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

• Sponsor: Alkahest, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03520998
• Collaborator: (none)
• Enrollment: 47
• Locations: 10
• Arms: 2
• Actual Duration (Months): 13.2
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study is evaluating the safety, tolerability, and feasibility of GRF6019, a plasma-derived product, administered as an intravenous (IV) infusion, to subjects with mild to moderate Alzheimer's disease.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease; Mild to Moderate Alzheimer Disease	Drug: GRF6019	Phase 2

Detailed Description

This is a randomized, double-blind, dose-comparison concurrent control study to assess the safety, tolerability, and feasibility of GRF6019, a plasma-derived product, administered by intravenous (IV) infusion to subjects with mild to moderate Alzheimer's disease.

Subjects will be randomized 1:1 to a low dose or a high dose of active treatment in a double-blind manner. All subjects will receive one infusion per day at the randomized dose for 5 consecutive days during Week 1 and, again, during Week 13 (for a total of 10 doses per subject). All IV infusions will take place at an inpatient research unit while the follow-up visits after each treatment period will be on an outpatient basis. Subjects will participate for a total of 6 months in this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Prospective, Randomized, Double-Blind, Dose-Comparison Concurrent Control Study to Assess the Safety and Tolerability of GRF6019 Infusions in Subjects With Mild to Moderate Alzheimer's Disease
• Actual Study Start Date: Apr 16, 2018
• Actual Primary Completion Date: May 24, 2019
• Actual Study Completion Date: May 24, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GRF6019 Low Dose Subjects will receive a low dose of GRF6019 for 5 consecutive days at Week 1 and Week 13.	Drug: GRF6019; GRF6019 for IV infusion
Experimental: GRF6019 High Dose Subjects will receive a high dose of GRF6019 for 5 consecutive days at Week 1 and Week 13.	Drug: GRF6019; GRF6019 for IV infusion

Outcome Measures

Primary Outcome Measures

1. Frequency of Treatment-emergent Adverse Events (Safety) [Baseline to 6 months]

   Treatment-emergent adverse events identified by MedDRA preferred term and grouped by MedDRA System Organ Class

Secondary Outcome Measures

1. The Mini-Mental State Examination (MMSE) [Baseline and 6 months]

   Changes in scores on the MMSE. 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 cognition.

2. Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADASCog/11) [Baseline and 6 months]

   Changes in scores on the 11-item ADASCog/11. The ADAS-Cog/11 includes 11 items assessing cognitive function. The domains include memory, language, praxis, and orientation. There are 70 possible points. Higher scores reflect greater cognitive impairment.

3. The Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) [Baseline and 6 months]

   Changes in the CDR-SOB. The CDR characterizes functioning in 6 domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. The score is obtained by summing each of the domain box scores. Scores range from 0 to 18 with higher scores reflecting worse cognition.

4. The Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23) [Baseline and 6 months]

   Changes in the ADCS-ADL23. The ADCS-ADL23 assesses basic and instrumental activities of daily living covering physical and mental functioning and independence in self-care. The score ranges from 0 to 78 with higher scores indicating less functional impairment.

5. The Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) [Baseline and 6 months]

   The ADCS-CGIC focuses 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 7-point scale with lower values (<4) representing an improvement, higher values (>4) representing a worsening, and a value of 4 indicating no change.

6. The Neuropsychiatric Inventory Questionnaire (NPI-Q) [Baseline and 6 months]

   Change on the NPI-Q. The NPI-Q comprises 12 domains: delusions, hallucinations, dysphoria, apathy, euphoria, disinhibition, aggressivity and restlessness, irritability, anxiety aberrant motor behavior, appetite and eating disorders, and nocturnal behavior. The severity of the reported symptoms is assessed on a 3-point scale. The total severity score can range from 0 to 36 with higher scores representing worse severity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of probable AD based upon the National Institute on Aging-Alzheimer's Association (NIA-AA) Criteria

• MMSE Score 12-24 inclusive

• Modified Hachinski Ischemia Scale (MHIS) score of ≤ 4

• Provided a signed and dated informed consent form (either the subject and/or subject's legal representative as well as the trial partner)

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.

• Initiation or change in the dosage of cholinesterase inhibitors (AChEI), memantine, Axona, vitamin E supplementation or selegiline within 3 months prior to screening.

• Heart disease (or history thereof), as evidenced by myocardial infarction, unstable, new onset or severe angina, or congestive heart failure (New York Association Class II, III or IV) in the 6 months prior to dosing; uncontrolled high blood pressure (systolic blood pressure of 160 mmHg or higher and/or diastolic blood

• 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

	Site	City	State	Country	Postal Code
1	Synergy East	Lemon Grove	California	United States	91945
2	CNS Network	Long Beach	California	United States	90806
3	Pacific Research Network	San Diego	California	United States	92103
4	MD Clinical	Hallandale Beach	Florida	United States	33009
5	Miami Jewish Health Systems	Miami	Florida	United States	33137
6	Behavioral Clinical Research	North Miami	Florida	United States	33161
7	Bioclinica Research	Orlando	Florida	United States	32806
8	Princeton Medical Institute	Princeton	New Jersey	United States	08540
9	Serenity Inpatient	DeSoto	Texas	United States	75115
10	PRA Health Sciences	Salt Lake City	Utah	United States	84124

Sponsors and Collaborators

• Alkahest, Inc.

Investigators

• Study Director: Alkahest Medical Monitor, Alkahest, Inc.

Study Documents (Full-Text)

• Study Protocol - Nov 2, 2018
• Statistical Analysis Plan - Jun 9, 2019

More Information

Publications

None provided.

• Responsible Party: Alkahest, Inc.
• ClinicalTrials.gov Identifier: NCT03520998
• Other Study ID Numbers: ALK6019-201
• First Posted: May 11, 2018
• Last Update Posted: Jan 29, 2021
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Alzheimer Disease

Study Results

Participant Flow

Arm/Group Title	GRF6019 Low Dose	GRF6019 High Dose
Arm/Group Description	Low dose of GRF6019 for 5 consecutive days at Weeks 1 and 13	High dose of GRF6019 for 5 consecutive days at Weeks 1 and 13
Period Title: Overall Study
STARTED	24	23
COMPLETED	18	21
NOT COMPLETED	6	2

Baseline Characteristics

Arm/Group Title	GRF6019 Low Dose	GRF6019 High Dose	Total
Arm/Group Description	Low dose of GRF6019 for 5 consecutive days at Weeks 1 and 13	High dose of GRF6019 for 5 consecutive days at Weeks 1 and 13	Total of all reporting groups
Overall Participants	24	23	47
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	75.9 (6.26)	72.7 (7.21)	74.3 (6.85)
Sex: Female, Male (Count of Participants)
Female	15 62.5%	14 60.9%	29 61.7%
Male	9 37.5%	9 39.1%	18 38.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 33.3%	7 30.4%	15 31.9%
Not Hispanic or Latino	16 66.7%	16 69.6%	32 68.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 4.3%	1 2.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 4.2%	3 13%	4 8.5%
White	23 95.8%	19 82.6%	42 89.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	24 100%	23 100%	47 100%

Outcome Measures

1. Primary Outcome

Title	Frequency of Treatment-emergent Adverse Events (Safety)
Description	Treatment-emergent adverse events identified by MedDRA preferred term and grouped by MedDRA System Organ Class
Time Frame	Baseline to 6 months

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	GRF6019 Low Dose	GRF6019 High Dose
Arm/Group Description	Low dose of GRF6019 for 5 consecutive days at Weeks 1 and 13	High dose of GRF6019 for 5 consecutive days at Weeks 1 and 13
Measure Participants	24	23
Count of Participants [Participants]	18 75%	20 87%

2. Secondary Outcome

Title	The Mini-Mental State Examination (MMSE)
Description	Changes in scores on the MMSE. 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 cognition.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Evaluable Set and Per Protocol Set

Arm/Group Title	GRF6019 Low Dose	GRF6019 High Dose
Arm/Group Description	Low dose of GRF6019 for 5 consecutive days at Weeks 1 and 13	High dose of GRF6019 for 5 consecutive days at Weeks 1 and 13
Measure Participants	21	22
Mean (Standard Deviation) [score on a scale]	-1.0 (4.3)	1.5 (3.9)

3. Secondary Outcome

Title	Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADASCog/11)
Description	Changes in scores on the 11-item ADASCog/11. The ADAS-Cog/11 includes 11 items assessing cognitive function. The domains include memory, language, praxis, and orientation. There are 70 possible points. Higher scores reflect greater cognitive impairment.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Evaluable Set and Per Protocol Set

Arm/Group Title	GRF6019 Low Dose	GRF6019 High Dose
Arm/Group Description	Low dose of GRF6019 for 5 consecutive days at Weeks 1 and 13	High dose of GRF6019 for 5 consecutive days at Weeks 1 and 13
Measure Participants	21	22
Mean (Standard Deviation) [score on a scale]	-0.4 (5.1)	-0.9 (4.3)

