| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| 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 assess the safety and tolerability of up to 7 repeated injections of CAD106 with Alum or MF59 in patients with mild Alzheimer’s Disease (AD) over 90 weeks.
• To compare the immunogenicity of CAD106 with Alum or MF59 in patients with mild Alzheimer’s Disease (AD) as measured by the titers of Aβ-specific IgG in serum across regimens and in reference to non-adjuvanted CAD106. |
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| E.2.2 | Secondary objectives of the trial |
• To characterize the Aβ- and Qβ-specific antibody response to CAD106 (with Alum or MF59) in serum and CSF, e.g. by measuring Aβ-specific IgMs and Qβ-specific IgGs in serum, and markers of the quality of the immune response.
• To characterize Aβ-specific and Qβ-specific T-cell response to CAD106 (with Alum or MF59) using PBMCs.
• To evaluate changes over time of the concentrations of disease related markers (Aβ1-40 and Aβ1-42 in plasma; Aβ1-40, Aβ1-42, total-tau, phospho-tau in CSF, or other markers) in patients with mild AD receiving CAD106 (with Alum or MF59) compared to placebo. |
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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 |
1. Participation in the pharmacogenetics and blood pharmacogenomics study is optional and consent from the patient will be documented in a separate Informed Consent. For further details, please refer to Section 6.7 "Pharmacogenetics and Pharmacogenomics"of the enclosed protocol.
2. PET-substudy with florbetapir F18 Title:
A 90-week, multi-center, randomized, double-blind, placebo-controlled study in patients with mild Alzheimer’s Disease (AD) to investigate the safety, tolerability and Abeta-specific antibody response following repeated i.m. injections of adjuvanted CAD106
Objectives:
•To determine the signal change (SUVr) of florbetapir F18 in selected brain regions at the selected time points.
•To explore the effect of adjuvanted CAD106 on the progression of AD as measured by the florbetapir F18 signal (SUVr) change in selected brain regions over time.
Rationale:
Development of specific and sensitive biomarkers of AD would be of great value for early detection, diagnosis, and monitoring of AD and could be used as surrogate markers for monitoring the efficacy or a pharmacodynamic effect. Positron emission tomography (PET) imaging using an amyloid ligand appears promising as a diagnostic biomarker and biomarker of pharmacodynamic effects and has been used in clinical and observational studies of AD (Rinne et al, 2010).
The time course and nature of effect of CAD106-induced antibodies on β-amyloid in brain in humans is not known. Autopsy cases from the AN1792 trial have shown depletion of neocortical β-amyloid in patients who died at least 1 year after last treatment as well as the appearance of active clearance of β-amyloid deposits by glial cells in a patient who died 4 months after last treatment (Nicoll et al., 2003, Gilman et al., 2005). This suggests that it is reasonable to conduct florbetapir F18 PET scans at screening and at weeks 40 and 78 to test for possible pharmacodynamic of adjuvanted CAD106 effect on fibrillar amyloid as represented by florbetapir F18 distribution. The number of patients (not more than 25) to be included was chosen based on operational limitations.
Florbetapir F18, is an amyloid ligand under clinical development by Avid Radiopharmaceuticals (Philadelphia). It binds to β-amyloid (Aβ peptide) aggregates with a high affinity (Kd= 2.9nM). Florbetapir has been safely used in more than 1000 people, and, underscoring its promise as a biomarker, has been selected to be used in the Alzheimer Disease Neuroimaging Initiative 2 (ADNI 2). Radiation dosimetry is in the range of typical PET ligands. Florbetapir contains F18, which allows wider distribution compared to Pittsburgh compound (PIB) with C11.
The pattern of uptake in patients with AD is consistent with the pattern of fibrillar amyloid deposition in the brain. It is thought to bind to multiple Aβ amyloid pathologies: neuritic plaques, diffuse plaques and vascular amyloid. A large signal difference of between 50-100% (SUV ratio) is seen between healthy volunteers. The florbetapir F18 signal should therefore be sensitive to changes in the amyloid deposition pathways that are likely to be affected by an amyloid reduction therapy. Treatment:
Patients participating to the PET sub-study will receive, in addition to the study medication, an injection of florbetapir F18 (target and maximum dose 260 MBq, minimum acceptable 180 MBq), followed by a 10mL saline flush, at 3 times during the study: at Screening, week 40 and week 78. Injection procedure for florbetapir F18 is given in Section 6.6.4 |
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| E.3 | Principal inclusion criteria |
1. Written informed consent obtained before any assessment is performed according to local requirements for obtaining consent in mild AD patients. For PET sub-study in addition: Written informed consent to participate in the sub-study.
