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: June 6, 2014
Last verified: January 2014

December 8, 2012
June 6, 2014
November 2012
December 2014   (final data collection date for primary outcome measure)
Safety and tolerability [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
Same as current
Complete list of historical versions of study NCT01747213 on ClinicalTrials.gov Archive Site
Pharmacokinetics [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Bisnorcymserine in Healthy Adult Volunteers
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

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.

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.

Interventional
Phase 1
Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Alzheimer's Disease
Drug: BNC
N/A
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
200
December 2014
December 2014   (final data collection date for primary outcome measure)
  • INCLUSION CRITERIA:

Age greater than or equal to 55 years.

Women of childbearing potential (WOCBP) must be using an adequate method of contraception (such as a barrier method, i.e. condoms with spermicide) to avoid pregnancy throughout the study and for up to 30 days after the study drug administration. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as:

  • Amenorrhea > 12 consecutive months without another cause, or
  • For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL.

Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) are considered to be of childbearing potential.

WOCBP 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 health as determined by medical history, a baseline physical examination, vital signs, clinical laboratory tests and electrocardiogram (EKG), at the clinical judgment of the Principal Investigator. Participants may have common age-related disorders (such as hypertension, type II diabetes, dyslipidemia, hypothyroidism) as long as these disorders are being controlled by diet or medication with a stable dose and regimen of medication for at least 2 months at the clinical judgment of the Principal Investigator.

Participant is willing and able to sign written informed consent prior to receipt of any study medication or beginning study procedures.

Participant is willing and able to follow instructions, comply with the protocol requirements and make all required study visits.

EXCLUSION CRITERIA:

Pregnant or lactating females.

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

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

Out-of range laboratory value at screening that has not been reviewed, approved and documented as not clinically significant by the Principal Investigator.

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 pulse rate greater than 100 bpm or less than 50 bpm on two consecutive measurements taken up to 10 minutes apart.

Subject has taken any alcohol within 48 hours of any study-related activities and cannot abstain from drinking alcohol during the entire duration of the subject s study participation.

Subject has used any tobacco products in the past 12 months.

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

A general medical or psychological condition or behavior, including current substance dependence or abuse that, in the opinion of the investigator, might not permit the subject to complete the study or sign the informed consent.

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 certain medications or herbal supplements that the subject is unwilling or advised by her/his physicians to not discontinue prior to and during the study. In particular, the following herbal/dietary supplements are not permitted, if used within 2 weeks prior to study drug administration at doses higher than the recommended daily intake: Omega-3 fatty acids (> 1000 mg/day), Vitamin E (> 400IU/day). Ginkgo biloba and ginseng are not permitted, if used at any dose within 2 weeks prior to study drug administration.

Medications that are excluded are:

  • Insulin
  • Anti-parkinsonian medications (such as sinemet, amantadine, bromocriptine, pergolide, selegiline)
  • Typical or atypical neuroleptics
  • Narcotic analgesics at any dose within 4 weeks prior to screening.
  • Long-acting benzodiazepines or barbiturates 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 or herbal medications) that would, in the opinion of the Principal Investigator, 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.

Inability to understand or follow study instructions.

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

Known allergy or hypersensitivity to the investigational study drug/placebo components.

Both
55 Years and older
Yes
Contact: Vickie L Schaffner (410) 350-7319 schaffnervl@mail.nih.gov
Contact: Dimitrios I Kapogiannis, M.D. (410) 350-3953 kapogiannisd@mail.nih.gov
United States
 
NCT01747213
130034, 13-AG-0034
Not Provided
National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) )
National Institute on Aging (NIA)
Not Provided
Principal Investigator: Dimitrios I Kapogiannis, M.D. National Institute on Aging (NIA)
National Institutes of Health Clinical Center (CC)
January 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP