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A Phase II, Randomized Placebocontrolled Trial of the Safety and Efficacy of Stimulin as a New Treatment of Fatigue and “Chemobrain” in Adult Cancer Patients Purpose of Study To evaluate the efficacy and safety of Stimulin (POD, phunonadate) a CNS stimulant, for the treatment of fatigue and neurobehavioral (cognitive) impairment associated with chemotherapy Study Objectives Primary objective Evaluate the efficacy of POD in the treatment of chemotherapy-related fatigue in adult cancer subjects using the FACIT-F Secondary objectives Evaluate the efficacy of POD in improving cognitive dysfunction Explore the efficacious dose range required to maintain effectiveness Assess the safety of POD doses up to 50 mg/day in this population Patient Eligibility M/F, ages 18-70 Cancer dx, excl. 10 or metastatic brain tumors 4 cycles of cytotoxic chemotherapy (minimum), completed > 2 months prior to study entry Life expectancy >6 months No focal neurological deficit ECOG < 2 ICD-10 criteria for Cancer Related Fatigue Mini-Mental Status Exam (MMSE) score > 20 Beck Depression Inventory-II (BD-II) score <18 Clinical Global Impression-Severity (CGI-S) score > 3 Proposed ICD-10 (1998) Criteria for Cancer-Related Fatigue A1 Significant fatigue, diminished energy, or increased need to rest disproportionate to any recent change in activity level A2 Complaints of generalized weakness or limb heaviness A3 Diminished concentration or attention A4 Decreased motivation or interest to engage in usual activities A5 Insomnia or hypersomnia A6 Experience of sleep as unrefreshing or nonrestorative A7 Perceived need to struggle to overcome inactivity A8 Marked emotional reactivity (e.g. sadness, frustration, or irritability) to feeling fatigued A9 Difficulty completing daily tasks attributed to feeling fatigued A10 Perceived problems with short-term memory A11 Post exertional malaise lasting several hours B The symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning C There is evidence from the history, PE or laboratory findings that the symptoms are a consequence of cancer or cancer therapy D The symptoms are not primarily a consequence of comorbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder or delerium Efficacy Assessments Efficacy assessments utilized to measure fatigue and cognitive changes: FACIT-F = Functional Assessment of Chronic Illness Therapy-Fatigue Subscale CGI-S = Clinical Global Impression – Severity CGI-I = Clinical Global Impression – Improvement Modified SNAP = Modified Attention Deficit/Hyperactivity Disorder (ADHD) Scale HSCS = High Sensitivity Cognitive Screen 6 cognitive domains of memory, language, visual-motor, spatial, attention/concentration, and self-regulation and planning Predicts overall qualitative results of formal neuropsychologic testing with 93% accuracy Study Design Pre-Randomization Visit 1 Baseline/Randomization Visit 2 POD Dose Maintenance (2-wk minimum) Screening Period Single-Blind Treatment Period Placebo Double-Blind Treatment Phase Pre-Randomization Phase Visit # Week # 1 2 3 4 5 6 7 8 9 10 (-1) (0) (1) (2) (3) (4) (5) (6) (7) (8) Patient Demographics Age 52.8 yrs Gender 94% female Race 79% white, 9% African-American Education 50% post HS, 28% adv degree Work Status 63% empl., 24% unempl, 13% ret. Cancer type 76% breast, 14% ovarian FACIT-F score at baseline comparable to published surveys of patients post- chemotherapy Treatment groups were well-matched for all baseline characteristics Change in FACIT-F (fatigue) Total Score at Each Week Treatment Week 0 1 2 3 4 5 6 7 8 Change from Baseline 0 -2 -4 -6 -8 -10 -12 -14 * * p < 0.05 ** p < 0.01 POD POD LOCF ** PLCBO LOCF = Last observation carried forward PLCBO LOCF Clinical Global ImpressionImprovement % of subjects achieving very much or much improved at each week 80 70 ** *p<0.05, **p<0.01 % subjects 60 50 40 30 20 10 0 bsln wk1 wk2 wk3 POD wk4 wk5 wk6 placebo wk7 wk8 LOCF Conclusions Phunonadate (POD) significantly reduced chemotherapy–related fatigue in adult cancer subjects compared to placebo.