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Application for IRB Approval of Interventional StudiesCHRISTIAN MEDICAL COLLEGE, VELLORE
Please complete and submit Sections I –III and supporting documents.---------------------------------------------------------------------------------------------------------------------
SECTION I
Fluid Research Funding
If for external funding, please provide name of funding agency and the application for submission in the funding agency’s format, in addition to this application.
1. Title of Research Project: A randomized control trial to compare the effect of scalp block using
ropivacaine alone or ropivacaine along with adjuvant dexamethasone in patients undergoing
supratentorial craniotomy under General Anaesthesia (G.A.).
2. Title of Study (for lay public): A study to compare the pain relief and other associated effects during
surgery and in the immediate post-operative period of a local anesthetic drug ropivacaine alone and
along with a steroid (which prolongs the drug effect) injected into the scalp, in patients undergoing
brain surgery.
3. Acronym, if any: None
4. Unique protocol IDs (if allotted by sponsor/ trial registration number - please list as many as is
relevant): none
5. Name and Designation of Principal Investigator and Address for communication (including
telephone and fax numbers and email id):
Dr. Riya Jose, C/O Dr. Jacob Jose,
Department of Cardiology, Unit 2,
C.M.C. Hospital, Vellore.
Telephone (residence) : 04162282180; mobile : 94861 70456
e mail : [email protected]
6. Contact person for scientific queries (including telephone and fax numbers and email id):
Dr. Riya Jose, C/O Dr. Jacob Jose,
Department of Cardiology, Unit 2,
C.M.C. Hospital, Vellore.
Telephone (residence) : 04162282180; mobile : 9486170456
e mail : [email protected]
7. Contact person for public queries(including telephone and fax numbers and email id):
Dr. Riya Jose, C/O Dr. Jacob Jose,
Department of Cardiology, Unit 2,
C.M.C. Hospital, Vellore.
Telephone (residence) : 04162282180; mobile : 94861 70456
e mail : [email protected]
8. Name of Guide (for Post-Graduates) and Department :
Dr. Grace Korula,
Prof.& Head of Anaesthesiology unit 3
9. Name and Designation of Co-Investigator (s) : Dr. Kalyana Chakravarthy, Dr. Mathew Joseph, Dr.
Shalini Nair
10. Source/s of Monetary or Material Support
Internal : Institutional Review Board
External : None
11. Primary Sponsor: none
12. Secondary Sponsor: none
13. Countries of recruitment: India
14. Sites of the study (including departments where the study will recruit participants):
Neurosurgery, Neuro ICU, Anaesthesiology
15. Has Drug Controller General of India (DCGI) clearance been obtained?
Not necessary (no new drug is being tested)
16. Objectives of the study:
To compare the post-operative analgesic effect of using ropivacaine alone versus ropivacaine
along with dexamethasone for scalp block in patients undergoing supratentorial craniotomy
under G.A.
17. Brief Summary (in 250 words): Eligible patients undergoing elective craniotomy under G. A. will
be randomly assigned to receive a pre-incision scalp block with either plain 0.2% ropivacaine or
0.2% ropivacaine along with 8 mg dexamethasone (expected to prolong analgesic effect).
Standard anaesthesia protocols for induction and maintenance will be followed for all patients.
Intra-operative monitoring of heart rate and blood pressure response to cranial pin application,
skin incision, craniotomy and dural opening will be noted to evaluate effectiveness of scalp block
and similar readings with be noted at conclusion of surgery during dural, bone flap and skin
closing and at removal of cranial pins.
As the total opioid used intra-operatively would be fixed at a maximum of 3 – 3.5 mcg/kg, any
significant response to intra-operative noxious stimuli (example, cranial pin application,
craniotomy, dural opening) that warrants treatment over and above the opioid limit, would be
treated by increasing the depth of anaesthesia with a bolus of intravenous propofol (each bolus
measuring 0.5 mg/kg). The total dose of anaesthetic agent propofol used intra-operatively will be
noted in both groups. Post-operatively, pain scores measured by Visual Analogue Scale (VAS) will
be serially documented in the ICU at 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12
hours, 16 hours and 24 hours. Patients with a post-operative VAS score of 4 or more would be
treated with 1 gram of intravenous paracetamol as the first rescue analgesic. If this seems
insufficient in treating patient’s pain and an additional rescue analgesic (for example, intravenous
diclofenac) is required within 2 hours, the total duration of scalp block would be taken as the
time from performing the scalp block ( zero hour) till the time of the second rescue analgesic.
18. Health Condition or problem studied: Effect of pre-incision scalp block with either plain
ropivacaine or ropivacaine with dexamethasone with respect to prolonging postoperative
analgesia as well as attenuation of intra-operative anaesthetic requiremen in patients
undergoing elective craniotomy
19. Study Type: Prospective double blinded randomized control study
20. Present Knowledge and relevant bibliography (Is there a justification for this trial? Please provide a
brief review of the relevant literature and appropriate references)
Different levels of nociception accompany various stimuli during craniotomy, specifically during
insertion of cranial pins, skin incision, periosteal dural contact, brain manipulation and at dural,
bone and skin closing. These noxious events can result in sudden increases in blood pressure and
heart rate, which may further increase intracranial pressure in patients with impaired
autoregulation, resulting in increased patient morbidity and mortality.
