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IHAST2 Operations Manual.doc

  1. 1. Created 1/30/15 IHAST 2 Operations Manual Table of Contents Introduction 1 I.A History and Background of the Problem..................................................................................1 I.A.1. Surgical Outcome.............................................................................................................1 I.A.2. Intraoperative Protective Efforts......................................................................................2 I.A.3. This Trial..........................................................................................................................3 I.B Trial Development....................................................................................................................4 Chapter II. Protocol Overview (Brief) 1 Chapter III. Organizational Structure and Personnel 1 III.A Steering Committee...............................................................................................................1 III.B Advisory Committee..............................................................................................................2 III.C Clinical Coordinating Center (CCC).....................................................................................2 III.D Data Management Center (DMC).........................................................................................2 III.E Physician Protocol Monitor (PPM).......................................................................................3 III.F Physician Safety Monitor (PSM)...........................................................................................3 III.G NIH Protocol Safety Monitoring Committee (NIH PSMB)..................................................4 III.H University of Iowa Division of Sponsored Programs...........................................................4 Chapter IV. Participating Centers 1 IV.A Requirements for Participation..............................................................................................1 IV.A.1. Minimum Case Load.....................................................................................................1 IV.A.2. Selection Bias and Demographics.................................................................................1 IV.A.3. Principal Investigator and Co-Investigator Agreements................................................2 IV.A.4. Institutional Agreements................................................................................................3 a) Consortium Agreements.....................................................................................................3 b) Financial Subcontract........................................................................................................4 c) Human Studies Approval...................................................................................................5 IV.A.5. Organizational Meeting Attendance..............................................................................6 IV.A.6. Subsequent Yearly Meetings.........................................................................................6 IV.A.7. Centers Recruited Later.................................................................................................7 IV.A.8. On-site Audits................................................................................................................7 i
  2. 2. Created 1/30/15 IHAST 2 Operations Manual IV.A.9. Local Documentation....................................................................................................7 a) Operations Manual.............................................................................................................7 b) Case Report Forms/Patient Notebooks..............................................................................7 c) Site Regulatory Binder.......................................................................................................8 IV.B Personnel Required, Duties and Certification Requirements ...............................................8 IV.B.1. Local Principal Investigator (PI)...................................................................................8 IV.B.2. Local Co-Investigator..................................................................................................10 IV.B.3. Anesthesiologists.........................................................................................................10 a) Protocol............................................................................................................................10 b) Blinding...........................................................................................................................10 c) Data Collection.................................................................................................................11 d) Certification.....................................................................................................................12 IV.B.4. Neurosurgeons.............................................................................................................12 a) Recruitment/Notification.................................................................................................12 b) Protocol ..........................................................................................................................12 c) Data Collection................................................................................................................13 d) Certification ....................................................................................................................13 IV.B.5. Study Coordinators......................................................................................................13 a) Responsibilities................................................................................................................13 b) Certification ...................................................................................................................16 IV.B.6. Neurologic Examiners.................................................................................................17 a) Responsibilities................................................................................................................17 b) Examiner Selection and Blinding....................................................................................17 c) Certification ....................................................................................................................18 IV.B.7. Neuropsychologic Examiners......................................................................................19 a) Certification.....................................................................................................................19 IV.C Funding 20 IV.C.1. General.........................................................................................................................20 IV.C.2. Start Up Funds.............................................................................................................20 a) Local Human Studies Committee approval.....................................................................20 b) Consortium arrangement completion...............................................................................20 c) Financial Subcontract completion....................................................................................20 ii
  3. 3. Created 1/30/15 IHAST 2 Operations Manual d) Organizational meeting attendence ................................................................................20 IV.C.3. “Practice” Patients.......................................................................................................21 IV.C.4. Initial 10 Patients.........................................................................................................21 IV.C.5. Subsequent Patients.....................................................................................................21 IV.C.6. General Payment Schedule .........................................................................................21 IV.C.7. Payment Procedures.....................................................................................................22 IV.C.8. Local Institutional Overhead/Indirect Costs................................................................22 Chapter V. Patient Assessment Instruments and Training 1 V.A WFNS1 and GCS....................................................................................................................1 a) Training and Certification..................................................................................................3 V.B Rankin Disability Score2,3.....................................................................................................4 a) Training and Certification..................................................................................................5 V.C NIHSS4,5,6,7..........................................................................................................................5 a) Training and Certification..................................................................................................6 V.D Barthel's Activities of Daily Living (ADL)8,9.......................................................................7 a) Training and Certification..................................................................................................8 V.E Mini-Mental State Exam (MMSE)..........................................................................................8 a) Training and Certification..................................................................................................9 V.F Neuropsychologic Testing Battery..........................................................................................9 V.F.1. Benton Visual Retention Test (BVRT).............................................................................9 V.F.2. Controlled Oral Word Association (COWA)...................................................................9 V.F.3. Complex Figure Test (CFT).............................................................................................9 V.F.4. Grooved Pegboard (GP).................................................................................................10 V.F.5. Trail Making Test (TMT)...............................................................................................10 a) Training and Certification................................................................................................10 V.G Glasgow Outcome Score (GOS)...........................................................................................10 a) Training and Certification................................................................................................11 V.H Summary12 Chapter VI. Enrollment and Randomization Procedures 1 VI.A Randomization Scheme.........................................................................................................1 VI.A.1. What Constitutes Randomization?...............................................................................2 VI.A.2. Envelopes, Patient Notebooks, and Other CRF’s.........................................................2 iii
  4. 4. Created 1/30/15 IHAST 2 Operations Manual VI.A.3. Brown or White?...........................................................................................................3 VI.B Eligibility Assessments.........................................................................................................3 VI.B.1. Enrollment Criteria........................................................................................................3 a) Inclusion Criteria................................................................................................................3 b) Exclusion Criteria..............................................................................................................4 c) Procedural Criteria.............................................................................................................4 VI.C Enrollment Telephone Call....................................................................................................4 VI.C.1. Enrollment Call Instructions.........................................................................................5 a) Calling the automated telephone randomization system....................................................5 b) Tips for success with the system:.......................................................................................5 c) Telephone Scripts...............................................................................................................5 VI.C.2. Enrollment Call Problems.............................................................................................9 a) PCC is not yet approved to commence patient enrollment. .............................................9 b) Individual making the call is not yet certified...................................................................9 c) Incorrect Menu Choice.......................................................................................................9 d) Entry indicates that a patient does not meet enrollment criteria......................................10 e) Incorrect date entry.........................................................................................................10 f) Incorrect interval between SAH and surgery...................................................................10 VI.C.3. Practice Obtaining a Randomization Assignment.......................................................10 VI.D Study Packets......................................................................................................................11 VI.E 24-hour Patient Randomization Status Call.......................................................................12 Chapter VII. Reporting and Data Submission 1 VII.A Organization of Data Collection Materials..........................................................................1 VII.A.1. Patient Notebooks........................................................................................................1 VII.A.2. Screening and Eligibility Forms..................................................................................1 VII.A.3. Study Packets...............................................................................................................1 a) Access to Envelopes, Patient Notebooks, and Other CRF’s..............................................2 VII.A.4. PCC Correction Report Forms.....................................................................................3 VII.A.5. Site Regulatory Binder ...............................................................................................4 VII.A.6. Patient Log Binder.......................................................................................................4 VII.B Distribution of Materials......................................................................................................5 VII.C General Guidelines for Completing Case Report Forms.....................................................6 iv
  5. 5. Created 1/30/15 IHAST 2 Operations Manual VII.C.1. Once Randomized, Data Collection Continues...........................................................6 VII.C.2. Recording Data on Case Report Forms.......................................................................6 a) Zero-fill..............................................................................................................................6 b) Dates..................................................................................................................................7 c) Daily Post-op Screen and Medications (tabular forms).....................................................7 d) Correcting Mistakes...........................................................................................................7 e) Correcting TEMPERATURE Forms..................................................................................8 VII.C.3. Header Information......................................................................................................8 a) Patient ID...........................................................................................................................9 b) Center Identification Number............................................................................................9 c) Patient Log Number...........................................................................................................9 d) Date10 e) Time.................................................................................................................................10 VII.C.4. Footer Information.....................................................................................................10 a) Initials of Person Completing the Form...........................................................................11 b) Signature..........................................................................................................................12 c) Certification Number.......................................................................................................12 d) Form Completion Date....................................................................................................12 VII.C.5. Types of Data Collection Item...................................................................................12 a) Example with No-Yes......................................................................................................12 b) Example with No-Probable-Definite data........................................................................13 c) Lists - Example with No-Yes options..............................................................................13 d) Lists - Example with No-Probable-Definite....................................................................13 e) Lists - Example with categorical data..............................................................................13 f) Unknown or Questionable Items......................................................................................14 g) Tabular Forms..................................................................................................................14 VII.D Case Report Forms to be Completed by StudyCoordinator .............................................16 VII.E Case Report Forms to be Completed by Certified IHAST2 physicians............................16 VII.F Case Report Forms to be completed by Neurologic Examiners .......................................17 VII.G Case Report Forms to be completed by Neuropsychologists............................................17 VII.H DMC Reports to PCC, CCC, etc.......................................................................................17 VII.H.1. No Patient Randomization Status Call......................................................................17 v
  6. 6. Created 1/30/15 IHAST 2 Operations Manual VII.H.2. IHAST2 Patient Calendar..........................................................................................17 VII.H.3. Weekly Patient Summary Report...............................................................................18 VII.H.4. Data Edit Reports.......................................................................................................18 VII.H.5. Update Newsletter.....................................................................................................18 VII.I Data Submission/Collection................................................................................................18 VII.J Task Personnel Spreadsheet................................................................................................21 VII.K How to ship Case Report Forms to the DMC ...................................................................25 VII.L The IHAST2 Data Management System............................................................................25 VII.L.1. Overview....................................................................................................................25 VII.L.2. Data Quality Assurance..............................................................................................25 VII.L.3. The Data Edit Report.................................................................................................26 VII.L.4. On-Site Audits............................................................................................................27 VII.M Communication...............................................................................................................28 Chapter VIII. Detailed Protocol 1 VIII.A Overview............................................................................................................................1 VIII.B Patient Recruitment/Study Activation................................................................................1 VIII.C Initial Assessment/Patient Eligibility..................................................................................1 VIII.D Specific Eligibility criteria.................................................................................................2 a) Comment: Medical Contraindications..............................................................................3 VIII.D.1. Consent and Enrollment.............................................................................................4 a) Enrollment Questions.........................................................................................................4 b) Enrollment Follow-up........................................................................................................5 VIII.E Preoperative Assessments...................................................................................................5 VIII.F Anesthetic Management...................................................................................................6 VIII.F.1. Equipment Required....................................................................................................6 VIII.F.2. CRFs/Materials for the Anesthesiologist.....................................................................7 VIII.F.3. Room Conditions prior to Patient arrival to the Operating Room..............................8 a) Room Temperature.............................................................................................................8 b) Water Mattress...................................................................................................................8 c) Temperature Devices/Displays...........................................................................................8 VIII.F.4. Monitoring...................................................................................................................9 a) Required Monitoring..........................................................................................................9 vi
  7. 7. Created 1/30/15 IHAST 2 Operations Manual b) Other Monitoring...............................................................................................................9 VIII.F.5. Intraoperative Anesthetic Agents.................................................................................9 VIII.F.6. Basic Protocol............................................................................................................10 a) Blinding............................................................................................................................10 b) Prior to Induction of Anesthesia......................................................................................11 c) Induction and Maintenance of Anesthesia.......................................................................11 d) Temperature Monitor and Blanket Placement ................................................................12 e) Initial Intraoperative Temperature....................................................................................12 f) Post-clip Temperature Management.................................................................................13 g) End of Surgery.................................................................................................................14 h) Other Intraoperative Surgical and Anesthetic Management ..........................................15 VIII.F.7. Neurosurgical Management......................................................................................16 a) Patient Selection .............................................................................................................16 b) Blinding...........................................................................................................................16 c) Temperature Guess .........................................................................................................17 d) Intraoperative Protective Agents......................................................................................17 e) Other drugs ......................................................................................................................17 f) Temporary Clipping .........................................................................................................17 VIII.F.8. Postoperative Care/0-2-hours...................................................................................18 VIII.F.9. Intraoperative & Early Postoperative Intercurrent Events.......................................18 VIII.F.10. Early postoperative NIHSS.....................................................................................19 VIII.F.11. Postoperative Care/Later.........................................................................................19 VIII.F.12. Daily Assessments...................................................................................................19 VIII.F.13. Intercurrent Events..................................................................................................20 a) Severe/Indicator IEs.........................................................................................................20 b) Routine IEs......................................................................................................................20 VIII.F.14. Postoperative Neurologic Assessments...................................................................21 VIII.F.15. Discharge.................................................................................................................21 VIII.F.16. Post-Discharge Follow-up.......................................................................................22 a) Interim Contacts...............................................................................................................22 b) Three-month Follow-up...................................................................................................22 c) Follow-up Difficulties......................................................................................................23 vii
  8. 8. Created 1/30/15 IHAST 2 Operations Manual Chapter IX. Data Forms/Completion Instructions 1 IX.A Screening Form.....................................................................................................................1 IX.A.1. Overview: ....................................................................................................................1 IX.A.2. Data Items.....................................................................................................................1 IX.B Eligibility Form.....................................................................................................................2 IX.B.1. Overview:......................................................................................................................3 IX.B.2. Data Items.....................................................................................................................4 IX.C Contact Form.........................................................................................................................9 IX.C.1. Overview:......................................................................................................................9 IX.C.2. Data Items...................................................................................................................10 IX.D Pre-SAH History Form.......................................................................................................10 IX.D.1. Overview:....................................................................................................................10 IX.D.2. Data Items...................................................................................................................11 a) Section A. Neurologic History Prior to Current SAH.....................................................11 b) Section B. Cardiovascular History Prior to Current SAH..............................................14 c) Section C. Respiratory History Prior to Current SAH....................................................17 d) Section D. Coagulation Disorders Prior to Current SAH...............................................18 e) Section E. Other Disorders Prior to Current SAH..........................................................19 IX.E Post-Admit Screen...............................................................................................................22 IX.E.1. Overview: ..................................................................................................................22 a) Section A. Neurology.......................................................................................................23 b) Section B. Other Events...................................................................................................25 IX.F Neurosurgeon.......................................................................................................................30 IX.F.1. Overview: ...................................................................................................................30 IX.F.2. Data Items...................................................................................................................30 IX.G Anesthesiologist..................................................................................................................33 IX.G.1. Overview:....................................................................................................................33 IX.G.2. Data Items...................................................................................................................34 a) Section A. Patient Eligibility...........................................................................................34 b) Section B. Physical Examination Prior to Induction......................................................36 c) Section C. Induction.........................................................................................................38 d) Section D. Randomization...............................................................................................40 viii
  9. 9. Created 1/30/15 IHAST 2 Operations Manual e) Section E. Conditions at Definitive Clip Placement*......................................................40 f) Section F. Intraoperative Fluids.......................................................................................43 g) Section G. Events occurring during the first 0-2 hours after leaving the operating room 44 h) Section H. Perioperative Events.....................................................................................45 IX.H Temperature.........................................................................................................................54 IX.H.1. Overview:....................................................................................................................54 IX.H.2. Data Items...................................................................................................................54 IX.I Daily Post-Op Screen...........................................................................................................57 IX.I.1. Overview: ...................................................................................................................58 IX.J Intercurrent Events...............................................................................................................65 IX.J.1. Overview:.....................................................................................................................65 IX.J.2. Data Items.....................................................................................................................66 IX.K IE Definitions .....................................................................................................................70 IX.L Contact Follow-up Form.....................................................................................................70 IX.M Outcome Follow-up............................................................................................................75 IX.N 3-Month Visit......................................................................................................................76 IX.O Death/Patient Withdrawal...................................................................................................77 IX.O.1. Overview:....................................................................................................................77 IX.P NIHSS79 IX.P.1. Overview .....................................................................................................................79 IX.P.2. Certification .................................................................................................................80 Special Situations .......................................................................................................................88 Coma 88 Persons Who Refuse to Cooperate .....................................................................................89 IX.Q Neuropsychology Forms and Test Performance.................................................................89 IX.Q.1. Overview.....................................................................................................................89 IX.Q.2. Data Items...................................................................................................................90 a) Benton Visual Retention Test (BVRT).............................................................................90 b) Controlled Oral Word Association (COWA)...................................................................91 c) Complex Figure Test (CFT).............................................................................................91 d) Grooved Pegboard Test....................................................................................................92 e) Trail Making Test.............................................................................................................93 ix
