Clinical trials open-label studies

There is much controversy over the use of open or open-label studies. It is a golden rule of clinical trial design that, wherever practicable and possible, open studies should not be conducted, but there are circumstances when they can or must be used (see Box 6.2). 

Crawford P, Brown S, Kerr M Parke Davis Clinical Trials Group. A randomized open-label study of gabapentin and lamotrigine in adults with learning disability and resistant epilepsy. Seizure 2001 10(2) 107-15. 

Conducting open-label studies can be a liberating and fascinating experience. When both the patient and the prescriber know the treatment being administered, many of the complexities of early-phase studies go away. Furthermore, when it is appreciated that double-blind clinical trials are always an abstraction from the ordinary clinical situation, to observe how one s new drug actually works in that latter environment is often eye-opening one common and pleasant experience is to see with one s own eyes how conservative was the estimate of product efficacy prior to its approval. 

Although infant botulism was not recognized until a large outbreak occurred in Califomia in 1976 (Pickett et ah, 1976), it is currently the most prevalent form of botulism in the United States, accounting for approximately 70% of all cases (Shapiro et al., 1998). Because infant botulism results from a continual production of BoNT, it appears to be more effectively treated by antitoxin than is foodborne botulism. In a recently concluded 5 year randomized clinical trial carried out with a human botulinum immune globulin (BIG-IV), it was found that administration of BIG-IV within 3 days of hospitalization resulted in a 3 week reduction in the mean hospital stay, as well as substantial reductions in the time needed for intensive care and mechanical ventilation (Amon et al., 2006). In a nationwide open label study, BlG-lV was found to be effective even when administered 4—7 days after hospital admission, although to a somewhat lesser extent than when infusion was initiated at 3 days (Arnon et al., 2006). 

For phase III clinical trials, the first of these studies recruited adults and adolescents (mean age of 26 years) with CF and a mean FEVi of 63.6% at entry to the study. The treatment effect of ivacaftor (1) was an increase in FEVi of 10.6%. This was seen within 2 weeks of treatment and was sustained to week 48 and then to week 96 in the extended open-label study. Those treated with ivacaftor (1) also had a 55% decrease in respiratory exacerbations, a reduction in sweat chloride values in the order of 50-60 mmol/L, and a weight gain of 2.7 kg more than in the placebo group. 

Observational studies Safety data pooled from phase 11 and 111 clinical trials and an open-label study showed 1.3% of patients with serious infections, and 2.6% wilh malignancies. Four cardiovascular risk factors were retrospectively found to be predictors for the major adverse cardiovascular events seen in 27 patients during briakinumab treatment history of cardiovascular disease diabetes body mass index 0 baseline blood pressure systolic >140 and diastolic >90. Overall, the pooled briakinumab safety data indicated increased rates of infections, malignancies and major adverse cardiovascular events [123 ]. 

We have recently prepared an open-label phase 1/lla clinical trial (the INDOR study a phase I/Ha open-label multicenter study to assess the inhibitory effects of NF-kB decoy ODN on restenosis after stenting in coronary artery) to evaluate the safety and efficacy of NF-kB decoy ODN. Seventeen patients were treated with NF-kB decoy ODN after percutaneous coronary intervention (PCI) using bare metal stents. As a result, the stenosis improved to 1.4 5.9% after the intervention. Serum monocyte chemotactic protein-1 (MCP-1) levels were significantly suppressed in NF-kB decoy ODN-treated patients on day 3 after the PCI. Significant restenosis was found in (Mily one of the 17 patients after 6 months, and the average restenosis rate was 39.6 22.3%. No in-stent thrombosis was found and no... 

Ad.TNF gene therapy is presently in clinical trials in patients receiving radiotherapy. An open-label, phase I, dose-escalation study of tumor necrosis factor-alpha (TNFerade) gene transfer with radiation therapy for locally advanced, recurrent, or metastatic solid tumors is currently accruing patients and has several endpoints (82), including toxicity and tolerable dose. Pharmacokinetics will be evaluated and biological correlates will determine the histologic response to therapy. 

There have been three randomized clinical trials and multiple case reports and open-label trials with the tricyclic antidepressants (TCAs) in PTSD, although only one study of childhood PTSD (Southwick et al., 1994) has been reported. Robert et al. (1999) reported the use of low-dose imipramine (1 mg/kg) to treat symptoms of ASD in children with burn injuries. In this study, 25 children ages 2 to 19 years were randomized to receive either chloral hydrate or imipramine for 7 days. Ten of 12 subjects receiving imipramine experienced from half to full remission of ASD symptoms, whereas 5 of 13 subjects responded to chloral hydrate. Sleep-related flashbacks and insomnia appeared to be particularly responsive to treatment. 

Phase III studies represent the confirmatory phase of drug development, which takes several years and usually involves several thousand patients at multiple trial centers. Large patient numbers are required in these trials to provide convincing documentation of clinical efficacy and safety, a more complete adverse event profile and covariates and estimates of variability in dose response relationship due to individual differences in pharmacokinetics and pharmacodynamics. They are aimed at definitively determining a drug s effectiveness and side-effect profile. Most of these studies are double-blind and placebo-controlled, sometimes with the option of open-label long-term extensions. 

The second Serono trial was a multicenter randomized study of Rebif at 44 mg subcutaneously three times per week compared to Avonex at 30 mg intramuscularly weekly. The primary efficacy outcome was the incidence of exacerbations through week 24. Avonex was administered according the recommended regimen in the FDA-approved labeling, and / eb/f according to the recommended regimen in Serono s proposed labeling. Serono elected to conduct the study open label, but with a blinded clinical evaluator. 

Few data are available to guide this decision beyond clinical experience. There is a modest amount of evidence that nonresponders to TCAs, principally desipramine or imipramine, alone may respond to a SSRI alone and vice versa (136). No compelling evidence exists showing that nonresponders to one SSRI as a result of a lack of efficacy will respond to a second trial with another SSRI. There is limited confidence in the results of studies that have been done switching nonresponders from one SSRI to another for two reasons. First, virtually all have been open label and, second, most were conducted by the manufacturer of the second SSRI. Until there is more substantive evidence that switching from one SSRI to another is worthwhile, it may be more prudent to switch to a class of antidepressants with a different putative mechanism of action. 

Risperidone Acute Clinical Trials. Hillert et al. (107) found risperidone to have both antipsychotic and antidepressive properties in 10 patients with schizoaffective disorder, depressed type. These investigators prescribed 2 to 10 mg/day for 6 weeks in an open-label pilot study, and found marked improvement in psychosis in all patients and clinically significant overall improvement in psychosis in 7 to 10 patients. Two patients required antiparkinsonian drugs otherwise risperidone was well tolerated by the group. 

Most studies in children and adolescents have been conducted with neuroleptics. A computerized literature search for the period 1974 to 1999 identified only five double-blind, placebo-controlled clinical trials that investigated the use of atypical antipsychotic medications in children and adolescents ( 166, 167). These studies involved a total of 105 patients. Numerous open-label and case series were also found. 

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