Methods to blunt these noxious stimuli include administration of systemic opioids, deepening the
level of anaesthesia, scalp nerve blocks and scalp infiltration with local anaesthetics. High doses of
opioids and anaesthetic agents may result in hypotension during low levels of stimuli and may
prolong emergence from anaesthesia.
Hence, regional anaesthetic techniques, such as scalp blocks, may be a better choice to blunt
hemodynamic response to these noxious stimuli, as well as reduce post-operative pain.
Craniotomies were generally thought to be less painful than other operations. However, this
assumption has been challenged after De Benedettis et al (1) undertook a pilot study in 1996 to
assess post-operative pain in neurosurgery and quoted a figure of 60%.
In 2007, Gottschalk et al (2) prospectively studied 187 patients who underwent major intracranial
surgery and found that nearly 70% of patients experience severe pain (score > 4 on 0-10 scale) on
first post-operative day.
In 2011, a study to evaluate post-operative pain in patients undergoing supratentorial craniotomy
was done in our Institution by Drs. Shalini Nair and Vedantam Rajshekhar (3) who noted inadequate
analgesia in 63% of patients in the first 12 hours post-op, with severe pain in 12%.
This undertreated pain in intracranial surgery stems from the fear of causing respiratory depression
and masking changes in consciousness due to surgical complications by the sedative effect of
opioids. A scalp block, which may potentially provide excellent analgesia without the apparent
hazards of opioids could be useful, especially when given with an adjuvant that might prolong the
quality and duration of analgesia well into the post-operative period. 3 studies on scalp block given
after skin closure have shown lower pain score and lesser analgesic requirement. (4-6). Lawan et al
showed that pre-incision scalp block with bupivacaine (2 groups of patients receiving 0.5%, 0.25%
bupivacaine) decreases intra-operative opioid requirement; however, post-operative pain score,
time to first morphine administration and total post-op morphine consumption were not
significantly different compared to the control group (received saline in the scalp block) (7). Farnaz
et al showed similar results when studied the effect of pre-incision scalp blocks with ropivacaine in
30 patients undergoing supratentorial craniotomy (8).
We chose ropivacaine for the scalp block (rather than bupivacaine, which is used more commonly in
our institution for nerve blocks) due to similar potency and duration of action as bupivacaine but
better safety profile (lesser cardiotoxicity). The reason for opting for adjuvant dexamethasone was
based on the benefit shown in terms of prolonging duration of analgesia when used with
ropivacaine and bupivacaine in patients undergoing shoulder surgery under interscalene nerve
block (9) as well as in prolonging the duration of axillary block with lignocaine in patients
undergoing forearm and hand surgery (10).
Bibliography :
1. De Benedittis G, Lorenzetti A, Spagnoli D, et al : Post operative pain in neurosurgery : a pilot
study in brain surgery. Neurosurgery 1996; 38 : 466-70i
2. Gottschalk A, Berkow LC, Stevens RD, Mirski M, Thomson RE, White ED, et al : Prospective
evaluation of pain and analgesic use following major elective intracranial surgery. J.
Neurosurg 106 : 210 – 216, 2007ii
3. Shalini Nair, Vedantam Rajshekhar : Evaluation of pain following supratentorial craniotomy.
British Journal of Neurosurgery, February 2011; 25 (1) : 100-103 iii
4. Nguyen A, Girard F, Boudreault D, Fugere F, Ruel M, Moumdjian R, et al : Scalp nerve blocks
decrease the severity of pain after craniotomy. Anesth Analg. 2001; 93 : 1272-6 iv
5. Bala I, Gupta B, Bhardwaj N : Effects of scalp block on post operative pain relief in
craniotomy patients. Anesth intensive Care. 2006 ; 34 : 224-7v
i 1. De Benedittis G, Lorenzetti A, Spagnoli D, et al : Post operative pain in neurosurgery : a pilot study in brain surgery. Neurosurgery 1996; 38 : 466-70ii 2. Gottschalk A, Berkow LC, Stevens RD, Mirski M, Thomson RE, White ED, et al : Prospective evaluation of pain and analgesic use following major elective intracranial surgery. J. Neurosurg 106 : 210 – 216, 2007iii 3. Shalini Nair, Vedantam Rajshekhar : Evaluation of pain following supratentorial craniotomy. British Journal of Neurosurgery, February 2011; 25 (1) : 100-103 iv v 5. Bala I, Gupta B, Bhardwaj N : Effects of scalp block on post operative pain relief in craniotomy patients. Anesth intensive Care. 2006 ; 34 : 224-7
6. Ayoub C, Girard F, Boudreault D, Chouinard P, Ruel M, Moumdjian R : A comparison
between scalp nerve block and morphine for transitional analgesia after remifentanil-based
anaesthesia in neurosurgery. Anesth Analg. 2006 ; 103 : 1237-40vi
7. Lawan T, Wanna S, Kaew S, Sukhamakorn W, Supodjanee L : Bupivacaine scalp nerve block :
hemodynamic response during craniotomy, intraoperative and postoperative analgesia.
Asian Biomedicine Vol. 4, no. 2, April 2010 : 243-251vii
8. Farnaz M, Gazoni, M.D, Nader P, Edward C.N : Effect of ropivacaine skull block on
perioperative outcomes in patients with supratentorial brain tumours and comparison with
remifentanil : a pilot study. J Neurosurg 109 : 44-49, 2008viii
9. K.C. Cummings III, D.E. Napierkowski, I. Parra-Sanchez, A. Kurz, J.E. Dalton, J.J. Brems, D.I.
Sessler : Effect of dexamethasone on duration of interscalene nerve blocks with ropivacaine
or bupivacaine. Brihish Journal of Anaesthesia 107 (3) : 446-53 (2011), Advance Access
Publication 14 June 2011, doi : 10.1093/bja/aer159ix
10. Ali. M, Mehran R, Fatemeh H, Alipasha M : Dexamethasone added to lignocaine prolongs
axillary brachial plexus blockade. Anesth Analg 2006 ; 102 : 263-7 x
Preliminary work already done by the investigator in this problem :
Number of craniotomiesin adults (> 18 years of age) done in 2010: 469
Number of supratentorial craniotomies (for space occupying lesion/abscess) in 2010: 354
Number of post-op ventilated patients in 2010: 27
These numbers indiccate that in about 7.6% (27 out of 354) of patients, it may not be possible to
assess post-op VAS and duration of analgesia due to complications (that required post-op
ventilation). Hence, an additional 7 – 10% of patients may have to be added to the calculated sample
size to account for this.
List of publications of the investigator in the field : Publications of coinvestigators :
Publications : Dr. Shalini Nair1. Nair S, Sen N, Peter JV, Raj JP, Brahmadattan KN. Role of quantitative endotracheal aspirate and cultures as a surveillance and diagnostic tool for ventilator associated pneumonia: a pilot study. Indian Journal of Medical Sciences 2008; 62:304-313.
2. Joseph M, Nair S. Sodium – water disturbances in a Neuro ICU. Critical Care Update 2008.
3. Nair S, Jacob J, Aaron S, Thomas M, Joseph M, Alexander M. Pulmonary distress following attempted suicidal hanging. Indian Journal of Medical Sciences 2009; 63:53- 57.
4. Christopher DJ, Nair S, Balamugesh T, Shyamkumar NK, Vinu M. Near- fatal hemorrhage after bronchoscopic resection of a carcinoid tumor: successful management by bronchial artery embolization. Journal of Bronchology & Interventional Pulmonology 2010; 17:152-154.
5. Prabhu K, Ramamani A, Nair S, Chacko AG. Acute submandibular sialadenitis as acause of unilateral neck swelling after posterior fossa surgery in sitting position. Neurology India 2010; 58: 963-964.
6. Nair S, Vedantam R. Evaluation of pain after suoratentorial craniotomy. British journal of Neurosurgery 2011; 25: 100-103.
Publications : Dr. Mathew Joseph
1) Joseph M, Rajshekhar V, Chandy MJ: Choroid plexus papilloma of the fourth ventricle.
Neurology India, in press
2) Nates JL, Joseph M: Percutaneous tracheostomy techniques (letter to the editor).
Anesthesia Analgesia 1999; 89: 1068-1069.
3) Joseph M, Rajshekhar V, Chandy MJ: Hematopoietic tissue presenting as a sphenoid
sinus mass: case report. Neuroradiology 2000; 42(2):153-154.
4) Alexandrov AV, Joseph M: Transcranial Doppler: an overview of its clinical
applications. The Internet Journal of Emergency and Intensive Care Medicine 2000; Vol 4
No 1.
5) Joseph M, Nates JL: Stable xenon computed tomography cerebral blood flow
measurement in neurological disease. The Internet Journal of Emergency and Intensive Care
Medicine 2000; Vol 4 No 2.
6) Sankar A, Joseph M, Chandy MJ: Interhemispheric subdural hematoma: an uncommon
Joseph M, Ziadi S, Nates J, Dannenbaum M, Malkoff M. Increases in cardiac output can reverse
flow deficits from vasospasm independent of blood pressure: a study using xenon computed
tomographic measurement of cerebral blood flow. Neurosurgery. 2003; 53(5):1044-52.
7) G.S.S. Kumar, A.G. Chacko, M. Joseph: Superior sagittal sinus and torcula thrombosis
in minor head injury. Neurology India, 2004; 52(1): 123-4.
8) Joseph M: ICP monitoring in a resource-constrained environment: technical note.
Neurology India, 2003; 51(3): 333-5.
sequel of trauma. Neurology India 2003; 51(1): 63-4.
9) Joseph M: ICP monitoring in a resource-constrained environment: technical note. Neurology India, 2003; 51(3): 333-5.10) M Alexander, M Joseph, C Gnanamuthu, U Vaid: Recurrent cerebral venous and peripheral arterial thrombosis. Neurology India. 2004; 52(2):275-611) Singh S, Kumar S, Joseph M, Gnanamuthu C, Alexander M: Cerebral venous sinus thrombosis presenting as subdural haematoma. Australas Radiol. 2005;49(2):101-3. 12) Mathew J: Airway safety for patients receiving intraventricular sodium nitroprusside therapy. Neurology India 2003; 51(4): 560-1.13) Kumar S, Alexander M, Joseph M, Gnanamuthu C: Symmetrical peripheral gangrene: association with adrenaline administration. Critical Care Asia, 2004; 2(1): 19-21.14) S Kumar, J Vijayan, J Jacob, S Aaron, M Joseph, M Alexander, C Gnanamuthu. Occurrence of
cervical spine injuries in suicidal hanging. Tropical Doctor 2005; 35(4): 198-200.
15) Joseph M, Sarkar H: Are we ready for hypertonic saline in brain injury? Critical Care Update
2004. Ed: Vineet Nayyar, Jaypee Brothers Ltd. Pg 112-21.
16) M Joseph: Intracranial pressure monitoring: Vital information ignored. Indian Journal of
Critical Care 2005; 9(1):35-41.
17) Biji Bahuleyan, Kirit C Shah, Mathew Joseph. Extensive skull base fractures with multiple
cranial nerve palsies. Indian Journal of Neurotrauma 2007; 4(1): 71-2.
18) Joseph M, Nair S: Sodium-Water disturbances in a Neuro ICU. Critical Care Update 2008. Ed:
Vineet Nayyar, Jaypee Brothers Ltd. Ch 13.
19) Shalini Nair, Joe Jacob, Sanjith Aaron, Maya Thomas, Mathew Joseph, Mathew Alexander.
Pulmonary distress following attempted suicidal hanging. Ind J Med Sci 2009; 63(2): 53-7.
Publications : Dr. Grace Korula
1. G.Korula, V.MajorEffect of different inspired oxygen concentrations on the wakefulness of mothers during cesarean sectionsInd.J.Anaesth 1987;35(5) 27-31
2. Tharien S, Korula G, Mathew MP, Major VComparison of the effect of four different techniques of Anaesthesia on intraocular pressureInd. J.Anaesth 1990; 38(6) 304-9
3. Korula G, Gulati MS., M.Zachariah, Nagamani NSCardiovascular collapse during laparoscopyAsian Archives of anaesthesiology& resuscitation 1992; 37(1) 179-82
4. M. Zachariah, G.Korula, S. NagamaniBronchospasm under spinal anaesthesia for transurethral resection of prostateAnaesthesia and Intensive care 1992; 20(3): pp 363-5
5. Colin John, Stanley John, Grace Korula Atrio-pulmonary connection (modified Fontan) for double outlet right ventricle with superior inferior ventricles and criss-cross circulationIndian Heart Journal 1992; 44(4): pp 247-8
5. Colin John, Stanley John, Grace Korula Atrio-pulmonary connection (modified Fontan) for double outlet right ventricle with superior inferior ventricles and criss-cross circulationIndian Heart Journal 1992; 44(4): pp 247-8
6. Gita Nath, Grace Korula, Mathew ChandyEffect of intrathecal saline and valsalva maneuver on cerebral perfusion pressure during trans-shenoidal surgery for pituitary macroadenomaJ Neurosurg Anaesthesiol.1995; 7(1) p1-6
7. Cherian VT, Korula GPregnancy with co-arctation of the aorta: Anaesthetic Management for cesarean sectionJournal of Anaesthesiology Clinical Pharmacology, 1996;12(2) 143-5
8. Korula G, Kirubakaran G.P, Ganesh GEffect of Phenyleprine enriched irrigant solution on the fluid absorption during transurethral resection of prostateAnaesthesiology. 1998; 89(3) suppA. 1185
9. G. Korula, P. FarlingAnaesthetic management for a combined Cesarean section and Posterior Fossa CraniotomyJ Neurosurg Anaesthesiol 1998; 10(1) 30-310. M.N. Cherian, G.Korula, A Immanuel, M. Zachariah, A.P. PandeyPostoperative analgesia with intramuscular wound irrigation with bupivacaine in renal surgeryActa Anaesthesiologica Scandinavica 2000; 44 (4): 497-498
11. Mohideen Abdul Khader, Grace KorulaIntraoperative pulmonary edema during ophthalmic surgery. A case reportInd Journal Anaesth 2000; 44:40-3
12. Grace Korula, Sajan Philip George, Rajsekhar V, Haran RP, Jayaseelan LEffect of controlled hypercapnia on cerebrospinal Fluid pressure and operating conditions during trans-sphenoidal operations for Pituitary macroadenomaJ Neurosurg Anaesthesiol 2001; 13(3): 255-9
13. Anaesthetic Management of a patient with AchondroplasiaBS Krishnan, Naveen Eipe, Grace Korula
Paediatric Anesthesia 2003;13(6): 547-9
14. Krishanan BS, Eipe N, Korula GAcute coronay vasospasm during thoracic spine surgeryJ Neurosurg Anaesthesiol 2003;15 (3): 286-9
15. Usha G, Korula GUnsuspected pheochromocytomaJ Neurosurgical Anaesthesiol 2004; 16 (1): 26-8
16. Ann Miriam, Grace KorulaA simple Glucose Insulin Regimen for perioperative blood glucose control. The Vellore Regimen.Anesth Analg 2004: 99: 598-560 17. Anju Ann Bendon, BS Krishnan, Grace KorulaCT guided lung biopsies in children; anaesthetic management and complicationsPaediatric Anesthesia; 200515(4): 321-4
18. Adhikary SD, George SP, Korula GFailure of endotracheal cuff deflationActa Anaesth Scand 2005; 49(4): p590
19. Venkatesan T, Korula GA comparative study between effects of 4% endotracheal cuff lignocaine and 1.5 mg/kg intravenous lignocaine on coughing and hemodynamics during extubation in neurosurgical patients – A randomized controlled double blind trial. J Neurosurg Anaesthesiol 2006 ;18(4): 230-33
20. Grace Korula, M Ramamani, R Raviraj, Sujatha BhaskarIntubating Laryngeal Mask Airway Fastrach : an alternative to stabilizing rodAnesth Analg.2007; 105: 1518
21. BS Krishnan, DA Sanjib, D Harikrishna , B Rajlakshmi, Grace Korula Cricoid Pressure; A survey of its practice in India Indian Journal of Anaesthesia 2007; 51(6): 510-515
22. M. Ramamani, G. Korula, J.Chacko. A large foreign body in the bronchus: Anaesthetic and Surgical Challenges . The Internet Journal of Anesthesiology 2008 : Volume 17 Number 2
23. S Chitra, Grace KorulaAnaesthetic Management of a patient with hypokalemic periodic Paralysis – A case report. IJA 2009; 53(2):226-9
24. Kummar P, Korula G, Kumar S, Saravanan PA.
Unusual cause of leak in Datex Aisys.Anesth Analg 2009; 109: 1350-1
25. Raviraj R, Nandhakumar A, Korula G, James JNA cost effective alternative to wire-guided endobronchial blocker for lung isolationPediatric Anesthesia 2009; 19: 1249-50.
26. Prashant Kummar, Grace Korula, Saravanan PACapnography in non-intubated patients with standard equipment: A boon for awake craniotomy IJA 2009;53(3):387-38827. Joselyn AS, Korula G, George SE, Saravanan P.A. Spontaneous Intracranial Hypertension – A case for Recurrent Chronic Subdural Haematoma J. Anaesth Clin Pharmacol. 2010; 26(1): 107-8.
28. Rai E, Korula G, Saravanan PA, Ashok D. Isolated Uvular Edema following uneventful General Anaesthesia J. Anaesth Clin Pharmacol. 2010; 26(1): 111-12. 29. Kummar P, Korula G, Ninan S, Karthikeyan C An anesthetic in use with bronchodilator inhaler: A fact less knownAnnals of Cardiac Anaesthesia 2010; 13: (1) 77-8
30. Serina Ruth Salins, Kalyan Chakravarthy Pothapragada, Grace Korula Difficult oral intubation in Acromegalic patients – A way out.31. R Raviraj, Grace Korula, Kandasamy subramaniam, S. Shalini Cynthia A Simple Method of Electrocardiogram controlled Central Venous Catheterisation Annals of Cardiac Anaesthesia 2011; 14(2)154-5 Journal of Neurosurgical Anaesthesiology Oct 2010; 22(4)
21. Methods in detail:
i. Intervention and Comparator agent : Patients undergoing elective craniotomy for space occupying lesions will be randomly allocated to one of 2 groups : scalp block with plain 0.2% ropivacaine or scalp block with 0.2% ropivacaine with 8 mg dexamethasone.
ii. Key Criteria
a. Inclusion Criteria: 1. Adult patients (> 18 years) with space occupying lesions scheduled for resection 2. ASA I to III
b. Exclusion Criteria : Previous craniotomyHypertensive patients diabetics
pre-operative GCS < 15/15 known allergy to local anaesthetics pregnancyscalp infectioncoagulopathy peptic ulcer disease
iii. Method of randomization: computer generated randomized numbers using block randomisation
iv. Method of allocation concealment: opaque serially numbered envelopes specifying whether ‘drug A’ or ‘drug B’ is to be given in the scalp block
v. Blinding and masking: Intraoperative drug administered for the scalp block would be prepared by the pharmacy and only the serial number (on the envelope) would be known to the anaesthetist administering the block; the ICU personnel monitoring the VAS post-op would also be blinded to the study drug
vi. Primary Outcomes: duration of post-operative analgesia
vii. Secondary Outcome/s: intra-operative anaesthetic requirement, time to emergence from anaesthesia, post-operative analgesia (VAS), post-operative nausea and vomiting
viii. Target sample size and rationale: 162 (81 in each arm)
ix. Phase of trial: not applicable
x. Expected date of first enrolment: September\October 2011
xi. Estimated duration of trial: 2 years
xii. Protocol variations: Any rules for
a. interim analyses : noneb. For withdrawal of participants : nonec. For premature stopping of trial: none
xiii. Has a Data monitoring committee been appointed? No
xiv. If yes: supply name and email address of contact person: NA
xv. Post Trial benefits and care: Has provision been made for post-trial access to the best
proven intervention from this trial or best available care for participants after the study
is completed?
