Primary: To evaluate the tolerability and safety of the treatment with rhC1INH (conestat alfa) on top of Standard Care, for patients with pre-eclampsia.Secondary: To evaluate the efficacy of treatment with rhC1INH (conestat alfa) on top of Standard…
ID
Source
Brief title
Condition
- Maternal complications of pregnancy
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
• Incidence and severity of adverse events
• Number and percentage of patients who discontinue study drug or withdraw from
the study
Secondary outcome
Secondary endpoints:
• Time from start of rhC1INH (conestat alfa) to day of delivery
• Proportion of patients reaching gestation week 37.
Background summary
Pre-eclampsia (PE) is a relatively common complication of pregnancy, marked by
the onset of hypertension and proteinuria in the second or third trimester of
gestation. The symptoms of PE may progress rapidly and, if left untreated, may
be ultimately fatal to the mother and the child. Even when treated, PE is
associated with significantly increased fetal and maternal morbidity.
Currently the only cure for the mother is delivery of the placenta, which means
early delivery of the baby.
C1 esterase inhibitor (C1INH) is an important regulatory protein that controls
several inflammatory cascades. It regulates the complement and contact systems,
and through these pathways C1INH plays an important role in limiting
inflammation reaction and tissue damage. Therefore, it is hypothesized that
C1lNH can impact the PE process.
The current trial intends to evaluate the tolerability and safety of
recombinant human C1 esterase inhibitor (rhC1INH - conestat alfa) in the
patient with PE and further explore the efficacy of such a treatment.
Study objective
Primary:
To evaluate the tolerability and safety of the treatment with rhC1INH (conestat
alfa) on top of Standard Care, for patients with pre-eclampsia.
Secondary:
To evaluate the efficacy of treatment with rhC1INH (conestat alfa) on top of
Standard Care, for patients with pre-eclampsia.
Study design
This is an open label, proof of concept study on the treatment with rhC1INH
(conestat alfa) of patients with pre-eclampsia between 27-34 weeks gestation.
The study will consist of a screening visit, an enrolment visit, a treatment
period and a follow-up period.
As per Standard Care, pregnant patients diagnosed with pre-eclampsia will often
be hospitalized until delivery of the baby. After the diagnosis of PE, patients
will be asked for their interest in participating into the study, and their
Informed Consent Form will be collected if they agree to participate. During
the screening visit, inclusion and exclusion criteria will be verified,
demographics and medical history will be collected. Vital signs will be
recorded, and physical examination will be performed.
If the patient is eligible, she will have an enrolment visit.
Urine and blood samples will be collected to determine baseline safety and
immunologic parameters. Vital signs will be recorded, physical examination,
fetal doppler ultrasound, echocardiography and cardiotocography (CTG) will be
performed.
After re-confirming eligibility, patients will be allocated to a twice weekly,
intravenous (IV) treatment with rhC1INH (conestat alfa) at a dose level of 50
U/kg (based on weight at start of treatment) up to a maximum of 4200 Units in
addition to Standard Care.
To monitor the safety of patients for the first injection of the study
medication, they will stay under close observation for at least two hours after
administration. During that time, additional blood samples will be collected,
in the order to determine the pharmacokinetic profile of rhC1INH (conestat
alfa) in this population.
The first two patients will be treated twice weekly for two weeks. The
following patients will be treated twice weekly, until spontaneous delivery,
induced labor or C-section, followed by one follow-up visit (6 weeks after
delivery). Therefore, the number of treatments will vary per patient.
At each treatment visit, vital signs will be recorded, physical examination
will be performed, patients will be asked about any adverse events, changes in
concomitant medication use and patients will receive their investigational
product. They will be monitored for HELLP syndrome, eclampsia, placental
abruption, and Disseminated Intravascular Coagulation (DIC) throughout the
study.
For regular treatment visits, patients will stay under observation for one hour
after administration of the investigational product.
Every week (once every 2 treatment visits), blood samples and urine samples
will be taken for safety and immunologic parameters.
At every treatment, or more frequently, if clinically indicated, fetal doppler
ultrasound and CTG will be performed. For the first two patients the CTG will
be performed daily. A fetal echocardiography will be performed after 4 weeks of
treatments.
Upon spontaneous delivery, induced labor or C-section, the health of the baby
and the mother will be evaluated, and any abnormalities, neonatal complication
or adverse events will be recorded. Placenta and cord blood samples will be
taken to measure complement activation and inflammation. Blood and urine
samples will be collected. A pediatric echocardiography to be performed within
4 days after delivery.
One follow-up visit will be planned, at 6 weeks after delivery of the baby. At
this follow-up visit, physical examination will be performed, and vital signs
will be taken. The health of both the mother and baby will be evaluated, any
adverse events, hospitalization and changes in concomitant medication use will
be recorded. A pediatric echocardiography will be performed.
Patients who withdraw or are withdrawn from the study prior to delivery of the
baby will be asked to return to the study site for an end of study visit as
soon as possible after the withdrawal decision.
Intervention
Twice weekly open label intravenous treatment with rhC1INH (conestat alfa) at a
dose of 50 U/kg (based on body weight at start of treatment) up to a maximum of
4200 Units on top of Standard Care.
Study burden and risks
There are no suitable treatments available for patients diagnosed with
pre-eclampsia. The Standard Care usually consists of management of the symptoms
and eventually delivery of the baby. In this trial, all patients will receive
Standard Care and rhC1INH (conestat alfa) treatment. All patients will be
hospitalized during the study.
An independent Data and Safety Monitoring Board (DSMB) will be installed to
evaluate, on an ongoing basis, the accumulating safety assessments to ensure
the safety of study patients. The DSMB will also review the conduct of the
study, data on participant recruitment, and data quality including
completeness. The DSMB may also consider factors external to the study when
relevant information becomes available, such as scientific or therapeutic
developments that may have an impact on the safety of the participants or the
ethics of the study. A safety assessment will be done after completion of the
first 2 patients and if no safety concerns are observed, the recruitment will
continue and formal safety evaluation meetings will take place after after 5,
10 and 15 patients complete the study, and ad hoc meetings may also be
scheduled to evaluate any potential urgent safety concerns. After these
meetings, the DSMB will make recommendations to continue, modify, or terminate
the study. Additional details on the DSMB procedures will be defined in the
DSMB charter. The DSMB will consist of a pediatric cardiologist, pediatric
immunologists, statistician and an obstetrics and gynecology specialist.
C1INH is a plasma glycoprotein naturally occurring in the human body. The
recombinant human C1 inhibitor has an identical amino acid sequence to the
human C1INH and it has been proven to be safe and effective for the treatment
of acute angioedema attacks in patients with hereditary angioedema (HAE) at
equivalent dose. It has been approved for the treatment of acute HAE attacks in
adult and adolescent patients in the EEA countries and the United States of
America (USA), and for adults in South Korea and Israel.
After compiling the most recent PSUR (Data lock point 29 October 2018) for
conestat alfa (indication: treatment of acute angioedema attacks in adults and
adolescents with hereditary angioedema due to C1 esterase inhibitor
deficiency), Pharming can now confirm that cumulatively, there were 268
patients that have been exposed to conestat alfa in the clinical program.
Approximately 2400 patients have been commercially prescribed conestat alfa
with more than 93,600 post-marketing doses administered without any change to
the risk-benefit profile.
51 reports were done regarding the use of conestat alfa during pregnancy or
lactation. Review of the new information that became available in the reporting
interval did not suggest any new safety signal regarding the use of conestat
alfa during pregnancy or lactation.
To date, the only known relevant clinical risk associated with rhC1INH
(conestat alfa) is the possibility of an allergic reaction to Host-Related
Impurities (rabbit). Patients with medical history of allergy to rabbits or
rabbit-derived products including rhC1INH (conestat alfa), are excluded from
participation.
To minimize the risk for allergic reactions to rhC1INH (conestat alfa),
patients treated with rhC1INH (conestat alfa) will be monitored for clinical
symptoms of hypersensitivity, all treatments will be administered in the clinic
and all patients will stay under observation for a minimum of 2 hours after
receiving the first injection of investigational product and 1 hour for the
following injections.
The level of risk may evolve over time, during the study: consequently, the
Sponsor and Data Safety Monitoring Board will monitor the safety of all
participants, as well as the continuing validity and scientific merit of the
study.
Darwinweg 24
Leiden 2333 CR
NL
Darwinweg 24
Leiden 2333 CR
NL
Listed location countries
Inclusion criteria
1. Hospitalized pregnant females, aged >= 18 years
2. Singleton pregnancy
3. Between 27 and 34 weeks of gestation
4. Diagnosis of pre-eclampsia defined as hypertension developing after 20 weeks
gestation and the coexistence of one or more of the following new onset
conditions:
a. Proteinuria (spot urine protein/creatinine >=30 mg/mmol [0.3 mg/mg] or >=300
mg/day or at least 1 g/l [*2+*] on dipstick testing)
b. Other maternal organ dysfunction:
- renal insufficiency (creatinine >=90 Umol/l)
- liver involvement (elevated transaminases - at least twice upper limit of
normal ± right upper quadrant or epigastric abdominal pain)
- neurological complications (examples include eclampsia, altered mental
status, blindness, stroke, or more commonly hyperreflexia when accompanied by
clonus, severe headaches when accompanied by hyperreflexia, persistent visual
scotomata)
- hematological complications (thrombocytopenia - platelet count below
150,000/dL, hemolysis))
c. Uteroplacental dysfunction
- fetal growth restriction
5. Provided written informed consent.
6. Willingness and ability to comply with all protocol procedures.
Exclusion criteria
1. Impending Fetal death compromise - absent end-diastolic umbilical artery
flow, pathological CTG
2. Any known fetal abnormality
3. Patients diagnosed with hereditary angioedema (HAE)
4. Medical history of allergy to rabbits or rabbit-derived products (including
conestat alfa)
5. Treatment with any investigational drug during the current pregnancy
6. Patient with known chronic hypertension requiring antihypertensive treatment
7. Patient with abnormalities in their clotting system before pregnancy.
8. Patient with known renal and/or hepatic abnormality before pregnancy
9. Patient with a history of malignancy (except if determined cured or on
remission for at least 5 years)
10. Medical history of any organ transplants
11. Uncontrolled diabetes, defined as HbA1C > 7%
12. Currently treated with statins
13. Any other condition or treatment that, in the opinion of the Investigator,
might interfere with the evaluation of study objectives
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 | EUCTR2018-002904-14-NL |
| CCMO | NL67087.000.19 |