By Y. Ronar. Schreiner College. 2018.
In the second discount 500mg metformin fast delivery, a definite outcome such as one comparing oral clomiphene citrate such as pregnancy has the natural effect of (a drug treatment) versus expectant management preventing women from completing later phases of the trial purchase 500mg metformin amex. From a practical the treatment as well as the associated placebo point of view metformin 500mg lowest price, only data from the first phase effect as this best reflects the likely clinical of the crossover trial may be valid metformin 500mg overnight delivery. TRIAL DESIGN SIMPLE PARALLEL GROUP FACTORIAL This is the simplest and commonest trial design Factorial designs are often efficient as they can involving a comparison between two groups, address two questions within the context of a 340 TEXTBOOK OF CLINICAL TRIALS Women with unexplained infertility Randomisation A B Expectant management Clomiphene C D Intra-uterine insemination Clomiphene + intra-uterine (IUI) insemination (IUI) Figure 21. Women with unexplained infertility is not targeted at individual patients, but at can be randomised to receive either expectant groups of patients. This can happen where the management (no treatment), insemination alone, intervention is an information package for the clomiphene alone or clomiphene and insemina- management of menorrhagia in primary care9 tion treatment as shown in Figure 21. In been expected to manage both study (information this case, the effect of IUI alone can be assessed leaflet, clinical guidelines) and control patients. Cluster C and D with A and B, while the effect of randomisation should only be carried out when clomiphene can be evaluated by comparing B and there is a strong justification for doing so. The primary implication of cluster randomised trials is that the measurements on individuals CLUSTER RANDOMISED TRIALS IN are not statistically independent of one another; GYNAECOLOGY AND INFERTILITY that is measurements from individuals within the A potential problem that can occur with ran- same cluster will be correlated to one another. Cluster randomised trials should ence in implantation rates was likely to be wider adjust for this clustering when determining the than that reported due to failure to adjust for number of patients required. The sample size the clustering of embryos/oocytes transferred to that would be required if patients were to be each woman. Studies where oocytes have been randomised must be inflated by a factor which randomised have no clustering implications since takes into account the extent of the clustering oocytes retrieved from the same women are ran- and the size of the cluster. When there is implicit clustering that fail to adequately inflate the sample size will in the data, the statistical analysis should account for this using the methods described above. Similarly, the correlated responses obtained from each cluster have an implication for the QUASI-RANDOMISED TRIALS statistical analysis, since standard statistical tests These are controlled experimental studies where (e. There are a number of patient unit numbers or days of the week when approaches to analysing cluster randomised tri- 13 the patients are recruited. Failure to treatment allocation affords an element of chance, account for the correlated responses in the anal- it cannot be considered to be genuine randomi- yses will result in an increased type I error. This type of design may still appeal to Clustering of outcomes can also occur in infer- those involved in laboratory trials involving incu- tility trials where alternative treatments are being bation or cryopreservation of human embryos. For example, in randomised controlled In these cases, it may be easier and cheaper to trials comparing IVF with ICSI the unit of allo- 14 15 use a certain protocol for all embryos on alter- cation varies between patients, oocytes and 16 nate days or alternate weeks rather than change cycles. Often, outcomes such as implantation the protocol or a freezer setting for each embryo rate and fertilisation rate are considered. The consequent loss of allo- are both expressed as percentages out of the total cation concealment will lead to serious inclu- number of oocytes retrieved. Hence, in trials that sion bias as some patients may be deliberately randomise patients (couples) or cycles and report excluded. This, is turn, can exaggerate treatment implantation or fertilisation rates, there will be effects. In trials that randomise by patients and be randomised on grounds of strong treatment report fertilisation of implantation rates, some preferences. However, for outcomes affect the generalisability of the results as par- such as live birth rate or pregnancy rate no ticipants may not be representative. Yet recruit- adjustment is required since the percentages are ment of these patients may introduce substantial expressed out of the total number of patients ran- bias especially when it is impossible to blind domised. In addition, compliance and satisfaction and reported implantation rates per transferred may be higher with the preferred intervention. Dissatisfaction number of patients into either the randomised or with the allocation may lead to differential com- the preference arms is also a problem, as the trial pliance and follow-up resulting in groups which will not be completed unless the appropriate num- cannot then be assumed to be similar. The out- ber have been recruited into the two components of come measures could also be affected by how the trial. The situation may be further complicated satisfied patients are with their allocated treat- by patients favouring one treatment over another, ment. The effect of patient preference on outcome making comparison of the two groups in the pref- would depend to a great extent on the specific erence arm more difficult.
