COGNUTRIN in Breast Cancer Survivors

Mean change in cognitive function scores measured from baseline to post intervention with Cognutrin compared to placebo arms of the trial. Mean cognitive function scores by group and compared by time of testing (Time 1, Time 2). Tests: Color Trails 1 & Color Trails 2. Color Trails 1 consists of a page with scattered circles numbered from 1-25. Even numbered circles are colored yellow and odd numbered ones are colored pink. Respondents are instructed to connect the circles in consecutive numeric order with a continuous line as quickly as possible. Score is determined by recording the number of seconds required to complete the task. Color Trails 2 consists of a page containing 25 pink circles and 25 yellow circles numbered 1-60. Respondents are instructed to connect circles in consecutive order while alternating colors. A total score is determined by recording the number of seconds required to compete the task.

Time frame: Baseline (Time 1) and at 3 months +/- 7 days (Time 2)

Population: All evaluable participants at time of analysis.

Mean change in cognitive function scores measured from baseline to post intervention with Cognutrin compared to placebo. Mean cognitive function scores by group and compared by time of testing (Time 1, Time 2). The Digit Span assesses immediate verbal memory and auditory attention. The examiner reads increasingly longer series of numbers and the respondent is required to repeat them in the same order. The examiner then reads additional sequences of numbers and the respondent is required to repeat them in reverse order. Digit Span yields one score, number of items completed correctly. Scores are scaled from the Wechsler Adult Intelligence Scale. The values for these scaled scores indicated that values from 1-7 indicate below average performance, corresponding to 1-16 percentile ranks. Scores between 8-12 indicate average performance, corresponding to percentile ranks of 25-75. Scores between 13-19 correspond to areas of strength and 84-99 percentile ranks.

Time frame: Baseline (Time 1) and at 3 months +/- 7 days (Time 2)

Population: All evaluable participants at time of analysis.

Mean change in cognitive function scores measured from baseline to post intervention with Cognutrin compared to placebo. Mean cognitive function scores by group and compared by time of testing (Time 1, Time 2). The HVLT test assesses verbal learning and memory. Subjects are given a list of words and asked to repeat as many words as they can recall at 3 times. There is no absolute low & high, as scores are age adjusted. Reported scores are T-scores- average score should be 50, with a standard deviation of 10. Any score below 50 indicates performance below population averages and any score above 50 indicates higher than population averages.The COWA test is a verbal fluency test that measures spontaneous production of words belonging to the same category or beginning with a designed letter. The scores are converted to z-scores. A Z score of -1 is 1 standard deviation below mean. The lowest and highest Z scores could be ≤ -3.0 and ≥3.0. A lower Z score is indicative of poor fluency.

Time frame: Baseline (Time 1) and at 3 months +/- 7 days (Time 2)

Population: All evaluable participants at time of analysis.

Mean change in cognitive function scores measured from baseline to post intervention with Cognutrin compared to placebo arms of the trial. Mean cognitive function scores by group and compared by time of testing (Time 1, Time 2). The Symbol Digit Modalities Test requires respondents to write the number that corresponds with each symbol for a series of 110 items in which the symbol but not the number appears. Respondents identify the correct number using a key provided in which symbols are matched with numbers. Total score is determined by calculating the number of items correctly completed in 90 seconds Scale uses z-scores which have a mean of 0 and a standard deviation of 1. Scores cores above 0 indicate better than average performance whereas scores below 0 indicate poorer than average performance.

Time frame: Baseline (Time 1) and at 3 months +/- 7 days (Time 2)

Population: All evaluable participants at time of analysis.

The primary safety endpoint is incidence and severity of AEs occurring during intervention with either COGNUTRIN or placebo. All AEs that are reported by the subject, detected during a visit, physical examination, or laboratory work-up will be recorded in the participant's medical record and recorded on the case report form (CRF). All AEs that occur after the informed consent is signed will be recorded on the AE CRF whether or not related to study agent, using the NCI Common Terminology Criteria for AEs (CTCAE) version 4.0.

Time frame: 3 months from baseline +/- 7 days

Population: Evaluable participants who received treatment.

The primary safety endpoint is incidence and severity of AEs occurring during intervention with either COGNUTRIN or placebo. All AEs that are reported by the participant, detected during a visit, physical examination, or laboratory work-up will be recorded in the participant's medical record and recorded on the case report form (CRF). All AEs that occur after the informed consent is signed will be recorded on the AE CRF whether or not related to study agent, using the NCI Common Terminology Criteria for AEs (CTCAE) version 4.0.

Time frame: 3 months from baseline +/- 7 days

Population: All evaluable participants who received treatment.

Functional: Improved cortical activation in multiple areas of the brain on examination of functional MRI post study intervention. Imaging including: 1) Extended resting state functional MRI with data post-processed on Philips EWS. Performed with patient's eyes closed and minds wandering. 2) Diffusion tensor imaging (DTI) with effective slice thickness of 2.3mm. Post-processed on Philips EWS with color-coded DTI tractography images obtained, absolute FA calculations performed in 9 anatomic areas in both right and left brain with total of 18 FA values obtained per examination. Structural: Improved white matter signal changes which correlate with ischemic changes or microvascular ischemic changes, cortical atrophy, hippocampal atrophy, brain volume and gray-white matter ratio. Anatomic sequences including: 1) Coronal 3-D volume T1 weighted gradient echo images with effective slice thickness of 1mm. 2) Axial FLAIR (fluid attenuated inversion recovery)

Time frame: 3 months

Population: All participants with both pre- and post-therapy brain MRI examinations.

Number of Adverse events according to relation to study treatment category: Definitely related, Probably related, Possibly related, Unlikely to be related, Unrelated.

Time frame: 3 months from baseline +/- 7 days

Population: Participants with Adverse Events.

Mean change plasma cytokines from baseline to post intervention with Cognutrin vs. placebo. Inflammatory markers-Cytokines were measured with a panel including IFN-g, IL-6, IL-8 and INF-alpha.

Time frame: 3 months

Population: All evaluable participants at time of analysis