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

• ClinicalTrials.gov Identifier: NCT03765762
• Recruitment Status: Completed
• First Posted: December 5, 2018
• Results First Posted: January 27, 2021
• Last Update Posted: January 27, 2021
• Sponsor: Alkahest, Inc.
• Information provided by (Responsible Party): Alkahest, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Severe Alzheimer Disease	Drug: GRF6019; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Tolerability of Pulsed GRF6019 Infusions in Subjects With Severe Alzheimer's Disease
• Actual Study Start Date: January 15, 2019
• Actual Primary Completion Date: December 17, 2019
• Actual Study Completion Date: December 17, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: GRF6019; Subjects will receive intravenously 250 mL of GRF6019 each day for 5 consecutive days.	Drug: GRF6019; GRF6019 for IV infusion
Placebo Comparator: Placebo; Subjects will receive intravenously 250 mL of placebo each day for 5 consecutive days.	Other: Placebo; Placebo for IV infusion; Other Name: Normal Saline

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. The Mini-Mental State Examination (MMSE) Score [ Time Frame: 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.
2. Severe Impairment Battery (SIB) Total Score [ Time Frame: 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.
3. Alzheimer's Disease Cooperative Study Group Activities of Daily Living Inventory for Severe Alzheimer's Disease (ADCS-ADL-Severe) [ Time Frame: 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.
4. Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change Plus Caregiver Input (ADCS-CGIC) [ Time Frame: 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.
5. Neuropsychiatric Inventory Nursing Home (NPI-NH) Total Score [ Time Frame: 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.
6. Neuropsychiatric Inventory (NPI) Caregiver Total Score [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 60 Years to 95 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Arizona

Cognitive Clinical Trials

Gilbert, Arizona, United States, 85297

Cognitive Clinical Trials

Mesa, Arizona, United States, 85209

Cognitive Clinical Trials

Phoenix, Arizona, United States, 85037

United States, California

Pacific Research Network

San Diego, California, United States, 92103

United States, Florida

Riverside Clinical Research

Edgewater, Florida, United States, 32132

United States, New Jersey

Bio Behavioral Health

Toms River, New Jersey, United States, 08755

Sponsors and Collaborators

Alkahest, Inc.

Investigators

• Study Director: Alkahest Program Physician; Alkahest, Inc.

  Study Documents (Full-Text)

Documents provided by Alkahest, Inc.:

Study Protocol  [PDF] July 10, 2019

Statistical Analysis Plan  [PDF] December 11, 2019

More Information

• Responsible Party: Alkahest, Inc.
• ClinicalTrials.gov Identifier: NCT03765762
• Other Study ID Numbers: Alkahest study 6019-202
• First Posted: December 5, 2018
• Results First Posted: January 27, 2021
• Last Update Posted: January 27, 2021
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Alkahest, Inc.:

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

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders