TO STUDY THE CLINICAL EFFECTIVENESS OF

DIACEREIN AS ADD ON THERAPY TO DICLOFENAC

SODIUM IN PATIENTS OF OSTEOARTHRITIS KNEE

PLAN OF THESISFOR APPROVAL OF SUBJECT OF THESIS

TO BE SUBMITTEDIN PARTIAL FULFILMENT OF THE REQUIREMENTS

FOR THE DEGREE OF M.D. (PHARMACOLOGY)

OF THEBABA FARID UNIVERSITY OF HEALTH SCIENCES,

FARIDKOT.

2006 DR KULJINDER SINGH

DEPARTMENT OF PHARMACOLOGY,GOVERNMENT MEDICAL COLLEGE, AMRITSAR

BABA FARID UNIVERSITY OH HEALTH SCIENCES

FARIDKOT

APPLICATION FORM FOR APPROVAL OF THE SUBJECT

OF THESIS FOR MD (PHARMACOLOGY)

1. Name of the Candidate Dr. Kuljinder Singh

2. Father’s Name S. Balwinder Singh

3. Mother’s Name Smt. Bachan Kaur

4. Address of the candidate for

correspondence

House no. 566/11,Onkar nagar Gurdaspur

5. Month and year of passing

MBBS Examination

December, 2005

6. Name of the University from

which Graduated

Baba Farid University of Health Sciences,

Faridkot

7. Present Occupation Postgraduate Student, Department of

Pharmacology, Government Medical College,

Amritsar.

9. Date of Joining M.D. Course 15th June, 2006

10. Likely date of appearing June, 2009

11. Proposed Subject of Thesis TO STUDY THE CLINICAL

EFFECTIVENESS OF DIACEREIN AS

ADD ON THERAPY TO DICLOFENAC

SODIUM IN PATIENTS OF

OSTEOARTHRITIS KNEE

12. Facilities for work on the Facilities are available in the Department of

subject of thesis Pharmacology and Orthopedics.

13. Detailed scheme according to

which the candidate proposes to

work

Plan attached

14. Name and address of the

Supervisor(s)

Dr.Jaswant Rai.

M.D.

Professor and Head,

Department of Pharmacology,

Government Medical College,

Amritsar.

( SUPERVISOR )

Dr. Rakesh Sharma

M.S.

Assistant Professor,

Department of Orthopedics,

Government Medical College,

Amritsar.

( CO-SUPERVISOR )

CERTIFICATE OF SUPERVISORS

This is to certify that facilities for work on the subject of thesis titled “ TO

STUDY THE CLINICAL EFFECTIVENESS OF DIACEREIN AS

ADD ON THERAPY TO NSAIDS IN PATIENTS OF

OSTEOARTHRITIS KNEE” exist in the department of Pharmacology and

Orthopaedics, Government medical College, Amritsar and will be provided

to the candidate. We will see that data being included in the thesis are

genuine and collected by the candidate himself under supervision and

guidance.

Dr.Jaswant Rai

M.D.

Professor and Head,

Department of Pharmacology,

Government Medical College,

Amritsar

(SUPERVISOR )

Dr. Rakesh Sharma

M.S.

Associate Professor,

Department of Orthopedics,

Government Medical College,

Amritsar.

( CO-SUPERVISOR )

ABSTRACT OF PLAN OF THESIS

Title TO STUDY THE CLINICAL EFFECTIVENESS OF DIACEREIN AS ADD ON THERAPY TO DICOFENAC SODIUMIN PATIENTS OF OSTEOARTHRITIS KNEE

For the degree of M.D. PharmacologyName of the Candidate Dr. Kuljnder SinghSupervisor Dr. Jaswant Rai, MD, FAIMS, FIMSA, Professor

& Head, Dept. of PharmacologyCo-Supervisor Dr. Rakesh Sharma, MS, Assistant Professor, Dept.

