To evaluate the efficacy based on the histological response
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the efficacy based on the histological response:
- absolute change in peak eosinophil count from Baseline to EOT
Secondary outcome
To evaluate the efficacy based on histological response and clinical symptoms:
- Proportion of patients with histological remission, defined as the reduction
of peak eosinophil count in all esophageal samples to
<15 eosinophils/hpf at EOT, overall and determined differentially in each of
the 3 esophageal segments
- Proportion of patients with a peak eosinophil count in all esophageal samples
of <6 eosinophils/hpf at EOT, overall and determined differentially in each of
the 3 esophageal segments
- Proportion of patients with an improvement in the dysphagia severity score
from Baseline to EOT
- Absolute and relative change in mean eosinophil count from Baseline to EOT
- Proportion of patients with a relative reduction in peak eosinophil count of
>=30%, >=50%, or >=75% from Baseline to EOT
- Proportion of patients with histological remission and improvement in the
dysphagia severity score from Baseline to EOT
To evaluate the efficacy based on clinical response assessed by
patient-reported outcome:
- Absolute and relative change in dysphagia and odynophagia severity scores
from Baseline
- Time to achieve symptom relief (defined as 50% improvement in the dysphagia
or odynophagia symptoms on an NRS compared to Baseline)
To evaluate the efficacy based on endoscopic response
- Change in the EREFS1 from Baseline to EOT
To evaluate the safety and tolerability
- Incidence of treatment-emergent AEs and SAEs
- Incidence of AESI
- Local tolerability
To evaluate patient-reported treatment satisfaction
- Patient-reported treatment satisfaction at EOT based on questions about
handling, taste, and time necessary for administration
To evaluate the efficacy based on histological response
- Change in further histological parameters from Baseline to EOT
Background summary
Eosinophilic esophagitis (EoE) is a chronic, local immune-mediated esophageal
disease, characterized by symptoms related to esophageal dysfunction and by
eosinophil-predominant inflammation. Infiltration of the esophageal mucosa with
eosinophils is the histologic hallmark of EoE. Because the esophagus does not
usually harbor eosinophils, their infiltration in the epithelium, where they
are found as isolated cells, in groups, or even in small abscesses, is abnormal.
The incidence of EoE increases with age and peaks at 30-50 years. In clinical
practice, EoE is suspected when a patient presents with symptoms of dysphagia,
food impaction, and retrosternal pain or in children with feeding intolerance,
abdominal pain, or vomiting. EoE can include various forms of esophageal
dysfunction primarily associated with dysphagia. In adults and adolescents,
dysphagia affects between 25% and 100% of EoE patients. EoE can be the cause of
food impaction, which in rare cases may result in esophageal rupture.
ESO-101 consists of a hard gelatin capsule (Size 0) containing a mucoadhesive
thin film loaded with 800 µg mometasone furoate. The film has a length of
approximately 25 cm to enable a therapy for the entire length of the esophagus.
The film is rolled up in a capsule. The capsule is
slit allowing the end of the rolled film to be threaded through the slit and
attached to a retainer outside of the capsule. At the other end, the retainer
is attached to the capsule holder. The capsule also contains a sinker to
increase the weight of the capsule and thereby avoiding buoyancy of the capsule
in the mouth during swallowing. Upon swallowing, the film unrolls and sticks to
the mucosa where it dissolves slowly while releasing mometasone furoate.
Mometasone furoate, a potent synthetic corticosteroid with anti-inflammatory
activity, is a well-known active substance licensed since the early 1990s in
various topical formulations (e.g. cream, ointment, lotion or emulsion) for the
treatment of patients with inflammatory skin conditions such as psoriasis,
eczema, atopic dermatitis, or seborrheic dermatitis. Mometasone furoate is also
licensed as a spray for the treatment of symptoms of seasonal allergic or
perennial rhinitis and nasal polyps, and as a powder for the treatment of astma.
Mometasone furoate has a significantly lower systemic bioavailability (<1%)
than older corticosteroids such as the oral agent budesonide. Unlike with other
corticosteroids with low bioavailability, no activation by esterases is
necessary for mometasone furoate. Hence, mometasone furoate is well-suited as a
locoregional treatment.
Up until now, the use of mometasone furoate as a swallowed aerosol formulation
has been studied in 3 trials assessing its effect on EoE in adults.
In all 3 trials, patients were treated with 200 µg mometasone furoate aerosol
swallowed 4 times daily for 2 months. The results of these trials showed a
significant improvement in the dysphagia scale scores and a reduced entry of
eosinophils into the esophagus in EoE patients treated with mometasone.
The goal of EoE therapy is to maximize locoregional efficacy by an
esophagus-adjusted drug delivery and drug formulation and increasing the
mucosal contact time while reducing systemic bioavailability and thus reducing
systemic effects. The mode of delivery and the resulting mucosal contact time
play an important role for the effectiveness of EoE therapy. The administration
of ESO-101 ensures a targeted drug delivery to the esophagus allowing for a
higher efficacy which should lead to histologic improvement directly related to
higher mucosal contact time and subsequent clinical improvement of symptoms of
EoE.
In contrast, esophageal transit times of tablets and capsules are shorter and
depend on the swallowed water volume. Importantly, due to systemic side effects
of corticosteroids, including hyperphagia, weight gain, and/or cushingoid
features in patients receiving oral prednisone, systemic administration of
corticosteroids is no longer recommended in the latest consensus guideline.
Due to its efficient and targeted administration of a potent corticosteroid,
ESO-101 is administered only once daily, unlike the only EoE treatment
currently on the European market that requires twice daily administration
(Jorveza®; an orodispersible tablet containing budesonide). The once-daily
administration at bedtime also removes one major inconvenience for patients,
which is the restriction in eating or drinking. It is also expected that fungal
infections of the oral mucosa, one of the most common adverse reactions of
Jorveza, can be avoided. A once-daily administration also minimizes the total
time each day that steroids are taken, which could have a safety benefit for
topical side effects such as oral and esophageal
candidiasis, or throat irritation. Only minimal enteral absorption of
mometasone furoate and systemic bioavailability is expected, and the portion of
mometasone furoate dose that is swallowed and absorbed in the gastrointestinal
tract is extensively metabolized primarily in the liver. Further, since
mometasone furoate is highly lipophilic and binds strongly to its receptor,
systemic side effects are expected to be uncommon.
The aim of this proof-of-concept trial is to investigate the efficacy, safety
and tolerability of mometasone furoate administered via the ESO-101 delivery
system.
Study objective
To evaluate the efficacy based on the histological response
Study design
This is a randomized, placebo-controlled, double-blind trial to evaluate the
efficacy, tolerability, and safety of ESO-101 in adult patients with active
eosinophilic esophagitis (EoE).
Patients will be screened at 2 visits (Visit 1 and Visit 2) during which their
eligibility will be assessed based on endoscopy-independent criteria (Visit 1)
and based on the histologic assessment of esophageal biopsy samples taken
during the screening endoscopy (Visit 2).
Eligible patients will be randomized 2:1 to once-daily treatment with ESO-101
or placebo and treated for 28 days starting on Day 0. Further clinic visits
will be performed at Day 14 (Visit 4) and Day 28 (Visit 5, end of treatment
[EOT]) to assess the efficacy, tolerability, and safety. In
addition, a safety follow-up call will be scheduled 2 weeks after the EOT (Day
42, Visit 6).
Intervention
Tested product:
ESO-101 is a unique drug delivery system for the upper gastrointestinal tract,
consisting of a capsule holder containing a hard gelatin capsule with a rolled,
thin mucoadhesive film, a sinker, and a dissolvable retainer. The capsule
holder is screwed onto the lid of a drinking cup to
facilitate swallowing while drinking from the cup. Upon swallowing, the film
unrolls and sticks to the mucosa where it dissolves while slowly releasing
mometasone furoate. In the tested product, ESO-101, the film is loaded with 800
µg mometasone furoate. Dosing: 1 capsule taken once daily in the evening at
bedtime for 28 days.
Reference product:
The reference product (placebo) contains a thin adhesive film without active
substance. The placebo is administered and dosed like ESO-101.
Study burden and risks
ESO-101 may have side effects. As nobody has been treated with ESO-101 to date,
there is not yet any data about possible side effects or symptoms caused by
taking ESO-101. The following unwanted side effects have been observed to date
during treatment with other approved formulations containing mometasone furoate
(nasal spray and powder for inhalation).
These side effects are common (occurs in 1 in 10 people or more):
- Fungal infection (candidiasis)
- Nosebleeds
These side effects occur, but not often (in 1-10% of people):
- Pharyngitis (inflammation in the troat)
- Headache
- Burning sensation in the nose, nose irritation, nasal ulcer
- Upper respiratory tract infection
- Hoarse voice
- Sore throat
The frequency of the following side effects is unknown:
- Blurred vision
- Glaucoma (increased pressure inside the eye)
- Cataract
- Altered smell and taste
ESO-101 may also cause side effects that are unknown.
In addition to the side effects described above, there are other risks that may
in general be associated with the use of any medicine: itchy skin, shortness of
breath, sensation of heat, nausea, and maybe even vomiting. Symptoms such as
these typically suggest an allergic reaction. In rare cases, life-threatening
conditions with severe breathing difficulties and circulatory shock may occur,
requiring immediate medical intervention. .
The tests that will be performed in this study also include some risks:
- During the swallowing test, it is possible that the patient experiences
problems swallowing the test tablet as a result of the disease.
- Collection of the blood samples may cause mild pain caused by the needle
prick, and dizziness, local irritation, infection, bleeding or bruising have
also been observed. There is also the risk of nerve damage with impaired
sensation. In total, 30 mL blood will be collected. This amount should not
cause any problems in adults. In comparison: at the blood bank, 500 mL of blood
is collected at one time.
- During the imaging of the esophagus with sample collection, the endoscope may
trigger the gag reflex of the patient as it is inserted. Hoarseness or problems
swallowing may occur occasionally due to irritation of the voice box. More
common complaints include flatulence and belching, as well as a feeling of
fullness (caused by residual quantities of gas). There is also the risk of
damage to the teeth, injury to the mucosa, or perforation (creation of a hole)
in the wall of the esophagus, stomach or duodenum.
Possible benefit:
Decrease in dysphagia symptoms
Improvement in quality of life
Malzgasse 9
Basel 4052
CH
Malzgasse 9
Basel 4052
CH
Listed location countries
Age
Inclusion criteria
1. Adult patients aged 18-70 years;
2. Confirmed clinicopathological diagnosis of EoE;
3. Active and symptomatic EoE, defined as:
a. peak eosinophil count >=15 eosinophils/high-powered field (hpf) at 2 levels
of the
esophagus at the screening endoscopy (Visit 2) as measured in a total of 6 hpfs
derived from 6 biopsies, 2 each from the proximal, mid, and distal segment of
the
esophagus;
b. either a dysphagia or odynophagia severity sore of >=4 on a 11-point numeric
rating
scale for >=1 day during the 7 days before Screening (Visit 1);
4. Written informed consent;
5. Willingness and ability to comply with the protocol for the duration of the
trial;
6. Negative pregnancy test at Screening (Visit 1) and Day 0 (Visit 3) in women
of
childbearing potential (i.e. fertile, following menarche and until becoming
post-menopausal unless permanently sterile. Permanent sterilization methods
include
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy);
7. Women of childbearing potential must be willing to use (for a least 3
monthly cycles
before the screening endoscopy [Visit 2] and until 4 weeks after the last
intake of IMP) a
highly effective method of contraception or birth control (failure rate less
than 1% per
year when used consistently and correctly). Reliable methods for this trial are:
a. combined (estrogen and progestogen containing) hormonal contraception
associated
with inhibition of ovulation (oral, intravaginal, transdermal);
b. progestogen-only hormonal contraception associated with inhibition of
ovulation
(oral, injectable, implantable);
c. intrauterine device or intrauterine hormone-releasing system;
d. bilateral tubal occlusion;
e. a vasectomized sexual partner;
f. sexual abstinence (only accepted as true abstinence when this is in line
with the
preferred and usual lifestyle of the patient; periodic abstinence [e.g.
calendar,
ovulation, symptothermal, post-ovulation methods, and withdrawal] is not an
acceptable method of contraception).
