Primary Objective:• To investigate the efficacy of KVD900 compared to placebo in halting the progression of a peripheral or abdominal attack of hereditary angioedema (HAE).Secondary Objectives:• To investigate the safety and tolerability of KVD900…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoints:
• Time to use of conventional attack treatment.
Secondary outcome
Secondary Efficacy Endpoints:
• Proportion of HAE attacks that progress by one level or more on the 5LS or
that require conventional attack treatment within 12h of study drug.
• Time between treatment and (1) progression of global attack severity on the
5LS by one level or more, or (2) use of conventional attack treatment,
whichever comes first within 12h.
Exploratory Endpoints:
• Cumulative global attack severity on the 5LS following study drug expressed
as area under the curve (AUC) for KVD900 600 mg vs. placebo.
• Proportion of HAE attacks that require conventional attack treatment.
• Proportion of HAE attacks that are rated *worse* or *much worse* on the TQ.
Proportion of HAE attacks that are rated *better* or *much better* on the TQ.
• Time from study drug administration to complete HAE attack resolution (rating
of none) on global attack severity scale (5LS).
• Time to HAE attack being rated worse or much worse on the TQ.
• Time to HAE attack being rated better or much better on the TQ.
Background summary
Bradykinin is formed by the action of a protease enzyme, plasma kallikrein
(PKa), on a precursor molecule, kininogen, leading to the release of active
bradykinin into the circulation. In the absence of the natural inhibitor of
PKa, C1 inhibitor (as is the case in HAE), excessive bradykinin activity
triggers the HAE attacks. It is therefore logical to target inhibition of PKa
as a treatment strategy in HAE.
In study KVD900-101, the pharmacodynamic profile of KVD900 tablets resulted in
95% inhibition of plasma kallikrein within 30 minutes, a timeframe that
potentially compares favorably to approved injected therapies. KVD900 displays
a profile well-suited for use as an on-demand therapy for HAE attacks, with a
combination of rapid and high uptake into the plasma resulting in fast and
strong inhibition of plasma kallikrein.
It is therefore a plausible hypothesis that treatment with a single dose of
KVD900 600 mg may halt the progression of HAE attacks.
Study objective
Primary Objective:
• To investigate the efficacy of KVD900 compared to placebo in halting the
progression of a peripheral or abdominal attack of hereditary angioedema (HAE).
Secondary Objectives:
• To investigate the safety and tolerability of KVD900.
• To investigate the pharmacokinetic (PK) profile of KVD900 when taken during
the intercritical period between HAE attacks.
• To investigate the pharmacodynamic (PD) profile of KVD900 in reducing the
concentration of residual cleaved high molecular weight kininogen (HK) during
the intercritical period between HAE attacks.
• To investigate the PD profile of KVD900 in reducing activated plasma enzyme
activity during the intercritical period between HAE attacks.
Study design
This is a phase 2, two-part, two-sequence, two-period (2x2) cross-over clinical
trial: Subjects with HAE type I or II will be recruited through HAE treatment
centres in Europe.
In Part 1, subjects will receive a single oral dose of 600 mg KVD900 to
investigate the safety, PK and PD of KVD900 during the intercritical period
between HAE attacks.
Eligible adult subjects >=18 years old will undergo a screening assessment for
study inclusion, receive study drug, followed by a 4h, in-clinic, safety and PK
/ PD assessment.
In Part 2, the subjects will be randomized 1:1 to 2 treatment sequences.
This part of the study will be conducted away from the clinic or hospital.
In Sequence 1 (study arm 1) subjects will receive a single dose of 600 mg
KVD900 to treat the first eligible HAE attack. Following resolution of this
attack, subjects will receive a second single dose of placebo to treat the
second eligible HAE attack.
In Sequence 2 (study arm 2) subjects will receive a single dose of placebo to
treat the first eligible HAE attack. Following resolution of this
attack,subjects will receive a second single dose of 600 mg KVD900 to treat the
second eligible HAE attack.
A minimum of 48-hour washout period required between each dose of study drug.
