Part ATo evaluate the safety and tolerability of single and split intravenous doses of Apta-1 in healthy volunteers.Part BTo evaluate the safety and tolerability of split intravenous doses of Apta-1 after LPS infusion in healthy volunteers.
ID
Source
Brief title
Condition
- Immune disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Parts A+B
• Treatment-related (serious) adverse events ([S]AEs).
• Concomitant medication.
• Vital signs: Systolic blood pressure (mmHg), diastolic blood pressure (mmHg),
heart rate (bpm), respiratory rate (bpm), body temperature (°C).
• Clinical laboratory tests: hematology, coagulation, blood chemistry and
urinalysis as listed in section 6.1.5.
• Electrocardiogram (ECG) parameters (Heart Rate (HR) (bpm), PR, QRS, QT,
QTcF).
Secondary outcome
Part A
Single intravenous dose administration (cohort 1):
o AUCinf, AUCinf(%extrap), AUClast, AUC0-1h, CL, Cmax, t1/2, tmax, tlast, Vz.
o Dose-normalized PK parameters: AUCinf, AUClast, Cmax.
Single intravenous dose with split (two equal doses) administration (cohort
2-6):
o AUC0-1h, AUCinf, AUCinf(%extrap), AUClast, CL, Cmax-dose1, Cmax-dose2,
t1/2, tmax, tlast, Vz.
o Dose-normalized PK parameters on total dose: Cmax, AUCinf, AUClast
o Dose-normalized PK parameters on separate dose: AUC0-1h, Cmax-dose1,
Cmax-dose2
Part B
Single intravenous dose with split (two equal doses) administration:
o AUC0-1h, AUCinf, AUCinf(%extrap), AUClast, CL, Cmax-dose1, Cmax-dose2, t1/2,
tmax, tlast, Vz.
o Dose-normalized PK parameters on total dose: AUCinf, AUClast
o Dose-normalized PK parameters on separate dose: AUC0-1h, Cmax-dose1,
Cmax-dose2
Background summary
Sepsis, including septic shock, is a dysregulated immunological host response
to infection leading to life-threatening organ dysfunction. It is a worldwide
leading cause of critical illness and mortality and, with its increasing
incidence, a major public health concern accounting for more than $20 billion
(5.2%) of total United States hospital costs in 2011. Despite decades of
clinical experience and research, we still lack approved treatments
specifically targeting sepsis or septic shock. This condition remains a
significant challenge as it frequently results in high morbidity and mortality.
Currently applied treatments exist of supportive care, for instance fluid
resuscitation, antibiotics, vasopressors, and organ replacement therapy.
Apta-1, an aptamer which is a mixture of single-stranded ribonucleic acid
(RNA)-oligonucleotides, is proposed as a new treatment for sepsis and septic
shock. This first-in-human study will primarily assess the safety and
tolerability and pharmacodynamic activity of Apta-1 in healthy volunteers. As
additional objective, its effects on systemic LPS challenges, resulting in a
systemic inflammatory response, will be evaluated.
Study objective
Part A
To evaluate the safety and tolerability of single and split intravenous doses
of Apta-1 in healthy volunteers.
Part B
To evaluate the safety and tolerability of split intravenous doses of Apta-1
after LPS infusion in healthy volunteers.
Study design
This is a first-in-human, randomized, double-blind, placebo-controlled, single,
and split ascending dose study, consisting of two parts (part A and part B).
Part A - Safety, tolerability, pharmacokinetics and pharmacodynamic effects of
a single dose of Apta-1
Part B - Exploration of safety, tolerability, pharmacokinetics and
pharmacodynamic effects of a single dose of Apta-1 with LPS as a challenge
agent.
Intervention
Apta-1 or placebo
Study burden and risks
This is a study in healthy volunteers, so no direct benefit is expected for
participants. For a structured risk assessment see Section 10 of the protocol.
Healthy males and female, women of childbearing potential (WOCBP) and women of
non-childbearing potential (WONCBP) volunteers are recruited for this study,
which is deemed an appropriate population for this first-in-human study. The
in- and exclusion criteria (see section 4.2 and 4.3 of the protocol) have been
defined to minimize associated risks to the mechanism of action of the IMP
and/or study procedures.
Norra Vallgatan 58
Malmo 211 22
SE
Norra Vallgatan 58
Malmo 211 22
SE
Listed location countries
Age
Inclusion criteria
1. Has the ability to communicate well with the Investigator in the Dutch
language and is willing and able to comply with all study procedures and give
written informed consent prior to any study-mandated procedure.
2. Healthy male and female subjects,18 to 55 years of age, inclusive, at
screening.
3. Body mass index (BMI) between 18 and 30 kg/m2 and with a weight between 50
and 100 kg, both inclusive, at screening.
4. Female subjects of childbearing potential and male subjects who have sexual
intercourse with a woman of childbearing potential must be willing to practice
effective contraception (see paragraph 4.5.1.) during the study and be willing
and able to continue contraception for respectively at least 180 days (females)
and 90 days (males) after their last dose of study treatment.
Women of childbearing potential are defined as all women physiologically
capable of becoming pregnant, unless they meet one of the following conditions:
• Post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 weeks
after surgical bilateral oophorectomy with or without hysterectomy;
• Post-hysterectomy.
Exclusion criteria
1. Evidence of any active or chronic disease or condition (e.g. history of
sepsis, cardiovascular disease, syncope or malignancy) that could interfere
with, or for which the treatment of might interfere with, the conduct of the
study, or that would pose an unacceptable risk to the subject in the opinion of
the investigator (following a detailed medical history, physical examination,
vital signs (systolic and diastolic blood pressure, pulse rate, body
temperature) and 12-lead electrocardiogram (ECG)). Minor deviations from the
normal range may be accepted, if judged by the Investigator to have no clinical
relevance.
2. Clinically significant abnormalities, as judged by the investigator, in
laboratory test results (including hepatic and renal panels, complete blood
count, chemistry panel and urinalysis). In the case of uncertain or
questionable results, tests performed during screening may be repeated before
randomization to confirm eligibility or judged to be clinically irrelevant for
healthy subjects.
3. Hemorrhagic diathesis (e.g. nose bleeds, mucosal bleedings, easy bruising,
gastrointestinal bleeding, menorrhagia), as judged by the investigator.
4. Use of any prescription or OTC medications, antibiotics, NSAIDs (such as
ibuprofen), aspirin, anti-platelet therapy, anti-coagulation therapy,
prophylactic and therapeutic LMWH or un-fractioned heparin within 4 weeks, or 5
half-lives (whichever is longer), prior to first IMP administration. Exception
for prescription contraceptives.
5. Any active or ongoing chronic inflammatory or infectious disease including
periodontitis except for common viral or fungal skin infections such as plantar
warts or athlete*s foot.
Additional criteria for part B:
1. Previous participation in a systemic (i.v./inhaled) LPS challenge trial or
prior exposure to systemic endotoxin within a year before LPS administration in
this study.
2. Significant risk or history of cardiac failure, overfilling and/or
developing edema.
3. Estimated glomerular filtration rate (eGFR) of <90mL/min/1.73m2.
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 | EUCTR2022-002473-28-NL |
CCMO | NL81960.056.22 |