A Study Assessing Bryostatin in the Treatment of Moderate... | NCT02431468

Label	Type	Description	Intervention Names
Bryostatin 1 20ug	Experimental	Bryostatin 20 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks.	Drug: Bryostatin 1
Bryostatin 1 40ug	Experimental	Bryostatin 40 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 48 micrograms administered weekly. A total of 7 doses administered over 12 weeks.	Drug: Bryostatin 1
Placebo	Placebo Comparator	Placebo administered IV over 45 minutes every other week after 2 initial doses administered weekly. A total of 7 doses administered over 12 weeks.	Other: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Bryostatin 1	Drug	The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Safety: Number of Subjects With Treatment-emergent Adverse Events and Serious Adverse Events	Evaluations of adverse events (AEs), serious adverse events (SAEs), Adverse event of special interest - myalgia	Baseline through 30 days post end of treatment (up to Day 107)
Efficacy: Change From Baseline in Severe Impairment Battery (SIB) in the Full Analysis Set (FAS)	The primary statistical objective for efficacy was to estimate the effect of bryostatin on the mean change in the total SIB score after 12 weeks of treatment, assessed at Week 13 (day 91). Efficacy analyses were conducted according to randomized groups. The SIB is used to assess cognition in subjects with moderate and severe AD. It is divided into nine subscales that include attention, language, orientation, memory, praxis, visuospatial ability, construction, social skills, orienting head to name. Non-verbal responses are allowed, thus decreasing the need for language output. Forty questions are included with a point score range of 0-100. Lower scores indicate greater cognitive impairment.	Primary analysis at Week 13 (day 91) after 12 weeks of treatment (up to day 107)

Secondary Outcomes

Measure	Description	Time Frame
Secondary Efficacy Endpoints	Change from baseline in the Severe Impairment Battery (SIB) at Weeks 5 and 9. Assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment. Change from baseline in Alzheimer Disease Cooperative Study Activities of Daily Living Inventory-Severe Impairment Version (ADCS-ADL-SEV) at Weeks 5, 9,13. A 19-item test of the performance of activities of daily living. Total score range 0-54; lower scores indicate greater functional impairment. Change from baseline in MMSE-2 at Weeks 5, 9 and 13. Tests selected aspects of cognition on a scale of 0-30. Lower scores indicate greater cognitive impairment. Change from baseline in Neuropsychiatric Inventory (NPI) at Weeks 5, 9,13. Caregiver interview assesses 12 behavioral disturbances. Scores range from 0-144; higher scores indicate greater behavioral disturbances. Clinical Global Impression of Improvement (CGI-I) at Weeks 5, 9, 13. A 7-point scale range from (1) very much improved to (7) very much worse.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Written informed consent from caregiver and subject (if possible) or legally acceptable representative if different from caregiver
Male and female subjects 55-85 years of age inclusive
Cognitive deficit present for at least 2 years that meet the diagnostic criteria for probable Alzheimer's
Mini Mental State Exam (MMSE-2) score of 4-15
Patients must be able to perform at least one item on the Severe Impairment Battery Scale
Neuroimaging (computerized tomography (CT) or Magnetic Resonance Imaging (MRI)) within the last 24 months consistent with a diagnosis of probable Alzheimer's disease (AD)
Reliable caregiver(s) or informant(s) who attends the subject at least an average of 3 hours or more per day for 3 or more days per week
Adequate vision and motor function to comply with testing
If taking drugs approved for treatment of Alzheimer's disease (e.g. cholinesterase inhibitors, memantine), must be on a stable dose for at least 3 months prior to entry into study and the dose must not change during the study unless a change is required due to an adverse event or a clinically significant change in the patient's status.

Exclusion Criteria:

Dementia due to any condition other than AD, including vascular dementia (Rosen-modified Hachinski lschemic score ≥ 5)
Evidence of significant central nervous system (CNS) vascular disease on previous neuroimaging including but not limited to: cortical stroke, multiple infarcts, localized single infarcts in the thalamus, angular gyrus, multiple lacunar infarcts or extensive white matter injury
Clinically significant neurologic disease or condition other than AD, such as cerebral tumor, chronic subdural fluid collections, Huntington's Disease, Parkinson's Disease, normal pressure hydrocephalus, or any other diagnosis that could interfere with assessment of safety and efficacy
Evidence of clinically significant unstable cardiovascular, pulmonary, renal, hepatic, gastrointestinal, neurologic, or metabolic disease within the 6 months prior to enrollment
Poorly controlled diabetes, at the discretion of the Principal Investigator
Creatinine clearance (CL) of <45ml/min
Use of an active Alzheimer's vaccine within 2 years prior to screening
Use of a monoclonal antibody for treatment of AD within 1 year prior to screening
Any medical or psychiatric condition that is likely to require initiation of additional medication or surgical intervention during the course of the study
Use of an investigational drug within 30 days prior to screening
Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in the study drug
Any other concurrent medical condition, which in the opinion of the PI makes the subject unsuitable for the clinical study

