A Study to Assess the Safety of GRF6021 Infusions in Subjects With Parkinson's Disease and Cognitive Impairment

• ClinicalTrials.gov Identifier: NCT03713957
• Recruitment Status: Completed
• First Posted: October 22, 2018
• Results First Posted: May 9, 2022
• Last Update Posted: May 9, 2022
• Sponsor: Alkahest, Inc.
• Collaborator: Michael J. Fox Foundation for Parkinson's Research
• Information provided by (Responsible Party): Alkahest, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Parkinson Disease
• Interventions: Drug: GRF6021; Other: Placebo
• Enrollment: 79

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	GRF6021	Placebo
Arm/Group Description	Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Period Title: Overall Study
Started	53	26
Completed	35	16
Not Completed	18	10

Baseline Characteristics

Arm/Group Title		GRF6021	Placebo	Total
Arm/Group Description		Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion	Total of all reporting groups
Overall Number of Baseline Participants		53	26	79
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	53 participants	26 participants	79 participants
		67.1 (7.63)	68.4 (8.88)	67.5 (8.03)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	53 participants	26 participants	79 participants
	Female	16 30.2%	10 38.5%	26 32.9%
	Male	37 69.8%	16 61.5%	53 67.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	53 participants	26 participants	79 participants
	Hispanic or Latino	25 47.2%	13 50.0%	38 48.1%
	Not Hispanic or Latino	28 52.8%	13 50.0%	41 51.9%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	53 participants	26 participants	79 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	9 17.0%	2 7.7%	11 13.9%
	White	44 83.0%	24 92.3%	68 86.1%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	53 participants	26 participants	79 participants
United States		47 88.7%	23 88.5%	70 88.6%
Australia		1 1.9%	0 0.0%	1 1.3%
France		5 9.4%	3 11.5%	8 10.1%

Outcome Measures

1. Primary Outcome

Title	Incidence of Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description	Treatment-emergent adverse events identified by MedDRA preferred term and grouped by MedDRA System Organ Class
Time Frame	Approximately 24 Months

Outcome Measure Data

Analysis Population Description

The Safety Set includes all subjects at least one dose of the study agent. All safety analyses were performed using the Safety Set, based on treatment received.

Arm/Group Title	GRF6021	Placebo
Arm/Group Description:	Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed	51	25
Measure Type: Number; Unit of Measure: participants
Participants with at least one TEAE	45	20
Participants with at least one SAE	5	0

2. Secondary Outcome

Title	The Montreal Cognitive Assessment (MoCA) Score.
Description	Change from baseline in the The Montreal Cognitive Assessment (MoCA). The MoCA is a 30-point test, which assess the attention and concentration, executive functions, memory, visuospatial abilities, language abilities, conceptual thinking, calculations, and orientation. Higher scores indicate better cognitive function; the total possible score is 30 and a score of 26 or more is considered normal. A positive value of change means an improvement, and a negative value of change means deterioration. Score range [0 (min) - 30 (Max)].
Time Frame	Change from Baseline to Week 16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GRF6021	Placebo
Arm/Group Description:	Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed	44	22
Mean (Standard Deviation); Unit of Measure: score on a scale
	1.30 (3.62)	0.80 (3.13)

3. Secondary Outcome

Title	Continuity of Attention, Reaction Time Variability, Working Memory, and Episodic Memory on the Cognitive Drug Research Computerized Cognition Battery (CDR-CCB) as Assessed by Change From Baseline in CDR-CCB.
Description	The CDR-CCB is an automated cognitive function assessment system. The secondary efficacy outcomes involved the following composite scores: Continuity of Attention: Min: - 20 # ; 35 #; Reaction Time Variability: Min: 0 #; Max: 900 #; Quality of Working Memory: Min : 0 # ; Max: 2 #; Quality of Episodic Memory: Min: -400 #; Max: 400 # Note: # denotes "no specific unit" Lower scores reflect poorer ability for Continuity of Attention, Quality of Working Memory, and Quality of Episodic Memory; thus, a negative change from baseline reflects impairment compared to baseline. Whereas, for Reaction Time Variability, higher scores reflect poorer ability, and a positive change from baseline reflects impairment compared to baseline.
Time Frame	Change from Baseline to Week 20

Outcome Measure Data

Analysis Population Description

A subset of the Evaluable set comprised of subjects who receive all 10 planned doses, who complete Visit 18 and Visit 19 in window, and who do not have any of the deviations listed below or any other deviation that could potentially affect the assessment of efficacy identified prior to database lock.

Arm/Group Title		GRF6021	Placebo
Arm/Group Description:		Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed		35	16
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
Continuity of Attention	Number Analyzed	35 participants	16 participants
		-0.42 (1.12)	-0.28 (1.12)
Reaction Time Variability	Number Analyzed	35 participants	16 participants
		4.67 (8.40)	2.87 (8.40)
Quality of Working Memory	Number Analyzed	34 participants	16 participants
		0.09 (0.12)	-0.04 (0.12)
Quality of Episodic Memory	Number Analyzed	33 participants	16 participants
		-10.02 (15.82)	8.65 (15.82)

4. Secondary Outcome

Title	The Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency.
Description	Change from baseline in the Delis-Kaplan Executive Function System (D-KEFS). The D-KEFS Verbal Fluency test is used for assessment of executive function and has three conditions: Letter Fluency, Category Fluency, and Category Switching. Higher scores indicate more correct responses. A positive value of change means an improvement and a negative value of change means deterioration. The minimum score is 0 and there is no concrete maximum score.
Time Frame	Change from Baseline to Week 20

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GRF6021	Placebo
Arm/Group Description:	Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed	40	20
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	5.00; (-3.12 to 13.13)	-1.59; (-11.77 to 8.58)

5. Secondary Outcome

Title	The Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 1, 2, 3, and Total Score.
Description	Change from baseline in the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UPDRS contains 4 subscales: Part 1, Mentation, Behavior, and Mood; Part 2, Activities of Daily Living; Part 3, Motor; Part 4, Complications nonmotor experiences of daily living (13 items), motor experiences of daily living (13 items), motor examination (18 items), and motor complications (six items). The rating for each item is from 0 (normal) to 4 (severe). The total score for each Part is obtained from the sum of the corresponding item scores. For this study, Parts 1-3 will be completed. Part 1 score ranges from 0 to 52. Part 2 score ranges from 0 to 52. Part 3 score ranges from 0 to 132. Total score possible is 0 to 236.
Time Frame	Change from Baseline to Week 16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GRF6021	Placebo
Arm/Group Description:	Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed	44	22
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-8.89; (-13.74 to -4.04)	-9.53; (-16.43 to -2.64)

6. Secondary Outcome

Title	The Schwab and England Activities of Daily Living (SE-ADL) Scale.
Description	Change from baseline in the Schwab and England Activities of Daily Living (SE-ADL). The SE-ADL evaluates patients' perceptions of global functional capacity and dependence. Scoring is expressed in terms of percentage, in 10 steps from 100 to 0 (100%, normal status; 0%, bedridden with vegetative dysfunction), so that the lower the score, the worse the functional status. The range is 0% to 100%.
Time Frame	Change from Baseline to Week 24

Outcome Measure Data

Analysis Population Description

The difference between the Number Analyzed at Baseline and week 24 timepoint is due the withdrawal of participants or missed assessments.

Arm/Group Title		GRF6021	Placebo
Arm/Group Description:		Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed		50	25
Measure Type: Count of Participants; Unit of Measure: Participants
Baseline	Number Analyzed	50 participants	25 participants
	100% Independency	2 4.0%	2 8.0%
	90% Independency	10 20.0%	2 8.0%
	80% Independency	21 42.0%	11 44.0%
	70% Independency	9 18.0%	4 16.0%
	60% Independency	3 6.0%	4 16.0%
	50% Independency	1 2.0%	0 0.0%
	40% Independency	1 2.0%	1 4.0%
	30% Independency	3 6.0%	0 0.0%
	20% Independency	0 0.0%	1 4.0%
	10% Independency	0 0.0%	0 0.0%
	0% Independency	0 0.0%	0 0.0%
Week 24	Number Analyzed	43 participants	21 participants
	100% Independency	2 4.7%	1 4.8%
	90% Independency	10 23.3%	4 19.0%
	80% Independency	15 34.9%	7 33.3%
	70% Independency	6 14.0%	4 19.0%
	60% Independency	4 9.3%	2 9.5%
	50% Independency	3 7.0%	1 4.8%
	40% Independency	1 2.3%	0 0.0%
	30% Independency	1 2.3%	1 4.8%
	20% Independency	0 0.0%	1 4.8%
	10% Independency	1 2.3%	0 0.0%
	0% Independency	0 0.0%	0 0.0%

7. Secondary Outcome

Title	The Clinical Impression of Severity Index - PD (CISI-PD).
Description	Change from baseline in The Clinical Impression of Severity Index PD (CISI-PD). The CISI-PD is a severity index formed by four items (motor signs, disability, motor complications, and cognitive status), rated 0 (not at all) to 6 (very severe or completely disabled); the possible scores range from 0 to 24. A total score is calculated by summing the item scores. Higher scores indicate worse severity. A negative value of change means an improvement and a positive value of change means deterioration.
Time Frame	Change from Baseline to Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GRF6021	Placebo
Arm/Group Description:	Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed	43	21
Least Squares Mean (95% Confidence Interval); Unit of Measure: change from baseline score
	-0.54; (-1.91 to 0.83)	-0.55; (-2.34 to 1.24)

8. Secondary Outcome

Title	The Parkinson's Disease Quality of Life Questionnaire-39 (PDQ-39).
Description	Change from baseline in the Parkinson's Disease Quality of Life Questionnaire-39 (PDQ-39). The PDQ-39 is a self-administered questionnaire of 39 questions relating to 8 key areas of health and daily activities, including both motor and non-motor symptoms. It is scored on a scale of 0 -100 with lower scores indicating better health and high scores indicating more severe symptoms.
Time Frame	Change from Baseline to Week 20

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GRF6021	Placebo
Arm/Group Description:	Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed	40	18
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-4.88; (-11.46 to 1.69)	-6.29; (-14.81 to 2.23)

9. Secondary Outcome

Title	The Geriatric Depression Scale-15 (GDS-15).
Description	Change from baseline in the Geriatric Depression Scale (GDS-15). The GDS-15 is a 15-item yes/no questionnaire of depression in older adults. Each depressive answer is 1 point. The final score is the tally of the number of depressive answers with the following scores indicating depression: 0-4 No depression; 5-10 Suggestive of a mild depression; 11 + Suggestive of severe depression. The possible scores range from 0 - 15.
Time Frame	Change from Baseline to Week 20

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GRF6021	Placebo
Arm/Group Description:	Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed	41	20
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	0.30; (-1.30 to 1.89)	0.27; (-1.74 to 2.27)

10. Secondary Outcome

Title	The Digital Clock Drawing Test (dCDT).
Description	Change from baseline in the digital clock drawing test (dCDT). The pen-like dCDT device will be used to gather the x-y coordinates that describe the movement of the stylus as it changes its position during the assessment. It also assesses when the stylus or writing device is not exerting pressure on the writing surface. The dCDT score is a number from 0 and 100 that represents a person's overall cognitive function as assessed by DCT clock. The total possible score is 100. A negative value of change means a deterioration and a positive value of change means an improvement.
Time Frame	Change from Baseline to Week 20

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GRF6021	Placebo
Arm/Group Description:	Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed	36	20
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	9.25; (1.69 to 16.80)	1.58; (-7.61 to 10.77)

11. Secondary Outcome

Title	Power of Attention, Cognitive Reaction Time, and Speed of Memory on the Cognitive Drug Research Computerized Cognition Battery (CDR-CCB) as Assessed by Change From Baseline in CDR-CCB.
Description	The CDR-CCB is an automated cognitive function assessment system. The secondary efficacy outcomes involved the following composite scores: Power of Attention: Min: 350 ms ; Max: 60000 ms; Cognitive Reaction Time: Min: - 30000 ms; Max : 30000 ms; Speed of Memory: Min 800 ms; Max: 120000 ms Higher scores reflect poorer ability, and a positive change from baseline reflects impairment compared to baseline.
Time Frame	Change from Baseline to Week 20

Outcome Measure Data

Analysis Population Description

A subset of the Evaluable set comprised of subjects who receive all 10 planned doses, who complete Visit 18 and Visit 19 in window, and who do not have any of the deviations listed below or any other deviation that could potentially affect the assessment of efficacy identified prior to database lock.

Arm/Group Title		GRF6021	Placebo
Arm/Group Description:		Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion	Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
Overall Number of Participants Analyzed		35	16
Least Squares Mean (Standard Error); Unit of Measure: ms
Power of Attention	Number Analyzed	35 participants	16 participants
		28.14 (90.89)	133.32 (90.89)
Cognitive Reaction Time	Number Analyzed	35 participants	16 participants
		-49.49 (75.69)	35.45 (75.69)
Speed of Memory	Number Analyzed	33 participants	16 participants
		46.97 (331.56)	232.33 (331.56)

Adverse Events

Time Frame	24 Months
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	GRF6021		Placebo
Arm/Group Description	Subjects will receive GRF6021 for 5 consecutive days at Week 1 and Week 13. GRF6021: GRF6021 for IV infusion		Subjects will receive Placebo for 5 consecutive days at Week 1 and Week 13. Placebo: Placebo for IV infusion
All-Cause Mortality
	GRF6021		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/51 (0.00%)		0/25 (0.00%)
Serious Adverse Events
	GRF6021		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/51 (9.80%)		0/25 (0.00%)
General disorders
Gastritis †	1/51 (1.96%)	1	0/25 (0.00%)	0
Injury, poisoning and procedural complications
Road Traffic Accident †	1/51 (1.96%)	1	0/25 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer †	1/51 (1.96%)	1	0/25 (0.00%)	0
Psychiatric disorders
Mental Changes †	1/51 (1.96%)	1	0/25 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism †	1/51 (1.96%)	1	0/25 (0.00%)	0
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	GRF6021		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/51 (88.24%)		20/25 (80.00%)
Gastrointestinal disorders
Diarrhoea †	3/51 (5.88%)	3	1/25 (4.00%)	1
General disorders
Oedema peripheral †	2/51 (3.92%)	2	2/25 (8.00%)	2
Infections and infestations
Upper respiratory tract infection †	4/51 (7.84%)	4	1/25 (4.00%)	1
Injury, poisoning and procedural complications
Fall †	7/51 (13.73%)	7	1/25 (4.00%)	1
Laceration †	3/51 (5.88%)	3	1/25 (4.00%)	1
Investigations
Blood pressure diastolic decreased †	2/51 (3.92%)	2	4/25 (16.00%)	4
Musculoskeletal and connective tissue disorders
Arthralgia †	4/51 (7.84%)	4	0/25 (0.00%)	0
Back Pain †	1/51 (1.96%)	1	3/25 (12.00%)	3
Nervous system disorders
Headache †	8/51 (15.69%)	8	2/25 (8.00%)	2
Dizziness †	5/51 (9.80%)	5	1/25 (4.00%)	1
Vascular disorders
Hypotension †	6/51 (11.76%)	6	2/25 (8.00%)	2
Hypertension †	2/51 (3.92%)	2	2/25 (8.00%)	2
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Clinical Trial Agreement contains language that restricts the PI from discussing or publishing Sponsor confidential and/or proprietary information. The embargo period may be extended by mutual agreement of the Sponsor and PI.

Results Point of Contact

• Name/Title: Head of Communications
• Organization: Alkahest, Inc.
• Phone: (650) 801-0474
• EMail: info@alkahest.com

• Responsible Party: Alkahest, Inc.
• ClinicalTrials.gov Identifier: NCT03713957
• Other Study ID Numbers: Alkahest study 6021-201
• First Submitted: October 18, 2018
• First Posted: October 22, 2018
• Results First Submitted: December 8, 2021
• Results First Posted: May 9, 2022
• Last Update Posted: May 9, 2022