Predictors of the Placebo Response in Functional Dyspepsia
Background: Trials in functional dyspepsia report placebo response rates of 30% to 40%.
Aim: We aimed to identify predictors of the placebo response.
Methods: Patients from primary, secondary and tertiary practices with functional dyspepsia defined by Rome II criteria were enrolled into one of four clinical trials; 220 patients were randomized to receive placebo. Scintigraphic assessment of gastric emptying at baseline was repeated at the end of the treatment in those with delayed emptying. After a 2 week run-in period, patients were followed for 8 weeks on placebo. Response was assessed on a weekly basis and a responder was defined as satisfactory relief of meal-related symptoms on at least 50% of weeks.
Results: The mean age was 44 years (range 18-82) and 74% were female; 76 (35%) were placebo responders. The predominant symptom was an unstable measure over the trial. Independent predictors of a lower placebo response were lower body mass index and a more consistent predominant symptom pattern (both P < 0.05). No association was seen with age, gender, centre type, baseline symptom score, baseline or change in gastric emptying, or baseline quality of life.
Conclusion: In functional dyspepsia, a consistent predominant symptom pattern and lower body mass index may be associated with a lower placebo response rate.
The natural history of functional dyspepsia (FD) remains poorly defined. It is appreciated that the symptoms can fluctuate and, in some cases, will spontaneously disappear for long periods. However, predictors of such symptom change remain to be defined. The placebo response in FD is approximately 30% to 40% among patients in randomized-controlled trials. The placebo response may in part reflect the natural fluctuations of upper gastrointestinal tract symptoms, although this is not the only likely factor. The placebo response in the functional gastrointestinal disorders remains poorly understood and only a few studies have evaluated predictors of the placebo response, mainly in the irritable bowel syndrome. A better understanding of this response would be helpful in terms of planning future trials and could possibly provide useful data for optimizing long-term management in practice.
Patients with FD have a variety of symptoms, and they may have a number of underlying pathophysiologic disturbances including delayed gastric emptying, impaired fundic accommodation and visceral hypersensitivity. Research, particularly from Europe, has suggested that identification of the predominant symptom is one way of predicting the presence of a specific physiologic abnormality. For example, relevant postprandial fullness has been reported to predict delayed gastric emptying, while early satiety has been associated with impaired fundic relaxation. For these reasons, the Rome II criteria for FD specify that a dysmotility-like subgroup can be identified based on the predominant symptom, but the value of this approach has undergone little empiric testing. In particular, it is unclear whether the predominant symptom remains stable over time. If it does, this would support the value of the predominant symptom. A few studies of patients with dyspepsia in general practice have suggested that the predominant symptom was not stable over time. Such data may not apply to patients seen in gastroenterology practice with moderate to severe symptoms, although this hypothesis has not been tested.
Gastric emptying is delayed in 25-40% of patients with FD. Little information, however, exists regarding changes in gastric emptying over time in patients with this condition, although it has been assumed that gastric emptying rates remain stable despite symptoms improving or worsening. Indeed, any link between symptoms and gastric emptying has been controversial, with both positiveand negative studies in the literature.
We aimed to address all of these issues by analysing data from a large clinical trial database of four studies, using the placebo arm data. In particular, we aimed to identify predictors of the placebo response. Secondly, we aimed to determine if the predominant symptom reported by patients with FD remains stable over time. Thirdly, we aimed to determine if gastric emptying rates are stable and predict symptom change over time.
Summary and Introduction
Summary
Background: Trials in functional dyspepsia report placebo response rates of 30% to 40%.
Aim: We aimed to identify predictors of the placebo response.
Methods: Patients from primary, secondary and tertiary practices with functional dyspepsia defined by Rome II criteria were enrolled into one of four clinical trials; 220 patients were randomized to receive placebo. Scintigraphic assessment of gastric emptying at baseline was repeated at the end of the treatment in those with delayed emptying. After a 2 week run-in period, patients were followed for 8 weeks on placebo. Response was assessed on a weekly basis and a responder was defined as satisfactory relief of meal-related symptoms on at least 50% of weeks.
Results: The mean age was 44 years (range 18-82) and 74% were female; 76 (35%) were placebo responders. The predominant symptom was an unstable measure over the trial. Independent predictors of a lower placebo response were lower body mass index and a more consistent predominant symptom pattern (both P < 0.05). No association was seen with age, gender, centre type, baseline symptom score, baseline or change in gastric emptying, or baseline quality of life.
Conclusion: In functional dyspepsia, a consistent predominant symptom pattern and lower body mass index may be associated with a lower placebo response rate.
Introduction
The natural history of functional dyspepsia (FD) remains poorly defined. It is appreciated that the symptoms can fluctuate and, in some cases, will spontaneously disappear for long periods. However, predictors of such symptom change remain to be defined. The placebo response in FD is approximately 30% to 40% among patients in randomized-controlled trials. The placebo response may in part reflect the natural fluctuations of upper gastrointestinal tract symptoms, although this is not the only likely factor. The placebo response in the functional gastrointestinal disorders remains poorly understood and only a few studies have evaluated predictors of the placebo response, mainly in the irritable bowel syndrome. A better understanding of this response would be helpful in terms of planning future trials and could possibly provide useful data for optimizing long-term management in practice.
Patients with FD have a variety of symptoms, and they may have a number of underlying pathophysiologic disturbances including delayed gastric emptying, impaired fundic accommodation and visceral hypersensitivity. Research, particularly from Europe, has suggested that identification of the predominant symptom is one way of predicting the presence of a specific physiologic abnormality. For example, relevant postprandial fullness has been reported to predict delayed gastric emptying, while early satiety has been associated with impaired fundic relaxation. For these reasons, the Rome II criteria for FD specify that a dysmotility-like subgroup can be identified based on the predominant symptom, but the value of this approach has undergone little empiric testing. In particular, it is unclear whether the predominant symptom remains stable over time. If it does, this would support the value of the predominant symptom. A few studies of patients with dyspepsia in general practice have suggested that the predominant symptom was not stable over time. Such data may not apply to patients seen in gastroenterology practice with moderate to severe symptoms, although this hypothesis has not been tested.
Gastric emptying is delayed in 25-40% of patients with FD. Little information, however, exists regarding changes in gastric emptying over time in patients with this condition, although it has been assumed that gastric emptying rates remain stable despite symptoms improving or worsening. Indeed, any link between symptoms and gastric emptying has been controversial, with both positiveand negative studies in the literature.
We aimed to address all of these issues by analysing data from a large clinical trial database of four studies, using the placebo arm data. In particular, we aimed to identify predictors of the placebo response. Secondly, we aimed to determine if the predominant symptom reported by patients with FD remains stable over time. Thirdly, we aimed to determine if gastric emptying rates are stable and predict symptom change over time.
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