2. Male and female patients below the age of 85 years. For PET sub-study in addition: Patients must be 50 years of age or above to participate in the sub-study.
3. Female patients must be without childbearing potential (post-menopausal or surgically sterilized).
4. Diagnosis of dementia of the Alzheimer’s type according to the DSM-IV criteria.
5. Patients who satisfy the criteria for a clinical diagnosis of probable AD.
6. Mild AD as confirmed by a MMSE score of 20 to 26 (both inclusive) at screening, and either untreated or on stable dose of cholinesterase inhibitor and/or other AD treatment over the last 4 weeks prior to the clinical assessments.
7. Sufficient education to have been able to read, write, and communicate effectively during the pre-morbid state.
8. Cooperative, willing to complete all aspects and attend all visits of the study including lumbar puncture/CSF samplings (primarily for safety reasons), and capable of doing so, either alone or with the aid of a responsible caregiver.
9. Residing with someone in the community throughout the study or, if living alone, who have daily contact with a primary caregiver.
10. Primary caregiver is present and willing to assent in writing to taking the responsibility for assessing the condition of the patient throughout the study, and for providing input to safety and tolerability assessments in accordance with all protocol requirements.
For a detailed description of the Inclusion Criteria, please refer to Section 4.1 of the enclosed protocol. |
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| E.4 | Principal exclusion criteria |
Exclusion criteria related to CNS:
1. Any medical or neurological condition, other than AD, that contributes significantly to the patient’s dementia, including any CSF and/or brain MRI findings at screening.
2. History in the past two years or current diagnosis of CNS inflammation.
3. Evidence of vascular dementia or other cerebrovascular disease, assessed by investigator and/or MRI central reader.
4. Current DSM-IV diagnosis of major depression and/or any other DSM-IV Axis 1 diagnosis that may interfere with the evaluation of the patient’s response to study medication, including other primary neurodegenerative dementia, schizophrenia, or bipolar disorder.
5. History or current diagnosis of seizure disorder.
Exclusion criteria related to other medical conditions:
6. Any advanced, severe, progressive, or unstable disease that may interfere with the safety, tolerability and pharmacodynamic assessments and/or with the antibody titer response in the study or put the patient at special risk
7. History or current diagnosis of an active autoimmune disease.
8. Evidence of systemic inflammation.
9. Coronary heart disease.
10. Symptomatic heart failure fulfilling the criteria of New York Heart Association (NYHA) Category > II or known left ventricular dysfunction with left ventricular ejection fraction <45%, or any other severe or unstable cardiovascular disease.
11. Vital signs outside of the following ranges at screening and baseline evaluations.
12. A QTc value greater or equal to 500 msec on the screening electrocardiogram as assessed by the central ECG reader using either Bazett or Fredericia formula, whichever the highest.
13. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases.
Exclusion criteria related to PET sub-study
25.Contraindication to PET scan investigations.
26.Participation in PET or Nuclear Medicine investigations in the previous year. 27.Intolerance to previous PET scans; i.e. previous hypersensitivity reactions to any PET ligand or imaging agent or failure to participate in and comply with previous PET scans
For a detailed description of the Exclusion Criteria, please refer to Section 4.2 of the enclosed protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•Adverse events, serious adverse events, discontinuation due to an AE •Cerebral safety MRI (including signs of inflammation, microhemorrhages, and other findings)
•CSF findings related to inflammation (white blood cells, IgG index, oligoclonal bands in blood and CSF)
•All other safety assessments (eg. laboratory tests, ECGs, vital signs) •Injection-related reactions from the adverse events and the patient’s diary such as Bruising (Ecchymosis), Redness, Induration, Swelling, Local pain, Chills, Malaise, Muscle pain (Myalgia), Joint pain (Arthralgia), Headache, Sweating, and Fatigue
•Immune response after repeated up to 7 injections of CAD106 in each treatment arm as measured primarily by the profile of Abeta-specific IgG titers in serum. The immune response will be assessed by CMAX, TMAX, and AUC (area under the curve) and by responders status
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 22 visits post baseline over 90 weeks (details see protocol table 6-1) |
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| E.5.2 | Secondary end point(s) |
| As listed in protocol section 9.5 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 22 visits post baseline over 90 weeks (details see protocol table 6-1). |
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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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
|
| 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
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| 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 | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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