Clinical Study Plan. Mapping of brain tau deposition in tauopathy by PET with [ 11 C]PBB3

Transcription

1 Clinical Study Plan Mapping of brain tau deposition in tauopathy by PET with [ 11 C]PBB3 Name of study organization Molecular Imaging Center National Institute of Radiological Sciences Principal investigator Name: Hitoshi Shimada Address: 4-9-1, Anagawa, Inage-ku, Chiba-shi, Chiba , Japan Phone: FAX: Address: shimada@nirs.go.jp Prepared on: July 2, 2014 (English-Version 1) Prepared on: Aug 25, 2014 (English-Version 1.1) Prepared on: Sep 3, 2014 (English-Version 1.2) Prepared on: Nov 5, 2014 (English-Version 2) Approved on: Sep 8, 2014 (English-Version 1.1) Approved on: Oct 21, 2014 (English-Version 1.2) Approved on: Dec, 16, 2014 (English-Version 2)

2 1 OUTLINE OF THE STUDY... 3 PATIENTS WITH FAMILIAL PARKINSON S DISEASE (FPD 6 ), 20 YEARS OF AGE OR OLDER AT THE TIME OF OBTAINING CONSENT BACKGROUND STUDY DESIGN OBJECTIVES AND EVALUATION INDICATORS (ENDPOINTS) STUDY OBJECTIVES EVALUATION INDICATORS (ENDPOINTS) SELECTION OF STUDY SUBJECTS SUBJECT ENTRY METHOD Recruitment of healthy volunteers Patients with MCI, AD, CBD, PSP, FTD, fpd Muro disease or patients who declare the assignment of post-mortem autopsy INCLUSION AND EXCLUSION CRITERIA OF THE SUBJECTS Healthy volunteers Patients with MCI, AD, CBD, PSP, FTD, fpd or Muro disease Patients who declare the assignment of post-mortem autopsy, 20 years of age or older at the time of obtaining consent INFORMED CONSENT EXPLANATION TO THE SUBJECTS CONSENT OBTAINMENT ENROLLMENT TARGET SAMPLE SIZE AND STUDY PERIOD TARGET SAMPLE SIZE STUDY PERIOD STUDY METHOD EXAMINATION ITEMS PET examinations Head MRI examinations (or head CT examinations) Psychological examinations Neurological examinations EXAMINATION SCHEDULE DATA ANALYSIS

3 10 EXPECTED CLINICAL BENEFITS AND RISKS OR INCONVENIENCE EXPECTED CLINICAL BENEFITS EXPECTED RISKS OR INCONVENIENCE WAY OF DEALING WITH INCIDENTAL FINDINGS RESPONSES TO ADVERSE EVENTS RESPONSE TO SUBJECTS REPORT OF SERIOUS ADVERSE EVENTS OR DEFECTS PROTOCOL DEVIATIONS CHANGES TO THE PROTOCOL REPORT OF THE IMPLEMENTATION STATUS OF THE STUDY COMPLETION, DISCONTINUATION OR SUSPENSION OF THE STUDY COMPLETION OF THE STUDY DISCONTINUATION OR SUSPENSION OF THE STUDY ETHICAL MATTERS MEASURES FOR THE PROTECTION OF PERSONAL INFORMATION OF THE SUBJECTS COMPENSATION/LIABILITY FOR HEALTH DAMAGE TO THE SUBJECTS AND INSURANCE PURCHASING COMPENSATION FOR HEALTH DAMAGE INSURANCE PURCHASING MAINTENANCE OF RECORDS STORAGE OF SAMPLES REGISTRATION OF THE STUDY PLAN AND PUBLICATION OF THE STUDY RESULTS STUDY SYSTEM SOURCE OF FUNDING FOR THIS STUDY AND POSSIBLE CONFLICTS OF INTEREST LITERATURE LIST

4 1 OUTLINE OF THE STUDY Title of the study Study of a radioactive drug [ 11 C]PBB3 for brain imaging of tau in degenerative dementia Objectives The objective of this study is to analyze the correlation between various types of dementia and distribution / degree of brain tau deposition evaluated by using a radioactive drug [ 11 C]PBB3 for brain tau imaging. Design An interventional clinical study, and also a multi-group comparison, nonrandomized, and healthy volunteer controlled exploratory study. Study subjects Healthy volunteers 20 years of age or older at the time of obtaining consent Patients with mild cognitive impairment (MCI 1 ), 20 years of age or older at the time of obtaining consent Patients with Alzheimer s disease (AD 2 ), 20 years of age or older at the time of obtaining consent Patients with corticobasal degeneration (CBD 3 ), 20 years of age or older at the time of obtaining consent Patients with progressive supranuclear palsy (PSP 4 ), 20 years of age or older at the time of obtaining consent Patients with frontotemporal dementia (FTD 5 ), 20 years of age or older at the time of obtaining consent Patients with familial Parkinson s disease (fpd 6 ), 20 years of age or older at the time of obtaining consent Patients with Muro disease, 20 years of age or older at the time of obtaining consent Patients who declare the assignment of post-mortem autopsy, 20 years of age or older at the time of obtaining consent Target sample size Healthy volunteers: 40 Patients with mild cognitive impairment (MCI): 35 Patients with Alzheimer s disease (AD): 20 Patients with corticobasal degeneration (CBD): 20 Patients with progressive supranuclear palsy (PSP): 20 Patients with frontotemporal dementia (FTD): 20 Patients with familial Parkinson s disease (fpd): 6 Patients with Muro disease: 6 Patients who declare the assignment of post-mortem autopsy: 10 The number of subjects who have completed the [ 11 C]PBB3 & [ 11 C]PIB PET & MRI examinations for every group Study method 1)Examination items The PET examinations with [ 11 C]PBB3, [ 11 C]PIB and [ 18 F]FDG will be 3