of Orthopaedics.Institution Department of Pharmacology and Orthopaedics,

Govt. Medical College, Amritsar

BACKGROUND

Osteoarthritis is a chronic progressive degenerative disease involving the articular system. Medical therapy of osteoarthritis consists of NSAIDS and Disease modifying drugs for Osteoarthritis (DMOAD’s). NSAIDS provide symptomatic relief and have their adverse effects. In the present study clinical effectiveness of Diacerein as add on therapy to NSAIDS and prevention of their side effects will be evaluated. This study will be prospective, single blinded, parallel, placebo controlled, intention to treat study lasting three months, involving 60 patients of osteoarthritis attending the department of Orthopaedics, Guru Teg Bahadur Hospital, Amritsar, randomized into 2 groups, A and B of 30 patients each. Group A will receive Tab. Diclofenac sodium 100 mg sustained release mg once daily for three months and matched placebo as capsule once daily for first month and twice daily for second and third month. Group B patients will receive Tab. Diclofenac 100 mg sustained release once daily for three months and capsule Diacerein 50 mg once daily for first month and twice daily for second and third month. Patients will be examined on day zero, three & six weeks and then at third and fourth month according to the Visual Analogue Scale(VAS), Patient’s and Physician’s Global Assessment & X-ray. Results will be analysed using appropriate statistical methods.

GOVERNMENT MEDICAL COLLEGE, AMRITSAR

Name of the candidate Dr Kuljinder Singh

Department Department of Pharmacology

Topic

TO STUDY THE CLINICAL EFFECTIVENESS OF DIACEREIN AS

ADD ON THERAPY TO DICLOFENAC SODIUM IN PATIENTS OF

OSTEOARTHRITIS KNEE

Examination M.D. Pharmacology

Date of enrolment 15th June, 2006

Professor of speciality Dr. Jaswant Rai, M.D.

Supervisor(s) of the Thesis Dr. Jaswant Rai. M.D. Professor and Head,

Department of Pharmacology, Government Medical College, Amritsar.

(Supervisor )

Dr. Rakesh Sharma M.S.

Assisstant professor, Department of Orthopedics, Government Medical College,

Amritsar. ( Co-Supervisor )

MEMBERS OF THE THESIS/

RESEARCH COMMITTEE

SIGNATURE WITH STAMP

1. Head of institute/ college

2. Chairman of Thesis Committee

. Member of Thesis Committee

. Member of Thesis Committee

. Member of Thesis Committee

3. Chairman Ethical Committee

. Member Ethical Committee

. Member Ethical Committee

TO STUDY THE CLINICAL EFFECTIVENESS OF DIACEREIN AS

ADD ON THERAPY TO DICLOFENAC SODIUM IN PATIENTS OF

OSTEOARTHRITIS KNEE

Osteoarthritis is a chronic progressive degenerative disease involving the

articular system. It is an insidious and progressive condition that mainly

affects the weight bearing joints and is seen most commonly late in life.1

Although men and women are equally affected, onset of osteoarthritis is

earlier in women.2 The prevalence of the condition in the 75 to 90 year old

population is about 85%.3 Osteoarthritis is characterised by the degradation

of cartilage, subchondral sclerosis, cyst formation and osteophyte

formation.1,4 Risk factors associated with the development of osteoarthritis

include increasing age, obesity, postmenopausal women, occupation and

sporting activities.4

More than 80% of all people over the age of 55 years have

radiographic evidence of osteoarthritis. The primary impact of arthritis in the

elderly is a decrease in physical functioning. This can be a cause of other

health related problems such as weight gain, cardiovascular disease,

gastrointestinal distress, decreased social functioning, increased work

disability and increased health care utilization. Currently, the objective of

therapy for osteoarthritis is the reduction of pain and improvement in the

functional status of the patient. So when treating for osteoarthritis goals have

been suggested three fold. The first is the management of pain and other

symptoms, the second is the need to maintain or improve joint function and

the third, so far not completely achievable goal is to modify the long term

biochemical process of osteoarthritis.5 The main symptom is pain especially

with the use of the joints. Other clinical signs and symptoms of osteoarthritis

are tenderness, limitation of movement, crepitus, occasional effusion,

varying degrees of local inflammation without systemic effects and mild to

severe discomfort during the activities of daily living.6

Management of osteoarthritis of the knee is based on

both non-pharmacological as well as pharmacological measures in addition

to surgical ones. Non-pharmacological measures are in the form of patient

education to reduce over weight, physical therapy and occupational therapy.

Medical therapy of osteoarthritis mainly includes non-steroidal anti-

inflammatory drugs (NSAIDS) which have been found useful in relieving

pain, stiffness and joint swelling in Osteoarthritis.7 Common side effects of

NSAIDS are upper gastrointestinal events like dyspepsia, nausea, abdominal

pain, mucosal lesions, serious complications such as bleeding and

perforations have been associated with their use which is due to non-

selective inhibition of COX enzyme.8 Selective COX-2 inhibitors have

adverse effects on the cardiovascular system and may contribute to the onset

of acute myocardial infarction and thromboembolic events.9 This has been

the major limitation to their use and has kept the pharmacological options

open to develop newer drugs which could provide relief in pain, reduce the

side effects of NSAIDS and modify the pathology of Osteoarthritis.10 Drugs

which modify the pathology of Osteoarthritis include Glucosamine-

Chondroitin sulphate and Diacerein. There is weak evidence to

support the use of glucosamine hydrochloride in combination

with chondroitin sulphate to manage symptoms of OA in

patients with moderate to severe disease and also these do

not prevent the cartilage destruction by NSAIDS.11-12

There is evidence that cytokines such as interleukin-1β (IL-1β)

and tumour necrosis factor α cause degradation of the cartilage.13 Diacerein,

a purified compound with anthraquinone structure, has been shown to

inhibit, in vitro14and in vivo15, the production and activity of interleukin- 1

and the secretion of metalloproteases16, without affecting the synthesis of

prostaglandins.17 This drug is administered orally as 50 mg twice daily.

Diacerein is entirely converted into rhein before reaching the systemic

circulation. Rhein itself is either eliminated by the renal route (20%) or

conjugated in the liver to rhein glucuronide (60%) and rhein sulfate (20%);

these metabolites are mainly eliminated by the kidney. The pharmacokinetic

characteristics of diacerein are about the same in young healthy volunteers

and elderly people with normal renal function, both after a single dose (50

mg) or repeated doses (25 to 75 mg twice daily). Rhein kinetics after single

oral doses of diacerein are linear in the range 50 to 200 mg. However, rhein

kinetics are time-dependent, since the non-renal clearance decreases with

repeated doses. This results in a moderate increase in maximum plasma

concentration, area under the plasma concentration-time curve and

elimination half-life. Nevertheless, the steady-state is reached by the third

administration and the mean elimination half-life is then around 7 to 8 hours.

