A Study to Assess the Safety of GRF6019 Infusions in Subjects With Severe Alzheimer's Disease

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability, and potential cognitive benefit of the experimental treatment GRF6019 in subjects with severe Alzheimer's disease.

Detailed Description
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This is a randomized, double-blind, placebo-controlled study to assess the safety, tolerability and potential cognitive benefit of GRF6019, a human plasma protein fraction. GRF6019 or placebo will be administered intravenously to subjects with severe Alzheimer's disease every day for 5 consecutive days. The total study duration for each subject is approximately 9 weeks.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Tolerability of Pulsed GRF6019 Infusions in Subjects With Severe Alzheimer's Disease

Conditions
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Severe Alzheimer Disease

Intervention / Treatment
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* Drug: GRF6019
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of probable AD according to the National Institute on Aging-Alzheimer's Association (NIA-AA) Criteria MMSE Score 0-10 inclusive Modified Hachinski Ischemia Scale (MHIS) score of 4 or less Provided a signed and dated informed consent form (either the subject and/or subject's legal representative) Exclusion Criteria: Evidence of clinically relevant neurological disorder(s) other than probable AD History of blood coagulation disorders or hypercoagulability; any concurrent use of an anticoagulant therapy. (e.g., heparin, warfarin, thrombin inhibitors, Factor Xa inhibitors). Use of antiplatelet drugs (e.g., aspirin or clopidogrel) is acceptable. Unstable coronary heart disease, e.g. myocardial infarction or severe or unstable angina in the 6 months prior to dosing. Moderate to severe congestive heart failure (New York Association Class III or IV). Poorly controlled high blood pressure (systolic blood pressure of 160 mmHg or higher and/or diastolic blood pressure of 100 mmHg or higher) despite treatment during the 3 months prior to dosing, or treatment refractory high blood pressure, defined as treatment requiring 3 or more antihypertensives from different classes. Prior hypersensitivity reaction to any human blood product or intravenous infusion; any known clinically significant drug allergy. Treatment with any human blood product, including transfusions and intravenous immunoglobulin, during the 6 months prior to screening. History of immunoglobulin A (IgA), haptoglobulin or C1 inhibitor deficiency; stroke, anaphylaxis, or thromboembolic complications of intravenous immunoglobulins. Hemoglobin <10 g/dL in women; and <11 g/dL in men.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GRF6019<br>Subjects will receive intravenously 250 mL of GRF6019 each day for 5 consecutive days. | Drug: GRF6019<br>* GRF6019 for IV infusion<br>|
| Placebo Comparator: Placebo<br>Subjects will receive intravenously 250 mL of placebo each day for 5 consecutive days. | Other: Placebo<br>* Placebo for IV infusion<br>* Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Treatment-emergent Adverse Events (Safety) | Number of Subjects with at Least One Treatment-emergent adverse event by MedDRA preferred term and grouped by MedDRA System Organ Class | 5 weeks | 
| Tolerability of GRF6019 | Tolerability of treatment defined by the number of subjects completing 4 weeks of study after receiving 5 daily infusions | 5 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Mini-Mental State Examination (MMSE) Score | Mean change from Baseline to 5 Weeks in the Mini-Mental State Examination (MMSE) score. The MMSE consists of 5 components: orientation to time and place, registration of 3 words, attention and calculation, recall of 3 words, and language. The scores from the 5 components are summed to obtain the overall MMSE total score. The MMSE total score can range from 0 to 30, with higher scores indicating better mental status. | Baseline and 5 weeks | 
| Severe Impairment Battery (SIB) Total Score | Mean change from baseline in the SIB total score. The SIB assesses cognition; test questions measure orientation, attention, language, praxis, visuospatial perception, construction, memory, orientation to name, and social interaction. There are 57 items and the range of possible scores is 0-133. Lower scores indicate greater cognitive impairment. | Baseline and 5 weeks | 
| Alzheimer's Disease Cooperative Study Group Activities of Daily Living Inventory for Severe Alzheimer's Disease (ADCS-ADL-Severe) | Mean change from baseline in the ADCS-ADL-Severe score. The ADCS-ADL-Severe contains 19 items covering physical and mental functioning and independence in self-care and assesses the competence in performing basic activities of daily living. The scores range from 0 to 54, with higher scores indicating less functional impairment. | Baseline and 5 weeks | 
| Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change Plus Caregiver Input (ADCS-CGIC) | Mean ADCS-CGIC score. A CGIC score is based on clinicians' observations of change in the subject's cognitive, functional, and behavioral performance since the beginning of a trial. The ADCS-CGIC is a rating of change and not of severity. It provides a semi structured format to enable clinicians to gather necessary clinical information from both the subject and informant to make a global impression of change. After completing the interviews, the clinician records the clinical impression of change on a 7-point Likert-type scale (from marked improvement to marked worsening). A score of 4 indicates no change, while scores > 4 indicate worsening and scores < 4 indicate improvement. | Baseline and 5 weeks | 
| Neuropsychiatric Inventory Nursing Home (NPI-NH) Total Score | Mean change from Baseline to 5 weeks in the NPI-NH total score. The NPI-NH is a questionnaire that quantifies behavioral changes in dementia in nursing home patients and evaluates 12 behavioral domains (Delusions, Hallucinations, Agitation/Aggression, Depression/Dysphoria, Anxiety, Elation/Euphoria, Apathy/Indifference, Disinhibition, Irritability/Lability, Aberrant Motor Behavior, Sleep and Nighttime Behavior Disorders, Appetite/Eating Changes). For each of the 12 behavioral domains the Frequency (scale:1=occasionally to 4=very frequently) is multiplied by the Severity (scale:1=Mild to 3=Severe) to obtain a domain score (frequency x severity), with a possible summed total score of 0 to 144. Lower scores correspond to less severity. A negative change score from baseline indicates improvement. | Baseline and 5 weeks | 
| Neuropsychiatric Inventory (NPI) Caregiver Total Score | Mean change from Baseline to 5 Weeks in NPI Total Score. NPI is based on responses from the informed caregiver during an interview. It consists of 12 sub-domains (Delusions, Hallucinations, Agitation/Aggression, Dysphoria/Depression, Anxiety, Euphoria/Elation, Apathy/Indifference, Disinhibition, Irritability/Lability, Aberrant Motor, Nighttime Behavior, Appetite/Eating). For each of the 12 behavioral domains the Distress (scale:0=Not distressing at all to 5=Extreme) is multiplied by the Severity (scale:1=Mild to 3=Severe) to obtain a domain score (distress x severity), with a possible summed total score of 0 to 180. Lower scores correspond to less severity. A negative change score from baseline indicates improvement. | Baseline and 5 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain Diseases, Nervous System Diseases, Central Nervous System Diseases, Neurodegenerative Diseases, Neurocognitive Disorders, Mental Disorders, Dementia, Tauopathy