Primary:* To assess the efficacy of a 48-week treatment with 2 x 0.5 mg/d or 2 x 1 mg/d budesonide effervescent tablets vs. placebo for the maintenance of clinico-pathological remission in adult patients with eosinophilic esophagitis (EoE).Secondary…
ID
Source
Brief title
Condition
- Gastrointestinal infections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Rate of patients free of treatment failure after 48 weeks of treatment.
Treatment failure after 48 weeks of treatment is *yes*, if at least one of the
following criteria is met at any time during the DB treatment phase:
- Clinical relapse, i.e., experiencing dysphagia or pain during swallowing in
the past seven days (7-day recall period) of a severity of *4 points on a 0*10
NRS for dysphagia or pain during swallowing, respectively, confirmed by a
severity of *4 points on at least 1 day during the subsequent week on the
respective 0 10 NRS for dysphagia or pain during swallowing (24-hours recall
period).
- Histological relapse, i.e., a peak of *48 eos/mm2 hpf at DB V6/EOT,
- Experiencing a food impaction which needed endoscopic intervention,
- Need for an endoscopic dilation,
- Premature withdrawal for any reason.
Secondary outcome
A priori ordered key secondary endpoints (DB-phase [48 weeks]):
1. Rate of patients with histological relapse, defined as peak of *48 eos/mm2
hpf at week 48 DB,
2. Change in the peak eos/mm2 hpf from DB V1 to week 48 DB,
3. Rate of patients with a clinical relapse, have experienced a food impaction
which needed endoscopic intervention, or needed an endoscopic dilation during
the DB treatment phase,
4. Rate of patients with a total weekly Eosinophilic Esophagitis Activity Index
(EEsAI) * Patient-Reported Outcome (EEsAI-PRO) score of *20 at week 48 DB.
Further exploratory secondary endpoints (DB-phase [48 weeks]):
* Rate of patients with histological remission, defined as a peak of <16
eos/mm2 hpf at week 48 DB,
* Course and change from DB V1 in total modified EEsAI endoscopic instrument
score,
* Course and change from DB V1 in the *inflammatory signs* subscore of the
modified EEsAI endoscopic instrument score,
* Course and change from DB V1 in the *fibrotic signs* subscore of the modified
EEsAI endoscopic instrument score,
* Rate of patients with *none* or only *mild* endoscopic findings
(endoscopist*s overall assessment of EoE activity) at week 48 DB,
* Course and change from DB V1 in blood eosinophil counts,
* Course and change from DB V1 in the Physician*s Global Assessment of EoE
activity (0-10 NRS),
* Course and change from DB V1 in the dysphagia rating (0 10 NRS, 7-day recall
period) in the week prior to a visit,
* Course and change from DB V1 in the pain during swallowing rating (0 10 NRS,
7-day recall period) in the week prior to a visit,
* Rate of patients with increase of *3 points from DB V1 in the PatGA
concerning the severity of EoE symptoms (0-10 NRS) in the course of the DB
treatment phase,
* Rate of patients with PatGA concerning the severity of EoE symptoms of *2
points (0 10 NRS) in the course of the DB treatment phase,
* Course and change from DB V1 in the PatGA concerning the severity of EoE
symptoms (0-10 NRS),
* Rate of patients with a total weekly EEsAI-PRO score of *20 in the course of
the DB treatment phase,
* Rate of patients with deterioration in the total weekly EEsAI-PRO score of
>20 points compared to DB V1 for at least 2 consecutive weeks,
* Course and change from DB V1 in the total weekly EEsAI-PRO score and its
individual components,
* Course and change from DB V1 in the Adult EoE-QoL questionnaire (EoE-QoL-A),
* Course and change from DB V1 in modified Short Health Scale (modSHS),
* Time in DB-phase,
* Time to relapse (clinical or histological), experiencing a food impaction
which needed endoscopic intervention, or need for an endoscopic dilation,
* Time to treatment failure,
* Time to first occurrence of clinical relapse,
* Rate of patients experiencing a food impaction during the DB treatment phase
which needs endoscopic intervention,
* Rate of patients needing endoscopic dilation during the DB treatment phase,
* Patient*s Global Satisfaction at the end of the DB treatment phase,
* Course and change from DB V1 in esophageal distensibility (i.e., minimum
esophageal diameter at 40 mmHg distending pressure as measured by Endo FLIP®),
* Course and change from DB V1 of potential biomarkers (e.g., eotaxin-3).
