protocol writing

1. PROTOCOL NO : 4590 GMCSF
VERSION NO : VERSION 1.1
DATE : 05/04/2023
SPONSOR : Sun Pharmaceutical Industries Ltd.
CTS No. 201 B/1,
Western Express Highway,
Goregaon (E),
Mumbai 400063
Tel. No: 9562562841
A RANDOMIZED, DOUBLE BLIND, PARALLEL GROUP
STUDY OF FIXED DOSE COMBINATION OF
TRAMADOL 50 MG +PARACETAMOL 650 MG TDS
V/S FLUPIRTINE 150 MG TDS MANUFACTURED BY
SUN PHARMACEUTICAL INDUSTRIES LTD FOR
TREATMENT OF PAIN IN OSTEOARTHRITIS OF THE
KNEE IN GOA MEDICAL COLLEGE

2. FIXED DOSE COMBINATION OF TRAMADOL 50 MG
+PARACETAMOL 650 MG TDS V/S FLUPIRTINE 150
MG FOR TREATMENT OF PAIN IN OSTEOARTHRITIS
OF THE KNEE

3. Investigators : Dr ABC
MS Orthopaedics
GMC, Bambolim
Ph no. 9850469201
Dr XYZ
MD Pharmacology
GMC, Bambolim
Ph no. 9404147858
Clinical Laboratory : Goa Medical College
08322491345

4. CONTENTS
• ABBREVIATIONS
• BACKGROUND INFORMATION
• PHARMACOTHERAPY OF OSTEOARTHRITI
• STUDY RATIONALE
• OBJECTIVES
• STUDY DESIGN
• STUDY INTERVENTIONS
• INCLUSON CRITERIA
• EXCLUSION CRITERIA
• WITHDRAWAL CRITERIA
• ADVERSE DRUG REACTION
• STUDY ENDPOINTS
• ASSESSMENT OF EFFICACY
• ASSESSMENT OF SAFETY
• ADHERENCE ASSESSMENT
• STATISTICS
• ETHICS
• FINANCE AND INSURANCE
• PUBLICATION POLICY
• STUDY MONITORING AND
SUPERVISION
• UNDERTAKING BY INVESTIGATOR
• APPENDICES

5. LIST OF ABBREVIATIONS
ACE-Inhibitors Angiotensin – converting – enzyme
inhibitors
ICH International Conference on Harmonisation
ACR American College of Rheumatology IEC Independent Ethics Committee
AEs Adverse Events IRB Institutional Review Board
ALT Alanine transaminase IUD Intrauterine Device
AST Aspartate aminotransferase LFT Liver Function Test
CH Complete Hemogram NMDA N-Methyl-D-Aspartate
COX-2 Cyclooxygenase – 2 NSAID Non Steroidal Anti Inflammatory Drug
CRF Case Report Form OA Osteoarthritis
DCGI Drug Controller General of India POM Pain On Movement
ESR Erythrocyte Sedimentation Rate RFT Renal Function Test
GCP Good Clinical Practice SAEs Serious Adverse Events
ICF Informed Consent Form WOMAC Western Ontario McMaster Osteoarthritis

6. Background Information
• Osteoarthritis (OA) is a highly prevalent chronic degenerative joint disease
which is characterized by cartilage loss, synovial inflammation, and bone
remodeling.
• It occurs most frequently in the knee, the prevalence increasing with age
from approximately 1% in people aged 25-34 years, to >30% in people aged
>65 years. Radiographic evidence of knee OA is present in 37% of adults
aged >60 years.
• Clinical manifestations include joint pain, stiffness, restricted motion and
crepitus on motion. OA is associated with substantial disability and
diminished productivity.
• The Western Ontario and McMaster Universities Osteoarthritis Index
(WOMAC) is used to assess pain, stiffness, and physical function in patients
with OA.