If the intervention proves beneficial, it could be incorporated into routine practice.
xvi. Statistical Analyses: a. Statistical methods to be used for the primary outcome; include description of
methods to estimate the strength of the effect (e.g.: Odds ratios, relative risks, etc) Kaplan Meier estimates were calculated to assess the mean time when the second complaints( ie, second rescue analgesic was needed) were made in each of the two groups.Log rank test will be done to compare the time to the second complaint was made after the treatments were assigned. Secondary outcomes:VAS will be recorded in both the groups and will be presented in both the groups in terms of mean and standard deviation.The dose requirement will be compared using the mean and standard deviations
in both the groups. The proportion of nausea will also be compared between the two groups by calculating the proportions in each group.
b. Methods for additional analyses, if indicated : none
24. Complete budget plan for all studies
(From Fluid Research Fund, there are no grants for personnel except in a major grant
application, funding is limited Rs. 40,000 per year for two years for standard applications, Rs.
200,000 per year for two years for major applications)
Please note : although calculated sample size is 162 patients (81 in each arm), an additional 10% will
have to be included to account for post op complications due to which primary outcome cannot be
assessed as mentioned prior). Hence, the budget is calculated for 178 patients.
Cost of ropivacaine per patient : Rs. 140
Number of patients using ropivacaine : 178
Total cost of ropivacaine : Rs. 24,920
Cost of Dexamethasone 8mg: Rs 9.18
No. of patients requiring Dexamethasone: 89
Total cost of dexamethasone : Rs. 817.02
Cost of Quincke needle : Rs. 75
Number of patients using Quincke needle : 178
Total cost of Quincke needle : Rs. 13,350
Cost of a 10cc syringe : Rs. 12.25
Number of 10cc syringes to be used : 178
Total cost of 10cc syringes : Rs. 2180.50
Pharmacy costing : Rs. 30 per patient
Total pharmacy costing for 178 patients : Rs. 5340
Stationery: Rs. 100
Total : Rs. 46,707.52
25. If this is an application for Fluid Research Funding, please provide name and account number of
any other Fluid Research grant held by the PI.
None
26. Informed Consent Documents (patient information sheet, investigator’s brochure, drug
information etc and informed consent document) Please submit all translations with the proposal.
27. Publication Plans: Yes
Dr. Riya Jose : principal investigator
Dr. Grace Korula : Guide, idea, supervision.
28. Inter-departmental cooperation: Neurosurgery: Consent obtained from both Heads of
Neurosurgery departments for recruiting patients.
Neuro ICU: Consent obtained from Dept. Head for post-operative monitoring of patients
Letters enclosed. (Please describe the arrangements with institutional diagnostic service
units/departments that are being used for this research project, if applicable).
29. Signature of Principal Investigator
Dr Riya Jose:
30. Signature of Guide/Head of the Department/ Unit: Dr. Grace Korula :
31. Co-Investigators’ Consent (all co-investigators have to sign this form or supply separate letters of
consent)
I/We give my/our consent to be a Co-Investigator and provide my/our expertise to the project. I/We have approved this version of the protocol and have contributed substantially to its development.
Name Department Signature Date
Section II
APPLICATION FOR ETHICS APPROVAL FOR ALL INTERVENTIONAL STUDIES IN HUMAN PARTICIPANTS
1. Please provide a brief summary of the justification, objectives and methods in lay language, avoiding technical terms. Patients undergoing a particular type of brain surgery usually have general anaesthesia during the operation. But it is found that specific stimuli during the surgery evoke pain, which requires local anaesthetic to be injected at various sites on the scalp to supplement the general anaesthetic.Recently, the addition of steroid injection along with the local anaesthetic drug into the shoulder in patients undergoing surgery in the upper limb has been found to enhance the pain relief effect of the local anaesthetic drug and also prolongs the effect into the post-operative period. We would like to test this effect of addition of steroid to the local anaesthetic in the scalp in patients undergoing brain surgery, in the faith that this will prolong the pain relief effect of the local anaesthetic well after the surgery is over, thus, reducing the use of additional pain killers which may be more harmful.This study is to compare the effect of local anaesthetic drug ropivacaine alone or along with steroid dexamethasone on the pain relief effect.
2. Please describe if the study uses procedures already being performed on patients for diagnosis or treatment or if modified or novel procedures are to be used?Scalp block (injection of drug into the scalp) is being performed in our institution in certain types of brain surgeries, usually with local anaesthetic drugs only. In this study, we would like to see if the addition of another drug (dexamethasone) to the local anaesthetic will prolong its effect well after the surgery is completed so that use of other pain killer drugs can be avoided or minimised.
3. Please describe what benefits might be reasonably be expected by the participant as an outcome of participation The patient may have adequate pain relief during the surgery so that a lesser dose of general anaesthetic drugs can be used; consequently, he would emerge from anaesthesia faster and without pain; if this effect continues well into the post-operative period, high doses of other pain killer medications may be avoided. If the intervention proves to be good, it will be used in the future for other patients undergoing this surgery.
