To test the hypothesis: the mode of action of benralizumab being ADCC will target both resident and inflammatory eosinophils whereas mepolizumab only targets inflammatory eosinophils. This will achieved by a head-to-head comparison of the presence…
ID
Source
Brief title
Condition
- Allergic conditions
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Number of eosinophils per high power field in rectal biopsies
Secondary outcome
1. Number of eosinophils in the peripheral blood (million/ml)
2. Kinetics of eosinophils in tissue and blood.
Background summary
Overall rationale: the production of eosinophils in the bone marrow is not
dependent on IL-5, but reactive eosinophilia is. The prevailing idea is that
eosinophil progenitors are formed independently of IL-5 but the cells express
the IL-5R (IL-5 KO mice have terminally differentiated eosinophils in the
peripheral blood). When IL-5 is produced during T2 inflammation this cytokine
acts as growth/proliferation factor for these IL-5R-positive cells. This
implicates that anti-IL-5 therapy can only act on reactive eosinophilia.
The situation with benralizumab is different. This antibody is directed against
IL-5R and kills these cells by antibody-dependent cellular cytotoxicity (ADCC).
This implicates that benralizumab kills all IL-5R positive cells (eosinophils
and basophils)(1).
The recent study and review by Mesnil et al (2) again shows the presence of
resident eosinophils in homeostasis in healthy tissues as well as in the lung.
Following the above-mentioned reasoning these cells are likely not sensitive
for IL-5 targeted therapy whereas they are sensitive for benralizumab therapy.
Conus et al. (3) supports this hypothesis as treatment with mepolizumab does
not affect eosinophil numbers in duodenal mucosa. In addition, the expected
depletion of eosinophils in the gut tissue by benralizumab has been recently
demonstrated in patients with HES (4,5)..
Study objective
To test the hypothesis: the mode of action of benralizumab being ADCC will
target both resident and inflammatory eosinophils whereas mepolizumab only
targets inflammatory eosinophils. This will achieved by a head-to-head
comparison of the presence of (healthy) resident eosinophils in the rectal
(gut) tissue.
Study design
Investigation part 1: comparative study between 20 patients treated with
mepolizumab (Nucala) and 20 patients treated with benralizumab (Fasenra).
Investigation part 2: longitudinal cross over study with 12 (2x6) biological
naïve patients that either start with mepolizumab and cross after 6 months to
benralizumab or vice versa
Study burden and risks
Burden is limited:
Cross-sectional study (part 1):
Three visits: 1 initiation visit (1 hr), 1 day in UMCU (glucose labeling), 1
visit for taking biopsies/2 hr
Total: 6-26 days depending on the length of the labeling: 11 hrs in total
Clinical samples: 4 small rectal biopsies, 1 tube of NaHep blood and 6 finger
pricks
Prospective cross-over study (part 2)
Four visits: 1 initiation visit (1 hr), 3 visits for taking biopsies/2 hr and
10 short visits for determination of weight and blood differentiation
Total: 4 visits in 52 weeks: 17 hrs in total
Clinical samples: 4 small rectal biopsies, 3x1 tube of NaHep blood and 3x1
urine sample
There are very small risks associated with
1. Venipuncture: potential small leakage of blood, bruise
2. Rectal biopsy: potential small leakage of blood
3. 2H-gluocse: no known side effects at doses used in this investigation
4. Treatment with Nucala en Farenza: mild complaints such as head ache, colds,
low fever.
Heidelberglaan 100 Heidelberglaan 100
UTRECHT 3584CX
NL
Heidelberglaan 100 Heidelberglaan 100
UTRECHT 3584CX
NL
Listed location countries
Age
Inclusion criteria
* Age * 18
* Diagnosis of severe refractory eosinophilic asthma
* Eligible for mepolizumab or benralizumab therapy according the national
recommendations for severe asthma of the Dutch society for lung diseases and
tuberculosis (NVALT guideline 2013): Patients with asthma, for whom alternative
diagnoses are excluded, comorbidity optimally treated, provoking factors
minimized and therapy compliance optimized, but despite this still have
insufficient asthma control (* 1.5 ACQ-7 or other questionnaire) or frequent
(*2 annually) severe exacerbations (systemic CS needed) while routinely using
high-dose asthma medication (* 1000 mcg/day fluticasone propionate equivalent
and/or daily OCS in combination with LABA or other controller medication); or
patients who can achieve asthma control only with systemic CS and are therefore
are risk for adverse effects or the corticosteroids.
* Treated with mepolizumab or benralizumab for at least 4 months.
* Before treatment with biologics a blood eosinophilia (* 150
eosinophils/microl blood) irrespective of steroid use
Exclusion criteria
* Any infection (eg. HIV, Hepatitis, STDs)
* Insulin dependent diabetes
* Smoking at present or in the last 12 months and/or a past history of more
than 10 pack years
* Proven allergic bronchopulmonary aspergillosis
* Auto-immune diseases
* Use of medication, excluding:
o Anticonceptives
o Pain killers, if used on average less than once a week
* exuberant alcohol consumption (for males > 36 glasses per week, for females
>24 glasses per week)
* Drug use
* History of cancer
* Use of biologicals other than mepolizumab or benralizumab
* daily oral steroid therapy during the three months preceding inclusion
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 | EUCTR2019-004676-18-NL |
| CCMO | NL72258.041.20 |