Safety of Bryostatin in Patients With MS

• ClinicalTrials.gov Identifier: NCT06190912
• Recruitment Status: Recruiting
• First Posted: January 5, 2024
• Last Update Posted: May 2, 2024
• Sponsor: Robert Fox
• Collaborator: Synaptogenix, Inc.
• Information provided by (Responsible Party): Robert Fox, The Cleveland Clinic

Study Description

Brief Summary:

This is a single-site, single-arm, single-dose, Phase 1 study of the safety of bryostatin in participants with multiple sclerosis (MS) receiving any disease modifying therapy (DMT).

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis	Drug: Bryostatin 1	Phase 1

Detailed Description:

The study is 42 weeks in duration, including safety and exploratory outcomes evaluation at 30 days after the last full assessment (Week 28) and long-term follow-up at 12 weeks after the last full assessment (Week 40). Participants will receive a total of 14 doses over 26 weeks.

Eligible participants will be treated with bryostatin over a 26-week period. Doses 1, 2, 8, and 9 of the study drug will be a loading dose 20% higher (i.e., 24 µg) than the assigned fixed dose and will be administered one week apart. Otherwise, the assigned fixed dose is 20 µg. Drug is administered intravenously (IV) by continuous infusion over 45 (±5) minutes. Participants are scheduled to receive 14 doses over 26 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single-Arm, Single-Site, Single-Dose Phase 1 Study Assessing the Safety of Bryostatin in the Treatment of Patients With Multiple Sclerosis
• Actual Study Start Date: April 11, 2024
• Estimated Primary Completion Date: April 2026
• Estimated Study Completion Date: August 2026

Arms and Interventions

Arm

Intervention/treatment

Experimental: Bryostatin 1; Participants in this arm will receive treatment with Bryostatin 1

Drug: Bryostatin 1; Eligible participants will be treated with bryostatin over a 26-week period. Doses 1, 2, 8, and 9 of the study drug will be a loading dose 20% higher (i.e., 24 µg) than the assigned fixed dose and will be administered one week apart. Otherwise, the assigned fixed dose is 20 µg. Drug is administered intravenously (IV) by continuous infusion over 45(±5) minutes. Participants are scheduled to receive 14 doses over 26 weeks.

Outcome Measures

Primary Outcome Measures :

1. Adverse Events [ Time Frame: Over 40 weeks ]
   Frequency of Adverse Events [Treatment Emergent AEs (TEAEs), Serious Adverse Events (SAEs), and Suspected Unexpected Serious Adverse Reactions (SUSARS)]
2. Study Medication Discontinuation [ Time Frame: Over 40 weeks ]
   Frequency of study medication discontinuation and reason thereof
3. CNS inflammatory effects [ Time Frame: Over 40 weeks ]
   Potential CNS inflammatory effects as captured by clinical monitoring and MRI

Other Outcome Measures:

1. Exploratory outcome: MRI Biomarkers (lesion volume) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
   Lesion volume
2. Exploratory outcome: MRI Biomarkers (BPF) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
   Brain parenchymal fraction
3. Exploratory outcome: MRI Biomarkers (default mode network) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
   Default mode network
4. Exploratory outcome: MRI Biomarkers (microstructural complexity of dendrites and axons) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
   Diffusion MRI measures of tissue integrity
5. Exploratory outcome: MRI Biomarkers (anatomical connectivity of transcallosal motor pathway) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
   Anatomical connectivity of transcallosal motor pathway
6. Exploratory outcome: MRI Biomarkers (MWF) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
   Myelin water fraction
7. Exploratory outcome: MRI Biomarkers (measure of myelination) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
   Magnetization transfer ratio
8. Exploratory outcome: MRI Biomarkers (measure of myelination) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
   Quantitative T2*
9. Exploratory outcome: MRI Biomarkers (measure of myelination) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
   Quantitative susceptibility mapping
10. Exploratory outcome: MRI Biomarkers (GMA) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
    Grey matter atrophy
11. Exploratory outcome: MRI Biomarkers (GMF) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
    Grey matter fraction
12. Exploratory outcome: MRI Biomarkers (WMF) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
    White matter fraction
13. Exploratory outcome: MRI Biomarkers (CA) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
    Cortical atrophy
14. Exploratory Outcome: MoCA [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
    Montreal Cognitive Assessment test
15. Exploratory Outcome: EDSS [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
    Expanded Disability Status Scale
16. Exploratory Outcomes: MS Performance Test Domains (Lower Extremity) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
    Walking Speed Test (WST)
17. Exploratory Outcomes: MS Performance Test Domains (Upper Extremity) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
    Manual dexterity test (MDT)
18. Exploratory Outcomes: MS Performance Test Domains (Cognition) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
    Processing speed test (PST)
19. Exploratory Outcomes: Quality of life (NEURO-QoL) [ Time Frame: Changes from baseline to Week 11, Week 28, and Week 40 ]
    Quality of Life in Neurological Disorders (NEURO-QoL)
20. Exploratory Outcomes: CVLT3 [ Time Frame: Change from baseline to Week 28 and Week 40 ]
    California Verbal Learning Test 3rd Edition (CVLT3)
21. Exploratory Outcomes: BVMT-R [ Time Frame: Change from baseline to Week 28 and Week 40 ]
    Brief Visuospatial Memory Test - Revised (BVMT-R)
22. Exploratory Outcomes: JOLO [ Time Frame: Change from baseline to Week 28 and Week 40 ]
    Judgement of Line Orientation (JOLO)
23. Exploratory Outcomes: BNT [ Time Frame: Change from baseline to Week 28 and Week 40 ]
    Boston Naming Test (BNT)
24. Exploratory Outcomes: D-KEFS (Sorting) [ Time Frame: Change from baseline to Week 28 and Week 40 ]
    Delis-Kaplan Executive Function System (D-KEFS) Sorting Test
25. Exploratory Outcomes: COWAT [ Time Frame: Change from baseline over 40 weeks ]
    Controlled Oral Word Association Test

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion

1. Written informed consent signed by participant
2. English-speaking
3. Hospital Anxiety and Depression Scale <11
4. Male and female participants, 18-60 years of age inclusive
5. Established diagnosis of MS, as defined by the 2017 revision of McDonald Diagnostic Criteria (any form of MS). A diagnosis of MS must be confirmed at the time of the screening visit.
6. Processing Speed Test (PST) z-score between -1.0 and -2.5
7. EDSS between 0.0 and 7.0, inclusive.
8. Adequate vision and motor function to participate in assessment procedures
9. Participants must be on a stable dose of a DMT for at least 1 year prior to entry into the study, and the dose should not change during the study unless a change is required by a clinically significant change in the participant's status.

10. Females participating in the study must meet one the following criteria:

    1. Surgically sterilized (e.g., hysterectomy, bilateral oophorectomy or tubal ligation) for at least 6 months or postmenopausal (postmenopausal females must have no menstrual bleeding for at least 1 year) or
    2. If not postmenopausal, agree to use a double method of contraception, one of which is a barrier method (e.g., intrauterine device plus condom, spermicidal gel plus condom) 30 days prior to dosing until 30 days after last dose and have negative human chorionic gonadotropin (β-hCG) test for pregnancy at screening. Contraception methods resulting in an overall failure rate of <1 % per year are required for women of childbearing potential.
11. Males who have not had a vasectomy must use appropriate contraception methods (barrier or abstinence) from 30 days prior to dosing until 30 days after last dose
12. Participants should be in reasonably good health over the last 6 months and any chronic disease should be stable.