4. Please describe what benefits to others or new knowledge might be expected as a result of this study
If the intervention is proved to reduce intraoperative pain and prolong the pain relief post operatively as expected, it will of utmost use to patients undergoing this surgery in future.
5. Who are to be enrolled? Adult patients who are scheduled for elective brain surgery for removal of tumour
6. If any vulnerable groups (e.g., pregnant women, children, economically disadvantaged individuals, etc) are to be enrolled, please provide a justification for their inclusion.
NA
7. What are the potential risks to participants in this study? <1% risk of allergic reaction to local anaesthetic; we routinely use local anaesthetics lignocaine, bupivacaine and ropivacaine in the scalp blocks. In this study, we chose ropivacaine because of its long duration of action ( about 6 hours, similar to bupivacaine) and safety profile compared to bupivacaine ( less harmful to the heart compared to bupivacaine).
8. Are the risks to participants reasonable in relation to the benefits that might reasonably be expected as an outcome to the participant or to others, or the importance of the knowledge that may reasonably be expected to result? Please provide a detailed description of the above.
The risk of allergic reaction to local anaesthetic is very small; while the expected benefits to the patient in terms of intra-operative pain relief, decreased anaesthetic requirement, faster awakening from anaesthesia and post-operative pain relief seem to far outweigh the risk involved.
9. Regarding informed consent to obtained from research participants or their legally authorized representative(s):a. Does the informed consent document include all the required elements (See appendix IV)?
yesb. Are the participant information sheet and the consent document in language understandable
to participants? (PLEASE PROVIDE WITH THIS SUBMISSION TRANSLATIONS IN ALL LOCAL LANGUAGES ANTICIPATED TO BE USED).yes
c. Who will obtain informed consent (PI, nurse, other?) and in what setting?PI will obtain informed consent on the evening prior to surgery
d. If appropriate, is there a children’s assent? If yes, please submit a copy of this form.NA
e. Is the EC requested to waive or alter any informed consent requirement? No
10. Is there provision of free treatment for research related injury? If yes, who will provide it?If the patient develops an allergic reaction to the drug being tested, the hospital will bear the expenses toward treatment of the same.
11. Is there provision for compensation of participants for disability or death resulting from research related injury. If yes, who will provide it? In the event of disability or death resulting from the research, the hospital will provide for appropriate compensation.
12. Is the study covered by insurance? If yes, please provide insurance documents from an Indian insurance company.No
13. In addition to the overall budget in Section I, please provide details of the following
i) Justification, timing and amount of payments to study participants NAii) Justification, timing and amount of payments to investigators/departments NA
iii) Any other study related financial or in kind incentives to participants or study staff NA
14. Please describe the plan for maintaining confidentiality of study participant information.All study related documents will be securely kept by the Principal Investigator and details will
not be divulged.15. Please describe the plans for monitoring the safety of participants, reporting and managing
adverse events. If this is an externally funded study with a Data Safety Monitoring Board, please provide the name and contact information of the DSMB chairperson.
NA16. If applicable; please provide all significant previous decisions (e.g., those leading to a negative
decision or modified protocol) by other ECs or regulatory authorities for the proposed study (whether in the same location or elsewhere) and an indication of the modification(s) to the protocol.
NA17. If appropriate, has permission from the Drug Controller General of India been obtained?
NA18. If this is international collaborative research, has permission from the Health Minstry’s
Screening Committee been obtained? NA
19. For exchange of biological material in international collaborative studies, please provide a MoU/ Material Transfer Agreement between the collaborating partners.
NA
20. Declaration (to be signed by all investigators)
By signing this form we give our consent to provide our expertise to the project. In addition:
a. We confirm that all investigators have approved this version of the protocol and have contributed substantially to its development.
b. We confirm that all potential authors are included in this protocol. c. We also affirm that we shall register the trial in the Clinical Trials Register- India (www.ctri.in) in
accordance with the details submitted here and submit the registration details before getting final IRB approval and enrolling the first participant.
d. We confirm that we shall submit any protocol amendments, adverse events reports, progress reports (if required) and a final report and participate in any audit of this study.
e. We confirm that we shall conduct this study in accordance with the Declaration of Helsinki; the ICMR Guidelines for Biomedical Research in Human Subjects 2006, with any subsequent amendments; Schedule Y of the Drugs and Cosmetics Act; GCP guidelines; and all applicable laws of the Republic of India.
f. We agree to submit the results of this study for publication to a peer reviewed journal, within two years of completion.
g. We declare that we have no conflicts of interest that may affect the conduct or reporting of this study (OR) we declare the following conflicts of interest below.
h. We are aware of the institution’s policies regarding scientific misconduct and agree to abide by them.
