Primary* To characterize the dynamics of viral clearance (incl. viral cultures, qPCR, antigen clearance) following ensovibep administration * To characterize the serum pharmacokinetics of two single i.v. flat dose levels of ensovibep in patients…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Changes from baseline to each time point of measurement in viral load
(quantitative PCR) and viral cultures, as per assessment schedule
* Duration in days to PCR negativity
* Measurement of ensovibep in serum and assess PK paramenters (including Cmax,
T1/2, Tmax, AUCinf, AUClast, CL, Vss)
Secondary outcome
* Changes in the Assessment of 14 Common COVID-19-Related Symptoms score per
the assessment schedule
* Treatment-emergent (serious) adverse events ((S)AEs) throughout the study at
every study visit
* Adverse events of special interest (AESIs)
* Infusion-related reactions (IRRs)
* Concomitant medication throughout the study at every study visit
* Vital signs (pulse rate (bpm), systolic blood pressure (mmHg), diastolic
blood pressure (mmHg), respiratory rate, temperature (ºC), and oxygen
saturation (%)) as per the assessment schedule
* Clinical laboratory tests (hematology and blood chemistry) as per the
assessment schedule
* Physical examinations (symptom directed) at every study visit
* Assessment of local tolerability at injection site (Visual Infusion Phlebitis
score)
Background summary
Ensovibep (MP0420) is a multi-DARPin® molecule which has been designed to bind
specifically to the receptor binding domains of SARS-CoV-2 coronavirus spike
protein and thus to block binding of the virus to the receptors used by the
virus to enter and infect human cells. Based on preclinical evidence, it is
expected to provide potent anti-SARS-CoV-2 efficacy and an attractive safety
profile. The initial assessment of safety and PK of ensovibep (administered as
60-min infusion) is being performed in study MP0420-CP101, a dose-escalation
study in healthy volunteers, exploring doses of 3, 9, and 20 mg/kg.
The present study will assess the dynamics of viral clearance, PK, and the
tolerability profile of two flat doses (225 and 600 mg, approximately
corresponding to 3 mg/kg and 8 mg/kg in a 75 kg subject) of ensovibep in
patients with symptomatic mild COVID-19 disease in a well-controlled
environment. Viral cultures and quantitative PCR (qPCR) will be assessed to
determine the presence of infective virus versus the time course of the decline
in viral load as measured by qPCR. This will help to guide interpretation of
qPCR in subsequent studies in patients. Furthermore, this phase 2a study will
assess the same virological and clinical outcome parameters as foreseen for
large studies in a comparable ambulatory population. By open-label design, it
will allow rapid awareness of any needs for adjusting these assessments (viral
and clinical, including symptom questionnaires) if applicable for future
patient studies.
Study objective
Primary
* To characterize the dynamics of viral clearance (incl. viral cultures, qPCR,
antigen clearance) following ensovibep administration
* To characterize the serum pharmacokinetics of two single i.v. flat dose
levels of ensovibep in patients with symptomatic COVID-19 disease
Secondary
* To observe the evolution of clinical symptoms for COVID-19 following
ensovibep administration
* To characterize the tolerability of two single i.v. flat dose levels of
ensovibep in patients with symptomatic COVID-19 disease
Study design
This is an open-label, non-comparative phase 2a study, that will include 2
single-dose cohorts
Intervention
Cohort 1:
Ensovibep 225 mg
Cohort 2:
Ensovibep 600 mg
Study burden and risks
Ensovibep is a protein designed to bind the RBD of SARS-CoV-2 coronavirus spike
protein with high affinity. It also binds human serum albumin to extend the
compound half-life in vivo. Ensovibep is anticipated to provide benefit to
patients with ongoing active virus replication, in patients who have not (yet)
activated their own specific immunologic response, and in whom duration and/or
severity of the disease can be expected to be reduced by an antiviral compound.
In addition, ensovibep has potential to provide prophylaxis for subjects at
risk of infection. Ensovibep has no known toxicities and no cross-reactive
binding to any human protein is expected. Up till 9mg/kg it was well tolerated
in a FIH trial in healthy volunteers, and a higher dose level (20 mg/kg) is
planned to be evaluated in February 2021.
Administration of ensovibep has a potential for infusion related reactions
(IRRs), but these are manageable in the clinical setting. Moreover, as the
cognate target of ensovibep does not have any equivalent human expression and
is directed to the viral spike protein, IRRs are considered unlikely. All study
drug administrations will be done in the clinic under medical supervision. The
patients receiving any study drug will remain in the clinic for at least 2
hours after study drug administration. Thus, the patients will be closely
monitored for any adverse signs. Careful observation and medical management
will minimize any associated risk in this study.
