We want to thank everyone for coming to the Organizational Meeting in Chicago in September. It took us a bit longer to accomplish some of the tasks we promised, but we are now on track. Our major efforts have been directed at getting certification materials prepared and distributed (and you've now all seen our Hollywood-level movie-making abilities, edited personally by your PI), and everyone should now be well into the certification process (see Item 5 below). We've also now established our Supplementary Studies Committee, recruited our Physician Protocol Monitor, and started the distribution of the Site Regulatory Binders and Patient Notebooks. Most importantly, 

      WE'VE ACTUALLY ENROLLED PATIENTS!!!

 at least "practice" patients (Congratulations to the Cleveland Clinic for being Numero Uno!). 

 We've also encountered a small snag with the US Office for Protection from Research Risks (OPRR) - but this will be solved shortly. 

 For more information on these and other matters, read on.
 

In Chicago, there was a great deal of interest in Supplementary Studies to be performed on IHAST2 patients at individual centers or on a multicenter basis. We are definitely interested in encouraging such studies, but everyone must recognize that carelessly adding a study, altering the protocol, or doing something that could introduce bias or risk unblinding could seriously damage the integrity of the primary trial. This means that proposed studies need to be carefully reviewed. 

We now have our Supplementary Studies Committee in place. The individuals below have graciously agreed to serve on this group: 

Basil Matta (Anesthesia) & Peter Kirkpatrick (Neurosurgery), Addenbrooks Hospital, Cambridge, Great Britain

Samra Satwant (Anesthesia) and Greg Thompson (Neurosurgery), University of Michigan, Ann Arbor, MI, USA

Arthur Lam (Anesthesia) and Richard Winn (Neurosurgery), University of Washington, Seattle, WA, USA

William Lanier (Anesthesia) and David Piepgras (Neurosurgery), Mayo Clinic, Rochester, MN, USA.

IHAST2 is organized in such a way as to maximize the blinding of as many people as possible. Since this is a procedural trial, this has involved some interesting tricks. This is quite different from a drug trial in which blinding is easy - the pharmacy just makes up drug syringes with "numbers" instead of labels. One by-product of this blinding is that the intraoperative records must be kept concealed from members of the CCC - including our on-site auditors. In effect, this would mean we would be unable to audit the actual performance of the protocol (cooling). 

To provide oversight for this critical aspect of the study, the NIH has now approved a Physician Protocol Monitor (PPM). 

We are happy to announce that David Warner MD, Dept. of Anesthesia at Duke University (and one of the founders of IHAST2 before leaving Iowa) has agreed to serve as the PPM. 

The DMC will provide the PPM with unblinded copies of the ANESTHESIOLOGIST and the TEMPERATURE forms and a copy of your local hospital anesthesia and early postoperative records. He will then examine the records to verify compliance with the trial protocol. He will, however, have no information concerning patient outcome.

As the trial progresses, don't be surprised if you receive phone calls from David. Part of his job is to contact participating centers with questions regarding various actions in the O.R. and immediate postoperative period. 
 
 
 

The IHAST2 web site is now available at the following web address: 

http://ctsdmc.public-health.uiowa.edu/ihast2

This is a central source for participating centers to enter comments from case report forms, to obtain information, and learn more about the operations of the DMC and CCC. The IHAST2 web site contains the following:

 

     a.  info about the origins of IHAST2

     b.  info about the DMC and CCC

     c.  HTML and PDF versions of Updates

     d.  the Operations Manual in HTML & PDF

     e.  the Comments web entry system

ihast2@mail.public-health.uiowa.edu

When you e-mail the DMC, include your first and last name, the name of your local center, your role in IHAST2 (Coordinator, Co-PI, etc.), and your complete phone number.

Item e (the Comments system) can only be accessed with your official IHAST2 certification number. Multiple comments for a patient can be entered (i.e., you can enter comments in the morning and then again that afternoon if you remembered something you may have left out earlier). However, once a comment is submitted to the DMC, it can’t be changed.
 

Certification 

As you know, each center must have a certified Local Study Coordinator, Anesthesiologist, Neurosurgeon and Neurologic Examiner before patients can be enrolled. In addition, all anesthesiologists and neurosurgeons caring for enrolled IHAST2 patients need to be certified. We have "relaxed" the rules a little bit - your Neurologic Examiner does not need to be "on board" prior to doing your two "practice" patients (since no neurologic outcomes will be tracked). However, you will need a certified Neurologic Examiner before enrolling the first "real" patient. In addition, don't forget to send us the name, CV/resume and identifying information about your Neuropsychology Examiner. certification of these people will be done on a more "personal" basis by Steve Anderson and the Neuropsych staff here at Iowa. 

Every center has now received its certification materials (for the Local Study Coordinator, Anesthesiologist, Neurosurgeon and Neurologic Examiner); we have been getting completed "exams" back on a daily basis. We would like to thank those of you who have been so diligent. The biggest "lag" involves neurosurgeons. One suggestion is for the Local PI or CoPI and/or Study Coordinator to meet with a group of surgeons and complete the material. The same approach might be taken with anesthesiologists. 

Remember, the goal of our Anesthesiologist and Neurosurgeon certification procedures is to ensure that everyone understands the protocol, data collection efforts, etc. The "tests" are not meant to be onerous - they are intended to help participants to understand 
 
 
 
 

Are You Ready to Begin?

Each center needs to carry out the hypothermic protocol on two "practice" patients. This is intended to a) give each center the chance to work through the notification and enrollment procedures; b) to use the telephone enrollment procedures (although both practice patients will be assigned the "hypothermic" group); c) to actually carry out the cooling protocol; and d) to become experienced with data collection and case report form submission, etc. It also provides us with a chance to work out the "bugs" in our systems at both the CCC and the DMC. 

Following is a checklist of items which each center, in conjunction with University of Iowa IHAST2 DMC/CCC, must accomplish prior to enrolling the first "practice" patient:

 
a. Each center must have three members certified including an Anesthesiologist, a Local Study Coordinator, and a Neurosurgeon. Since no neurologic follow-up is required in these patients, a Neurologic Examiner is not mandatory - although such a person will be required before a center will be approved to enroll "real" patients. 

b. SPA (Single Project Assurance) numbers must be obtained for PCC’s outside of the United States. We are working with PCCs on an individual basis to obtain these numbers. This

basically means that OPRR approves your local consent documents.

c. Each PCC must have a PolarAir™ unit from Augustine Medical and a box of 20 esophageal stethoscope/temperature probes from Mallinckrodt. Delivery of PolarAir™ units are being prioritized according to theorder in which items a. and b. above are completed. Hopefully, everyone will have their temperature probes 
and connecting cables just after the first of the year. 

d. Each PCC should have received two Practice Patient Notebooks. If you do not have these notebooks please contact the DMC at 

On December 10th, we were contacted by the Office for Protection from Research Risk (OPRR). This is the US Federal Agency charged with protecting research subjects. Many of you have heard about their shutting down all human studies work at Duke, Colorado, Illinois, etc - these guys play "hardball." Anyway, they expressed concerns regarding our basic consent document - specifically the one that was accepted here at the University of Iowa and used by almost all of you as a template for your own IRB applications and consents. Not only did they have some concerns - but they asked us to halt patient enrollment!

How did OPRR get involved in this? They don't normally look at individual consent forms. The reason is related to the "Single Project Assurance (SPA)" process for nonUS centers. In the US, almost all Human Studies Committees are covered by "Multiple Project Assurance (MPA)" agreements. In essence, this means that OPRR approves each local Human Studies Committee to handle all consent issues, as long as that committee operates according to the rules. The reason behind most of the recent shutdowns has been related to local problems with administrative issues. 

Human Studies Committees outside the US typically don't have "MPA's". However, if a nonUS center wishes to participate in a US Federally funded trial (i.e. get US taxpayer's money!) they must meet OPRR's standards. This means OPRR reviews each IRB approval and issues a "Single Project Assurance (SPA)" number for each nonUS center. The University of Iowa, as the actual recipient of the grant, is under contractual obligation not to send money to any center without an SPA.

Fortunately, all of the changes they suggested are related to the language of the document - not the protocol per se. Once we got the details of their concerns, we were able to alter the consent document easily (about an hour's work). In addition, our local Human Studies Committee was able to approve these changes administratively (i.e. without sending the document back to the entire committee). 

I wish this were only a UI problem but it's not: 

They have also suggested that patient enrollment not proceed until this is done. 

A copy of the newly approved Iowa consent document is attached to this Update. We are also working very hard to review each local consent form that we have on file. In some cases, we suspect that no changes will be needed. In others, greater changes may be required. We will be contacting each center individually to detail the changes that need to be made. [NOTE: OPRR mandates the changes - but we are charged with doing the actual work and making sure that the forms are all in compliance.]

Please - this does not mean you should stop with the process of "getting ready". With some luck this can be sorted out in a few weeks. When we sort out what needs to be done, we would strongly recommend that you 

A number of people have had problems with the NIH Stroke Scale certification process. In retrospect, we think this may stem from a description in the Operations Manual that was too brief. In an effort to help, we have attached a more extensive description of the various test items, their assessment and their completion. The document was modified from one created for the t-PA study (the same source as the videotapes). This material is not a substitute for what you've already received - simply a supplement to it. 

Please distribute a copy of these instructions to members of your team who will be certified to administer the NIH Stroke Scale.

8. Money

We would like to get centers paid! On December 1^st, 1999, an e-mail was sent to centers that had not yet returned a "Generic Invoice" to the CCC so that we could initiate payments to your center. The memo requesting a "Generic Invoice" was sent with the subcontract in late September. If you haven't seen it, check with your institution’s Sponsored Programs Office, or equivalent; the form may be there and they have not yet attended to its completion. 

If you would like the address to which this memo and your subcontract were sent, please e-mail the CCC. In addition, a copy of a prototype "MEMO" is attached at the end of this Update.

Interim NIH Stroke Scale (NIHSS) exams are required prior to surgery and 2-, 24- and 72-hours after surgery, and on the day of discharge. An NIHSS exam is also required three months after surgery.

Some questions and concerns have been raised in the last several weeks about who can do which exams. We want to address these questions - and to make a change in the trial protocol. 

3-month Follow-up Exam

The assessments done at the 3-month postoperative visit are really the key to this study - they represent our primary outcome variables and must be defended "at all costs." The final outcome assessments (Glasgow Outcome Scale, NIHSS, Barthel’s, neuropsychology battery, etc.) must must must be made by an IHAST2-certified Neurologic Examiner who is not aware of the patient’s temperature group assignment and/or any intraoperative or early (first two hours) postoperative temperature data.

PLEASE UNDERSTAND - IF THIS FINAL EXAM IS NOT "DONE RIGHT" EVERYTHING THAT HAS GONE BEFORE IS A WASTE OF TIME!!!

The Neurologic Examiner performing the final assessments cannot be the Local Study Coordinator, the Local P.I., the Local Co-P.I., or any participating Neurosurgeon or Anesthesiologist. The Neurologic Examiner performing the final assessments should not be routinely involved in the day-to-day surgical, 
 

a. A neurology faculty, fellow, or resident not routinely involved in the postoperative care of SAH patients; 

b. An Emergency Room physician not routinely involved in the postoperative care of SAH patients; 

c. A neurology nurse not routinely involved in the postoperative care of SAH patients; 

d. A surgical or anesthesia faculty or fellow with no routine involvement in the care of SAH patients; 

e. A neurosurgery or neuroanesthesia fellow with no clinical commitments at the time of the final outcome assessments and no prior knowledge of specific study patients. 