7. PHARMACO-THERAPY OF OA
• Current pharmacotherapy for pain associated with OA includes the use of
NSAIDs, either selective or cylcooxygenase-2 (COX-2) selective, as well as
paracetamol and opioid analgesics like Tramadol. (American College of
Rheumatology Recommendations, 2000).
• Though effective, non-selective NSAIDs have been associated with high risk of
gastrointestinal adverse effects. Although the incidence of gastrointestinal
complications has been reported to be lower with COX-2 selective NSAIDs,
they have been linked to increased risk of renal and cardiovascular effects.
• Use of Tramadol, in combination with paracetamol has been found to be
effective in relief of pain associated with osteoarthritis. However, long term
use of paracetamol has been found to have risk of hepatotoxicity, while
tramadol use has been reported to cause dizziness, nausea, vertigo, anxiety.
• Long-term use of high doses of tramadol may be associated with physical
dependence and a withdrawal syndrome as well.

8. PHARMACO-THERAPY OF OA
• Flupirtine is an aminopyridine that functions as a centrally acting analgesic. It is
unique among analgesics in that it is a non-opioid, non-NSAID, non-steroidal
centrally acting analgesic.
• Flupirtine produces its analgesic action through blockade of glutamate N-methyl-D-
aspartate receptor. It is devoid of adverse effects of routinely used analgesic drugs,
but is equally efficacious in reducing pain sensation. It has a distinctive mechanism
of action, exerting a dual therapeutic effect with both analgesic and muscle relaxant
properties that has utility in the treatment of pain.
• Flupirtine acts indirectly as NMDA receptor antagonist by activation of K+ channels.
It causes a dose-dependent reduction of NMDA receptor mediated glutamate
induced rise in intracellular Ca++ concentration. It binds to and activates G- protein
coupled inwardly rectifying K+ channels. Activation of this channel leads to
hyperpolarization of neuronal membrane and the neuron becomes less excitable;
thus, there is stabilization of resting neuronal membrane.
• The muscle relaxation is due to inhibition of the spinal polysynaptic flexor reflex,
mediated by NMDA receptors.

9. STUDY RATIONALE
• The study medication in the present study is Flupirtine in tablet form in a dosage
of 150mg to be taken tds.
• A similar double blind, parallel group study has shown that flupirtine showed an
overall pain-relieving efficacy comparable to tramadol. Adverse events (AEs)
occurred significantly less in patients after flupirtine (33%) vs. tramadol (49%) (p
= 0.02) and both the respective severity grading and the AE-related dropout rates
were significantly lower after flupirtine than after tramadol (1% vs. 15%, p <
0.001). ( Li C, Ni J, Wang Z et al; Curr Med Res Opin 2008.)
• The current study is designed to test the therapeutic equivalence and safety of
oral flupirtine 150mg tds (test product) compared to the oral fixed dose
combination of tramadol 50mg + paracetamol 650 mg (reference product) , for
relief in pain associated with osteoarthritis of the knee.

10. OBJECTIVES
• PRIMARY :
To establish the therapeutic equivalence of Flupirtine 150mg
tds compared to fixed dose combination of Tramadol 50mg +
Paracetamol 650 mg tds in relief of pain associated with
osteoarthritis of the knee.
• SECONDARY :
To monitor adverse effects of the medications.

11. STUDY DESIGN
• This will be a comparative , randomized, double blind, parallel
group study carried out among 200 patients diagnosed with
osteoarthritis randomized into two groups of 100 each groups
using computer-generated Randomized sequence (1:1) in Goa
Medical College.
• The entire set of subjects will be subjected to a 7 day washout
period during which they will refrain from taking any medication for
pain relief.
• Two balanced parallel groups of subjects will be created using
computer-generated Randomized sequence (1:1), each group
receiving either a fixed dose combination of tramadol 50mg +
paracetamol 650 mg tds, or flupirtine (dolpiritin) 150 mg tds over
an observation period of 6 weeks duration.
• Both the Study combinations are manufactured and will be
provided by Sponsor.

