This study has been transitioned to CTIS with ID 2023-505904-41-00 check the CTIS register for the current data. Primary Objective: To assess the safety of long-term administration of KVD900 in adolescent and adult patients with HAE type I or II.…
ID
Source
Brief title
Condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The proportion of patients with at least one AE in adolescent and adult
patients with HAE type I or II who have taken at least one dose of IMP.
Secondary 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 initial dose of IMP
administration.
PGI-S: Time to first incidence of 2 time points in a row decrease from baseline
within 12 hours of initial dose of IMP administration.
PGI-S: Time to HAE attack resolution, defined as ''none'' within 24 hours of
initial dose of 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 clinical efficacy of 2 dose levels of KVD900 will
be investigated in a Phase 3 trial, KVD900-301, a double-blind, randomized,
placebo-controlled, multicenter, clinical trial in patients 12 years of age 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 be treated with
placebo, 300 mg, or 600 mg KVD900 per attack (with the option for patients to
take a second dose of IMP to treat each attack) with a minimum 48-hour washout
period between attacks. The current trial, KONFIDENT-S, is an open-label,
multicenter extension trial to evaluate the long-term safety of a single dose
of 600 mg KVD900 (with the option for patients to take a second dose of IMP to
treat each attack) in patients who are 12 years of age or older with HAE type I
or II. Long-term efficacy is also being evaluated as a secondary objective. The
trial will be conducted in parallel with KVD900-301.
Study objective
This study has been transitioned to CTIS with ID 2023-505904-41-00 check the CTIS register for the current data.
Primary Objective: To assess the safety of long-term administration of KVD900
in adolescent and adult patients with HAE type I or II.
Secondary Objectives:
• To assess the long-term efficacy of KVD900 in the treatment of attacks in
adolescent and adult patients with HAE type I or II.
• To assess the safety and efficacy of KVD900 when used as short-term
prophylaxis in adolescent and adult patients with HAE types I or II.
Study design
KONFIDENT-S is an open-label, multicenter extension trial to evaluate the
long-term safety of KVD900 in patients who are 12 years of age or older with
HAE type I or II.
This trial will be conducted on an outpatient basis and includes in-clinic or
home health visits and televisits. A televisit can be conducted via a telephone
call or via an interactive audio/video system. The maximum duration of this
trial for individual patients will be 2 years.
Intervention
• KVD900 300 mg Film-Coated Tablet.
• IMP will be packaged in a carton containing 4 drawers with 6 tablets (300 mg
each) in each drawer. Resupply will occur on an as-needed basis.
• For the on-demand treatment of HAE attacks, patients will treat each attack
with a single dose of 2 x 300 mg (600 mg total) KVD900. A second dose is
allowed if separated by at least 3 hours following the first dose in cases
where symptoms persist without improvement.
• For short-term prophylaxis prior to undergoing surgical, dental, or medical
procedures, patients will be permitted to take up to 3 doses of KVD900 in a
24-hour period,
• No IMP dose modifications are allowed in this trial except for the
protocol-allowed dosing for short-term prophylaxis.
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.
The KONFIDENT-S trial 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
Patients may roll over from KVD900-301.
1) Confirmed diagnosis of HAE type I or II at any time in the medical history
2) Patient has had at least 2 documented HAE attacks within 3 months prior to
the Enrollment Visit.
3) If a patient is receiving long-term prophylactic treatment with one of the
protocol-allowed therapies, they must have been on a stable dose and regimen
for at least 3 months prior to the Enrollment Visit.
4) Male or female patients 12 years of age and older.
5) Patients must meet the contraception requirements.
6) Patients must be able to swallow trial tablets whole.
7) Patients, as assessed by the Investigator, must be able to appropriately
receive and store IMP, and be able to read, understand, and complete the eDiary.
8) Investigator believes that the patient is willing and able to adhere to all
protocol requirements.
9) Patient provides signed informed consent or assent (when applicable). A
parent or LAR must also provide signed informed consent when required.
Exclusion criteria
1) Discontinued from the KVD900-301 trial for reasons of noncompliance,
withdrawal of consent, or safety. 2) Presence of any safety concerns that would
preclude participation in the open-label trial as determined by the
investigator. 3) 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. 4) 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. 5) Use of attenuated androgens (e.g., stanozolol, danazol,
oxandrolone, methyltestosterone, testosterone), or anti-fibrinolytics (e.g.,
tranexamic acid) within 28 days prior to the Enrollment Visit. 6) Use of ACE
inhibitors within 7 days prior to the Enrollment Visit. 7) Any
estrogen-containing medications with systemic absorption (such as oral
contraceptives including ethinylestradiol or hormonal replacement therapy)
within 7 days prior to the Enrollment Visit. 8) Inadequate organ function,
including but not limited to: a) Alanine aminotransferase (ALT) >2x ULN b)
Aspartate aminotransferase (AST) >2x ULN c) Bilirubin direct >1.25x ULN d) INR
>1.2 e) Clinically significant hepatic impairment defined as a Child-Pugh B or
C 9) 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. 10) History of substance abuse or dependence that
would interfere with the completion of the trial, as determined by the
Investigator. 11) Known hypersensitivity to KVD900 or to any of the excipients.
12) Participation in any gene therapy treatment or trial for HAE. 13)
Participation in any interventional investigational clinical trial, including
an investigational COVID-19 vaccine trial, within 4 weeks of the last dosing of
investigational drug prior to the Enrollment Visit. 14) 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
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 |
|---|---|
| EU-CTR | CTIS2023-505904-41-00 |
| EudraCT | EUCTR2021-001176-42-NL |
| CCMO | NL80192.018.22 |