Master thesis clinical trial study

Mahatma Gandhi Mission
MGM Institute of Health Sciences, Navi Mumbai
(Deemed University)
M.Sc. Thesis
School of Biomedical Sciences, Aurangabad
This Thesis is submitted in partial fulfillment of
the requirements for the Degree of Master of Science.
© MGM Institute of Health Sciences, Navi Mumbai. All rights reserved. No
part of this publication may be reproduced without the written permission
of the copyright holder.

CERTIFICATE
This is to certify that, the Project work entitled “A randomized, parallel,
comparative clinical study to assess Safety & Efficacy of Topical
Dexketoprofen Gel in the Treatment of Knee Osteoarthritis” is
carried out by,
Mr. Lahare Nikhil Ashok, in partial fulfillment of the requirement of the
award of degree for Masters of Science in Clinical Research at
School of Biomedical Sciences, Aurangabad.
Seat No.
Director Research Guide
Date:
Place:

DECLARATION
I hereby declare that the Project Work entitled,
“A randomized, parallel, comparative clinical study to assess Safety
& Efficacy of Topical Dexketoprofen Gel in the Treatment of Knee
Osteoarthritis”, in partial fulfillment of the requirements for
the award of the degree of “Masters of Science In
Clinical Research”.
I further declare that the contents presented in this thesis are
my own original research contribution and the same are not
submitted to any other institute or university for the award
of any degree or diploma.
Mr. Lahare Nikhil Ashok

Dissertation
(2008-2010)
“A randomized, parallel, comparative clinical study to assess Safety
& Efficacy of Topical Dexketoprofen Gel in the Treatment of Knee
Osteoarthritis”
Submitted To
School of Biomedical Sciences
Aurangabad
For the award of
Masters of Science in Clinical Research
By
MGM’s School of Biomedical Sciences
Aurangabad

THE PROJECT WORK
Title of the Project Work:
“A randomized, parallel, comparative clinical study to assess
Safety & Efficacy of Topical Dexketoprofen Gel in the Treatment
of Knee Osteoarthritis”.
Work carried at :- Hardikar Hospital,
Pune
Name of the Student :- Mr. Lahare Nikhil Ashok .
Roll No. :- MCLR081004
Name of the Institute :- MGM’s School of Biomedical Sciences
Aurangabad.
Year :- 2008-2010
Project work submitted for the partial fulfillment of Second year of
degree under the supervision of Mr. Abhijit Jadhav, Head Dept.
of Clinical Research, MGM’s, School of Biomedical Sciences,
Aurangabad.

ACKNOWLEDGEMENT
It is humble graduated with sense of indebtedness. I thank my respected
and estimated Guide Dr. Madan Hardikar (MS ortho), Principal
Investigator, Hardikar Hospital, Pune, for his valuable guidance
suggestions and constant support which leads towards successful
completion of this Project Work apart from his busy job schedule
encouraging project work is a really astonishing for which I shell ever
remain grateful to him.
I take this opportunity to extent my regard and thanks to our
beloved Principal Dr. Sanjay Harke, Head of Department (Clinical
Research) Mr. Abijit Jadhav and former Lecturer Mr. Rahul Mayee for their
supervision and support, apart from routine department and academic
schedule with constant encouragement, motivation and suggestions and
have help me a lot in completing project work.
I express my special thanks to my beloved parents specially my
father for his constant support during my Graduation and Post Graduation
period.
I also thank the whole team of Hardikar Hospital for their free and
helpful nature which helped me complete my project work successfully
and also my classmates for their support, co-operation and keeping
completion tuff the whole time.

 Table of Contents:
Sr.
No.
Content Page No.
1. Introduction 1
1.1 General 1
1.3 Orthopedic Trials 3
1.4 Clinical Study Report 4
2. Aim & Objective 8
3. Materials 9
4. Research Methodology 10
5. 5.1 Overall study design and plan description 11
5.2 Selection of study population 12
5.3 Treatments 13
5.4 Efficacy and safety variables 14
5.5 Statistical Methods planned in the protocol and determination
of sample size
15
6 Project Management 17
7 Statistical Analysis 18
7.1 Tables 19
7.2 Graphs 22
7.3 Listings 24
8 Result & Conclusion 26
9 Discussion 31
10 Reference 34

School of Biomedical Science, Aurangabad
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 Introduction
1. General:
In 1996, according to ICH definition of clinical research is “any investigation in
human subjects intended to discover or verify the clinical, pharmacological
and/or other pharmacodynamic effects of an investigational product(s), and/or to
identify any adverse reactions to an investigational product(s), and/or to study
absorption, distribution, metabolism, and excretion of an investigational product(s) with
the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical
study are synonymous”.
After Pre-clinical, the data obtained from the studies are submitted as an IND
(Investigational Drug Application) to the regulatory authorities for permission to conduct
human studies. Human studies or the actual clinical trials are conducted in four phases.
The first phase usually deals with the trial of the medicine in a few people, usually
healthy volunteers. This is mainly targeted at identifying the safety, tolerability, PK & PD
of the drug in humans. These are conducted in special places called CPUs (Central
Pharmacological Unit) where participants receive 24hr medical attention.
The second phase usually deals with a population of about 50-500 people. This is an
efficacy study. Also, the dose needed for the next phase is finalized. It is conducted in
hospitals.
The third phase usually deals with the trial on more than 1000 patients. This phase
is usually multi-centric and focuses on the effects on drugs in different ethnic groups,
comparison with the standard drugs on the market and also study of the effect on the drug
on different variants of the disease. Then, an NDA (New Drug Application) is filed to the
regulatory authority containing the study data regarding permission to market the drug.
The fourth phase is usually conducted after the launch of the drug on the market.
The aim is to identify newer and unknown adverse reactions, effects in different ethnic
groups and newer therapeutic indications among others. The entire journey of a drug
from lab to market may take approximately 12-18 years.
However, clinical research does not stop here. It continues throughout the lifetime
of the drug to include post marketing surveillance where a periodic 'progress report' is
submitted to the regulatory authorities once every 2 years after the drug is released into

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the market and also into Pharmacovigilance where safety of marketed drugs, biologics or
medical devices are monitored. The focus of clinical research is wide enough to include
data management, medical writing, regulatory consultation, biostatistics to name a few.
1.1 Background:
There are two distinct study designs used in health research: observational and
experimental. Observational studies do not intentionally involve intervening in the way
individuals live their lives, or how they are treated. However, clinical trials are
specifically designed to intervene, and then evaluate some health-related outcome, with
one or more of the following objectives:
 to diagnose or detect disease
 to treat an existing disorder
 to prevent disease or early death
 to change behavior, habits or other lifestyle factors.
Some trials evaluate new drugs or medical devices that will later require a license(or
marketingauthorization) for human use from a regulatory authority, if a benefit is shown.
This allows the treatment to be marketed and routinely available to the public. Other
trials are based on therapies that are already licensed, but will be used in different ways,
such as a different disease group, or in combination with other treatments.3
An interventioncould be a single treatmentor therapy, namely an administered substance
that is injected, swallowed, inhaled or absorbed through the skin; an exposure such as
radiotherapy; a surgical technique; or a medical/ dental device. A combination of
interventions can be referred to as a regimen, such as, chemotherapy plus surgery in
treating cancer. Other interventions could be educational or behavioral programs, or
dietary changes. Any administered drug or micronutrient that is examined in a clinical
trial with the specific purpose of treating; preventing or diagnosing disease is usually
referred to as an Investigational Medicinal Product (IMP) or InvestigationalNew Drug
(IND).An IMP could be a newly developed drug, or one that already is licensed for
human use. Most clinical trial regulations that are part of law in several countries cover
studies using an IMP, and sometimes medical devices.4

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People who take part in a trial are referred to as ‘subjects’ or ‘participants’ (if they are
healthy individuals), or ‘patients’ (if they are already ill). They are allocated to trial or
intervention arms or groups. Well-designed clinical trials with a proper statistical analysis
provide robust and objective evidence. One of the most important uses of evidence-based
medicine is to determine whether a new intervention is more effective than another, or
that it has a similar effect, but is safer, cheaper or more convenient to administer. It is
therefore essential to have good evidence to decide whether it is appropriate to change
practice.4
2. Orthopedic Trials:
Orthopedic trials are mostly involves the trials of surgery and devices. In orthopedic
major disease is osteoporosis. Osteoporosis is defined as brittle bones occurring in the
elderly that could lead to facture. “Orthopedics is the branch of medicine concerned with
diseases, injuries, and conditions of the musculoskeletal system, or the body's muscles
and skeleton, and including the joints, ligaments, tendons, and nerves”.
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.
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 guidelines where this modality of therapy is considered.
[Osteoarthritis and Cartilage
On osteoporosis number of trials has been conducted and books are written for its trial.
After osteoporosis one of the major diseases is osteoarthritis which involves pain in the
knee. The drugs generally used for relieving pain. Various orthopedic diseases causes’
pain and thus management of pain is more important. Pain is an unpleasant experience
for the patient but it is also associated with a number of physiological responses that are
thought to contribute to organ dysfunction and post-operative morbidity. Apart from the
obvious decrease in suffering, analgesia has the benefits of improving recovery. Hence,

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hospital stay may be reduced and cost minimized. Although there have been great
advances in the field of pain management with a greater number of analgesic agents and
techniques available, study shows that a significant number of patients still experience
moderate or severe pain.10
3. Clinical Study Report:
Reports are designed to convey and record information that will be of practical use to
thereader. It is organized into discrete units of specific and highly visible information
Types of Reports:
Informational
 Inform or instruct – present information
 Reader sees the details of events, activities or conditions.
 No analysis of the situation, no conclusion, no recommendations.
Analytical
 Written to solve problems
 Information is analyzed.
 Conclusions are drawn and recommendations are made
Persuasive
 An extension of analytical reports: main focus is to sell an idea, a service, or
product.
 Proposals are the most common type.
Research information has limited value unless it is collected and published in a usable
form and presented to those who may apply it. For these reasons never assume that your
job is finished when the experimental or analytical phase has been completed. It is also
your responsibility as scientist to show promptly that your results are worthwhile and that
you have reason to believe the field will be advanced by your efforts. The only way to
convey these thoughts is by writing a good report.12
The five major stages of report preparation are:

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1. Gathering the data (or developing the theory)
2. Analyzing and sorting the results
3. Outlining the report
4. Writing the rough draft
5. Revising the rough draft
Extensive and complete documentation must be submitted for obtaining a marketing
authorization of an investigational medicinal product in the European Union, Japan, or
the United States. One of the most critical of the documents submitted as part of the
Common Technical Document, masterpiece of a marketing authorization application, is
the Clinical Study Report, which represents the integrated full report of efficacy and
safety data for an individual study of a therapeutic or diagnostic agent. The content and
format of a Clinical Study Report is recommended by the International Conference on
Harmonization of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH) guideline E3 on Structure and Content of Clinical Study Reports,
which was approved in 1996. Some of the studies conducted during product development
may ultimately not contribute to the evaluation of the effectiveness of a product for a
specific indication. In these cases, abbreviated Clinical Study Reports are required to be
submitted to the regulatory authorities. However, the ICH E3 guideline only provides
information on the structure and content of full Clinical Study Reports.5
The CSR integrates the clinical and statistical descriptions, presentations, and analyses
into a single integrated report, incorporating tables and figures. This integrated report not
only outlines the original plan of the protocol, but also describes in more depth and
explains any practices in the clinical trial that were different from those originally
planned. By reading the CSR, one can understand why and how the study was conducted,
the types of data collected and analyzed, and the nature and extent of the conclusions that
may be drawn from the results. The results of pivotal clinical trials and human
pharmacology investigations that contribute to the evaluation of effectiveness and safety
for a proposed indication or that otherwise support information included in the product
labeling are to be presented as a full CSR, which addresses all the elements of the
template report described in the ICH E3 guideline.4-5

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In clinical study report, introduction should be concise and near about 1-2 page only
highlighting important points with brief discussion. Guideline also provides guidance on
how to prepare title page of the clinical study report and what elements should be
described on that. The introduction should contain a brief statement (maximum: 1 page)
placing the study in the context of the development of the test drug/investigational
product, relating the critical features of the study (e.g., rationale and aims, target
population, treatment, duration, primary endpoints) to that development. Any guidelines
that were followed in the development of the protocol or any other agreements/meetings
between the sponsor/company and regulatory authorities that are relevant to the particular
study should be identified or described.
Thus for given study introduction part can be written as follows:
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.
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 guidelines where this modality of therapy is considered. 5
Dexketoprofen is an NSAID with analgesic, anti-inflammatory and antipyretic actions
belonging to the 2 – 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 traumatic origin of the joints, tendons or muscles has been developed.

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The stratum corneum, the rate limiting barrier to percutaneous absorption, is made up of
keratin and ceramides which could 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.
In acute conditions like strains and sprains topical non-steroidals were significantly better
than placebo over 1 week with a number needed to treat of 3.9 (3.4 to 4.4). For drugs
with at least three placebos controlled trials ketoprofen (number needed to treat 2.6) had
significant efficacy. In chronic conditions like arthritis and rheumatism topical non-
steroidals were significantly better than placebo over 2 weeks with a number needed to
treat of 3.1 (2.7 to 3.8). In both acute and chronic pain local and systemic adverse events
and withdrawal related to tested drug had a low incidence and were no different from
placebo.6
For the efficacy assessment, pain intensity on VAS and WOMAC index were used.
WOMAC is a three-dimensional, disease-specific and self-administered heath status
questionnaire, which is commonly used in OA outcomes research. For the present study,
the Likert scale version 3.1 was used, which contains 24 items for rating symptoms and
functional impairments with five response categories (0=none, 1=mild, 2=moderate,
3=severe, 4=extreme). The WOMAC items are aggregated into three subscales: pain (five
items), stiffness (two items) and overall physical function (17 items). The three WOMAC
subscales can be analyzed separately into a total score. The WOMAC is valid, reliable
and sufficiently sensitive to detect clinically important changes following interventions.

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 Aim & Objectives
Aim
To prepare clinical study report (CSR) for the clinical study titled: “A randomized, parallel,
comparative clinical study to assess Safety & Efficacy of Topical Dexketoprofen Gel in the
Treatment of Knee Osteoarthritis” according to ICH E3 guideline.
Objectives
 To conduct study at site
 To collect all necessary documents and data needed for the CSR with permissions
from principle investigator.
 To analyze the data as per the protocol with SAS software
 Write CSR according to ICH E3 guideline

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 Materials
Well-furnished hospital and drugs provided by the sponsor. Well- furnished hospital include:
 Laboratory facilities:- ECG, DMLT lab facilities etc.
 Qualified staff for their respective work
o Principle investigator – For conduct of the study at study site
o Clinical Research Coordinator – For managing documents and other trial
related data etc.
Following list of documents is mandatory for the sponsor to send at investigator site for the
purpose of IRB approval:
 Protocol
 Investigator Brochure
 Case Report Form (CRF)
 Informed Consent Form (ICF)
 Patient information sheet
 Study synopsis
 DCGI approval
Sponsor need to also send test articles (drugs), and logs required to maintain drug
accountability and storage information for those drugs.
At the investigator site whole responsibilities of the drug is of investigator or the duties
transferred to person. CRC maintain the documents and files at the investigator site.

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 Research Methodology
In presenting the detailed description of how the study was carried out, it may be possible
simply to restate the description in the initial protocol. Often, however, it is possible to
present the methodology of the study more concisely in a separate document. In each section
describing the design and conduct of the study, it is particularly important to clarify features
of the study that are not well-described in the protocol and identify ways in which the study
was conducted differed from the protocol, and to discuss the statistical methods and analyses
used to account for these deviations from the planned protocol.
The full integrated report of the individual study should include the most detailed discussion
of individual adverse events or laboratory abnormalities, but these should usually be
reexamined as part of an overall safety analysis of all available data in any application.
The report should describe demographic and other potentially predictive characteristics of the
study population and, where the study is large enough to permit this, present data for
demographic (e.g., age, sex, race, weight) and other (e.g., renal or hepatic function)
subgroups so that possible differences in efficacy or safety can be identified. Usually,
however, subgroup responses should be examined in the larger database used in the overall
analysis.
The data listings requested as part of the report (usually in an appendix) are those needed to
support critical analyses. Data listings that are part of the report should be readily usable by
the reviewer. Thus, although it may be desirable to include many variables in a single listing
to limit size, this should not be at the expense of clarity. An excess of data should not be
allowed to lead to overuse of symbols instead of words or easily understood abbreviations or
to too small displays etc. In this case, it is preferable to produce several listings.
Data should be presented in the report at different levels of detail: overall summary figures
and tables for important demographic, efficacy and safety variables may be placed in the text
to illustrate important points; other summary figures, tables and listings for demographic,
efficacy and safety variables should be provided appendices.

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In any table, figure or data listing, estimated or derived values, if used, should be identified in
a conspicuous fashion. Detailed explanations should be provided as to how such values were
estimated or derived and what underlying assumptions were made.
The guidance provided below is detailed and is intended to notify the applicant of virtually
all of the information that should routinely be provided so that post-submission requests for
further data clarification and analyses can be reduced as much as possible. Nonetheless,
specific requirements for data presentation and/ or analysis may depend on specific
situations, may evolve over time, may vary from drug class to drug class, may differ among
regions and cannot be described in general terms; it is therefore important to refer to specific
clinical guidelines and to discuss data presentation and analyses with the reviewing authority,
whenever possible. Detailed written guidance on statistical approaches is available from
some authorities.
Each report should consider all of the topics described (unless clearly not relevant) although
the specific sequence and grouping of topics may be changed if alternatives are more logical
for a particular study. Some data in the appendices are specific requirements of individual
regulatory authorities and should be submitted as appropriate.
For the given study all parameters can be arranged and describes as follows:-
 Overall study design and plan description
The study is conducted to assess the efficacy and safety of Dexketoprofen Gel against the
Diclofenac Gel in pain management of knee osteoarthritis. Study design is open label,
parallel, randomized comparative study. Patients attending outpatient clinic for the treatment
of osteoarthritis of knee those are willing to participate in the trial will be included in the
study. Patients having knee osteoarthritis within age group of 40-65(both male and female)
were selected population for the study. Patient not willing to participate in the study were
excluded as well as those taking medication which likely to be cause deviation from true
results also excluded.
Diclofenac Gel was used as control in parallel design (with Dexketoprofen Gel) which was
mostly used for treatment of pain in knee osteoarthritis. Patient assignment to treatment
group was done by randomization using computer generated randomization sheet; 20 patients

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were randomized and either subjected to treatment A (Dexketoprofen Gel) or treatment B
(Diclofenac Gel). Randomization sheet was generated before the screening and used to
assign the patients to treatment group. Treatment period was about 2 weeks from enrollment
and dose of 2g TID scheduled for patients then it may be raised to 4g TID if clinically needed
and patients were assessed for efficacy variable like VAS Score, WOMAC score etc. along
with safety variable e.g. AEs. Within that period patients were free to withdraw from study as
well as Investigator can also withdraw patient at any time if they believe that continuation of
the study will be detrimental to the health of the patient. Failure to follow up also remarked
as withdrawal or failure to treatment compliance. No any interim analysis was carried out for
this trial.
 Selection of study population
Study population selected on the basis of following inclusion and exclusion criteria.
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.

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 Drug addiction or alcoholism
 Current participation or participation within the previous three month in other
clinical trials.
 Treatments
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).
Identity of investigational product(s)
Since study was open label, the investigational products were already labeled with names.
Only consideration was kept that on randomization sheet there will be A or B in front of
patient number; A for Dexketoprofen and B for Diclofenac treatment.
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.
Selection of Doses in the study
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.
Selection and Timing of dose for each patient

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The timing for each patient starts from his/ her enrollment and follow up will be after two
weeks. Patient has to apply the gel for 2 weeks at 2g TID. After two weeks he / she had to
give follow up visit. If the patient misses follow up it should be considered as failure to
treatment compliance.
Since each tube of gel (i.e. both Dexketoprofen Gel and Diclofenac Gel) contain the 50 g
of gel so that 2 tubes will be handled to the patients having dose of 2g TID for 2 weeks,
whereas 4 tubes will be handled to the patients having dose of 4g TID for 2weeks.
Blinding
Study was open label so no blinding was done. Randomization was carried out for
avoiding bias. Open label also kept because efficacy variables were assessed by subject
itself.
Prior and Concomitant Therapy
Any medication which is considered necessary for the patient may be given at the
discretion of investigator provided it does not interfere with the evaluation of study drug.
Data for concomitant medication was collected on Case Report Forms (CRF) for
evaluation if needed.
Treatment Compliance
Failure of the patient to come for follow up will be considered as failure to compliance.
 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) or WOMAC total score (0-4 Likert
Scale) will be termed as responders.
 Secondary Efficacy Variables
 Improvement in average VAS scores.
 Improvement in WOMAC scored for pain, stiffness and physical function.
 Improvement in patients and physicians global assessment of arthritis.

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 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.
 Statistical Methods planned in the protocol and determination of sample size
 Statistical and Analytical Plans
Efficacy analysis:
The patients with at least 20% improvement in pain intensity difference (PID) or
WOMAC total score (0-4 Likert Scale) will be termed as responders. The PID will be
calculated as the difference between baseline and the subsequent visit after therapy on
Visual Analogue Scale (VAS). WOMAC scores, VAS scores, patient’s and
physician’s global assessment of arthritic condition after treatment will be compared
with baseline readings using unpaired „t‟ test.
Safety analysis:
Tolerability will be assessed by evaluating the total number of patients reporting side
effects. Any adverse event reported by the patient will be measured as the percent of
patients reporting side effects. For the adverse effect analysis, two sided Fisher’s
exact test will be used. For all statistical calculations „p‟ values less than 0.05 will be
considered as statistically significant.
 Determination of Sample Size
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.

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 Project Management:
Project management is the application of knowledge, skills, tools, and techniques to project
activities in order to meet or exceed stakeholder needs and expectations.
This project has timeline of only four months. During this period, study completion, data
entry, and statistical analysis and has to write clinical study report (CSR). First IRB approval
is necessary and it takes about 10 days from 1st
January 2010. As far as study completion is
concerned, it depends on the subject recruitment rate. Since it is orthopedic hospital, the
patient suffering from knee osteoarthritis is more at site hence it take 52 days for the
completion of study. After completion of the study12 days are required for the data entry
and 7 days are required for statistical analysis. At the remaining days, clinical study report
had been prepared. This project is carried out with minimum budget for it. It has been
designed so that minimum budget would be required and study will be completed without
any hindrances. During the study only major concern is follow up of study subjects. Time
period required for each major milestones are shown in the Gantt chart below. Subjects
enrolled with their willingness, and consent has been taken. Study started only after the IRB
approval. Compensation was not given for the subjects in the form of money, only standard
treatment would be provided in case of any adverse event occurs. Subject only get benefit of
treatment.
Gantt chart:
Following Gantt chart shows the timeline required for the completion of this thesis. This
chart shows all important milestones.
By using Microsoft Project 2010(beta)

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 Statistical Analysis
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
Graph showing difference after two weeks for efficacy variables (i.e. VAS score, WOMAC
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
 WOMAC Score- pain scale, stiffness scale, physical function, total WOMAC scale
 Safety variable- Number of AEs
T-test is carried out for efficacy variables
 VAS score
 WOMAC Score- pain scale, stiffness scale, physical function, total WOMAC scale

18 | P a g e
These listings are generated from the data generated in the study:
Tables 6.1:
Summary Table for Demographic Data:
Dexketo
profen
(N=10)
Diclofenac
(N=10)
Overall
(N=40) P-value*
Age (years)0.4698
N 10 10 20 .
Mean 51.4 50.2 50.8 .
Standard Deviation 5.02 7.00 5.96 .
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 .
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 .
Minimum 145.0 146.0 145.0 .
Maximum 157.0 170.0 170.0 .
Summary Statistics for efficacy variables:
Summary Statistics for efficacy variables
Dexketo
(N=10)
Diclofenac
(N=9)
Overall
(N=38) P-value*
VAS (0-100) 0.7665
N 10 9 19 .
Mean 64.0 62.2 63.2 .
Minimum 50.0 50.0 50.0 .
Maximum 80.0 80.0 80.0 .
Total WOMAC 0.4371
N 10 9 19 .

19 | P a g e
Summary Statistics for efficacy variables
Dexketo
(N=10)
Diclofenac
(N=9)
Overall
(N=38) P-value*
Mean 27.1 23.7 25.5 .
Minimum 17.0 10.0 10.0 .
Maximum 40.0 41.0 41.0 .
Physical Function (WOMAC) 0.4844
N 10 9 19 .
Mean 19.6 17.1 18.4 .
Minimum 14.0 5.0 5.0 .
Maximum 27.0 32.0 32.0 .
Pain WOMAC 0.4274
N 10 9 19 .
Mean 6.1 4.9 5.5 .
Minimum 3.0 2.0 2.0 .
Maximum 10.0 8.0 10.0 .
Stiffness WOMAC 0.8266
N 10 9 19 .
Mean 1.4 1.7 1.5 .
Minimum 0.0 0.0 0.0 .
Maximum 3.0 3.0 3.0 .
Summary Table for Adverse Events:
---------------------------------------------------------------------
Body System
Preferred Term Dexketo Diclofenac Overall
Severity N= 10 N= 10 N= 20
---------------------------------------------------------------------
Any Event 1 (10%) 3 (30%) 4 (20%)
Mild 1 (10%) 3 (30%) 4 (20%)
Skin Disorder 1 (10%) 3 (30%) 4 (20%)
Mild 1 (10%) 3 (30%) 4 (20%)
Redness 1 (10%) 3 (30%) 4 (20%)
Mild 1 (10%) 3 (30%) 4 (20%)

20 | P a g e
---------------------------------------------------------------------
---------------------------------------------------------------------
Summary table for concomitant medications:
Preferred Medication Term
TEST
N= 10
CONTROL
N= 10
Total
N= 20
ANY MEDICATION 15 (150%) 10 (100%) 25 (125%)
Amledepine 0 ( 0%) 1 ( 10%) 1 ( 5%)
Atonolol 0 ( 0%) 1 ( 10%) 1 ( 5%)
Calcium Carbonate 4 ( 40%) 6 ( 60%) 10 ( 50%)
Chondroin Sulfate 3 ( 30%) 1 ( 10%) 4 ( 20%)
Deviphylline 1 ( 10%) 0 ( 0%) 1 ( 5%)
Diallvin 2 ( 20%) 0 ( 0%) 2 ( 10%)
Glucosamine 3 ( 30%) 1 ( 10%) 4 ( 20%)
Theophylline 1 ( 10%) 0 ( 0%) 1 ( 5%)
Triiodothyronine 1 ( 10%) 0 ( 0%) 1 ( 5%)
6.2 T-test Results:
For VAS Score change variable:
T-Tests
Variable Method Variances DF t Value Pr > |t|
vaschg Pooled Equal 17 2.54 0.0212
vaschg Satterthwaite Unequal 16.8 2.54 0.0213
Equality of Variances
Variable Method Num DF Den DF F Value Pr > F
vaschg Folded F 9 8 1.00 1.0000
For Total WOMAC score change variable:
T-Tests
Variable Method Variances DF t Value Pr > |t|
totalchg Pooled Equal 17 2.13 0.0482
totalchg Satterthwaite Unequal 12.5 2.21 0.0462

21 | P a g e
Equality of Variances
Variable Method Num DF Den DF F Value Pr > F
totalchg Folded F 9 8 5.32 0.0276
6.3 SAS Graphs:
For VAS score change:

22 | P a g e
For Total WOMAC change:
6.3 Listings:
Demographic Listings:
Subject
ID
Subjects
Initials Treatment
Age
(years)
Weight
(Kg)
Height
(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 .

23 | P a g e
Subject
ID
Subjects
Initials Treatment
Age
(years)
Weight
(Kg)
Height
(cm)
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
Listing for Efficacy Variables:
Subject
Number
VAS
Baseline
VAS
2
weeks
after
WOMAC
Pain
Baseline
WOMAC
Stiffness
Baseline
WOMAC
Physical
Function
Baseline
WOMAC
Pain 2
weeks
WOMAC
stiffness 2
weeks
WOMAC
Physical
Function
2 weeks
Subject
Global
Assessment
Physicians
Global
Assessment
1 60 30 10 3 27 3 1 14 2 3
2 60 40 9 0 27 6 0 21 1 2
3 70 50 6 2 32 1 1 30 1 1
4 50 40 2 0 8 0 0 3 3 3
5 70 50 8 0 24 3 0 17 2 2
6 50 20 3 3 14 2 1 8 3 3
7 80 70 3 0 9 3 0 12 1 1
8 50 30 3 2 5 1 1 2 2 2
9 70 30 3 0 14 1 0 6 2 2
10 80 50 6 0 17 3 0 10 2 1
11 50 20 3 2 14 1 1 6 2 2
12 70 30 3 0 14 1 0 8 3 3

24 | P a g e
Subject
Number
VAS
Baseline
VAS
2
weeks
after
WOMAC
Pain
Baseline
WOMAC
Stiffness
Baseline
WOMAC
Physical
Function
Baseline
WOMAC
Pain 2
weeks
WOMAC
stiffness 2
weeks
WOMAC
Physical
Function
2 weeks
Subject
Global
Assessment
Physicians
Global
Assessment
13 50 20 4 2 5 1 1 2 2 2
14 70 40 8 3 24 3 2 20 2 2
15 70 50 6 3 32 4 1 25 1 1
16 60 30 10 3 26 3 1 14 2 3
17 80 60 3 0 16 1 0 12 2 1
18 50 20 4 3 8 1 2 4 2 2
19 80 50 6 3 17 2 0 12 2 2
20 60 40 8 0 26 3 0 21 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.
Listing for Adverse Events:
Subject
Number Treatment
Relatedness:
1=not,2=Possibly,
3=Probably
Severity / Intensity : 1=mild,
2=moderate,3=severe
Body System
of Event
Preferred
Term for
Event
7 B 2 1 Skin Disorder Redness
20 A 2 1 Skin Disorder Redness
Listing for Concomitant Medication:
Subject
Number
Name of Drug Content Purpose
1 Rewalk Glucosamine & Chondroitin sulphate Articular surface remodeling
Gemcol Calcium carbonate Ca++ supplement
2 Artilage Glucosamine & Chondroitin sulphate Articular surface remodeling
Calintzkit Calcium carbonate Ca++ supplement
3 Shaleel Calcium carbonate Ca++ supplement
4 Gemcol Calcium carbonate Ca++ supplement
5 Bonedus Calcium carbonate Ca++ supplement
6 Cevin Diallvin --------
7 Stamlobetz Amledepine&Atonolol Hypertension
9 Deviphylline Theophylline Asthma
Asthaln inhaler Theophylline Asthma
10 Elxsoxin Triiodothyronine Hypothyroid
11 Cevin Diallvin -------
Gemcol Calcium carbonates Ca++ supplement
13 Gemcol Calcium carbonates Ca++ supplement

25 | P a g e
14 Bonedus Calcium carbonates Ca++ supplement
Gemcol Calcium carbonates Ca++ supplement
19 Bonedus Calcium carbonates Ca++ supplement
 Result & Conclusion
After analysis of the data generated from the 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.
Thus following is the manner in which one can write clinical study report for this study.
 EFFICACY EVALUATION
Data sets analyzed
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, WOMAC change etc.
Demographic and other baseline characteristics
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.
Measurement of the treatments compliance
Subjects have to bring the used medication tubes as measure of the treatment compliance.
From the tubes it can be determined whether subject has used his medication or not. Subjects
failing to the follow up also termed as failure to treatment compliance.

