| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with early degree of Alzheimer's Disease |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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 |
| The primary objective is to assess the clinical activity based on assessment of cognitive and functional domains of repeated immunizations of AD patients in an early stage with AFFITOPE® AD02. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective is to assess immunological activity, the overall clinical activity, the impact on health-related quality of life, the treatment effect on the biomarker brain atrophy as well as the safety and tolerability of the Alzheimer AFFITOPE® AD02 vaccine. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Diagnosis of probable Alzheimer’s disease based on the NINCDS/ADRDA criteria. AD of early degree has been confirmed if the Mini Mental State Examination (MMSE) score is ≥20 (1).
or
-Patients fulfilling inclusion criteria 4/4a and 6 (2).
PLEASE NOTE: the study manual (version 1, based on study protocol V04 (22Jul2010) contained some more explanations regarding inclusion criterion (1). These were provided following comments of investigators. A more specific update of these explanations is now provided in the protocol:
Regarding (1): NINCDS/ADRDA criteria, it is obvious that patients with a MMSE ≥27 might not fulfill all NINCDS/ADRDA. This encompasses primarily criteria referring to or requiring a state of dementia (e.g., under section I, “dementia was established by clinical examination and documented by MMSE, …”). In such a case, inclusion criterion (2) ensures the specificity of the diagnosis (predementia stage of AD/AD-type MCI). Patients with a MMSE ≤19 are clearly excluded by criterion (1) which reflects the overall goal of recruiting patients with “early” AD.
-Hachinski Ischemia Scale is used to distinguish AD from vascular dementia. A score of ≤ 4 suggests AD (3).
-The result of the Magnetic Resonance Imaging scan (MRI) of the patient’s brain has to be consistent with the diagnosis of AD, central reading. This includes medial temporal lobe atrophy as assessed by the Scheltens scale (score ≥2) (4).
-Patients fulfilling all inclusion criteria and none exclusion criteria with the exception of a Scheltens score of ≥2 can be enrolled into the study based on an AD-type CSF signature reflecting cerebral amyloidosis and neuronal injury (as defined on page 47 pf the CSP V05) (4a).
Further Conditions for Inclusion into the Clinical Trial
-Written informed consent signed and dated by the patient and the caregiver. The patient’s capability to give informed consent has to be confirmed by an independent professional (psychiatrist, neurologist or psychologist dependent on the regulations in a given country)(5).
-A FCSRT result of total recall ≤40 or free recall ≤17 indicative of hippocampal damage in the patient’s episodic memory according to Dubois and colleagues to enrich the population for AD patients. (6).
-Age between 50 and 80 years, if not approved by AFFiRiS (7).
-Availability of a partner/caregiver knowing the patient and being able to accompany the patient at the visits and being available for the telephone interviews. This is necessary because some of the neuropsychiatric tests require information by a person knowing the patient well. In addition, it increases the safety of a study participant (8).
-Adequate visual and auditory acuity to allow neuropsychological testing (9).
-Female patients of childbearing potential are eligible if they use a medically accepted contraceptive method (10).
-Availability of the APOE genotype (11).
-A potential participant receiving conventional AD and hypothyreoidism therapies must be on stable doses for at least 3 months prior to Visit 1 and during the entire trial period (12).
-A potential participant has to be on stable doses of all medications he/she is taking because of consisting illnesses according to medical history (except AD and hypothyreoidism therapies, AD therapies will be recorded separately) for at least 30 days prior to Visit 1, in case of uncertainty please contact sponsor (13).
-Scheduled elective hospitalization for diagnostic work-up is allowed for inclusion into the clinical trial (14). |
|
| E.4 | Principal exclusion criteria |
-Pregnant women (1).
-Sexually active women of childbearing potential who are not using a medically accepted birth control method and unreliable contraception in male subjects (2).
-Participation in the active treatment phase of another clinical trial within 3 months before Visit 1 (3).
-History of questionable compliance to visit schedule; patients not expected to complete the clinical trial (4).
-Presence or history of allergy to components of the vaccine, if considered relevant by the investigator (5).
-Contraindication for MRI imaging, including but not limited to pacemakers; cochlear implants, cerebral aneurysm clips; implanted infusion pumps; implanted nerve stimulators; metallic splinters in the eye; other magnetic, electronic, or mechanical implants; or any other clinical history or examination finding that, in the judgement of the investigator, would pose a potential hazard in combination with MRI (6).
-Inability to tolerate MRI procedure (e.g., claustrophobia, inability to lie motionless for 30 minutes, noise sensitivity) (7).
-MRI findings at Visit 1 excluding participation: a significant number of microhemorrhages, a single prior hemorrhage > 1 cm3, 2 or more lacunar infarcts , a single prior infarct > 1 cm3, a single strategically located subcortical infarct (e.g., thalamus, hippocampus, left caudate head), evidence of a meningioma, cerebral contusion, encephalomalacia, or aneurysms, evidence of other dementia (non-AD) pathology (8).
-Operation under general anaesthesia within 3 months prior to study entry and scheduled elective operation under general anaesthesia during the whole study period (9).
-History and/or presence of autoimmune disease; please note: for example, positive ANAs without clinical symptoms do not represent “disease”, in case of uncertainty please contact sponsor for more detailed information (10).
-Recent (≤5 years since last specific treatment) history of cancer (Exceptions: basal cell carcinoma, intraepithelial cervical neoplasia) (11).
-Active infectious disease (e.g., Hepatitis B, C) (12).
- Presence and/or history of Immunodeficiency (e.g., HIV infection) (13).
-Significant systemic illness (e.g., chronic renal failure, chronic liver disease, poorly controlled diabetes, poorly controlled congestive heart failure, other deficiencies) (14).
-Hypothyroidism, defined as any significant thyroid-stimulating hormone elevation. Patients with corrected hypothyroidism are eligible for the study provided that treatment has been stable for 3 months before study entry (15).
-History of significant psychiatric illness such as schizophrenia, bipolar affective disorder or psychotic depression (16).
-Current depressive episode (Geriatric Depression Scale (GDS) >5 at Visit 1)(17).
-Metabolic or toxic encephalopathy or dementia due to a general medical condition (18).
-Alcoholism or substance abuse within the past year (alcohol or drug intoxication) (19).
-Wernicke’s encephalopathy (20).
-History or evidence of any other CNS disorder that could be interpreted as a cause of dementia (infectious or inflammatory/demyelinating CNS conditions, Creutzfeld Jacob disease, Parkinson’s disease, Huntington’s disease, brain tumor, subdural haematoma, etc.)(21).
-History or evidence of cerebrovascular disease (stroke, transient ischemic attack, hemorrhage), or diagnosis of possible, probable or definite vascular dementia in accordance with NINDS-AIREN criteria (22).
-Epilepsy (23).
-Prior and/or current treatment with experimental immunotherapeutics including IVIG, AD antibody therapy and/or vaccines for AD including AFFITOPE® AD01&AD02 (24).
-Prior and/or current treatment with immunosuppressive drugs (25).
-Treatment with benzodiazepines and/or nootropics administered at high doses and/or as newly started treatment (26).
-Treatment with anticholinergic drugs including Parkinson treatments, antidepressants (tricyclics), neuroleptics with anticholinergic properties, certain bladder relaxants, anticholinergic drugs for use in lung diseases (27).
-Change in dose of standard treatments for AD or hypothyroidism within 3 months prior to Visit 1 (28).
-Change in dose of previous and current medications which the patient is taking because of consisting illnesses according medical history (except AD and hypothyreoidism therapies, AD therapies will be recorded separately) within the last 30 days prior to Visit 1, if clinically relevant (29). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective of the present clinical trial is to assess the clinical activity of various doses / formulations of AFFITOPE® AD02 following its repeated s.c. administration to patients with early AD, based on the evaluation of the cognitive and functional domains.
This clinical trial will be considered positive if one or all treatment groups do better than the pooled placebo group in the primary endpoints of the study (cognitive and functional disease domain) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| ADAScog: week -4, 0, 4, 12, 28, 40, 52, 65, 78; ADCS-ADL: week 0, 12, 28, 40, 52, 65, 78; |
|
| E.5.2 | Secondary end point(s) |
| immunological and clinical efficacy, safety, cognitive performance, quality of life and brain atrophy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at all visits: week -4, 0, 4, 8, 12, 28, 40, 52, 65, 78; |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | 4 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 |
| France |
| Austria |
| Croatia |
| Slovakia |
| Czech Republic |
| Germany |
|
| 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
|
| LVLP (the last visit of last patient) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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