Protocol of Thesis to be submitted to the Tripura University towards the partial fulfilment of the requirement for the degree of M.D. (Pharmacology)

TITLE OF THESIS

POSTOPERATIVE ANALGESIA BETWEEN INTRAVENOUS PARACETAMOL VS INTRANASAL TAPENTADOL IN OPEN CHOLECYSTECTOMY PATIENTS:

A NON-INFERIORITY CLINICAL TRIAL

Submitted by: DR. PRAJNAPARMITA SAHA

Signature:

Name of Guide: PROF. (DR.) DEBASIS RAY

Professor& H.O.D, Department of Pharmacology

Signature:

Name of Co-Guide: DR. SHANTA SUTRADHAR

Assistant Professor, Department of Pharmacology

Signature:

Name of Co-Guide: DR. DIPTENDU CHAUDHURI

Associate Professor, Department of General Surgery

Signature:

Name of Co-Guide: DR. SAMBIT DEBBARMAN

Assistant Professor, Department of General Surgery

Signature:

Contents

INTRODUCTION

Pain is described by International Association for study of pain as“anunpleasant sensory and emotional experience associated with actual orpotential tissue damage, or described in terms of such damage”^[1]. Painis a major public health issue throughout theworld and represents a major clinical, social, and economic problem ^[2].

Pain can be Acute (lasts few days), Sub acute (lasts few weeks) andChronic (lasts to months). Acute Pain is of sudden onset and shortduration. Once the inflammation subsides and wound heals pain ceasesand the condition of patient improves. The severity of pain can beassessed by various scales such as visual analogue scale and verbal painintensity scale. Chronic Pain is long standing pain that persists beyond the usual recovery period. It commonly persists for long duration^[3]. Among the 70 million surgeries performed worldwide everyyear, over 80% patients suffer from moderate to severe post-operative pain ^[4,5].

It has a huge impact upon the qualityof life, as poorly controlled acute post-operative pain can leadto central neuronal sensitization precipitating chronic pain^[6,7]. Proper pain management, particularly postoperative pain management,is a major concern for clinicians as well as for patients undergoingsurgery. Patients commonly enquire about the level of pain they mayexperience after an operation. Postoperative pain not only affects thepatients’ operative outcome, well-being, and satisfaction from medicalcare, but also directly affects the development of tachycardia, hyperventilation,decrease in alveolar ventilation, transition to chronic pain,poor wound healing, and insomnia, which in turn may impact the post-operative outcomes^[8]. Individual variations in the response to painare influenced by the genetic makeup, cultural background, age, andgender^[9].

Paracetamol is one of the most frequently used analgesic and antipyreticagent, presents with no unwanted side effects of NSAIDs^[10]. Primary mechanism of these analgesic drugs is to inhibit thecyclooxygenase and prostaglandin synthesis which is considered as animportant environmental factor in the prevention of hypersensitivity andpain^[11]. To date, at least two types of cyclooxygenase (COX) havebeen identified: Cyclooxygenase1 (COX-1) which is involved in plateletaggregation, hemostasis, and protects the gastric mucosa, andcyclooxygenase 2 (COX-2) which is effective in pain, inflammation, andfever^[12].Nonsteroidal anti-inflammatory drugs are usually effective for mild tomoderate pain control. The effectiveness of these drugs has beenidentified as opioids adjuvant for moderate to severe pain. Recentstudies have shown that nonsteroidal anti-inflammatory drugs areeffective for pain control rather alone or combined with opioids, whichare more than what has been assumed so far^[13,14].

Tapentadol stands out as a centrally acting analgesic with a distinctiveprofile, combining μ- opioid receptor agonism and noradrenaline(norepinephrine) re-uptake inhibition while exerting minimal serotoninre-uptake inhibition. This dual mode of action renders tapentadolhighlyvaluable for addressing both nociceptive and neuropathic pain. Clinicaltrials have consistently demonstrated its efficacy in acute and chronicnoncancerous pain, cancer- related pain, and neuropathic pain. Notably,tapentadol exhibits an opioid-sparing effect, leading to a reduction inopioid-related adverse effects, particularly gastrointestinal issues. Thisimproved tolerability and enhanced adherence to therapy maketapentadol an optimal choice for effective pain management^[15].

The results of various study show that patients who were given tapentadol nasal spray post operatively were found to have ease in administration of medication,early onset of analgesia and significantly better VAS scores. After extensive literature search, very few studies could be retrieved which has compared the efficacy of postoperative analgesia between intravenous paracetamol and intranasal tapentadol in patients undergone open cholecystectomy, especially from this part of the country.

Different studies revealed that both the regimes are useful in different post-operative pain management but as there is no such neck to neck comparison of postoperative analgesia between intravenous paracetamol and intranasal tapentadol in open cholecystectomy patients,further research in this topic would be beneficial to draw healthy conclusion and establish facts around the same.

REVIEW OF LITERATURE

Sunil Shetty, Sachin Kale et al, in their original research article published in November 2023, mentioned in their observational study, that they conducted head to head comparison of Tapentadol Nasal Spray & Intravenous Tramadol for managing postoperative moderate to severe pain. The study was conducted on 600 subjects divided into two groups. Group 1 comprised of 300 subjects receiving intravenous Tramadol 50 mg BD & Group 2 comprised of the other 300 subjects receiving intranasal Tapentadol 45 mg QID for 3 days. The mean pain score with Tapentadol Nasal Spray was 3.2+/-0.6 which was significantly lower compared to intravenous Tramadol being 4.4+/-0.7 (p<0.0001). There was 36.8% greater decrease in mean pain score with Tapentadol Nasal Spray as compared with Tramadol IV. The study highlighted that sleep scores are also better with Tapentadol Nasal Spray as compared with Tramadol IV ^[16].

In 2023 Dr. Sumitoj Singh, Dr. Raghav Sawal et al , published their research article on a comparative study on Tapentadol Nasal Spray & intramuscular Diclofenac Sodium in the postoperative In pain management. This Randomized Controlled Trial was conducted using Sequentially Numbered Opaque Sealed Envelope (SNOSE) technique on 200 postoperative cases. Half set of postoperative cases were prescribed Tapentadol Nasal Spray 45 mg TID & were assigned as Group A. Rest half of the postoperative cases were prescribed intramuscular Diclofenac Sodium 75 mg TID & were assigned as Group B. Pain scores were evaluated by Visual Analogue Scale (VAS). The mean VAS score of Group B was significantly more [POD 0: 6.74 to POD 3: 3.03] when compared to Group A [POD 0: 5.54 to POD 3: 0.79]; thus showing that Tapentadol Nasal Spray is better analgesic in postoperative pain management than intramuscular Diclofenac Sodium ^[17].

Priyanka Suresh et al, Kempegowda Institute of Medical Sciences, uploaded their comparative study between Intranasal Tapentadol vs IV Paracetamol for post- operative analgesia in lower limb orthopaedic surgeries under spinal analgesia, in Clinical Trail. gov.NLM in August 21, 2023. The Randomised clinical trial was conducted on 74 participants between 18-60 years age who underwent elective lower limb orthopaedic surgery with ASA1 & ASA2. Half set of post operative cases received IV Paracetamol 1 gram 5- 6 hourly, designated as Group A. Rest half of the participants received Intranasal Tapentadol 44.5 mg every 5-6 hourly, designated as Group B. Patients were assessed for pain by using VAS half an hour after administration of both the drugs and pain scores were recorded. Pain scores were recorded for 72 hours after the intervention. However the result of the study was not concluded but the study was published in Clinical Trial.gov, NLM[10].

Mazhari, M.K.H, Chandra.J Et al published their original research article on April 2023 on Tapentadol nasal spray as an effective way of pain management after tooth extraction: A Randomised Clinical Trail. The study was conducted on 15 patients (9 male & 6 female) between age group of 18- 50 years, who has underwent bilateral tooth extraction( 30 procedures). In the first setting, all the 15 patients underwent tooth extraction on the right side & were administered intranasal tapentadol 45mg every 6 hourly for 3 days. After 3^rd day of extraction, pain assessment was done using VAS & number of emergency analgesic, if required. In the second setting, patients were recalled after 7 days of first extraction procedure to undergo the 2^nd extraction procedure on the left side & were administered tablet Diclofenac50mg 6 hourly for 3 days. pain score were assessed using VAS after 3^rd day of second extraction. The study concluded that subjects administered with intranasal tapentadol after the first extraction on the right side, did not experience any pain and no rescue analgesics were required. Whereas when Diclofenac tablet was used, 60% of patients suffered from mild pain and 33.3% suffered annoying pain after secondary pain after secondary extraction on the left side. The two tailed P value was less than 0.0001 which was extremely significant^[18].