Laryngeal or facial attacks are not eligible for treatment. HAE attacks must be
treated within the first hour of onset and before reaching severe on the global
attack severity scale. Subjects must also be able to identify the start of a
HAE attack. Upon onset of the eligible HAE attack, subjects will notify the
dedicated study physician or qualified designee with a description of the HAE
attack. The dedicated study physician or qualified designee will confirm
eligibility of the HAE attack and agree to study drug being administered. HAE
attacks require documentation, on the Subject Diary, of attack location, attack
symptoms, time of onset, attack severity, and time of last substantial meal
prior to dosing. Subjects will take study drug, as instructed, and will
complete timed assessments of their HAE attack symptoms for a 48h period as
documented below in Table 1 (S) from the protocol. The dedicated study
physician or qualified designee will contact the subject within 24h of the
eligible HAE attack to confirm the subject*s safety and wellbeing. Subjects
will be instructed to contact the dedicated study physician or qualified
designee in case of any safety concerns. In the case of hypersensitivity,
subjects are to contact the dedicated study physician or qualified designee or
contact the nearest emergency service. The dedicated study physician or
qualified designee will be available 24h/day and 7 days/week to receive subject
calls.
Subjects will return to the clinic following the first HAE attack, prior to the
second HAE attack, to undergo safety checks including adverse event (AE)
reporting, vital sign recording, and Subject Diary review.
Once two HAE attacks have been treated in Part 2, the subject will return to
the clinic to undergo final safety checks including AE reporting, vital sign
recording and blood sampling for laboratory safety measurements.
Conventional attack treatment is permitted after 4h, or earlier as warranted,
following study drug intake, provided HAE attack symptoms are judged severe
enough by the subject to require treatment as per the subject*s usual treatment
regimen, or are deemed ineligible for study drug treatment, or are associated
with laryngeal or facial symptoms. Prior to use of conventional attack
treatment, subjects will notify the dedicated study physician or qualified
designee who will confirm conventional treatment is appropriate per protocol
and subject report of symptom severity. Subjects are permitted to treat their
HAE attacks with their conventional attack treatment (pdC1INH or rhC1INH
intravenous [iv] or icatibant).
Intervention
Non clinical interventions/procedures:
Study Informed Consent,
Review of Inclusion/Exclusion Criteria,
Demographic data and medical history,
Concomitant medications
Clinical interventions/procedures:
Height, Weight and Physical
Vital Signs
ECG
Pregnancy test
Blood sampling (various including PK)
Study burden and risks
In contrast to other available on-demand treatments for HAE attacks, KVD900 is
orally-administered, is rapidly absorbed from the tablet formulation and has
been shown in healthy volunteers to have a time profile for kallikrein
inhibition (30 min to 10h post-dose) which is appropriate for the treatment of
this condition. A single dose of 600 mg may be reasonably expected to bring
relief to or halt the progression of an attack of HAE. The double-blind,
placebo-controlled crossover design of Part 2 of the study has been chosen as
an appropriate initial test of that hypothesis.
Good Laboratory Practice (GLP) repeat dose toxicology studies in the rat (28
day) and monkey (35 day) were conducted to support the clinical development of
KVD900. The No-observed Adverse Effect Levels (NOAELs) were 300 mg / kg / day
in the rat and 50 mg / kg / day in the monkey.
In the completed healthy volunteer study, single doses of 600 mg were well
tolerated with no serious adverse events (SAEs) or deaths. There were 26
adverse events (AEs) shared by 19 of 84 subjects in all parts of the study.
All AEs were mild, except for one AE (headache) in the 10 mg cohort of Part A,
which was considered moderate. A total of 9 events were considered by the
Investigator to be possibly or probably related to KVD900 treatment: dizziness
(x1) in the 5 mg cohort of Part A, and headache (x4), fatigue (x2), and
lethargy (x2) with 600 mg in subjects of Part C. All AEs had resolved by the
end of the study.
The two-part design of the current study has been chosen in order to confirm
under open-label, clinic-supervised conditions (Part 1) that administration of
a single 600 mg dose of KVD900 is tolerated by individual subjects before that
dose is administered away from the clinic or hospital in Part 2 of the study.
Further safety features of Part 2 include the exclusion of laryngeal or facial
attacks and the availability of conventional attack treatment from 4h after
study treatment, or earlier, as warranted.
Overall, study KVD900-201 is considered to have a positive benefit-risk balance
Electrocardiogram (ECG)
This test is also non-invasive and not painful. The electrocardiogram (ECG) is
a tracing of patients heart beating, made by recording tiny changes of
electricity produced by their heart at the surface of the skin. To record these
changes electrode stickers will be put on patients chest with wires attached to
them. It will take about 5-10 minutes
Blood sample analysis
Blood samples will be collected for examination at each visit. Collecting the
blood samples might cause discomfort during the study. An anaesthetic cream can
be apply to make the area numb and reduce the discomfort.