  10. 10. Created 1/30/15 IHAST 2 Operations Manual IX.R Medications.........................................................................................................................95 IX.R.1. Overview ...................................................................................................................95 IX.S DETAILED IE DEFINITIONS.........................................................................................100 Chapter X. The First Two “Practice” patients 1 X.A.1. Overview........................................................................................................................1 X.A.2. Procedure........................................................................................................................1 Chapter XI. Appendices 1 XI.A UI Contact Information.........................................................................................................1 XI.B Participating Centers Contact Information............................................................................1 XI.C Pilot Trial Publication............................................................................................................1 XI.D The University of Iowa IRB documents...............................................................................1 XI.E Consortium letter template...................................................................................................1 XI.F NIH Subcontract template.....................................................................................................1 XI.G DMC Forms .........................................................................................................................1 a) No Patient Randomization Status Call...............................................................................1 b) IHAST2 Patient Calendar..................................................................................................1 c) Weekly Patient Summary Report.......................................................................................1 d) Data Edit Report (DER).....................................................................................................1 e) PCC Correction Report......................................................................................................1 f) Script for Interval Contacts................................................................................................1 g) IHAST2 Comment Entry System......................................................................................1 XI.G.2. GOS/Rankin Testing Vignettes.....................................................................................1 XI.G.3. Case Report Forms........................................................................................................2 a) SCREENING.....................................................................................................................2 b) ELIGIBILITY....................................................................................................................2 c) CONTACT.........................................................................................................................2 d) NIH STROKE SCALE......................................................................................................2 e) PRE-SAH HISTORY.........................................................................................................2 f) POST-ADMIT SCREEN....................................................................................................2 g) ANESTHESIOLOGIST.....................................................................................................2 h) NEUROSURGEON...........................................................................................................2 i) TEMPERATURE-H...........................................................................................................2 x
  11. 11. Created 1/30/15 IHAST 2 Operations Manual j) TEMPERATURE-N...........................................................................................................2 k) DAILY POST-OP SCREEN..............................................................................................2 l) DPS SUPPLEMENT..........................................................................................................2 m) CONTACT FOLLOW-UP................................................................................................2 n) OUTCOME FOLLOW-UP................................................................................................2 o) NEUROPSYCHOLOGY FORMS....................................................................................2 p) MEDICATIONS................................................................................................................3 q) INTERCURRENT EVENTS.............................................................................................3 r) IE SUPPLEMENT..............................................................................................................3 s) DEATH/PATIENT WITHDRAWAL..................................................................................3 xi
  12. 12. Created 1/30/15 IHAST 2 Operations Manual INTRODUCTION Welcome to IHAST2! This is a large multi-center, prospective, randomized, partially blinded clinical trial, designed to determine whether mild intraoperative hypothermia results in improved neurologic outcome in patients with an acute subarachnoid hemorrhage (SAH), undergoing an open craniotomy to clip their aneurysms. To the best of our knowledge, this is the only NIH funded trial to examine the impact of an intraoperative intervention on neurologic outcome following any neurosurgical procedure. It is certainly the largest trial of its kind yet undertaken. In this manual we have tried to cover all aspects of trial design and organization, participant and participating center requirements, training, eligibility rules, enrollment procedures, study protocols, form completion, data submission, etc. There is an enormous amount of material here. We strongly urge you to make this manual available to everyone in your PCC who will be involved - and to encourage him or her to read at least those portions that pertain to their activities. If you have questions, we ask that you first refer to the Table of Contents, or try searching for the relevant terms on the electronic version of the manual when it becomes available. However, please don’t hesitate to contact the Clinical Coordinating Center (CCC) or Data Management Center (DMC) at Iowa with any and all questions that you may have—at any time. I.A HISTORY AND BACKGROUND OF THE PROBLEM While alternative therapies are being evaluated, the definitive “solution” to aneurysmal SAH remains surgical obliteration of the aneurysm via open craniotomy. Unfortunately, surgery remains an imperfect therapy. Although it can prevent recurrent bleeding, it does not reverse the consequences of the original hemorrhage. More importantly, surgery performed in these patients is not benign, and may result in additional morbidity and mortality. I.A.1. Surgical Outcome The long term outcome of patients who undergo surgery to clip ruptured intracranial aneurysms has not changed a great deal in the last decade, in spite of the introduction of nimodipine and improvements in surgical and anesthetic techniques. Among patients with SAH, between 55% and 65% of patients will be classified as having a “Good Outcome” by the Glasgow Outcome Scale (GOS=1) when examined three months after admission. Since poor grade patients often do not undergo surgery (and do poorly regardless), it is reasonable to assume that outcomes in the surgical subgroups will be somewhat better than noted above. Unfortunately, only the 1990 Cooperative Trial report provided specific outcome results for patients who actually underwent surgery (2922 patients, 68% GOS=1). 1
  13. 13. Created 1/30/15 IHAST 2 Operations Manual Of course, these results imply that 30-45% of SAH patients either die or suffer neurologic disabilities severe enough to reduce their quality of life. The results may be even worse than this since cognitive abnormalities are common, even among patients with GOS scores =1. Most of these suboptimal outcomes are the direct result of the initial SAH and its complications. Nevertheless, a certain fraction of the adverse outcomes may be related to surgery itself, either due to a direct neurologic injury (e.g., misplaced aneurysm clips, prolonged temporary clipping, retraction, dissection, induced vasospasm, hemorrhage, etc.), or due to surgically/anesthetically- induced exacerbation of underlying damage (a so-called “secondary injury”). For example, in the European Tirilazad trial, 28% of patients with admission World Federation of Neurologic Surgeons (WFNS) scores of I-III had poor outcomes (GOS=3-5). More importantly (and of greater relevance to this proposal), a certain fraction of patients develop new postoperative neurologic deficits. In the Cooperative Trial, approximately one-third of all surgical patients had a decline in neurologic status immediately (1-2 days) following surgery - even in patients who were neurologically normal preoperatively. The fact that good-grade patients suffer poor outcomes, or that new neurologic deficits appear postoperatively, supports our contention that surgery and anesthesia per se may lead to dysfunction. It is tempting to conclude that these estimates of surgery-related injuries are too high, or that the deficits stem from the disease itself (e.g., vasospasm). Superficially, support for this view comes from patients undergoing elective surgery for unruptured aneurysms. Presumably, any postoperative deficit in such patients must be surgically related. In 1994, King et al., reported a meta-analysis of elective surgery performed in 733 patients (from 28 published reports). They noted an overall combined morbidity/mortality rate of only ≈5%, a rate much lower than for SAH patients. Unfortunately, this review almost certainly deals with selectively reported results and underestimates the true incidence, particularly the incidence of less severe deficits. It is also likely that the excellent results reported by some surgeons - while perhaps reflecting what can be achieved - do not necessarily reflect “community wide” results. The limited reliability of such data resulted in the NIH-funded “International Study of Unruptured Intracranial Aneurysms”. The results of this epidemiological study indicate that overall 30 day surgical mortality and morbidity is between 12 and 17% (95% confidence interval). In our own pilot trial (see Appendix), 22% of the patients with unruptured aneurysms suffered some degree of morbidity or mortality. This is very similar to the results recently reported by Khanna et al., who noted that 22% of 172 patients undergoing surgery for unruptured aneurysms suffered either a mild or severe neurologic deficit; 2% of patients died (5 of 172). I.A.2. Intraoperative Protective Efforts The most evident “acknowledgment” of the potential for surgery to result in direct neurologic complications is the effort expended by neurosurgeons and anesthesiologists to “protect” the brain during surgery. Unfortunately, in spite of these efforts, an extensive review of the literature fails to reveal even a single controlled trial of any form of intraoperative protective modality. Many protective interventions have been advocated, and even employed in an uncontrolled fashion. These include barbiturates, etomidate, propofol, isoflurane, desflurane, high-dose mannitol, vitamin E (and other antioxidants) - and of course, hypothermia. 2
  14. 14. Created 1/30/15 IHAST 2 Operations Manual Hypothermia is clearly the oldest protective modality to be employed clinically. There is no question that deep hypothermia (T<20o C) can protect the brain against prolonged periods of complete ischemia (circulatory arrest). However, this degree of deep hypothermia requires the use of complete anticoagulation and cardiopulmonary bypass, making its widespread use in routine aneurysm surgery impractical. More recently, studies have shown that much smaller reductions in brain temperature (32-35o C) also have protective value in experimental animals subjected to both global and focal ischemic insults. Enthusiasm for the use of mild hypothermia during surgery has grown. There are several reasons. First, the animal data mentioned above is reasonably unambiguous. Second, several clinical studies examining the impact of mild hypothermia (T>30o C) on ICP and outcome following head trauma have been modestly positive - although the definitive, multi-center trial of hypothermia in trauma failed to demonstrate any benefit (Guy Clifton M.D., personal communication). Third, unlike deep hypothermia, mild hypothermic temperatures are easily achieved, particularly in anesthetized patients; in fact, a 1.5-2o C drop in temperature is “normal” under general anesthesia unless actively prevented. This makes it easy to employ “hypothermia by default”. I.A.3. This Trial The decision to examine the protective effects of hypothermia during aneurysm surgery was made only after extensive consideration and discussions with numerous anesthesiologists and neurosurgeons. There are two major reasons to pursue this investigation. First, laboratory data demonstrating the protective efficacy of mild hypothermia in the face of multiple different insults suggests that this modality is the one “most likely to succeed”. By contrast, barbiturate therapy, while consistently beneficial during focal ischemia, has not proven useful in the face of other insults (e.g., global ischemia, hypoxia, trauma). Second, this method is already in widespread use “by default”, in spite of the lack of demonstrated clinical benefit; some centers even believe that maintaining normothermia is unethical. We believe that this application of an unproven therapy is unwise. It either assumes that mild hypothermia works in humans, or, at the very least, it is harmless. The problem is that efficacy has not been shown. Moreover, there is clear evidence that hypothermia need not be risk free. Hypothermia is known to inhibit normal coagulation and to increase perioperative blood loss during hip surgery. Hypothermia can increase the risk of ventricular dysrhythmias and is associated with an increased incidence of postoperative myocardial ischemia, which may occur long after body temperature has been normalized. Hypothermia also impairs the immune response and results in an increase in surgical wound infections following “dirty” surgery (e.g., colon resections). Lastly, hypothermia can delay emergence from anesthesia, can markedly increase metabolic demands even when shivering is prevented, and can be followed by “rebound hyperthermia.” 3
