Interventionelle Studien

In partnership with the Coalition for Epidemic Preparedness Innovations (CEPI), CureVac AG is developing a new SARS-CoV-2 (mRNA) vaccine formulated with lipid nanoparticles (referred to as CVnCoV). This first-in-human (FIH) Phase 1 trial will evaluate the safety, reactogenicity and immunogenicity of CVnCoV at different dose levels using an adaptive dose-finding design.
This will allow dose escalation or de-escalation using predefined safety criteria and select the CVnCoV dose for further clinical development.

The primary objective of this study is to evaluate the efficacy of 2 remdesivir (RDV) regimens compared to standard of care (SOC), with respect to clinical status assessed by a 7-point ordinal scale on Day 11.

Randomisierte Phase 3 Studie zur Sicherheit und antiviralen Wirksamkeit von Remdesivir bei schwerem Covid-19-Verlauf. Verglichen werden zwei Remdesivir Regime bezüglich des klinischen Verlaufes innerhalb von 14 Tagen.

This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of tocilizumab (TCZ) compared with a matching placebo in combination with standard of care (SOC) in hospitalized patients with severe COVID-19 pneumonia.

Antibody binding sequences are generated using an antibody phage library at the Department of Biotechnology, Technische Universität Braunschweig. These sequences are tested for binding to the receptor binding domain of the viral spike protein and for virus neutralizing capacity in vitro. A lead candidate will then be equipped with a silenced human Fc part in cooperation with the Section of Experimental Antibody Therapy, Department of Immunology, Tuebingen University. This measure will avoid antibody dependent enhancing (ADE) effects that may be responsible for SARS-CoV-2 mediated lung injury. After initial toxicology studies in Collaboration with Bayer, Leverkusen a rapid production approach, will be conducted by Fraunhofer ITEM, Braunschweig to obtain material for a first-in-man study. After approval by the regulatory authority (PEI) the study will be supported and performed by the ZKS of the MHH Hannover and the Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, University Hospital Tuebingen.

Ziel ist die Durchführung einer klinischen Phase-I-Studie, in der eine therapeutische Vakzinierung mit zwei vordefinierten Peptidcocktails (Arm 1: HLA-Klasse II/ Arm 2: HLA-Klasse I) in Kombination mit dem TLR1/2-Agonisten XS15 in Montanide bei Patienten ≥ 65 Jahre mit nachgewiesener SARS-CoV-2-Infektion evaluiert wird. Der primäre Endpunkt der Studie ist die Sicherheit und Verträglichkeit der Kombination aus Peptidvakzine und XS15. Sekundäre Endpunkte sind die SARS-CoV-2 Negativität an den Tagen 3, 7, 15 und 21 nach Vakzinierung, die Hospitalisierungsrate, die Dauer der Hospitalisierung, die Mortalitätsrate (Gesamt- und COVID19-assoziiert-Mortalität innerhalb von 8 Wochen), Anteil an invasiver Beatmung und Intensivaufenthalten, die Induktion von SARS-CoV-2-Antikörpern, die Induktion Peptid-spezifischer T-Zell-Antworten und die Verbesserung der klinischen Symptomatik.

Ziel ist die Durchführung einer klinischen Phase-I-Studie, in der zwei vordefinierte Peptidcocktails (Arm 1: HLA-Klasse II/ Arm 2: HLA-Klasse I) in Kombination mit dem TLR1/2 Agonisten XS15 in Montanide bei Patienten ≥ 75 Jahre mit einem hohen Risiko für schwere Verläufe der COVID-19 Erkrankung präventiv appliziert werden. Der primäre Endpunkt der Studie ist die Sicherheit und Verträglichkeit der Peptid-Vakzine in Kombination mit dem Adjuvanz XS15. Sekundäre Endpunkte sind die Rate der symptomatischen und asymptomatischen Infektionen, die Hospitalisierungsrate bei Infektion, die Dauer der Hospitalisierung, Anteil an invasiver Beatmung und Intensivaufenthalten bei Infektion, die Induktion von SARS-CoV-2-Antikörpern, die Induktion Peptid-spezifischer T-Zell-Antworten innerhalb der Beobachtungszeit der Studie von drei Monaten, sowie als explorative Endpunkte die Mortalitätsrate (Gesamt- und COVID19-assoziiert-Mortalität), die Rate der symptomatischen und asymptomatischen Infektionen, die Hospitalisierungsrate bei Infektion, die Dauer der Hospitalisierung, Anteil an invasiver Beatmung und Intensivaufenthalten bei Infektion sowie der Verlauf von SARS-CoV-2 Antikörpern und Peptid-spezifischer T-Zell-Antworten nach sechs und zwölf Monaten.

