Placebo run-in period

Quitkin, Frederic M., Patrick J. McGrath, Jonathan W. Stewart, Katja Ocepek-Welikson, Bonnie P. Taylor, Edward Nunes, Deborah Delivannides, Vito Agosti, Steven J. Donovan, Donald Ross, Eva Petkova and Donald F. Klein, Placebo Run-in Period in Studies of Depressive Disorders Clinical, Heuristic and Research Implications , British Journal of Psychiatry 173 (1998) 242-48... 

Fortunately, there is a methodological feature of these clinical trials that makes the charge of falsifying the initial data somewhat less problematic than it might otherwise be - as long as those are the only data that were fudged. All of the trials we analysed had what is called a placebo run-in or wash-out phase. The way this works is as follows. After people are assessed for inclusion in the trial, they are all given a placebo for a week or two. After this run-in period, the patients are reassessed, and anyone who has improved is excluded from the trial. The baseline severity scores that we used in our analyses were those taken after the placebo... 

A larger randomized double-blind placebo-controlled trial [5] of 59 migraine sufferers (who had not taken feverfew before) found that feverfew treatment was associated with a reduction in the mean number and severity of attacks and the degree of vomiting, but the duration of each individual attack was unaltered. The study period was 9 months in total consisting of 1 month placebo run-in followed by 2 x 2 months of either feverfew ( 82 mg/day) or placebo after which patients were switched to the other leg of... 

In a multicenter, double-blind, placebo-controlled study, 81 patients, in whom treatment with metformin was inadequate, received extra acarbose or placebo during 24 weeks after a 4-week run-in period to establish the optimal dose of acarbose (28). HbAic was reduced by 1.02% and fasting blood glucose by 1.13 mmol/1. Gastrointestinal adverse effects were more common in the acarbose group. 

In 303 patients who took placebo or rosiglitazone for 8 weeks after a run-in period, rosiglitazone 4 mg bd had the same effect as 6 mg bd, but hemoglobin and hematocrit were lower with 6 mg bd (101). In another study troglita-zone produced small reductions in hemoglobin, hematocrit, and erythrocyte counts and increases in lactate dehydrogenase and blood urea nitrogen (102). 

Three cannabis-based medicinal extracts in sublingual form recently became available for use against pain. In a randomized, double-blind, placebo-controlled, crossover study for 12 weeks in 34 patients with chronic neuropathic pain THC extracts were effective in symptom control (59). Drowsiness and euphoria/dysphoria were common in the first 2 weeks. Dizziness was less of a problem. Anxiety and panic were infrequent but occurred during the run-in period. Dry mouth was the most common complaint. 

Many trials are planned with a placebo run-in, that is to say a period before the trial proper starts and during which all patients receive placebo. There seem to he two common reasons. First, the run-in period may permit the trialist to operate some screening procedure, in particular as regards compliance with a treatment regime, which may help to decide which patients will enter the trial proper. Second, it is argued that a run-in period is necessary to permit a clean comparison of the treatments in the trial. 

The results of a 1-year open extension of two randomized, double-blind studies of zaleplon have been reported (9). In 316 older patients who took zaleplon nightly from 6 to 12 months and were then followed through a 7-day singleblind, placebo-controlled, run-out period, the safety profile was similar to that observed in a short-term trial in an equivalent population. The data also suggested that therapy for up to 12 months produced and maintained statistically significant improvement in time to persistent sleep onset, duration of sleep, and the number of nocturnal wakenings. Withdrawal was not associated with rebound insomnia. The authors concluded that placebo-controlled, double-blind trials are needed to confirm these results. 

Trials also sometimes actively recruit patients who are likely to respond well to treatment (often termed enrichment ). For example, some trials of antipsychotic drugs have selectively recruited patients who had a good response to antipsychotic drugs previously (Rothwell 2005a). Other trials have excluded non-responders in a run-in phase. One trial of a cholinesterase inhibitor, tacrine, in Alzheimer s disease recruited 632 patients to a six-week enrichment phase in which they were randomized to different doses of tacrine or placebo (Davis et al. 1992). After a washout-period, only the 215 (34%) patients who had a measured improvement on tacrine in the enrichment phase were randomized to tacrine (at their best dose) versus placebo in the main phase of the trial. External vaUdity is clearly undermined here. 

A quantity of an appropriate sterilized placebo powder is blended with sterile excipients prior to filling (if needed) in a manner similar to the production process being simulated. The medium is passed through the run as though it were an actual product batch, and all routine procedures used in manufacture of a batch are performed. Once the medium has been processed, it is held for a period of time at least equal to that for aseptically produced materials. Any aseptic manipulations performed during and at the end of the hold period should be simulated hold times and product recalculation. 

The validation of lyophilization cycles is a complicated issue because the process parameters and the characteristics of the product are closely interrelated. The process affects the final product, but the characteristics of the product undergoing lyophilization impact the dependent operating parameters, the freeze-drying pattern, and dictate the basic requirements for a successful process. This interdependence limits the opportunities of using placebo formulations and most of the validation runs must be performed with active product. The high cost and limited availability of some materials, as well as the need to validate the process under conditions that are representative of routine production, justify that part of the validation is performed in a concurrent fashion. The concurrent validation should then be completed by a retrospective review of the data accumulated for commercial batches, so as to track the reproducibility, the reliability, and the trends of the process over a longer period of time. 

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