Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT04332666 |
| Other study ID # |
P2020/201 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
December 30, 2021 |
| Est. completion date |
June 15, 2023 |
Study information
| Verified date |
August 2020 |
| Source |
Erasme University Hospital |
| Contact |
filippo annoni, MD |
| Phone |
0032(0)483141483 |
| Email |
filippo.annoni[@]erasme.ulb.ac.be |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Background: A novel Coronavirus (SARS-CoV-2) described in late 2019 in Wuhan, China, has led
to a pandemic and to a specific coronavirus-related disease (COVID-19), which is mainly
characterized by a respiratory involvement. While researching for a vaccine has been started,
effective therapeutic solutions are urgently needed to face this threaten. The
renin-angiotensin system (RAS) has a relevant role in COVID-19, as the virus will enter host
's cells via the angiotensin-converting enzyme 2 (ACE2); RAS disequilibrium might also play a
key role in the modulation of the inflammatory response that characterizes the lung
involvement. Angiotensin-(1-7) is a peptide that is downregulated in COVID-19 patient and it
may potentially improve respiratory function in this setting.
Methods/Design: The Investigators describe herein the methodology of a randomized,
controlled, adaptive Phase II/Phase III trial to test the safety, efficacy and clinical
impact of the infusion of angiotensin-(1-7) in COVID-19 patients with respiratory failure
requiring mechanical ventilation. A first phase of the study, including a limited number of
patients (n=20), will serve to confirm the safety of the study drug, by observing the number
of the severe adverse events. In a second phase, the enrollment will continue to investigate
the primary endpoint of the study (i.e. number of days where the patient is alive and not on
mechanical ventilation up to day 28) to evaluate the efficacy and the clinical impact of this
drug. Secondary outcomes will include the hospital length of stay, ICU length of stay, ICU
and hospital mortality, time to weaning from mechanical ventilation, reintubation rate,
secondary infections, needs for vasopressors, PaO2/FiO2 changes, incidence of deep vein
thrombosis, changes in inflammatory markers, angiotensins plasmatic levels and changes in
radiological findings. The estimated sample size to demonstrate a reduction in the primary
outcome from a median of 14 to 11 days is 56 patients, 60 including a dropout rate of 3%
(i.e. 30 per group), but a preplanned recalculation of the study sample size is previewed
after the enrollment of 30 patients.
Expected outcomes/Discussion: This controlled trial will assess the efficacy, safety and
clinical impact of the Angiotensin-(1-7) infusion in a cohort of COVID-19 patients requiring
mechanical ventilation. The results of this trial may provide useful information for the
management of this disease.
Description:
Rationale for the study The cellular entry of the SARS-CoV-2 can result in a functional
reduction of ACE2 activity and this could lead to an increased activity of the Ang II/AT1
axis and decreased levels Ang-(1-7)/MasR expression that could contribute to the severity of
the disease. The administration of Ang-(1-7) could reestablish this equilibrium, contributing
to decrease pulmonary inflammation e thus decreasing the symptoms of the disease.
Eligible patients and the next of kin (whenever possible) should be informed about the
rationale and the aims of the study and potential risks of drug infusion. Local ethical
regulations should be otherwise followed. Due to the eligibility criteria and the urgency
setting, a delayed written consent may be obtained after randomization from the next of kin
and/or the patient (i.e. after ICU discharge).
Randomization will be performed using sealed envelopes with a ratio of 1:1 including
information on treatment assignment and a five-digit number, which will be open by the person
responsible for drug constitution. Each vial or syringe will be then labeled with the
randomly allocated number it will be assigned to the nursing personnel. The doctors and
nurses administering the drugs, as well as the local investigators and research personnel who
collected data, were unaware of the treatment assignments. Randomization should occur within
24 hours since orotracheal intubation and drug infusion initiated within 4 hours from
randomization.
Trial will be conducted in adherence to the current Helsinki Declaration and the standard of
good clinical practice. Screening of patients will only start after approval of the ethical
committees (EC) in the trial sites. No deviation of the protocol will be implemented without
the prior review and approval of the ECs.
Study Treatment Ang-(1-7) is a pre-constitute intravenous lyophilized formulation containing
0.5 mg/ ampoule and will be administered to patients via a dedicated central venous line at
the initial dose of 0.1 mcg/Kg/h (equivalent to 2.5 mcg/Kg/day). After the first hour of
infusion, if no decrease in mean arterial pressure (decrease superior to 30% or need to
increase vasopressors ≥ 50% of an initial dosage to maintain a MAP ≥ 65mmHg), the infusion
rate will be increased to 0.2 mcg/Kg/h (equivalent to 5 mcg/Kg/day). The infusion will be
continued for up to 48 hours and then stopped. To this end, the substance solution,
prepackaged, will be diluted in 1000ml of NaCl 0.9% and then infused using an infusion pump
at corresponding speed. The placebo substance, made up of the vehicle alone, will also be
intravenously administrated using the same procedure as that for the substance containing the
active principle.
Patient's management Management of any underlying comorbidity will be at discretion of the
attending physicians; the use of international guidelines for the monitoring and the adequate
therapeutic interventions are recommended in all patients.
In particular, patients ventilation should be managed according to ATS/ESICM/SCCM 2017
consensus for the ventilation in ARDS patients which suggest low tidal volume ventilation
(4-8 mL/Kg predicted body weight) associated with low plateau pressure (<30 cmH2O), high
positive end-expiratory pressure (PEEP) associated with recruitment maneuvers and prone
positioning for periods longer than 12h in severe ARDS patients. Arterial gas analysis
assessment should be performed at maximum intervals of six hours or more often according to
the attending physician beliefs. Maintenance fluid should be chosen among balanced
crystalloids and the quantity will be decided by the attending physician. Glucose management,
nutrition protocols, decision to administer neuromuscular blockade, prone positioning, ECMO,
nitric oxide or any other adjunctive therapies will be continued according to center current
clinical practice and will be recorded in the CRF file.
Weaning procedure Regarding the weaning from mechanical ventilation, in order to standardize
and reduce bias we will comply with the following procedures based on ARDS Network protocol
(ARDSnet).
Each day the patients enrolled will be assessed by the medical staff for the following
weaning criteria:
1. FiO2 ≤ 0.40 and PEEP ≤ 8 cmH2O OR FiO2 < 0.50 and PEEP < 5 cmH2O
2. PEEP and FiO2 ≤ values of previous day.
3. No neuromuscular blocking agents
4. Patient has acceptable spontaneous breathing efforts (It will be allowed to decrease the
respiratory rate on the ventilator up to 50% for 5 min to detect inspiratory effort)
5. Systolic BP ≥ 90 mmHg
If all the above conditions will be met, medical staff will start a spontaneous breathing
test (SBT) for up to 120 minutes using one of the following methods and maintaining a: FiO2 ≤
0.5:
1. T-piece Tube
2. Pressure Support Ventilation ≤ 5 cmH2O with PEEP ≤ 5 cmH2O
3. CPAP with PEEP ≤ 5 cmH2O
4. Tracheal Collar mask
To test the tolerance at such measures the medical staff will evaluate the following goals
for a minimum of 30 minutes up to 120 minutes:
1. SpO2 ≥ 90% and / or PaO2 ≥ 60 mm Hg
2. Mean spontaneous tidal volume ≥ 4 ml/kg PBW (if measured)
3. Respiratory Rate ≤ 35 / min
4. pH ≥ 7.30 (if measured)
5. No respiratory distress (defined as 2 or more of the following):
1. Heart rate ≥ 120% of the rate (≤ 5 min at > 120% may be tolerated)
2. Marked use of accessory muscles
3. Abdominal paradox
4. Diaphoresis
5. Marked subjective dyspnea
If all these goals will be met, the medical staff will consider extubation, otherwise the
patient will be treated with the pre-weaning settings.