  15. 15. Created 1/30/15 IHAST 2 Operations Manual For these reasons, we believe that it is appropriate to undertake a prospective trial of mild intraoperative hypothermia during aneurysm surgery. Without the knowledge derived from such a trial, patients will either, a) continue to be subjected to a therapy with unknown risk/benefit characteristics - which may in fact be detrimental, or b) be denied a valuable intervention which can be delivered easily and very inexpensively with readily available equipment. I.B TRIAL DEVELOPMENT IHAST2 has been a long time in development. The project grew out of a series of discussions held among members of the Society for Neurosurgical Anesthesia and Critical Care (SNACC) as long ago as 1991. The decision to focus on hypothermia in patients with SAH was made at a small research meeting of neuroanesthesiologists held in 1992. This, in turn, lead to the design and execution of a small (114-patient) randomized, prospective pilot trial that was conducted at five clinical centers between 1994 and 1997 (and which was published in January 1999, see Appendix). This pilot trial was designated as IHAST1. This lead to the formal preparation of a grant to NIH which was submitted in June 1998 and which was approved for funding in January, 1999. Actual organization of IHAST2 began in the fall of 1998, and commenced “full time” in April, 1999. 4
  16. 16. Created 1/30/15 IHAST 2 Operations Manual CHAPTER II. PROTOCOL OVERVIEW (BRIEF) Title: Intraoperative Hypothermia for Aneurysm Surgery Trial, Part 2 (also known as IHAST2). Principal Investigator: Michael M. Todd, M.D. Institution: University of Iowa (UI) College of Medicine. Biostatisticians: Robert F. Woolson, Ph.D., William R. Clarke Ph.D., (Director, UI Data Management Center-DMC). Epidemiologist: James C. Torner, Ph.D. Project phase or primary methodology: Randomized, prospective, partially blinded clinical trial. Target disease: Acute aneurysmal subarachnoid hemorrhage (surgical patients). Intervention: Mild intraoperative cooling (core temperature 33°C) with immediate post-clip rewarming. Number of patients to be enrolled: 1000 (power analysis indicates ≈ 920 completed patients needed). Number of clinical centers: Approximately 30 Primary hypothesis: Mild hypothermia limited to the intraoperative period in patients undergoing craniotomies for the clipping of intracranial aneurysms will improve neurologic outcome at three months as quantitated by Glasgow Outcome Scale score (GOS) as compared with outcome in patients remaining normothermic during surgery. Secondary hypotheses: Mild hypothermia will also improve outcome as assessed by other neurologic or neuropsychologic measures, and will beneficially influence hospital course, including: At three months: NIH Stroke Score, Barthel Index (Activities of Daily Living), Rankin Disability Score, Mini-Mental State Exam (MMSE) and five-test neuropsychology battery. In hospital: Duration of intubation/ventilation, duration of ICU care, duration of hospitalization, discharge destination, other intercurrent events and intensity of therapy. Patient selection criteria: Adult, non-obese, non-pregnant WFNS Grade I, II or III patients with SAH scheduled to undergo craniotomies for aneurysm clipping within 14 days of SAH. No contraindications to cooling, pre-SAH Rankin scores of 0 or 1, nimodipine therapy planned. 1
  17. 17. Created 1/30/15 IHAST 2 Operations Manual Description of pre-randomization procedures or process: Patients will be examined to verify eligibility. After consent is obtained, the DMC will be contacted and the color of a sealed envelope containing the temperature group assignment will be provided. This envelope will not be opened until after the induction of general anesthesia – and the patient will not be considered randomized and entered until the envelope is opened. Precise treatment dose description for protocol: In hypothermic patients, core temperature will be reduced to a target of 33o C, using water mattresses, forced air cooling and cold intravenous fluids. Cooling will begin after the induction of anesthesia in the operating room, and rewarming will commence immediately after the aneurysm is clipped. Normothermia will be restored within two hours after patient arrival in the postoperative care area. Plan for follow-up: Patients will be examined daily for 14 days postoperatively, or until discharge from hospital. They will be seen again at ≈six weeks after surgery, with an extensive, final evaluation to be completed at three months following surgery. Extent and type of blinding/masking: The Anesthesiologist in the O.R. cannot be blinded. However, every effort will be made to ensure that the operating surgeon remains blinded. The individual responsible for all neurologic outcome assessments, both in the hospital and at three months postoperatively, will be completely blinded, as will the Local Study Coordinator. Endpoints and outcomes: Primary outcome will be Glasgow Outcome Score at three months. Secondary outcomes will include NIH Stroke Score, employment status, place of residence, Rankin Disability Scale, Barthel's Activities of Daily Living Scale, and Neuropsychology. Statistical design and sample size calculations: The trial is designed to achieve a power of 0.90 and alpha=0.05 (two-sided) to detect an improvement of 10% (absolute) in the number of patients with a Glasgow Outcome Score =1 (Good Outcome) (i.e., from 65% in the control (normothermia) group to 75% in the treatment group). Patient entry will be randomized with stratification by center and by interval between SAH and surgery (0-7 and 8-14 days). This will be done only to ensure equal distributions of normothermic and hypothermic patients within each center and within each interval subgroup (i.e., no restriction on the number of patients in each subgroup). 2
  18. 18. Created 1/30/15 IHAST 2 Operations Manual Proposed safety and efficacy monitoring boundaries: The NIH Patient Safety & Monitoring Board (PSMB) will have final say over boundaries. We intend to monitor primary efficacy (GOS at three months) with the Lan & DeMets interim monitoring procedure, using an alpha-spending function approach with O’Brien-Fleming boundaries. Two formal efficacy analyses are planned after entry (through three-month follow-up) of 300 and 600 patients. With these boundaries, the significance level required for the first interim analysis is 0.00052; for the second it is 0.01429. Safety analysis will involve comparison of adverse events between treatment groups by body system and specific COSTART term. Interim analysis for safety will examine all adverse event comparisons; those with P<0.05 will be flagged for the attention of the PSMB. Local safety monitoring will be done on an ongoing basis by the Local Safety Monitor (Harold P. Adams, Jr., M.D.), reviewing mortality and serious IEs. Regular safety analysis by the local monitor will be reported to the PSMB. Patient accrual plan: First patient to be entered late in 1999. Thereafter, target accrual rate is 30 patients per month. Sufficient PCC’s will be recruited to maintain this accrual rate. Ethical and consent considerations: Since no form of intraoperative management has ever been evaluated, there do not appear to be any evident ethical concerns regarding randomization; both normothermia and hypothermia are used by personal preference by many teams (no PCC has an established temperature monitoring protocol). There are theoretical risks to cooling, and several studies have demonstrated some increase in the incidence of myocardial ischemia and dysrhythmias, and in the incidence of wound infections. However, these data were not obtained in a neurosurgical setting, and available data in this population (including in our own pilot study) have failed to demonstrate any risk to moderate hypothermia limited to the intraoperative period. Regarding consent; study consent will be obtained from either the patient or the next of kin/consenting person. Specifically, consent will be obtained from the same individual who signed the surgical consent document. Participating pharmaceutical or device manufacturing company: Augustine Medical Inc., Prairie View, Minnesota (will provide forced air cooling equipment only). Mallinckrodt Medical, St. Louis, Missouri will provide combined esophageal stethoscope/thermistors and cables. PAYMENT: $3,000 per completed patient, paid in two $1500 increments (first after discharge data filed and verified, second after final three-month data filed and verified.) $10,000 advance payment prior to initiation (charged against the first 10 patients in each center). Travel funds for one meeting per year (Local PI and Study Coordinator). AUDITS: Intraoperative records will be audited by the Physician Protocol Monitor (PPM - blinded as to outcome). All data forms and patient records will be subjected to two onsight data audits. The first audit will take place as soon after enrollment of the first patient as possible, but before the end of the first year. The second audit will occur sometime in the second or third year. Funding agencies: National Institutes of Health (NIH), National Institute of Neurologic Disease and Stroke (NINDS) 3
  19. 19. Created 1/30/15 IHAST 2 Operations Manual 4
  20. 20. Created 1/30/15 IHAST 2 Operations Manual CHAPTER III. ORGANIZATIONAL STRUCTURE AND PERSONNEL There is a complex organizational/administrative structure to a trial of this magnitude. This structure is shown graphically below, and is described in detail in the paragraphs that follow. III.A STEERING COMMITTEE Overall responsibility for the trial rests with the “Steering Committee”, chaired by Dr. Todd, and made up of the primary individuals of the Clinical Coordinating Center (CCC) and the Data Management Center (DMC) as well as Drs. Matthew Howard, III (UI Neurosurgery), Patricia Davis (UI Neurology) and Dan Tranel (UI Neurology-Neuropsychology). All decisions regarding, a) protocol changes, b) continued participation of PCC’s, c) expenditures, case report forms (CRF’s) and Operations Manual development, etc., are vested in the Steering Committee. Individual Steering Committee members will also be available to the Physician Safety Monitor (Harold P. Adams, Jr., M.D.) to assist in the assessment of safety issues related to their specific specialties (anesthesiology, neurosurgery, neurology, or neuropsychology). 1 Data Management Center (University of Iowa) Participating Centers SubmissionVerification Submission Verification PhysicianProtocol Monitor Verification Physician SafetyMonitor Verified IE’s Steering Committee Todd(PI andChair),Hindman, Woolson, Torner, Clarke,Tranel,Howard, Davis Advisory Committee Loftus, Gelb Schubert,Clifton NIH Protocol Safety & Monitoring Committee WilliamYoung,Chair IntercurrentEvent Reports CaseReport Forms Anesthesia& PACURecords Audits Enrollment & Verification 319-353-4708 Other Committees (To be Named) Publications Concurrent Studies IESummaries Clinical Coordinating Center (University of Iowa)