Exclusion criteria
1. Women who are pregnant, lactating, possibly pregnant or planning a pregnancy
during
the trial period;
2. Current or past (within the last 3 months) alcohol or drug abuse;
3. Initiation of a diet-modifying food restriction within 4 weeks before the
screening
endoscopy (Visit 2) until EOT;
4. Use of systemic corticosteroids or biologic immunomodulators within 3 months
before
the screening endoscopy (Visit 2) until the EOT;
5. History of non-response to treatment of EoE with topical corticosteroid
drugs (defined as
no improvement of clinical symptoms of EoE after a minimum of 4 weeks
corticosteroid
therapy used at appropriate doses according to the investigator*s judgment) or
requirement of cessation of corticosteroid therapy for EoE treatment due to oral
candidiasis or systemic corticosteroid side effects;
6. Use of corticosteroids for treatment of EoE within 4 weeks before the
screening
endoscopy (Visit 2) until the EOT;
7. Use of inhalable (pulmonary or nasal) corticosteroids within 4 weeks before
the screening
endoscopy (Visit 2) until the EOT;
8. Asthma requiring corticosteroid therapy in the seasonal allergy period
according to the
investigator*s judgment based on anamnesis until the EOT;
9. Change in proton pump inhibitor (PPI) dosing regimen within 4 weeks before
the
screening endoscopy (Visit 2) until the EOT;
10. Use of systemic leukotriene receptor antagonists, immunosuppressant
therapy, or chronic
oral or systemic anticoagulants (such as coumarin derivates, novel oral and
subcutaneous
anticoagulants) within 2 weeks before Screening (Visit 1) until the EOT;
11. Unable to swallow a test tablet of about the size of the IMP capsule used
in the trial;
12. History of diabetes mellitus;
13. Other severe comorbid condition, concurrent medication, or other issue that
renders the
patient unsuitable to participate in the trial in the judgment of the
investigator, including
but not limited to: comorbid condition with an estimated life expectancy of <=12
months,
dialysis, severe pulmonary (requiring home oxygen, uncontrolled chronic
obstructive
pulmonary disease Gold III/IV) or cardiovascular conditions (heart failure New
York
Heart Association III and IV, uncontrolled hypertension systolic blood pressure
by
repeated measurement >180mmHg);
14. History of cancer (except non-melanoma skin cancer, or carcinoma in situ of
cervix) or
treatment with anticancer therapy (chemotherapy, immunotherapy, radiotherapy,
hormone therapy for cancer treatment, targeted therapy or gene therapy) within
12 months before Screening (Visit 1) until the EOT;
15. Known intolerability or hypersensitivity to mometasone furoate or any of
the IMP
excipients (e.g. bovine gelatin, polyvinyl alcohol, polyvinyl acetate,
glycerol, sorbitol);
16. Systemic autoimmune disorders or any condition requiring immunosuppression
(e.g.
methotrexate, cyclosporine, interferon alpha, tumor necrosis factor alpha
inhibitors,
antibodies to immunoglobulin E) within 3 months before Screening (Visit 1);
17. Mental condition rendering the patient unable to understand the nature,
scope, and
possible consequences of the trial or presence of any condition that impacts
compliance
with the trial procedures;
18. Use of any investigational or non-registered product (medicinal product or
medical
device) within 4 weeks before the screening endoscopy (Visit 2) until the EOT;
19. Employee at the trial center, spouse, partner or child of investigators or
sub-investigators
or employee of the sponsor.
20. History of active eosinophilic gastroenteritis and colitis, inflammatory
bowel disease, celiac disease, oral or esophageal
mucosal infection of any kind, and esophageal varices;
21. Gastroesophageal reflux disease with Los Angeles Grade B or higher, or
erosive
esophagitis Grade 2 or above;
22. Presence of Barrett*s esophagus with a maximum length of >=3 cm with
intestinal
metaplasia or dysplasia, peptic stricture, achalasia, significant hiatal hernia
>3 cm,
esophageal scleroderma, or diagnosis of Lichen planus;
23. Emergency endoscopy for bolus impaction within 2 weeks before Screening
(Visit 1);
24. Any mouth or dental condition that prevents normal eating;
25. History of (dilation within the previous 8 weeks) or current severe
endoscopic structural
abnormality in esophagus (e.g. high-grade stenosis where an 8-10 mm endoscope
cannot
pass without dilatation at the screening endoscopy [Visit 2]);
26. Diagnosed liver cirrhosis or portal hypertension;
27. History of upper gastrointestinal bleeding within 8 weeks before Screening
(Visit 1);
28. Known allergy to β-lactoglobulin (cow milk protein).
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 | EUCTR2020-000082-16-NL |
| CCMO | NL73856.018.20 |