12. STUDY DESIGN
• At the end of each week, the subject will be asked to rate their pain via
WOMAC pain score, and the means will be tallied to find efficacy of drugs in
pain relief at the end of the observation period.
• The study will involve a first visit by the subjects for screening purposes,
followed by a 7 day washout period, further followed by six visits by the
subject, once a week for the 6 weeks of duration of the study, in which they
will rate their pain via WOMAC pain score.
• Audio visual and Written informed consent will be taken.
• After signing the written informed consent, subjects will have to provide
medical and medication history.
• Baseline laboratory parameters : CH +ESR, RFTs, LFTs, X-Ray knee joint will be
required. ( For which 5ml blood will be drawn from anterior cubital vein)

13. s
• Urine routine examination will be done.
• Xray Chest, ECG will be taken.
• For purposes of safety evaluation, physical examinations and evaluation of vital
signs (Pulse, Blood pressure, Body Temperature) will be carried out for each
subject at each visit and 5ml of blood will be drawn to evaluate RFT and LFT at
each visit.
• Medication allowed at screening visit may be continued.
• Travel allowance will be given according to rupees 50 per kilometer.
• Loss of daily wages will be compensated for the day of the visit.
• For every ml of blood lost , the subject shall receive Rs. 20.
• An interim illness during the trial , caused due to either of drugs will be treated
free of cost.

14. INCLUSION CRITERIA
Subjects must meet the following inclusion criteria to be eligible for
enrollment into the study :
• Healthy, ambulatory male or non-pregnant female subjects aged ≥35
years with a clinical diagnosis of OA of the Knee including :
1. Presence of at least 3 of the American College of Rheumatology (ACR)
criteria( age ≥ 50; stiffness lasting< 30 minutes; bony tenderness;
crepitus; bony enlargement; no palpable warmth)
2. Symptoms for at least 6 months prior to screening AND
3. Knee (not referred) pain for 15 days of the preceding month (peri-
articular knee pain due to OA)
• Evidence of a signed and dated informed consent document indicting
that the subject has ben informed of all pertinent aspects of the study.
• X-ray of the knee, taken no more than one year before baseline,
showing evidence of OA with a Kellgren-Lawrence grade 1-3 disease.

15. INCLUSION CRITERIA
• After discontinuing pain medication for a period of 7 days, has at least
moderate pain on movement for the knee, judged by a baseline
Western Ontario McMaster Osteoarthritis (WOMAC) pain source of at
least 9 immediately prior to randomization.
• If female and of child-bearing potential, agree to abstain from sexual
intercourse or use a reliable method of contraception during the study
(e.g., condom+spermicide, or IUD)
• Able to tolerate rescue medication with NSAIDs.
• Willing and able to comply with study requirements.

16. EXCLUSION CRITERIA
• Pregnant or lactating or planning to become pregnant during the study
period.
• X-ray showing evidence of OA with Kellgren Lawrence grade 4 disease.
• History of secondary osteoarthritis, rheumatoid arthritis, chronic
inflammatory disease or fibromyalgia.
• History of asthma, hypertension, myocardial infarction, thrombotic
events, stroke , Congestive Heart Failure, impaired renal function or
liver disease.
• History of gastrointestinal bleeding or peptic ulcer disease.
• Elevated transaminases at screening (AST or ALT more than 2 times the
upper limit of normal at screening visit)
• Use of Warfarin or other anticoagulant therapy within 30 days of study
randomization.

17. EXCLUSION CRITERIA
• Known allergy to tramadol, paracetamol or NSAIDs.
• Concomitant use of corticosteroids, or use within 30 days of study
randomization.
• Any other acute or chronic illness that, in the opinion of the investigator,
could compromise the integrity of study data or place the subject at risk
by participating in the study.
• Receipt of any drug as a part of a research study within 30 days prior to
screening.
• An use between screening and baseline of a treatment or medication
that may potentially confound study assessment.
• Recent history of major knee injury or surgery.

18. WITHDRAWAL CRITERIA
• Unexpected adverse drug event
• Lack of cooperation by the subject
• Need for rescue medication
• Pregnancy

19. STUDY INTERVENTIONS
Interventions, Administration and duration:
• Test Product : Flupirtine tablet, 150mg
• Reference Product : Combination tablet of Tramadol 50mg +
Paracetamol 650mg
• One group will receive the test product and the other will receive
the reference product.
• All tablets will be over-encapsulated, every capsule being the
same size, shape, and colour to maintain blinding.
• Each subject will take the assigned medication via oral route,
three times a day after meals , every day for a period of 6 weeks,
with a visit to the investigator at the end of each week.

