NSAIDs, including high doses of salicylates ( 3 g/day):

– Corticosteroids: there is an increased risk of gastrointestinal ulceration or bleeding.

– Methotrexate, used at high doses of 15 mg/week or more: increased haematological toxicity

– Diuretics, ACE inhibitors and angiotensin II receptor antagonists: Dexketoprofen may

– Sulfonylureas: NSAIDs can increase the hypoglycaemic effect of sulfonylureas by

2.2.7 Pregnancy and Lactation

Dexketoprofen tablet are contraindicated during pregnancy and lactation

2.2.9 Adverse Reaction:

Eye disorders Blurred vision

General disorders and Fatigue, pain, Peripheral oedema

2.3 Diclofenac Sodium:

Diclofenac sodium has a molecular weight of 318.13.

Structure of diclofenac Sodium

The chemical name for Diclofenac sodium is:

2.3.6 Drug Interactions:

2.3.7 Adverse Reactions:

2.3.8 Precautions and Contraindications:

3 Aim and objectives:

4.1 Study title

4.2 Study Plan: flow chart

Patient information and informed consent

Thorough clinical history and examination

Enrollment and Assigning the serial number

Randomize the patient to either ‘Test’ or ‘Control’ group

Baseline assessment of VAS

Topical application of a gel thrice a day for total of 2 weeks

Assessment of VAS scores at the end of 2 weeks

Record adverse events, if any, throughout the study period &

4.3 Ethical Considerations:

 Ethical Conduct of the study:

4.4 Study design:

4.5 Dosage regimen and Study duration

4.6 Selection of subject

4.7 Treatments administered

4.8 Method of assigning patients to treatment groups

4.9 Sample Size determination

4.10 Dose Selection

4.11 Efficacy and safety variables

– Improvement in patients and physicians global assessment of arthritis.

 Adverse Events (Clinical )

Any serious adverse reaction would be recorded and informed immediately

5.2 Types of pain:

 Nociceptive (Tissue) Pain

 Neuropathic (Nerve) Pain

5.3 Pain Rating Scales:

 Visual Analogue Scale [VAS]

Visual analogue scale [VAS]

6.1 Listing and Summary Table for Demographic Variable:

* Patient 3 to 11 Height was not detected due to its absences.

6.1.2 Demographic Summary of Parameters:

6.2 Listing and Summary for efficacy Variable:

6.1.2 Summary Statistics for efficacy variables:

Summary Statistics for efficacy variables

6.3 Listing and Summary for safety (AE) variable

Subject Relatedness: Severity / Intensity : Body Preferred