E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild to moderate Alzheimer’s disease (AD) |
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E.1.1.1 | Medical condition in easily understood language |
Mild to moderate Alzheimer’s disease (AD) |
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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 | 19.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10001897 |
E.1.2 | Term | Alzheimer's disease (incl subtypes) |
E.1.2 | System Organ Class | 100000004852 |
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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 IGIV, 10% treatment on change in cognitive performance and functional activities in subjects with mild to moderate AD, as compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the effects of IGIV, 10% treatment on additional outcomes, including global clinical status, neuropsychiatric behaviors, and changes in volumetric magnetic resonance imaging (MRI) parameters.
2. To examine the effects of IGIV, 10% treatment on quality of life of subjects with mild to moderate AD and of their caregivers.
3. To assess the safety of IGIV, 10% treatment in subjects with mild to moderate AD.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Males or females of age 50 to 89 years inclusive at the time of screening.
2.Written informed consent obtained from either the subject or the subject’s legally acceptable representative prior to any study-related procedures.
3.Written informed consent obtained from an able and competent caregiver who is willing to comply with the requirements of the protocol pertaining to him/her, including facilitating the subject’s participation in the study.
4.Diagnosis of Probable AD according to National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) 1984 criteria.
5.Dementia of mild to moderate severity (MMSE 16-26 inclusive at the time of screening).
6.Neuroimaging (computed tomography [CT] or MRI) performed after symptom onset consistent with AD diagnosis.
7.Willingness to comply with the requirements of the protocol and ability to comply with testing and infusion regimen, including adequate corrected visual acuity and hearing ability.
8.For at least 12 weeks prior to screening, on stable doses of AD medication(s) approved by local regulatory authorities.
9.Venous access for repeated infusion and phlebotomy.
10.If receiving psychoactive medications (e.g., antidepressants other than monoamine oxidase inhibitors [MAOIs] and most tricyclics, antipsychotics, anxiolytics, anticonvulsants, mood stabilizers, etc.), must be on stable doses for at least 6 weeks prior to screening.
11.For women of childbearing potential, the subject must have a negative pregnancy test at screening and must agree to employ adequate contraceptive measures (e.g. birth control pills/patches, intrauterine device, or diaphragm or condom [for male partner] with spermicidal jelly or foam) throughout the course of the study. |
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E.4 | Principal exclusion criteria |
1.Possible AD by NINCDS-ADRDA criteria or non-Alzheimer dementia (e.g. vascular dementia, dementia with Lewy bodies, frontotemporal dementia, or dementia arising from other diseases or conditions such as Parkinson’s disease, vitamin B12 deficiency, thyroid abnormalities).
2.Current residence in a skilled nursing facility.
3.Contraindication to undergoing MRI (e.g. pacemaker, severe claustrophobia, ferromagnetic implants such as a metal plate).
4.Clinically significant congestive heart failure (e.g. New York Heart Association [NYHA] Class III/IV symptoms or untreated Class II).
5.History of unstable angina or myocardial infarction within the 12 months prior to screening.
6.Uncontrolled hypertension defined as systolic blood pressure > 160 mm Hg and/or diastolic > 100 mm Hg confirmed upon repeated measures.
7.History of thrombosis and/or thromboembolic disease (central or peripheral) within the 12 months prior to screening.
8.Known history of procoagulant abnormalities (e.g. factor V Leiden, antiphospholipid syndrome, protein S/protein C deficiency, AT III deficiency).
9.History of intracerebral hemorrhage within the 5 years prior to screening.
10.Evidence of greater than 4 microhemorrhages (regardless of their anatomical location or diagnostic characterization as “possible” or “definite”), a single area of superficial siderosis, a macrohemorrhage, major stroke, or multiple lacunae by a recent (within 3 months prior to screening) and/or the baseline MRI, as confirmed by an independent qualified central reviewer.
11.Head trauma with loss of consciousness, contusion, or open head injury within the 12 months prior to screening.
12.Uncontrolled seizure disorder as defined by two or more breakthrough seizures per year despite adequate antiepileptic drug (AED) treatment.
13.Modified Hachinski score > 4 at time of screening.
14.Subjects with active malignancy or history of malignancy within 5 years prior to screening with the exception of the following: adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and stable prostate cancer not requiring treatment.
15.Active autoimmune or neuro-immunologic disorder.
