COVID-19Phase 4ARCHAICNCT04362332
Chloroquine, Hydroxychloroquine or Only Supportive Care in Patients AdmItted With Moderate to Severe COVID-19
A Phase 4 study testing Chloroquine Sulfate, Hydroxychloroquine and Standard supportive care in people with COVID-19, run by UMC Utrecht at 1 site in Netherlands.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 110 yearsHealthy volunteers can take part
- Conditions the study is for
- COVID-19
- What is being tested?
- Chloroquine Sulfate, Hydroxychloroquine and Standard supportive care
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 1 siteNetherlands
- Study dates
- 14 Apr 2020to 8 Jun 2020
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 110 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- - 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
Who cannot join
- - 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
Show all 11Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read more
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.
Read the 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.
- Conditions
- COVID-19
- Being tested
- Chloroquine Sulfate, Hydroxychloroquine, Standard supportive care
- Keywords
- chloroquine, hydroxychloroquine, randomized
- Medical subject headings
- COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Chloroquine SulfateDrug
cluster randomized
cluster randomized
Standard supportive careOther
cluster randomized
| Study group | Role | What they receive |
|---|---|---|
| chloroquine | Active comparator | 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 Receives: Drug: Chloroquine Sulfate; Other: Standard supportive care |
| hydroxychloroquine | Active comparator | 2. Supportive care + hydroxychloroquine arm: loading dose 400mg bid, followed by 200mg bid for 4 days; total treatment duration of 5 days. Receives: Drug: Hydroxychloroquine; Other: Standard supportive care |
| Supportive care only | No intervention | 3. Supportive care only. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 14 days
Secondary outcomes (1)
Side effects
Secondary study parameters/endpoints Side effects of different drugs leading to regimen change or discontinuation of the antiviral treatment
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Apr 2020
- Study start14 Apr 2020
- Primary completion8 Jun 2020
- Study completion8 Jun 2020
Why it stopped: Currently, almost no patients admitted to Dutch hospitals. If any effect of HCQ is to be expected we need more than 1000 inclusions
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for COVID-19Studies of the same condition, open and under way.
- More trials run by UMC UtrechtThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model 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.
- Masking
- None (open label)
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- UMC Utrecht
- Sponsor type
- University, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Responsible party
- Principal investigator, Andy I.M. Hoepelman, UMC Utrecht
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04362332
- Sponsor's protocol ID
- NL73529.041.20 versie 3
- Acronym
- ARCHAIC
- Status last verified
- Jun 2020
- First submitted
- 20 Apr 2020
- Last updated
- 19 Jun 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 19 Jun 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04362332
- Acronym / sponsor ID
- ARCHAIC / NL73529.041.20 versie 3
- Conditions
- COVID-19
- Keywords
- chloroquine, hydroxychloroquine, randomized
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Currently, almost no patients admitted to Dutch hospitals. If any effect of HCQ is to be expected we need more than 1000 inclusions
- Enrolment
- 25 participants (actual)
- Lead sponsor
- UMC UtrechtUniversity, hospital or other
- Collaborators
- ZonMw: The Netherlands Organisation for Health Research and Development
- Study start
- 14 Apr 2020 (actual)
- Primary completion
- 8 Jun 2020 (actual)
- Study completion
- 8 Jun 2020 (actual)
- First posted
- 24 Apr 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model 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.
| Arm | Type | Receives |
|---|---|---|
| chloroquine | Active comparator | Drug: Chloroquine Sulfate, Other: Standard supportive care1. 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 |
| hydroxychloroquine | Active comparator | Drug: Hydroxychloroquine, Other: Standard supportive care2. Supportive care + hydroxychloroquine arm: loading dose 400mg bid, followed by 200mg bid for 4 days; total treatment duration of 5 days. |
| Supportive care only | No intervention | –3. Supportive care only. |
Who may qualify
- Ages
- 18 to 110 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- - 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
Key exclusion criteria (11 listed)
- - 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Chloroquine Sulfatecluster randomized | Drug | chloroquine |
| Hydroxychloroquinecluster randomized | Drug | hydroxychloroquine |
| Standard supportive carecluster randomized | Other | chloroquine, hydroxychloroquine |
Primary outcome
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
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.
1 secondary outcome
Side effects
Time frame: 28 days
Results and safety
The study was stopped early (reason given: Currently, almost no patients admitted to Dutch hospitals. If any effect of HCQ is to be expected we need more than 1000 inclusions). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jun 2020.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Chloroquine Sulfate, Hydroxychloroquine and Standard supportive care in people with COVID-19, run by UMC Utrecht at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 19 Jun 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Currently, almost no patients admitted to Dutch hospitals. If any effect of HCQ is to be expected we need more than 1000 inclusions). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jun 2020.