In their original research article, Ghanshyam Yadav, Gaurav Jain et al in 2016, penned down the role of pre-emptive Tapentadol in reduction of postoperative analgesic requirements after Laparoscopic Cholecystectomy. This Randomized Controlled Trial comprised of 60 patients posted for Laparoscopic Cholecystectomy divided into Group A & Group B. Group A patients received 75 mg Tapentadol tablet orally while Group B patients received starch tablets 1 hour before induction of general anaesthesia. The perioperative analgesic requirement was significantly lower in Group A. Verbal Numerical Score (VNS) was significantly lower in Group A at the time point, immediately after shiftingthe patient to PACU. Time to first analgesia in PACU was 96.5+/-22.5 minutesin Group A, which was significantly longer when compared to Group B i.e. 16.9+/-7.0 (p<0.001). Requirement of rescue analgesia was also significantly low in Group A (26.6%) when compared to Group B (56.7%) (p=0.01). The study concluded that Tapentadol is anappropriate choice as a pre-emptive analgesia for Laparoscopic Cholecystectomy having a favourable safety profile^[19].

Gousheh SM, Nesioonpour S et al in 2013, conducted a study on intravenous paracetamol for postoperative analgesia in Laparoscopic Cholecystectomy. This double blinded Randomized Controlled Trial comprised of 30 patients, posted for Laparoscopic Cholecystectomy, were divided into Group A & Group B. Group A patients received paracetamol 1 g IV & Group B patients received placebo 10 minutes after induction of anaesthesia. Morphine 0.1 mg/kg was administered intravenously based on patient’s complaints and pain score > 3. Pain score & opioid consumption were recorded in first 6 hours postoperatively. Patient’s pain was recorded by VAS score. The pain score was significantly lower in Group A (p=0.01), but the morphine consumption showed no significant difference between the groups (p=0.24) during first 6 hours postoperatively

[11].

Publication by Mustafa Arslan, Bahadir Celep et al in 2013, compared the efficacy of pre- emptive IV paracetamol on the reducing effect of opioid usage in Cholecystectomy. This study was performed on 300 patients, where the subjects were randomized into 3 groups. Group I patients received pre-emptive paracetamol infusion. Group II patients received postoperative paracetamol infusion and Group III subjects received placebo. Time to first analgesic requirement was significantly lower in Group I patients followed by Group II and then Group III patients (p<0.05). Total analgesic consumption & postoperative VAS score were significantly lower in Group I & II, compared to Group III  (p<0.05). The study concluded that pre-emptive IV paracetamol provided most effective and reliable pain control after Cholecystectomy & reduced postoperative pain scores, the need for use of supplementary opioid^[20].

AIM & OBJECTIVES

Aim: Aim of the study is to compare the efficacy of intravenous Paracetamol and intranasal Tapentadol.

Objectives:

Primary Objective:

Ø  To determine and compare the degree of analgesia of intravenous Paracetamol and intranasal Tapentadol in post operative pain management following open Cholecystectomy.

Secondary Objective:

Ø  To demonstrate the adverse events of intravenous paracetamol among the study participants.

Ø  To demonstrate the adverse events of intranasal Tapentadol among the study participants.

HYPOTHESIS

Null Hypothesis:There is no difference of efficacy betweenintranasal Tapentadol and intravenous Paracetamol in post operative pain management in cases of open cholecystectomy.

Alternate Hypothesis:Intranasal Tapentadol is not inferior than intravenous Paracetamol in post operative pain management in cases of open cholecystectomy.

MATERIALS & METHOD

v Study Design:An open label parallel group randomized clinical trial.

v Study Setting: The study will be conducted in the Department of Surgeryand in the department of pharmacology, AGMC and GBP Hospital.

v Study Duration:One and half year.

v Study Type: Experimental study.

v Eligibility Criteria of   Studied Population/ Participants:

Ø  Inclusion Criteria:All the newly diagnosed Cholecystitis patients undergoing Open Cholecystectomy with ASA 1 & 2 at General Surgery Department of AGMC, in the age group of 18 years and above, shall be included in the study.

Ø  Exclusion Criteria: - Subjects with ASA grade 3 or above status.

-    Patients on immunosuppressive drugs.

-  Patients unwilling for giving consent.

-  Pregnant and lactating women.

v Intervention:After Randomization, one group of participants shall receive Paracetamol 1 gram IV 8 hourly for 24 hour and another group of participants shall receive Tapentadol Nasal Spray 45 mg (22.5 mg/nostril) 8 hourly for 24 hour.

v Outcome Variable:

VAS score: It will be recorded 2 hours after administration of each dose of either Paracetamol or Tapentadol for 24 hour.

Time to first analgesic request: Time in minutes measured from the end of procedure to time when patients request analgesics.

Mean VAS score: It will be calculated for 24 hours.

v Participant Timeline:

Randomization

Group A (Patients receiving Tapentadol)       Group B (Patients receiving Paracetamol)

Intranasal Tapentadol 45 mg TID                         Intravenous Paracetamol 1 gram TID

Assessment of Efficacy by VAS scale for 24 hour &

Rescue analgesia time

STATISTICAL ANALYSIS

v Sample Size:Based on data taken from last three years OT records, it has been observed there were almost 100 cases of open cholecystectomy  procedures performed per year in our setup.So we expect 150 cases of open cholecystectomy during the one and half year of the study period. All the patients who will undergo Open Cholecystectomy during the one and half year study period and shall satisfy the inclusion criteria will be recruited in this present study.

v Recruitment/ Sampling Technique: Consecutive sampling.

v Data Collection Methods:

After obtaining permission from the institutional ethics committee, all the Cholecystitis patients who are planned for open Cholecystectomy in the department of General Surgery, AGMC & GBP Hospital will be screened for eligibility as per the inclusion & exclusion criteria.Informed written consent will be taken from all the eligible patients. The eligible subjects shall be randomized.

v Allocation:

a.      Randomization/ Sequence Generation: Permuted variable block randomisation. It shall be done by online software sealed envelope Ltd.2017 to create        a     blocked randomization                  list                       online, [availablefrom:http//www.sealedenvelop.com/simple-randomizer/v1/lists]

b.     Allocation Concealment Mechanism:Shall be done by sequentially numbered opaque sealed envelope.

c.      Implementation:Sequence generation or randomization shall be done by independent faculty members from the Department of Pharmacology.

v Blinding: It shall be an open label study.

Participants shall be recruited in either of the two study group. Drugs will be administered postoperatively for 24 hours, 8 hourly and assessment of efficacy of the administered drug will be evaluated by VAS scale at regular intervals and rescue analgesia time during this first 24 hour.

POST-OPEN CHOLECYSTECTOMY PATIENTS

Sample size = N

Group A (n=N/2)                                                                          Group B (n)

Drug: Tapentadol Nasal Spray                                            Drug: Paracetamol Injection

Dose: 45 mg TID                                                                Dose: 1 gram TID

Assessment of Efficacy of both the drug

v Study tool: Visual Analogue Scale is a psychometric response scale which is used in subjective assessment of pain. The scale comprises of a 10 cm line with two end points representing 0 (no pain) & 10 (worse pain). Scores are recorded by marking a hand written mark on this 10 cm line that represents a continuum between “No pain”& “Worse pain”.

v  Rescue Medication: Injection Diclofenac 75 mg intramuscular stat dose to be administered if the VAS score is more than 5 during assessment of pain score.

v  The Investigator will bear the necessary expenses for conducting this study.

v DATA MANAGEMENT AND ANALYSIS:The recorded data will be analysed by using SPSS version 25.0 software.Descriptive statistics will be expressed in mean, SD, frequency and percentage as applicable. To assess the significant difference between the groups, for continuous variable student’s t-test and for categorical variable chi-square test will be applied. P value of <0.05 will be taken as significant.

v Ethical Committee Approval: Study will be carried out after approval from the Institutional ethics committee, AGMC & GBP Hospital.

v CTRI Registration: This academic clinical trial will be registered in CTRI after approval of protocol by IEC. Recruitment of participants will be started after CTRI registration.

REFERENCES

     1. Raja SN, Carr DB, Cohen M et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976-82.

2. Jahromi SA, Valami SM, Hatamian S. Comparison between effect of lidocaine, morphine and ketamine spray on post-tonsillectomy pain in children. Anesthesiologyand pain medicine. 2012;2(1):17-23.

