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By: Daniel James George, MD

  • Professor of Medicine
  • Professor in Surgery
  • Member of the Duke Cancer Institute


Combined laparoscopic-endo for continuous dilatation of benign stenoses in gastrointestinal tractd scopic method using an omental plug for therapy of gastroduodenal first results of long-term follow-up in interim stent application in py ulcer perforation medications interactions generic eldepryl 5mg with mastercard. Multimedia article: manage ment of duodenal ulcer perforation with combined laparoscopic and endoscopic methods treatment zinc toxicity order eldepryl with american express. Thousands of people annually undergo ostomy surgery for various reasons and return to medications 512 order 5mg eldepryl with mastercard a healthy treatment by lanshin 5mg eldepryl with mastercard, functioning lifestyle. The real change is having a bowel m ovem ent from an opening m ade in the abdom en. There are m any ways to gain a greater understanding of your life with a colostom y. Your physician, ostom y nurse, or other nurses are im portant sources of inform ation and support. When certain conditions are present in the large intestine, it m ay be necessary to give that portion a rest. When the end portion of the colon or the rectum becom es diseased, construction of a perm anent colostom y m ay becom e necessary. Such a colostom y provides an exit for stool that will not be closed at any tim e in the future. W here on the abdom en the colostom y is located depends on which part of the colon is used to create it. The ostom y nurse or surgeon will determ ine the correct location for your stom a. The appearance of the stom a depends on the type of colostom y and on individual differences in the hum an body. W hile the stom a m ay be quite large at first, it will shrink gradually and attain its final size in six to eight weeks. When you look at a stom a, you are actually looking at the lining (the m ucosa) of the intestine. The colon’s work consists prim arily of absorbing water from, transporting and the storage of stool. At this point, a m ass reflex, stronger than peristalsis, propels the stool into the next portion of the colon. Large Intestine: Approxim ately 5-7 feet long, consisting of: • Cecum – contains the ileocecal valve, which prevents reflux into the ileum; contentsare highly acidic liquid. The prim ary functions of the large intestine are absorption of water and electrolytes, transport of stool by peristalsis, and storage of digestive waste until it is elim inated from the body. Since nutrients are absorbed in the sm all intestine, a colostom y does not affect the body’s ability to be nourished. When a colostom y interrupts the passage of stool, storage becom es m ore difficult. The higher up in the colon the colostom y is m ade, the less tim e the bowel has to absorb water and the m ore liquid (or soft) the stool is likely to be. A colostom y far down in the colon, near the rectum, will discharge stool that has been in the intestine a longer tim e and barring the effects of illness, m edications or other form s of treatm ent, m ay produce a m ore form ed stool. It m ay continue to secrete m ucus that can be harm lessly passed whenever the urge occurs. Care of the Posterior Wound In som e patients, the rectum and anus are rem oved and there will be a posterior wound. Care of the posterior wound is based on sim ple hygiene and the use of dressings or pads to collect and contain any secretions. The proximal opening expels stool as it travels down through the bowel and the distal opening allows mucous to exit the distal or lower portion of the bowel. The distal end of a loop-end stoma ends in a simple blind pouch which is nothing more than a piece of bowel that has been disconnected from the rectum. Indications: Discharge: • diverticulitis • semi-solid • traum a (injury) • unpredictable • birth defects • contains som e digestive enzym es • cancer/descending or sigm oid colon Management: • bowel obstruction • skin protection • paralysis • drainable pouch • closed-end pouch for convenience or special m om ents 4 Ascending Colostomy the ascending colostomy is located on the right side of the abdomen. This type of stoma is rarely used since an ileostomy is a better stoma when the discharge is liquid. When a colostomy is located in the right half of the colon, only a short portion of colon remains. Caring for an ascending colostomy is similar to caring for a transverse colostomy. Depending on the healing process, the colostom y m ay be necessary for a few weeks, m onths, or even years. Eventually given your good health, the colostom y is likely to be closed and norm al bowel continuity restored. A perm anent transverse colostom y is m ade when the lower portion of the colon m ust be rem oved or perm anently rested. Generally, a transverse colostom y will be placed higher on the abdom en so concealing the pouch m ay be m ore of a challenge. The m anagem ent of the transverse colostom y consists of skin protection and a drainable pouch. Gas and odor are part of the digestive process and can be som ewhat controlled by your selection of foods. A one-piece pouch should not be changed m ore than once a day, unless using a pouching system designed for disposal (closed-end), to prevent skin irritation. The sigm oid colostom y is probably the m ost frequently perform ed of all the colostom ies. The stool of a descending or sigm oid colostom y is firm er than that of the transverse colostom y and does not have the caustic enzym e content. Spilling m ay happen between m ovem ents because there is no anus to hold the stool back. W hile m any descending and sigm oid colostom ies can be m anaged to m ove regularly, others cannot. You m ust realize that satisfactory m anagem ent, with or without stim ulation, is likely to happen only in those people who have had regular bowel m ovem ents before they becam e ill. Som e people have two or three m ovem ents a day, others have one every two or three days or even less often. Caring for a Descending or Sigmoid Colostomy Natural Evacuation the descending or sigm oid colostom y can be m anaged by natural evacuation, that is, just let it happen naturally. M any individuals with a descending or sigm oid colostom y will return to a predictable bowel m ovem ent pattern. There are specific ostom y supplies needed for this procedure that will include: 1) plastic irrigating container with a long tube, and a cone to introduce water into the colostom y, 2) an irrigation sleeve is worn to direct the output into the toilet, 3) an adjustable belt to attach the irrigation sleeve and 4) a tail closure for the end of the irrigation sleeve. Irrigation sleeve Irrigation system Adjustable belt Tail closure 7 Irrigation Information Only for Those Who Irrigate • First, speak to your physician and ostom y nurse before irrigating your colostom y. You m ay shut the clam p or press the walls of the tube together to slow or stop the water flow. Once the water has been instilled, a bowel-m ovem ent-type cram p m ay precede the return of the water and stool. As soon as the m ajor portion of stool has been expelled, you m ay clip the bottom of the irrigating sleeve to the top with a clasp. They are m ade of disposable m aterials and designed to be worn once and then discarded. Everyone, including those who irrigate, needs som e type of stom a pouch on hand, if only for em ergency purposes. One-piece stom a cap Storage For the sake of convenience and discretion, keep all your equipm ent together on a shelf or in a sm all box in a cool dry area. Ostom y supplies can be ordered from pharm acies, m edical supply distributors and on the Internet. Perspiration during the sum m er m onths in warm, hum id clim ates m ay shorten the num ber of days you can wear the pouching system. Physical activities will have som e influence on the length of tim e you can wear your pouch. Peristomal Skin A colostom y that discharges firm stool usually causes few, if any, skin problem s. If the stool is loose, as is often the case with transverse colostom ies, it can irritate the skin. If you have a skin irritation that is caused by the pouch m aterial, you m ight try a pouch cover. Intestinal Gas During the early weeks and m onths after surgery, you m ay experience excessive gas.

Hand surgery is a crossover specialty drawing from both disciplines with the national Training Interface Group fellowships in Hand Surgery co-ordinated by the intercollegiate Joint Committee of Surgical Training medications 1040 purchase genuine eldepryl, reflecting that collaboration symptoms zenkers diverticulum eldepryl 5mg visa. The Professional and Clinical Standards Committee sets standards for members professional conduct and promotes best clinical practice respectively symptoms whiplash buy eldepryl 5mg otc. The direction of policy is the responsibility of the Strategy Committee working with Council treatment resistant schizophrenia cheap eldepryl 5 mg with amex. The Education, Research and Audit Committees and the Committee of Management of the European Journal of Hand Surgery oversee their respective areas of responsibility. Communications policy exists to promote public understanding of health policy and surgical care related to hand surgery. Advanced Training in Hand Surgery • Registrars seeking advanced training in hand surgery, may choose to undertake a fellowship in Hand Surgery, prior to commencing their consultant post. Surgeons are appointed at competitive interview regulated by the South West Deanery. The Diploma covers a syllabus orientated course of study over 12-24 months using a system of tutorials, projects and work place based assessments usually delivered in the surgeon’s base hospital. The course content is spread over eight modules with four tutorials and three assessments of various types in each. There is an established Alumni group which is active in professional networking and peer support. All candidates must complete an online programme called ‘Good Clinical Practice’ and attend a two-day design and skill course which takes place in June. It may comprise a grant application, systematic review or service development study. They contain instructional lectures, seminars, presentations of new research and a business meeting. Sponsors from implant distributors, booksellers and the pharmaceutical industry support the meetings. Covering the hand surgery curriculum in a series of six 2-day courses, over a 3-year rolling cycle. It is aimed at senior trainees studying for their Hand Diploma as well as consultants as part of their revalidation. Practical Courses • There are several practical courses run at various centres around the country covering all aspects of hand surgery. Journals • There are several hand surgery journals, including the