Placebo can be ethically acceptable in studies of asthma patients depending on the severity of the disease and on the supervised control provided to patients.

In patients with well controlled mild persistent asthma, discontinuation of inhaled corticosteroids almost never will precipitate a sudden deterioration of the disease. If deterioration should occur, it will be progressive and can be easily aborted by reintroducing inhaled corticosteroids.

In patients with a well controlled asthma treated with a combination of an inhaled corticosteroid and a LABA, discontinuation of the LABA can also be ethically acceptable, particularly if patients are allow to use rescue medication in case of disease deterioration. Discontinuation of the combination (inhaled corticosteroid+LABA) is more problematic, but in my opinion still ethically possible if treatment is discontinued for only a few days (less than one week) and patients are closely supervised.

In my opinion, thall participants should have basic symptomatic treatment. In the case of corticosteroids and asthmaI porpose a fixed dose of longacting beta-2-agonists, free but measured use of shortacting beta-2-agonists, and maybe (dependneing on patient samle and the severity of asthma among patients included) a basic dose of inhaled corticosteroids. The Active or placebo should be added to the Groups. I ofen find the run in periods too short. I also oppose to those who use several types of beta-2 agonists and/or basic steroids.

Most often evaluation is by symptom scores that is an unprecice tool. I would prefer allergen challenge (in the case of mono-allergen sensitivity,e.g. Birch, grass or olvie) or in the case of mixed groups of perennial asthma, a challenge test like metacholine BPT, exersice or the like. The threshold concnetration of challenge tests has repeatably been shown to be more precice than any type of score (but certainly scores are indicating the patients perception). But scores are more influnced by external factors.

Just an opinion

Dear Dr. M. Sardina

From the ethic view, in clinical trial design you must use, to compare, the best treatment avalaible (WMA Helsinki Declaration, principle 33)

"WMA Helsinki Declaration"

"Use of Placebo

33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances:

Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or

Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention

and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention.

Extreme care must be taken to avoid abuse of this option"

Maybe you can fit in the last 2 exceptions based in the patient's quality of mild asthma

Best Regards

Justo Padilla, MD

Many thanks for the feed back. I share many points in you replies. There are however some specific conditions that in my opinion deserve further discussions.

Assume you have a fixed combination product (e.g. ICS/LABA or LAMA/LABA) and you need to confirm dose strenghts.

Assay sensitivity is required as well as that the lowest strenght is a non-zero effect dose.

A fixed combination is clinically indicated if patients are not adequately controlled by a single agent, in asthma usually a corticosteroid (ICS).

I doubt that patient not adequately controlled by low fixed dose of ICS could be assigned to placebo. Possibly they can be kept on the same dose of ICS allowing standard reliever interventions (duly recorded etc) for a period of 8-12 weeks.

What's you opinion?

POINTS

1. Combinations of LAMA/LABA are not accepted in asthma therapy. LAMA or LABA should always be given associated to inhaled corticosteroid.

2. For obvious ethical reasons a patient with not controlled asthma cannot be assigned to placebo. The argument is very simple: the risk of an asthma exacerbation in patients with a not well controlled disease and on low dose inhaled corticosteroid therapy (ICT) is relatively high. Discontinuation of ICT will further increase the risk of asthma exacerbation.

Dear Dr. Sardina

the best design to conduct an equivalence or non superiority trial is double dummy method. ethically patient is getting a treatment and even we can compare the outcomes objectively.

Double dummy means patient gets placebo of std inhalar/tab and treatment drug in first gruop , patient gets placebo for treatment drug and real standard drug.

If deterioration should occur, it will be progressive and can be easily aborted by reintroducing inhaled corticosteroids. Please give me more facts about that situation.

Clinical and epidemiological studies have shown that asthma exacerbations can occur in a short period of time (rapid-onset exacerbations) or come on slowly for days of progressive deterioration (slow-onset). Rapid-onset exacerbations represent around 15% of all severe exacerbations and can be precipitated by an NSAID (8%), the remaining severe exacerbations are cause by exposure to potent allergens (in young patients alternaria alternata) or by undetected precipitants. Slow onset usually occur in asthma patients with not well controlled asthma (inadecuate assessment, insufficient therapy, poor compliance).

In patients with well controlled asthma discontinuation of therapy will not result in a sudden dererioration, the way these patients deteriorate clinically and functionally is progressive over various days. A close control of patients will allow to detect the initial symptoms of clinical deterioration and PF and FeNO recording will show the initial steps of a potential asthma excerbation. If treatment is restablished asthma will be quickly controlled.