3. Verhaak PF, Kerssens JJ, Dekker J et al. Prevalence of chronic benign pain disorder among adults: a review of the literature. Pain. 1998;77(3):231-39.

4. Imani F, Safari S. “Pain relief is an essential human right”, we should be concerned about it. Anesthesiology and pain medicine. 2011;1(2):55.

5. Imani F, Rahimzadeh P. Gabapentinoids: gabapentin and pregabalin for postoperative pain management. Anesthesiology and pain medicine. 2012;2(2):52-3.

6. Imani F, Rahimzadeh P, Faiz SH. Comparison of the efficacy of adding clonidine, chlorpromazine, promethazine, and midazolam to morphine pumps in postoperative pain control of addicted patients. Anesthesiology and Pain Medicine. 2011;1(1):100-6

7.    Imani F, Rahimzadeh P, Faiz SH. Comparison of the efficacy of adding clonidine, chlorpromazine, promethazine, and midazolam to morphine pumps in postoperative pain control of addicted patients. Anesthesiology and Pain Medicine. 2011;1(1):110-16

8. Shoar S, Esmaeili Shoar S, Esmaeili S, Safari S. Pain management after surgery: a brief review. Anesthesiology and pain medicine. 2012;1(3):184-85

9. Jahromi SA, Valami SM, Javadi A. Effects of suppository acetaminophen, bupivacaine wound infiltration, and caudal block with bupivacaine on postoperative pain in pediatric inguinal herniorrhaphy. Anesthesiology and pain medicine. 2012;1(4):243-48.

10.  Priyanka Suresh.Comparison of Postoperative Analgesia between intravenous paracetamol and intranasal tapentadol.ClinicalTrials,gov, NIH.U.S National Library of Medicine. ID NCT05999890.

11.  Gousheh SM, Nesioonpour S, Akhondzadeh R et al. Intravenous paracetamol for postoperative analgesia in laparoscopic cholecystectomy. Anesthesiology and pain medicine. 2013;3(1):214-18.

12.  Beck DH, Schenk M, Doepfmer U et al. Rectal paracetamol has a significant morphine- sparing effect after hysterectomy. British journal of anaesthesia. 2000;85(4):658-9.

13.  Schug SA, Sidebotham DA, McGuinnety M et al. Acetaminophen as an adjunct to morphine by patient-controlled analgesia in the management of acute postoperative pain. Anesthesia& Analgesia. 1998;87(2):368-72.

14.  Warner TD, Mitchell JA. Cyclooxygenase-3 (COX-3): filling in the gaps toward a COX continuum.Proceedings of the national academy of sciences. 2002;99(21):13371-3.

15.   Singh DR, Nag K, Shetti AN et al. Tapentadol hydrochloride: A novel analgesic. Saudi journal of anaesthesia. 2013;7(3):322-26.

16.  Shetty S, Kale S, Singh S et al. Head-to-Head Comparison of Tapentadol Nasal Spray and Intravenous Tramadol for Managing Postoperative Moderate-to-Severe Pain: An Observational Study. Indian Journal of Pain. 2023;37(Suppl 1):S41-42.

17.    Singh S, Sawal R. A comparative study of tapentadol nasal spray and intramuscular diclofenac sodium in postoperative pain management. Journal of Cardiovascular Disease Research:2023;14(4):426-31.

18.  Mazhari MK, Chandra J, Sequeira JP. Tapentadol Nasal Spray is an Effective Way of Pain Management after Tooth Extraction: A Randomized Control Clinical Trial. Journal of Pharmaceutical Research International. 2023;35(8):9-14.

19.  Yadav G, Jain G, Samprathi A et al. Role of preemptivetapentadol in reduction of postoperative analgesic requirements after laparoscopic cholecystectomy. Journal of Anaesthesiology Clinical Pharmacology. 2016;32(4):492-96

20.  Arslan M, Celep B, Ciçek R et al. Comparing the efficacy of preemptive intravenous paracetamol on the reducing effect of opioid usage in cholecystectomy. J Res Med Sci. 2013;18(3):172-78.

.

ANNEXURE-I

Case Record Form

    CR.NO:

AR.NO:

Particulars of the Patient:

Age: 

Sex:

Religion:

State: 

Race:

Rural/Urban:

Presenting Complaint:

H/O Present Illness:

H/O Past Illness:

Family History

Personal History:

Socioeconomic History:

Examination

GENERAL PHYSICAL EXAMINATION

LOCAL EXAMINATION:

Per-Abdominal Examination for POD 0 & POD 1

VAS Score Assessment:Mean VAS score shall be calculated for 24 hour.

ANNEXURE-II

(PATIENT INFORMATION SHEET)

Name of Investigator: Dr.PrajnaparmitaSaha

Name of Guide: Prof. (Dr.)Debasis Ray

My Name is Dr. PrajnaparmitaSaha, currently working in a study in AGMC & GBP Hospital, Agartala, Tripura collecting data for a study called “POSTOPERATIVE ANALGESIA BETWEEN INTRAVENOUS PARACETAMOL VS INTRANASAL TAPENTADOL IN OPEN CHOLECYSTECTOMY PATIENTS: A NON-INFERIORITY CLINICAL

TRIAL”.You are being requested for participation by chance and not for any reason. This consent form will give you information about this study to participate in it. Therefore, you have to read this form, or somebody will read it for you. If you are willing to participate in this study, you will put up, todays date & sign in this consent form.

Purpose of the study: determine and compare the efficacy of intravenous Paracetamol and intranasal Tapentadol in terms of clinical response in post operative open cholecystectomy patient.

Procedure of Study: Hospital Based Open Label Randomized Control Trial.

I have been offered a copy of my consent form. I understand that anytime I can contact my investigator in case of doubt. I have promised to supply any new development or information which has bearing on the study.

Date:

Signature Of Witness: -                                                 Signature of Subject:-

ANNEXURE-III

(INFORMED CONSENT FORM IN BENGALI LANGUAGE)

(সন্মতিপএ)

এইগবেষণারউদ্দেশ্য,বিষয়বস্তুএবংইহারসমস্যাগুলিডাক্তারবাবুআমাকেবিস্তারিতভাবেব্যাখ্যাকরেছেন।আমিস্বেচ্ছায়এইগবেষনায়যোগদানকরছিএবংআমারইচ্ছানুসারেএইগবেষণাথেকেনিজেকেপ্রত্যাহারকরতেপারি।

আমাকেএইসম্মতিপত্রেরএকটিপ্রতিলিপিদেওয়াহবে।আমিসমস্তভেবেজেনেএইযোগদানকরারপূর্ণসম্মতিদিলাম।

অংশগ্রহণকারীরনাম :-

স্বাক্ষর:-

তারিখ:

গবেষকেরনাম:-

স্বাক্ষর:-

তারিখ:

ANNEXURE-IV

(INFORMED CONSENT FORM IN KOKBOROK LANGUAGE)

                                                                                                                                               (Gosimungbwlai)

O cherwiamjokmungninaharmung, kokbokhri, khlaijaknairaidateiabonikahamhamyarok Doctor swbaisukhrubwianosauikhnarwkha. Angbaithangmuchungwi no o cherwiamjokmung no                        khlairwoteianimuchungtwi                     no                    nangmajora                        o cherwiamjokmungninongkhorwiphaimano.Abonibagwimunsajurbandaangsanglak.

Cherwiamjoktongmabising o mungsaswkwngkheDoctornoangbebaknosanai.

Ano o gosimungbwlainisoi sol laibwlaikangsarwjaknai.

Angkahamkhesisogwi no o cherwiamjokmaomanjaknanigosimungbwlairwkha.

Amjokmungomanjaknainimung:-

Mungswirwma:

Salmari:

Amjoknainimung:-

Mungswirwma:

Salmari:

ANNEXURE-V

(INFORMED CONSENT FORM IN ENGLISH LANGUAGE)

I…………………………………S/O       or,      D/O       or,                                                                  W/O………………………......

Age………….....a resident of…………………………………...…do hereby give my free & voluntary consent to be included in the above-mentioned clinical study.

I have been explained to my full satisfaction the nature and purpose of treatment and possible complications by Dr.PrajnaparmitaSaha, the principal investigator of this study.

During the course of the study, I shall give my voluntary consent, to undergo treatment and any relevant investigation that shall be required.

I shall  immediately  inform  about  any  adverse  effect  events  related  to  my  treatment

/investigations.

I shall give my full co-operation to the concerned treatment doctor & hospital staff. I give consent for publication of the result of the study.

I shall not seek any reward or, compensation for the study.

I am also informed that I can withdraw from this study at any time, at my own will.