Journal of Hand Surgery (European) the Journal of Hand Surgery (American), Hand as well as a few smaller circulation ones. In the first round of selection, academic institutions competed to host a new clinical academic position and subsequently Nottingham appointed a Clinical Professor of Hand Surgery. The centre is producing monthly updates of systematic reviews of relevance to hand surgery and held its first Hand Fracture Research forum in 2016. It will expand and develop over the coming years to provide a focus for hand surgery research. Within just 3 years the organisation has delivered on many large-scale projects and obtained over 1. Hand surgery projects include studies on mallet injury, the use of antibiotics in clean hand injuries, paediatric nail bed injuries, the use of steroids versus surgery in carpal tunnel syndrome and a national large scale hand trauma audit (>900 patients). Details of ongoing and future projects can be found on the website reconstructivesurgerytrials. Two training days have been established annually, one in the summer and one in the winter. Both meetings are free of charge and aim to cater to all levels of research ability. These partnerships identify and prioritise uncertainties, or ‘unanswered questions’, about the effects of treatments that they agree are the most important. The aim of this is to help ensure that those who fund health research are aware of what really matters to both patients and clinicians. Patients, carers, clinicians, therapists and other health professionals have been surveyed to identify a list of potential uncertainties. The top 10 priorities for research will be decided with input from representatives from all interested parties. It will also provide compelling evidence to funding bodies of the importance of that research. Ideally, the process involves a standardised system for producing guidelines in a multidisciplinary transparent manner that minimises bias. This is through its competitive research fellowship scheme which provides sufficient funding (50, 000) to support one year of full time research. This award helps fund the first year of a trainee’s academic higher degree which significantly enhances their chance of obtaining pilot data and larger grant success. This will further encourage young surgeons to undertake significant research training and help build future capacity in hand surgery research expertise for years to come. Project funding Annual awards for clinical and basic science funding (10, 000) continue to be popular and highly competitive. These smaller grants help obtain preliminary data which enhances chances of larger grant success. Recent funding includes a small award to establish the feasibility and acceptability of placebo surgery to hand surgeons and patients. Because of the requirement to closely monitor innovations, newly developed techniques and joint replacements will be integrated into the registry. Joint replacement survivorship is also monitored and the large volume of data gathered will be invaluable for research. This has ranged from disaster response, through one off educational visits or surgical missions to long-term placements or projects. Hand trauma care is provided by tribal healers, non-medical health workers (for example Orthopaedic Clinical Officers in Malawi) or limited state provided healthcare by general orthopaedic surgeons. Sierra Leone this long-term project in collaboration with ReSurge Africa is to support the development of the first reconstructive surgical unit in this desperately poor country. After a two and a half year hiatus due to Ebola the missions recommenced in November 2016 with the goal of a reconstructive surgical unit staffed by local surgeons by 2020. Malawi Working in collaboration with World Orthopaedic Concern and the country’s only hand surgeon we have supported delivery of a Hand Trauma Workshop. This workshop delivered to the countries Orthopaedic Clinical Officers who provide the initial care for all hand injuries. Sudan We have responded to a request from local surgeons to develop and deliver educational workshops covering the hand curriculum. The long-term goal is to support the development of a Sudanese Society for Surgery of the Hand bringing together the currently separate and generalist groups of plastic and orthopaedic surgeons. There may be an opportunity to broaden the training to include hand fractures on future visits. Future Projects In addition to our established projects we are exploring potential for members to support surgeons in Ethiopia and Uganda. They will return with clinical and surgical skills sharpened, better team players and with renewed perspective. Ministerial responsibility is with the Secretary of State for Health in Westminster. This has led to a ‘post code lottery’ of provision of hand surgery, since the funds available and priority given to various treatments differ. The maximum waiting time from non-urgent referral to treatment of hand conditions in England is currently supposed to be 18 weeks. The Trauma Networks consist of a Major Trauma Centre linked to satellite Trauma Units. Of those, 11 treat both adults and children, 11 only treat adults and 5 only treat children. The major trauma centres offer specialist services treating serious hand injuries such as limb replantation. Therefore, there is not a separation of the providers for hospital services and the health boards.

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The proteolytic enzymes urokinase-type plasminogen activator and plasminogen activator-inhibitor type-1 are involved in angiogenesis process medicine tour purchase eldepryl from india, and thus has a direct role in cell proliferation medications related to the blood purchase eldepryl 5 mg without a prescription, inflammation and ulcer healing symptoms endometriosis purchase eldepryl 5 mg otc. Matrix metalloproteases are involved in extracellular matrix reconstitution and tissue remodeling and thus may have an impact in gastric ulcer healing (Tomita et al medicine 832 order 5mg eldepryl with mastercard. Secretory leucocyte protease inhibitor exerts antimicrobial and anti-inflammatory effects. However, the expression is significantly decreased during Helicobacter pylori-mediated gastritis. This is due to local down-regulation of this proteolytic enzyme in gastric mucosa in response to Helicobacter pylori infection (Tulassay and Herszenyi, 2010). They also promote cell survival during various cellular stresses, as they are generated by gastric epithelial cells in response to oxidative stress, cytotoxicity and high temperature. This is done through acting on enzymes related to cyto-protection, gastric inflammation and gastric ulcer healing. Heat shock proteins act by refolding these partially damaged functional enzymes or increasing delivery of their precursor proteins to important organelles such as mitochondria and endoplasmic reticulum. This results in improvement of mucosal defense, protection against gastric ulcer and promotion of healing of existing damage (Choi et al. Cell proliferation and repair of injured gastric mucosal epithelium are controlled by a number of these growth factors activated as a response to tissue injury. Growth factors such as epidermal growth factor, hepatocyte growth factor, platelet derived growth factor and basic fibroblast growth factor activate epithelial cell migration and proliferation and accelerate ulcer healing by binding to their specific receptors on the cell surface, triggering a number of intracellular signaling events that result in cell migration and proliferation. In the stomach, epidermal growth factor triggers mitogenic response and is important for epithelial cell proliferation, migration, re-epithelization and reconstruction of gastric glands. Vascular endothelial growth factor is important for angiogenesis, vascular remodeling and mucosal regeneration. Transforming growth factor protects against gastric mucosal injury and promotes wound healing. Receptors for epidermal and transforming growth factors are Prevention of Gastric Ulcers 451 expressed in gastric progenitor cells and are trans-activated by gastrin and prostaglandin E2 that trigger cell proliferation and repair of gastric mucosa (Tulassay and Herszenyi, 2010). These growth factors are mainly derived from platelets, macrophages and injured tissue. Ulceration also triggers induction of genes encoding these growth factors in cells lining mucosa of the ulcer margin. These locally produced growth factors activate epithelial cell migration and proliferation via actions on autocrine and/or paracrine systems. These receptors are expressed in the gastrointestinal tract, liver, skeletal muscle, heart, adipose tissue, breast and skin. Stimulation of peroxisome proliferation-activated receptors plays an important role in the mechanism of non-steroidal anti-inflammatory drugs action. Peroxisome proliferation-activated receptors cause subsequent inhibition of nuclear factor B and other transcription factors. These receptors regulate transcription of target genes involved in lipid and lipoprotein metabolism, glucose homeostasis and cell differentiation. In addition, peroxisome proliferation-activated receptors inhibit the activation of certain inflammatory response genes. Thus, activation of peroxisome proliferation-activated receptors during non-steroidal anti-inflammatory drugs administration blocks the production of inflammatory response markers, such endothelin-1, vascular cell adhesion molecule-1 in endothelial cells and tissue factors as matrix metalloproteinase-3 and tumor necrosis factor in macrophages. These anti-inflammatory actions are mediated by inhibition of pro-inflammatory transcription pathways as nuclear factor B, activator protein-1 and nuclear factor of activated T cells (Lim et al. Ghrelin is also a neuropeptide associated with gastro-protective effects with important effects on energy homeostasis and gastrointestinal motility. Ghrelin mediates its gastro-protective effects also via stimulation of nitric oxide production and calcitonin gene related peptide release from sensory afferent nerves, enhancing gastric mucosal blood flow. Orexins are another family of neuropeptides having gastro-protective role, especially orexin-A. Orexin-A prevents mucosal injury and gastric ulceration through several mechanism including increasing gastric blood flow, elevating luminal nitric oxide, reducing lipid peroxidation, generating prostaglandin E2 and enhancing vagal and sensory nerve activity (Nayeb-Hashemi and Kaunitz, 2009). It is highly inducible as a response to stress, as oxidative stressors, ultraviolet irradiation, inflammatory cytokines, heavy metals and non steroidal anti-inflammatory drugs. Up-regulation of hemeoxygenase-1 infers anti-apoptotic resistance to the cells due to potent antioxidant effect of bilirubin, biliverdin and carbon 452 Peptic Ulcer Disease monoxide formed. Hemeoxygenase was shown to protect gastric mucosal cells against non steroidal anti-inflammatory drugs (Aburaya et al. Therapeutic interventions in prevention of gastric ulcer Several therapeutic interventions may aid in preventing gastric ulcer. Enhancement of normal physical barriers and physiological protective factors can aid in prevention of gastric ulcer. Some endogenous gastro-protective factors (see above) may be enhanced to decrease the risk of gastric ulcer formation. Conventional medications used in treatment of gastric ulcer can also be used in prevention as well, especially in predisposed people. Several investigations also tested drugs not conventionally used in treatment of gastric ulcer for having possible ulcerogenic protective effects. The main aim of most of these studies is to decide which drug to preferentially use in treating conditions presenting concomitantly with high risk of development gastric ulcer. Successful classes in treating gastric ulcer include Helicobacter pylori eradication therapy, prostaglandin analogs, cyto-protective drugs, histamine H2 receptor antagonist and proton pump inhibitor groups. In terms of acid inhibition, proton pump inhibitors possess higher acid inhibitory potency. Histamine H2 receptor antagonists have, thus, been gradually replaced with the more potent class of acid inhibitory drugs, the proton pump inhibitors. Current ulcer therapy consists of Helicobacter pylori eradication in Helicobacter pylori-positive gastric ulcer and proton pump inhibitors for healing and preventing peptic ulcers induced by drugs. These proton pump inhibitors are the most popular group of drugs used in Helicobacter pylori eradication regimens (see before; section 2. Misoprostol, a prostaglandin analog, has been the most widely used but its application is limited by abdominal side-effects as abdominal cramps and diarrhea. Sucralfate also acts by reducing acid secretion and suppressing Helicobacter pylori infection. Bismuth salts, having mild anti-Helicobacter pylori activity, are used in treatment of gastric ulcer therapy in combination with antibiotics (Malfertheiner et al. All of these drugs have been used successfully to treat gastric ulcers and prevent remittent attacks. Nevertheless, their efficiency in prevention of gastric ulcers in individual predisposed groups is still controversial. Histamine H2 receptor antagonist is one example, as their standard dosage succeeded only in reducing the risk of duodenal ulcer, but not gastric ulcer induced by non-steroidal anti-inflammatory drugs. The benefit from histamine H2 receptor antagonists was limited to preventing the risk of ulcers induced by Helicobacter pylori infection (Chan and Graham, 2004). Contrarily, in another study, histamine H2 receptor antagonists were effective for prevention of low dose aspirin-induced ulcers and showed similar potency as proton pump inhibitors (Nakashima et al. Another example is the use of cyto-protective drugs (as in Table 1) for prevention of gastric ulcer, whose efficacy is still controversial. Using these conventional anti-ulcer drugs in prevention of gastric ulceration is, thus, dependent on the type of predisposing risk factor. Risk factors used in assessment are old age, presence of cardiovascular diseases, use of high dose or multiple non-steroidal anti Prevention of Gastric Ulcers 453 inflammatory drugs, concomitant use of low-dose aspirin and other anti-platelet drugs, corticosteroids or warfarin. When one or two of these factors are present, presenting a moderate risk, an anti-secretory agent or misoprostol may be used. If three or more risk factors are combined, presenting a high risk, switching from non-selective, to selective cyclooxygenase inhibitors is recommended. In addition, misoprostol can be used for prevention of aspirin or warfarin-induced gastric ulcers. In very high risk patients, who have been subjected to previous ulcer complications, avoidance of non-steroidal anti inflammatory drugs and intake of proton pump inhibitor and/or misoprostol is recommended.

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Biostatistics is an important science of clinical trials treatment dynamics florham park eldepryl 5mg, since it provides an estimate of probability for making any of those two false conclusions medications look up purchase generic eldepryl canada. For example: when we flip a fair coin 100 times medications memory loss cheap eldepryl 5 mg fast delivery, we expect 50 heads and 50 tails – but we can also get different numbers such as 60 and 40 medicine 524 trusted eldepryl 5 mg. In clinical trials the same variation arises because the random selection of participants typically involves a large number of difficult or easy participants to one treatment over the other. Treatment A, which has a true treatment success rate of say 50%, could show 30 successes in 100 participants, while treatment B, which has a true rate of say 40%, could show 50 successes in 100 participants. Based on our total combined sample of 200, we could come to the wrong conclusion that treatment B is better than treatment A (a false result). The basic problem is that the important characteristics of the random sample may or may not match the reality of the world, namely the entire participant population. The point of clinical trial design and interpretation is to control the risk of making an error in order to discover the truth. Note that a false negative trial result will in practice end a particular development programme. This is costly not only to the trial sponsor, but also to society, which loses out on finding a potentially useful treatment. Four different interpretations can be made from a clinical trial: either the two aforementioned errors or correct interpretations that reflect the real world, i. The level of risk that we are prepared to take in reaching a wrong conclusion can also be measured by the cost of the trial. From a research ethics point of view, we may also unnecessarily put a large number of trial participants at risk by increasing the sample size without making a proper risk assessment. Clinical Equipoise Equipoise can be defined as “balance” or “equability of distribution. Under the principle of equipoise, a participant should be enrolled in a randomised controlled trial only if there is substantial uncertainty about which intervention will likely benefit the participant more than the other intervention(s). It can also be the rationale behind interim data analysis during the course of a trial, to identify findings that might change the clinical equipoise picture. This guidance contains a section addressing the type of comparisons made in certain clinical trials. The most common type of comparison trial is the so-called superiority trial, whereby efficacy is most convincingly established by demonstrating superiority to a placebo in a placebo-controlled trial or by showing superiority to an active control treatment. However, sometimes an investigational product is compared to a reference treatment without the objective of showing superiority. Some active control trials are designed to show that the efficacy of an investigational product is no worse than that of the active comparative treatment, i. Other trials – equivalence trials – have the primary objective of showing that the response to two or more treatments differs by an amount that is clinically unimportant. This is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and upper equivalence margin of clinically acceptable differences. The choice of the type of comparison will influence some technical aspects of the study design, sample size and statistical analysis, but this will not be further elaborated in this Guide, where superiority trials are generally assumed to be the design of choice. Types of Clinical Trial Designs the vast majority of clinical trials use a fixed design that remains virtually unchanged during the duration of the trial. But some trials might not have enough information to correctly estimate the sample size beforehand. Here, the protocol might spell out that the sample size will be reassessed and revised at a certain point in time – it usually happens after a specific number of participants have completed a certain Chapter 2. Increasing Treatment group A Parallel group trial design the number of visits or duration of Standard/placebo the follow-up is also quite common with protocol amendments. Standard/placebo No treatment (“wash out”) Test article A clinical trial design has many features and some of them are covered in other sections of this Chapter, i. Here, we Test article No treatment (“wash out”) address a few general, common Standard/placebo trial design characteristics based on the number of groups and the most common clinical trial study design – the parallel group design – with two groups. The cross-over design is sometimes utilised in clinical trial treatment alternatives. In most cases, trial participants are randomised to one of the two treatment groups, with randomisation commonly giving each participant the same possibility or chance to be allocated to either treatment section. One group – say group B – is given the test article, and the other group frequently given placebo (dummy) treatment, or the current best available treatment on the market (standard treatment). It is also possible to give both groups the standard treatment with the addition – as an add-on