4. Secondary Outcome

Title	The Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB)
Description	Changes in the CDR-SOB. The CDR characterizes functioning in 6 domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. The score is obtained by summing each of the domain box scores. Scores range from 0 to 18 with higher scores reflecting worse cognition.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Evaluable Set and Per Protocol Set

Arm/Group Title	GRF6019 Low Dose	GRF6019 High Dose
Arm/Group Description	Low dose of GRF6019 for 5 consecutive days at Weeks 1 and 13	High dose of GRF6019 for 5 consecutive days at Weeks 1 and 13
Measure Participants	21	22
Mean (Standard Deviation) [score on a scale]	-0.03 (2.3)	0.21 (1.7)

5. Secondary Outcome

Title	The Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23)
Description	Changes in the ADCS-ADL23. The ADCS-ADL23 assesses basic and instrumental activities of daily living covering physical and mental functioning and independence in self-care. The score ranges from 0 to 78 with higher scores indicating less functional impairment.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Evaluable Set and Per Protocol Set

Arm/Group Title	GRF6019 Low Dose	GRF6019 High Dose
Arm/Group Description	Low dose of GRF6019 for 5 consecutive days at Weeks 1 and 13	High dose of GRF6019 for 5 consecutive days at Weeks 1 and 13
Measure Participants	21	22
Mean (Standard Deviation) [score on a scale]	-0.7 (7.4)	-1.3 (4.6)

6. Secondary Outcome

Title	The Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC)
Description	The ADCS-CGIC focuses 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 7-point scale with lower values (<4) representing an improvement, higher values (>4) representing a worsening, and a value of 4 indicating no change.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Evaluable Set and Per Protocol Set

Arm/Group Title	GRF6019 Low Dose	GRF6019 High Dose
Arm/Group Description	Low dose of GRF6019 for 5 consecutive days at Weeks 1 and 13	High dose of GRF6019 for 5 consecutive days at Weeks 1 and 13
Measure Participants	21	22
Mean (Standard Deviation) [score on a scale]	4.1 (0.8)	4.1 (0.7)

7. Secondary Outcome

Title	The Neuropsychiatric Inventory Questionnaire (NPI-Q)
Description	Change on the NPI-Q. The NPI-Q comprises 12 domains: delusions, hallucinations, dysphoria, apathy, euphoria, disinhibition, aggressivity and restlessness, irritability, anxiety aberrant motor behavior, appetite and eating disorders, and nocturnal behavior. The severity of the reported symptoms is assessed on a 3-point scale. The total severity score can range from 0 to 36 with higher scores representing worse severity.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Evaluable Set and Per Protocol Set

Arm/Group Title	GRF6019 Low Dose	GRF6019 High Dose
Arm/Group Description	Low dose of GRF6019 for 5 consecutive days at Weeks 1 and 13	High dose of GRF6019 for 5 consecutive days at Weeks 1 and 13
Measure Participants	21	22
Mean (Standard Deviation) [score on a scale]	-2.3 (3.8)	-1.2 (3.1)

Adverse Events

Time Frame	6 months
Arm/Group Title	GRF6019 Low Dose		GRF6019 High Dose
Arm/Group Description	Low dose of GRF6019 for 5 consecutive days at Weeks 1 and 13		High dose of GRF6019 for 5 consecutive days at Weeks 1 and 13
All Cause Mortality
	GRF6019 Low Dose		GRF6019 High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/23 (0%)
Serious Adverse Events
	GRF6019 Low Dose		GRF6019 High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		2/23 (8.7%)
Injury, poisoning and procedural complications
Infusion related reaction	0/24 (0%)	0	1/23 (4.3%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/24 (0%)	0	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	GRF6019 Low Dose		GRF6019 High Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/24 (50%)		14/23 (60.9%)
Gastrointestinal disorders
Diarrhoea	1/24 (4.2%)	1	2/23 (8.7%)	2
General disorders
Infusion site extravasation	3/24 (12.5%)	3	2/23 (8.7%)	2
Infusion site haematoma	1/24 (4.2%)	1	4/23 (17.4%)	4
Injury, poisoning and procedural complications
Fall	1/24 (4.2%)	1	2/23 (8.7%)	2
Investigations
Amylase increased	1/24 (4.2%)	1	2/23 (8.7%)	3
Lipase increased	1/24 (4.2%)	1	2/23 (8.7%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	2/24 (8.3%)	2	0/23 (0%)	0
Nervous system disorders
Headache	3/24 (12.5%)	4	5/23 (21.7%)	7
Vascular disorders
Hypertension	1/24 (4.2%)	1	2/23 (8.7%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.