Whole Coffee Fruit Concentrate Pilot Study 1
Condition: Brain-derived Neurotrophic Factor (BDNF); Cognitive Function; Affect
Study type: Interventional

Summary: 
      The purpose of this pilot study is to evaluate the potential effects of whole coffee fruit
      concentrate (WCFC, Neurofactor), a product that elevates circulating brain-derived
      neurotrophic factor (BDNF), on cognition and mood in healthy adults.

      The projected outcome of this study is that self-administration of Neurofactor for 28 days
      (or even 14 days) will be associated with an improvement in mood and scores on cognitive
      tests, and that the change will exceed that observed with administration of Nutrim (placebo).

      Volunteers will be recruited from the greater Los Angeles community. Participants will be
      middle-aged nonsmokers, in good health, and between the ages of 40-55 to enhance the chance
      of demonstrating pro-cognitive effects. Younger participants, whose cognitive performance is
      expected to be higher, may perform at a ceiling level, with less room for improvement by the
      product under study.

      Participants who call our lab will be told about the study in more detail, and will complete
      a 5 minute phone screener to determine preliminary eligibility. After the initial telephone
      screening, participants will visit Dr. London's laboratory at UCLA to provide written
      informed consent.

      The first study visit will be an in-person screening visit to determine full eligibility. The
      evaluation will include a psychiatric diagnostic interview, using the SCID, blood tests,
      urine samples (to test for drug use and pregnancy). Participants will also be interviewed
      about their prior and current drug use, including tobacco use. In addition, participants will
      be interviewed about the nature of their employment and physical exercise habits: endurance
      training has been shown to increase plasma BDNF in young men.

      Participants meeting the inclusion criteria will attend the Semel Institute for Neuroscience
      and Human Behavior at UCLA to take part in baseline measurements, and to be randomized to
      receive either WCFC or placebo. During the active treatment time (28 days), they will visit
      the UCLA Semel Institute on a weekly basis. At each of these weekly visits, questionnaires
      regarding compliance will be completed, and blood samples will be taken for assay of BDNF. A
      cognitive test battery and mood-rating scales will be completed at baseline and at 14 and 28
      days of treatment. At the midpoint assessment (14 days) and at completion of treatment (28
      days) blood will be drawn for assay of a blood chemistry panel (as at baseline) as well as
      for biomarkers in addition to BDNF.
    

Detailed description: 
      Participants (n=23; 20 completing with usable data) will come to UCLA for 1 in-person
      screening visit and 4 weekly study visits, culminating in a total of 5 study visits. Those
      who meet eligibility criteria will take part in a baseline test session (before
      randomization) to collect cognitive and behavioral data as well as baseline plasma BDNF
      level. There will also be two test sessions at 14 and 28 days of treatment to collect data on
      the effects of the active and placebo treatments. The questionnaires, cognitive tasks, and
      diagnostic interviews will be conducted on an outpatient basis at the Semel Institute for
      Neuroscience and Human Behavior, and the medical procedures will take place at the UCLA
      Clinical and Translational Research Center (CTRC).

      In-person screening procedures:

      First, investigators will thoroughly explain the study and obtain informed consent from
      interested participants. Immediately after consent is obtained, the following questionnaires/
      diagnostic interviews will be completed:

        -  Study Admission & Intake Form- This questionnaire administered at intake collects
           demographic information (i.e. ethnicity, education, employment), general and mental
           health history, as well as substance abuse history. This questionnaire takes
           approximately 15-45 min to complete.

        -  Psychiatric evaluation using the SCID-IR-TR. The SCID will be administered during intake
           screening to determine whether the participant meets the DSM-IV-TR criteria for drug
           dependence and to rule out any major psychiatric disorders (e.g., affective disorders,
           schizophrenia; Spitzer et al., 1995).

        -  The International Physical Activity Questionnaires (IPAQ). The purpose of the IPAQ
           (Craig et al., 2003) is to record any exercise that participants engage in as this may
           impact findings. It takes approximately 5 min to complete.

      Urine testing (40 ml) will be done to test for pregnancy (females only) and drugs of abuse.
      Urine testing will be done at screening as well as each of the study visits. Once the urine
      has been analyzed, it will be disposed of in a sanitary manner.

      Medical Procedures completed during in-person screening:

      Participants will give a blood sample taken for Rapid Plasma Reagin (RPR), and Hepatitis B
      and C testing [25-ml sample to including a complete chemistry panel (5 ml), hepatic panel (3
      ml), Hepatitis B and C, RPR test (7 ml), plasma BDNF (0.1 ml)]. The study physician will
      inform participants of the implications if their status for RPR, hepatitis B or hepatitis C
      test results is positive, and will refer participants to further information. Study staff
      will inform participants with negative RPR, hepatitis B and hepatitis C test results of their
      health status. Height and weight will be assessed, as body mass index (BMI) values provide
      inclusion criteria (18 ≤ BMI ≥ 25 kg/m2). In addition, vital signs such as heart-rate (ECG),
      pulse, and blood pressure will be measured. Plasma BDNF (and other biomarkers) will be
      measured by a blood sample (finger stick) obtained prior to, and at each weekly visit to UCLA
      after initiating WCFC or placebo administration.

      The maximum time period allowable between the screening visits and attendance at the UCLA
      CTRC will be 4 weeks. If this time elapses, the potential subject will be screened again.

      Study Visit Timeline:

      Day Up to -28: Telephone screening Day 0- In-person medical screening, baseline cognitive
      testing session and rating of subjective mood states. BDNF assay. Randomization to group, and
      initiation of WCFC/placebo treatment, with 14-day supply provided to the participant.

      Day 7- Collection of compliance questionnaire, BDNF assay. Day 14- Cognitive testing and
      rating of subjective mood states. Collection of compliance questionnaire; re-supply
      WCFC/placebo; and phlebotomy for blood chemistry and assay of BDNF and other biomarkers.

      Day 21- Collection of compliance questionnaire, BDNF assay. Day 28- Completion of
      WCFC/placebo treatment. Final cognitive testing session and rating of subjective mood states.
      Collection of compliance questionnaire. Phlebotomy for blood chemistry, and assay of BDNF and
      other biomarkers.

      Study Visit Procedures (~2-3 hrs):

      Participants meeting the inclusion criteria will be randomized to receive either WCFC or
      placebo. During the active treatment time (28 days), they will visit the UCLA Semel Institute
      on a weekly basis. On day 0 (at baseline) and day 14, WCFC or placebo will be provided, in
      amounts sufficient for a 2-week supply, so that they can self-administer the respective
      treatments. At each of these weekly visits, questionnaires regarding compliance will be
      completed, and blood samples will be taken for assay of BDNF. A cognitive test battery and
      mood-rating scales will be completed at baseline and at 14 and 28 days of treatment. At the
      midpoint assessment (14 days) and at completion of treatment (28 days) blood will be drawn
      for assay of a blood chemistry panel (as at baseline) as well as for biomarkers in addition
      to BDNF.

      Nutraceutical Administration and Dose Justification:

      WCFC (NeurofactorTM): A dose of 100 mg will be administered twice daily (once before
      breakfast and again before dinner). The dose was chosen on the basis of published work from
      Applied Bioclinical, Inc. (Reyes-Izquierdo et al., 2013; Pietrzkowski et al., in press).
      Specifically, Reyes-Izquierdo and colleagues (2013) reported that 100 mg of WCFC resulted in
      increased plasma BDNF by 143% from baseline (n=10, healthy adults aged between 18 and 55
      years old). More recently Pietrzkowski and co-workers (unpublished manuscript in press)
      observed a 90% increase in plasma BDNF during the first 60 minutes after a single 100 mg dose
      of WCFC. The effect is sustained for 2-3 hours. Therefore, testing will always take place in
      the morning within 2 hours of WCFC ingestion with breakfast. As a quality control measure,
      WCFC batches will be tested to delineate the same chemical profile of polyphenols to make
      sure that if more than one batch is used, the chemical profiles are identical between
      batches.

      Placebo: The placebo will be Nutrim®, supplied by Abclinical and administered twice daily,
      identical to WCFC treatment (other participant group).

