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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03765762

Enrollment

Registered

2018-12-05

Start date

2019-01-15

Completion date

2019-12-17

Last updated

2021-01-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Severe Alzheimer Disease

Keywords

Brain Diseases, Nervous System Diseases, Central Nervous System Diseases, Neurodegenerative Diseases, Neurocognitive Disorders, Mental Disorders, Dementia, Tauopathy

Brief summary

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

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.

Interventions

DRUGGRF6019

GRF6019 for IV infusion

OTHERPlacebo

Placebo for IV infusion

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

60 Years to 95 Years

Healthy volunteers

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.

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Alzheimer's Disease Cooperative Study Group Activities of Daily Living Inventory for Severe Alzheimer's Disease (ADCS-ADL-Severe)	Baseline and 5 weeks	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.
Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change Plus Caregiver Input (ADCS-CGIC)	Baseline and 5 weeks	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.
The Mini-Mental State Examination (MMSE) Score	Baseline and 5 weeks	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.
Neuropsychiatric Inventory (NPI) Caregiver Total Score	Baseline and 5 weeks	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.
Neuropsychiatric Inventory Nursing Home (NPI-NH) Total Score	Baseline and 5 weeks	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.
Severe Impairment Battery (SIB) Total Score	Baseline and 5 weeks	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
GRF6019 GRF6019 250 mL IV for 5 consecutive days	18
Placebo Placebo 250 mL IV for 5 consecutive days	8
Total	26

Baseline characteristics

Characteristic	GRF6019	Placebo	Total
Age, Continuous	75.2 years STANDARD_DEVIATION 8.25	69.5 years STANDARD_DEVIATION 8.12	73.5 years STANDARD_DEVIATION 8.49
Duration of Alzheimer's Disease	5.0 years STANDARD_DEVIATION 1.81	6.0 years STANDARD_DEVIATION 3.59	5.3 years STANDARD_DEVIATION 2.46
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	1 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants	7 Participants	25 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	17 Participants	8 Participants	25 Participants
Region of Enrollment United States	18 participants	8 participants	26 participants
Sex: Female, Male Female	11 Participants	5 Participants	16 Participants
Sex: Female, Male Male	7 Participants	3 Participants	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 18	0 / 8
other Total, other adverse events	8 / 18	3 / 8
serious Total, serious adverse events	0 / 18	0 / 8

Outcome results

Primary

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

Time frame: 5 weeks

Population: Safety: All subjects who received any amount of study treatment

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
GRF6019	Frequency of Treatment-emergent Adverse Events (Safety)	8 Participants
Placebo	Frequency of Treatment-emergent Adverse Events (Safety)	3 Participants

Primary

Tolerability of GRF6019

Tolerability of treatment defined by the number of subjects completing 4 weeks of study after receiving 5 daily infusions

Time frame: 5 weeks

Population: Safety: All subjects who received any amount of study treatment

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
GRF6019	Tolerability of GRF6019	18 Participants
Placebo	Tolerability of GRF6019	8 Participants

Secondary

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.