Target e*CRF Version 1.7 Released

Target Health is pleased to announce the release of Target e*CRF® version 1.7 with the following major features:

1.       Communication tool for CRAs with Data Managers

2.       Cross-form edit checks

3.       Batch edit checks

4.       On-line randomization

5.       User management by sponsor

Target e*CRF® Version 1.8, to be released at the end of July, will have a robust pharmacovigilance module and integration with the eClinical Trial Record (Target e*CTRTM).

Target e*CRF® has been used in over 160 studies, with 4 approved NDAs, 1 approved BLA, and 10 approved PMAs, as well as for approvals in Canada and Europe. One NDA was approved this year as well as 1 PMA. We expect another European approval this year. In addition, two NDAs will be submitted this year which used Target e*CRF® for the pivotal trials. Target Health will do a full eCTD submission for one of the NDAs and will prepare Module 1 for the second NDA.

For more information about Target Health and any of our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website

Triglycerides Implicated In Diabetes Nerve Loss 

A common blood test for triglycerides – a well-known cardiovascular disease risk factor – may also, for the first time, allow doctors to predict which patients with diabetes are more likely to develop the serious, common complication of neuropathy. In a study published online in the June issue of Diabetes, University of Michigan and Wayne State University researchers analyzed data from 427 diabetes patients with 1) ___, a condition in which nerves are damaged or lost with resulting numbness, tingling and pain, often in the hands, arms, legs and feet. The data revealed that if a patient had elevated triglycerides, he or she was significantly more likely to experience worsening neuropathy over a period of one year. Other factors, such as higher levels of other fats in the blood or of blood glucose, did not turn out to be significant. Elevated serum 2) ___ were the most accurate at predicting nerve fiber loss, compared to all other measures. These results set the stage for clinicians to be able to address lowering lipid levels with their diabetes patients with neuropathy as vigilantly as they pursue glucose control. Triglycerides are measured as part of routine 3) ___ testing, and doctors and patients can take pro-active steps when interventions can do some good. Aggressive treatment can be very beneficial to patients in terms of their neuropathy. People can reduce blood triglyceride levels with the same measures that reduce 4) ___ levels: by avoiding harmful fats in the diet and exercising regularly. Diabetic neuropathy affects around 60% of the 23 million people in the US who have diabetes. It is a complication in both type 1 and type 2 diabetes. Until now, doctors have lacked an effective way to predict which diabetes patients are at greatest risk of neuropathy. Most often, the condition becomes evident when irreversible 5) ___ damage has already occurred. Neuropathy is the leading cause of diabetes-related hospital admissions and amputations that are not secondary to trauma. Triglycerides are a type of lipid, or fat, that the body makes from calories it doesn’t need immediately. Triglycerides are stored in fat cells until they are needed to provide 6) ___. When higher-than-normal amounts circulate in the blood, a person is at higher risk of cardiovascular disease. The new finding adds to an emerging picture of the close connections between cardiovascular disease and diabetes. Elevated triglycerides are one of the most common features of the lipid disorders found in patients with type 2 diabetes, by far the most common form of 7) ___. Cardiovascular disease is the main cause of excess mortality among patients with diabetes. Research also has shown that the presence of neuropathy is an important predictor of these deaths. This study demonstrates that the same lipid particles that contribute to the progression of 8) ___ are also very important players in peripheral nerve fiber loss. In addition, the study confirms a growing belief among some diabetes researchers that elevated blood levels of certain lipids, rather than solely elevated blood sugar, are key in the progression of diabetic neuropathy. The study pinpoints triglycerides as the critical indicator.

ANSWERS

neuropathy; 2) triglycerides; 3) blood; 4) cholesterol; 5) nerve; 6) energy; 7) diabetes; 8) atherosclerosis

Opioids have been used for treating pain and disease, as well as pleasure, for almost 6 millennia. Use of the opium poppy, Papaver somniferum, predates written history. Images of opium poppies have been found in ancient Sumerian artifacts (ca. 4000 BCE). At least 17 finds of poppies from Neolithic settlements have been reported throughout Switzerland, Germany, and Spain, including the placement of large numbers of poppy seed capsules at a burial site (the Cueva de los Murci?lagos, or “Bat cave”, in Spain), which have been carbon dated to 4200 BCE. Numerous finds from Bronze Age and Iron Age settlements have also been reported. The first known cultivation of opium poppies was in Mesopotamia, approximately 3400 BCE, by Sumerians who called the plant Hul Gil, the “joy plant.” Tablets found at Nippur, a Sumerian spiritual center south of Baghdad, described the collection of poppy juice in the morning and its use in production of opium. Cultivation continued in the Middle East by the Assyrians, who also collected poppy juice in the morning after scoring the pods with an iron scoop; they called the juice aratpa-pal, possibly the root of Papaver. Opium was used with poison hemlock to put people quickly and painlessly to death, but it was also used in medicine. The Ebers Papyrus, ca. 1500 BCE, describes a way to “prevent the excessive crying of children” using grains of the poppy-plant strained to a pulp. Sponges soaked in opium (Spongia somnifera), were used during surgery. The Egyptians cultivated opium thebaicum in famous poppy fields around 1300 BCE and was traded from Egypt by the Phoenicians and Minoans to destinations including Greece, Carthage, and Europe. By 1100 B.C., opium was cultivated on the Mediterranean island of Cyprus, where surgical-quality knives were used to score the poppy pods, and opium was cultivated, traded, and smoked. Opium was also mentioned after the Persian conquest of Assyria and Babylonia in the sixth century B.C. From the earliest finds, opium has appeared to have ritual significance, and anthropologists have speculated that ancient priests may have used the drug as a proof of healing power. In Egypt, the use of opium was generally restricted to priests, magicians, and warriors, its invention credited to Thoth, and it was said to have been given by Isis to Ra as treatment for a headache. A figure of the Minoan “goddess of the narcotics”, wearing a crown of three opium poppies, ca. 1300 BCE., was recovered from the Sanctuary of Gazi, Crete, together with a simple smoking apparatus. The Greek gods Hypnos (Sleep), Nyx (Night), and Thanatos (Death) were depicted wreathed in poppies or holding poppies. The opium poppy was well known to the ancient Greeks, from whom it gained its modern name of opium. Remains have been discovered at sites such as Kalapodi and Kastanas. Opium was used for treating asthma, stomach illnesses, and bad eye sight. Homer wrote in The Odyssey that a daughter of Zeus served a grieving Odysseus a drink containing opium. In 460 BC, Hippocrates, the great Greek physician, used opium to treat everything from headaches and coughing to asthma and melancholy. Opium use disappeared from record in Europe for 200 years during the Catholic Inquisition. The drug reappeared in 1527 when it was reintroduced for its medicinal properties by Paracelsus. Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in 1804 in Paderborn, Germany and first marketed to the general public by Sert?rner and company in 1817. It was marketed for analgesia, and as a “cure” for opium and alcohol addiction. Later it was found out that morphine was even more addictive than either alcohol or opium, and its extensive use during the American Civil War allegedly resulted in over 400,000 sufferers from the “soldier’s disease” of morphine addiction. This idea has been a subject of controversy, as there have been suggestions that such a disease was in fact a hoax. The standard medical use of opium persisted well into the nineteenth century. U.S. president William Henry Harrison was treated with opium in 1841, and in the American Civil War, the Union Army used 2.8 million ounces of opium tincture and powder and about 500,000 opium pills. During this time of popularity, users called opium “God’s Own Medicine” Opioid abuse became prevalent during the second half of the 19th century, after the invention of the hypodermic syringe. Injecting opium allowed for a more rapid, potent effect. In 1898, the Bayer Company began marketing a cough suppressant featuring a new ingredient called “heroin.” In part because it did not produce many of the side effects common to morphine, heroin was widely assumed to be nonaddictive – so much so that in the early 1900s, free samples of heroin were available by mail to recovering morphine addicts as a “step-down” cure. By 1914, however, heroin’s addictive properties were no longer in doubt. That year, the US government tried to curb heroin use by imposing a hefty tax on heroin. Then, in 1924, the government banned the nonmedical use of heroin, and in 1970 banned the medical use of heroin, as well.

Scientists funded by the National Institute of Neurological Disorders and Stroke (NINDS) have identified a gene associated with narcolepsy, a disorder that causes disabling daytime sleepiness, sleep attacks, irresistible bouts of sleep that can strike at any time, and disturbed sleep at night. The gene has a known role in the immune system, which strongly suggests that autoimmunity, in which the immune system turns against the body’s own tissues, plays an important role in the disorder. The new study, which appeared online in Nature Genetics (3 May 2009 | doi:10.1038/ng.372), focused on narcolepsy with cataplexy – a sudden loss of muscle tone that can cause a person to collapse, with or without falling asleep. About 1 in 2,000 Americans have narcolepsy-cataplexy. The symptoms of narcolepsy-cataplexy have been shown to result from the death of a small group of brain cells that normally regulate the sleep-wake cycle by releasing chemicals called hypocretins. Until now, the best evidence for autoimmunity as a cause of the disorder was the discovery that nearly everyone with the disorder has unique variants of a gene called HLA-DQB1*0602. This is one of the genes that encodes HLA proteins, which dot the surface of the body’s cells and help the immune system identify foreign proteins. Some researchers theorize that the HLA variants found in people with narcolepsy-cataplexy predispose them to an autoimmune reaction that destroys their hypocretin-producing cells. HLA variations, however, do not fully account for narcolepsy-cataplexy. As a result, a study was performed to search for other genes associated with narcolepsy-cataplexy. These studies involve scanning the genome – the entire set of DNA – for small differences between people who have a disorder and people who do not. The study included more than 4,000 individuals, all of whom had the HLA variants that predispose to narcolepsy-cataplexy but only about half of whom had the disorder. Participants were recruited so that many genetic groups were represented. Subjects were from the United States and eight countries in Europe and Asia; hundreds were African-American, Korean, and Japanese, groups known to have a high incidence of the disorder. Results showed that in addition to unique HLA variants, people with narcolepsy-cataplexy are also more likely to have unique variants of the TCRA gene, which encodes a receptor protein on the surface of T cells. T cells are the mobile infantry of the immune system. In concert with the HLA proteins, the T cell receptor enables T cells to recognize and attack foreign invaders, such as bacteria and viruses. Changes to the T cell receptor could increase the likelihood that the cells will direct their attack against the body. It was therefore, hypothesized that narcolepsy-cataplexy is linked to autoimmunity and involves T-cells and that the research could lead to new approaches to prevention and treatment. One possibility may be preventing the disorder by stopping the effects of the autoimmune process by developing drugs that block the protein’s abnormal activity and prevent the onset of the disorder. Current treatments such as stimulant drugs for combating daytime sleepiness and antidepressants for cataplexy are only able to control symptoms, and do not address the underlying loss of hypocretin cells. It is important to note that this study, like most genome-wide association studies, did not identify genetic variants that directly cause narcolepsy-cataplexy. Instead it identifies groups that are more likely to show narcolepsy-cataplexy and groups that are less likely to show the disorder. In people with the HLA variants that predispose to narcolepsy-cataplexy, there is about a 20-fold higher frequency of the disorder if variants in the TCRA gene are present. It is yet to be known which people with the genetic variants will go on to develop narcolepsy-cataplexy.

