Norwegian Coronavirus Disease 2019 Study (NO COVID-19)

• ClinicalTrials.gov Identifier: NCT04316377
• Recruitment Status: Active, not recruiting
• First Posted: March 20, 2020
• Last Update Posted: June 5, 2020
• Sponsor: University Hospital, Akershus
• Information provided by (Responsible Party): Olav Dalgard, University Hospital, Akershus

Tracking Information

• First Submitted Date: March 13, 2020
• First Posted Date: March 20, 2020
• Last Update Posted Date: June 5, 2020
• Actual Study Start Date: March 25, 2020
• Actual Primary Completion Date: May 25, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2020)

Rate of decline in SARS-CoV-2 viral load [ Time Frame: Baseline (at randomization) and at 96 hours ]

Viral load assessed by real time polymerase chain reaction in oropharyngeal samples

Original Primary Outcome Measures (submitted: March 18, 2020)

Rate of decline in SARS-CoV-2 viral load [ Time Frame: Baseline (at randomization) and at 96 hours ]

Viral load assessed by real time polymerase chain reaction in nasopharyngeal samples

Current Secondary Outcome Measures (submitted: June 4, 2020)

• Change in National Early Warning Score score [ Time Frame: Baseline (at randomization) and at 96 hours ]
  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.
• Admission to intensive care unit [ Time Frame: At all times after randomization during index admission (between admission and discharge, approximately 21 days) ]
  Transfer from regular ward to intensive care unit during index admission
• In-hospital mortality [ Time Frame: At all times after randomization during index admission (between admission and discharge, approximately 21 days) ]
  All-cause mortality during index admission
• Duration of hospital admission [ Time Frame: During index admission (between admission and discharge, approximately 21 days) ]
  Total days admitted to the hospital (difference between admission date and discharge date of index admission)
• Mortality at 30 and 90 days [ Time Frame: At follow-up 30 and 90 days ]
  All-cause mortality assessed at 30 and 90 days
• Clinical status [ Time Frame: 14 days after randomization ]
  Percentage of subjects reporting each severity rating on a 7-point ordinal scale:

  1. Death
  2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation
  3. Hospitalized, on non-invasive ventilation or high flow oxygen devices
  4. Hospitalized, requiring supplemental oxygen
  5. Hospitalized, not requiring supplemental oxygen
  6. Not hospitalized, but unable to resume normal activities
  7. Not hospitalized, with resumption of normal activities
• Change in C-reactive protein concentrations [ Time Frame: Baseline (at randomization) and at 96 hours ]
  Change in C-reactive protein concentrations from randomization to 96 hours after randomization
• Change in alanine aminotransferase concentrations [ Time Frame: Baseline (at randomization) and at 96 hours ]
  Change in alanine aminotransferase concentrations from randomization to 96 hours after randomization
• Change in aspartate aminotransferase concentrations [ Time Frame: Baseline (at randomization) and at 96 hours ]
  Change in aspartate aminotransferase concentrations from randomization to 96 hours after randomization
• Change in bilirubin concentrations [ Time Frame: Baseline (at randomization) and at 96 hours ]
  Change in bilirubin concentrations from randomization to 96 hours after randomization
• Change in estimated glomerular filtration rate [ Time Frame: Baseline (at randomization) and at 96 hours ]
  Change in estimated glomerular filtration rate from randomization to 96 hours after randomization
• Change in cardiac troponin concentrations [ Time Frame: Baseline (at randomization) and at 96 hours ]
  Change in cardiac troponin concentrations from randomization to 96 hours after randomization
• Change in natriuretic peptide concentrations [ Time Frame: Baseline (at randomization) and at 96 hours ]
  Change in natriuretic peptide concentrations from randomization to 96 hours after randomization

Original Secondary Outcome Measures (submitted: March 18, 2020)

• Change in National Early Warning Score score [ Time Frame: Baseline (at randomization) and at 96 hours ]
  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.
• Admission to intensive care unit [ Time Frame: At all times after randomization during index admission (between admission and discharge, approximately 21 days) ]
  Transfer from regular ward to intensive care unit during index admission
• In-hospital mortality [ Time Frame: At all times after randomization during index admission (between admission and discharge, approximately 21 days) ]
  All-cause mortality during index admission
• Duration of hospital admission [ Time Frame: During index admission (between admission and discharge, approximately 21 days) ]
  Total days admitted to the hospital (difference between admission date and discharge date of index admission)
• Mortality at 30 and 90 days [ Time Frame: At follow-up 30 and 90 days ]
  All-cause mortality assessed at 30 and 90 days
• Clinical status [ Time Frame: 14 days after randomization ]
  Percentage of subjects reporting each severity rating on a 6-point ordinal scale:

  1. Death
  2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation
  3. Hospitalized, on non-invasive ventilation or high flow oxygen devices
  4. Hospitalized, requiring supplemental oxygen
  5. Hospitalized, not requiring supplemental oxygen
  6. Not hospitalized

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Two-arm, open label, pragmatic randomized controlled trial.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Corona Virus Infection

Intervention

Drug: Hydroxychloroquine Sulfate

400 mg hydroxychloroquine sulphate (equalling 310 mg base) twice daily for seven days

Other Name: Plaquenil

Study Arms

• Active Comparator: Treatment
  Chloroquine therapy in addition to standard of care
  Intervention: Drug: Hydroxychloroquine Sulfate
• No Intervention: No Treatment
  Standard of care

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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 3, 2020): 53
• Original Estimated Enrollment (submitted: March 18, 2020): 202
• Estimated Study Completion Date: March 3, 2025
• Actual Primary Completion Date: May 25, 2020 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Norway

Administrative Information

• NCT Number: NCT04316377
• Other Study ID Numbers: REC 121446
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Olav Dalgard, University Hospital, Akershus
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital, Akershus
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Olav Dalgard, MD PhD; Akerhus University Hospital

• PRS Account: University Hospital, Akershus
• Verification Date: June 2020