21. Signature of Principal Investigator
22. Signature of Guide/Head of the Department/ Unit
23. Co-Investigator’s Consent (all co-investigators have to sign this form or supply separate
letters of consent)
Name Department Signature Date
Conflicts of interest if any: None
Section III
CHECKLIST FOR PROTOCOLS SUBMITTED TO IRB OF CMC VELLORE FOR INTERVENTIONAL TRIALS IN HUMANS
Please tick the appropriate boxes below to indicate that the following have been submitted and if not, please explain why:
1. Application form for protocols of interventional trials with all sections (I, and II) completed [ ]
2. Informed consent and participant information form in all relevant local languages [ ]
3. Names, affiliations and signatures of all investigators/co-investigators for the declaration [ ]
4. Signature of the Head of the department or unit as applicable (for interdepartmental studies, an
agreement letter from concerned departmental heads is desirable, if they are not co-investigators). [ ]
5. Recent curriculum vitae of all investigators, with qualifications, experience and relevant publications
during the past five years. [ ]
6. If applicable, data on safety of proposed intervention and any drug/device or vaccine to be tested,
including results of relevant laboratory, animal and human research. [ ]
7. If applicable, proposed compensation and reimbursement of incidental expenses and management of
research related and unrelated injury/ illness during and after research period. [ ]
8. If applicable (in study-related injuries), a description of the arrangements for insurance coverage for
research participants and copy of insurance documents from an Indian insurance agency. [ ]
9. If applicable; all significant previous decisions (e.g., those leading to a negative decision or modified
protocol) by other ECs or regulatory authorities for the proposed study and an indication of the modification(s) to the protocol made on that account. The reasons for negative decisions should be provided. [ ]
10. Plans for publication of results, positive or negative, with names of proposed authors and their
expected contributions. [ }
11. All other relevant documents related to the study protocol, e.g., investigator's brochure for trial on
drugs/ devices/ vaccines/ herbal remedies, and statement of relevant regulatory clearances. [ ]
12. If applicable, any material used for advertisement to recruit participants to the study - this may
include flyers, brochures, posters, radio and TV advertisements. [ ]
13. For externally funded trials, details of Funding agency/ Sponsors and breakdown of fund allocation. [ ]
14. One hard copy of Form I and a soft copy on CD of all the above. [ ]
Please list below all additional documents that are being submitted along with this application including all appendices.
Notes for filling in this form
1. Section I is required for Research Committee Approval. Section II is required for Ethics Committee Approval. Section III contains a checklist that should accompany this submission. Incomplete submissions will be rejected.
2. The Senatus has resolved that all clinical trials conducted in CMC should be prospectively registered before enrolment of the first participant in the CTRI. Only items submitted in the proposal and approved by the Research and Ethics committees should be submitted to the CTRI.
3. Please see Appendix I-IV of this form for detailed description of items required for submission of applications before filling this form. Appendix I contains the Clinical Trials Registry India: Dataset and Description; Appendix II: Instructions for registering trials in the CTRI; Appendix III: The Revised CONSORT Statement: CONSORT checklist (the full statement can be obtained from www.consort.org). Instructions for preparing informed consent documents based on Schedule Y (Drugs and Cosmetics Act) 2005, and a sample consent form are provided in Appendix IV
4. Please also read the Standard Operating Procedure of the IRB of CMC Vellore (available from the Research website) for additional guidance on policies and procedures that will be followed at CMC for IRB approval.
5. One hard copy of the project proposal signed by all investigators and the Guide/Head of the Department/Unit along with all supporting documents and one soft copy in MS WORD format on a CD with all supporting documents (in word or pdf or scanned formats), should be submitted so as to reach the Office of the Additional Vice-Principal (Research) on or before the 1 st of every month.
vi 6. Ayoub C, Girard F, Boudreault D, Chouinard P, Ruel M, Moumdjian R : A comparison between scalp nerve block and morphine for transitional analgesia after remifentanil-based anaesthesia in neurosurgery. Anesth Analg. 2006 ; 103 : 1237-40vii 7. Lawan T, Wanna S, Kaew S, Sukhamakorn W, Supodjanee L : Bupivacaine scalp nerve block : hemodynamic response during craniotomy, intraoperative and postoperative analgesia. Asian Biomedicine Vol. 4, no. 2, April 2010 : 243-251viii 8. Farnaz M, Gazoni, M.D, Nader P, Edward C.N : Effect of ropivacaine skull block on perioperative outcomes in patients with supratentorial brain tumours and comparison with remifentanil : a pilot study. J Neurosurg 109 : 44-49, 2008ix 9. K.C. Cummings III, D.E. Napierkowski, I. Parra-Sanchez, A. Kurz, J.E. Dalton, J.J. Brems, D.I. Sessler : Effect of dexamethasone on duration of interscalene nerve blocks with ropivacaine or bupivacaine. Brihish Journal of Anaesthesia 107 (3) : 446-53 (2011), Advance Access Publication 14 June 2011, doi : 10.1093/bja/aer159x 10. Ali. M, Mehran R, Fatemeh H, Alipasha M : Dexamethasone added to lignocaine prolongs axillary brachial plexus blockade. Anesth Analg 2006 ; 102 : 263-7
6. For externally funded projects with commercial sponsors, please also submit the receipt of payment of the non-refundable processing fee.
7. Please submit only Sections I, II & III, supporting documents and the patient information and consent forms.