OLE-phase (if applicable and optional up to 96 weeks):
* Course and change from baseline of DB and OLE phase, respectively in blood
eosinophil counts,
* Course and change from baseline of DB and OLE phase, respectively in the
Physician*s Global Assessment of EoE activity (0-10 NRS),
* Course and change from baseline of DB and OLE phase, respectively in the
dysphagia rating (0 10 NRS, 7-day recall period) in the week prior to a visit,
* Course and change from baseline of DB and OLE phase, respectively in the pain
during swallowing rating (0-10 NRS, 7-day recall period) in the week prior to a
visit,
* Rate of patients with a clinical relapse, experiencing a food impaction which
needed endoscopic intervention, or need for an endoscopic dilation during the
OLE treatment phase,
* Rate of patients with increase of *3 points from baseline of DB and OLE
phase, respectively in the PatGA concerning the severity of EoE symptoms (0-10
NRS) in the course of the OLE treatment phase,
* Rate of patients with PatGA concerning the severity of EoE symptoms of *2
points (0-10 NRS) in the course of the OLE treatment phase,
* Course and change from baseline of DB and OLE phase, respectively in the
PatGA concerning the severity of EoE symptoms (0-10 NRS),
* Rate of patients with a total weekly EEsAI-PRO score of *20 in the course of
the OLE treatment phase,
* Course and change from baseline of DB and OLE phase, respectively in the
total weekly EEsAI-PRO score and its individual components,
* Rate of patients with deterioration in the total weekly EEsAI-PRO score of
>20 points compared to baseline of DB and OLE phase, respectively,
* Course and change from baseline of DB and OLE phase, respectively in the
adult EoE-QoL-A,
* Course and change from baseline of DB and OLE phase, respectively in the
modSHS,
* Time in OLE-phase,
* Time to clinical relapse, experiencing a food impaction which needed
endoscopic intervention, or need for an endoscopic dilation,
* Patient*s Global Satisfaction at OLE V4/EOT and OLE V8/EOT resepctively,
* Course and change from baseline of DB and OLE phase, respectively in
potential biomarkers,
* Rate of patients with histological relapse, defined as a peak of *48 eos/mm²
hpf, at OLE V4/EOT and OLE V8/EOT,
* Change in the peak eos/mm² hpf from baseline of DB phase and (where
available) from baseline of OLE phase, respectively to OLE V4/EOT and OLE
V8/EOT,
* Rate of patients with histological remission, defined as a peak of <16
eos/mm2 hpf, at OLE V4/EOT and OLE V8/EOT,
* Course and change from baseline of DB phase and (where available) from
baseline of OLE phase, respectively in the total modified EEsAI endoscopic
instrument score,
* Course and change from baseline of DB phase and (where available) from
baseline of OLE phase, respectively in the *inflammatory signs* subscore of the
modified EEsAI endoscopic instrument score,
* Course and change from baseline of DB phase and (where available) from
baseline of OLE phase, respectively in the *fibrotic signs* subscore of the
modified EEsAI endoscopic instrument score,
* Rate of patients with *none* or only *mild* endoscopic findings
(endoscopist*s overall assessment of EoE activity) at OLE V4/EOT and OLE V8/EOT.
OLRI-phase:
* Rate of patients with resolution of symptoms (i.e., no or only minimal
problems) defined as a severity of *2 points (0-10 NRS, 7-day recall period)
for dysphagia AND a severity of *2 points (0-10 NRS, 7-day recall period) for
pain during swallowing in the week prior to OLRI V1/EOT (LOCF),
* Rate of patients with no or only minimal problems in dysphagia defined as a
severity of *2 points (0-10 NRS, 7-day recall period) for dysphagia in the week
prior to OLRI V1/EOT (LOCF),
* Rate of patients with no or only minimal problems in pain during swallowing
defined as a severity of *2 points (0-10 NRS, 7-day recall period) for pain
during swallowing in the week prior to OLRI V1/EOT (LOCF),
* Rate of patients with total weekly EEsAI-PRO score of *20 points at OLRI
V1/EOT (LOCF),
* Rate of patients with clinical response (decrease in the total weekly
EEsAI-PRO score of *20 points) at OLRI V1/EOT (LOCF) compared to EOT/withdrawal
DB visit,
* Patient*s Global Satisfaction at OLRI V1/EOT (LOCF).