5 Evaluation indicators performed on the study subjects at the National Institute of Radiological Sciences (NIRS). As well, in order to obtain morphological and functional images of the brain, MRI examinations will be performed, and T1- and T2-weighted images, diffusion-weighted images and functional MRI at rest will be obtained. In patients who cannot undergo MRI, plain head CT scans will be obtained. Psychological and neurological examinations will also be performed. 2)Data analysis From the time activity curve (TAC) of [ 11 C]PBB3 obtained from the PET examinations, the degree and distribution of brain tau deposition will be quantitatively assessed based on model analysis using the reference site. In addition, from the TAC of [ 11 C]PIB, the degree and distribution of brain amyloid deposition will also be quantitatively assessed based on model analysis using the reference site. The PET examination data with [ 18 F]FDG will be used to evaluate the sites of decreased gulcose metabolism. By comparing each set of PET data, the accumulation property and selectivity of [ 11 C]PBB3 for brain tau deposition and brain amyloid deposition and the correlations with nerve disorders will be evaluated. In data analysis, the data of 5 subjects (2 healthy volunteers and 3 patients with AD) obtained from a. Proper evaluation of the previous study already completed, entitled Evaluation of binding property to tau protein, systemic pharmacokinetics and effective dose of [ 11 C]PBB3, and the data of the subjects from whom consent to store their data for other studies to be planned in the future (other than the previous studies) had been obtained during the study entitled Quantification of tau deposition using positron emission tomography with [ 11 C]PBB (target sample size: 10 healthy volunteers and 10 patients with AD) will also be analyzed simultaneously including individual data (images and psychological examination data, etc.). Primary endpoint Distribution volume and binding potential in the brain measured by positron emission tomography with [ 11 C]PBB3 Secondary endpoints Difference in spatial distributions of [ 11 C]PBB3 and [ 11 C]PIB Correlations between tau deposition by PET with [ 11 C]PBB3 and 4

6 nerve disorders evaluated by PET with [ 18 F]FDG Study period February 1, 2013 January 31, 2016 Institution and Institution collaborating study NIRS (Recruitment and selection of healthy volunteers, confirmation of institutions the eligibility of patients/subjects referred by collaborating study institutions, PET, MRI (or CT), psychological and neurological examinations) Collaborating study institutions Department of Neurology, Chiba University Hospital; Chiba East Hospital; Hakuyo-kai Kashiwado Hospital; Neurology Chiba Clinic; Japanese Red Cross Narita Hospital; Tokyo Dental College Ichikawa General Hospital; Shirogane Orthopedic Hospital; Department of Neurology, Juntendo University Hospital; Department of Neurology, Toho University Medical Center Sakura Hospital; Department of Neuropsychiatry, Keio University Hospital; Asai Hospital; Department of Neurology, Tokyo Metropolitan Geriatric Hospital; Mayo Clinic; Brain Research Institute, Niigata University; Department of Neuropsychiatry, Nippon Medical School Hospital; Department of Mental Health, Nippon Medical School Chiba Hokusoh Hospital; Shinkemigawa Mental Clinic; Soubu Hospital; Kashiwa Ekimae Nakayama Mental Clinic; Komagino Hospital; Japanese Red Cross Ashikaga Hospital; Edogawa Hospital; Vihara Hananosato Hospital; Asahi Neurology and Rehabilitation Hospital; Kyoto Prefectural University of Medicine Graduate School of Medical Science; Department of Neurology, Tokyo Dental College Ichikawa General Hospital; National Hospital Organization Shimofusa Psychiatric Medical Center; Department of Neurology, Kitasato University Hospital; Higashi Nagoya National Hospital; Mie University; Department of Neurology, Minamiise Municipal Hospital; and Department of Geriatric Medicine, Tokyo Medical University hospital (Referral of patients/subjects and clinical evaluation) The NIRS coordinates sufficiently in the study system with the medical institutions above which refer patients/subjects. 1 MCI:Mild Cognitive Impairment 2 AD:Alzheimer's Disease 3 CBD:Corticobasal degeneration 4 PSP:Progressive Supranuclear Palsy 5 FTD:Frontotemporal Dementia 6 fpd:familial Parkinson's Disease 5

7 2 BACKGROUND Major pathological changes in AD are β-amyloid deposition and tau deposition (neurofibrillary tangles) widely observed in the cerebral cortex. Quantification of β-amyloid accumulation in vivo has already been established using radioactive drugs which bind specifically to β-amyloid and positron emission tomography (PET examinations), and the elucidation of the pathology underlying AD using this method has been pursued both here in Japan and abroad. As a radioactive drug for measuring β-amyloid, [ 11 C] Pittsburg Compound-B (PIB) 1-3) developed by Klunk et al. at the University of Pittsburgh is widely used in Japan and other countries, and our study group has also recently promoted the application of new radioactive drugs for imaging brain β- amyloid, other than [ 11 C]PIB, [ 18 F]FACT and [ 11 C]AZD2184, in a clinical setting. From the investigations conducted to date, it has become clear that brain β-amyloid deposition in AD had already reached a plateau before the onset or at a very early stage, and this observation has significance as a requirement for AD development or a marker predicting its onset, but it is not a good marker for the progression of this disease (nerve disorder) 4) (Fig. 1). Fig. 1. Progression of biomarkers of AD (modified from the figure by Jack et al.) Meanwhile, besides β-amyloid, tau deposition is also a characteristic pathological change in AD. Tau deposition is considered to be closely involved in the nerve damage occurring in degenerative neurological disorders other than AD, including FTD 5), which is the next most common after AD as a cause of juvenileonset degenerative dementia, PSP and CBD, which are associated with movement disorder and has a poor functional prognosis (wheelchair use is required within a few years and patients become bedridden in 4-5 years), familial Parkinson s disease and Muro disease which shows atypical parkinsonism with dementia frequently observed in the Kii peninsula of Japan and Guam of the United States, in particular. In FTD and PSP, only tau deposition is observed without β-amyloid deposition, which is observed in AD. For the imaging 6