26 | P a g e
All the subjects were passed the treatment compliance and there was no failure to this.
Efficacy results and tabulations of individual patient data
Analysis of Efficacy
Null hypothesis tested for the efficacy variable was that there is no significant difference
between two treatments while alternative hypothesis was that there is significant difference
between two treatments i.e. dexketoprofen gel is more efficacious than the diclofenac gel in
the treatment of knee osteoarthritis.
For the efficacy analysis VAS scale and WOMAC scale were used. VAS is continuous
variable while WOMAC was categorical variable. Since both scales are universally accepted
so they are both reliable and valid.
Statistical / Analytical Issues
Complete analysis set was used for the analysis of demographic data and safety data while
per protocol for efficacy variables. Statistical tests will be carried out at 5% level of
significance.
 Adjustment of covariates
As there was no prognostic factor which was used or determined during trial, there was
no need of adjusting any covariates.
 Handling out of dropout or missing data
As the period of study was only two weeks (short period), thus chance of dropout was
very less. By consideration of this, drop out data of subjects was excluded from the
analysis. Two assessments were done during the study; one for baseline and second was
after two weeks, hence missing data generated was very less and excluded from the
analysis. The data of dropout or missing data was not included in the analysis so it may
not introduce bias in results generated.
 Interim Analysis and Data Monitoring
Since it was short term trial, interim analysis was not carried out.
 Multicenter Studies
This was a single center study so there was no any time of center specific analysis were
carried out for the data generated during the trial.

27 | P a g e
 Multiple Comparison / Multiplicity
As we are using both VAS and WOMAC as efficacy variable there was problem of
multiple comparison. There was no adjustment was done for control of type I error. It is
considered unnecessary because both efficacy variables used independently to show the
efficacy.
 Use of “Efficacy Subset” of patients
No efficacy subset was generated for analysis. “Per protocol set” was used for the
analysis of efficacy data. According to protocol, for the analysis of efficacy variables
only responder patients should be used. Responder patients or subjects were those which
show at least 20% difference / decrease in the pain intensity after treatment of two weeks.
Those subjects not showing 20% PID were not used for statistical analysis of efficacy.
This provides a fair comparison between two treatments.
 Examination of Subgroups
There were no subgroups created for the analysis of both safety and efficacy data.
Tabulation of Individual response data
Tabulation of individual response data was shown in statistical analysis.
 Efficacy Conclusions
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. Total
WOMAC score change for Dexketoprofen was 12.20 ± 5.03 (N=10) vs. 8.33 ± 2.18
(N=9) for Diclofenac Gel. As far as individual change for pain, stiffness and physical
function on WOMAC scale was considered, for Dexketoprofen Gel was 3.60 ± 2.12, 1.00
± 1.15, 7.60 ± 2.80 and for Diclofenac Gel 3.22 ± 1.39, 0.78 ± 0.67, 4.33 ± 1.73
respectively.
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. The unpaired t-
test carried for total WOMAC score change after two weeks shown significant difference

28 | P a g e
between two treatments (p value= 0.0462 with Satterwaitecorrection). Though there was
significant difference between two treatments for the total WOMAC score, it fails to
show difference at WOMAC pain and WOMAC stiffness which might be due to small
sample sized selected for the analysis.
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.
 SAFETY EVALUATION
Extent of exposure
About 20 subjects (20 subjects & no standby subjects) having knee osteoarthritis were
exposed for study medications. 50% subjects were exposed to Dexketoprofen while 50%
subjects were exposed to Diclofenac.
 Duration: Subjects were exposed to study medication for 2 weeks only after
enrollment.
 Dose: The first 50 % patients in each group will apply 2 g 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.
 Concentration: Dexketoprofen Gel contains dexketoprofen 1.25 % of drug
concentration whereas Diclofenac gel contains diclofenac about 1 %.
Adverse Event(s)
 Brief Summary of Adverse Events
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.
 Display of Adverse Events

29 | P a g e
Display of adverse events was shown in the summary table of adverse event given at the
Table 10.3, Subjects showing adverse event were subject id 20 in test group whereas 7,
14, 15 were shown adverse events in control group. All subjects have shown common
adverse event of mild redness.
 Analysis of adverse event
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.
Deaths, other serious adverse events and other significant adverse event
There was no serious adverse events occur during the study period.
Clinical Laboratory evaluations
There were no clinical laboratory evaluations which were carried out. Because study
enrolled the patients of knee osteoarthritis and only physical examination were the
inclusion criteria for the study.
Vital signs, physical findings and other observations related to safety
No vital signs, physical findings and other observations related to safety concern found
during the trial period.
Safety conclusions
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 (1) subject
shown adverse event whereas three (3) subjects shown adverse event. Thus 10% adverse

30 | P a g e
events were shown by subjects receiving Dexketoprofen Gel vs. 30% adverse event were
shown by subjects receiving Diclofenac Gel.
 Discussion
Discussion in the clinical study report is to describe the aspects from the results. This part of
the study helps regulatory to know study result in short. Discussion about the results obtained
from the study can be written as follows:
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 arthritis, mediating the production of prostaglandin that may cause
or aggravate inflammation. 5,7,8
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. 7,9
For the efficacy assessment, pain intensity on VAS and WOMAC index were used.
WOMAC is a three-dimensional, disease-specific and self-administered heath status
questionnaire, which is commonly used in OA outcomes research. For the present study, the