An arm that conclusion is still not clear order 500 mg metformin with amex, dropping arms or performs sufficiently poorly gets dropped order metformin 500 mg mastercard. All of these arm that does well enough graduates to Phase III generic metformin 500mg with amex, BREAST CANCER 97 and if it does sufficiently well it might even yet fully evaluable discount metformin 500 mg on-line. These include available, they are added to the mix and the the simultaneous incorporation of efficacy results process can continue indefinitely. However, randomised to treatments with weights propor- breast cancer stands out for several reasons. First, tional to the probability that a treatment is better it is common, and it is becoming even more than the standard therapy. The result is that supe- common with the improvements in and greater rior therapies move through quickly and poorer use of detection methods. Patients in the trial are pro- ability to investigate the potential for therapeutic vided with better treatment (when the arms are agents and combinations. Patients outside the trial get have been hundreds of randomised clinical trials access to better treatments more rapidly. Second, it is a disease that is Dose-finding trials of new agents are also con- fatal in only a minority of cases. Third, patient ducted adaptively at MDACC, with dose assign- advocates in the breast cancer community have ment based on Bayesian updating of a model been very influential, both as a research force which relates dose and toxicity, using results and a political force, in lobbying for research from preceding patients. Each to be sensitive to a number of chemotherapies patient is assigned to the dose having a prob- and hormonal therapies. The advances that have ability of toxicity closest to some predetermined been made in breast cancer therapy are more target value. This is the Bayesian posterior proba- impressive than for any other type of cancer, bility calculated from the data available up to that except for testicular cancer and some forms of point (and so it is based on sufficient statistics). These The CRM more effectively finds the maximum advances have been built on a foundation of tolerated dose (MTD) than does the conventional clinical trials. Surveillance, Epidemiology, and End Results they cause logistical problems. Trials should be Program (SEER) Public-Use Data (1973–1998), paused or stopped if there are safety concerns, National Cancer Institute, DCCPS, Surveillance not because the design cannot get out of its own Research Program, Cancer Statistics Branch, Bethesda, MD, August 2000 submission; released way. In getting information about toxicity (or April 2001 [online database, available at http:// efficacy), there is seldom a magical dose that the seer. Rather than stopping, one should Network (CISNET) [online information site]. Available through the National Cancer Institute, use a design that models dose–response (toxicity US government, at http://cisnet. American Joint Committee on Cancer (AJCC) Hopkins Hospital from June 1889 to January 1894. Singletary SE, Allred C, Ashley P, Bassett LW, the cure of carcinoma of the breast. Ann Surg Berry D, Bland KI, Borgen PI, Clark G, Edge SB, (1907) SLVI: 1–19. Page DL, Recht A, Theriault RL, Thor A, Weaver Cancer Invest (1996) 14: 371–7. A great leap backward in the American Joint Committee on Cancer Staging treatment of carcinoma of the breast. Greenberg PA, Hortobagyi´ GN, Smith TL, Ziegler Borland D, Fisher ER, Deutsch M, Schwarz G, LD, Frye DK, Buzdar AU. Long-term follow-up Margolese R, Donegan W, Volk H, Konvolinka C, of patients with complete remission following Gardner B, Cohn I, Lesnick G, Cruz AB, Law- combination chemotherapy for metastatic breast rence W, Nealon T, Butcher H, Lawton R. Tamoxifen for early breast cancer: an of results from a prospective randomized clinical overview of the randomised trials. Twenty-five-year follow-up of a inhibition: clinical efficacy and tolerability in the randomized trial comparing radical mastectomy, treatment of breast cancer. Clin Cancer Res (2001) total mastectomy, and total mastectomy followed 7: 2620–35. Thor AD, Berry DA, Budman DR, Muss HB, Rossi A, Brugnatelli L, Brambilla C, DeLena M, Kute T, Henderson IC, Barcos M, Cirrincione C, Tancini G, Bajetta E, Musumeci R, Veronesi U.
Insulin-like growth fac- until a new steady state of smaller muscle mass tor levels are affected by all of these events purchase metformin 500mg with amex. Protein synthesis and degradation The trophic agent activates several intracellu- eventually come into balance metformin 500 mg sale. Closely parallel- lar signaling pathways in muscle buy metformin 500 mg amex, including ing the net loss of muscle mass is a correspon- the mitogen-activated protein kinase cascade purchase metformin 500 mg, ding loss of proteins for the contractile ma- which participates in catabolic and anabolic ac- chinery, particularly MHC. These alterations leave patients tributes to skeletal muscle degeneration asso- with less muscle mass to perform activities that ciated with illnesses that cause cachexia. Skeletal muscle be- Muscle activity directly influences the for- comes less economical as its force production mation and maintenance of synaptic sites and increases. For example, NT- may be related to an increased dependence on 4 is produced by active muscle. NT-4 has an levels, one of the goals for neurorehabilitation activity-dependent influence on motoneuron is to devise countermeasures to conserve mus- survival and axonal sprouting onto muscle cle mass and maintain the contractile pheno- fibers. Agrin, after being released into the The subcellular events that regulate contractile synaptic cleft, binds to the basal lamina and protein turnover during muscle hypertrophy triggers the muscle fiber to aggregate acetyl- and atrophy pose a work in progress. Autocrine choline, acetylcholinesterase, and other post- and paracrine processes involving muscle-de- synaptic components. The maximal tension in of remodeling proteins that restore the motor the paretic muscle was low as well, suggesting unit, so exercise serves as a critical component the combination of fiber atrophy, a reduced of any neurologic rehabilitation prescription. A better un- derstanding of the interactions of each element NEURAL INFLUENCES of the motor unit should lead to hypothesis- Biopsies of affected muscle after hemiplegic driven interventions to maintain muscle mor- stroke and paraplegic SCI in humans reveal at- phology and forces. Although mostly related to the molecular sequelae of inactivity of the NONUSE muscle, the pattern of fiber type grouping may also arise from loss of supraspinal inputs onto Muscle wasting can be attributed more to spinal motoneurons. Muscle in humans at complete rest tentials and positive sharp waves by elec- is said to initially atrophy at the rate of 1% to 6% tromyography. These signs of lower motoneu- daily for the first week and strength in an im- ron denervation peak at 4 to 10 weeks after a mobilized limb can fall 30% to 40% in 6 stroke or cervical SCI and have been reported weeks. Transsynaptic Pase, hexokinase, oxidative and anaerobic me- degeneration of anterior horn cells has been in- tabolism, and alteration of the myosin mole- voked as the cause. Recent data offer clues about the cross-sectional area of lower motoneurons possible interventions for disabled patients. Passive the degree of degeneration of the medullary stretch, alone, can induce some muscle en- pyramid and of muscular weakness parallel the largement. A number of cellular signals trans- decrease in the size of the motoneurons. Motoneuron and muscle tion of the cord by transection and deafferenta- fiber atrophy is also evident after denervation tion of lumbar roots, or by spaceflight, a num- of muscle. Hemiparetic subjects muscles and in the deeper portions of muscles with severely weak tibialis anterior muscles had that contain the greatest proportion of slow low rates of motor unit firing during walking twitch and high oxidative fibers. Limb unloading, as in the hindlimb sus- to fire far more than it would in a normal sub- pension model, led to a rapid phase of atrophy ject, contained 75% type I fibers, a bit more in the first 1 to 2 weeks, so countermeasures are Biologic Adaptations and Neural Repair 117 perhaps most important in this phase after on- strength in patients with neurologic disease. For a muscle fiber Genetic studies suggest that healthy people to maintain or increase its usual size, it had to with a gene polymorphism that reduces the ex- produce some minimum level of force for pression of ACE have greater muscular effi- some minimum time each day. In rats whose ciency and a higher anabolic response to exer- hindlimbs were suspended so they bore no load, cise training. The identification of myogenic precursor cells and stem cells points to the possibility of de- HORMONES AND DRUGS veloping techniques to reverse atrophy and the Receptors for hormones are present on the effects of aging on muscle, as well as repair in- muscle membrane and contribute to plasticity. Myoblasts have been derived from hormones, testosterone, and other anabolic satellite cells and other cells within muscle, as steroids,206 and beta-2 agonists. For example, experimental animal them still controversial and less reliable than models show that hypothyroidism can prevent others, identify satellite and other myoblast the loss of slow MHC mRNA in the nonweight cells, so they can be collected and cultured. Indeed, all hormone replacement that imitate heparan sulfates and other extracel- strategies include some risk for medical com- lular matrix molecules may accelerate regenera- plications (see Chapter 12).
Three groups of subjects were compared discount 500 mg metformin mastercard, performed by the same operator and was iden- edentulous/edentate subjects who requested and tical for all the test and control sites metformin 500 mg line. Abut- received complete implant-stabilised oral pros- ment connection was carried out at 35 Ncm theses (IG 500 mg metformin amex, n = 26) order 500 mg metformin visa, edentulous/edentate subjects 6 weeks post-surgery for test sites and 12 weeks who requested implants but received conven- for the controls by the same dentist who was tional dentures (CDG1, n = 22), and edentulous blinded to the type of surface of the implant. Simi- the most comprehensive instruments available in lar gold–ceramic restorations were cemented on evaluating oral health-related quality of life. Clinical measures and radiographic changes were TRIALS RELATED TO PERIODONTAL DISEASE recorded by the same operator who was blinded In order to prevent periodontal disease, plaque to the type of surface of the implant, 1 year post- 34 removal and prevention of calculus deposit surgery. Thus ways to In a study to compare two designs of maxil- improve toothbrushing (mechanical means to lary implant overdentures, a crossover trial was remove plaque) or the use of mouthrinse or designed to measure differences in patient satis- toothpaste with active ingredients like chlorhex- faction with maxillary long-bar implant overden- idine and pyrophosphate ion (chemical means to tures with and without palatal coverage opposed remove plaque and to prevent calculus deposi- by a fixed mandibular implant-supported prosthe- tion) were investigated. A mandibular fixed prosthesis was inserted therapy existed: non-surgical and surgical ther- in 13 total edentulous participants, who were apy. The aims for these studies were to investi- then divided into two groups. One group (n = 7) gate the effectiveness of the treatment modalities received maxillary long-bar overdentures with in reducing the depth of the periodontal pocket palate, then long-bar overdentures without palate. The other group (n = 6) received the same treat- Similar to the caries research, different study ments in the reverse order. For each overdentures designs in RCT have been applied to periodon- design, mastication tests and patient satisfaction tal research; one particular design issue that has were assessed 2 months after the fitting of the been discussed more in periodontal research com- overdenture to allow adaptation. This is based outcomes such as patient satisfaction important because clinical trials for testing supe- and quality of life measures were also mea- riority and for testing equivalency should have sured in these oral rehabilitation studies. As in different designs and there has been a tendency the above quoted example, patients were asked by the clinicians in periodontal research to con- to rate (1) their general satisfaction with the fuse the difference between the two. Thus if no and (3) satisfaction on the psychosocial func- statistical differences are found, this only demon- tions such as a esthetics, self-confidence, etc. He has also urged journal superiority studies investigating products used in editors to promote the publication of RCTs. Hopefully, there should be a paradigm shift It was found that since equivalence clinical trials in conducting RCTs in orthodontic research in require much smaller differences between groups, future years. Various studies making use of the have been summarised in explaining why the EBD approach have been applied to different move to conduct RCTs in orthodontic research areas in dental research and the journal Evidence- has been slow. First, there is a remarkable Based Dentistry has also been published since level of non-acceptance that the highest level of November 1998. It differs from narrative there is the argument that it is not ethical review as in the latter case the authors or experts to subject patients to a random allocation of do not use standardised ways to retrieve articles treatments if it is already known that one of the and summarise information. Third, there is a feeling ers may arrive at different conclusions for the that RCTs are very large and difficult to manage same question. In systematic review, standards in and then they are expensive and a large amount finding, evaluating and synthesising evidence are of funding is required. In an influential book, treatments are superior to another without being Cochrane49 drew attention to the importance tested in an unbiased manner, thus it is actually of organising critical summaries of all relevant unethical to provide treatment that has not RCTs by specialty or subspecialty areas of health been properly evaluated; (3) careful planning and care, so that people can make more informed DENTISTRY AND MAXILLO-FACIAL 201 decisions. More examples have rently, there are 15 Cochrane Centres around the been given by Macfarlane and Worthington50 world. This is the responsibil- which assume observations being independent, ity of international collaborative review groups, are not appropriate for the analysis. Thus spe- which also maintain registers of systematic cial statistical analysis is required when data have reviews currently being prepared or planned, so a hierarchical structure. Analysing data without that unnecessary duplication of effort can be recognising the hierarchical structure and treat- minimised and collaboration promoted. Currently ing the observations as independent will lead to there are about 50 review groups covering all a spurious increase in the sample size, and corre- of the important areas of health care and den- sponding spurious significant relationship. The prin- up to six site measurements for each tooth and cipal output of the collaboration is the Cochrane with 28 teeth (not including the wisdom teeth) for Reviews which are published electronically in an individual, the total number of observations successive issues of The Cochrane Database of for one individual could then be 168. Ten Cochrane Reviews have easy to have thousands of observations with only been finished in the Cochrane Oral Health Group, 20 subjects.