Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Bisnorcymserine in Healthy Adult Volunteers

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) )
ClinicalTrials.gov Identifier:
NCT01747213
First received: December 8, 2012
Last updated: November 8, 2014
Last verified: January 2014
  Purpose

Background:

- Alzheimer s disease (AD) is a brain disease that impairs memory, cognitive abilities and the ability to function independently. It is the most common cause of dementia in older people. It is caused by abnormal proteins in the brain that affect how neurons communicate with each other. Researchers are looking for drugs that can slow down the disease or treat its symptoms. One drug, called bisnorcymserine (BNC), may help improve brain function and symptoms in people with AD. BNC is designed to block a chemical that affects how neurons communicate with each other. Researchers want to see how BNC works in healthy older volunteers.

Objectives:

- To look at how the body processes bisnorcymserine taken by mouth and how safe it is for healthy older volunteers.

Eligibility:

- Healthy volunteers at least 55 years of age.

Design:

  • Participants will be screened with a physical exam, medical history, and blood and urine tests.
  • Within 3 weeks from the screening visit, participants will come to the National Institute on Aging clinical unit for a 2-night stay. On the morning of the second day, they will take either a BNC capsule or a placebo. They will not know which tablet they are taking.
  • Blood samples will be collected frequently throughout the second and third days of the study visit. The last blood sample will be collected about 32 hours after taking the study capsule. Participants will have heart function tests and other exams during the visit. Once the tests are done, they will leave the clinical center.
  • Participants will have a final follow-up visit about 1 week after leaving the clinical center.

Condition Intervention Phase
Alzheimer's Disease
Drug: BNC
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: Phase I, Double-Blind, Placebo-Controlled, Ascending, Single-Dose, Safety, Tolerability and Pharmacokinetic Study of Bisnorcymserine (BNC), a Highly Selective Inhibitor of Butyrylcholinesterase, in Healthy Adult Volunteers

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Safety and tolerability [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacokinetics [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 200
Study Start Date: November 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: BNC
    N/A
Detailed Description:

Alzheimer s disease (AD) is an irreversible, progressive brain disease that slowly impairs memory and other cognitive abilities, as well as behavior and the ability to carry out tasks. It is the most common cause of dementia among older people. Alzheimer s disease is caused by deposits of abnormal proteins throughout the brain, causing neurons to lose their ability to communicate with each other effectively, and eventually die. Communication between neurons uses chemicals called neurotransmitters that are secreted from one neuron to another across a synapse. Acetylcholine (Ach) is one of the most important neurotransmitters. Damage to the Ach (-producing) system in the brain is associated with the cognitive and functional deficits in Alzheimer's disease. Restoring this deficit in the cholinergic system is one approach to treat the symptoms of Alzheimer's disease. The action of Ach in brain is stopped/ blocked mainly by two brain enzymes called cholinesterases (ChEs): acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Inhibitors of these enzymes therefore augment the activity of surviving Ach neurons in AD. All ChEs currently approved for the treatment of AD mainly inhibit AChE and, secondarily and to a varying extent, BChE activities. Nevertheless, BChE remains a viable target in AD and potent, reversible and brain-targeted BChE inhibitors have been developed (as a class of drugs called cymserine analogs). Scientists at the NIA/NIH have developed a novel BChE inhibitor called Bisnorcymserine (BNC). Pre-clinical evidence suggest that BNC may be a safe treatment for Alzheimer s disease. Based on this, we propose this first-in-human study to evaluate the safety, tolerability and pharmacokinetics of single doses of BNC tartrate administered orally to healthy volunteers aged 55 years and older using a double-blind placebo-controlled design. The proposed doses are: 20mg, 40mg, 80mg, 160mg, 270mg and 380mg given as a single oral dose. Each dose will be tested in groups of 8 subjects. Six subjects in each cohort will receive active drug and two will receive placebo. Subjects will be kept in the unit and followed clinically and with laboratory tests for adverse effects for 32 hours; they will return for a follow-up visit to assess safety in about 7 days. A Data Safety Monitoring Board will evaluate the safety and tolerability associated with each dose level before the next higher dose is tested in a new cohort. All research will be performed at the National Institute on Aging (NIA) Clinical Research Unit located on the 5th floor of MedStar Harbor Hospital.

  Eligibility

Ages Eligible for Study:   55 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

Age greater than or equal to 55 years.

Mini Mental State Examination (MMSE) > 27 at screening and at Visit 2-Day 1.

Women who are able to become pregnant must have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at screening and prior to study drug administration

Men must be using an adequate method of contraception (such as a barrier method, i.e. condoms with spermicide) to avoid conception throughout the study and for up to 30 days of study drug administration.

Body mass index (BMI) of 18.5 to 34.0, inclusive, and a total body weight of > 50 kg (110 pounds).