Facility	Status	City	State	ZIP	Country	Contacts
Xenoscience, Inc/ 21st Century Neurology		Phoenix	Arizona	85004	United States
ATP Clinical Research, Inc.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Bryostatin 1 20ug	Bryostatin 20 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Mar 3, 2017	Apr 26, 2018

Arm/Group Information

ID	Title	Description
BG000	Bryostatin 1 20ug	Bryostatin 20 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.
BG001	Bryostatin 1 40ug	Bryostatin 40 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 48 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.
BG002	Placebo	Placebo administered IV over 45 minutes every other week after 2 initial doses administered weekly. A total of 7 doses administered over 12 weeks. Placebo: The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the active drug, intended for IV infusion upon reconstitution and dilution.
BG003	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Safety: Number of Subjects With Treatment-emergent Adverse Events and Serious Adverse Events

Evaluations of adverse events (AEs), serious adverse events (SAEs), Adverse event of special interest - myalgia

Safety Analysis Set

Posted

Number

participants

Baseline through 30 days post end of treatment (up to Day 107)

ID	Title	Description
OG000	Bryostatin 1 20ug	Bryostatin 20 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.
OG001	Bryostatin 1 40ug	Bryostatin 40 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 48 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.
OG002	Placebo	Placebo administered IV over 45 minutes every other week after 2 initial doses administered weekly. A total of 7 doses administered over 12 weeks. Placebo: The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the active drug, intended for IV infusion upon reconstitution and dilution.

Units	Counts
Participants	OG00046 OG00147 OG00248

Title

Denominators

Categories

Number of Subjects w Treatment Emergent AE (TEAE)

Title	Measurements
	OG00030 OG00139 OG00228

# of Subjects w Treatment Related TEAE

Primary

Efficacy: Change From Baseline in Severe Impairment Battery (SIB) in the Full Analysis Set (FAS)

The primary statistical objective for efficacy was to estimate the effect of bryostatin on the mean change in the total SIB score after 12 weeks of treatment, assessed at Week 13 (day 91). Efficacy analyses were conducted according to randomized groups. The SIB is used to assess cognition in subjects with moderate and severe AD. It is divided into nine subscales that include attention, language, orientation, memory, praxis, visuospatial ability, construction, social skills, orienting head to name. Non-verbal responses are allowed, thus decreasing the need for language output. Forty questions are included with a point score range of 0-100. Lower scores indicate greater cognitive impairment.

The Full Analysis Set (FAS), consistent with a modified intention-to-treat principle (mITT), was defined as all randomized subjects who received at least one dose of randomized trial medication and who had at least one post-baseline assessment.

Posted

Mean

Standard Deviation

mean change from baseline in SIB score

Primary analysis at Week 13 (day 91) after 12 weeks of treatment (up to day 107)

ID	Title	Description
OG000	Bryostatin 1 20ug	Bryostatin 20 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.

Secondary

Secondary Efficacy Endpoints

Change from baseline in the Severe Impairment Battery (SIB) at Weeks 5 and 9. Assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment.
Change from baseline in Alzheimer Disease Cooperative Study Activities of Daily Living Inventory-Severe Impairment Version (ADCS-ADL-SEV) at Weeks 5, 9,13. A 19-item test of the performance of activities of daily living. Total score range 0-54; lower scores indicate greater functional impairment.
Change from baseline in MMSE-2 at Weeks 5, 9 and 13. Tests selected aspects of cognition on a scale of 0-30. Lower scores indicate greater cognitive impairment.
Change from baseline in Neuropsychiatric Inventory (NPI) at Weeks 5, 9,13. Caregiver interview assesses 12 behavioral disturbances. Scores range from 0-144; higher scores indicate greater behavioral disturbances.
Clinical Global Impression of Improvement (CGI-I) at Weeks 5, 9, 13. A 7-point scale range from (1) very much improved to (7) very much worse.

The number of participants analyzed over the course of the study diminished as a result of attrition.

Posted

Mean

Standard Deviation

mean change from baseline

Week 5, Week 9, Week 13

ID	Title	Description
OG000	Bryostatin 1 20ug	Bryostatin 20 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.

Post-Hoc

Severe Impairment Battery (SIB) Scores by Memantine Use at Baseline

Change from baseline in SIB score was compared between subjects receiving concurrent treatment with memantine and subjects not being treated with memantine.

Participants in the 3 treatment groups were further sorted by use of memantine. The number of participants in each category at each timepoint is noted. Attrition occurred through the course of the study.

Posted

Mean

Standard Deviation

mean change from baseline in SIB score

Assessments at weeks 5, 9, 13, and 30 days after end of treatment (up to day 107).