Both benign prostatic hyperplasia (BPH) and cataract formation are common in older men. The alpha-adrenergic receptor blocker tamsulosin (Flomax) is frequently prescribed to treat BPH, and previous studies have suggested that tamsulosin may increase the intraoperative difficulty of cataract surgery. No studies have documented whether use of tamsulosin, or other alpha1a selective alpha blocker drug therapies, affect the risk of serious postoperative adverse events. As a result, a study published in the Journal of the American Medical Association (2009;301:1991-1996), was performed to assess the risk of adverse events following cataract surgery in older men prescribed tamsulosin or other alpha-blocking drugs used to treat BPH. The study included 96,128 men aged 66 years or older who had cataract surgery between 2002 and 2007. The main outcome measure was a composite of procedures signifying retinal detachment, lost lens or lens fragment, or endophthalmitis occurring within 14 days after cataract surgery. The risk of these adverse events was compared between men treated with tamsulosin or other alpha blockers and men with no exposure to these medications in the year prior to cataract surgery. Separately, the association of drug exposure that was either recent (within the 14 days before surgery) or previous (15-365 days before surgery) was examined. Overall, 3,550 patients (3.7%) in the cohort had recent exposure to tamsulosin and 7,426 patients (7.7%) had recent exposure to other alpha blockers. Two hundred eighty-four patients (0.3%) had an adverse event. Adverse events were significantly more common among patients with recent tamsulosin exposure (7.5% vs 2.7%) but were not associated with recent exposure to other alpha blockers (7.5% vs 8.0%) or to previous exposure to either tamsulosin (1.8% vs 1%; adjusted OR, 0.94; 95% CI, 0.27-3.34) or other alpha blockers (2.9% vs 2.1%).According to the authors, exposure to tamsulosin within 14 days of cataract surgery was significantly associated with serious postoperative ophthalmic adverse events. There were no significant associations with exposure to other alpha blocker medications used to treat BPH.

According to an article published in the Journal Obesity (2009;17:1178-1183), a study was performed to assess the effect of weight loss on sleep-disordered breathing (SDB) in obese teenagers attending a residential treatment center. The study also assessed whether the presence of SDB at the start of the weight management therapy was correlated with the amount of weight loss achieved. For the study, obese teenagers were recruited and underwent anthropometry and sleep screening. Subjects with SDB (apnea hypopnea index (AHI) >2) received a follow-up screening after weight loss therapy. Sixty-one obese subjects were included (age = 14.8 + 2.3). Thirty-one subjects were diagnosed with SDB with 38% continuing to have residual SDB after a median weight loss of 24.0 kg. Results showed that subjects with SDB had a higher median relative decrease in BMI compared to subjects without SDB. AHI of the baseline screening study correlated significantly with the relative decrease in BMI (P = 0.003), controlling for gender, age, initial BMI score, and time between both studies. According to the authors, weight loss was successful in treating SDB in obese teenagers and there was a positive association between the severity of SDB at the start of the treatment and the amount of weight loss achieved. The authors added that the findings are in favor of considering weight loss as a first-line treatment for SDB in obese children and adolescents.

Target Health Inc. excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. Target Health receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

When sodium levels drop in the fluid outside of cells throughout the body, water moves into cells to balance the sodium levels and causes the cells to swell. Swelling of the brain cells is thought to cause many of the symptoms of hyponatremia. Those symptoms may include fatigue, weakness, headache, nausea, confusion or decreased consciousness, and convulsions. The FDA has approved Samsca tablets (tolvaptan) to treat hyponatremia, an abnormally low concentration of sodium in the blood. Samsca is approved to treat hyponatremia associated with congestive heart failure, liver cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion. Severe hyponatremia, which has not been studied with Samsca, can lead to coma and death. Samsca helps raise sodium levels in the blood by removing extra body water in the urine. Patients using the drug in clinical trials had a greater degree of increase in sodium levels in the blood compared with patients taking a pill containing no active drug (placebo). Samsca is being approved with a boxed warning to alert health care professionals and patients that the drug should be started only in a hospital where blood sodium can be monitored closely. Too rapid a rise in sodium can cause a serious condition called osmotic demyelination syndrome (ODS). ODS can lead to coma or death and can also cause symptoms such as trouble speaking, trouble swallowing, drowsiness, confusion, mood changes, seizures and trouble controlling body movement with muscle weakness in the arms and legs. Although no cases of ODS were seen in clinical trials of Samsca, ODS is a known risk and it is essential that physicians be aware of it and avoid rapid rises in sodium. Additionally, the FDA is requiring a Risk Evaluation and Mitigation Strategy (REMS) that requires a patient Medication Guide be given out when the drug is dispensed. The Medication Guide will provide information about the drug’s benefits and risks. The most common adverse reactions with use of Samsca reported by patients in clinical trials include thirst, dry mouth, weakness, constipation, making large amounts of urine, urinating often, and increased blood sugar levels. Samsca is marketed by Otsuka Pharmaceuticals Co. Ltd., Tokyo, Japan.

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.  www.targethealth.com