Participants should be in good general physical and mental health as determined by medical history, a baseline physical examination, vital signs, clinical laboratory tests and electrocardiogram (EKG). Participants may have common age-related disorders (such as hypertension, type II diabetes, dyslipidemia, hypothyroidism) as long as these disorders are being under good control by diet or medications.

EXCLUSION CRITERIA:

Any clinically significant medical and psychiatric condition (including asthma active within the last 10 years or COPD, drug abuse and dependency).

Subject has used any tobacco products in the past 3 months.

A history of significant allergy to any drug or systemic allergic disease (e.g., urticaria, atopic dermatitis).

Pregnant or lactating females.

Subject with a positive urine test for drugs of abuse at screening or at admission to the clinic on study Day 1.

Subject has consumed any alcohol within 48 hours prior to Visit 2; and cannot, thereafter, abstain from drinking alcohol for the remainder of the subject s study participation.

Subject is positive for HIV, hepatitis B surface antigen or hepatitis C antibody tests at screening.

Any clinically significant laboratory abnormality. These include,

  • CBC: WBC < 3000 /mm3, Hb < 12 g/dL
  • Liver function tests: ALT, AST, Bilirubin (total, direct, indirect), Alkaline Phosphatase > 1.5 x the upper normal limit of the laboratory
  • Serum Creatinine > 1.5 mg/dL
  • Serum Glucose > 150mg/dL

Subject who has resting supine blood pressure outside of a systolic blood pressure range of 90-140 mmHg or a diastolic blood pressure outside a range of 50-90 mmHg on two consecutive measurements taken up to 10 minutes apart.

Subject who has resting supine heart rate greater than 100 bpm or less than 60 bpm on two consecutive measurements taken up to 10 minutes apart.

Any clinically significant abnormality on screening 12-lead EKG (e.g., heart block, conduction disorders, ventricular and/or atrial arrhythmias).

Routine or PRN consumption of the following herbal/dietary supplements are not permitted, if used within 2 weeks before the screening visit at doses higher than the recommended daily intake: Omega-3 fatty acids (> 1000 mg/day), Vitamin E (> 400IU/day). Ginkgo biloba, St. John's wort and ginseng are not permitted, if used at any dose within 2 weeks before the screening visit.

Medications that are excluded are:

  • Insulin
  • Anti-parkinsonian medications (such as levodopa/carbidopa, amantadine, bromocriptine, pergolide, selegiline)
  • Typical or atypical neuroleptics
  • Narcotic analgesics at any dose within 4 weeks prior to screening.
  • Long-acting benzodiazepines or barbiturates (such as clonazepam, diazepam, phenobarbital) within 4 weeks prior to screening
  • Short-acting anxiolytics or sedative hypnotics more frequently than 2 times per week within 4 weeks prior to screening (sedative hypnotics should not be used within 102 hours of study drug administration)
  • Medications with known significant cholinergic or anticholinergic side effects (such as pyridostigmine, tricyclic antidepressants, meclizine, oxybutynin) within 4 weeks prior to screening
  • Anti-convulsants (such as phenytoin, Phenobarbital, carbamazepine) within 2 months prior to screening
  • Medications for Alzheimer s disease (such as donepezil or memantine)
  • Beta-Blockers
  • Corticosteroids (Systemic)
  • Neuromuscular-Blocking Agents (non-depolarizing)
  • Succinylcholine
  • Any other drug (including prescription, over the counter medications and supplements) that may pose a risk to the subject or produce overlapping side effects with the study medication.

Donation or loss of 400 mL or more of blood within 56 days prior to and subsequent to screening.

Participation in another research study involving an investigational drug within 30 days or 5 half-lives, whichever is longer.

Known allergy or hypersensitivity to the investigational study drug and to the starch used as placebo.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01747213

Contacts
Contact: Onyinye U Erondu, R.N. (410) 350-7319 onyinye.erondu@nih.gov
Contact: Dimitrios I Kapogiannis, M.D. (410) 350-3953 kapogiannisd@mail.nih.gov

Locations
United States, Maryland
National Institute on Aging, Clinical Research Unit Recruiting
Baltimore, Maryland, United States, 21224
Contact: NIA Studies Recruitment    410-350-3941    niastudiesrecruitment@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Dimitrios I Kapogiannis, M.D. National Institute on Aging (NIA)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) )
ClinicalTrials.gov Identifier: NCT01747213     History of Changes
Other Study ID Numbers: 130034, 13-AG-0034
Study First Received: December 8, 2012
Last Updated: November 8, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Neurodegenerative
Cholinergic
Single Dose
Inhibitor
Tolerability

Additional relevant MeSH terms:
Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Dementia
Mental Disorders
Nervous System Diseases
Neurodegenerative Diseases
Tauopathies

ClinicalTrials.gov processed this record on November 23, 2014