16.Untreated major depression, psychosis, or other major psychiatric disorder(s).
17.Poorly controlled diabetes, defined as glycosylated (or glycated) hemoglobin (HbA1c) ≥ 6.5% for subjects with abnormal fasting glucose at screening.
18.Creatinine clearance < 50% of normal adjusted for age and gender, as calculated according to the Cockcroft-Gault formula, at the time of screening.
19. Known history of untreated vitamin B12 deficiency within 6 months prior to screening, or clinically significant abnormally low vitamin B12 at the time of screening
20.Abnormal clinical chemistry panel or hematology panel meeting any one of the following criteria:
a.Serum alanine aminotransferase (ALT) > 2.5 x upper limit of normal (ULN)
b.Clinically significant anemia that precludes repeated blood sampling or hemoglobin (Hgb) < 10.0 g/dL
c.Absolute neutrophil count (ANC) < 1000 cells/µL
d.Known coagulopathy or platelet counts < 100,000 cells/µL
e.Total serum protein > 9 g/dL
21.Known history of or positive serology at screening for one or more of the following: hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) type 1/2 antibody.
22.Immunoglobulin A (IgA) deficiency (< 7 mg/dL).
23.Known history of hypersensitivity following infusions of human blood or blood components (e.g. human immunoglobulins or human albumin).
24.Currently receiving or received any immunomodulatory monoclonal antibody therapies within 12 weeks prior to screening.
25.Currently receiving or has received IGIV treatment within the 2 years prior to screening.
26.Currently receiving or has received any investigational biologic(s) (e.g. active immunization or passive immunotherapies with monoclonal or polyclonal antibodies) for AD at any time.
27.Subject has participated in another clinical study involving an IP or investigational device within 12 weeks prior to screening or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.
28.The subject is nursing or intends to begin nursing during the course of the study.
29. Any disorder or disease, or clinically significant abnormality on laboratory or other clinical test(s) (e.g. blood tests, urine tests, electrocardiogram, chest x-ray), that in medical judgment may impede the subject’s participation in the study, pose increased risk to the subject, or confound the results of the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
1. The cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog)
2. Alzheimer’s Disease Cooperative Study (ADCS)-Activities of Daily Living (ADL) inventory |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. ADAS-Cog: Baseline, 3 months, 6 months, 9 months, 12 months, 15 months and 18 months (as well as at the early termination visit if applicable)
2. ADCS-ADL: Baseline, 3 months, 6 months, 9 months, 12 months, 15 months and 18 months (as well as at the early termination visit if applicable) |
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E.5.2 | Secondary end point(s) |
Efficacy
1.ADCS-Clinical Global Impression of Change (CGIC)
2.Neuropsychiatric Inventory (NPI)
3.Logsdon Quality of Life in Alzheimer’s Disease (QOL-AD)
4.Impact of Alzheimer’s Disease on Caregiver Questionnaire (IADCQ)
5.Rate of whole brain atrophy and ventricular enlargement using volumetric MRI
Safety
1.Number (percentage) of subjects experiencing related adverse events (AEs) and/or serious adverse events (SAEs)
2.Number (percentage) of subjects experiencing any AEs and/or SAEs
3.Number (percentage) of infusions temporally associated (defined as during or within 72 hours of completion of an infusion) with AEs and/or SAEs
4.Number (percentage) of infusions associated with AEs and/or SAEs occurring during or within 7 days of completion of an infusion
5.Number (percentage) of infusions causally associated with AEs and/or SAEs
6.Number and proportion of infusions discontinued, slowed, or interrupted due to an AE
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. ADCS-CGIC: Baseline, 3 months, 6 months, 9 months, 12 months, 15 months and 18 months (as well as at the early termination visit if applicable)
2. NPI: Baseline, 3 months, 6 months, 9 months, 12 months, 15 months and 18 months (as well as at the early termination visit if applicable)
3. QOL-AD: Baseline, 6 months, 9 months, 12 months and 18 months
4. IADCQ: Baseline, 6 months, 9 months, 12 months and 18 months
5. Rate of whole brain atrophy and ventricular enlargement: Baseline, 9 months and 18 months |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 3 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 |
Australia |
Belgium |
Canada |
Germany |
Israel |
Poland |
Spain |
United Kingdom |
United States |
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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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |