The primary objective of this exploratory study is to test if prophylactic use of conestat alfa decreases the frequency of angioedema attacks in patients with InH-AAE. As secondary objectives, effects on disease severity, quality of life and drug…
ID
Source
Brief title
Condition
- Angioedema and urticaria
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of this study is the mean monthly attack frequency during
the 8-week treatment period as reported by the patient on the AAS form.
This primary parameter will be compared with the patient reported mean monthly
attack frequency over the past 6 months (primary outcome) and the mean monthly
attack frequency during the 8-week observational period.
Secondary outcome
Secondary endpoints are changes in disease severity, quality of life and
occurrence of adverse events. In addition, a panel of biomarkers will be
assessed for association with disease severity, proposed disease mechanism,
response to treatment and safety.
Background summary
Conestat alfa, a recombinant human C1 esterase inhibitor (C1INH), is an
effective treatment for acute attacks of angioedema in patients with hereditary
angioedema (HAE) caused by C1INH deficiency. C1INH inhibits the contact system,
this enzymatic system produces bradykinin. Bradykinin mediates swelling attacks
in HAE. Another mediator that can drive angioedema is histamine. Histamine is
held responsible for angioedema attacks in patients with chronic spontaneous
urticaria, anti-histamines can bring relief. In the case of idiopathic
angioedema the mediator is unknown, patients that do not responds to
anti-histamines are diagnosed with idiopathic non-histaminergic acquired
angioedema (InH-AAE). The anti-IgE biological Omalizumab has recently become
available for chronic spontaneous urticaria including InH-AAE patients. The
effectiveness of Omalizumab in InH-AAE was not yet investigated.
InH-AAE is suspected to be mediated by bradykinin, however biomarkers to
determine if bradykinin is indeed involved are not available. Case reports
describe that angioedema in InH-AAE responds well to medication used in HAE.
Currently, there is an urgent clinical need for therapy for InH-AAE patients,
conestat alfa might be used as a therapy for InH-AAE by inhibiting bradykinin
generation.
Study objective
The primary objective of this exploratory study is to test if prophylactic use
of conestat alfa decreases the frequency of angioedema attacks in patients with
InH-AAE.
As secondary objectives, effects on disease severity, quality of life and drug
safety will be reported. Further, potential novel biomarkers for bradykinin
mediated disease will be studied.
Study design
This study is a mono-center, open label, uncontrolled exploratory intervention
study.
Intervention
Study participants will receive 50IU/kg conestat alfa (max 4200 IU), twice
weekly via intravenous infusion for eight weeks. Four weeks prior to treatment,
during the 8-week treatment period and four weeks after treatment, attack
frequency will be reported. Blood samples will be collected for biomarker
studies.
Study burden and risks
There is currently limited therapy available for InH-AAE, this unmet clinical
need may be resolved with conestat alfa treatment. Conestat alfa is in general
a safe and well tolerated drug as was shown in extensive studies in HAE
patients and healthy volunteers.
Patients will be asked to fill in a very concise, daily angioedema activity
score reporting attack frequency and severity over the course of 16 weeks. In
addition, quality of life will be assessed four times. During the 16 weeks,
patients are asked to visit the out-patients* clinic 18 times; 1 visit at
inclusion,16 visits during the 8 week treatment period, and 1 visit at the end
4 weeks after treatment. They will receive conestat alfa via an iv bolus every
3 or 4 days during the 16 visits of the treatment period.
A total of 19 blood tubes will be collected at 6 time points, 5 times the
venepuncture set for drug infusion can be used , 1 time an extra venepuncture
will be performed..
We consider the risks of intervention to be low but acknowledge that
participation is demanding. We only include patients with a highly frequent of
angioedema attacks. This sub-population may benefit the most; would also be
considered eligible for twice weekly prophylactic treatment if therapy was
already available; and effect on monthly attack frequency may become apparent
fast allowing the relatively short treatment duration of two months.
Heidelberglaan 100
Utrecht 3584CX
NL
Heidelberglaan 100
Utrecht 3584CX
NL
Listed location countries
Age
Inclusion criteria
Age * 18 years. , Diagnosis idiopathic non-histaminergic acquired angioedema
(InH-AAE) were *non-histaminergic* is defined as following: insufficient effect
of treatment with antihistamines up to 4 times the standard dose (step 2 in
CSU-treatment regimen), defined as having breakthrough attacks. , Minimal mean
attack rate of 2 per month during the past six months despite treatment; with
at least one attack in the month prior to inclusion. , Written informed
consent.
Exclusion criteria
- Presence of recurrent wheals/ urticaria accompanying angioedema. Where wheals
are defined as recurrent, itchy, urticarial plaques that tend to appear and
resolve quickly (<24). A patient reported incidental wheal, that was unrelated
to angioedema is not considered an exclusion criteria. , - Diagnosis other than
InH-AAE is deemed more likely e.g. drug-hypersensitivity, HAE, mastocytosis. ,
- ACE-inhibitor use in the past 6 months., - Treatment with add on therapy
Omalizumab (wash-out period 2 months) use in the two months prior to visit 1.,
- Treatment with add on therapy cyclosporine (wash-out period 1 month) prior to
visit 1., - Treatment with add on therapy methotrexate, azathioprine or
mycophenolic acid (wash-out period 3 month) before visit 1., - History
suggesting allergy for rabbits or rabbit derived products (such as conestat
alfa). Defined as allergic symptoms occurring within hours after contact with
rabbits, and after every contact with rabbits. , - Currently trying to
conceive, pregnancy and women giving breastfeeding., - Inability to comply with
study and follow-up procedures., - Presence of clinically significant
conditions that could interfere with the interpretation of the study results
and or compromise the safety of the patients e.g. severe impaired renal or
hepatic function, active malignancy or currently treated for malignancies other
than non-melanomal skin cancer., - Participation in an investigational drug or
device trial within the last 30 days prior to screening., -*C4 levels lower
than 0.10 g/L. In this case additional investigations are necasarry to first
exclude the diagnosis HAE by repeating C4 measurement and perform a C1-esterase
inhibitor function test.
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 | EUCTR2016-005083-34-NL |
| CCMO | NL60248.041.16 |