treatment or as a combination therapy – of the test article for one of the two treatment groups. The cross-over design represents a special situation where there is not a separate comparison group. A cross-over design has the advantage of eliminating individual participant differences from the overall treatment effect. On the other hand, it is important in a cross-over trial that the underlying condition – for instance, a disease – does not change over time, and that the effects of one treatment disappear before the next is applied. With this, it follows that cross-over design is utilised much less commonly than parallel group design. The cross over design is also more sensitive to drop out during the course of the trial, since participants act as a control as well as active treatment participants. An open-label trial – though less common – is when both the investigators and participants know which treatment is being administered, with trial participants still commonly randomised to one of two treatment groups. Using historical controls is nowadays seen as a sub-standard research design, since standard medical treatments change over time and randomisation to treatment cannot apply. Sometimes a trial has 34 Reviewing Clinical Trials: A Guide for the Ethics Committee more than two concurrent treatment groups, for instance when different doses are to be compared. Adaptive Clinical Trial Design Stop A few, but an increasing number Proven of trials use the so-called adaptive efficacy clinical trial design – empowering Drop sponsors to respond to data 0ne group collected during the trial. Examples of adaptive trial designs include dropping a treatment Increase sample group, modifying the sample size, size balancing treatment assignments Interim Interim analysis using adaptive randomisation, or analysis 50% 70% Continue simply stopping a trial early due as to success or failure (see planned illustration). In a standard trial, safety and efficacy data are collected and reviewed by a data Stop Enrich Futility population safety and monitoring committee reasons during scheduled interim analyses. The term “futility” stopping a trial for safety reasons, refers to the inability of a clinical trial to achieve its objectives. In very little can be done in response particular, stopping a clinical trial when the interim results suggest that it is unlikely to achieve statistical significance can save resources that could be to these data. An interim statistical analysis is a trial must be designed to further temporary or provisional arrangement for decision making only and will not allow any details of the results to be passed on to the investigator or investigate key trial findings. In an adaptive trial, the sponsor might have the option of responding to interim safety and efficacy data in a number of different ways, including narrowing the trial focus or increasing the number of participants. An example of narrowing the trial focus includes removal of one or more of the treatment groups based on predetermined futility rules – the inability of a clinical trial to achieve its objectives. Alternatively, if data available at the time of the review do not allow for a clear decision between utility and futility, it might be decided to expand the enrolment of participants to one or more treatment groups beyond the initially targeted sample size. In this setting, participants are randomised to treatment groups based on response to treatment of previous participants. Real-time safety and efficacy data can be incorporated into the randomisation strategy to influence subsequent adaptive randomisation decisions on a participant-by-participant basis. An example of response-adaptive randomisation is play-the-winner, which assigns participants to treatment groups that have resulted in fewer adverse events or better efficacy. As these examples demonstrate, the adaptive design concept can be utilised in a number of different ways to increase trial flexibility. In a well-designed adaptive trial, that flexibility can result in lower drug development costs, reduced time to market and improved participant safety. Cost reduction is achieved by identifying successful trials sooner, dropping unnecessary treatment groups or determining effective dose regimens Chapter 2. Participant safety is improved because adaptive trials tend to reduce exposure to unsuccessful treatment groups and increase access to effective treatment groups. Adaptive trial design requires modern data collection technologies to provide the research team with real-time information, and enables them to plan and quickly implement seamless changes in response to that information. Key enabling technologies for adaptive trial design are, for instance, real-time electronic data capture over the Internet to a central database. The general impression is that utilising adaptive clinical trial design will become more and more popular. The adaptive trial design is still in its infancy and may become generally accepted in the future. A control group is chosen from the same population as the test group and treated in a defined way as part of the same trial studying the test treatment. Test and control groups should be similar at the initiation of the trial on variables that could influence outcome, except for the trial treatment.

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