Taking Diacerein with a standard meal delays systemic absorption, but is

associated with a 25% increase in the amount absorbed. Mild-to-severe

(Child Pugh's grade B to C) liver cirrhosis does not change the kinetics of

diacerein, whereas mild-to-severe renal insufficiency (creatinine clearance <

2.4 L/h) is followed by accumulation of rhein which justifies a 50%

reduction of the standard daily dosage. Rhein is highly bound to plasma

proteins (about 99%), but this binding is not saturable so that no drug

interactions are likely to occur, in contrast to those widely reported with

nonsteroidal anti-inflammatory drugs. Except for moderate and transient

digestive disturbances (soft stools, diarrhoea), diacerein is well tolerated and

seems neither responsible for gastrointestinal bleeding nor for renal, liver or

hematological toxicity.18

In several animal models, diacerein has shown

beneficial effects on cartilage by preventing the macroscopic or microscopic

lesions of the joint tissue.19 Further-more in several clinical trials of 2-6

months duration diacerein significantly reduced as compared with placebo

the pain and functional impairment in patients with hip or knee

osteoarthritis.20

Diclofenac sodium is an established therapy in treatment of

osteoarthritis of knee. It is an aryl–acetic acid derivative NSAID. It is a non-

selective inhibitor of prostaglandin synthesis. It is available in various

dosage forms for different routes of drug administration. Bioavailability of

diclofenac is 30-70% due to first pass metabolism. It accumulates in

synovial fliud with good tissue penetration. Gastrointestinal adverse effects

are more common in form of epigastric pain, nausea, gastric ulceration and

GIT bleeding.21 Diclofenac is eliminated following biotransformation to

glucoroconjugated and sulphate metabolites which are excreted in urine,

very little drug is eliminated unchanged.22 In present study, clinical

effectiveness of Diacerein as add on therapy to Diclofenac sodium will be

studied.

AIMS & OBJECTIVES

To study the clinical effectiveness of Diacerein, as add on therapy to

diclofenac sodium in management of osteoarthritis of knee

MATERIALS AND METHODS

Drugs to be investigated:-

1. Capsule Diacerein 50 mg once daily for first month and twice

daily for second and third month.

2. Tablet Diclofenac sodium 100 mg sustained release once

daily.

Patients:-

A total of 60 patients of symptomatic osteoarthritis knee visiting

the OPD/Wards of the Department of Orthopaedics, Guru Teg

Bahadur Hospital attached to the Government Medical College,

Amritsar will be selected for the present study once the inclusion

Criterion is fulfilled.

INCLUSION CRITERIA

1. Patients with symptomatic osteoarthritis of age 35 to 60 years who

fulfill American College of Rheumatology criterion for the diagnosis

of osteoarthritis will be enrolled.

2. Patients having symptomatic osteoarthritis either as a new case or as

an old case following discontinuation of treatment with NSAIDS or

other analgesic medications with a washout period of one week.

3. All these patients will be examined as per the baseline criterion and

included in the study if they fit this criterion.

EXCLUSION CRITERIA

1. Age less than 35 years or more than 60 years.

2. The patients who present with active concomitant gastroduodenal

disorders, hepatic and renal impairment within last 30 days prior to

receiving the study drug.

3. Patient with cardiovascular disorders.

4. Pregnant females or those who are planning their pregnancy during

the study.

5. Patients who have received oral, intramuscular, intraarticular or soft

tissue injections of corticosteroids within last four weeks before

receiving the first dose of the medication understudy.

6. Patients diagnosed to have any inflammatory arthritis, gout or acute

trauma of the knee, hip or spine.

7. Patients with a known hypersensitivity to NSAIDS.

8. Patients with any known contraindication of the said drugs.

9. Female patients on oral contraceptive pills.

The approval of the ethics committee of the institution will be

obtained.

Informed consent will be sought from all the patients included in

the present study.

EXPERIMENTAL METHODS

This study will be a prospective, single blind, placebo controlled, intention

to treat 60 patients of osteoarthritis visiting the OPD/Wards of the

Department of Orthopaedics, Guru Teg Bahadur Hospital attached to the

Government Medical College, Amritsar. This study will be conducted in

accordance with the principles of good clinical practice and the Decleration

of Helsinki.

Patients will be divided into 2 groups, A & B consisting of 30 patients

each. Patients will be randomly recruited into two groups A and B. The

duration of the study will be twelve weeks. Patients will be examined on day

zero, three & six weeks and at three month according to the Visual Analogue

Scale(VAS), Patient’s and physician’s Global Assessment & X-ray. Patients

will be followed up for further three weeks. Patients will be advised leg

raising exercises and to avoid squatting. Compliance will be ensured by

asking the patients to bring the empty blister packs of the medications at

every visit.

EXPERIMENTAL GROUPS

Group A

Patients in this group will receive Tab. Diclofenac 100 mg

sustained release mg once daily for three months and placebo as capsule

once daily for first month and twice daily for second and third month.

Group B

Patients in this group will receive Tab. Diclofenac 100 mg

sustained release once daily for three months and capsule Diacerein 50 mg

once daily for first month and twice daily for second and third month.