Porton Porton Science Park
Porton Down Salisbury SP4 0BF
GB
Porton Porton Science Park
Porton Down Salisbury SP4 0BF
GB
Listed location countries
Age
Inclusion criteria
1. Male or female adult subjects 18 years of age and older.
2. Confirmed diagnosis of HAE type I or II at anytime in the medical history:
3. At least 3 documented HAE attacks in the past 93 days, as supported by
medical history.
4. Access to and ability to use conventional attack treatment for attacks of
HAE.
5. Adequate organ functions as defined below:
a. Hemoglobin within normal range;
b. International normalized ratio (INR)< 1.2;
c. Activated partial thromboplastin time (aPTT) <= upper limit of
normal (ULN);
d. Creatinine < 1x ULN;
e. Creatinine clearance (CrCl) >= 60 mL/min;
f. Alanine aminotransferase (ALT) <= 2x ULN;
g. Aspartate aminotransferase (AST) <= 2x ULN;
h. Total bilirubin <= 1.5x ULN;
i. Leucocytes <= 1.5x ULN;
j. Thrombocytes <= 1.5x ULN.
6. Female of childbearing potential must agree to use highly effective birth
control from the Screening visit until the end of the trial follow-up
procedures.
7. Females of non-childbearing potential, defined as surgically sterile (status
post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or
post-menopausal for at least 12 months, do not require contraception during the
study.
8. Males with female partners of childbearing potential must agree to be
abstinent or else use a highly effective method of birth control as defined in
inclusion criterion 6 from the Screening visit until the end of the trial
follow-up procedures.
9. Provide signed informed consent and are willing and capable of complying
with study requirements and procedures.
Exclusion criteria
1. Any concomitant diagnosis of another form of chronic angioedema, such as
acquired C1 inhibitor deficiency, HAE with normal C1-INH (also known as HAE
type III), idiopathic angioedema, or
angioedema associated with urticaria.
2. Current use of C1INH, androgens, lanadelumab or tranexamic acid for HAE
prophylaxis.
3. Use of angiotensin-converting enzyme (ACE) inhibitors or any
estrogen-containing medications with systemic absorption (such as oral
contraceptives or hormonal replacement therapy) within
93 days prior to initial study treatment.
4. Use of androgens (e.g. stanozolol, danazol, oxandrolone,
methyltestosterones, testosterone) or antifibrinolytics within 30 days prior to
initial study treatment.
5. Use of lanadelumab within 10 weeks prior to initial study treatment
6. Use of strong CYP3A4/CYP2C9 inhibitors and inducers during participation in
the trial.
Note: These medications include but are not limited to the following:
cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, voriconazole,
ritonavir, boceprevir, telaprevir, troleandomycin, clarithromycin,
carbamazepine, enzalutamide, mitotane, phenytoin,
phenobarbital, fluconazole, isoniazid, metronidazole, paroxetine,
sulfamethoxazole, rifampicin, St. John*s Wort, diltiazem, idelalisib,
nefazodone and nelfinavir.
7. Clinically significant abnormal electrocardiogram (ECG) at Visit 1 and
pre-dose at Visit 2. This includes, but is not limited to, a QTcF > 470 msec
(for women) or > 450 msec (for men), a
PR > 220 msec or ventricular and/or atrial premature contractions that are more
frequent than occasional and/or occur as couplets or higher in grouping.
8. Any clinically significant history of angina, myocardial infarction,
syncope, clinically significant cardiac arrhythmias, left ventricular
hypertrophy, cardiomyopathy, or any other cardiovascular
abnormality.
9. Any other systemic dysfunction (e.g., gastrointestinal, renal, respiratory,
cardiovascular) or significant disease or disorder which, in the opinion of the
Investigator, would jeopardize the
safety of the subject by taking part in the trial.
10. History of substance abuse or dependence that would interfere with the
completion of the study, as determined by the Investigator.
11. Known lactose allergy or intolerance.
12. Known hypersensitivity to KVD900 or placebo or to any of the excipients.
13. Participation in an interventional investigational clinical study within 93
days or within 5 half-lives of the last dosing of investigational drug
(whichever is longer) prior to initial study treatment.
14. Any pregnant or breast-feeding subject.
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 | EUCTR2018-004489-32-NL |
| CCMO | NL69091.018.19 |