  21. 21. Created 1/30/15 IHAST 2 Operations Manual III.B ADVISORY COMMITTEE The “outside” Advisory Committee is chaired by Dr. Loftus (University of Oklahoma, Neurosurgery) and also includes Drs. Gelb (University of Western Ontario, Anesthesiology), Schubert (Cleveland Clinic, Anesthesiology) and Clifton (University of Texas, Houston, Neurosurgery). The primary role of this group is to provide consultative services regarding protocols, protocol changes, CRF development, etc., to the Steering Committee. III.C CLINICAL COORDINATING CENTER (CCC) The CCC, chaired by Dr. Todd, is made up of two physicians (Drs. Todd and Hindman), three clinical coordinators (Ms. Weeks, Mrs. McAllister and Ms. Moss) and a secretary (Mrs. Janan Winn). This group will be the primary liaison with PCCs, will answer any protocol, eligibility and enrollment questions, and will receive and evaluate any emergently submitted “INTERCURRENT EVENTS (IE)” forms, with the primary goal being to ensure that all information needed to “define” the circumstances surrounding the IE is adequately collected. If any certified individual at any PCC has any questions regarding the conduct of the trial or regarding an individual patient, these should be directed to the CCC. Personnel at the CCC will be available “on-call” 24 hours-per-day. In addition, the CCC will be responsible for the performance of on-site audits of PCCs. Plans call for each center to be visited twice during the period of the study, once during the first 12 months, and one additional time during the following three years. Note that all members of the CCC will remain blinded regarding the temperature assignment of individual patients and will not receive information regarding outcomes until the time of on-site audits. In particular, they will have access to submitted CRFs only when these forms are “closed.” Ongoing group-related outcome information will not be provided to the CCC until the study is completed. III.D DATA MANAGEMENT CENTER (DMC) The DMC, chaired by Dr. William Clarke, is made up of a center coordinator (Mrs. Wichman), a database analyst (Mr. Reardon), a systems analyst (Mr. Peters), a biostatistician (Mr. Hansen), and a research assistant III (Ms. Anderson), responsible for all data entry and analysis. The DMC, in conjunction with the CCC, Steering and Advisory Committees developed the CRFs, the Operations Manual, the automated telephone enrollment system, RANDOMIZATION ENVELOPES, etc., and will construct and maintain the database, receive, enter and oversee the quality of all patient data, and perform interim and final outcome analysis. They will also provide regular “blinded” reports to the Physician Safety Monitor (PSM) (identified only by “Group A vs. Group B”) and additional outcome and safety information to the NIH Protocol Safety and Monitoring Board (NIH PSMB). They will provide “completed” CRFs to the CCC at the time of planned on-site audits. 2
  22. 22. Created 1/30/15 IHAST 2 Operations Manual III.E PHYSICIAN PROTOCOL MONITOR (PPM) It is critical that members of the CCC remain blinded as to temperature assignment at all times. This blinding will be maintained even at the time of on-site audits. However, it is necessary to have a knowledgeable individual audit the actual intraoperative conduct of the study. This individual is the Physician Protocol Monitor (PPM). The PPM – David S. Warner, M.D, - who will receive “immediate” unblinded copies of the intraoperative records (local hospital anesthesia records, early (0-2 hours) postoperative records) as well as copies of the ANESTHESIOLOGIST and TEMPERATURE forms. The TEMPERATURE form, and your local hospital anesthesia and recovery records (in sealed envelopes), will each be sent to the DMC at the time of the 48- hour postoperative data submission. The DMC will, in turn, forward the needed documents to the PPM. It is the PPM’s responsibility to verify that the assigned protocols have been followed, to direct necessary questions regarding management (i.e., patient safety, intercurrent events) to the local investigators, and to provide feedback to the PCCs in the event of protocol violations/deviations in individual patients. If the PPM questions the patient’s eligibility or intercurrent event(s), then the DMC will include these in the Data Edit Reports (DERs) that will be sent by email within 24 hours to the PCC and resolved in their usual manner (see Chapter VII.L.3 of the IHAST2 Operations Manual for details). The CCC and Steering Committee will never see individual PPM protocol reviews. When four new patients for a center are entered into the database, two summaries of the PPM reviews will be prepared by the DMC. One summary will contain data from the four newest patients from the specified center. The second summary will contain data from all patients from the specified center. These summaries will be reviewed by the Director of the DMC, the Physician Safety Monitor, the PSMB, the Steering Committee, and the CCC. The CCC will also receive notification when inconsistencies are found by the PPM between reported serious intercurrent events and the local hospital anesthesia and/or early recovery records. In response to the PPM-derived information and DMC summaries, the Steering Committee will be empowered to notify PCCs of persistent/recurring protocol problems and, if not corrected, to drop a center from the study. III.F PHYSICIAN SAFETY MONITOR (PSM) 3
  23. 23. Created 1/30/15 IHAST 2 Operations Manual It is critical that patients enrolled in this trial not be subjected to any inordinate risks. This requires early detection of any “disproportionate” morbidity in one group, or excess morbidity relative to published information concerning this disease and its treatment. The Physician Safety Monitor (PSM) – Harold P. Adams, Jr., M.D. - is the primary person responsible for ensuring the safety of the trial. His source of information will be regular summary reports of IEs provided by the DMC. While he will remain “strictly” blinded as to group assignment, he will be provided with group-related information (Group A vs. Group B) without identifying which is the hypothermic group. His task is to detect and evaluate evidence that suggests a disproportionate number of adverse events occurring in one group, events that may indicate a disproportionate risk of injury in one specific group. He may draw on the expertise of others on the Steering Committee as needed to assist in determining the likelihood that reported events are related to group assignment rather than to the disease itself or surgery (as distinct from hypothermia or normothermia). The PSM will also communicate regularly with the NIH PSMB. III.G NIH PROTOCOL SAFETY MONITORING COMMITTEE (NIH PSMB) The PSMB is a committee appointed by NIH, consisting of anesthesiologists, neurosurgeons, neurologists, statisticians, etc. with appropriate expertise in SAH and clinical trials. The committee is chaired by Dr. William Young, Dept. of Anesthesia, University of California, San Francisco. The PSMB has oversight responsibilities. After communications with the PI and Steering Committee, it has the power to temporarily or permanently halt patient enrollment if, in their view, patient safety is compromised (e.g., excess morbidity/mortality in one of the two study groups). Alternatively, it may stop the trial if continuation is unwarranted based on information provided at one of the two interim analysis (after ≈300 and 600 patients). Such a “stop” may result from either the demonstration of efficacy (a significant difference between the groups) or futility (i.e., continued enrollment of patients cannot result in a statistical difference between the groups). The PSMB may also mandate changes in the study protocol, and will approve protocol changes recommended by the Steering Committee. III.H UNIVERSITY OF IOWA DIVISION OF SPONSORED PROGRAMS Financial administration of the trial will be vested in the UI Division of Sponsored Programs. This office will be the primary liaison with the NIH Grants Management Office. 4
  24. 24. Created 1/30/15 IHAST 2 Operations Manual CHAPTER IV. PARTICIPATING CENTERS IV.A REQUIREMENTS FOR PARTICIPATION IV.A.1.Minimum Case Load Our overall goal is to enroll approximately 30 patients per month for 30 - 34 months, or until a total of 1000 patients have been studied. To achieve this goal, we have set a target of one patient per PCC per month. We realize that caseloads at individual PCC’s will vary; some PCC’s will contribute far more than this, others will contribute fewer. What is critical is that all PCC’s enroll as many eligible patients as possible, at a consistent pace over the duration of the study. There are reasons for these “requirements”. It is very difficult to assess “quality” of care at a given center if very few patients are enrolled. A center which contributes only one or two patients to the study may be a serious detriment. Conversely, even if a center contributes only five to 10 well-managed patients over the duration of the study, their contribution would be quite valuable. Hence we do not intend to implement rigid “minimum criteria” except for one. Any center, which fails to enroll its first eligible patient within four months after being notified that all requirements for “startup” have been met, will be dropped from the study. PCC’s, which enroll patients at a rate less than five patients per year, will be considered “on probation” and their caseload and patient selection activities will be carefully reviewed by the Steering Committee. Theoretically, the trial could also be biased by too much data coming from too few centers (i.e., too great a fraction of the total patient numbers coming from two or three institutions). IV.A.2.Selection Bias and Demographics 1
  25. 25. Created 1/30/15 IHAST 2 Operations Manual There are other enrollment issues. Our intention is to have the study sample represent the overall “population” of patients undergoing surgery for aneurysm clipping, within the limits set out by the protocol (acute SAH, WFNS Grades I, II or III, etc.). If a center were to “selectively” enroll only certain patients and exclude others (e.g., exclude patients whom the local study physicians “believe” would benefit from hypothermia and hence should not be subjected to the “risk” of being randomized to normothermia, and thus enroll only patients in whom the physicians believe that temperature management “doesn’t matter”), the study sample could be seriously skewed and unrepresentative. For this reason, we need to carefully monitor the total relevant surgical caseload (including patients with unruptured aneurysms). This is the primary reason that we ask all PCC’s to complete the initial SCREENING form for all patients undergoing craniotomies for aneurysm clipping, and to complete the ELIGIBILITY form for all surgical patients with aneurysmal SAH. Data from these forms will provide an accurate measure of the “denominator” of the study, (i.e., the total number of patients, eligible or not, who undergo surgery at the PCC’s). If it is apparent that only a small and potentially “selected” sample of patients are being enrolled at a given center, it may be necessary to review a center’s continued participation. Examples of potential “selection bias” would include a very high “failure to consent” rate, or a large proportion of patients who the surgeon and/or anesthesiologist “decline to enroll”, or a large number of patients excluded for “Procedural Criteria” (e.g., lack of a Study Coordinator, lack of certified personnel, etc.). Our intent is not to “micromanage” the activities of PCC’s, and we definitely do not wish to exclude PCC’s whose caseload is unavoidably low, but which make every effort to recruit, enroll and successfully manage as many patients as possible. However, “reluctant” participation can be fatally damaging to the trial. IV.A.3.Principal Investigator and Co-Investigator Agreements This trial demands a close cooperative working relationship between anesthesiologists and neurosurgeons. For a center to participate, both a Local Principal Investigator (Local PI) and a Local Co-Investigator (Local Co-PI) must be identified. One of these individuals must be an anesthesiologist, the other a neurosurgeon (although the specific role played by which specialist is irrelevant; the Local PI can be either an anesthesiologist or neurosurgeon). Both individuals must acknowledge in writing that they understand the basic goals of the study and that they agree to accept the conditions set forth in the protocol, commensurate with the safety of individual patients. The Local PI will be the primary “official” contact person for the CCC and DMC (although most day-to-day communications will be via the Study Coordinator). The Local PI will also be responsible for supervising the activities of the Local Study Coordinator. Together with the Co-PI and Study Coordinator, the PI will be responsible for educating other participating anesthesiologists, neurosurgeons, coordinators, neurologic examiners etc., and for ensuring that only “certified” anesthesiologists, neurosurgeons, coordinators and neurologic examiners are involved in the specific operative care and follow-up of enrolled patients (certification procedures will be described below). If protocol or data-related difficulties are noted by the DMC, the PPM or others, the Local PI will be the primary individual contacted to aid in resolving any problems. 2
