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Various Combination of Protease Inhibitors, Oseltamivir, Favipiravir, and Hydroxychloroquine for Treatment of COVID-19 : A Randomized Control Trial (THDMS-COVID-19)

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ClinicalTrials.gov Identifier: NCT04303299
Recruitment Status : Not yet recruiting
First Posted : March 11, 2020
Last Update Posted : June 16, 2020
Sponsor:
Information provided by (Responsible Party):
Dr Subsai Kongsaengdao, Rajavithi Hospital

Brief Summary:
A 6-Week Prospective, Open label, Randomized, in Multicenter Study of, Oseltamivir 300mg per day plus Hydroxychloroquine 800 mg per day versus Combination of Lopipinavir 800mg (or 10 mg/kg ) per day and Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Oseltamivir 300 mg ( or 4-6 mg /kg ) per day versus Combination of Darunavir 400 mg every 8 hours plus ritonavir 200 mg (or 2.5 mg/kg ) per day plus Oseltamivir 300mg ( or 4-6 mg /kg ) per day plus Hydroxychloroquine 400 mg per day in mild COVID-19 and Combination of Lopipinavir 800 mg (or 10 mg/kg ) per day and Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Oseltamivir 300 mg ( or 4-6 mg /kg ) per day versus Favipiravir 2400 mg, 2400 mg, and 1200 mg every 8 h on day 1, and a maintenance dose of 1200 mg twice a day plus Lopipinavir 800 mg ( or 10 mg/kg ) per day and Ritonavir 200 mg ( or 2.5 mg/kg ) per day versus Combination of Darunavir 400 mg every 8 hours plus ritonavir 200 mg (or 2.5 mg/kg ) plus Oseltamivir 300 mg (or 4-6 mg /kg ) per day plus Hydroxychloroquine 400 mg per day versus Favipiravir 2400 mg, 2400 mg, and 1200 mg every 8 h on day 1, and a maintenance dose of 1200 mg twice a day plus Darunavir 400 mg every 8 hours Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Hydroxychloroquine 400 mg per day in moderate to critically illness in COVID-19

Condition or disease Intervention/treatment Phase
SARS-COV-2 Infections COVID-19 Drug: Oral Phase 3

Detailed Description:

Overall Study Design and Plan Various Combination of Protease inhibitors, Oseltamivir, Favipiravir, and Chloroquin for treatment of COVID-19. Non parametric and parametric statistical analysis will be analysed in the efficacy of treatment. For the pair-wise comparison, 2-sided p-value was used to ensure that the overall Type I error=0.05. Beta error 80%. Demographic and safety analyses were based on the summary of descriptive statistics.

Pre-randomization Phase The pre-randomization phase consisted of a screening period (0 to 1 day prior to randomization).

Screening Period (Day -1 to 0) At the screening visit and prior to performance of any study procedures, the investigators would explain the details of the study and the subject would have to sign on the written informed consent, exclusion criteria, and inclusion criteria Each subject who was willing to enrol into the study was asked about their medical history as well as their recent and current medications being taken. All enrolled subjects were asked to undertake an initial physical examination and had to satisfy the criteria for the inclusion /exclusion before being enrolled into the study.

All patients were asked to complete physical examination, CXR, CBC plt, proBNP, High sensitive C reactive protein and Laboratory blood (livers tests, haematology,) examinations, urine pregnancy test) were performed amount 5.5 mL for safety reasons. Nasopharyngeal swabs were collected to detect the ORF 1ab and E genes (sensitivity: 1000 copies per milliliter) by polymerase chain reactions. Will be performed The inclusion visit included the following examination and tests: - physical examination,- vital signs,- weight,- CBC laboratory test result,-Chest X ray or CT chest Blood for plasma cytokine assay -Pro BNP and High sensitive C reactive protein, D dimer Treatment period All patient will be treated with specific arm for 10-14 days or until negative for Nasopharyngeal swabs were collected to detect the ORF 1ab and E genes of SARS -CoV-2 for 3 consecutive tests every 24 -48 hours. ECG monitoring for prolonged QTcB in Hydroxychloroquine arm will be closed monitored The quarantine period will be performed for 7-14 days after swab negative All cases may be treated with Antibiotics as prophylaxis or specific treatment Other standard treatment will be allowed for investigator judgments. CXR nasoparyngeal swab will be performed every 1-2 days or up to investigator judgments Follow up Visits Patient will be check up CXR and CT scan, nasoparyngeal swab will be performed every 1-2 day until negative test and until 4-6 weeks or clinical complete recovery.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:

The study is described as 'open' unblinded, however all clinical, virological and laboratory data, as well as adverse events were reviewed by two independent physicians, and all radiological images were reviewed by two independent radiologists who were blinded to the treatment assignments.

The study outcomes assessed blinded to randomized group ( PROBE design - prospective randomised open blinded evaluation)

Primary Purpose: Treatment
Official Title: A 6 Week Prospective, Open Label, Randomized, in Multicenter Study of, Oseltamivir Plus Hydroxychloroquine Versus Lopipinavir/ Ritonavir Plus Oseltamivir Versus Darunavir/ Ritonavir Plus Oseltamivir Plus Hydroxychloroquine in Mild COVID-19 AND Lopipinavir/ Ritonavir Plus Oseltamivir Versus Favipiravir Plus Lopipinavir / Ritonavir Versus Darunavir/ Ritonavir Plus Oseltamivir Plus Hydroxychloroquine Versus Favipiravir Plus Darunavir and Ritonavir Plus Hydroxychloroquine in Moderate to Critically Ill COVID-19
Estimated Study Start Date : July 15, 2020
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : March 30, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Oseltamivir

Arm Intervention/treatment
Experimental: Oseltamivir plus Chloroquine in Mild COVID19
Oseltamivir 300mg ( or 4-6 mg/kg) per day plus Hydroxychloroquine 800 mg per day In mild COVID19
Drug: Oral
Anti virus treatment

Experimental: Darunavir and Ritonavir plus oseltamivir
Darunavir 400 mg every 8 hours Ritonavir 200 mg (or 2.5 mg/kg ) per day plus plus Oseltamivir 300mg ( or 4-6 mg/kg) per day plus Hydroxychloroquine 400mg per day in Mild COVID19
Drug: Oral
Anti virus treatment

Experimental: Lopinavir and Ritonavir plus Oseltamivir in mild COVID19
Lopinavir 800 mg ( or 10 mg/kg ) per day and Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Oseltamivir 300 mg ( or 4-6 mg /kg ) per day In mild COVID19
Drug: Oral
Anti virus treatment

Experimental: Lopinavir and Ritonavir Oseltamivir moderate to severe COVID19
Lopinavir 800 mg ( or 10 mg/kg ) per day and Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Oseltamivir 300 mg ( or 4-6 mg /kg ) per day In moderate to critically ill COVID19
Drug: Oral
Anti virus treatment

Experimental: Favipiravir lopinavir /Ritonavir for mod. To severe
Lopinavir 800 mg (or 10 mg/kg ) per day and Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Favipiravir 2400 mg, 2400 mg, and 1200 mg every 8 h on day 1, and a maintenance dose of 1200 mg twice a day in Mild COVID19 In moderate to critically ill COVID19
Drug: Oral
Anti virus treatment

Experimental: Darunavir /ritonavir oseltamivir chloroquine mod-severe
Darunavir 400 mg every 8 hours Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Oseltamivir 300 mg (or 4-6 mg /kg ) per day plus Hydroxychloroquine 400 mg per day In moderate to critically ill COVID19
Drug: Oral
Anti virus treatment

Experimental: Darunavir /ritonavir favipiravir chloroquine mod-severe
Darunavir 400 mg every 8 hours Ritonavir 200 mg ( or 2.5 mg/kg ) per day plus Favipiravir 2400 mg, 2400 mg, and 1200 mg every 8 h on day 1, and a maintenance dose of 1200 mg twice a day plus Hydroxychloroquine 400 mg per day In moderate to critically ill COVID19
Drug: Oral
Anti virus treatment

No Intervention: Conventional Qurantine
Patient who unwilling to treatment and willing to quarantine in mild COVID19



Primary Outcome Measures :
  1. SARS-CoV-2 eradication time [ Time Frame: Up to 24 weeks ]
    Eradication of nasopharyngeal SARS-CoV-2


Secondary Outcome Measures :
  1. Number of patient with Death [ Time Frame: Up to 24 weeks ]
    Any death after treatment adjusted by initial severity in each arm

  2. Number of patient with Recovery adjusted by initial severity in each arm [ Time Frame: Up to 24 weeks ]
    Normal pulmonary function, normal O2 saturation after treatment Adjusted by initial severity in each arm

  3. Number of day With ventilator dependent adjusted by initial severity in each arm [ Time Frame: Up to 24 weeks ]
    Number of day with ventilator assistant

  4. Number of patient developed Acute Respiratory Distress Syndrome After treatment [ Time Frame: Up to 24 weeks ]
    Number of patient developed new ARDS


Other Outcome Measures:
  1. Number of patient with Acute Respiratory Distress Syndrome Recovery [ Time Frame: Up to 24 weeks ]
    Acute Respiratory Distress Syndrome Recovery rate



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   16 Years to 100 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The subject has to grant permission to enter into the study by signing and dating the informed consent form before completing any study-related procedure such as any assessment or evaluation not related to the normal medical care of the subject.
  • Able to give written inform consent and retained one copy of the consent form
  • Male or female subject, aged between 16 - 100 years old.
  • Subject diagnosed to be COVID19
  • Female subject in good health and sexually active was instructed by the investigator to avoid pregnancy during the study and to use condom or other contraceptive measure if necessary. The subject was required to have a negative urine pregnancy test before being eligible for the study. (At each of the subsequent visit, a urine pregnancy test was performed).
  • Subject judged to be reliable for compliance for taking medication and capable of recording the effects of the medication and motivated in receiving benefits from the treatment.and compliance to quarantine procedure 7-14 days after treatment

Exclusion Criteria:

  • The subject was pregnant or lactating.
  • The subject was a female at risk of pregnancy during the study and not taking adequate precautions against pregnancy.
  • The subject had a known hypersensitivity to any of the test materials or related compounds.
  • The subject was unable or unwilling to comply fully with the protocol.
  • Treatment with investigational drug (s) within 6 months before the screening visit.
  • The subject had previously entered in this study.
  • Patient who planned to schedule elective surgery during the study
  • The used of other antiviral agents

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04303299


Contacts
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Contact: Subsai Kongsaengdao, M.D. 66818180890 skhongsa@gmail.com
Contact: Narumol Sawanpanyalert, M.D., M.P.H 66818424148 thailandemt2019@gmail.com

Locations
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Thailand
Assistant Professor Subsai Kongsaengdao
Bangkok, Thailand, 10400
Sponsors and Collaborators
Rajavithi Hospital
Study Data/Documents: Data references  This link exits the ClinicalTrials.gov site
Identifier: Thai government data
News  This link exits the ClinicalTrials.gov site

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Responsible Party: Dr Subsai Kongsaengdao, Associate Professor, Rajavithi Hospital
ClinicalTrials.gov Identifier: NCT04303299    
Other Study ID Numbers: TH-DMS-COVID19 study
First Posted: March 11, 2020    Key Record Dates
Last Update Posted: June 16, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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