A randomized, double-blind, placebo-controlled, multicenter trial to evaluate the clinical efficacy of a single intrapyloric injection of botulinum toxin type A (Botox®) in patients with Idiopathic Gastroparesis. The BIG study.

Introduction:

Gastroparesis is defined as delayed gastric emptying in the absence of mechanical gastric outlet obstruction. The true prevalence of gastroparesis is unknown. The etiology of gastroparesis is multifactorial; related to diabetes (1/3), postsurgical or due to systemic diseases, e.g. SLE, sclerodermia. The remaining cases (1/3) are idiopathic, i.e. of unknown cause.

Treatment of gastroparesis usually consists of dietary advice and administration of antiemetic and/or prokinetic agents. Dietary advice consists of frequent small-size meals. Antiemetics, like 5-HT3 receptor antagonists (e.g. granisetron, ondansetron, tropisetron), are used to relieve symptoms, whereas prokinetics are used to promote and increase gastric emptying rate. Metoclopramide, domperidon and erythromycin are frequently used, but their effects are variant and doubtful. Cisapride, a 5-HT4 receptor agonist, is no longer available due to serious adverse effects, i.e. prolongation of QT-interval and severe cardiac arrhythmias.
In therapy resistant cases enteral nutrition is provided to ensure adequate nutritional support. Enteral nutrition can be administered through a nasoduodenal tube, via a gastrostomy tube, i.e. a percutaneous endoscopic gastrostomy (PEG) or a jejunostomy tube. More recently intrapyloric botulinum toxin injection and gastric electrical stimulation have been proposed as possible solutions.
In recent years several open-label pilot studies have shown the effect of intrapyloric botulinum toxin injection in severe gastroparesis. Ezzeddine et al. were the first to publish data on the effect of intrapyloric botulinum toxin injection in patients with severe diabetic gastroparesis and concluded that their results were encouraging. In a recent article Lacy et al. published their data and concluded intrapyloric botulinum toxin to be a possible addition in the treatment of mild-to-moderate diabetic gastroparesis. Miller et al. published their data on the effect of intrapyloric botulinum toxin injection in patients with severe idiopathic gastroparesis and concluded that intrapyloric injection of botulinum toxin accelerated gastric emptying and reduced symptoms of gastroparesis. Arts et al. showed improvement in gastric emptying for solids and symptom score after botulinum toxin injection, but did not show improvement in gastric emptying for liquids. All authors acknowledged the need for further evaluation of intrapyloric botulinum toxin injection in a double-blind, placebo-controlled design.


Drug under study:

botulinum toxin type A (Botox®).


Indication:

Idiopathic gastroparesis.


Study Design:

Randomized, double-blind, placebo-controlled, multicenter.


Primary objective:

To evaluate the efficacy of intrapyloric injection of botulinum toxin type A in idiopathic gastroparesis.


Patient population:

Patients with idiopathic gastroparesis.


Number of patients:

48 patients.


Number of centers:

Multicenter.


Dose levels:

Botulinum toxin type A (Botox®) 200 IU single injection or placebo single injection.


Route of administration:

Intrapyloric injection through gastroscopy.


Duration of study:

14 weeks (1 week wash-out; 1 week eligibility; treatment; 12 weeks follow-up).


Primary parameters:

- Half-emptying time (min), emptying rate per hour (%/h), one, two and four hour retention (%).

- Gastroparesis Cardinal Symptom Index (GCSI) outcome.


Secondary parameters:

Quality of life, psychometric evaluation.


Main criteria for inclusion:

- Presence of clinical symptoms associated with idiopathic gastroparesis; nausea, vomiting, early satiety, postprandial fullness and a baseline GCSI score ≥ 1;

- Delayed gastric emptying for solids as measured with scintigraphy;

- Absence of an obstructing structural lesion in the stomach or small intestine at prior diagnostic gastrointestinal endoscopy (performed within the previous 5 years) or judged absent by the responsible physician;

- Written informed consent prior to any study procedures being performed;

- Patients aged between 18 and 70 years inclusive.

Several open-label pilot studies have shown a promising effect of intrapyloric botulinum toxin injection on symptoms in severe gastroparesis. However, data from randomized, double-blind, placebo-controlled studies are not yet available. We intend to evaluate the clinical efficacy of a single intrapyloric injection of botulinum toxin type A in patients with idiopathic gastroparesis.

N/A

Intrapyloric injection of botulinum toxin type A 200 IU single injection or placebo single injection.

Scintigraphy for solid/liquid gastric emptying (before and after treatment).

Gastroparesis Cardinal Symptom Index questionnaire
QOL questionnaires.

Psychometric assessment and patient perception questionnaires.