8 of tau deposition, there have been no radioactive drugs with superior specific or non-specific binding property to tau protein, such that quantification of tau deposition in vivo has not yet been established. However, the preclinical and clinical evaluations already completed ( Evaluation of binding property to tau protein, systemic pharmacokinetics and effective dose of [ 11 C]PBB3 (Protocol No ) ) confirmed that tau deposition in the brains of patients with AD can be specifically visualized by PET examinations using 2- [4-(6-[ 11 C]methylaminopyridinyl)-1,3-butadienyl]-benzothiazol-6-ol (also known as: pyridinyl-butadienylbenzothiazole 3; [ 11 C]PBB3), which was developed in our institution. In addition, in the ongoing study entitled Quantification of tau deposition using positron emission tomography with [ 11 C]PBB3 (Protocol No ), we have come close to developing a method of quantification. We have also obtained knowledge allowing brain tau deposition to be characterized using evaluation based on calculation of binding potential by a simple quantification procedure using the reference site in the brain with no need for arterial blood collection. Fig. 2 Correlations between the degree of cognitive impairment and [ 11 C]PBB3 accumulation pattern (SUVR images) [ 11 C]PBB3 accumulation is essentially limited to the mesial temporal lobe in patients with MCI. It has been observed that the more severe cognitive impairment becomes, the wider the distribution of areas showing accumulation becomes, with even the neocortex showing involvement. This accumulation pattern closely resembles the mode of tau deposition progression supported by pathological studies (right figure: partial excerpts from the figure by Braak H, et al. 7) ), which differs from the amyloid deposition evaluated with [ 11 C]PIB. PET examinations using this drug are performed only rarely, worldwide, employing PET with a visually 7

9 assessable imaging drug for tau deposition. Such examinations are anticipated to be very useful for diagnosing AD and tauopathy, and to potentially be essential for the assessment of treatment effects of novel drugs targeting tau deposition which pharmaceutical companies are now developing. However, the correlations between the distribution/degree of tau deposition as assessed by PET and various degenerative neurological disorders have not yet been fully considered. In this study, in healthy volunteers, patients with MCI, patients with AD, patients with CBD, patients with PSP, patients with FTD, patients with fpd and patients with Muro disease and patients who declare the assignment of post-mortem autopsy, PET examinations using [ 11 C]PBB3 will be performed, and by comparing the results with those of PET examinations using [ 11 C]PIB and [ 18 F]FDG, the degree of specific binding to tau protein, the degree of nonspecific binding in brain tissues and correlations with nerve disorders will be determined quantitatively. Based on the above, the correlations between the distribution/degree of tau deposition assessed by PET with [ 11 C]PBB3 and brain pathology will be clarified. If the correlations between the distribution/degree of tau deposition as evaluated by PET with [ 11 C]PBB3 and brain pathology can be clarified in this study, the findings will contribute to the establishment of an objective and safer early diagnostic method, a differential diagnostic method, and a method for pathologically evaluating dementia. Furthermore, the development of a specific evaluation method for future treatments targeting tau is also highly anticipated. 3 STUDY DESIGN This is an interventional study with an exploratory multi-group comparison, non-randomized component involving healthy volunteers. 4 OBJECTIVES AND EVALUATION INDICATORS (ENDPOINTS) 4-1STUDY OBJECTIVES The objective of this study is to analyze the correlation between various types of dementia and distribution / degree of brain tau deposition evaluated by using a radioactive drug [ 11 C]PBB3 for brain tau imaging. 4-2 EVALUATION INDICATORS (ENDPOINTS) Primary endpoint Distribution volume and binding potential measured by PET with [ 11 C]PBB3 Secondary endpoints Difference in spatial distributions of [ 11 C]PBB3 and [ 11 C]PIB Correlations between tau deposition by PET with [ 11 C]PBB3 and nerve disorders evaluated by PET with [ 18 F]FDG 5 SELECTION OF STUDY SUBJECTS 5-1 SUBJECT ENTRY METHOD Recruitment of healthy volunteers Doctors with responsibilities in this study at the NIRS will recruit healthy volunteers who may become the study subjects, as follows: 8

10 Recruitment by the investigators or through the acquaintances of study collaborators. However, the staff members at the NIRS will not be recruited in order to not unduly affect the subjects. Recruitment through the recruitment system of clinical study volunteers managed by the Molecular Imaging Center at the NIRS Patients with MCI, AD, CBD, PSP, FTD, fpd Muro disease or patients who declare the assignment of post-mortem autopsy Doctors in charge in the collaborating study institutions: Department of Neurology, Chiba University Hospital; Chiba East Hospital; Hakuyo-kai Kashiwado Hospital; Neurology Chiba Clinic; Japanese Red Cross Narita Hospital; Tokyo Dental College Ichikawa General Hospital; Shirogane Orthopedic Hospital; Department of Neurology, Juntendo University Hospital; Department of Neurology, Toho University Medical Center Sakura Hospital; Department of Neuropsychiatry, Keio University Hospital; Asai Hospital; Department of Neurology, Tokyo Metropolitan Geriatric Hospital; Mayo Clinic; Brain Research Institute, Niigata University; Department of Neuropsychiatry, Nippon Medical School Hospital; Department of Mental Health 4, Nippon Medical School Chiba Hokusoh Hospital; Shinkemigawa Mental Clinic; Soubu Hospital; Kashiwa Ekimae Nakayama Mental Clinic; Komagino Hospital; Japanese Red Cross Ashikaga Hospital; Edogawa Hospital; Vihara Hananosato Hospital; Asahi Neurology and Rehabilitation Hospital; Kyoto Prefectural University of Medicine Graduate School of Medical Science; Department of Neurology, Tokyo Dental College Ichikawa General Hospital; National Hospital Organization Shimofusa Psychiatric Medical Center; Department of Neurology, Kitasato University Hospital; Higashi Nagoya National Hospital; Mie University; Department of Neurology, Minamiise Municipal Hospital; and Department of Geriatric Medicine, Tokyo Medical University hospital will refer each patient with the potential to become a study subject to the NIRS. 5-2 INCLUSION AND EXCLUSION CRITERIA OF THE SUBJECTS Healthy volunteers Doctors with responsibilities in this study at the NIRS will select healthy volunteers who may become the study subjects according to the following inclusion criteria: Inclusion criteria (1) Healthy volunteers 20 years of age or older at the time of obtaining consent. However, regarding age, subjects will be selected to match the ages of the patient groups to the maximum extent possible. At the same time, subjects with a wide range of ages will be selected to assure that the features of tau deposition in healthy subjects can be evaluated by age. For the judgment of whether or not subject cognitive function can be deemed normal, see Attachment 1 <Inclusion criteria>. (2) In order to reduce gender bias, subjects will be selected to match the male-to-female ratios of the patient groups to the maximum extent possible. (3) Healthy subjects who have the ability to consent to participate in this study, to read and understand the informed consent form. Exclusion criteria 9

11 (1) Subjects with organic brain complications/disorders (including a history of symptomatic cerebral infarction, Parkinson s disease and similar conditions). (2) Patients with substance-related disorders (including drug abuse). For the acceptable range of allowable drugs, see Attachment 1 <Inclusion criteria>. (3) Subjects with severe physical complications/disorders or a history of such conditions and who are considered to be inappropriate for participation by the aforementioned doctors with responsibilities in this study. (4) Subjects with a pacemaker or other metallic medical device in the body (brain clip, bolts, etc.). (5) Subjects with tattoos. Subjects with claustrophobia. (6) Pregnant, possibly pregnant or lactating women. (7) From the standpoint of radiation exposure from a nuclear medicine scan, subjects who have participated in other nuclear medicine scans as healthy volunteers in the 6 months prior to the start of this study. (8) Subjects who are considered to be inappropriate for participation by doctors with responsibilities in this study Patients with MCI, AD, CBD, PSP, FTD, fpd or Muro disease Doctors with responsibilities in this study at the NIRS will confirm the following inclusion and exclusion criteria for patients/subjects referred to us for this study based on the judgments made in collaborating study institutions (using Attachment 2 <Patient referral checklist>) and the examinations conducted on the day of study participation. Attachment 2 <Patient referral checklist> will be entered by doctors in charge in the collaborating study institutions, sent to doctors with responsibilities in this study at the NIRS, and maintained at the NIRS. Inclusion criteria (1) Patients 20 years of age or older at the time of obtaining consent. (2) Patients with MCI and patients with AD: Patients meeting the inclusion criteria in the J-ADNI core study entitled Comprehensive Research on Aging and Health, The Ministry of Health Labour and Welfare, ( ) except for age. However, the range of CDR (Clinical dementia rating) in patients with AD will be 0.5-2, and the range of MMSE (Mini Mental State Examination) will be 26 points or less, and the acceptable range of drugs that can be used will be partially changed. (See Attachment 2 <Inclusion criteria>.) And/or patients diagnosed with familial AD based on genetic testing (including presymptomatic carriers). Patients with CBD: Patients meeting the diagnostic criteria of the Mayo Clinic (Boeve BF, 2003) 6) and/or the modified version of the Cambridge diagnostic criteria (Mathew R, 2011) 7). * As the diagnostic criteria in clinical studies, those of the Mayo Clinic have been widely used, but since the Cambridge criteria reportedly show higher sensitivity for early cases 7), both diagnostic criteria are to be used. Patients with PSP: Patients meeting the NINDS-SPSP diagnostic criteria (Litvan I, 1996) 8). 10

12 Patients with FTD: Patients meeting the diagnostic criteria of Neary et al. (Neary D, 1998) 9), and/or patients diagnosed with FTD and parkinsonism linked to chromosome 17; FTDP-17 (MAPT) based on genetic testing (including presymptomatic carriers). Patients with fpd: Patients diagnosed based on genetic testing (including presymptomatic carriers). Patients with Muro disease: Patients diagnosed as possible, probable or definite Muro disease based the clinical diagnostic criteria of the Japanese Society of Neurology. (3) Patients who can be accompanied by a legal guardian (see 6-2 for the definition of a legal guardian) on the day of study participation at the NIRS. (4) Patients who can understand the outline of this study at the time consent is obtained. Two or more doctors in the collaborating study institutions and the NIRS will judge whether or not the patient can understand the study outline. Exclusion criteria (1) Patients with other organic brain complications/disorders (including a history of symptomatic cerebral infarction, Parkinson s disease and similar conditions). (2) Patients with substance-related disorders (including drug abuse). For the acceptable range of allowable drugs, see Attachment 1 <Inclusion criteria>. (3) Patients with severe physical complications/disorders or a history of such conditions and who are considered to be inappropriate for participation by doctors with responsibilities in this study. (4) Patients with claustrophobia. (5) Pregnant, possibly pregnant or lactating women. (6) Patients who are considered to be inappropriate for participation by doctors with responsibilities in this study. * The age limit for the subjects has been set based on an arbitrary judgment arising from the frequent onset age and the age composition of patients in the collaborating study institutions Patients who declare the assignment of post-mortem autopsy, 20 years of age or older at the time of obtaining consent Doctors with responsibilities in this study at the NIRS will confirm the following inclusion and exclusion criteria for patients/subjects referred to us for this study based on the judgments made in collaborating study institutions (using Attachment 2 <Patient referral checklist>) and the examinations conducted on the day of study participation. Attachment 2 <Patient referral checklist> will be entered by doctors in charge in the collaborating study institutions, sent to doctors with responsibilities in this study at the NIRS, and maintained at the NIRS. Inclusion criteria (1) Patients 20 years of age or older at the time of obtaining consent. Primary illness is not restricted. (2) Patients who declare the assignment of post-mortem autopsy. (3) Patients who can be accompanied by a legal guardian (see 6-2 for the definition of a legal guardian) on the day of study participation at the NIRS. 11

13 (4) Patients who can understand the outline of this study at the time consent is obtained. Two or more doctors in the collaborating study institutions and the NIRS will judge whether or not the patient can understand the study outline. Exclusion criteria (1) Patients with claustrophobia. (2) Pregnant, possibly pregnant or lactating women. (3) Patients who are considered to be inappropriate for participation by doctors with responsibilities in this study. 6 INFORMED CONSENT 6-1 EXPLANATION TO THE SUBJECTS Doctors with responsibilities in this study at the NIRS will fully explain the following contents to the subjects using the informed consent form at the start of the study. This study will be performed for research purposes The significance, objectives, method and period of the study The reason for being selected as a subject Scheduled period for the subject to participate in the study The number of subjects who will participate in the study How incidental findings will be dealt with Expected clinical benefits and risks as well as any physical and/or mental discomfort entailed (If no benefits are expected, the subject must be informed of this.) Compensation and treatment for study-related health damage to the subject Participation in the study is voluntary, and the subject can refuse participation or withdraw from the study at any time. The subject will not be unfavorably treated due to refusal/withdrawal, nor will the benefits from the treatment be lost in the event that he/she does not participate in the study. The subject will be promptly informed of any information which may affect his/her willingness to continue participating in the study. Conditions or reasons for discontinuing participation in the study The members of the Ethics Review Board can access the study records. The privacy of the subject will be protected in this event. If the subject signs or signs and seals the consent form, he/she is considered to have given permission for the records to be accessed. At the request of the subject, he/she can obtain or access the protocol and the data on the study method provided that no issues arise regarding protection of the personal information of other subjects or the originality of the study. There is a possibility that a patent may be granted based on the study results. In such an event, the patent belongs solely to the patent holder, i.e. the developer of the material or device to be patented, not to the study subject. 12

14 Even when the study results are published, the privacy of the subject will be protected. Source of funding for the study, possible conflicts of interest and the relationships of the investigators with the organizations involved Storage, usage and storage period of the samples The contents in the event of money being paid to the subject Names and affiliations of the investigators, etc. Contact information for inquiry on the study and complaints 6-2 CONSENT OBTAINMENT After confirming that the subject has understood the contents of the study, voluntary consent from the subject him/herself to participate in the study will be obtained in writing. The signature or signature and seal of the subject him/herself, and the signature or signature and seal of a legal guardian written by the guardian him/herself in the case of a patient, is required on the consent form. The legal guardian is a legal representative of the subject including a guardian, a relative within the third degree of relationship or other equivalent person, who can act in the best interest of the subject. The original of the consent form will be retained in the Research Ethics Planning Support Section of the Planning Department under the direction of the principal investigator, and a copy will be handed to the subject him/herself or the legal guardian. 7 ENROLLMENT Those individuals meeting the conditions of the study and from whom a signed written consent form has been obtained will be enrolled as subjects of this study. The enrollment will be completed when the number of subjects who have completed the [ 11 C]PBB3 & [ 11 C]PIB PET&MRI examinations has reached the target sample size. 8 TARGET SAMPLE SIZE AND STUDY PERIOD 8-1 TARGET SAMPLE SIZE Healthy volunteers: 40 Patients with MCI: 35 Patients with AD: 20 Patients with CBD: 20 Patients with PSP: 20 Patients with FTD: 20 Patients with fpd: 6 Patients with Muro disease: 6 Patients who declare the assignment of post-mortem autopsy: 10 * For each group, the target sample size will be the number of subjects who have completed the [ 11 C]PBB3 & [ 11 C]PIB PET&MRI examinations. * In data analysis for this study, the data of 5 subjects (2 healthy volunteers and 3 patients with AD) obtained from a. Proper evaluation of the previous study, already completed and entitled 13