Interim NIH Stroke Scale Exams

An interim NIHSS must be performed at 2-, 24- and 72-hours after surgery, and at discharge. This exam must be done by an IHAST2-certified person who has passed the NIHSS examination (i.e., NIHSS qualified).

Specifically, the protocol now permits the Local Study Coordinator to perform the interim NIHSS exams. 

There are two reasons behind this change. The first is entirely practical - we recognize the difficulties related to having a Neurologic Examiner (particularly a highly qualified one) "on call" for these interim exams. We also realize that the patient will be seen daily by the Study Coordinator who is already a certified to perform NIHSS exams. However, more importantly, we wish to defend the quality of the data, both for the interim exams AND for the 3-month exam. In an effort to meet the "outside blinded examiner" requirements, some centers were finding it necessary to enlist and train individuals with little or no medical/neurology/neurosurgical experience. We felt that, overall, NIHSS's performed at 2-, 24-, and 72-hrs by a Local Study Coordinator would be more reliable than one performed by a less experienced - even though perfectly blinded - examiner. In addition, we did not want to see the "pool" of Neurologic Examiners in a given center unduly expanded in an effort to meet this requirement. The danger, of course, would be that the 3-month exams would now be more likely to be performed by less qualified individuals. 

This does not mean that the Study Coordinator MUST perform these interim exams. Certified 
 

If the Local Study Coordinator or a Neurologic Examiner is not available, interim (BUT NOT THE FINAL!!) NIHSS exams may be conducted by other IHAST2 certified personnel when all of the following conditions are met: 

a. The person performing the interim NIHSS exam has passed the NIHSS certification exam (i.e., they are NIHSS qualified); 

b. The person performing the interim NIHSS exam is not aware of the patient’s temperature group assignment and/or any intraoperative or early (first two hours) postoperative temperature data; 

c. The person performing the interim NIHSS exam was not in the operating room during the patient’s primary aneurysm surgery nor was in the presence of the patient for the first two hours after surgery. 

The process of selecting and opening the correct Study Packet - and more importantly, the process of getting the right things back into the various envelopes at the end of the case - is critical. The more we looked at this step, the more we recognized the potential for confusion - there are a lot of things that must be done correctly. In an effort to avoid such confusion, we've put together a step-by-step set of instructions that we hope will clear things up. 

Note: The Study Packets are provide with the first shipment of Patient Notebooks. 

The Study Packet

The Study Packet is a large (10 x 13 in.) envelope which is prelabeled with an IHAST2 patient identification (PID) number. The PID number on the outside of the Study Packet envelope must correspond to the PID number assigned to the patient by the phone enrollment system. The Study Packet envelope contains the following items:

a. One (1) (9 x 12 in.) sealed white RANDOMIZATION ENVELOPE pre-labeled with the same PID number. 

b. One (1) (9 x 12 in.) sealed brown RANDOMIZATION ENVELOPE pre-labeled with the same PID number. 

c. Two (2) white (6.5 x 9.5 in.) unsealed envelopes pre-labeled with the same PID number. 

d. Eight (8) white (0.5 x 1.75 in.) adhesive labels pre-labeled with the same PID number.

Paperwork the Anesthesiologist Needs While in the O.R.

While in the O.R., the Anesthesiologist must have:

a. One (1) ANESTHESIOLOGIST form (6 pages). 

b. The one (1) sealed RANDOMIZATION ENVELOPE which matches the PID and color assigned to the patient. 

The RANDOMIZATION ENVELOPE contains a TEMPERATURE form which indicates the temperature group to which the patient has been randomized, and which is the only place where intraoperative temperature data for IHAST2 is to be recorded. 

c. Two (2) white (6.5 x 9.5 in.) unsealed envelopes pre-labeled with the PID number. 

