Chloroquine, Hydroxychloroquine or Only Supportive Care in Patients AdmItted With Moderate to Severe COVID-19 (ARCHAIC)
Primary Purpose
COVID-19
Status
Terminated
Phase
Phase 4
Locations
Netherlands
Study Type
Interventional
Intervention
Chloroquine Sulfate
Hydroxychloroquine
Standard supportive care
Sponsored by
About this trial
This is an interventional treatment trial for COVID-19 focused on measuring chloroquine, hydroxychloroquine, randomized
Eligibility Criteria
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
Sites / Locations
- UMCU
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Active Comparator
No Intervention
Arm Label
chloroquine
hydroxychloroquine
Supportive care only
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Side effects
Secondary study parameters/endpoints Side effects of different drugs leading to regimen change or discontinuation of the antiviral treatment
Full Information
NCT ID
NCT04362332
First Posted
April 20, 2020
Last Updated
June 17, 2020
Sponsor
UMC Utrecht
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development
1. Study Identification
Unique Protocol Identification Number
NCT04362332
Brief Title
Chloroquine, Hydroxychloroquine or Only Supportive Care in Patients AdmItted With Moderate to Severe COVID-19
Acronym
ARCHAIC
Official Title
An Open Label Cluster Randomized Controlled Trial of Chloroquine, Hydroxychloroquine or Only Supportive Care in Patients AdmItted With Moderate to Severe COVID-19
Study Type
Interventional
2. Study Status
Record Verification Date
June 2020
Overall Recruitment Status
Terminated
Why Stopped
Currently, almost no patients admitted to Dutch hospitals. If any effect of HCQ is to be expected we need more than 1000 inclusions
Study Start Date
April 14, 2020 (Actual)
Primary Completion Date
June 8, 2020 (Actual)
Study Completion Date
June 8, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
UMC Utrecht
Collaborators
ZonMw: The Netherlands Organisation for Health Research and Development
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
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:
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
Supportive care + hydroxychloroquine arm: loading dose 400mg bid, followed by 200mg bid for 4 days; total treatment duration of 5 days.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19
Keywords
chloroquine, hydroxychloroquine, randomized
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
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
Supportive care + hydroxychloroquine arm: loading dose 400mg bid, followed by 200mg bid for 4 days; total treatment duration of 5 days.
Supportive care only.
Masking
None (Open Label)
Masking Description
cluster randomized design
Allocation
Randomized
Enrollment
25 (Actual)
8. Arms, Groups, and Interventions
Arm Title
chloroquine
Arm Type
Active Comparator
Arm Description
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
Arm Title
hydroxychloroquine
Arm Type
Active Comparator
Arm Description
2. Supportive care + hydroxychloroquine arm: loading dose 400mg bid, followed by 200mg bid for 4 days; total treatment duration of 5 days.
Arm Title
Supportive care only
Arm Type
No Intervention
Arm Description
3. Supportive care only.
Intervention Type
Drug
Intervention Name(s)
Chloroquine Sulfate
Intervention Description
cluster randomized
Intervention Type
Drug
Intervention Name(s)
Hydroxychloroquine
Intervention Description
cluster randomized
Intervention Type
Other
Intervention Name(s)
Standard supportive care
Intervention Description
cluster randomized
Primary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
14 days
Secondary Outcome Measure Information:
Title
Side effects
Description
Secondary study parameters/endpoints Side effects of different drugs leading to regimen change or discontinuation of the antiviral treatment
Time Frame
28 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
110 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Facility Information:
Facility Name
UMCU
City
Utrecht
ZIP/Postal Code
3508GA
Country
Netherlands
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Time Frame
12 months
Learn more about this trial
Chloroquine, Hydroxychloroquine or Only Supportive Care in Patients AdmItted With Moderate to Severe COVID-19
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