15 Evaluation of binding property to tau protein, systemic pharmacokinetics and effective dose of [ 11 C]PBB3 (Protocol No ), and the data of the subjects from whom consent to store the data for other studies to be planned in the future (other than the previous studies) had been obtained for the study entitled Quantification of tau deposition using positron emission tomography with [ 11 C]PBB3 (Protocol No ) (target sample size: 10 healthy volunteers and 10 patients with Alzheimer s disease) will also be analyzed simultaneously including individual data (images and psychological examination data, etc.). * On the premise that the data from the previous study will also be analyzed, the above target sample size has been planned as the number required for obtaining meaningful statistical results * Considering that it is necessary to test in a wide range of ages according to each disease group with different frequent onset ages in healthy volunteers, and that the possibility of differences in brain pathologies between early-onset and late-onset patients has been reported for AD, the total sample sizes (with the sizes in the previous study) for both groups have been set at higher target numbers. * Regarding each target disease other than AD, considering that it is a rare disease and that it may be difficult to obtain referrals for enough patients meeting the inclusion criteria, the target sample size has been set as above in this study with reference to the sample sizes in the pathological studies conducted in the past. 8-2STUDY PERIOD February 1, January 31, 2016 * Regarding the study period, since it is expected that the enrollment of the number of subjects meeting the target sample sizes may be achieved within 3 years based on research performance in the past, the period above has been set. 9 STUDY METHOD 9-1 EXAMINATION ITEMS In this study, in both healthy volunteers, patients diagnosed with MCI, AD, CBD, PSP, FTD, fpd or Muro disease, and patients who declare the assignment of post-mortem autopsy in the collaborating study institutions, and from whom consent to participate in the study has been obtained, PET, MRI (or CT), psychological and neurological examinations, as described below, will be performed. Prior to the PET examinations, in women with childbearing potential, it will be confirmed by an interview with a doctor that there is no possibility of pregnancy. If this possibility cannot be ruled out, the PET examinations will be cancelled or postponed PET examinations Examination method The PET device installed at the NIRS will be used. The PET examinations will be performed in two days, and examinations using 3 types of radioactive drugs will be performed within a period of essentially 2 months. On the first day, PET examinations using [ 18 F]FDG will be performed to evaluate gulcose metabolism in the brain. On the second day, PET examinations using [ 11 C]PBB3, a tau protein 14

16 imaging radioactive drug, and [ 11 C]PIB, a β-amyloid imaging radioactive drug, will be performed. For the examinations on the first day, the [ 18 F]FDG PET imaging will be performed, and the subjects will be instructed to fast for at least 4 hours prior to the [ 18 F]FDG PET imaging. However, they will be allowed to drink water not containing gulcose, and blood glucose levels will be measured with a simple self-blood glucose meter prior to the [ 18 F]FDG PET imaging. Approximately 5 mci (185 MBq) [ 18 F]FDG will be administered intravenously. [ 18 F]FDG will be administered with the subject at rest in an armchair or on a bed in an articulated and light-modulated room, and the subject will then be made to maintain the resting state until a few minutes before the PET imaging. The brain site will be imaged for 30 minutes, starting 30 minutes after administration and the transmission scan will then be performed for about 10 minutes. For the PET examinations on the second day, the [ 11 C]PIB PET imaging is to be performed after the [ 11 C]PBB3 PET imaging. For the [ 11 C]PBB3 PET examinations, after the transmission scan which will last about 10 minutes, approximately 15 mci (555 MBq) [ 11 C]PBB3 will be administered intravenously, and the dynamic imaging of the brain site will be performed for a total of 70 minutes at the same time as the start of administration (time required including preparation: about 85 minutes). After an interval of at least 30 minutes, the transmission scan lasting about 10 minutes will be performed, then approximately 15 mci (555 MBq) [ 11 C]PIB will be administered intravenously, and the dynamic imaging of the brain site will be performed for a total of 70 minutes at the same time as the start of administration (time required including preparation: about 85 minutes). However, if prolonged PET imaging is considered to be difficult due to the subject s condition, changing the [ 11 C]PBB3 PET and [ 11 C]PIB PET imaging to a method in which the dynamic imaging of the brain site will be performed for minutes, starting minutes after administration of the drug, with the transmission scan then being performed for about 10 minutes, may be considered as an alternative examination protocol. If PET-CT is used instead of PET, low-dose CT will be performed for about 5 minutes as transmission scan. When the head movement which could seriously affect PET data is observed, transmission scan could be also performed after PET scan; however, transmission scan will be performed six times in the same participant at most. Dosages of the drugs [ 11 C]PBB3: Approximately 15 mci (555 MBq) [Weight (kg)/5] + 1 (mci) (If the subject s weight is 50 kg or less, the dosage will be 10 mci, uniformly) [ 11 C]PIB: Approximately 15 mci (555 MBq) [ 18 F]FDG: Approximately 5 mci (185 MBq) Head MRI examinations (or head CT examinations) At the NIRS, on the same day as the PET examinations or within 2 months, head MRI examinations will be performed to obtain morphological images and functional information on the brain, and T1- and T2- weighted images, diffusion-weighted images and functional MRI at rest will be obtained (time required: about 30 minutes). In order to make the functional assessment multisided, a tensor analysis using 15

