Clinical trial NCT04316377: Norwegian Coronavirus Disease 2019 Study
Official title: Norwegian Coronavirus Disease 2019 Study: An Open Labeled Randomized Controlled Pragmatic Trial to Evaluate the Antiviral Effect of Chloroquine in Adult Patients With SARS-CoV-2 Infection
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Corona Virus Infection
Keywords: Corona virus infection
Chloroquine
Pragmatic trial
Lead sponsor: University Hospital, Akershus
Sponsor class: OTHER
First posted: 2020-03-20
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two-arm, open label, pragmatic randomized controlled trial.
Primary purpose: TREATMENT

Brief summary: In the current proposal, the investigators aim to investigate the virological and clinical effects of chloroquine treatment in patients with established COVID-19 in need of hospital admission. Patients will be randomized in a 1:1 fashion to standard of care or standard of care with the addition of therapy with chloroquine.

Detailed description: Chloroquine is one of two therapeutics (in addition to remdesivir) that has demonstrated in vitro inhibitory effects on SARS-CoV-2 and the drug is immediately available from national pharmacies. No delay is accordingly expected in treatment initiation after study commencement. In light of the evidence supporting chloroquine as a promising therapeutic in patients with COVID-19, the expected impact of the current proposal is considerable both in the short- and long-term. If successful, treatment with chloroquine has the potential to be the first evidence based treatment for COVID-19. The drug is affordable and the risk of side effects is low, making it an attractive therapeutic in large proportions of the population on a global scale.

In the current proposal aims to investigate the virological and clinical effects of chloroquine treatment in patients with established SARS-CoV-2 in need of hospital admission. The investigators hypothesize that early treatment with chloroquine in patients with established COVID-19 is safe and will significantly improve prognosis and impact clinical outcomes. More specifically, the investigators hypothesize that early treatment with chloroquine will increase the virological clearance rate of SARS-CoV-2, and lead to more rapid resolve of clinical symptoms, decreased proportion of patients with clinical deterioration and a decreased admission rate to intensive care units and in-hospital mortality. Considering the immediate and worldwide health emergency associated with the SARS-CoV-2 outbreak and the current lack of evidence based medical interventions for this patient group, studies investigating such possible treatment modalities in COVID-19 are direly needed.

The study is a two-arm, open label, pragmatic randomized controlled trial (RCT) designed to assess the virological and clinical effect of chloroquine therapy in patients with established COVID-19. Pragmatic clinical trials are characterized by focus on informing decision-makers on optimal clinical medicine practice and an intent to streamline procedures and data collection in the trial. By utilizing resources already paid for by the hospitals (physicians and nurses in daily clinical practice), pragmatic clinical trials can include a larger number of patients at a short time duration and at a lower cost. Due to the immediate need for study commencement and the time frame of the current proposal, a pragmatic approach will enable swift initiation of randomization and treatment. Data will be extracted from the data warehouse at Akershus University Hospital for eligible patient identification (i.e. electronic surveillance) and for automatic data extraction to the study specific database. The study will not be able to procure an acceptable placebo treatment and the study will accordingly not be placebo-controlled.

All patients at Akershus University Hospital with suspicion of acute respiratory tract infections are examined with a nasopharyngeal swab, with subsequent microbiological examination, including SARS-CoV-2 specific RT-PCR. Participants will be recruited from the entirety of the inpatients at the participating hospitals. Electronic real-time surveillance of laboratory reports from the Department of Microbiology will be examined regularly, with maximum interval 24 hours, for SARS-CoV-2 positive subjects.

The study aims to include patients by a sequential adaptive approach, where analyses are planned after the inclusion of 51 patients, with subsequent analyses after 101, 151 and 202 completed patients. All patients included in each sequence will be used for the final analyses of the entire study. This approach will enable frequent assessment of all outcome measures.

Data will be collected from the hospital electronic record system, including electronic patient records, laboratory and medical imaging systems, and prescribing systems. The data warehouse at Akershus University Hospital will be utilized for automatic data extraction to the study specific database. All clinical variables will be registered in the study eCRF system, including clinical endpoints and quantitative virological results from serial oropharyngeal specimens.

Eligibility criteria: Inclusion Criteria:

* Hospitalised
* Adults 18 year or older
* Moderately severe disease (NEWS score ≤ 6)
* SARS-CoV-2 positive nasopharyngeal swab
* Expected time of admission \> 48 hours
* Signed informed consent must be obtained and documented according to ICH GCP, and national/local regulations.

Exclusion Criteria:

* Requiring ICU admission at screening
* History of psoriasis
* Known adverse reaction to hydroxychloroquine sulphate
* Pregnancy
* Prolonged QT interval (\>450 ms)

Primary outcomes:
measure: Rate of decline in SARS-CoV-2 viral load
timeFrame: Baseline (at randomization) and at 96 hours
Secondary outcomes:
measure: Change in National Early Warning Score score
timeFrame: Baseline (at randomization) and at 96 hours
measure: Admission to intensive care unit
timeFrame: At all times after randomization during index admission (between admission and discharge, approximately 21 days)
measure: In-hospital mortality
timeFrame: At all times after randomization during index admission (between admission and discharge, approximately 21 days)
measure: Duration of hospital admission
timeFrame: During index admission (between admission and discharge, approximately 21 days)
measure: Mortality at 30 and 90 days
timeFrame: At follow-up 30 and 90 days
measure: Clinical status
timeFrame: 14 days after randomization
measure: Change in C-reactive protein concentrations
timeFrame: Baseline (at randomization) and at 96 hours
measure: Change in alanine aminotransferase concentrations
timeFrame: Baseline (at randomization) and at 96 hours
measure: Change in aspartate aminotransferase concentrations
timeFrame: Baseline (at randomization) and at 96 hours
measure: Change in bilirubin concentrations
timeFrame: Baseline (at randomization) and at 96 hours
measure: Change in estimated glomerular filtration rate
timeFrame: Baseline (at randomization) and at 96 hours
measure: Change in cardiac troponin concentrations
timeFrame: Baseline (at randomization) and at 96 hours
measure: Change in natriuretic peptide concentrations
timeFrame: Baseline (at randomization) and at 96 hours
Other outcomes:
Locations:
city: Lørenskog
country: Norway
facility: Akershus University Hospital
Study officials:
affiliation: Akerhus University Hospital
name: Olav Dalgard, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lyngbakken MN, Berdal JE, Eskesen A, Kvale D, Olsen IC, Rueegg CS, Rangberg A, Jonassen CM, Omland T, Rosjo H, Dalgard O. A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. Nat Commun. 2020 Oct 20;11(1):5284. doi: 10.1038/s41467-020-19056-6.
citation: Lyngbakken MN, Berdal JE, Eskesen A, Kvale D, Olsen IC, Rangberg A, Jonassen CM, Omland T, Rosjo H, Dalgard O. Norwegian Coronavirus Disease 2019 (NO COVID-19) Pragmatic Open label Study to assess early use of hydroxychloroquine sulphate in moderately severe hospitalised patients with coronavirus disease 2019: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Jun 5;21(1):485. doi: 10.1186/s13063-020-04420-0.