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Communications to the Editor |

How To Design a Negative Study FREE TO VIEW

Mathiéu Molimard, MD; Nicholas Moore, MD
Author and Funding Information

Affiliations: Hopital Pellegrin-Carreire, Bordeaux, France,  National Heart and Lung Institute, London, UK

Correspondence to: Professor Mathiéu Molimard, Pharmacologie, Hopital Pellegrin-Carreire, Université Victor Segalen Bordeaux 2, Bordeaux, France 33076



Chest. 2003;123(2):655-656. doi:10.1378/chest.123.2.655
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To the Editor:

In their article, published in the May issue of CHEST, Nightingale et al1 compared treatments using formoterol and salmeterol in patients with severe asthma. The absence of difference regarding the effects of the two treatments led the authors to conclude that there was no difference in efficacy between the two drugs. This study has severe methodologic flaws.

The number of subjects needed was computed on an expected difference between the two active treatment arms of 20 L/min. For this to happen, the difference between the controlled arm (formoterol) and its placebo should be > 20 L/min, unless it was expected that the effects of salmeterol would be worse than placebo. So, finding a difference of only 14.4 L/min between the effects of placebo and formoterol means either that the patient selection was not valid or the dose used in these patients was too low.

Essentially, this results in an invalid study, where either the patients are resistant to treatment or the treatment is ineffective. In any event, the study is no longer powered to detect any difference between the active treatments, especially considering the number of dropouts (36%).

Finally, the comparison of a blinded formoterol vs placebo study to an unblinded study of treatment with salmeterol, which had been the previous treatment of almost half of the patients, seems unorthodox, to say the least. A double-dummy placebo-controlled study could easily have been performed by using salmeterol metered-dose inhaler (MDI) or a placebo MDI, both administered with an inhalation chamber.

We do not believe this study shows anything, including any lack of difference between the drugs. At the least an equivalence or nonsuperiority approach could have been tested.

Nightingale, JA, Rogers, DF, Barnes, PJ (2002) Comparison of the effects of salmeterol and formoteral in patients with severe asthma.Chest121,1401-1406. [PubMed] [CrossRef]
 
To the Editor:

We thank Professors Molimard and Moore for their interest in our article. They have some concerns regarding study design. As they are not clinicians, perhaps they are unaware that studies in severe asthma are very difficult to conduct. These patients are a major management problem and are usually excluded from conventional drug therapy trials. Any improvement in treatment would be a valuable addition to management in this difficult group of patients. Our study aimed to determine whether these patients would be better treated with either salmeterol or formoterol, and we described in the article the theoretical reasons why differences might be expected. We found that both drugs significantly increased mean morning peak flow by approximately 15 L/min above placebo. Consequently, we should have detected a similar difference in peak flow between the two drugs. However, due to the high number of patient withdrawals, the power of our study was less than originally predicted. In regard to choice of drug doses, we wished to compare the drugs at doses used in current clinical practice. Therefore, doses were chosen on this basis rather than those most likely to give a positive result. A double-blind, double-placebo design would have been preferable to the use of just one placebo. However, a matching salmeterol placebo was not available from the manufacturers. We felt it was preferable to include a single placebo rather than no placebo at all. Finally, our study has shown that, albeit not differing in efficacy, both drugs improve lung function in severe asthma and should prove useful in treatment of this difficult patient group.


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References

Nightingale, JA, Rogers, DF, Barnes, PJ (2002) Comparison of the effects of salmeterol and formoteral in patients with severe asthma.Chest121,1401-1406. [PubMed] [CrossRef]
 
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