20. CONCOMITANT INTERVENTIONS
Allowed Interventions :
• Generally, subjects will be allowed to take other non-analgesic
medications that would not interfere with the metabolism of the
assigned medications.
• Physical Therapy will be permitted if started at least one month
prior to screening, but cannot be initiated or changed during the
study. Similarly, exercise regimens and application of heat and
cold cannot be started, discontinued, or changed during the study.
Rescue Medications :
• With the exception of the washout period, the use of NSAIDs like
etoricoxib will be permitted as rescue medications for residual
knee pain or any other pain throughout the study period.

21. Prohibited Interventions :
• ACE Inhibitors, Warfarin, Lithium, Benzodiazepines, Selective
Serotonin Reuptake Inhibitors, Tricyclic Antidepressants,
Carbamazepine, Alcohol, NSAIDs, Methotrexate.
• Corticosteroids or immunosuppressive drugs.
• Pain medication other than the rescue medications.

22. STUDY ENDPOINTS:
•Mean change from baseline to week 6 in the WOMAC
pain score (score = 0-20 )
•Safety of the medication

23. ADVERSE EFFECTS:
• PARACETAMOL
1. Allergic reactions
2. Hepatotoxicity
3. Dyspepsia
• TRAMADOL
1. Nausea
2. Vomiting
3. Constipation
4. Light headedness/dizziness,
5. Vertigo
6. Anxiety
7. Physical dependance/abuse
• FLUPIRTINE
1. Dizziness
2. Drowsiness
3. Dry mouth
4. Gastric fullness
5. Muscle tremor

24. ASSESSMENT OF EFFICACY
• Efficacy of the medication in relief of pain associated with OA of the
knee will be determined by use of the Western Ontario and
McMaster Universities Osteoarthritis (WOMAC) pain score (pain
score = 0-20) which is determined by the subject’s responses to five
questions using a 5 point Likert scale (i.e., 0=none, 1=mild,
2=moderate, 3=severe, 4=extreme).
• The questions pertain to the amount of pain the subject is currently
experiencing in the target knee :
• Ex: How much pain do you have when
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
• Subjects will be given a questionnaire with the aforementioned
questions at each visit, 6 visits in all, for the duration of the study.
• The mean change from baseline to week 6 in the WOMAC pain
score will determine the efficacy of the assigned medication.

25. ADHERENCE ASSESSMENT
• Each subject will be given a subject diary in which they must tick off
each dose they take every day.
• One week’s worth of medication will be given to them at the start of
the study, with further supplementation of a week’s worth of
medication when the subject makes a visit to the investigator at the
end of the week.
• Treatment compliance will be monitored by reviewing the subject
diaries, as well as checking whether any medication for the week
remains with the subject.
• The date of the first dose, date of last dose, the total number of doses
taken, and total number of missed doses will be recorded by the study
coordinator on the subject’s CRF.
• At the end of the study, the subject’s diary will be kept at the study
center as part of the documentation records.

26. ASSESSMENT OF SAFETY
• Safety will be evaluated from reported adverse events.
• Other safety assessments including vital signs (blood pressure, pulse,
temperature, respiration) , physical examinations, concomitant
medications, and laboratory tests will be evaluated at each visit for
the duration of the study.
• A urine pregnancy test will be performed in women of childbearing
potential.
• All adverse events will be recorded in the subjects CRF by the study
coordinator.
• All Serious Adverse Events (SAEs) must be reported immediately
(within 24 hours of the investigator becoming aware) to the Drugs
Controller General India, The Ethics Committee, and the Sponsor and
Medical Monitor of the study.