  26. 26. Created 1/30/15 IHAST 2 Operations Manual The PI, Co-PI and Study Coordinator must develop the local mechanisms by which patients scheduled to undergo operative aneurysm clipping are brought to the attention of study personnel. This system must allow identification of surgical patients with unruptured and ruptured aneurysms (patients without and with SAH), as well as patients with SAH who may be ineligible. Who calls whom is of little consequence – but some reasonably systematic procedure needs to be implemented. In addition to such administrative responsibility, it is assumed that the PI, Co-PI and Study Coordinator will meet on a regular basis to review the PCC’s activities, such as training, patient recruitment, data form completion, follow-up examinations etc., as well as for maintaining communication with other participating physicians and support staff. The Local Co-PI will be responsible for local trial management in the absence of the PI. IV.A.4.Institutional Agreements a) Consortium Agreements Consortium Agreement – A consortium agreement between each PCC and the UI is a requirement by the NIH. The following is a description of this agreement. The UI, as the direct and primary recipient of NIH grant funds, is accountable to the NIH for the performance of the project, the quality of data submitted, the appropriate expenditure of grant funds by all parties, etc. In general, the requirements that apply to the UI also apply to the consortium participant(s). Under consortium agreements: The award will be made to the UI and Dr. Michael M. Todd, Principal Investigator, even though institutions other than the UI will carry out portions of the planned programmatic activity. The UI must perform a substantive role in the conduct of the planned research and not merely serve as a conduit of funds to other institutions. Whether proposed at the application stage or subsequent to award, the following information must be provided to NIH for review and approval: A list of all proposed performance sites both at the UI and at the consortium participant(s) sites; Complete application budget pages (for the first year and each future year of support requested) for each consortium participant. The following statement or a similar statement, accompanied by the signatures of the authorized institutional officials (or equivalent) of the UI and consortium participants must be provided to NIH for review and approval: 3
  27. 27. Created 1/30/15 IHAST 2 Operations Manual “The appropriate programmatic and administrative personnel of each organization involved in this grant application are aware of the NIH consortium agreement policy and are prepared to establish the necessary inter-institutional agreement(s) consistent with that policy.” The agreement must be signed by an administrative official of your institution, such as your Vice President of Research, or the equivalent, and must be addressed to our Vice President of Research, Dr. David J. Skorton. See Appendix for a copy of the consortium agreement template. b) Financial Subcontract A copy of the subcontract template is provided in the Appendix. Following is a brief explanation of the NIH Subcontract and the contents. The grantee (UI) must enter into a formal written agreement with each consortium participant. This agreement includes the negotiated arrangements for meeting the scientific, administrative, financial, and reporting requirements of the grant, including those necessary to ensure compliance with all applicable Federal regulations and policies and facilitate a smoothly functioning collaborative venture. At a minimum, this agreement must include: Identification of the PI and individuals responsible for the research activity at each consortium participant along with their roles and responsibilities; Procedures for directing and monitoring the research effort; Procedures to be followed in reimbursing each consortium participant for its effort, including dollar ceiling, method and schedule of reimbursement, type of supporting documentation required, and procedures for review and approval of expenditures of grant funds at each organization; If different from those of the grantee, a determination of policies to be followed in such areas as travel reimbursement and salaries and fringe benefits. The policies of the consortium participant may be used as long as they meet NIH requirements; Incorporation of those generally applicable requirements included in Part II of this policy statement and provisions indicating the intent of each consortium participant to comply, including submission of applicable assurances (see “Public Policy Requirements and Objectives”). A provision addressing ownership and disposition of data produced under the consortium agreement; A provision making the inventions and patent policy (see “Administrative Requirements Availability of Research Results: Publications and Intellectual Property Rights, Including Unique Research Resources”) applicable to each consortium participant and it’s employees in order to ensure that the rights of the parties to the consortium agreement are protected and that the grantee can fulfill its responsibilities to NIH. The grantee should also obtain appropriate patent agreements from all persons who perform any part of the work under the grant and may be reasonably expected to make inventions, and agreements to govern disposition of rights to inventions resulting from screening compounds synthesized under the grant; and 4
  28. 28. Created 1/30/15 IHAST 2 Operations Manual As appropriate, provisions regarding property, program income, publications, reporting, and audit necessary for the grantee to fulfill its obligations to NIH. Negotiations regarding Subcontracts will take place between the UI Sponsored Programs office and appropriate individuals at each PCC. c) Human Studies Approval Participation of any PCC is dependent on approval of the protocol by a local Institutional Review Board (IRB) recognized by NIH, and which operates in a fashion compatible with US governmental rules for the protection of research subjects. The fundamental responsibility of an IRB is to assure that all ethical issues have been fully addressed in the protection of human subjects who volunteer to participate in research studies. The IRB is charged with the protection of human subjects in research, regardless of whether the research is subject to Federal regulation and regardless of sponsorship. IRBs must consider: the risks to the subjects, the anticipated benefits to the subjects and/or others, the importance of the knowledge that may be gained, and the informed consent process to be employed. Each PCC must have a protocol approved by their local IRB. Since the UI is the recipient of this NIH grant, the NIH requires that each PCC provide a copy of their institution’s IRB approval. The UI Principal Investigator (Dr. Todd) must review the documents from each PCC to be sure they meet the guidelines of the initial grant submitted for funding. This includes the Study Protocol, Patient Summary and Informed Consent. Each center’s IRB application should be based on the application already approved by the UI, with whatever modifications are required locally. A copy of the UI IRB documents can be found in the Appendix. Certain specific components of that application are required for participation. Specifically, each PCC’s Patient Summary and Informed Consent must contain material covering the following items: Standard of care (hypothermia, normothermia or at the discretion of the Anesthesiologist/Neurosurgeon) by which patients will be managed if they elect not to participate. A statement to the effect: “Records of all participation in this research will be maintained and kept confidential to the extent permitted by law or when ordered by a court of law. However, absolute confidentiality cannot be guaranteed. This is a large research study involving many patients at many different hospitals around the world. The study is being managed by the UI, and the PCC will retain a copy of the data collected. In addition, your medical records may be “audited” by someone from CCC to ensure accurate recording of information.” A statement to the effect: “The results of the study will be reported to the US Public Health Service/National Institutes of Health who are sponsoring this research. Representatives of the NIH may inspect and copy study records relating to this research study. These records may also be inspected by other Federal government regulatory agencies. In this event, some identifying information may be reviewed or retained by the government agencies.” 5
  29. 29. Created 1/30/15 IHAST 2 Operations Manual A statement to the effect: “In the event of any report or publication from this study, the identity of participants will not be disclosed.”  Comment: No supplementary studies should be included in the primary IRB application or documents. Any supplementary studies which are approved by the Concurrent Studies Committee must be handled as a supplementary application/consent. Ethics Committee/IRB approval will be usually given for a year and then the PCC will go through an annual review process. Some institutions will be given approval for a longer period of time, maybe several years. At the end of the approved time each center is responsible for submitting their continual annual review documents to their local review boards. Coordinators at the UI will be following up to be sure each PCC is reapproved and a continued annual review document must be sent to the the UI. IV.A.5.Organizational Meeting Attendance The startup investigator’s meeting is set for September 24-26, 1999. It will be held at The Westin O’Hare Hotel in Park Ridge, Illinois (just outside Chicago). The meeting is critical to ensure that everyone understands all aspects of the study and that we are all working “from the same game- plan”. Center-to-Center consistency is the key to the success of this project. Each PCC should send two individuals, preferably the Local Principal Investigator and the Local Study Coordinator. Everyone should consider this meeting to be “mandatory”. Members from the Advisory Committee, the CCC and the DMC will be attending. IV.A.6.Subsequent Yearly Meetings Subsequent annual meetings will usually be held in conjunction with the annual American Society of Anesthesiologists meeting in October. Two representative from each PCC will attend to receive updates (typically the Local PI and Study Coordinator), and communicate information that will facilitate consistent and correct performance of the IHAST2 protocol. 6
  30. 30. Created 1/30/15 IHAST 2 Operations Manual IV.A.7.Centers Recruited Later PCC’s that join the study after the initial organizational meeting are required to meet with the CCC and the DMC in Iowa City. The purpose of the meeting is to provide the Study Coordinator and PI with instruction/training prior to participation in the study. This meeting will be arranged only after a consortium agreement, IRB approval and a subcontract are received from the prospective center. IV.A.8.On-site Audits Site audits are performed to ensure compliance to the trial protocol, correct data collection, and to assist PCC’s with questions. Each PCC will be audited on at least two occasions during the trial period. The first audit will occur once within the first 6-12 months after enrollment of the first patient, and again prior to completion of data collection within the IHAST2 trial (by April 2003). The audit will involve two areas: the patient notebooks and the Site Regulatory Binder. To initiate the audit process, the Local Study Coordinator will be contacted approximately one month prior to the audit. At this time, the audit, which will take approximately two days, will be arranged. At one week prior to the audit date, the PCC Study Coordinator will be given the identification numbers of two-to-four patients randomly chosen for review and any other patients whose records that the CCC/DMC believes need to be reviewed. The Study Coordinator must arrange to have the patient charts available for the auditor on the day of the visit. The auditor will bring copies of the relevant CRF’s that have been sent to the DMC, and compare these with the copies contained in the PCC’s files, and also compare these forms with data from the patients chart. In addition, the PCC Study Coordinator must provide the Site Regulatory Binder for review. IV.A.9.Local Documentation a) Operations Manual Each PCC will need an updated copy of this Operations Manual. Periodic updates will be provided as changes/modifications occur. The earlier versions of the relevant sections should be replaced with these updates. b) Case Report Forms/Patient Notebooks The PCC’s copies of all completed CRF’s should be retained in clearly labeled, patient-specific binders. Randomly selected patient notebooks will be audited in conjunction with the patients’ medical record to determine completeness and consistency between the two documents. To maintain blinding of the auditors, anesthesia records, as well as the TEMPERATURE and ANESTHESIOLOGIST forms will not be audited during the site visit and should removed from the patient’s chart and patient notebook. Copies of all anesthesia records will be forwarded to the DMC (along with other submitted records). All anesthesia records will be audited by the PPM. 7
  31. 31. Created 1/30/15 IHAST 2 Operations Manual c) Site Regulatory Binder Each PCC must retain a “Site Regulatory Binder” that contains certain important paperwork and documentation. The purpose of this binder is to provide a central source to store material not kept in the individual patient notebooks. This binder will be reviewed during on-site audits. The specific contents of this binder can be found in Chapter VII.A.5. IV.B PERSONNEL REQUIRED, DUTIES AND CERTIFICATION REQUIREMENTS IV.B.1.Local Principal Investigator (PI) At each PCC, the Local PI is responsible for the overall conduct of the trial. The PI must be either a neurosurgeon or an anesthesiologist. In addition, a Co-PI, must also be designated. If the PI is a neurosurgeon, the Co-PI must be an anesthesiologist, and vice versa. The PI will be the primary communication person between each PCC and the CCC and DMC. The PI will be the local resource regarding all elements of the trial. Accordingly, the Local PI must be completely familiar with eligibility requirements, intraoperative protocols, and postoperative evaluations. The Local PI will be responsible for communication with the local human studies committee (or IRB). The Local PI will maintain local IRB approval for patient participation in IHAST2. Updated copies of the local Patient Information Summary, local Consent Form, and local IRB approval documentation are to be maintained at each PCC. Updated copies of each of these documents are also to be sent to the CCC on a timely basis. The Local PI is responsible for maintaining a Patient Log Binder that will record the age, gender, and ethnicity of all patients undergoing cerebral aneurysm surgery, regardless of study eligibility and/or participation (i.e., the log contains the canary copy of all SCREENING and ELIGIBILITY forms). This log is necessary to establish the overall surgical experience of a given PCC (cases per year). Accordingly, the Local PI will be responsible for establishing a system whereby all patients undergoing intracranial aneurysm surgery are screened, and all patients undergoing surgery for a ruptured intracranial aneurysm are evaluated for study eligibility in a timely manner prior to surgery. The specific contents of this binder can be found in Chapter VII.A.6. The Local PI is responsible for ensuring that all IHAST2 study materials are accurate, completed on a timely basis, and submitted to the DMC on schedule. The Local PI (or Co-PI) will be responsible for providing a written narrative describing the circumstances surrounding any patient death. The Local PI will be responsible for organizing personnel required to conduct the trial. As a practical matter, there are five functional roles to be fulfilled for each patient enrolled into IHAST2: 1) Neurosurgeon(s); 8
  32. 32. Created 1/30/15 IHAST 2 Operations Manual 2) Anesthesiologist(s); 3) Study Coordinator(s); 4) Neurologic Examiner(s); 5) Neuropsychology Examiner. In each PCC, the Local PI will need to establish a system to ensure that each of these roles are continuously “covered” (24 hours-per-day, 7 days-per-week).  Comment: In some instances, an individual may serve more than one role. However, in no instance may any person who is performing any postoperative outcome evaluation have been present during surgery, been in contact with the patient in the first two hours after surgery, or be aware of patient group assignment or intraoperative temperatures). All patients enrolled in IHAST2 must have their intraoperative care provided by a neurosurgeon and Anesthesiologist who are certified to participate in IHAST2. Consequently, in each PCC, the Local PI will need to organize teams of participating neurosurgeons and anesthesiologists continuously “on call”, so that all consenting patients may be enrolled and randomized, regardless of the time of day. The Local PI is responsible for designating a Study Coordinator, who will be largely responsible for pre- and postoperative patient evaluations, as well as data entry in the case report books. Given the vital role of the Study Coordinator in this trial, a “back-up” person must be available to ensure the Study Coordinator's role is fulfilled (by an appropriate IHAST2 participant) whenever the usual Study Coordinator is not available. The Neurologic Examiner is a person blinded to patient group assignment who is certified to perform NIH Stroke Scale (NIHSS) examinations at defined intervals before and after surgery. The Neurologic Examiner may not be involved in the daily care of the patient. Because NIHSS exams are critical to the trial, none of these exams can be missed (see comment below). Hence, once again, a 24 hour-per-day call system, and a “back-up” person must exist to ensure this role is continuously fulfilled. Although it is greatly preferred that postoperative NIHSS exams (3 to 6-, 24-, and 72- hours after surgery; and at discharge) be performed by a designated Neurologic Examiner, the Local Study Coordinator may perform these exams if necessary, so long as s/he is not aware of patient group assignment or perioperative temperature data. The final 3 month (12 week) NIHSS examination must be performed only by a certified Neurologic Examiner—no other IHAST2 participant may perform this exam.  Comment: If the patient has received pharmacologic agents (sedatives, hypnotics, anesthetics) which have resulted in a state of anesthesia, or a level of sedation that substantively impairs the patient’s ability to meaningfully cooperate with this exam; or the patient is pharmacologically paralyzed (neuromuscular blocker), then the NIHSS exam need not be performed for that time interval. Please see Chapter IX.P for further instruction. 9
  33. 33. Created 1/30/15 IHAST 2 Operations Manual Finally, at each PCC, provisions must be made for administration of the neuropsychology test battery at the final, three-month, postoperative evaluation. This battery must be administered by a Neuropsychology Examiner who has been certified by the CCC. Preferably, the Neuropsychology Examiner will be either a Neuropsychologist (M.D. or Ph.D.) or a professional Neuropsychology technician. If such a person does not exist at a given PCC, arrangements must be made via the CCC. The Local PI is responsible for local financial management. The Local PI will establish the salary and/or reimbursement rates for all participating personnel. The Local PI and the local administration (Sponsored Programs) will negotiate the institutional indirect cost rate (if any). IV.B.2.Local Co-Investigator The Local Co-PI must be either a neurosurgeon or an anesthesiologist. If the PI is an anesthesiologist, the Co-PI must be a neurosurgeon, and vice versa. The role of the Local Co-PI is to assist the Local PI in all elements of the trial and to assume the role of PI whenever the PI is not available. Accordingly, the Local Co-PI must be completely familiar with the responsibilities of the PI, as described above. IV.B.3.Anesthesiologists a) Protocol To be randomized, patients enrolled in IHAST2 must obtain their intraoperative anesthetic care by an anesthesiologist who is certified to participate in IHAST2 (see below for certification process). A patient whose anesthesia and temperature management is performed by an uncertified anesthesiologist may be classified as an enrollment error and protocol violation (and hence, payment may be jeopardized). When the patient arrives at the operating room, the Anesthesiologist will determine whether the patient is still eligible (WFNS score, general medical condition) and will characterize the patient’s condition immediately prior to surgery. The Anesthesiologist is responsible for providing anesthetic and cardiovascular management in accordance with protocol. The Anesthesiologist is responsible for managing the patient’s temperature in accordance with protocol. Only the Anesthesiologist caring for the patient during their primary aneurysm surgery may open the assigned RANDOMIZATION ENVELOPE; no exceptions, ever. b) Blinding 10
  34. 34. Created 1/30/15 IHAST 2 Operations Manual The Anesthesiologist is responsible for maintaining the blind. Only the Anesthesiologist caring for the patient during their primary aneurysm surgery may know the patient’s group assignment and intraoperative temperature data, which is recorded on the TEMPERATURE form. Only the Anesthesiologist caring for the patient during their primary aneurysm surgery may complete the TEMPERATURE form, which is sealed in an envelope at the end of the case; no exceptions, ever. The Anesthesiologist is not to reveal temperature information to anyone, including other anesthesiologists not participating in the case. Similarly, the Neurosurgeon, Local Study Coordinator, and Neurologic and Neuropsychology Examiner(s) are not to learn of the patient’s group (temperature) assignment and/or any intraoperative temperature data. There is only one exception: The Anesthesiologist may inform the Neurosurgeon of the patient’s group assignment and/or temperature only for immediate intraoperative safety reasons. However, in this instance, no one else may know: the Local Study Coordinator and Neurologic Examiner(s) are still not to be informed regarding patient temperature. c) Data Collection The Anesthesiologist is responsible for characterizing the patient’s condition at the time of aneurysm clipping (mean arterial pressure, glucose, etc.) and recording this information on the ANESTHESIOLOGIST form. The Anesthesiologist is responsible for postoperative warming (if needed) and continued management of any temperature-related or anesthetic-related problems that extend into the postoperative period. The Anesthesiologist is responsible for characterizing key events occurring during surgery, and for the first two hours after the patient leaves the operating room. Accordingly, only the Anesthesiologist who cared for the patient during their primary aneurysm surgery may complete the ANESTHESIOLOGIST form. If, during surgery, or the first two hours after surgery, events occur that warrant completion of an INTERCURRENT EVENTS (IE) form, it is strongly recommended that the IE form(s) be completed only by the Anesthesiologist. However, the Local Study Coordinator may assist in completion of the IE forms so long as the Coordinator is not informed of patient group assignment or intraoperative temperatures. The Anesthesiologist is responsible for providing “blinded” copies of the intraoperative anesthesia record and early (0-2-hours) postoperative recovery or critical care records to the Study Coordinator for submission to the DMC. These copies are to be provided to the Study Coordinator in the used Study Packet that contained the assigned RANDOMIZATION ENVELOPE. This is done to help prevent the Study Coordinator from accidentally learning of the patient’s intraoperative and early (0-2-hours) postoperative temperatures. The Anesthesiologist should use the large Study Packet containing the assigned RANDOMIZATION ENVELOPE to place and seal the local hospital anesthesia record and early (0-2 hour) postoperative data. 11

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