PARAMETERS

Screening or baseline clinical assessment of osteoarthritis will include

patient’s assessment of arthritic pain on a Visual Analogue Scale ( VAS ),

on a scale of 0-24 based upon the Western Ontario and Macmaster

Universities ( WOMAC ) osteoarthritis index, patients and physician’s

global assessment of osteoarthritis.

VISUAL ANALOGUE SCALE ( VAS ) :

A visual analogue scale which is a 100mm long line with the

extremes marked as ‘no pain’ (0)on one end while the extremely unbearable

pain [(100) at the start of treatment] on the other end will be used for this

study. In all these patients pain at the start of therapy will be taken as

marked on extreme end (100). During the treatment course patient will be

asked to put a mark on the line to correlate the amount of pain felt at that

time. Then with a scale the point marked will be quantified and accordingly

the improvement will be assessed.

__________________________________________________________

0 100

No pain Unbearable pain

WOMAC Osteoarthritis Index23

The WOMAC Osteoarthritis index score and the osteoarthritis

severity index score will be calculated on a scale based upon the Western

Ontario and Macmaster Universities ( WOMAC ) osteoarthritis index. The

WOMAC measures three separate dimensions, five regarding pain, two

regarding joint stiffness and seventeen concerning physical function.

The 24 items included in the WOMAC questionaire are:

Pain ( 5 Items )

How much pain do you have while

Walking on a flat surface

Going up or downstairs

At night while in bed

Sitting or lying

Standing upright

Stiffness ( 2 Items )

How severe is your stiffness after

First awakening in the morning

Lying resting later in the day

Function ( 17 Items )

What degree of difficulty do you have while

Descending stairs

Ascending stairs

Rising from sitting

Standing

Bending to floor

Walking on a flat surface

Getting in/out of a car or other vehicle

Going shopping

Putting on socks/stockings

Rising from bed

Taking off socks/stockings

Lying in bed

Getting in/out of bath

Sitting

Sitting on/off toilet

Heavy domestic duties

Light domestic duties

Each item will be rated on a 5- point scale

0 None,

1 Mild,

2 Moderate,

3 Severe,

4 Extreme,

Yielding maximum possible subscale scores of 20, 8 and 68 for pain,

stiffness and physical functioning respectively. WOMAC composite scores (

possible range 0-96 ) will be calculated by addition to individual item

scores.

Patient’s Global Assessment:

Patient’s global assessment will be utilized to know the patients overall

perception of his condition. Accordingly the patients will be put in various

categories in relation to their condition. This will be labelled as very good,

good, fair, poor and very poor. This will be first done to assess the patient’s

condition at the time of screening and then as a prognostic criteria post

treatment for ascertaining any improvement or deterioration in the patient’s

condition.

Physician’s global assessment:

Physician’s global assessment will be used to know the physician’s

assessment of the patient’s condition. Accordingly the physician will

categorize the patient’s condition as very good, good, fair, poor and very

poor. This will be done by the physician at the time of screening and then as

a prognostic criterion post treatment for assessing any improvement or

deterioration in patient’s condition.

Baseline Laboratory Investigations:

The investigation that will be carried out will be:

X-ray of both the knees AP view in standing position will be taken to

corroborate the diagnosis of osteoarthritis at day 0 and will be repeated at

three months to see the improvement if any. Routine investigations will be

done in the respective departments of Government Medical College,

Amritsar.

All the data generated from the study will be tabulated and expressed

as a mean ± S.D. of each variable. Comparison will be done by student’t’

test and expressed as 'p' value for each parameter.

