E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
MILD TO MODERATE ALZHEIMER’S DISEASE |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
|
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 |
1. To examine the safety and tolerability of PF-04360365 in subjects with mild-tomoderate AD dosed for 18 months and followed for a total of 24 months; 2. To characterize the pharmacokinetics of PF-04360365 following administration of multiple doses in subjects with mild-to-moderate AD. |
|
E.2.2 | Secondary objectives of the trial |
1. To examine the efficacy of PF-04360365, as assessed by the 70 point Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Disability Assessment for Dementia (DAD) scales, in subjects with mild-to-moderate AD;
2. To determine the effect of PF-04360365 on the following biochemical markers: Aβ species in CSF and plasma; CSF tau and phosphotau levels;
3. To examine the effect of PF-04360365 on CSF safety labs in the subset of subjects receiving lumbar punctures;
4. To determine the immunogenicity of PF-04360365 following repeat dosing;
5. To evaluate the PK/PD relationships for Aβ biomarkers, ADAS-cog, DAD and ECG. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet the following inclusion criteria to be eligible for study entry:
1. Males and females (of non-childbearing potential) ages ≥50 years of age at screening;
2. Diagnosis of probable AD, consistent with criteria from both: • NINCDS-Alzheimer’s Disease and Related Disorders Association (ADRDA); • DSM-IV-TR.
3. The subject must have a reliable caregiver with contact at least 3 times per week (combination of face to face visits and telephone contact acceptable) who will facilitate the subject’s full participation in the study. Caregivers must have sufficient subject interaction to be able to provide meaningful input into the CDR/CDR-SB, NPI, and DAD.
4. Subjects and caregivers must be able to read, write, and speak the language in which psychometric tests are provided with acceptable visual and auditory acuity;
5. MMSE score of 16–26 inclusive at screening;
6. Rosen-Modified Hachinski Ischemia Score ≤4;
7. Subjects must be on a stable dose of background cholinesterase inhibitor and/or memantine at least 60 days prior to dosing, with the following caveats: background cholinesterase inhibitor and/or memantine therapy is not required if the subject had previously demonstrated a lack of toleration. Additionally, although strongly encouraged, background therapy is not mandatory for a world region where it is not the standard of care;
8. Subjects must weigh 35-100 kg.
9. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) and caregiver have been informed of all pertinent aspects of the trial. Subject must be able to provide assent and assent may be re-evaluated during the study at regular intervals;
10. Subjects and caregivers are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures;
11. Women of non child-bearing potential defined as defined in the Lifestyle Guidelines;
12. Diabetic patients may be included provided that their disease and serum glucose values are controlled and being actively managed, as assessed by the PI using a fasting blood sugar and/or HgA1C (per the PIs medical judgment for diabetics);
13. 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. |
|
E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria will be ineligible for study entry. Exclusions Related to AD 1. known presenilin mutations in subject or in the family that may account for dementia. 2. Diagnosis or history of other possible cause for or significant contributor to dementia, 3. Diagnosis or history of cerebrovascular, severe carotid stenosis, cerebral hemorrhage, intracranial tumor, subarachnoid hemorrhage, or subdural hematoma that could either contribute to the patient’s current cognitive or functional status, impair their ability to fully participate in the trial or that may impact their status during the two year trial. 4. Specific exclusionary brain MRI findings that could either contribute to the patient’s current cognitive or functional decline, impair their ability to fully participate in the trial or that may impact their status during the two year course of the trial including: Exclusions Related to General Health 1. Women of childbearing potential. 2. diagnosis of major depressive disorder or other psychiatric illness as the primary diagnosis. 3. History or symptoms of autoimmune disorders 4. History of cancer within the last 5 years (except for cutaneous basal cell, squamous cell cancer resolved by excision, or non-progressive prostate cancer). 5. History of clinically significant cardiac arrhythmia or heart block 6. History or diagnosis of clinically significant ischemic heart disease, congestive heart failure, cardiomyopathy, myocarditis, left ventricular hypertrophy, valvular heart disease. 7. History of clinically significant renal disease 8. Subjects with uncontrolled hypertension even with therapeutic intervention (≥160/100). 9. History of clinically significant syncope, seizure, head trauma, or clinically significant unexplained loss of consciousness within the last 5 years. 10. 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. 11. Known positive HIV status. 12. Subjects who reside in a nursing home or that are inpatients in a hospital; assisted living facilities are permitted. Exclusions Related to Medications or Procedures 1. Any contraindications to the MRI procedure based on local operating procedures and instructions. 2. Previous exposure to investigational or non-investigational immune- or biologic therapies for Alzheimer’s 3. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody or IgG-fusion protein. 4. Use of any of the disallowed concomitant medications within the excluded time periods. 5. Medications that may negatively affect cognitive function 6. Subjects cannot participate in other clinical drug trials for the duration of the study. Subject may not donate blood within 8 weeks prior to the first infusion and for 6 months after the last administration of study drug. Exclusions Related to Findings on Screening Tests 1. Clinically significant laboratory abnormalities in the opinion of the investigator or Sponsor. 2. Screening creatinine clearance of <30 mL/min for AD subjects. 3. Active infection with hepatitis B or C. 4. Positive syphilis test, confirmed. 5. A clinically significant (as determined by the PI) abnormality in the 12-lead ECG, 6. Vitamin B12 levels lower than normal limits (and remains below on repeat testing). Subjects may be enrolled following the initiation of B12 therapy for 4 weeks prior to dosing and confirmed within normal limits upon repeat.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoints:
1. Safety endpoints will include adverse events, physical/neurological exams, vital signs, 12-lead ECG, clinical laboratory values, brain MRI and cognitive assessments;
2. Plasma and CSF concentrations (as available) of PF-04360365. |
|
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 |
Tolerability and Immunogenicity |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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.8.3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 | Information not present in EudraCT |
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 |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |