Letter to W R Bibb, Subject: Collaborative Research on Gallium-68-Edta Pet Brain Scanning (Encl: LTR to W E Felling Agreement Between Orau and the University of Tennessee; Agreement)

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Associated Post Office Box 117 Universities Oak Ridge, Tennessee 37831 -01 17 Energy Programs and Support Division Department of Energy Oak Ridge, Tennessee 37830 Subject: COLLABORATIVE RESEARCH ON 68GA-EDTA PET BRAIN SCANNING For some time now O M has been pursuing collaborative research arrangements with The University of 'Tennessee that would iwo l ve patients. You are aware of the current projects we a rearranging to involve UT and ORAU personnel in studies on drugs for the treatment of hypertension. ments with Pfizer Pharmaceuticals t o be i n place within the next 30 t o 60 days. We are enclosing a copy of a protocol entitled lt6'GA-EDTA PET Brain Scanning inPatients with Small Vessel Atherosclerosis" submitted t o us by UT. We have concluded that this research would contribute significantly to our ongoing DOE research efforts. with UT under which this research would be done. soon a s we reach agreement with UT. The protocol has been reviewed and approved by Therefore, we a r e pursuing arrangements A copy of our proposed We will seek your formal approval of the a gre ment as A copy of the patient consent form t o be used inthe project is also William E. Fell in 3. Patient Consent Form

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Oak Ridge Associated Unlv ers it les Post Office Box 117 Oak Ridge, Tennessee 37831 Dear Or. Felling : AGREEMENT BETYEEN ORAU AND THE UNIVERSITY OF TENNESSEE This letter it in response t o your August 9, 1985, letter to ne, subject as above. ORAU I s authorized to proceed with the work described i n the agreemnt. Two signed copies ofthe agreenent are enclosed. Willlam R. Bibb, Director ER- 122: Dunaway \ Research and Waste Managersent Dlvislon I OF3 t 9 3 4 OFFICIAL FILE COPY

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Associated Post Office Box 1 1 7 Universities Oak Ridge. Tennessee 37831-01 17 Research and Waste Management Division Oak Ridge, Tennessee 37831 Subject: AGREEMENT BETWEEN ORAU AND THE UNIVERSITY OF TENNESSEE Please find enclosed for your approval four copies of an agreement between ORAU and The University of Tennessee for brain scans on patients using the ECAT-I1 scanner. Ifthe agreement meets with your approval, please return the signed copies to Phillip M. Kannan.

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OAK RIDGE ASSOCIATED UNIVERSITIES THE UNIVERSITY OF TENNESSEE AT KKOXVILLE This agreement entered into this 1st day of February, 1985 by and between Oak Ridge Associated Universities, Inc. (ORAU), P.O. Box 117, Oak Ridge, Tennessee 37831-0117, acting under agreement No. DE-AC05-760R00033 with the United States Department of Energy, (DOE) and The University of Tennessee at Knoxville, (UT), Knoxville, Tennessee 37916. WHEREAS, UT has patients on whom it wishes to have brain scans performed; WHEREAS, ORAU operates for DOE a facility which has government-owned equipment for performing brain scans; and WHEREAS, ORAU is engaged in research in radiopharmaceuticals and recognizes this collaborative work with UT as beneficial to that research; and WHEREAS, DOE has determined that it has a programmatic interest in this collaborative work and is therefore willing to have it performed in Its facility using its equipment by ORAU under Contract No. DE-AC05-760R00033 and have the cost of ORAU'S participation be allowable under that contract;

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NOW THEREFORE, the parties agree as follows: 1. The research to be conducted is described in a protocol titled "68Ga-EDTA Pet Brain Scanning in Patients with Small Vessel Atherosclerosis" (dated December 1 9 8 4 ) which is attached to and incorporated into this The specific participation by ORAU staff will be as follows: UT will refer the patients to ORAU/MHSD (Oak Ridge Associated Universities/Medical and Health Sciences Division) where they will receive an IV injection of 68Ga-EDTA (furnished by ORAU) and subjected to brain scans using the ECAT-I1 scanner. b. During the scan, two ml samples of arteriolized venous blood will be drawn (a total of 12 samples) for assay of blood activity level needed for PET data correction. ORAU staff will draw the samples and assay them. c . ORAU will provide UT with the results of the scans. d. UT.wil1 assume responsibility for the patients at the conclusion of the scans. It is understood and agreed that these same patients will be subjected to repeat scans at six to ten month intervals. It is further understood that Dr. Karl Hubner will be the UT physician responsible f o r the study. Dr. James E. Crook will be the ORAU physician responsible for ORAU'S participation. patients' consent forms as prescribed by ORAU before the patients are accepted into ORAU's facilities. UT will be responsible for securing 2. Each party agrees to bear the c o s t s , including salaries and the cost of all equipment and supplies, of its paticipation.

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3 . The parties agree that each retains all liability for the a c t s or omissions of its employees, agents and officers. 4. UT hereby grants ORAU the right to publish reports, technical or scientific papers or other publications arising from or related to this work or its results provided that such publication does not identify individual patients. UT will be furnished a copy of any manuscript to be submitted f o r publication and have thirty (30) days in which to provide any comments or suggestions on the manuscript. be joint publications since the project being addressed in this agreement is It is expected that most publications will 5 . This agreement may be terminiated by either party thirty (30) days after receipt of a notice to terminate. There will be no cost associated with such termination. 6 . It is understood and agreed that this agreement is entered into by ORAU for and on behalf of the Government; that title to all supplies furnished hereunder shall pass directly to the Government, as purchaser, at the point of delivery; that ORAU is authorized to, and will make payment hereunder from Government funds advanced and agreed to be advanced to it by the DOE, and not from its own assets, and administer this Agreement in other respects for the DOE, unless otherwise specifically provided f o r herein; that administration of this Agreement may be transferred from ORAU to the DOE or its designee, and in case of such transfer and notice thereof to UT ORAU shall have no further responsibilities hereunder and that nothing herein shall preclude liability of the Government for any payment properly due hereunder, if for any reason such payment is not made by ORAU from such

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7. No member of, or delegate to, Congress or resident Commissioner shall be admitted to any share or part of this Agreement or any benefit that may arise therefrom; but this provision shall not be construed to extend to this Agreement if made with a corporation for its general benefit. 8. UT warrants that no person or selling agency has been employed or retained to solicit or secure this agreement upon an agreement or understanding for a commission, percentage, brokerage, or contigent fee, excepting bona fide empolyees or bona fide established commercial or selling agencies maintained by UT for securing business. For breach or violation of this warranty, ORAU or DOE shall have the right to annul this Agreement 9 . It is expressly agreed by the parties hereto that this Agreement supersedes any and all previous agreement or agreements and constitutes the entire and only agreement between the parties relative to this work; that there are no other agreements, understandings, or covenants between the parties hereto of.any kind, nature, or description, expressed or implied, which have not been set forth herein. 10. UT agrees that in any publication that results from this work, it will acknowledge the work of ORAU, and that it will submit a copy of any manuscript to ORAU thirty (30) days before submission for publication for ORAU'S comments or suggestions. 11. Any invention first conceived or reduced to practice, and all technical data produced, under this Agreement will be subject to the patent provisions of the DOE-ORAU Contract No. DE-AC05-760R00033 and The University 12. Neither the Government, the DOE, ORAU, nor persons acting on their behalf makes any warranty express or implied (1) with respect to the

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accuracy, completeness or usefulness of any information furnished hereunder, ( 2 ) that the use of any such information may not infringe privately owned rights, ( 3 ) that the services, materials, or information furnished hereunder will not result in injury or damage when used for any purpose, ( 4 ) that the services, materials, or information furnished hereunder will accomplish the intended results or are safe for any purpose including the intended purpose, (5) that materials accepted for analysis o r other service will not be . destroyed, lost or otherwise altered in physical or chemical properties, ( 6 ) nor shall any implied warranty of merchantability o r fitness for a particular purpose apply. Neither the Government, the DOE, ORAU, nor persons acting on their behalf will be responsible, irrespective of causes, for failure to perform the services or furnish the materials or information hereunder at any particular time or in any specific manner. 13. ORAU will have the right to make and keep patient records pertinant to the study assuring confidentiality of the information. 1 4 . No patient will be accepted by ORAU unless he o r she signs ORAU's form in which the patient consents to the treatment. 15. This agreement is of no force or effect until approved by the Department of Energy.

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IN WITNESS WHEREOF, the parties have executed this agreement as of the day and year first above written. OAK RIDGE ASSOCIATED UNIVERSITIES, INC. T H E UNIVERSITY OF TENNESSEE APPROVED BY U.S. DEPARTMENT OF ENERGY

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PROTOCOL FOR: %A-EDTA PET BRAIN SCANNING I N PATIENTS WITH SMALL VESSEL ATHEROSCLEROSIS. The purpose of this study is t o determine uhether areas of lou density o n CT scans of patients uith focal or diffuse ischemic disease represent areas of changed blood brain barrier (BBB?, permeability. CT attenuation in areas o f interest at the level of the basal ganglia and the centr m semi-ouale uill be compared analysis. It is felt that PET imaging giving quantstiuc infoFmation in tomograch'c display is more suitable for this Major objectives are (1)to explore the anatomical relationship between IOU density CT lesions and areas of increased BBB permeability, ( 2 ) to determine uhether disruption of the BBB is not only present in lou density a r e a s but also in areas remote but functionally related to the ischemic areac and (3)to determine uhether progression of t h e disease is associated uith increasing permeability of the BBB or t h e deuelopment of neu BBB 10 patients ( 5 males, 5 females) u i t h dementia ef Alzheimer's type ( D A T ) and 10 patients ( 5 males, 5 females) w i t h multi-infarct dementia (MID) uill be included i n this study. All Patients uill be over 60 years o f age and have undergone medical neurologic examination, psychometric testing (global deterioration scale and mer,tel status questionaire), CT scanning and uill be classified accordingly t o their Hachinski Ischemic Scale score. (See Ischemic Scores o n next page)

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The minimum diagnostic requirements for DAT are: For MID, the minimum diagnostic requirements are based on

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10 age-matched ambulatory patients ( 5 males, 5 females) uith unilateral strokes (at least 5 ueeks into their recovery) uill be asked t o participate in the 3tudy uith their informed consent. These control patient5 uill have the same medical examination, psychometric testing, etc. as the DAT and MID patients. The . res3on for choosing stroke patients forc ntrols is that IND-FDA approval t o study 3troke patients using k a - EDTA has been obtained already. 68Ga-EDTA concentrations in t h e non-affected hemisphere of stroke patient uill be considered u s standard for PET scans uill be obtained b y using the ORAU M&HSO's KAT - I 1 scanner. Transmission 9cans uill be done f o r attenuation correction purposes prior to the injection of %a-EDTA. (notto exceed a total of 5 mCi). Imaging o f the brain uill be started2 minutes post-injection and uill be continued fora maximum o f one hour. Samples of 2 ml arterialized venous blood uill be taken frequently (total of 12 samples) during the first 30 minutes after injection for a9say o f blood activity level needed for PET data correction. Cortical Regions: frontal pole Deep Structures: Caudate Temporal lobe uhite Occipital lobe uhite Results of ROI analysis will be expressed in uCi/gm at time post injection rather than as arate. In order to address,2 jective (3). CT and be repeated at 6 t o 10 months interuals. Ga-EDTA studies uill

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I N WITNESS WHEREOF, the parties have executed this agreement a s of the day and year first above written. OAK RIDGE ASSOCIATED UNIVERSITIES, INC. THE UNIVERSITY OF TENNESSEE AT TITL ET ITLE APPROVED BY U. S. DEPARTMENT OF ENERGY

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Oak Ridge, Tennessee Consent for Exp z r inen tal Test I authorize the perEormance upon (myself or name of patient) of the following test : ethylenediamine-h',N,t?'N'-tetraacetic acid (6SSa-EDTA) as an agent to detect brain, soft tissue or kidney tumors, and/or non-tunorous lesions in brain or kidneys. The nature and purpose of the test, t h ? risks involved, 2nd the possibilities of cox ? lica c ions I!mc hcsn ex plz in ed to me. tre aim air for my disorder nor is i t being done pri ics ril g for ny benefit, rather & hat the test is for experimental purposes and is being done only for gathering info ma - tion related to my disease,treatment or both. formation lear ocd from doing this test becomes the property of OKAU and may be publi shed in the scientific literature at the discretion of the staff of the Oak Ridge Associated Universities Medical & Health Sciences Division. I have read the following material; it is a summary of what was explained to m e . Phase XI Radiopharmaceutical Tests of '8Ga-labeled I uderstanc! th2t this test ' i s not a Dzte: (Patient or person eu thor i zed to consent I have talked with abour the proposed test to be given including the following: This is a modified radioactive drug: acid (a ch elating agent) ] which differs from the previously known and ne dic ally approved form of this drug only by the fact that it is labeled with %a, The drug contains the isotope 68Ga and ach elating agent in quantities much less than those required to produce any measurable chemical effect in the body. Patients should feel no effect from the drug. However, untoward effects are remotely possible with any new drug. The radiation dose will b e no more than 0.8 rad to the whole body, and probably (approximately twice the yearly approved occupational dose.) in a diagnostic test such as this ,hzs some possibility of contributing to an increased incidence of cancer o r …