Data Collection Data collection on admission will include: demographic characteristics,
comorbidities, including use of antihypertensive medications, source of admission, primary
and secondary diagnosis, delay since symptoms begin, APACHE II Score (the worst values within
the first 24 hours), SOFA score on admission, Chest X-ray and Thoracic CT scan results if
available, EKG trace, PaO2/FiO2 on admission. Daily data collection during ICU stay will
include: continuous hemodynamic monitoring, including invasive arterial pressure monitoring
and continuous EKG; SaO2 and PaO2/FiO2 every 2 hours; blood samples including Hb, glucose and
several other chemical variables will be collected at least once per day at 8 am (or the
first value of the day); ventilatory parameters and arterial gas analysis will be also
collected every six hours; SOFA score; presence of any other documented infection (site,
pathogen, treatment); presence of septic shock; daily diuresis and daily total fluid
infusion, urine analysis including main electrolytes (sodium, potassium, chloride, calcium)
and osmolarity every morning. The occurrence of serious adverse events (see specific
paragraph in the text). Duration of ICU stay, duration of mechanical ventilation, need for
tracheostomy. In case of death, reasons for withdrawal of care will be recorded. All the data
will be recorded using the specific CRF forms, divided into a core section and a daily
section and will be uploaded to a web-centralized protected database.
Statistical Analysis
First phase (Phase IIb) = 15 vs 15 patients Second phase (Phase III) = expected 30 vs 30
patients in total (recalculation of sample size after 15 vs. 15 patients included)
The primary outcome of this study is the number of ventilator free days at day 28.
Considering an expected median duration of mechanical ventilation in COVID-19 related
respiratory insufficiency patients of 14 days, to provide an absolute reduction of 22,5% with
an alpha error of 0.05 and to provide a power to detect the effect of 80% and a dropout rate
of 3%, 60 patients will need to be included in the primary analysis, 30 in each group.
Pre-planned Stratified group analysis will be performed for the following group of patients:
1. History of hypertension vs. no history of hypertension
2. Treatment with ACEi, ARB or DRI drugs vs no treatment
3. Age (<65 vs. ≥ 65 years)
4. PaO2/FiO2 values at randomization (<100 vs ≥ 100)
5. Confirmed vs highly suspected COVID-19
Data Safety Management Members of the Data Safety Monitoring Committee (DSMC) are individuals
free of conflicts of interest for this protocol; DSMC will analyze the safety of the study
and their membership within the DSMC will be for the duration of this clinical trial. Serious
Adverse Events (SAEs) will be recorded at the participating site on the specific CRF and
their occurrence will be monitored by the DSMC at the different interim analysis. Formal
meeting will be held for each interim analysis to review the data related to the primary
outcome, the safety findings as well as the quality of the trial conduct. To enhance the
integrity of the trial, the DSMC will have access to the different results aggregated by
treatment group and remain unaware of the treatment assignment (the groups will be encoded as
A and B). A report including data on recruitment and baseline characteristics and pooled data
on eligibility violations will be prepared by the statistician for each DSMC meeting. Only
the independent statistician will have access to the whole database. A closed report will be
then prepared to allow confidential discussion of clinical data and the DSMC has to prepare
minutes of their meetings, with a list of recommendations for the Steering Committee (to
continue, to hold or to terminate the trial). If the recommendation is to stop the trial, a
final decision will be made after the analysis of all patients included at the time
(including patients randomized after data collection for the DSMC meeting). The Steering
Committee will be responsible for deciding whether to continue, hold or stop the trial based
on DSMC recommendations. The DSMC will be notified of all changes to the trial protocol or
conduct.
Organization Data will be recorded using pre-printed CRF by the attending physician or a
trained research nurse. All data will be periodically introduced by trained personnel in the
central web-based database. The study coordinator will contact each time a patient is
included the local PI to ensure data collection and reporting as well as completion of
patient follow-up or on premature termination of the study protocol. The individual data
provided by a participating ICU are primarily property of the ICU who generated the data. All
investigators have the right to access their data every time.
The Principal Investigators of the study have the responsibility to perform periodic and spot
checks visits to monitor the progress of the clinical study. Completed CRFs will be reviewed
for completeness, compliance with investigation plan and appropriate device use and
accountability. Case report forms will be uploaded on a website with the help of an
independent statistician, which will be overseen data entry and data quality management. Data
on safety will be provided to the DMSC with regular time intervals. The steering committee
will review study integrity, safety and risk/benefit issues after 25 included patients. The
rate of these reviews could increase according to report of relevant safety issues.
Independent analyses of serious adverse events will be performed and adjudicated if the
frequency or nature of serious adverse events warrants it.