Theoretical concerns have also been raised about the potential for
antibody-dependent enhancement (ADE) by DARPin® molecules. ADE occurs when
virus specific antibodies facilitate virus entry into host immune cells
(monocytes, macrophages, granulocytes) that express Fc receptors. It is
hypothesised that enhanced virus replication within these target cells could
exacerbate disease. There is no evidence for this effect of ensovibep in
SARS-CoV-2 infection. Sub-neutralising (or non-neutralising antibodies) have
been implicated in ADE. ADE has generally been seen in conjunction with
vaccines, but by blocking the major antigenic domains DARPin® molecules could
expose sub-neutralising domains and lead to ADE. This risk is theoretical, and
antibody enhancement of disease has not been seen with any other DARPin®
molecules. The risk of ADE is reduced by the multiple binding of the DARPin®
molecule to various epitopes on the spike protein, thus hindering the
recognition of the molecule by the immune system. It is highly unlikely that
this trial will generate evidence to address this theoretical problem, due to
the size and likely low incidence of ADE. Patients will be carefully monitored
for the development of adverse effects that could be due to ADE, and the
prospect of ADE will be explored in the scientific programme.
Wagistrasse 14
Schlieren 8952
CH
Wagistrasse 14
Schlieren 8952
CH
Listed location countries
Age
Inclusion criteria
1. Men or non-pregnant women, between 18 and 70 years on the day of inclusion.
2. Presence of one or more mild or moderate COVID-19 symptoms: Fever, cough,
sore throat, malaise, fatigue, headache, muscle pain, gastrointestinal
symptoms, or shortness of breath with exertion.
3. Positive test for SARS-CoV-2 in upper respiratory swab on the day of dosing
(rapid antigen test).
4. Female subjects must agree to use highly effective contraception as
described in section 4.5.1 of the protocol or must be of non-child bearing
potential. A woman is considered to be of non-childbearing potential if she
meets one of the following criteria:
i. be post-menopausal (spontaneous amenorrhea for at least 12 months); or
ii. has no uterus, ovaries or fallopian tubes.
5. Agree to follow the contraception requirements of the trial as described in
section 4.5.1 of the protocol.
6. Understand and agree to comply with planned study procedures, including
nasopharyngeal swabs and venous blood samples.
7. Able to communicate well with the investigator in the Dutch language and has
provided signed informed consent.
Exclusion criteria
1. Requiring hospitalization at time of screening, or at time of study drug
administration.
2. Oxygen saturation (SpO2) * 93 percent (%) on room air at sea level,
respiratory rate * 30 per minute, or heart rate *125 per minute.
3. Known allergies to any of the components used in the i.v. formulation of
ensovibep.
4. Any serious concomitant systemic disease, condition, or disorder that, in
the opinion of the investigator, should preclude participation in this study.
5. Any co-morbidity requiring hospitalization or surgery within <7 days, or
that is considered life-threatening within 29 days.
6. A patient reported history (prior to the current episode) of a positive
SARS-CoV-2 serology test or a history of PCR confirmed SARS-CoV-2 infection.
7. Prior or concurrent use of SARS-CoV-2 antiviral medication, including
convalescent serum or anti-viral antibodies.
8. Concurrent enrollment in any other type of medical research for improving
COVID-19 outcomes or that is judged by the investigator not to be
scientifically or medically compatible with this study.
9. Women that are currently breast feeding, pregnant, or plan to get pregnant
during the duration of the trial.
10. Severe immunocompromised status (primary immunodeficiency,
supraphysiological dose of systemic corticosteroids, transplant patients, known
untreated HIV and CD4 T-cells <200/microliter) or use of any immunosuppressants
that, in the opinion of the investigator, should preclude participation in this
study.
11. Subjects at high risk for of COVID-19 related complications or mortality,
defined as:
a. Age 50 to 70 years and at least one of the following other risk factors:
i. BMI >35 kg/m2
ii. Chronic Cardiac or pulmonary disease (e.g. atrial fibrillation, CAD, heart
failure, COPD, asthma), that might pose additional risks in study
participation, as per investigator decision
iii. Ongoing clinically significant neurological disease (e.g. stroke or any
other chronic debilitating neurological disease)
iv. Chronic kidney disease with GFR <60 ml/min, as per medical history
v. Rheumatic disease (e.g. rheumatoid arthritis, Systemic lupus erythematosus,
psoriatic arthritis)
vi. Cancer not in complete remission for >1 year (excluding baso -or
spinocellular skin cancers)
vii. Chronic liver disease (liver cirrhosis Child Pugh A/B/C or other disease
leading to liver dysfunction) as per medical history
b. Age < 50 years with 3 or more of the above-mentioned risk factors.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.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 | EUCTR2021-000365-33-NL |
| CCMO | NL76642.058.21 |