The current outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is a global health emergency with a case fatality rate so far approximately 4% and a growing number of confirmed cases (>57.000) in Germany. There is no data available on the efficacy of antiviral agents for the treatment of COVID-19. In-vitro data show that hydroxychloroquine can inhibit SARS-CoV-2 [1] replication and anecdotal reports from Chinese COVID-19 patients [2, 3] suggest that chloroquine is a good candidate for treatment. No data have been published and reported evidence is based on non-controlled use of hydroxychloroquine.

Chloroquine is perhaps one of the most prescribed drugs in the world and in the past
Europeans visiting malaria-endemic areas for decades received chloroquine prophylaxis and
continued it for 2 months after their return. The recommended weight-adapted dose of
hydroxychloroquine (sulfate) for autoimmune diseases is a loading dose of 400-600 mg/day,
followed by 200-400 mg/day with two-monthly controls of laboratory and neurological
parameters. Hydroxychloroquine is used off-label in doses of up to 600 mg/day for the
treatment of several disease including autoimmune diseases (Lee et.al 2011), chronic Q Fever
(600 mg/day) (Van Roeden SE et.al 2018, Raoult D. et.al 1999), Whipple’s disease (600
mg/day for 12 months) (Lagier J.-C & Raoult) and it has been used in amebiasis at similar
doses.
Experiments confirm SARS-CoV-2 uses the angiotensin converting enzyme 2 receptor (ACE2)
as a cellular entry receptor. The anti-malarial and anti-rheumatic drug hydroxychloroquine
seems to be a potential candidate for the treatment of COVID-19 since it is able to block virus
infection by increasing the endosomal pH, required for virus/cell fusion (Wang et.al 2020), it
affects the activation of p38 mitogen-activated protein kinase (MAPK), involved in the
replication of HCoV-229E (Kono et.al. 2008) and can interfere with the terminal glycosylation
of ACE2, thus inhibiting SARS-CoV-2 infection (Vincent et al. 2005). Chloroquine, at an EC50
of 1.1 μM, was found to be effective in preventing replication of this virus (Wang et.al 2020).
Following the in vitro results, several studies on the use of hydroxychloroquine or chloroquine were launched in Chinese hospitals. Supposedly, the first results obtained from more than 100 patients showed the superiority of chloroquine compared with treatment of the control group in terms of reduction of exacerbation of pneumonia, duration of symptoms and delay of viral clearance, all in the absence of severe side effects (Gao et al. 2020). To date, the claimed findings have not been published and it is unclear on what data this is based (e.g. prospective or retrospective). Nonetheless, the multicenter collaboration group in China has recommended chloroquine phosphate tablet, 500 mg twice per day for 10 days for patients diagnosed as mild, moderate and severe cases of novel coronavirus pneumonia and without contraindications to chloroquine (Gao et al. 2020). The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future (Gao et al. 2020). From France, the results of an open-label non-randomized clinical trial using hydroxychloroquine and azithromycin as a treatment of COVID-19 showed that hydroxychloroquine treatment is
significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin (Gautret et al. 2020).
A total of 30 clinical trials are ongoing in China for the use of chloroquine or hydroxychloroquine as a therapeutic option in the treatment of SARS-CoV-2 infection causing COVID-19. However, no trial findings have been published and, with rapid reduction in new cases, it is unclear whether these studies will be completed.
Patients will be randomized in a 1:1 ratio to either hydroxychloroquine or placebo.
Randomization will be done with variable block sizes and allocated to the patient following screening, immediately before the first dose.
Patients and investigators, as well as treating physicians will be blinded to treatment-allocation.