27. STUDY DISCONTINUATION
A subject will be withdrawn from the study prior to completion for any
of the following reasons :
• Subject withdraws consent.
• Subject’s study medication is unblinded.
• The investigator decides that it is in the subject’s best interest to be
withdrawn.
• Serious adverse reaction to the medication.
• Intercurrent illness that may, in the investigator’s opinion,
significantly alter the assessment of the clinical status.
• A concomitant therapy is required that is likely to confound the
assessment of the subject’s OA.
• A significant protocol violation.

28. STATISTICS
• Statistical analysis will be calculated using a software to
determine significance of the mean from the baseline reading
of the WOMAC pain score.
• Differences between the two groups will be tested using chi-
square test
• The difference will be considered to be statistically significant if
p value is ≤0.05

29. ETHICS
• The investigator and sponsor will make sure that all aspects of this
trial are conducted in accordance with all regulations guiding the
protection of human subjects.
• The study will be conducted in accordance with the declaration of
Helsinki.
• The investigator should maintain complete documentation of all
events and the times in which they occur, in accordance with the
International Conference on Harmonisation (ICH) and Indian GCP
guidelines.
• The study must be approved in writing by an appropriate
Independent Ethics Committee (IEC) or Institutional Review Board
(IRB).
• Written informed consent will be obtained from all subjects before
any study related procedures are conducted.

30. DATA HANDLING AND RECORD KEEPING
• The investigator/delegate will be responsible for ensuring the
accuracy, completeness and timelines of the data reported.
• All source documents shall be completed in a neat, legible manner to
ensure accurate interpretation of the data.
• All the blood which is drawn will be destroyed after completion of
the research.

31. FINANCE AND INSURANCE
• The sponsor will provide insurance in order to indemnify (with both
legal and financial coverage) the investigator/site against claims
arising from the study, except for claims that arise from malpractice
and/or negligence.
• The compensation of the subject in the event of study-related
injuries will comply with applicable regulations.

32. PUBLICATION POLICY
• In accordance with the Good Publication Practices the results of the
study will be submitted for publication in peer-reviewed journal

33. STUDY MONITORING AND SUPERVISION
• Prior to study start, at a site, all required approvals must be obtained.
• A site initiation visit (SIV) will be performed after the required
essential study documents are approved by the sponsor.
• The sponsor representatives may audit the investigator site (during
the study or after its completion).
• Health authorities and/or IEC/IRB may also conduct an inspection of
this study (during the study or after its completion) at the site.

34. UNDERTAKING BY INVESTIGATOR

36. APPENDICES
• Informed Consent Form
• Consent form for Audio Visual recording
• Letter of Approval from IEC/IRB
• Case Record Form
• Subject diary
• Questionnaire with Likert’s Scale
• WOMAC Pain Score
• American College of Rheumatology (ACR) criteria for Osteoarthritis of the knee
• Kellgren Lawrence radiologic grades of Osteoarthritis of the knee.
• ADR reporting form

37. THANK YOU

38. • DATA HANDLING AND RECORD KEEPING
• Data Handling Data will be recorded at the site on eCRFs and reviewed by the Clinical
Research Associate (CRA) during monitoring visits. The CRAs will verify data recorded
in the EDC system with source documents. All corrections or changes made to any
study data must be appropriately tracked in an audit trail in the EDC system.
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study
product, regulatory documents, and other Sponsor correspondence pertaining to the
study must be kept in the appropriate study files at the site. Source data is defined as all
information in original records and certified copies of original records of clinical
findings, observations, or other activities in a clinical study necessary for the evaluation
and reconstruction of the clinical study. Source data are contained in source documents
(original records or certified copies). These records will be retained in a secure file for
the period as set forth in the Clinical Study Agreement. Prior to transfer or destruction
of these records, the Sponsor must be notified in writing and be given the opportunity
to further store such records.

39. • Publication Policy
Following completion of the study, the data may be considered for publication in a
scientific journal or for reporting at a scientific meeting. Each Investigator is
obligated to keep data pertaining to the study confidential. The Investigator must
consult with the Sponsor before any study data are submitted for publication. The
Sponsor reserves the right to deny publication rights until mutual agreement on
the content, format, interpretation of data in the manuscript, and journal selected
for publication are achieved