Primary Objective: To demonstrate the clinical efficacy of KVD900 compared with placebo for the on-demand treatment of HAE attacks.Secondary Objective: To investigate the safety and tolerability of KVD900.
ID
Source
Brief title
Condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• PGI-C: Time to beginning of symptom relief defined as at least *a little
better* (2 time points in a row) within 12 hours of the first IMP
administration.
Secondary outcome
Key Secondary Endpoints
• PGI-S: Time to first incidence of decrease from baseline within 12 hours of
the first IMP administration.
• PGI-S: Time to HAE attack resolution defined as *none* within 24 hours of the
first IMP administration.
Secondary Endpoints
• PGI-C: Proportion of attacks with beginning of symptom relief defined as at
least *a little better* (2 time points in a row) within 4 hours and within 12
hours of the first IMP administration.
• PGI-C: Time to at least *better* within 12 hours of the first IMP
administration.
• PGI-S: Time to first incidence of decrease from baseline within 24 hours of
the first IMP administration.
• Composite VAS: Time to at least a 50% decrease from baseline (3 time points
in a row) within 12 hours and within 24 hours of the first IMP administration.
Background summary
Recurrent swelling in patients with HAE is predominantly a consequence of
excessive generation of bradykinin due to dysregulated plasma kallikrein
activity. Therefore, inhibition of plasma kallikrein activation has emerged as
a target for the treatment of HAE. For example, treatment with ecallantide, a
specific inhibitor of plasma kallikrein given subcutaneously, led to
significantly better treatment outcome scores compared with placebo. The oral
small-molecule inhibitor of plasma kallikrein berotralstat and the plasma
kallikrein monoclonal antibody lanadelumab have been shown to lower the rate of
attacks in HAE patients compared with placebo, highlighting the role that
plasma kallikrein plays in this disease.
KVD900 has been shown in a range of nonclinical experiments to be a selective
inhibitor of plasma kallikrein. This activity was confirmed in a completed
trial (KVD900-101) of KVD900 in healthy volunteers at dose levels up to 600 mg.
Within 1 hour of dosing mean protection of high molecular weight kininogen (HK)
cleavage was >85%. Protection was maintained at >75% for 6 hours and >45% for
10 hours at a dose of 600 mg. Forty percent (40%) HK protection is achieved by
C1-INH levels typically present in control plasma samples. It is therefore a
plausible hypothesis that treatment with a single dose of KVD900 600 mg may
halt the progression of HAE attacks. This hypothesis was tested in a Phase 2
trial (KVD900-201) for the on-demand treatment of HAE attacks. The trial was a
cross-over in which 53 patients with either type I or II HAE completed. Results
showed a significant difference between 600 mg KVD900 and placebo for the
primary endpoint of time to conventional treatment use and secondary endpoints
of attack improvement using Patient Global Impression of Change (PGI-C),
Patient Global Impression of Severity (PGI-S), and a composite visual analogue
scale (VAS) measuring symptoms of the attack.
The current trial (KVD900-301) will evaluate two dose levels of KVD900 (with
the option for patients to take a second dose of IMP to treat each attack) for
the on-demand treatment of HAE attacks under randomized, double-blind,
placebo-controlled conditions. Ex vivo testing suggests that a dose of 300 mg
may also bring relief to an attack of HAE. The randomized, double-blind,
placebo-controlled, three-way crossover design of this trial has been chosen as
an appropriate test of that hypothesis.
Adolescents (12 to 17 years old) will be included in this trial. A population
PK model has been built which predicted KVD900 exposure in a simulation
population containing 600 subjects (400 females and 200 males) 12 to 17.9 years
of age with body weight ranging from 31.0 to 93.3 kg. The population PK model
predicted overall KVD900 exposure in an adolescent population (12 to 17 years
old) to be similar to that in healthy adults for a single 600 mg dose of KVD900
under fasted conditions.
Study objective
Primary Objective: To demonstrate the clinical efficacy of KVD900 compared with
placebo for the on-demand treatment of HAE attacks.
Secondary Objective: To investigate the safety and tolerability of KVD900.
Study design
This is a double-blind, randomized, placebo-controlled, multicenter clinical
trial in patients 12 years or older with HAE type I or II. Patients will be
randomized to 6 treatment sequences in a 3-way crossover design. Eligible
attacks will initially be treated with a single dose of placebo, 300 mg, or 600
mg KVD900 per attack. If needed (as determined by the patient), an additional
dose of IMP may be administered for each attack.
The trial duration from screening through to the final visit, including the
treatment of 3 eligible attacks during the treatment period, is approximately
25 weeks for each randomized participant.
Intervention
Each participant will receive the following treatments with the option for
participant to take a second dose of IMP to treat each attack:
• 300 mg KVD900 (1 x 300 mg tablet plus 1 matching placebo tablet)
• 600 mg KVD900 (2 x 300 mg tablets)
• 2 matching placebo tablets.
Study burden and risks
Study subjects are expected to undergo the assessments and tests as described
in the table 1 of the study protocol. These procedures include physical exam,
vital signs, demographic and medical history, ECG, questionnaire, blood and
urine tests, pregnancy tests in women of childbearing potential, and completion
of eDiary. The study medication is a non-registered medication. Possible known
side effects are described in the Investigators Brochure and patient
information and can also occur during this study. There is also a risk that
unknown side effects occur and there is a chance that the treatment will not be
efficacious for the patient.
KVD900-301 study is considered to have a positive benefit-risk balance.
Porton Science Park, Bybrook Road, Porton Down -
Salisbury SP4 0BF
GB
Porton Science Park, Bybrook Road, Porton Down -
Salisbury SP4 0BF
GB
Listed location countries
Age
Inclusion criteria
1) Male or female patients 12 years of age and older.
2) Confirmed diagnosis of HAE type I or II at any time in the medical history.
3) Patient has access to and ability to use conventional on-demand treatment
for HAE attacks.
4) If a patient is receiving long-term prophylactic treatment with one of the
protocol-allowed therapies. They must be on a stable dose and regimen for at
least 3 months prior to the Screening Visit and be willing to remain on a
stable dose and regimen for the duration of the trial.
5) Patient's last dose of attenuated androgens was at least 28 days prior to
randomization.
6) Patient:
a) has had at least 2 documented HAE attacks within 3 months prior to
randomization; or
b) is a completer of the KVD824-201 trial within 3 months prior to
randomization and meets all
other entry criteria to enroll in KVD900-301.
7) Patients must meet the contraception requirements.
8) Patients must be able to swallow trial tablets whole.
9) Patients, as assessed by the Investigator, must be able to appropriately
receive and store IMP, and be able to read, understand, and complete the
electronic diary (eDiary).
10) Investigator believes that the patient is willing and able to adhere to all
protocol requirements.
11) Patient provides signed informed consent or assent (when applicable). A
parent or legally authorized representative (LAR) must also provide signed
informed consent when required.
Exclusion criteria
1) Any concomitant diagnosis of another form of chronic angioedema, such as
acquired C1-inhibitor deficiency, HAE with normal C1-INH (previously known as
HAE type III), idiopathic angioedema, or
angioedema associated with urticaria.
2) A clinically significant history of poor response to bradykinin receptor 2
(BR2) blocker, C1-INH therapy or plasma kallikrein inhibitor therapy for the
management of HAE, in the opinion of the Investigator.
3) Use of angiotensin-converting enzyme (ACE) inhibitors after the Screening
Visit or within 7 days prior to randomization.
4) Any estrogen containing medications with systemic absorption (such as oral
contraceptives including ethinylestradiol or hormonal replacement therapy)
within 7 days prior to the Screening Visit.
5) Patients who require sustained use of strong cytochrome P450 3A4 (CYP3A4)
inhibitors or inducers.
6) Inadequate organ function, including but not limited to:
a) Alanine aminotransferase (ALT) >2x upper limit of normal (ULN)
b) Aspartate aminotransferase (AST) >2x ULN
c) Bilirubin direct >1.25x ULN
d) International normalized ratio (INR) >1.2
e) Clinically significant hepatic impairment defined as a Child-Pugh B or C
7) Any clinically significant comorbidity or systemic dysfunction, which in the
opinion of the Investigator, would jeopardize the safety of the patient by
participating in the trial.
8) History of substance abuse or dependence that would interfere with the
completion of the trial, as determined by the Investigator.
9) Known hypersensitivity to KVD900 or placebo or to any of the excipients.
10) Prior participation in trial KVD900-201.
11) Participation in any gene therapy treatment or trial for HAE.
12) Participation in any interventional investigational clinical trial (with
the exception of KVD824-201), including an investigational COVID 19 vaccine
trial, within 4 weeks of the last dosing of investigational drug prior to
screening.
13) Any pregnant or breastfeeding patient.
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
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 | EUCTR2021-001226-21-NL |
| ClinicalTrials.gov | NCT05259917 |
| CCMO | NL80191.018.22 |