31 | P a g e
Likert scale version 3.1 was used, which contains 24 items for rating symptoms and
functional impairments with five response categories (0=none, 1=mild, 2=moderate,
3=severe, 4=extreme). The WOMAC items are aggregated into three subscales: pain (five
items), stiffness (two items) and overall physical function (17 items). The three WOMAC
subscales can be analyzed separately into a total score. The WOMAC is valid, reliable and
sufficiently sensitive to detect clinically important changes following interventions. Previous
studies have suggested that a change of ≥ 10 % on WOMAC subscale indicates a minimal
clinically important difference (MCID).8,9
In the present study, the criteria for defining the
responders were stricter with ≥ 20 % response with 2 weeks therapy. All of the patients who
completed the study (Test, n=10 and Reference, n=9) demonstrated ≥ 20% response except
one subject in control group. Additionally, the WOMAC scores (pain, stiffness, physical
function and total score) and 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 Trometamol 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. Total
WOMAC score change for Dexketoprofen was 12.20 ± 5.03 (N=10) vs. 8.33 ± 2.18 (N=9)
for Diclofenac Gel. As far as individual change for pain, stiffness and physical function on
WOMAC scale was considered, for Dexketoprofen Gel was 3.60 ± 2.12, 1.00 ± 1.15, 7.60 ±
2.80 and for Diclofenac Gel 3.22 ± 1.39, 0.78 ± 0.67, 4.33 ± 1.73 respectively.
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. The unpaired t-test
carried for total WOMAC score change after two weeks shown significant difference
between two treatments (p value = 0.0462 with satterwaite correction). Though there was
significant difference between two treatments for the total WOMAC score, it fails to show
difference at WOMAC pain and WOMAC stiffness which might be due to small sample
sized selected for the analysis. Patient’s global assessment for the Dexketoprofen Gel was 2.1
± 0.568 whereas for Diclofenac Gel, it was 1.889 ± 0.601 and physician’s global assessment
was 2.3 ± 0.671 for Dexketoprofen gel and 1.778 ± 0.667 for Diclofenac Gel.

32 | P a g e
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 (1)
subject shown adverse event whereas three (3) subjects shown adverse event. Thus 10%
adverse events were shown by subjects receiving Dexketoprofen Trometamol Gel vs. 30%
adverse event were shown by subjects receiving Diclofenac Gel.

33 | P a g e
 Reference:
1. Glasser S. Essentials of clinical research Springer 2008; 15-21
2. Ahrens E. The Crisis in Clinical Research: Overcoming Institutional Obstacles. New
York:Oxford University Press; 1992
3. Hackshaw A. A concise guide to clinical trials BMJ Books; John Wiley & Sons
Ltd.Publication; 2009;
4. Alfaro V, Cullell-Young M, Tanovic A, “Abbreviated clinical study reports with
investigational medicinal products for human use: Current guidelines and
recommendations” Crot Med J.; 2007 December; 48(6): 871–877.
5. Kawaguchi H. &Nuki G., “Background to outlines of the OASRI treatment guidelines”, ORASI,
2008; 16; 137-162.
6. Moore R. & Borden J., “ The systemic review of dexketoprofen in acute and chronic pain” BMJ
1998; 316; 333-338.
7. Barbanoj M., Antoijoan R. &Gich J., “Clinical Pharmacokinetics of Dexketoprofen” Biomed
Central Ltd.; 2001; 40; 245-262.
8. Iohom G., Walsh M., Higgins G., &Shorte G., “Effect of perioperative administration od
dexketoprofen on opioids requirements & inflammatory response” British Journal of Anesthesia;
2002; 88; 520-526.;
9. 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.
10. Pearson G.& Miller C., “ Clinical Trials in osteoporosis”Springer, (2); 2007.
11. Jack Shostak, “SAS programming in the pharmaceutical industry”, SAS Press; AUG 2005; 126-
197.
12. Walker G., “Common statistical methods for clinical research with SAS examples”, SAS Press,
2006, 298-302.
13. Taylor R., “The clinicians guide to medical writing” Springer New York; 2006; 195-212.
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.

Date 02/05/2010
TO WHOM SO EVER IT MAY CONCERN
This is certified that, Mr. Nikhil A. Lahare student of M.Sc. Clinical Research in
MGM School of BioMedical Sciences, Aurangabad has successfully completed his
Project on “A randomized, parallel, comparative clinical study to assess
Safety & Efficacy of Topical Dexketoprofen Gel in the Treatment of
Knee Osteoarthritis” (Study Name: A clinical Study to assess Efficacy & Safety
of Topical Dexketoprofen Trometamol Gel in the Treatment of Knee osteoarthritis,
Study Code: Emc/KO/DEXKT/01/2009) of Emcure Pharmaceuticals Ltd).
The project was completed under the guidance of Dr. Madan Hardikar at
Hardikar Hospital, Pune from 01/01/2010 & 30/04/2010 and assisted in Phase II
& Phase III trials
Dr. Madan Hardikar
M.S. Ortho
Hardikar Hospital,
Pune

Master thesis clinical trial study

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