Norwegian Coronavirus Disease 2019 Study (NO COVID-19)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Corona Virus Infection
• Intervention / Treatment: Drug: Hydroxychloroquine Sulfate

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.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 4

Contacts and Locations

Study Locations

• Norway
  • Lørenskog, Norway, 1478
    • Akershus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Treatment; Chloroquine therapy in addition to standard of care	Drug: Hydroxychloroquine Sulfate; 400 mg hydroxychloroquine sulphate (equalling 310 mg base) twice daily for seven days; Other Names: Plaquenil
NO_INTERVENTION: No Treatment; Standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of decline in SARS-CoV-2 viral load	Viral load assessed by real time polymerase chain reaction in oropharyngeal samples	Baseline (at randomization) and at 96 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in National Early Warning Score score	National Early Warning Score score determines the degree of illness of a patient. Scores range from 0-20, with a higher score representing further removal from normal physiology and a higher risk of morbidity and mortality.	Baseline (at randomization) and at 96 hours
Admission to intensive care unit	Transfer from regular ward to intensive care unit during index admission	At all times after randomization during index admission (between admission and discharge, approximately 21 days)
In-hospital mortality	All-cause mortality during index admission	At all times after randomization during index admission (between admission and discharge, approximately 21 days)
Duration of hospital admission	Total days admitted to the hospital (difference between admission date and discharge date of index admission)	During index admission (between admission and discharge, approximately 21 days)
Mortality at 30 and 90 days	All-cause mortality assessed at 30 and 90 days	At follow-up 30 and 90 days
Clinical status	Percentage of subjects reporting each severity rating on a 7-point ordinal scale: Death; Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen; Not hospitalized, but unable to resume normal activities; Not hospitalized, with resumption of normal activities	14 days after randomization
Change in C-reactive protein concentrations	Change in C-reactive protein concentrations from randomization to 96 hours after randomization	Baseline (at randomization) and at 96 hours
Change in alanine aminotransferase concentrations	Change in alanine aminotransferase concentrations from randomization to 96 hours after randomization	Baseline (at randomization) and at 96 hours
Change in aspartate aminotransferase concentrations	Change in aspartate aminotransferase concentrations from randomization to 96 hours after randomization	Baseline (at randomization) and at 96 hours
Change in bilirubin concentrations	Change in bilirubin concentrations from randomization to 96 hours after randomization	Baseline (at randomization) and at 96 hours
Change in estimated glomerular filtration rate	Change in estimated glomerular filtration rate from randomization to 96 hours after randomization	Baseline (at randomization) and at 96 hours
Change in cardiac troponin concentrations	Change in cardiac troponin concentrations from randomization to 96 hours after randomization	Baseline (at randomization) and at 96 hours
Change in natriuretic peptide concentrations	Change in natriuretic peptide concentrations from randomization to 96 hours after randomization	Baseline (at randomization) and at 96 hours

Collaborators and Investigators

• Sponsor: University Hospital, Akershus
• Investigators: Principal Investigator: Olav Dalgard, MD PhD, Akerhus University Hospital

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 25, 2020
• Primary Completion (ACTUAL): May 25, 2020
• Study Completion (ANTICIPATED): March 3, 2025

Study Registration Dates

• First Submitted: March 13, 2020
• First Submitted That Met QC Criteria: March 18, 2020
• First Posted (ACTUAL): March 20, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 5, 2020
• Last Update Submitted That Met QC Criteria: June 4, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Chloroquine; Pragmatic trial; Corona virus infection
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections; Infections; Virus Diseases; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: REC 121446

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No