      Both WCFC and placebo are in powder form, and will be capsulated in size 1 gelatin capsules,
      white and blue, distributed in brown plastic bottles (28 caps/bottle: enough for 14 days of
      treatment). The first bottle will be provided at the time of randomization, and the second
      bottle will be provided on day 14 for dosing on days 15-28. The bottles will be labeled with
      the ABC logo and treatment code ABC#7UCLA01 and ABC#7UCLA12.

      The following questionnaires that assess mood will be administered during each of the study
      sessions:

        -  HAM-D- The Hamilton Depression Rating Scale is a multiple item questionnaire used to
           provide an indication of depression, and as a guide to evaluate recovery. The
           questionnaire is designed for adults and is used to rate the severity of their
           depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or
           retardation, anxiety, weight loss, and somatic symptoms. Assessment time is estimated at
           20 minutes. The HAM-D has been used previously, showing a correlation between increased
           plasma BDNF and improved (decreased) HAM-D scores (e.g., Shimizu et al., 2003, Gonul et
           al., 2005, Aydemir et al., 2005, Yoshimura et al., 2007).

        -  PANAS- The Positive and Negative Affect Schedule (Watson et al., 1988) is a 20-item
           questionnaire that comprises two mood scales, one measuring positive affect and the
           other measuring negative affect. Each item is rated on a 5-point scale ranging from 1 =
           very slightly or not at all to 5 = extremely to indicate the extent to which the
           respondent has felt this way in the indicated time frame. The participant will be
           instructed to provide these ratings of his or her affective state at the time of
           assessment.

        -  Adverse Events Log- At each visit after randomization, any adverse events that occur
           will be recorded, and evaluated in terms of frequency and severity (mild, moderate,
           severe) using this form.

      The following cognitive tests will be administered during each of the study sessions:

        -  Hopkins Verbal Learning Test- Revised (HVLT-R): This task is an assessment of verbal
           memory.

        -  Continuous Performance Test (CPT): This computer task is an assessment of attention &
           inhibition.

        -  Spatial Sternberg: This computer task is an assessment of spatial short term memory.

        -  Letter Number Sequencing: This task in an assessment of working memory.

        -  Attention Networks Task: This computer task is an assessment of attention & inhibition.

        -  Verbal fluency: This task is an assessment of executive function.

        -  Finger Tapping: This task is an assessment of psychomotor speed.

      These tests will assess multiple cognitive domains, and the total battery of tests will take
      approximately 1.5 hours to complete. Thus, the burden on participants will be low.
      Participants will be trained on the tasks before the baseline measurement is taken to reduce
      the effects of learning on performance.

      Biochemical Measures:

      The biochemical measurements that will be performed during the study will be the
      determination of plasma BDNF at baseline (conducted during medical screening procedure) and
      at each weekly visit following the initiation of WCFC and placebo administration, and assay
      of other biomarkers in serum at the 14- and 28-day test points. Determination of plasma BDNF
      must be performed at the same time of day for all subjects at all time-points, due to diurnal
      variation in plasma BDNF levels (Piccini et al., 2008). Weekly BDNF data will be used as an
      index of compliance with WCFC administration. Data at baseline, 14 days and 28 days will be
      used in tests of association with behavioral measures.
    

Intervention name(s): Whole Coffee Fruit Concentrate (WCFC); Nutrim
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Neurfactor is a powder dietary supplement patented by Futureceuticals, in which the active ingredient is WCFC. It is hypothesized that the whole fruit of the coffee plant, Coffea arabica, has very unique, important benefits for healthy aging not available from regular coffee, other coffee extracts, green coffee bean extracts, caffeine, or other leading botanicals. NeuroFactor is thought to increase Brain-Derived Neurotrophic Factor, a protein vital for neuron development, repair and protection and essential for learning, memory, alertness, controlling body weight, and energy metabolism.; Nutrim is an oat bran powder Nutrim is hypothesized to bestow a number of benefits such as cardiovascular health, glucose management and healthy digestion. However, improved cognition is not one of the hypothesized benefits. This product is free of caffeine and stimulants.
Other intervention name(s): NeuroFactor
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Brain-derived neurotrophic factor; Cognitive function; Dietary supplement; Coffee plant extract