Chloroquine, Hydroxychloroquine or Only Supportive Care in Patients AdmItted With Moderate to Severe COVID-19 (ARCHAIC)

An Open Label Cluster Randomized Controlled Trial of Chloroquine, Hydroxychloroquine or Only Supportive Care in Patients AdmItted With Moderate to Severe COVID-19

Rationale: Currently there are no approved treatments for COVID-19. In the Dutch treatment protocol guideline (SWAB) designated treatment is supportive care with the option to add chloroquine base (CQ) or hydroxychloroquine (HCQ). CQ and HCQ are implemented because of their in vitro activity, results from small animal studies, and anecdotal patient's data. There are no published randomized studies with these medications in patients with disease caused by any coronavirus.

Objective: To evaluate if treatment with only supportive care or addition of one of two anti-COVID_19 agents (chloroquine or hydroxychloroquine) results in less disease progression in patients with moderate to severe COVID-19 who require hospital admission.

Study design: Multicentre, cluster randomized cross-over, open label trial. Hospitals will be randomly allocated to one of 3 treatment arms in sequential periods of one week: chloroquine base versus hydroxychloroquine versus supportive care without any drug presumed active against SARS-COV-2. Patients will be treated based on the date of inclusion.

Study population: Adults aged of 18 years and older with moderate to severe, with a NEWS-2 score ≤ 5, laboratory confirmed COVID-19, who require hospital admission in a ward outside the Medium Care or Intensive Care.

Intervention (if applicable): Depending on the treatment arm, the study subject will receive only supportive care or an addition with one of the two agents active against SARS-CoV-2 (chloroquine or hydroxychloroquine).

Main study parameters/endpoints: Disease progression defined as a NEWS-2 score ≥ 7 within 14 days, or admission to Medium Care or Intensive Care Unit, or death.

Study Overview

• Status: Terminated
• Conditions: COVID-19
• Intervention / Treatment: Drug: Chloroquine Sulfate; Other: Standard supportive care; Drug: Hydroxychloroquine

Detailed Description

Study rationale CQ and HCQ were both employed in the treatment of COVID-19 in China. Based on unpublished anecdotal positive results in China, CQ is now implemented in China and the Netherlands in severe COVID-19. HCQ is an analog of CQ with more anti-viral effectivity ex vivo, better safety and tolerability profile.

Rationale for the employment of CQ and HCQ in China comes from the fact that both reduce COVID-19 replication ex-vivo. On top of this, both drugs have clear immunomodulating effects (which is used for various indications to treat rheumatologic diseases) and have shown promising results in patients with dengue and HIV.

Currently, in the Dutch guidelines, for moderate severely ill patients CQ base is the first line of therapy for patients admitted in hospital with moderate to severe COVID-19.

The time needed to "load" the body when using CQ and thus the possible late onset of action suggests that initiation of treatment should be timely. Moreover, the hypothesized mode of action suggests that both HCQ and CQ inhibit cellular replication of COVID-19 but do not have an intrinsic effect on the virus, thus could be best employed when the viral load is low (i.e. early phase of the disease) and thus safe time to improve the subsequent immune response. This underlines that both drugs should be implemented early rather than late in the course of SARS-COV-2 infection.

The investigators propose a cluster randomized controlled study evaluating the value of chloroquine and hydroxychloroquine compared to no antiviral therapy in admitted patients with moderate to severe COVID-19.

Study design:

Population Adult patients with confirmed COVID-19, with moderate to severe symptoms and admitted to the hospital and a NEWS-2 score ≤ 5, will be available for the study.

Intervention

All three treatment arms contain standard supportive care during hospital admission with in two arms an addition with either chloroquine (CQ) or hydroxychloroquine (HCQ) Despite the inclusion of CQ and HCQ as possible additional treatment for COVID-19 in the Dutch treatment guideline, there's no conclusion on the best treatment strategy in this population. Based on pharmacokinetic modelling, and the safety profile, HCQ seems to be more promising than CQ, but both drugs have to be studied in relation to COVID-19. Furthermore, the availability of both drugs might differ from country to country; in the Netherlands for instance, chloroquine is widely available. Therefore, a 1:1:1 trial including standard supportive care with in addition CQ or HCQ as suggested in the LCI/SWAB guideline, the optimal dosages in the different treatment arms are as follows:

1. Supportive care + chloroquine base arm: loading dose 600mg, followed by 300mg 12 hours later, followed by 300mg bid for 4 days; total treatment duration of 5 days
2. Supportive care + hydroxychloroquine arm: loading dose 400mg bid, followed by 200mg bid for 4 days; total treatment duration of 5 days.
3. Supportive care only. Dosage of chloroquine and Hydroxychloroquine will be adjusted, if the patients has a renal impairment with an estimated glomerular filtration rate (eGDR) <10, to 50% of the initial dosage.

If patient will be discharged from hospital before the end of the treatment, treatment is continued outside of the hospital. The general practitioner will receive note of the treatment at discharge.

Main studyendpoint Composite endpoint with disease progression defined as a NEWS2score ≥ 7 within 14 days or resulting in admission to Intensive/Medium Care unit or resulting in death within 14 days.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht, Netherlands, 3508GA
    • UMCU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 110 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• - Patients (≥18 years of age) admitted to the hospital with confirmed COVID-19 and not needing admission to MC or ICU
• Patient has moderate to severe COVID-19. This will be defined as patients with NEWS-2 score ≤ 5.
• Willing and able to give written informed consent

Exclusion Criteria:

• - Severe Covid-19 defined as NEWS-2 score >5 or admission to the ICU needing ventilation or pressure support.
• Contra-indications for hydroxychloroquine or chloroquine
• Unable to take oral medication (chloroquine and hydroxychloroquine can be administered through tube feeding which is considered oral administration)
• Identified allergies to 4-aminoquinoline
• Severe diseases of the blood system
• 6-phosphate dehydrogenase deficiency
• History of acute myocardial infarction, unstable angina pectoris, severe arrhythmia (frequent ventricular, ventricular tachycardia, ventricular fibrillation) in recent 6 months; New York Heart Association (NYHA) level III-IV
• Known corrected QT interval (QTc) ≥ 500ms.
• Uncorrected severe hypokalaemia (< 2,5 mmol/l) or uncorrected severe hypomagnesemia (< 0.6 mmol/l)
• Pancreatitis
• Refusal to participate expressed by patient or legally authorized representative if they are present

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: chloroquine; 1. Supportive care + chloroquine base arm: loading dose 600mg, followed by 300mg 12 hours later, followed by 300mg bid for 4 days; total treatment duration of 5 days	Drug: Chloroquine Sulfate; cluster randomized; Other: Standard supportive care; cluster randomized
Active Comparator: hydroxychloroquine; 2. Supportive care + hydroxychloroquine arm: loading dose 400mg bid, followed by 200mg bid for 4 days; total treatment duration of 5 days.	Other: Standard supportive care; cluster randomized; Drug: Hydroxychloroquine; cluster randomized
No Intervention: Supportive care only; 3. Supportive care only.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite endpoint with disease progression defined as a NEWS2score ≥ 7 within 14 days or resulting in admission to Intensive/Medium Care unit or resulting in death within 14 days.	Composite endpoint with disease progression defined as a NEWS2score ≥ 7 within 14 days or resulting in admission to Intensive/Medium Care unit or resulting in death within 14 days.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Side effects	Secondary study parameters/endpoints Side effects of different drugs leading to regimen change or discontinuation of the antiviral treatment	28 days

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2020
• Primary Completion (Actual): June 8, 2020
• Study Completion (Actual): June 8, 2020

Study Registration Dates

• First Submitted: April 20, 2020
• First Submitted That Met QC Criteria: April 23, 2020
• First Posted (Actual): April 24, 2020

Study Record Updates

• Last Update Posted (Actual): June 19, 2020
• Last Update Submitted That Met QC Criteria: June 17, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: hydroxychloroquine; randomized; chloroquine
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Amebicides; Filaricides; Antinematodal Agents; Anthelmintics; Chloroquine; Chloroquine diphosphate; Hydroxychloroquine
• Other Study ID Numbers: NL73529.041.20 versie 3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Time Frame: 12 months
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

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