E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cerebral Amyloid Angiopathy (CAA) |
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E.1.1.1 | Medical condition in easily understood language |
Cerebral Amyloid Angiopathy: A disease of the blood vessels of the brain |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10068044 |
E.1.2 | Term | Cerebral amyloid angiopathy |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of PF-04360365 (ponezumab) in subjects with probable CAA as compared to placebo on a BOLD fMRI measure of cerebrovascular reactivity. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
-To evaluate the efficacy of PF-04360365 (ponezumab) in subjects with probable CAA as compared to placebo on additional BOLD fMRI measures of cerebrovascular reactivity.
- To evaluate the effect of PF-04360365 (ponezumab) in subjects with probable CAA as compared to placebo on changes in the concentration of total plasma Aβ.
Exploratory Objective:
To evaluate the effect of PF-04360365 (ponezumab) in subjects with probable CAA as compared to placebo on cerebral blood flow.
Safety Objective:
To evaluate the safety, tolerability and pharmacokinetics of PF-04360365 (ponezumab) to subjects with probable CAA. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Additional Pharmacogenomic Research (Optional),
(Section 7.8.1.2 of the main study protocol)
Subjects will be asked to indicate on the consent form whether they will allow the Retained Pharmacogenomic Sample(s) to also be used for the following additional research:
- Investigations of the disease under study in the clinical trial, and related conditions.
- Samples may be used as controls. This includes use in case -control studies of diseases for which Pfizer is researching drug therapies; use in characterizing the natural variation amongst people in genes, RNA, proteins, and metabolites; and use in developing new technologies related to pharmacogenomics.
Subjects need not provide additional samples for the substudy the
samples collected in the main study will be used.
Subjects may still participate in the main study if they elect not to allow their Retained Pharmacogenomic Samples to be used for the additional purposes of the substudy. |
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E.3 | Principal inclusion criteria |
1. Men, and women of non-childbearing potential between the ages of 55 and 90 years old who have the diagnosis of probable CAA using the Boston criteria and have an acceptable sMRI in the previous 12 months for review. Male subjects must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned drug. Female subjects who are not of childbearing potential (ie, meet at least one of the following criteria):
- Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- Have medically confirmed ovarian failure; or
- Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; with laboratory confirmation (Serum follicle-stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females).
2. CAA disease has not resulted in any meaningful clinical cognitive or functional deficit as documented by the PI in consultation with the sponsor.
3. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial.
4. Subjects are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
5. In general good health, in the opinion of the Principal Investigator (PI), based on medical history, physical examination, vital signs, 12-lead ECG, and laboratory values, including hematology and chemistry values.
6. Subjects must have corrected vision at or better than 20/50 as assessed with a Snellen chart. If glasses are required to meet these criteria, they must be MRI-compliant glasses provided by the site.
7. An acceptable screening fMRI that passes QC requirements. |
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E.4 | Principal exclusion criteria |
1. Co-morbid diagnosis of clinically documented Alzheimer's disease or significant cognitive impairment.
- A score of <26 on the MMSE.
2. History of cancer within the last 5 years (except for cutaneous basal cell, squamous cell cancer resolved by excision, colon polyp resolved by excision, or non-progressive prostate cancer per investigator’s judgment).
3. History of clinically significant (as determined by the PI) cardiac arrhythmia or heart block (eg sick sinus syndrome, ventricular tachycardia or fibrillation, sustained supraventricular tachycardia, symptomatic bradycardia, congenital long QT interval syndrome, atrial fibrillation).
4. History or diagnosis of clinically significant (as determined by the PI) ischemic heart disease (eg, angina, clinically significant coronary artery disease, myocardial infarction in the past 2 years), congestive heart failure, cardiomyopathy, myocarditis, left ventricular hypertrophy, valvular heart disease.
5. History of clinically significant (as determined by the PI) renal disease, such as glomerulonephritis, nephrotic syndrome, single kidney or polycystic kidney.
6. Subjects with uncontrolled hypertension (≥170/100).
7. History of clinically significant (as determined by the PI) syncope, head trauma, or clinically significant unexplained loss of consciousness within the last 5 years.
8. History of photo-convulsive seizure, seizure disorder currently untreated or seizures in the past 18 months.
9. A diagnosis of major depressive disorder or other psychiatric illness as the primary diagnosis per the DSM-IV TR criteria per the investigator’s judgment.
10. History of schizophrenia, bipolar disorder, or other severe mental illness.
11. Known history of alcohol or drug abuse (as defined by the DSM-IV-TR) within 5 years prior to dosing or a positive result as a result of illicit drugs on the drug screening test.
12. Known positive HIV status.
13. Subjects who reside in a nursing home or that are inpatients in a hospital.
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
15. Pregnant females; breastfeeding females; females of childbearing potential; males of childbearing potential not using highly effective contraception or not agreeing to use highly effective contraception for at least 28 days after last dose of investigational product.
16. Subject’s body weight cannot exceed 105 kg. No more than 3 subjects are to be enrolled with weight > 100 kg.
Exclusions Related to Medications or Procedures
1. Previous exposure to investigational or non-investigational immune- or biologic therapies for Alzheimer’s disease such as anti-Aβ antibodies, or β- or γ-secretase inhibitors.
2. Any contraindications to MRI such as, but not limited to cardiac pacemaker; implanted cardiac defibrillator; aneurysm clips; carotid artery vascular clamp; neurostimulator; insulin or infusion pumps; implanted drug infusion device; bone growth/fusion stimulator; cochlear, otologic, ear implant; severe claustrophobia or requiring sedation; passive implants that may be weakly ferromagnetic in the vicinity of the RF coil that may cause image artifacts in the head scans; obesity or body habitus that exceeds MRI table weight limits or prevents subject from fitting into the scanner.
3. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody or IgG-fusion protein.
4. Medications that may negatively affect cognitive function, such as anticholinergics (including agents with pronounced anticholinergic properties such as amitriptyline) with the following caveats:
- Sedatives and tranquilizers (eg, benzodiazepine and non-benzodiazepine hypnotics) used as a sleeping aid and taken routinely are allowable provided that subjects have been on a stable dose for at least 60 days prior to dosing, with no anticipated change during the study participation;
- Anti-epileptic drugs for seizures or reasons other than seizures are permitted provided that subjects have been on a stable dose for at least 60 days prior to dosing, with no anticipated change during the study participation. Topiramate, phenytoin and barbiturates are excluded.
5. The following medications are excluded if used from 1 month prior to the Screening visit through the end of the study:
- Anti-coagulants;
- Approved cognitive enhancers (cholinesterase inhibitors, memantine).
6. The use of anti-inflammatory (NSAIDS and steroids) drugs prescribed specifically/solely for treatment of CAA (other stable use permitted).
For exclusion criteria 7 and 8 Related to Medications or Procedures please refer to the protocol amendment.
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E.5 End points |
E.5.1 | Primary end point(s) |
The change from baseline to Day 2 or Day 90 in cerebrovascular reactivity as measured by the slope (amplitude over time to peak) from visual task-evoked fMRI. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening visit, Visit 3, and Visit 8. |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints:
1. The change from baseline to Day 2 or Day 90 in cerebrovascular reactivity as measured by the time to peak, magnitude, and time to baseline from visual task-evoked fMRI.
2. The change from baseline of total plasma Aβ species at specified endpoints after the initial dose of study medication on the concentration.
Exploratory Endpoint:
The change from baseline to Day 2 or Day 90 on cerebral blood flow as measured by arterial spin labeling (ASL).
Safety Endpoints:
1. The change from baseline at specified time points on brain structural MRI following each dose of ponezumab: CMBs, VE, infarcts.
2. The change from baseline at specified time points on the Montreal Cognitive Assessment (MoCA).
3. Other safety endpoints include changes from baseline on C-SSRS, physical and neurological assessments, laboratory assessments, 12-lead ECG, vital signs, immunogenicity, AE monitoring. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to the schedule of assessments table in the protocol |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
Netherlands |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |