Writer #23. Objective: To evaluate the efficacy, safety and tolerability of oral MG01CI, an extendedrelease

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1 Writer #23 Writer #23 holds a PharmD as well as an MS in Journalism. Writer #23 is an experienced medical/pharmaceutical writer specializing in peer-reviewed journal articles/ supplements, review articles, PowerPoint presentations, monographs, patient education, sales rep training, and all other aspects of medical communication and education. Experience Handle all types of medical and pharmaceutical freelance writing, publishing and editing. Clients include pharmaceutical companies and the communication firms that serve them. Provide editorial assistance for journal reviews and clinical trial manuscripts for new drugs. Construct scripts, including audio, video, CD-ROM and slide shows. Design and publish award-winning newsletters. Manage book projects and other projects for nurses, physicians and pharmacists. Author ethics column for pharmacy journal. Write and publish Continuing Education programs; co-author numerous CME programs. Writing Sample 1 A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy, Safety and Tolerability of Extended-Release Metadoxine in Adults with Attention- deficit/hyperactivity Disorder (ADHD) (written in collaboration with nine other co-authors) ABSTRACT Objective: To evaluate the efficacy, safety and tolerability of oral MG01CI, an extendedrelease form of the non-stimulant metadoxine, in the treatment of adult attentiondeficit/hyperactivity disorder (ADHD). Method: This was a 1:1 randomized, double-blind, placebo-controlled, parallel design, phase 2 study of MG01CI 1,400 mg/day for 6 weeks following a 2-week baseline/screening period, involving 120 adults with ADHD. There was a 2 week follow-up assessment after the trial

2 was completed. Efficacy measures included changes in Conners' Adult ADHD Rating Scale- Investigator Rated Total ADHD Symptoms Score (CAARS-INV) with adult ADHD prompts (primary measure), response rates determined from CAARS Total ADHD Symptoms Score, Test of Variables of Attention (TOVA) performance, and Adult ADHD Quality of Life (AAQoL) total score. Results: Using an intent to treat analysis, subjects in the MG01CI group showed statistically significant decrease in CAARS Total ADHD Symptoms Score (P=.019), higher response rate on the CAARS Total ADHD Symptom Score (P=.03), increase in TOVA score (P=.02), and improvement in AAQoL score (P=.009) compared with the placebo group. Improvements in ADHD symptoms were significantly different in subjects treated with MG01Cl vs. placebo as early as 2 weeks following treatment initiation. MG01CI was generally well tolerated with nausea (17% vs. 0%), fatigue (31% vs. 27%) and headache (29% vs. 39%) being the most frequently reported adverse effects for MG01CI and placebo groups, respectively. Conclusion: Findings indicate that MG01CI is a well-tolerated and effective treatment for adults with ADHD. Key words: ADHD, metadoxine INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) is a common, debilitating neuropsychiatric condition. Once believed to only affect children, ADHD is now known to persist into adolescence and adulthood in a sizeable number of cases [Biederman, 2011; Biederman, 2010; Kessler, 2005]. One study showed that almost half (46%) of adults who had ADHD as children continue to have symptoms of the disorder as adults, with almost all of them (95%) experiencing attention-deficit symptoms and about 35% of them experiencing hyperactivity-impulsivity symptoms [Kessler, 2010]. It is estimated that 4-5% of adults worldwide have some type of ADHD [Kessler, 2006].

3 Adult ADHD is associated with increased health risks and healthcare costs, higher divorce rates, lower levels of socioeconomic attainment, lower academic achievement, unemployment and work place deficits, increased risks for motor vehicle accidents, greater likelihood of additional psychiatric disorders, increased criminal activity and incarceration, and higher rates of substance use and abuse [Rösler, 2004; Biederman, Faraone, et al, 2006; Reimer, 2010]. Yet, although the disease is highly treatable, most adults with ADHD remain undiagnosed and untreated [Kessler, 2006]. Although stimulants have been shown to be effective and safe for the treatment of ADHD, approximately 30% to 50% of those who are prescribed stimulants for ADHD either do not respond to or do not tolerate these treatments [Biederman, Arnsten, et al, 2006]. In addition, stimulants carry risk for abuse potential (REF). Consequently, it is important to develop safe and effective non-stimulant treatment alternatives. particularly one devoid of abuse potential. MG01CI is an extended-release oral non-stimulant formulation of metadoxine (pyridoxol L- 2-pyrrolidone-5-carboxylate). Immediate-release metadoxine has been used in the treatment of acute alcohol intoxication and alcohol withdrawal syndrome for more than 30 years. The new extended-release metadoxine formulation prolongs the serum levels of metadoxine, thereby heightening its clinical bioavailability which may result in enhanced efficacy. Following demonstration of delayed time to maximum plasma concentration (Tmax) and extended half-life of the extended-release formulation of MG01CI in the porcine model, safety and tolerability were demonstrated in 3 pilot, healthy volunteer, clinical studies.

4 These studies also assessed various parameters of cognitive performance following alcohol consumption and provided initial indication for the cognitive enhancement properties of MG01CI. Writing Sample 2 Aligning Patient Care and Asthma Treatment Guidelines (written in collaboration with one other co-author) In 2002, 72 Americans per 1,000 or 20 million people, currently had asthma. Children are most affected: 83 per 1,000 children 0-17 years (6 million) had asthma compared to 68 per 1,000 adults 18 years and older (14 million) [CDC, 2002, p2-3]. Asthma attack prevalence, that is, the number of people who had at least 1 severe exacerbation within the last 12 months, is a simple indicator of how many people have uncontrolled asthma and are at risk for a negative clinical outcome, such as hospitalization or death. In 2002, 43 people per 1,000 (12 million people) had experienced an asthma attack in the previous year. That is, about 60% of the people who had asthma at the time of the survey had an asthma attack in the previous year. Again, children are most at risk for asthma attacks: 58 per 1,000 children 0-17 years (4.2 million) had an asthma attack in the previous year compared to 37 per 1,000 adults aged 18 years and over (7.7 million). Thus, despite the many medications available to treat asthma, the disease remains a crucial public health issue. In response to this health concern, the National Institutes of Health (NIH) convened an expert panel that produced the National Asthma Education Program (NAEPP) in 1991, with updates in 1997 and These documents set forth guidelines that give the clinician a foundation by which to manage patients with asthma. They include the role of inflammation in the pathogenesis of

5 asthma, the importance of monitoring asthma both via patients symptoms and spirometry, recognizing the value of long-term controller medications, the significance of individualized written action plans, the role of patient education during each office visit, and setting appropriate treatment goals with the patient s involvement. Asthma is the third leading cause of preventable hospitalization in the US [Kowalski, 2000, abs]. According to the NAEPP, asthma care can be improved. Hospitalizations due to asthma are preventable or avoidable when patients receive appropriate primary care. A prospective survey study of patients who visited an urban emergency room (ER) over a 1-year period for symptoms of wheezing showed that inhaled corticosteroids were used by only 16% of patients [Friday, 1997, abs]. The study also showed that over one-third of patients were repeat offenders in that they had made repeated visits to the ER within the 1-year period. This data underscores the fact that there is a subset of patients who not only have recurrent wheezing but also lack the management skills to avoid costly hospital services. Because of this recurrent problems, the NAEPP has been heavily promoting their guidelines has a structured plan to manage disease. The guidelines have been shown to work. A 2005 published study assessed whether an organized, citywide asthma management program delivered by primary care physicians increased adherence to the guidelines and whether guideline adherence translated to decreased medical services in a cohort of 3,748 children with asthma in Hartford, Connecticut [Cloutier, 2005, abs]. Of those children enrolled in the disease management program, 48% had persistent asthma. After the 4-year study was completed, the results showed that provider adherence to the guidelines for antiinflammatory therapy, the mainstay of asthma management, rose from 38% to 96%. In turn, paid claims for inhaled corticosteroids (ICS) increased by 25% (P <.0001). Children in the program experienced a 35% decrease in overall hospitalization rates (P <.006), a 27%

6 decrease in ER visits for asthma exacerbations (P <.01), and a 19% decrease in outpatient visits (P <.0001). Thus, an organized guideline-based program designed to promote better living with asthma resulted in healthier children who had better controlled disease. What are the major recommendations the NAEPP guidelines make? [PractGuide, p3] The guidelines make basic recommendations: Diagnose asthma and have an action plan that includes the patient s involvement Reduce inflammation, symptoms, exacerbations Monitor and manage asthma over time Treat asthma episodes promptly Diagnose and have an action plan While no diagnostic tests exist for asthma, a diagnosis can be established if a history of airflow obstruction exists (e. g., wheezing, chest tightness) and whether such obstruction is at least partially reversible [PractGuide, p4]. Other problems must be ruled out, such as the presence of foreign bodies, other lung disease such as chronic obstructive pulmonary disorder [COPD]), and gastroesophageal reflux disease (GERD). Following a diagnosis, the first step in treatment is to set up a written action plan for managing asthma that specifies treatment goals.. These must be determined by both the clinician and the patient, with such goals agreed upon by the patient. For example, the patient s goal may be to more easily play sports without lung problems, or to sleep through the night without a breathing episode. The clinician will work with the patient by educating him about allergen avoidance and medication use, so that the goals can be realized. A written action plan in this case is concrete evidence that these goals are attainable and is a document to which the patient can refer as he gets more involved with his therapy.

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