On the outside of these envelopes are instructions telling the Anesthesiologist into which of these envelopes the two copies of the completed TEMPERATURE form

(upper white original and lower canary-colored copy) are to be placed and sealed at the end of surgery. (The blue paper inside each envelope is to reduce transparency—just leave it in). After these two envelopes are sealed, they are to be returned to the Local Study Coordinator (the sooner the better).

After leaving the O.R., the Anesthesiologist must have:

a. The same ANESTHESIOLOGIST form that was used in the O.R. 

This is needed in order to record early postoperative patient status (section G) as well as Intercurrent Events that take place over the first two hours after surgery (section H (page 6) of the ANESTHESIOLOGIST form). Once sections G and H are completed (~two hours after surgery), the ANESTHESIOLOGIST form may be returned to the Local Study Coordinator (the sooner the better). Section H is faxed to the CCC; Sections A- G (the entire form) is mailed to the DMC as part of the 48hr postoperative shipment.

b. The white (0.5 x 1.75 in.) adhesive labels which are pre-labeled with the PID number.

These labels are to be affixed to photocopies of the local hospital anesthesia record and early (first two hours) postoperative ICU (or recovery) records. Any data on these records which are specific to the patient (e.g., name, local hospital identification number, social security number, birth date, etc.) are to be removed or 

covered up. Any unused labels may be discarded.

c. The Study Packet envelope. The Study Packet envelope is used to place photocopies of the local hospital anesthesia record and 0-2 hour postoperative recovery or critical care records.

After these items are in place, the Study Packet envelope is sealed. Once sealed, it is to be returned to the Local Study Coordinator (the sooner the better). To preserve "blinding" the Local Study Coordinator is not to view the local hospital anesthesia record or early postoperative data, ever.

It is preferred that the Anesthesiologist complete all IE forms triggered by responses to section H (page 6) of the ANESTHESIOLOGIST form. However, the Local Study Coordinator may assist in completion of these forms provided that s/he remains unaware of patient group assignment and temperature data.

Suggested Practice and Time-Table Steps

Step 1. Once you have recorded the PID and envelope color from the telephone randomization system on page 3 of the ELIGIBILITY form, obtain the Study Packet with the corresponding PID.

Step 2. Remove the UNassigned RANDOMIZATION ENVELOPE from the Study Packet and set it aside. Thus, if randomized to the "White," remove the "Brown" RANDOMIZATION ENVELOPE; if randomized to "Brown," remove the

"White" RANDOMIZATION ENVELOPE. Only the RANDOMIZATION ENVELOPE which matches the PID and color assigned to the patient remains in the Study Packet envelope. 

(Remember, do not open and do notlose the UNassigned RANDOMIZATION ENVELOPE because it must be mailed to the DMC at 48hrs along with other completed forms).

Step 3. Remove one (1) adhesive label from the Study Packet and attach it to the spine of the patient notebook. Leave the rest of the adhesive labels in the Study Packet for the Anesthesiologist to use (see Step #8).

Step 4. Give the Anesthesiologist the entire Study Packet (only the UNassigned RANDOMIZATION ENVELOPE and one adhesive label have been removed) and the ANESTHESIOLOGIST form from the patient notebook.

Step 5. The RANDOMIZATION ENVELOPE which matches the PID and color assigned to the patient is opened only by the Anesthesiologist in the O.R. 

Step 6. At the end of surgery, the TEMPERATURE form (which was contained in the assigned RANDOMIZATION ENVELOPE) is to be completed by the Anesthesiologist. While still in the O.R., the Anesthesiologist separately seals the original (white) and underlying (canary-colored) copy of the TEMPERATURE form in the two (6.5 x 9.5 in.) white envelopes present in the Study Packet which are pre-labeled with the matching PID. If 

desired, the Anesthesiologist may return these two sealed envelopes to the Local Study Coordinator as soon as the patient leaves the O.R. However, we suggest the Anesthesiologist keep these two envelopes until two hours after surgery, at which time the ANESTHESIOLOGIST form will also be completed and returned to the Local Study Coordinator—see step #7. 

Step 7. Approximately two hours after leaving the O.R. the Anesthesiologist is to have completed the ANESTHESIOLOGIST form. By this time, it is anticipated that all patients randomized to hypothermia will be completely rewarmed. Accordingly, approximately two hours after leaving the O.R., the Local Study Coordinator is to perform an NIHSS examination. It is at this time (two hours after surgery) that we suggest that the Anesthesiologist transfer the two sealed envelopes (which contain the TEMPERATURE form—original and copy) and the completed ANESTHESIOLOGIST form to the Local Study Coordinator. If the 2-hour NIHSS exam is performed by a Neurologic Examiner, we suggest the Anesthesiologist contact the Local Study Coordinator two hours after surgery and arrange a time and place for the transfer of these materials.

(Remember, at two hours after surgery, the Local Study Coordinator (or Neurologic Examiner) is not to record any other data other than the NIH Stroke Scale. The person performing the NIH Stroke Scale at two hours after surgery must not to discuss the patient’s status with anyone, and must not review any postoperative data).

Step 8. In the interval between two and 24 hours after leaving the O.R., the Anesthesiologist is to make photocopies of the local hospital anesthesia record and early (first two hours) postoperative recovery or critical care records. Any information on these records that identifies the patient (e.g., name, local hospital identification number, social security number, birth date) must be removed or covered up. This is required required because patient-identifying information can only be kept by local centers, but not by the IHAST2 coordinating center. The Anesthesiologist is to label these records with the (0.5 x 1.75 in.) adhesive labels (which have the PID on them) that were provided in the Study Packet envelope. The records are then sealed inside the large (10 x 13 in.) Study Packet envelope, and returned to the Local Study Coordinator. Any unused adhesive labels can be discarded. 

Remember, the copies of the local hospital anesthesia record and early postoperative recovery/critical care records are to be sent to Data Management Center with the first data submission—48 hours after surgery. Hence, Anesthesiologists must be quite prompt in providing these copies. The Local Study Coordinator may not make the photocopies for the Anesthesiologist because information regarding patient temperature will be present on these records. The Local Study Coordinators are never to learn of group assignment, nor intraoperative or early postoperative patient temperatures. Thus, the Local Study Coordinators may not view these documents at any time.) 
 

The PCC Correction Report forms are to be used when personnel at the PCC find an error on a CRF which has already been sent to the DMC. Please refer to Chapter XI, H.c (Appendix) of the Operations Manual for a copy of this report. Its also attached to this Update as 

Below are the steps you should follow to complete this form:

Step 1
Item 1. Name of form being corrected. Write in the name of the CRF that is being corrected. The name of the form is found in the upper right side on the first page of the CRF (e.g., SCREENING, ELIGIBILITY, PRE-SAH, etc….)

Step 2
Item 2. Complete all applicable header information below. Applicable means list only the header variables from that particular CRF and leave all other header fields in Item 2 blank. For example, on the Contact Follow-up CRF, Patient ID number and Date of exam, follow-up or onset would be answered since they are applicable to the Contact Follow-up CRF, but Center ID number, Log number, and Time of exam or onset would be left blank since they are not applicable to this particular CRF.

Step 3
Item 3. Indicate which field(s) you wish to correct below, the old value, and the new correct value. Field to be corrected should be a few words describing the field; Old value is the erred value; New correct value is the correct value; and Comments provides 
 
 

Item #9 (page 2)  Field to be corrected

0                           Old value

1                           New correct value

Additional medical records found
    Comments

There are two sections available, allowing for two incorrect fields, per PCC Correction Report form. If you have more than two errors that need to be corrected, you must fill out another PCC Correction Report form with identical information in Items 1 and 2.

Step 4
Sign your name at the bottom of the PCC Correction Report form, write in your certification number and the date you completed the form.

Step 5
Return the white original of the PCC Correction Report form, and a photocopy