Exclusion

1. Evidence of significant 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
2. Clinically significant neurologic disease or condition other than MS, 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
3. Previous history of seizures or seizure disorders.
4. Evidence of clinically significant unstable cardiovascular, pulmonary, renal, hepatic, gastrointestinal, neurologic, or metabolic disease within the 6 months prior to enrollment. If there is a history of cancer, the participant should be clear of cancer for at least 2 years prior to screening. More recent history of basal cell or squamous cell carcinoma and melanoma in situ (Stage 0) may be acceptable after review by the Medical Monitor.
5. Estimated Glomerular Filtration Rate (eGFR) of <45ml/min
6. Poorly controlled diabetes (at the discretion of the Principal Investigator)
7. Use of vitamin E > 400 International Units (IU) per day within 14 days prior to screening
8. Use of valproic acid and/or lithium within 14 days prior to screening
9. Routine or intermittent use of benzodiazepines in the last year (rare use in the last year is allowed as long as use during the study is not expected).
10. Use of carbamazepine within 7 days prior to screening
11. Use of teriflunomide within 90 days prior to screening
12. Use of dalfampridine within 7 days of screening
13. Current use of acetaminophen, ciprofloxacin, and/or trimethoprim/sulfamethoxazole
14. At the discretion of the PI, any medical or psychiatric condition that is unstable or may require the initiation of additional medication or surgical intervention during the course of the study
15. Any screening laboratory values outside the laboratory reference ranges that are deemed clinically significant by the PI
16. Use of an investigational drug within 30 days prior to screening
17. Suicidality defined as active suicidal thoughts during the 6 months prior to screening or at Baseline [SBQ-R], or history of suicide attempt in previous 2 years, or at serious suicide risk in study neurologist or PI's judgment
18. Major psychiatric illness such as currently uncontrolled major depression according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, current or past diagnosis of bipolar disorder, schizophrenia, or any other psychiatric disorder that might interfere with the assessments of safety or efficacy at the discretion of the PI
19. Diagnosis of alcohol or drug abuse within the last 2 years
20. History of prolonged QT or prolonged QT on screening ECG [QT correction with Bazett formula (QTcB) or QT correction by Fridericia (QTcF)>499 per central reader]
21. Acute or poorly controlled medical illness: blood pressure >180 mmHg systolic or 100 mmHg diastolic; myocardial infarction within 6 months; uncompensated congestive heart failure [New York Heart Association (NYHA) Class III or IV]
22. Known to be seropositive for Hepatitis B or C, unless successful curative treatment for Hepatitis C (e.g., Harvoni) has been received, and there is documentation that there is no Hepatitis B/C virus detected 3 months after completion of treatment
23. Known to be seropositive for human immunodeficiency virus (HIV)
24. Pregnancy or breastfeeding during the study. A β-hCG serum pregnancy test will be performed at Screening for female patients of child-bearing potential.
25. Aspartate Amino Transferase (AST) or Alanine Aminotransferase (ALT) >3x upper limit of normal (ULN) and total bilirubin >2x ULN or International Normalized Ratio (INR) >1.5
26. History of significant bleeding disorders.
27. Moderate baseline thrombocytopenia (platelets <100K/uL).
28. Elevated INR (PTT >2.0).
29. Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in the study drug
30. Any other concurrent medical condition, which in the opinion of the PI makes the participant unsuitable for the clinical study

Contacts and Locations

Contacts

Contact: Alexis Novak; 216-445-8597; novaka5@ccf.org

Contact: Sarah M Planchon Pope, PhD; 216-636-1232; planchs@ccf.org

Locations

United States, Ohio

Cleveland Clinic; Recruiting

Cleveland, Ohio, United States, 44195

Contact: Ariel Bizon 216-445-9411 bizona@ccf.org

Contact: Bryan Davies, RN 216-444-5253 daviesb@ccf.org

Sponsors and Collaborators

Robert Fox

Synaptogenix, Inc.

Investigators

• Principal Investigator: Robert J Fox, MD; The Cleveland Clinic

More Information

• Responsible Party: Robert Fox, ice Chair for Research, Neurological Institute, Staff Neurologist, Cleveland Clinic Mellen Center for MS Treatment and Research, The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT06190912
• Other Study ID Numbers: 24-099
• First Posted: January 5, 2024
• Last Update Posted: May 2, 2024
• Last Verified: May 2024

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

Additional relevant MeSH terms:

Bryostatin 1; Multiple Sclerosis; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents