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 | 15.0 |
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 | 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 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 | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
2-Fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET) Imaging Sub-Study (voluntary neuroimaging)
To evaluate the effects of IGIV, 10% treatment on changes in cerebral glucose metabolism.
Restricted to a subset of study sites in North America. |
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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 authorized 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. Subjects must not be on two acetylcholinesterase inhibitors concurrently.
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, vit. B12 deficiency, thyroid abnormalities).
2.Current residence in a skilled nursing facility.
3.Contraindication to undergoing MRI (e.g. pacemaker [with the exception of an MRI-compatible pacemaker], severe claustrophobia, ferromagnetic implants such as a metal plate).
4.Clinically signif. congestive heart failure (e.g. New York Heart Association [NYHA] Class III/IV symptoms or untreated Class II).
5.History of unstable angina (angina at rest) or myocardial infarction within the 12 months prior to screening.
6.Uncontr. hypertension defined as syst. blood pressure >160mmHg and/or diast. >100mmHg 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 syndr., protein S/protein C deficiency, AT III deficiency).
9.History of intracerebral hemorrhage within the 5 yrs prior to screening.
10.Evidence of >4 microhemorrhages (regardless of their anatom. location or diag. 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 indep. qualified central reviewer.
11.Head trauma with loss of consciousness, contusion, or open head injury within the 12 months prior to screening.
12.Uncontr. seizure disorder as defined by ≥2 breakthrough seizures/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 yrs 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 & stable prostate cancer not requiring treatment.
15.Active autoimmune/neuro-immunologic disorder.
16.Uncontr. major depression, psychosis, or other major psych. disorder(s).
17.Poorly contr. diabetes, defined as glycosylated (or glycated) hemoglobin (HbA1c) ≥6.5% 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 vit. B12 deficiency within 6 months prior to screening, or clinically signif. abnormally low vit. B12 at the time of screening
20.Abnormal clinical chemistry panel or hemat. panel meeting any one of the following criteria:
a.Serum alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN)
b.Clinically signif. 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/positive serology at screening for one/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 (<8 mg/dL).
23.Known history of hypersensitivity following infusions of human blood/blood components (e.g. human Ig or human albumin).
24.Currently receiving or has received immunomodulatory therapies (e.g. anti-TNF, anti-IL-1, interferon, anti-CD20) within 12 weeks prior to screening, with the exception of topical, ophthalmic or inhaled glucocorticoids, & low-dose systemic corticosteroids (prednisone <10 mg/day or its equivalent).
25.Currently receiving or has received intravenous or subcutaneous Ig treatment within the 2 yrs prior to screening, or has received Ig in Baxter Protocol 160701.
26.Currently receiving or has received at any time active immunization aimed at modulating AD progression.
27.Currently receiving or has received within 12 months prior to screening any investig. device, drug or biologic (e.g. passive immunotherapies with monoclonal or polyclonal ab) aimed at modulating AD progression.
28.Subject has been exposed to an IP or investig. device (not covered under Exclusion Criteria #26 or #27) within 12 weeks prior to screening or is scheduled to participate in another clinical study involving an IP or investig. device during the course of this study.
29.Subject is a family member or employee of the investigator.
30.Subject is nursing/intends to begin nursing during the course of the study.
31.Any disorder or disease, or clinically signif. abnormality on laboratory or other clinical test(s) (e.g. blood tests, urine tests, electrocardiogram, chest xray), that in med. 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 (as well as at the early termination visit if applicable)
4. IADCQ: Baseline, 6 months, 9 months, 12 months and 18 months (as well as at the early termination visit if applicable)
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Japan |
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 | 8 |
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 |