RESPOND-2 trial

The efficacy of boceprevir as a treatment for chronic hepatitis C infection (genotype 1) was evaluated in phase III studies of -1500 adult patients. The SPRINT-2 trial was designed to assess boceprevir in treatment-naive patients, whereas the RESPOND-2 trial was designed for patients who had failed previons standaid-of-care PEG-INF/RBV (PR) therapy. 

In the RESPOND-2 trial, the addition of boceprevir to PR significantly increased the SVR rates (59-66% in triple therapy arms vs. 23% in PR48 control). 

HBV infection remains a major worldwide public health problem. The World Health Organization estimates that there are still 350 million chronic carriers of the vims, who are at risk of developing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The success of IFN-a treatment - mainly performed as combined treatment with adenine-arabinoside - has been measured by the normalization of liver enzymes, loss of HBe antigen and of detectable viral DNA in the serum of patients. It has been estimated from several clinical trials that as many as 40% of treated HBV patients would respond to therapy with IFN-a or combined treatment with nucleoside analogues and IFN-a. 

There is no systematic approach to exploiting flexibility. Upper management tends to make decisions that are too fixed and does not communicate well the trade-offs that should be applied when the future is different from its central assumption. For example, those implementing decisions may receive a deadline for completion of a trial, rather than a target completion date with guidelines on the value of different completion dates to the business and how to respond accordingly. 

Each of the analyses reported outcomes for patients responding to and continuing treatment after the original 6-week clinical trial that is, after the exclusion of patients withdrawing from the original trial for whatever reason (e.g. poor tolerability, lack of response). This probably introduced bias in favour of haloperidol, since there were significantly more responders to olanzapine. 

The first proper double blind trial of embryonic implants in 40 PD patients (20 undergoing just surgery without any implant), has shown no improvement in patients over 60 years but some clinical benefit (fewer symptoms between levodopa dosing) in those below that age. Unfortunately some of these responders eventually developed dyskinesias, a sign of too much dopamine, and further implants were halted until the technique has been re-evaluated, see Freed, CR et al. N EnglJ Med 2001, 344 710-719. 

The initial enthusiasm for tacrine and velnacrine, which are the anticholinesterases most studied clinically, has been tempered by the fact that not all patients respond. Most show the peripheral parasympathomimetic effects of cholinesterase inhibition, e.g. dyspepsia and diarrhoea, as well as nausea and vomiting, and about half of the patients develop hepatotoxicity with elevated levels of plasma alanine transaminase. While some peripheral effects can be attenuated with antimuscarinics that do not enter the brain, these add further side-effects and the drop-out rate from such trials is high (<75%) in most long-term studies. Donepezil appears to show less hepatotoxicity but its long-term value remains to be determined. 

Randomization refers to the process of assigning subjects by chance to treatments. This eliminates known and unknown sources of bias that could interfere with accurate interpretation of the study results. The main problem that randomization is intended to prevent is bias in subject selection. Without randomization, investigators might consciously or subconsciously select subjects to receive the active treatment, which, they believe, are most likely to respond. History shows that uncontrolled studies are much more likely to provide exaggerated support in favor of the effectiveness of a treatment than properly controlled trials (Pocock, 1983). Therefore, whenever possible, randomization should be used in order to help insure a fair and unbiased evaluation of the intervention under study. 

Venlafaxine extended release, in doses of 75 to 225 mg/day, improves social anxiety, performance, and avoidance behavior with a reduction in disability.61 Treatment with venlafaxine results in response rates similar to those seen with paroxetine.60 Venlafaxine may be effective in SSRI non-responders.62 As with SSRIs, doses should be tapered slowly when discontinuing therapy. Tolerability is similar to that observed in depression trials with venlafaxine extended release. Common side effects are anorexia, dry mouth, nausea, insomnia, and sexual dysfunction. 

If the patient is not responding to therapy after an adequate trial, assess compliance with the prescribed regimen. If the patient is not compliant, counsel the patient and caregivers and explore reasons for non-compliance. In some cases, switching to another stimulant formulation may improve compliance. 

At equipotent doses, the analgesic and anti-inflammatory activity of all NSAIDs and aspirin are similar. The selection of a specific NSAID should be based on tolerability, previous response, and cost. Some patients respond to one NSAID better than to another. If an insufficient response is achieved with one NSAID, another agent from the same or a different chemical class should be tried. Pain relief occurs rapidly (within hours), but antiinflammatory benefits are not realized until after 2 to 3 weeks of continuous therapy. This period is the minimal duration that should be considered an adequate NSAID trial. 

Monitor patients for relief of symptoms. Ensure an adequate trial of the agent. If no improvement is seen, follow a stepped-care approach to treatment. Refer severe cases that do not respond to an ophthalmologist for short-term topical corticosteroids. 

Hydroxyurea reduced the frequency of hospitalizations and the incidences of pain, acute chest syndrome, and blood transfusions by almost 50% in a landmark trial in adult SCD patients with moderate to severe disease. Hemoglobin and HbF concentrations increased, and hemolysis decreased.22 A follow-up study demonstrated a 40% reduction in mortality over a 9-year period in patients continuing to receive hydroxyurea.23 Not all patients responded equally, so hydroxyurea may not be the answer for all patients. 

A pooled analysis of 14 875 adults (Hispanic, n = 361 White, n = 10 108 African American, n = 547 Asian, n = 112) who participated in 104 double-blind, placebo-controlled paroxetine trials for mood and anxiety disorders was performed to ascertain minority group differences (Roy-Byrne et al., 2005). There were significant differences in rates of response by ethnicity (p = 0.014) with the odds of responding being lower for the Asian and Hispanic subjects compared to the African American and White subjects. There was also a higher placebo response rate in Hispanic subjects. Rapidity of response and emergence of adverse effects were similar across groups. 

Research in psychopharmacology has shown that ethnicity must be considered in psychiatry as well (Lawson, 1986 Pi 8c Simpson, 2005). Early clinical trials with antipsychotic and antidepressant medications showed that ethnic minorities may respond when given the same doses as Caucasians, and may have more side effects (Lawson, 1986 Lawson, 1990). However, dosing cannot be used as a measure of appropriate pharmacotherapy because an extensive literature has shown that African Americans often receive higher doses of antipsychotics despite evidence of more side effects. 

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