CASE HISTORY RECORD

Sr. No. Date

NAME OPD No.AGE/SEX

Father's/Husband's Name

Education

Occupation

ADDRESS Phone

PRESENT COMPLAINTS:HISTORY OF PRESENT ILLNESS:

PAST HISTORY:

H/O Diabetes

H/O Hypertension

H/O Angina / MI

H/O CAD

H/O Renal disease

H/O Liver disease

H/O Tuberculosis

H/O Stroke

FAMILY HISTORY:

H/O Diabetes

H/O Hypertension

H/O CAD

H/O Tuberculosis

H/O Stroke

PERSONAL HISTORY:

Obesity

Addictions Tobacco/alcohol/others

Life style

Food habits

Socioeconomic status

TREATMENT HISTORY

H/O Any drug allergy

H/O Medication for diabetes

Whether taking any concomitant medication

EXAMINATION

Height Weight

Pulse Blood Pressure Respiratory Rate

Anemia Edema Clubbing

Cyanosis Jaundice Cervical LN

CNS

CVS

ABDOMEN

RESPIRATORY SYSTEM

Arthritic Disorder:-

1.

2.

Duration of illness: Years________ Months__________

Treatment Group:

CLINICAL ASSESSMENT DETAILS

DAY O 3WEEKS 6WEEKS 3rd MONTH 4th MONTHPAIN ASSESSMENT ON V.A.S.WOMAC SCALE ASSESSMENT(A) PAIN 1. Walking on a flat surface 2. Going up or down stairs 3. At night while in bed 4. Sitting or lying 5. Standing upright (B) STIFFNESS 1. Severity of stiffness after first waking in the morning

2. Severity of stiffness after sitting/lying or resting later in the day.

(C) FUNCTION: DEGREE OF DIFFICULTY WHILE

1. Descending stairs 2. Ascending stairs 3. Rising from sitting 4. Standing 5. Bending to floor 6. Walking on a flat surface 7. Getting in/out of car or any other vehicle 8. Going shopping 9. Putting on socks/stockings/shoes 10. Rising from bed 11. Taking off socks/stockings/shoes 12. Lying in bed 13. Letting in/out of bath 14. Sitting 15. Getting on/off toilet 16. Heavy domestic duties 17. Light domestic dutiesPATIENT’S GLOBAL ASSESSMENT(1) Very Good(2) Good(3) Fair(4) Poor(5) Very PoorPHYSICIAN’S GLOBAL ASSESSMENT(1) Very Good(2) Good(3) Fair(4) Poor(5) Very Poor

SAFETY ASSESSMENTDAY 0 3WEEKS 6WEEKS 3 MONTHS

G.I.T

Pain Abdomen

Diarrhoea

Dyspepsia

Flatuence

Nausea

BODY AS A WHOLE

Back Pain

Peripheral Edema

Accidental Injury

CENTRAL AND PERIPHERAL

NERVOUS SYSTEM

Dizziness

Headache

PSYCHIATRIC

Insomnia

RESPIRATORY

Pharyngitis

Rhinitis

Sinusitis

U.R.I

Wheezing/Breathlessness

SKIN

Rash

OTHERS

SEVERITY OF ADVERSE EFFECTS:

-- Absent

+ Mild

++ Moderate

+++ Severe

Withdrawl from the study:_______________

Date of withdrawl from the study:_________

Reasons:___________________________________________________________

____________________________________________________________________

Investigators’s comments on the relationship between the adverse effects and the

drug________________________________________________________________

Informed Consent

I, _______________________________ exercising my free power of

choice , hereby give my consent to be included in the study entitled “TO STUDY

THE CLINICAL EFFECTIVENESS OF DIACEREIN AS ADD ON

THERAPY TO DICLOFENAC SODIUM IN PATIENTS OF

OSTEOARTHRITIS KNEE.” I have been informed to my satisfaction by the

attending doctor, in a manner and language that I understand the purpose and

nature of the study, nature of drug treatment, safety of the procedures and the side

effects associated with the drugs. I am also aware of my right to opt out of the trial

at any time during the course of the study without having to give the reasons for

doing so. I have been told about the procedures of the study and agree to take part

in the investigations required.

Patient’s Name____________________________

Signature ________________________________

Dated___________

Doctor’s Name Dr Kuljinder singh

Signature ________________________________

Witness________________________________

Signature ________________________________

Dated_____________

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