OLI-phase:
* Rate of patients with clinico-pathological remission at OLI V4/EOT (LOCF),
* Rate of patients with histological remission, defined as a peak of <16
eos/mm2 hpf at OLI V4/EOT (LOCF),
* Change in the peak eos/mm2 hpf from OLI V1 to OLI V4/EOT (LOCF),
* Rate of patients with resolution of symptoms (i.e., no or only minimal
problems) defined as a severity of *2 points (0-10 NRS, 24-hours recall period)
for dysphagia AND a severity of *2 points (0-10 NRS, 24-hours recall period)
for pain during swallowing on each day in the week prior to OLI V4/EOT (LOCF),
* Course and change from OLI V1 in the Physician*s Global Assessment of EoE
activity (0-10 NRS),
* Rate of patients with PatGA concerning the severity of EoE symptoms of *2
points (0-10 NRS, 7-days recall period) in the course of the OLI phase,
* Course and change from OLI V1 in the PatGA concerning the severity of EoE
symptoms (0-10 NRS, 7-days recall period),
* Rate of patients with total weekly EEsAI-PRO score of *20 at OLI V4/EOT
(LOCF),
* Course and change from baseline in the total weekly EEsAI-PRO score and its
individual components,
* Course and change from baseline in time to eat a regular meal (last 7 days;
EEsAI Further Item),
* Rate of patients with Patient*s Response Assessment (PRA) of at least: *A
little improved*, *moderately improved*, or *much improved*, respectively (on a
7-point Likert scale) compared to OLI V1 in the course of the OLI-phase,
* Course and change from OLI V1in the adult EoE-QoL-A,
* Course and change from OLI V1 in the modSHS,
* Patient*s Global Satisfaction at OLI V4/EOT (LOCF).
Background summary
Recent studies suggest that swallowing of budesonide is effective in the
treatment of EoE,and can bring the disease in remission, and possibly maintains
this for a longer period of time, while it might not be associated with the
toxicities of long term use of systemic corticosteroids.
Study objective
Primary:
* To assess the efficacy of a 48-week treatment with 2 x 0.5 mg/d or 2 x 1 mg/d
budesonide effervescent tablets vs. placebo for the maintenance of
clinico-pathological remission in adult patients with eosinophilic esophagitis
(EoE).
Secondary:
* To study safety and tolerability in the form of adverse events and laboratory
parameters,
* To assess patients* quality of life.
Open-label re-induction and open-label extension phase:
* To study re-induction of clinical response in patients with a clinical or
histological relapse or having experienced a food impaction which needed
endoscopic intervention,
* To study maintenance of clinical remission in patients who completed the
double-blind phase without a clinical or histological relapse.
Exploratory:
* To study biomarkers in EoE.
Study design
This is a double-blind, randomized, multicenter, placebo-controlled,
comparative, comfirmatory Phase III clinical trial with a 48-weeks double-bline
(DB) treatment period.
Intervention
The trial will be conducted with three treatment groups in the form of a
parallel group comparison and will serve to compare oral treatment with either
2 x 0.5 mg/d or 2 x 1 mg/d budesonide effervescent tablets vs. placebo for the
maintenance of remission in EoE.
Study burden and risks
physical examination 3-9 x
oesophageal endoscopy 2 x
questionnaires related to complaints and disease: 8 vragenlijsten, per
questionnaire variable amount
blood sampling 12-21 x
urine sampling 9 -15 x
examination of the eyes 4-6 x
The adverse events are characteristic for steroid medication, and can occur
depending on the dosage, treatment period, whether the subject is or has been
taking other corticosteroid preparations, and the individual sensitivity.
Leinenweberstrasse 5
Freiburg 79108
DE
Leinenweberstrasse 5
Freiburg 79108
DE
Listed location countries
Age
Inclusion criteria
- Signed informed consent,
- Male or female patients, 18 to 75 years of age,
- Confirmed clinico-pathological diagnosis of EoE according to established diagnostic criteria ,
- Clinico-pathological remission of EoE
- A documented trial with proton pump inhibitors (PPIs) in order to rule out PPI-responsive esophageal eosinophilia,
- Negative pregnancy test in females of childbearing potential at baseline visit
Exclusion criteria
- Clinical signs (i.e., acid regurgitation and/or heart burn) and/or endoscopic signs (at least Los Angeles Classification of Esophagitis Grade A) of gastroesophageal reflux disease (GERD),
- History of abnormal results in case of an optionally performed pH monitoring of the distal esophagus,
- Patients with PPI-responsive esophageal eosinophilia
- Achalasia, scleroderma esophagus, or systemic sclerosis,
- Other clinically evident causes than EoE for esophageal eosinophilia,
- Any concomitant esophageal disease and relevant gastro-intestinal disease (celiac disease, inflammatory bowel disease, oropharyngeal or esophageal bacterial, viral, or fungal infection [candida esophagitis]),
- Any relevant systemic disease (e.g., AIDS, active tuberculosis),
- If careful medical monitoring is not ensured: cardiovascular disease, diabetes mellitus, osteoporosis, active peptic ulcer disease, glaucoma, cataract, or infection,
- Liver cirrhosis or portal hypertension,
- History of cancer in the last five years, except for non-metastatic cancers, e.g. basalioma.
- History of esophageal surgery at any time or of esophageal dilation procedures within the last 8 weeks prior to screening visit,
- Upper gastrointestinal bleeding within 8 weeks prior to screening visit,
- Existing or intended pregnancy or breast-feeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-001485-99-NL |
| ClinicalTrials.gov | NCT02493335 |
| CCMO | NL56616.041.16 |