Primary: To evaluate the efficacy of repeated subcutaneous (SC) administrations of lanadelumab in preventing angioedema attacks in adolescents (12 to
ID
Source
Brief title
Condition
- Angioedema and urticaria
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Number of investigator-confirmed angioedema attacks during the treatment period
(Day 0 through Day 182)
Secondary outcome
1. Subjects that are attack-free during the treatment period (Day 0 through Day
182)
2. Number of investigator-confirmed moderate or severe angioedema attacks
during the treatment period (Day 0 through Day 182)
3. Number of investigator-confirmed angioedema attacks during the presumed
steady state period (Day 70 through Day 182)
4. Subjects that are attack-free during the presumed steady state period (Day
70 through Day 182)
5. Number of investigator-confirmed moderate or severe angioedema attacks
during the presumed steady state period (Day 70 through Day
182)
Background summary
Angioedema is a long-term, life-threatening disease caused by genetic changes
in the C1-INH protein. angioedema involves unpredictable, irregular attacks of
oedema under the skin or muscles of the face, throat, intestines, arms, legs,
and/or private parts.
For Hereditary Angioedema, a different type of angioedema, Lanadelumab has been
approved for use to prevent attacks, in the US and EU.
The precise events that trigger an HAE attack are not known yet, however
therapeutic strategies to treat HAE have been developed. These strategies are
working on changing the enzymes of the kallikrein-kinin pathway. Blocking or
inhibiting these enzymes are the therapeutic strategies to treat or prevent HAE
attacks.
Non-histaminergic angioedema have more unclear and inconsistent features, which
have limited the opportunity for the clinical investigation and new treatment
development. Consequently, there are still no approved treatments for
non-histaminergic angioedema patients, who are unresponsive to conventional
treatment. Lanadelumab is expected to prevent against acute attacks of
Non-histaminergic Angioedema with Normal C1-INH.
Firazyr® (icatibant) has been approved for use to treat hereditary angioedema
attacks in the US and EU and can be used for acute angioedema attacks during
the observation and treatment period this study.
Study objective
Primary: To evaluate the efficacy of repeated subcutaneous (SC) administrations
of lanadelumab in preventing angioedema attacks in adolescents (12 to <18 years
of age) and adults with non-histaminergic angioedema with normal C1-INH.
Secondary:
- To evaluate the safety of repeated SC administrations of lanadelumab
in preventing angioedema attacks in adolescents and adults with normal C1-INH
angioedema.
- To evaluate the PK of repeated SC administrations of lanadelumab in
preventing angioedema attacks
- To evaluate the PD of repeated SC administrations of lanadelumab in
preventing angioedema attacks
- To evaluate the immunogenicity of repeated SC administrations of
lanadelumab in preventing angioedema attacks
- To evaluate the effect of lanadelumab on health-related quality of life
(HR-QoL) assessments.
Study design
A Phase 3, Multicenter, Randomized, Placebo-controlled, Double-blind Study to
Evaluate the Efficacy and Safety of Lanadelumab for Prevention Against Acute
Attacks of Non-histaminergic Angioedema with Normal C1-Inhibitor (C1-INH).
This study targets to enroll approximately 120 subjects to ensure that around
75 subjects (12 years of age and above) with normal C1-INH angioedema are
randomized.
Screened subjects who have been on any long-term, are required to undergo a
minimum 2-week washout period prior to the observation period.
Enrolled subjects meeting all eligibility criteria at screening will enter an
observation period of 8 weeks to determine the baseline angioedema attack rate
and confirm their eligibility into either of the 2 angioedema indication
cohorts. Subjects meeting a minimum baseline angioedema attack rate of at least
1 investigator-confirmed angioedema attack per 4 weeks during the observation
period will be eligible for randomization and will enter the treatment period.
Subjects who experience 3 or more investigator-confirmed attacks within the
first 4 weeks will be allowed to exit the observation period early at 4 weeks
and proceed to randomization after agreement by the investigator and the
sponsor*s medical monitor. Subjects who do not meet the minimum attack rate
during the observation period will be considered screen failures.
After verification of eligibility in the observation period, subjects will be
randomized 2:1 to receive repeated SC administrations of lanadelumab or placebo
in a double-blind fashion. Acute angioedema attacks during the observation
period and the treatment period will be managed with icatibant. Therefore,
subjects >=18 years of age need to be willing to be tested for their response to
icatibant treatment for angioedema attacks that occur during the observation
period. For subjects 12 to <18 years of age, standard of care therapy per local
protocols should be provided.
Intervention
Subjects who enter the blinded treatment period will receive SC administration
lanadelumab 300 mg or placebo
every 2 weeks for 26 weeks.
The drug product is a sterile, preservative-free, ready-to-use solution of
lanadelumab at a concentration of
150 mg/mL. Drug product will be provided in a prefilled syringe (PFS) at a
dosage strength of 300 mg
(300 mg/2 mL). Each PFS is filled to deliver a nominal volume of 2.0 mL of drug
product subcutaneously.
The placebo product consists of the inactive formulation of the drug product.
Placebo will be provided in a PFS
and is filled to deliver a nominal volume of 2.0 mL subcutaneously.
Investigational product will be administered by SC injection in the abdominal
area (preferred), thigh, or upper
arm. Self-administration of investigational product will be permitted after a
subject (and/or parent/caregiver) has
received appropriate training by the investigator or designee and has
demonstrated their understanding of selfadministration.
Study burden and risks
- Based on the mechanism of action and past case studies with icatibant
(FIRAZYR®) and ecallantide (KALBITOR®), there is a strong scientific rationale
and high unmet medical need to expand the use of lanadelumab as a prophylactic
therapy for patients with likely bradykinin-mediated angioedema other than Type
I/II HAE. This study aims to evaluate the efficacy and safety of lanadelumab
for the prevention of angioedema attacks in subjects with non-histaminergic
angioedema with normal C1-INH.
- Lanadelumab has a convenient dosing schedule (once every 2 weeks) and a
favorable route of administration (subcutaneous [SC])-
- Lanadelumab has demonstrated safety and efficacy in preventing HAE attacks,
achieving a high proportion of patients being attack free while improving
health related quality of life
- Lanadelumab has been tested in 4 completed research studies. In addition,
lanadelumab is being studied in this ongoing research study, and one other
study, with others being planned.
In our studies of lanadelumab on subjects with HAE, the most common side
effects (reported in more than 10% of subjects) were
-- Injection site pain (53.6%),
- Viral upper respiratory tract infection (43.2%),
- Headache (27.7%),
- Upper respiratory tract infection (25.9%),
- Injection site redness (18.2%),
- Injection site bruising (13.6%),
- Joint pain (13.2%),
- Back pain (12.7%),
- Nausea (11.4%),
- Urinary tract infection (11.4%),
- Diarrhoea (10.9%),
- Sinusitis (10.9%),
- Abdominal pain (10.5%),
- Fatigue (10.0%),
- Influenza (10.0%),
- Pain in the extremities (10.0%).
Other less common side effects reported by >=5% and <10% of subjects were:
- joint pain
- diarrhoea
- nausea
- sinusitis
- pain in the extremities
- abdominal pain
- injection site swelling
- mouth or throat pain
- gastroenteritis
- muscle pain
- fatigue
- influenza
- acute sinusitis
- cough
- dizziness
- viral gastroenteritis
- ligament sprain
- rash
- myalgia
- toothache
- vomiting
- increased to liver enzyme levels
- bronchitis
- injection site itchiness
- procedural pain
- There is a chance subjects may experience these or other side effects. May
experience an allergic reaction with the use of lanadelumab or other medicines
to treat angioedema. There is a chance that the study drug may not help the
angioedema or that the condition could worsen. If subjects receive placebo,
angioedema will not be treated, so it may stay the same or become worse. During
the washout period, subjects will not be receiving active drug and angioedema
may stay the same or become worse. During the observation period, if subjects
are taking long term prophylaxis medication for angioedema, study doctor will
ask for this to stop. During this period, subjects will not be receiving
active drug and angioedema may stay the same or become worse.
- Subjects may have pain, bleeding, swelling, or bruising around the vein where
blood is collected. There may be a risk of infection from any blood draw and
they may feel dizzy/ faint.. Also may experience minimal discomfort from the
ECG during the attachment and removal of the ECG leads to and from the skin. It
is not known whether the study drugs affect pregnant females, unborn children
or children of nursing females. For this reason, subjects may not enter the
study if they are pregnant, breastfeeding, or trying to become pregnant. A
pregnancy test will be done before patients enroll in the study. During the
study, subjects should not become pregnant or father a child, and should not
nurse a baby.
- Subjects may not receive any benefits from taking part in the study. There
may be a direct benefit to subjects if they receive lanadelumab and it works as
it is intended. May have a reduction in angioedema attacks on lanadelumab.
However, if subjects receive placebo or the study drug does not work, may not
receive a medical benefit. The results of this study may provide information
that could help improve available treatment in the future.
Hayden Avenue 95
Lexington MA 02421
US
Hayden Avenue 95
Lexington MA 02421
US
Listed location countries
Age
Inclusion criteria
1. Males and females, 12 years of age and older for subjects with
non-histaminergic normal C1-INH angioedema at the time of signing of the
informed consent form (ICF).
2. Documented clinical history of recurrent attacks of angioedema in the
absence of wheals/urticaria.
3. Investigator-confirmed diagnosis of non-histaminergic bradykinin-mediated
angioedema with normal C1-INH as documented by a history of angioedema attacks
at screening and occurrence of attack(s) during the observation period.
4. History of recurrent angioedema with at least an average of 1 angioedema
attack per 4 weeks prior to screening and this attack rate must be confirmed
during the observation period while treated with chronic high-dose
antihistamine (cetirizine 40 mg/day or equivalent high-dose second-generation
antihistamine medication).
- Diagnostic testing results obtained during screening from a sponsor-approved
central laboratory that confirm C1-INH antigen and function >=50% of normal and
normal C4. With prior sponsor approval, subjects may be retested during the
observation period if results are incongruent with clinical history.
- Clinical history of not responding to high-dose antihistamine treatment
(cetirizine 40 mg/day or equivalent high-dose second-generation antihistamine
medication), which must be confirmed during the observation period with at
least 1 angioedema attack per 4 weeks with chronic high-dose antihistamine
treatment and no significant difference (as assessed by the investigator and in
consultation with the sponsor*s medical monitor, as necessary) from the
historic attack rate without high-dose antihistamine treatment.
5. Agree to adhere to the protocol-defined schedule of treatments, assessments,
and procedures.
Subjects >=18 years of age must be willing to use icatibant as the rescue
medication during the
observation and treatment period. During the observation period, subjects need
to be treated with icatibant for at least 2 angioedema attacks or at least 1
moderate or severe attack. In the opinion of the investigator, subjects with no
response to icatibant for acute angioedema attacks in the past medical
history/screening, or no improvement or worsened attack severity 2 hours after
icatibant treatment during the observation period (based on totality of
assessments), will not be included. Note: For subjects 12 to<18 years of age,
standard of care therapy per local protocols should be provided.
6. Males, or non-pregnant, non-lactating females who are of child-bearing
potential and who agree to be abstinent or agree to comply with the applicable
contraceptive requirements of this protocol for the duration of the study.
Female subjects of childbearing potential must have a negative serum pregnancy
test at screening and must be willing to undergo pregnancy tests throughout the
study. Females of non- childbearing potential are defined as surgically sterile
(status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation)
or post-menopausal for at least 12 months.
7. The subject (or the subject*s parent/legal guardian, if applicable) has
provided written informed consent approved by the institutional review
board/research ethics board/ethics committee (IRB/REB/EC).
If the subject is an adult, be informed of the nature of the study and provide
written informed
consent before any study-specific procedures are performed.
OR
If the subject is a minor (ie, <18 years of age), have a parent/legal guardian
who is informed of the nature of the study provide written informed consent
(ie, permission) for the minor to participate in the study before any
study-specific procedures are performed. Assent will be obtained from minor
subjects.
Exclusion criteria
1. Concomitant diagnosis of Type I or Type II HAE, or recurrent angioedema
associated with urticaria.
2. Dosing with any investigational drug or exposure to an investigational
device within 4 weeks prior to screening.
3. Exposure to angiotensin-converting enzyme (ACE) inhibitors or rituximab
within 6 months prior to screening.
4. For patients with normal C1-INH angioedema only: use of any
estrogen-containing medications with systemic absorption (such as oral
contraceptives or hormonal replacement therapy) within 4 weeks prior to
screening.
5. Response to omalizumab (prophylactic) or corticosteroid (acute/prophylactic)
or epinephrine (acute) or anti-leukotrienes (prophylactic) treatments in the
past.
6. Use of long-term prophylactic therapy for HAE, eg, C1-INH, attenuated
androgens (eg, danazol, methyltestosterone, testosterone), or
anti-fibrinolytics within 2 weeks prior to entering the observation period as
long as the investigator determines that doing so would not place the subject
at any undue safety risk, and that the subject is at least 18 years of age.
7. Any exposure to prophylactic plasma kallikrein inhibitors prior to screening.
8. Use of short-term prophylaxis for HAE within 7 days prior to entering the
observation period. Short-term prophylaxis is defined as C1-INH, attenuated
androgens, or antifibrinolytics used to avoid angioedema complications from
medically indicated procedures.
9. Have any active infectious illness or fever defined as an oral temperature
>38°C (100.4°F), tympanic >38.5°C (101.3°F), axillary >38°C (100.4°F),
or rectal/core >38.5°C (101.3°F) within 24 hours prior to the first dose of
study drug in the treatment period. Any angioedema attack must be resolved
prior to the first dose in the treatment period.
10. Any of the following liver function test abnormalities: ALT >3x upper
limit of normal, or AST >3x upper limit of normal, or total bilirubin >2x
upper limit of normal (unless the bilirubin elevation is a result of Gilbert*s
syndrome).
11. Pregnancy or breast feeding.
12. Subject has a known hypersensitivity to the investigational product or its
components.
13. Have any uncontrolled underlying medical condition which would require
treatment adjustment during the study treatment period, that, in the opinion of
the investigator or sponsor, may confound the results of the safety assessments
or may place the subject at risk. Subjects with stable treatment for at least 3
months prior to screening and NOT expecting any change to their treatment
regimen for 6 months during the study treatment period, will not be excluded.
14. Have any condition (surgical or medical) that, in the opinion of the
investigator or sponsor, may compromise their safety or compliance, preclude
the successful conduct of the study, or interfere with interpretation of the
results (eg, significant pre-existing illness or other major comorbidities that
the investigator considers may confound the interpretation of study results).
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 | EUCTR2019-001703-20-NL |
| ClinicalTrials.gov | NCT04206605 |
| CCMO | NL72986.056.20 |