The current outbreak of COVID-19 caused by SARS-CoV-2 is a global health emergency with a case fatality rate so far approximately 4% and a growing number of confirmed cases (>9500) 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 replication and anecdotal reports from COVID-19 patients in China and France suggest that chloroquine or hydroxychloroquine is a good candidate for treatment. In the French study a favourable effect was seen when hydroxychloroquine was used together with azithromycin in a small series of COVID-19 patients. However, so far all published evidence is based on non-controlled use of hydroxychloroquine. We propose to conduct a placebo-controlled trial in COVID-19 patients with mild to moderate disease in Germany to assess virological efficacy, tolerability and safety of hydroxychloroquine in the treatment of COVID-19. The objective of this trial is to identify an effect of hydroxychloroquine on viral clearance in vivo. This data will inform practice for the design of larger trials on clinical efficacy of hydroxychloroquine in the treatment and post-exposure prophylaxis of COVID-19.
The study is a randomized placebo controlled multicentric Phase III trial. The duration of
the trial for each subject is expected to be 6 months. The duration for each individual
subject includes 7 days study treatment and 6 months follow-up time. Recruitment of subjects
will start in April 2020.
Adult male and female patients with positive COVID-19 diagnosis and fulfilling the below
outlined inclusion criteria will be enrolled into the study. Trial population will consist of
both genders.
Name of IMP: Hydroxychloroquine sulfate (HCQ); Quensyl. All consenting adult patients having
confirmed COVID-19 will be recruited and randomly and blindly allocated in a 1:1 ratio to
either IMP or placebo. Each patient will be given a first dose of 800 mg IMP or the
equivalent number of placebo capsules (4 capsules) at the day of inclusion (Day 1). From the
2nd day on, each patient will get 600 mg or the equivalent number if placebo capsules (3
capsules) once a day until day 7 (6 more does of 600 mg). The patient will be given the daily
dose of IMP at once for a total of 7 days.
Patients will be monitored on a daily basis until the endpoint (2 measurements of viral load
below 100 copies at least 24 hours apart) is reached. During admission visits will be
performed by the attending physician or study-nurse, after discharge visits will be performed
by qualified and trained study-personnel. Daily procedures will include a pharyngeal swab for
qPCR diagnostics (until primary endpoint is reached) and symptom assessment by questionnaire
and clinical examination. Blood draw for assessment of full blood count, routine clinical
chemistry and assessment of markers of inflammation, and immune response will be performed on
days 1, 2, 4, 7, 14, 30 and last follow up. ECG and measurement of cardiac enzymes will be
performed on a weekly basis or if clinically indicated to identify new onset arrhythmias.
The efficacy will be assessed by the daily throat swaps and directly followed measurement of
SARS-CoV-2-specific RNA copy number until the result of this test will be below the level of
detection during at least 2 consecutive visits (24h apart).
Safety will be assessed daily by the study physician until the endpoint is reached and at all
subsequent scheduled visits and contacts as well as at any unscheduled visit.
Drug: Hydroxychloroquine Sulfate
Hydroxychloroquine Sulfate is an anti-malarial and anti-rheumatic drug and 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, it affects the activation of p38 mitogen-activated protein kinase (MAPK), involved in the replication of HCoV-229E and can interfere with the terminal glycosylation of ACE2, thus inhibiting SARS-CoV-2 infection.
Drug: Placebo
Placebo capsules
Inclusion Criteria:
- Written informed consent
- Age above 18 years
- Women of childbearing age only: Must agree to practice continuous effective
contraception for the duration of the study (a method which results in a failure rate
less than 1% per year)
- Disease severe enough to require hospitalization
- QTc interval lower than 450 msec
Exclusion Criteria:
- Respiratory rate >24/min
- Pregnancy (tested with a pregnancy test) or lactation
- Weight <50 kg
- Hemodynamic/rhythm instability
- Acute myocardial infarction Type 1
- Use of concomitant medications that prolong the QT/QTc interval.
- Any regular concomitant medication which is contraindicated in the use together with
HCQ
- Hypersensitivity to Hydroxychloroquine, Chloroquine or other 4-Aminoquinolines
- Pre-existing retinopathy or maculopathy
- Known Glucose-6-phosphate dehydrogenase deficiency (haemolytic anaemia, Favism)
- Haematopoietic systems diseases
- Myasthenia gravis
- Any other significant disease, disorder or finding which, in the opinion of the
investigator, may significantly increase the risk to the volunteer because of
participation in the study, affect the ability of the volunteer to participate in the
study or impair interpretation of the study data
Additionally, clinical evaluation and laboratory values inform eligibility of the patient
based on the judgement of the study team. These may include: total bilirubin, transaminase
level, albumin concentration, haematological parameters, troponin and BNP levels,
creatinine, creatinine kinase levels.
Zollernalb Klinikum Balingen
Balingen, Germany
Klinikum Darmstadt
Darmstadt, Germany
Universitätsklinikum Hamburg-Eppendorf
Hamburg, Germany
Johannes Wesling Klinikum Minden
Minden, Germany
Klinikum am Steinenberg
Reutlingen, Germany
RoMed Klinikum Rosenheim
Rosenheim, Germany
Robert-Bosch-Krankenhaus
Stuttgart, Germany
Institute for Tropical Medicine
Tübingen, Germany
Benjamin Mordmüller, Prof., Principal Investigator
University Hospital Tübingen