ID	Title	Description
OG000	Bryostatin 1 20ug With Memantine	Bryostatin 20 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.
OG001	Bryostatin 1 40ug With Memantine	Bryostatin 40 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 48 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Bryostatin 1 20ug	Bryostatin 20 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.	0	46	2	46	21	46
EG001	Bryostatin 1 40ug	Bryostatin 40 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 48 micrograms administered weekly. A total of 7 doses administered over 12 weeks. Bryostatin 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. Placebo is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.	1	47	6	47	46	47
EG002	Placebo	Placebo administered IV over 45 minutes every other week after 2 initial doses administered weekly. A total of 7 doses administered over 12 weeks. Placebo: The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the active drug, intended for IV infusion upon reconstitution and dilution.	0	48	4	48	12	48

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Pneumonia	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected46 at risk EG0010 events0 affected47 at risk EG0021 events1 affected48 at risk
Ovarian cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Systematic Assessment	EG0000 events0 affected46 at risk EG0010 events0 affected47 at risk EG0021 events1 affected48 at risk
Confusion postoperative	Nervous system disorders	Systematic Assessment	EG0000 events0 affected46 at risk EG0010 events0 affected47 at risk EG0021 events1 affected48 at risk
Bladder cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Systematic Assessment	EG0000 events0 affected46 at risk EG0010 events0 affected47 at risk EG0021 events1 affected48 at risk
Atrial fibrillation	Cardiac disorders	Systematic Assessment	EG0001 events1 affected46 at risk EG0010 events0 affected47 at risk EG0020 events0 affected48 at risk
Infusion Site Pain	General disorders	Systematic Assessment	EG0001 events1 affected46 at risk EG0010 events0 affected47 at risk EG0020 events0 affected48 at risk
Dementia Alzheimer's Type	Nervous system disorders	Systematic Assessment	EG0000 events0 affected46 at risk EG0011 events1 affected47 at risk EG0020 events0 affected48 at risk
Diabetic ketoacidosis	Metabolism and nutrition disorders	Systematic Assessment	EG0000 events0 affected46 at risk EG0011 events1 affected47 at risk EG0020 events0 affected48 at risk
Infusion site cellulitis	Infections and infestations	Systematic Assessment	EG0000 events0 affected46 at risk EG0012 events2 affected47 at risk EG0020 events0 affected48 at risk
Seizure	Nervous system disorders	Systematic Assessment	EG0000 events0 affected46 at risk EG0011 events1 affected47 at risk EG0020 events0 affected48 at risk
Syncope	Nervous system disorders	Systematic Assessment	EG0000 events0 affected46 at risk EG0011 events1 affected47 at risk EG0020 events0 affected48 at risk

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Myalgia	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0001 events1 affected46 at risk EG0016 events4 affected47 at risk EG0020 events0 affected48 at risk
Diarrhea	Gastrointestinal disorders	Systematic Assessment	EG0006 events5 affected46 at risk EG0015 events5 affected47 at risk EG0021 events1 affected48 at risk
Infusion site extravasation	General disorders	Systematic Assessment	EG0003 events3 affected46 at risk EG0014 events3 affected47 at risk EG0020 events0 affected48 at risk
Fatigue	General disorders	Systematic Assessment	EG0001 events1 affected46 at risk EG0015 events5 affected47 at risk EG0020 events0 affected48 at risk
Infusion site pain	General disorders	Systematic Assessment	EG0003 events3 affected46 at risk EG0010 events0 affected47 at risk EG0021 events1 affected48 at risk
Urinary tract infection	Infections and infestations	Systematic Assessment	EG0002 events2 affected46 at risk EG0013 events3 affected47 at risk EG0024 events4 affected48 at risk
Infusion site cellulitis	Infections and infestations	Systematic Assessment	EG0000 events0 affected46 at risk EG0014 events4 affected47 at risk EG0020 events0 affected48 at risk
Fall	Injury, poisoning and procedural complications	Systematic Assessment	EG0001 events1 affected46 at risk EG0015 events4 affected47 at risk EG0021 events1 affected48 at risk
Contusion	Injury, poisoning and procedural complications	Systematic Assessment	EG0001 events1 affected46 at risk EG0013 events3 affected47 at risk EG0020 events0 affected48 at risk
Weight decreased	Investigations	Systematic Assessment	EG0000 events0 affected46 at risk EG0015 events5 affected47 at risk EG0020 events0 affected48 at risk
Decreased appetite	Metabolism and nutrition disorders	Systematic Assessment	EG0001 events1 affected46 at risk EG0016 events6 affected47 at risk EG0022 events2 affected48 at risk
Headache	Nervous system disorders	Systematic Assessment	EG0004 events3 affected46 at risk EG0014 events4 affected47 at risk EG0023 events3 affected48 at risk

ID	Term
D003704	Dementia
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D024801	Tauopathies
D019636	Neurodegenerative Diseases
D019965	Neurocognitive Disorders
D001523	Mental Disorders

ID	Term
C046785	bryostatin 1
D054713	Bryostatins

ID	Term
D000095702	Polyether Toxins
D000095662	Polyether Polyketides
D004988	Ethers, Cyclic
D004987	Ethers
D009930	Organic Chemicals
D018942	Macrolides
D061065	Polyketides
D007783	Lactones
D047028	Macrocyclic Compounds
D011083	Polycyclic Compounds
D008387	Marine Toxins
D014118	Toxins, Biological
D001685	Biological Factors