Early diagnosis by testing in an early stage of disease and early intervention by
effective drugs might alter the course of the disease especially in the population most
at risk for severe course of disease.
In a population-based approach, altering the course of disease in this population
most at risk can prevent hospital admissions and intensive care thus alleviating the
pressure on the healthcare system.
In the proposed study patients will be randomized in a 2:1 ratio to either hydroxychloroquine
or placebo.
Patients and investigators, as well as treating physicians will be blinded to treatmentallocation.

1200 patients diagnosed with COVID-19 in Munich are monitored using a non-invasive sensor placed into the external ear canal. The sensor enables continuous measurement of body temperature, oxygen saturation (SpO2), respiratory and heart frequencies as well as the calculation of an autonomic Polyscore.
The transfer device calculates the current risk and automatically transmits the data to the server. If pre-set limits are exceeded, an alarm is automatically triggered at the study centre. Trained specialists (medical students/study nurses) check the plausibility of the current measurement (quality of the PPG raw signal, trends in the last hours). If the alarm triggering measurement is plausible, a physician is contacted who carries out the risk assessment according to an algorithm based on recent experience in China.
The data is transmitted via an encrypted Bluetooth channel to a Raspberry Pi. All data are automatically transmitted to a web server. The primary endpoint is total mortality within two months. Approximately 8% of COVID-19 patients in the over-60 age group are expected to die. To demonstrate a 33% reduction in mortality, the inclusion of 1200 participants in Munich is required (power 80%, α 5%). The control group in another German major city, e.g. Berlin, must be at least as large. The primary endpoint will be compared between groups using a Mantel-Haenszel Test with stratification for sex and age categories.

Background
REMAP-CAP is a trial designed by clinicians who cared for patients and conducted research during the 2009 H1N1 pandemic. Planning began in 2011. REMAP-CAP is supported by multiple government grants.
REMAP-CAP builds on the combined input of the world’s leading ICU trial networks and experts in infectious disease, immunology, critical care, emergency medicine, Bayesian statistics, and clinical trial execution.
These existing networks have enrolled tens of thousands of patients into trials. They have extensive experience designing, conducting, and reporting clinical trials that enroll patients who are severely ill.

Designed for the pandemic
For the past several years, REMAP-CAP has been recruiting patients with severe CAP in the inter-pandemic period. We are currently recruiting in more than 50 ICUs in 13 countries on 3 continents. Another 50 ICUs
are in start-up, and more countries and networks are being added daily. REMAP-CAP was designed to
adapt to an acute pandemic need: that time has come. Changes necessary for the pandemic have been
approved or submitted for approval and we are currently enrolling patients with COVID-19.

Designed to generate answers quickly
REMAP-CAP can recruit without dedicated research staff. The bedside clinician can enroll patients in
minutes. The trial is a Bayesian adaptive platform trial, generating answers to many questions rapidly.
• The platform is multifactorial: each patient can be randomized to multiple treatments.
• It uses frequent interim analyses: a question is concluded as soon as there is sufficient information to
support a conclusion. Analyses can occur every week.
• It detects superiority, inferiority, or equivalence of interventions within the platform.
• Additional interventions are added, as required, based on availability and external evidence.
• By assigning patients to 'recipes' of treatments, only a few patients receive no active therapy.

Current treatments
REMAP-CAP will study, on an open-label basis:
• Antiviral therapy (no antiviral, lopinavir/ritonavir (Kaletra), hydroxychloroquine being added)
• Corticosteroid strategy (no steroid, fixed 7 days, only while in septic shock)
• Immune modulation (no modulator, interferon-beta, anakinra, other agents being added)

The platform can evaluate interactions, e.g. do steroids work only when an active antiviral is administered.
The platform can study ALL hospitalized patients (as is happening in the US) OR coordinate with other preICU hospital-based trials (as is happening in Australia, New Zealand, Canada, and the UK).

Designed to be flexible
REMAP-CAP can co-enroll with other studies. Sites and regions can choose the domains and interventions
from the 'menu' of current questions, and need not adopt all domains or interventions.

Designed to improve outcome for participants
The platform uses response adaptive randomization. After each interim analysis, the weighting of
randomization is modified so that patients are more likely to receive those interventions that are
preforming best.