17 diffusion-weighted images and assessment of the default mode network by functional MRI at rest (* brain activity at rest involved in memory, etc. and damage caused by AD, etc.) will be performed. In patients/subjects with a pacemaker or metallic medical device in the body (brain clip, bolts, etc.) or tattoos who cannot undergo MRI, plain head CT examinations will be performed instead of head MRI examinations Psychological examinations In order to investigate correlations with the imaging findings, psychological examinations (about 100 minutes) will be performed at the NIRS within 2 months before or after the PET examinations. The following tests will be performed for the psychological examinations. Mini-Mental State Examination (MMSE) WMS-R (logical memory-Ⅰ/-Ⅱ) Frontal Assessment Battery (FAB) Frontal Systems Behavior Scale (FrSBe) Apathy Evaluation Scale (AES) Geriatric Depression Scale (GDS) Digit Span (forward/backward citation) Verbal Fluency Test (category and letter) Raven's Coloured Progressive Matrices (RCPM) Clinical Dementia Rating (CDR) However, if psychological examinations were performed within approximately 2 months of the PET examinations in the institution referring the subject, or if the examinations are judged to be difficult due to the subject s condition, the psychological examinations can be omitted, as appropriate, and a cognitive bias task will be added as needed Neurological examinations Neurological examinations will be performed by a neurologist to check for the presence or absence of clinical symptoms. 9-2 EXAMINATION SCHEDULE The examinations specified in 9-1 will be performed according to the schedule below. However, the order or the dates of examinations may be interchanged depending on the circumstances encountered. Example of the examination schedule: time required / about 10 hours in total over a period of 2 days <The first day: about 6 hours> Visiting the institution Interview/neurological examinations Psychological examinations 16

18 (about 100 minutes) Break (about 60 minutes) MRI examinations or CT examinations (about 30 minutes) Break (about 30 minutes) Administration of [ 18 F]FDG/waiting at rest (about 30 minutes) PET examinations ([ 18 F]FDG: about 40 minutes) <The second day: about 4 hours> Visiting the institution Interview PET examinations ([ 11 C]PBB3: about 85 minutes) Break (about 30 minutes) PET examinations ([ 11 C]PIB: about 85 minutes) 9-3 DATA ANALYSIS From the time activity curves (TACs) of [ 11 C]PBB3 and [ 11 C]PIB obtained from the PET examinations, the distribution and binding potential of [ 11 C]PBB3 and brain β-amyloid deposition will be quantified based on model analysis using the reference site. In addition, employing the data obtained from the [ 18 F]FDG PET examinations, gulcose metabolism in the brain will be evaluated using the ratio of the value standardized with the dosage per unit weight with that of the reference site. By comparing each set of PET data, the distribution/degree of brain tau deposition evaluated with [ 11 C]PBB3 and the correlations with various brain pathologies will be evaluated. Regarding the PET data results, correlations with the functional/morphological images obtained by MRI (or CT images), [ 11 C]PIB and [ 18 F]FDG PET images, the psychological examinations and clinical symptoms will also be considered. In data analysis, the data from 5 subjects (2 healthy volunteers and 3 patients with AD) obtained from a. Proper evaluation of the previous study, already completed and entitled Evaluation of binding property to tau protein, systemic pharmacokinetics and effective dose of [ 11 C]PBB3 (Protocol No ), and the data of the subjects from whom consent to store the data for other studies to be planned in the future (other than the previous studies) had been obtained during the study entitled Quantification of tau deposition using positron emission tomography with [ 11 C]PBB3 (Protocol No ) (target sample size: 10 healthy volunteers and 10 patients with AD) will also be analyzed simultaneously including individual data (images and psychological examination data, etc.). ( The information will be posted on the website of the NIRS. Attachment 3) 10 EXPECTED CLINICAL BENEFITS AND RISKS OR INCONVENIENCE 10-1 EXPECTED CLINICAL BENEFITS There will be no direct benefits to the subjects, but if correlations between the distribution/degree of tau deposition evaluated by [ 11 C]PBB3 PET and brain pathology are clarified, more detailed pathological studies focusing on various dementias will become possible, which may contribute to the establishment of an objective and safer early diagnostic method, differential diagnostic methods, and methods of pathologically evaluating dementia, as well as the development of new treatment strategies EXPECTED RISKS OR INCONVENIENCE The contents below will be specified in the informed consent form. Regarding the exposure dose from examinations, the effective dose by intravenous administration of 555 MBq [ 11 C]PBB3 is approximately msv (the effective dose calculated by extrapolating from animal 17

19 models to humans is msv/mbq, and that in one healthy male volunteer is approximately msv/mbq), and similarly the effective dose by intravenous administration of 555 MBq [ 11 C]PIB is approximately 2.9 msv (the effective dose by the whole-body dynamic PET measurement in humans is msv/mbq 10) ), and the effective dose by intravenous administration of 185 MBq [ 18 F]FDG is approximately 3.5 msv. The total exposure dose from all examinations (one intravenous administration each of [ 11 C]PBB3, [ 11 C]PIB and [ 18 F]FDG) will be approximately msv, which is equivalent to that from trunk CT scan. ( However, if plain head CT examinations are performed instead of MRI examinations, estimated exposure dose from plain head CT examination is less than 4 msv. Moreover, if PET-CT is used instead of PET, estimated exposure dose in transmission scan with low-dose CT in one session will be about 0.5 msv. Since transmission scan will be performed three to six times at most, if PET-CT is used instead of PET and CT is used instead of MRI, the total exposure dose in 3 PET/CT sessions will be about 13.7 to 17.5 msv, which will also be equivalent to that from trunk CT scan.) [ 11 C]PBB3 and [ 11 C]PIB will be prepared and used according to the standard procedures at the NIRS under the responsibility of the principle investigator or doctors with responsibilities in this study, and will thus be different from those manufactured by pharmaceutical companies. Regarding [ 18 F]FDG, the drug manufactured by pharmaceutical companies and which has passed the quality inspection, or the drug prepared according to the standard procedures at the NIRS under the responsibility of the principle investigator or doctors with responsibilities in this study will be used. At the NIRS, a quality inspection is performed every time the drugs are synthesized and only those drugs which have passed the quality inspection will be used. The PET examinations using [ 11 C]PBB3 are performed only at the NIRS, and in preclinical studies performed prior to clinical studies, no toxicity has been observed. In the previous studies as well, entitled Evaluation of binding property to tau protein, systemic pharmacokinetics and effective dose of [ 11 C]PBB3 (Protocol No ) (performed in a total of 6 cases) and Quantification of tau deposition using positron emission tomography with [ 11 C]PBB3 (Protocol No ) (performed in 9 cases as of June 2, 2014), no adverse events have been observed. In addition, in this study performed according to the approved protocol (Version 6) ( Mapping of brain tau deposition in tauopathy by PET with [ 11 C]PBB3 (Protocol No.: ) (performed in 89 cases as of June 2, 2014)), no adverse events have been observed. Also, PET examinations using [ 11 C]PIB have been performed in at least 200 cases since 2005 at the NIRS, and have been used for examinations of 3,000 patients in at least 40 institutions worldwide (as of June 2, 2014), and no adverse events due to this PET drug have occurred. Numerous PET examinations using [ 18 F]FDG have been performed throughout the world, and no serious adverse reactions have been reported (as of 2014). In clinical studies in Japan, adverse reactions (including abnormal laboratory values) were observed in 13 out of 287 patients (4.5%). Major adverse reactions included one case who described feeling bad (0.3%), one with fever (0.3%), one with vomiting (0.3%) and one with decreased blood pressure (0.3%). Since fetuses and lactating infants are more sensitive to radiation than adults and exposure should 18

20 thus be avoided, pregnant or lactating women cannot participate in this study. 11 WAY OF DEALING WITH INCIDENTAL FINDINGS The results of the PET, MRI (or CT), and psychological examinations performed in this study will still be in the laboratory stage, and the individual subject cannot be diagnosed as having a disease based on these results at the NIRS. However, if any findings raising suspicion of an obvious abnormality, including tumors, are observed incidentally by MRI, etc., the subject will be informed of the results and encouraged to see a specialist. 12 RESPONSES TO ADVERSE EVENTS 12-1 RESPONSE TO SUBJECTS If any adverse events are observed, doctors with responsibilities in this study will give appropriate treatment to the subject and enter the relevant events in the medical record. Regarding the response procedures, the procedures for emergency in the clinical studies performed at the Molecular Imaging Center (prepared on December 15, 2009, the Molecular Imaging Center) will be followed REPORT OF SERIOUS ADVERSE EVENTS OR DEFECTS If the principal investigator learns about the occurrence of serious adverse events or defects, he will immediately report them to the Director in writing according to the standard operating procedures for the study in humans, and disclose these events as needed. 13 PROTOCOL DEVIATIONS The principal investigator or investigators shall not deviate from or make changes to the protocol before obtaining approval from the Director based on a review conducted by the Ethics Review Board. The principal investigator or investigators can deviate from or make changes to the protocol before obtaining approval from the Director based on the review conducted by the Ethics Review Board for any compelling reason including the avoidance of an emergency situation. 14 CHANGES TO THE PROTOCOL If the necessity of changing the protocol, the informed consent form, etc. arises, the required changes or revisions can be made after obtaining approval from the Director based on the review conducted by the Ethics Review Board. 15 REPORT OF THE IMPLEMENTATION STATUS OF THE STUDY If the study period exceeds one year, the principal investigator should report the implementation status to the Director employing the study implementation status report every year, and undergo a review conducted by the Ethics Review Board as to whether or not to continue the study. 19

21 16 COMPLETION, DISCONTINUATION OR SUSPENSION OF THE STUDY 16-1 COMPLETION OF THE STUDY At the completion of the study, the study completion report will be submitted to the Director DISCONTINUATION OR SUSPENSION OF THE STUDY In the following cases, the principal investigator will consider whether or not to continue the study. (1) When it is difficult to recruit subjects and it is unlikely that the target sample size will be reached (2) When the study objectives have been achieved before reaching the target sample size or before the end of the study period (3) When the possible risks are considered to outweigh the benefits expected from the study (4) When it is difficult to accept instructions for changing the plan, etc. given by the Ethics Review Board (5) When it is considered difficult to continue the study In the following cases, individual studies will be discontinued. (1) When the subject offers to withdraw from the study or withdraws consent (2) When [ 11 C]PBB3 or [ 11 C]PIB cannot be synthesized (3) When it is difficult to continue the study due to adverse events (4) When the investigators judge it to be appropriate to discontinue the study for other reasons (5) When the Ethics Review Board instructs the investigators to discontinue the study The principal investigator will submit the report of the completion (discontinuation or suspension) of the study to the Director after the completion, discontinuation or suspension of the study according to the standard operating procedures for the study in humans. 17 ETHICAL MATTERS (1) Compliance with the ethical guidelines for the study This study will be performed in compliance with the ethical provisions and standard operating procedures for the study in humans by the NIRS based on the Ethical Guidelines for Clinical Studies (MHLW, revised in 2013), Declaration of Helsinki (World Medical Association, revised in 2013) and the protocol. (2) Ethics Review Board For the implementation of this study, approval from the Ethics Review Board established at the NIRS is required. The principal investigator will submit the study implementation status report to the Ethics Review Board every year, and comply with the Director s decision as to whether or not to continue the study based on the review conducted by the Ethics Review Board. The principal investigator will also submit the report of the completion (discontinuation or suspension) of the study to the Ethics Review Board after the completion, discontinuation or suspension of the study. In the following cases, the principal investigator will report all relevant matters to the Ethics Review Board, and comply with the Director s 20