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Efficacy of Favipiravir in Treatment of Mild & Moderate COVID-19 Infection in Nepal

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ClinicalTrials.gov Identifier: NCT04694612
Recruitment Status : Recruiting
First Posted : January 5, 2021
Last Update Posted : January 5, 2021
Sponsor:
Information provided by (Responsible Party):
Dr. Prabhat Adhikari, Nepal Health Research Council

Brief Summary:

COVID-19 has affected almost all countries in the world. Every other country is constantly working towards its treatment and development of vaccines, with little to no success so far. Recently, several regimens have been tried as antiviral medicine. Among these medicines, Favipiravir is considered a broad-spectrum antiviral with the spectrum of activity noted against a wide range of RNA viruses & a good oral antiviral drug with > 97% bioavailability. It has already proved its safety profile as it has received FDA indication for drug-resistant Influenza. There has been increasing evidence of favorable outcome against COVID-19 in terms of early viral clearance & quicker symptomatic relief however, most of these studies lack strong statistical significance & are not peer-reviewed. Subjects will be categorized into two arms based on the severity of infection due to COVID-19 defined by NMC guidelines. Each arm will have respective two groups as the study drug group and control group. Based on the sample size calculation, subjects will be stratified & randomly enrolled in the study after checking the eligibility criteria at the screening visit. About 276 mild patients will be recruited for this trial and 400 moderate patients (including 10% loss ). Study arm groups will receive a Favipiravir treatment of 1800 mg PO BID on day 1, then 800 mg PO BID from day 2 onwards and control groups will receive the same quantity of Placebo. Treatment will be continued till 5 days after for mild groups and 10 days for moderate groups. Eligible patients will be randomly assigned (1:1) to either Favipiravir or Placebo among mild cases; and Favipiravir or Remdesivir among moderate cases. Randomization will be stratified by age group (18 to 40 years, 40 to 60 years and 60 to 80 years) and co-morbidity. The permuted block (30 patients per block) randomization sequence, including stratification, will be prepared by a statistician using STATA-15 software. Eligible patients will be allocated to the respective arm and will receive individually numbered packs, according to the sequence order as informed by the hotline. Informed written consent will be taken from the participants before commencing the study. All safety data, patient's baseline, clinical outcome data, data from endpoints and variables should be reported by the clinician and his/her team in a pre-instructed case report form (CRF) via a designated website.

It is our assumption that if the study results come favorable, Favipiravir, when used in mild or moderate cases, might prevent progression of the disease to higher severity, helps achieve viral clearance early so as to positively impact disease transmission in the community, increase the quality of life by quicker symptom recovery & decrease health burden by shortening the length of stay at the hospital. These findings can also be useful in international scenarios where the world is looking for innovative measures to curb COVID-19 infection. The study findings will be disseminated within and outside the country and will be published in peer-reviewed journals.


Condition or disease Intervention/treatment Phase
Covid19 Drug: Favipiravir Drug: Placebo Drug: Remdesivir Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 676 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Eligible patients will be randomly assigned (1:1) to either Favipiravir or Placebo among mild cases; and Favipiravir or Remdesivir among moderate cases. Randomization will be stratified by age group (18 to 40 years, 40 to 60 years and 60 to 80 years) and comorbidity (presence or absence of self-reported diabetes, hypertension, Coronary Artery Disease, Coronary Heart Failure, Cancer or auto-immune disease). The permuted block (30 patients per block) randomization sequence, including stratification, will be prepared by a statistician using STATA-15 software. Once an eligible patient is enrolled in the participating center, the physician will call the central hotline that will inform the physician about the allocation based on the sequence. Eligible patients allocated to the respective arm will receive individually numbered packs, according to the sequence order as informed by the hotline.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy of Favipiravir in Treatment of Mild & Moderate COVID-19 Infection in Nepal: a Multi-center, Randomized, Open-labelled, Phase III Clinical Trial
Estimated Study Start Date : January 1, 2021
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : May 31, 2021

Arm Intervention/treatment
Placebo Comparator: Mild condition

Study arm groups will receive a Favipiravir treatment of 1800 mg po BID on day 1, then 800 mg po BID from day 2 onwards and control groups will receive the same quantity of Placebo.

Duration of treatment : 5 days in each group

Drug: Favipiravir
Comparison of clinical improvement and clinical deterioration between those receiving Favipiravir compared to placebo in the patients with mild COVID-19
Other Name: Favir 200

Drug: Placebo
Comparison of clinical improvement and clinical deterioration between those receiving Favipiravir compared to placebo in the patients with mild COVID-19

Active Comparator: Moderate condition

Study arm groups will receive a Favipiravir treatment of 1800 mg po BID on day 1, then 800 mg po BID from day 2 onwards and control groups will receive Inj Remdesivir 200 mg IV on day 1, followed by 100 mg IV daily.

Duration of treatment : 10 days in Favipiravir group & 5 days in Remdesivir group

Drug: Favipiravir
Comparison of clinical improvement and clinical deterioration between those receiving Favipiravir compared to placebo in the patients with mild COVID-19
Other Name: Favir 200

Drug: Remdesivir
Comparison of clinical improvement and clinical deterioration between those receiving Favipiravir compared to Remdesivir Injection in the patients with moderate COVID-19




Primary Outcome Measures :
  1. clinical improvements in mild cases [ Time Frame: 5 day ]

    Mild cases: Time to clinical improvements is defined as recovery in two out of the three common symptoms that includes fever (body temperature more than 99.5 degrees F), cough, and headache/malaise (scored more than 3 in a pain likert scale of 1 to 10).

    Moderate cases: Time to clinical improvement defined as Improvement in at least 2 out 3 selected common symptoms as above as in mild cases PLUS improvement in shortness of breath (*For the assessment of clinical improvement in moderate cases, we did not include imaging findings because radiological changes lag behind clinical improvement by a few weeks.)


  2. clinical improvements in moderate cases [ Time Frame: 10 days ]
    Moderate Case: Efficacy of Favipiravir on clinical improvement among COVID-19 patients with moderate symptoms compared to Remdesivir


Secondary Outcome Measures :
  1. Clinical deterioration in mild & moderate cases [ Time Frame: up to 14 days ]

    In case of mild cases :

    progression of the case into moderate or worse category, as per current NMC guideline, verified/validated by site-PI.

    However, following alarming signs & symptoms should be taken into consideration : patient complaining of shortness of breath or difficulty in breathing, Respiratory rate > 30 per minute, chest pain on coughing or deep breathing, cyanosis of lips & fingertips, feeling dizzy, oxygen saturation < 94 % in room air, etc.

    In case of moderate cases :

    progression of the case into severe or worse category, as per current NMC guideline, verified/validated by site-PI.


  2. Radiological improvement in moderate cases [ Time Frame: 11 days ]

    In moderate cases, chest-X Ray will be done at time of enrollment +/- 24 hours, on day 11 +/- 24 hours & on day 17 +/- 24 hours (if day 11th day chest-X Ray is abnormal) or any time as per clinical decision of the on-site PI.

    Lungs involvement based on Chest X-ray will be categorized into 25 % - 100 % based on visual input by the medical team.


  3. 28 days mortality in mold & moderate cases [ Time Frame: 28 days ]
    Any mortality of the study participant, from day of enrollment until 28th day, whether attributed to Favipiravir or other treatment

  4. symptomatic improvement or worsening in mild & moderate cases [ Time Frame: 28 days ]
    Besides the symptoms of primary interest (cough, fever, headache/malaise), the rest of the symptoms are also taken into account & followed for improvement vs worsening

  5. compare change in SARS-CoV-2 viral load in nasopharyngeal swab in mild & moderate cases [ Time Frame: 6 days ]

    Nasopharyngeal swab for RT-PCR test to detect SARS-CoV-2 virus will be performed at screening & day 6 +/- 24 hours to compare the change in viral load, measured by change in Ct (Cycle threshold) value.

    Ct value is indirectly proportional to viral load and has been used as a marker in several studies Ct value > 35 correlates with non-cultivable SARS-CoV-2 viruses


  6. Length of stay in hospital beyond 10 days in mild & moderate cases [ Time Frame: 28 days ]
    Length of stay means total number of days spent in hospital (for mild & moderate cases) after day 10 from day of randomization * (*As of current practice, generally patients with mild or moderate COVID-19 infections are discharged as soon as they are clinically stable , while some cases are held at hospitals until 10th day & sent home without PCR in some sites)



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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:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

A. Inclusion Criteria:

  1. Minimum 18 - 80 years of age
  2. Clinical Diagnosis of COVID 19 with RT-PCR test for SARS-CoV-2 (If a patient is COVID19 positive based on Antigen test, they can participate in the trial while awaiting result form PCR test with Ct-value)
  3. Signed informed consent provided by patient's or patient's healthcare proxy.
  4. Fulfills enrollment criteria ( within 6 days of symptoms onset)
  5. Willing to practice celibacy OR take contraception during the study & within 7 days after treatment
  6. Mild clinical condition with at least 3 of these of these symptoms : fever, cough, malaise/headache
  7. Moderate clinical condition with at least 3 of these of these symptoms : fever, cough, malaise/headache

B. Exclusion Criteria:

  1. Pregnant (female of childbearing age with positive urine pregnancy test) or miscarriage or within 2 weeks after delivery
  2. Severe or critical clinical condition as per NMC clinical guideline for COVID19 Chronic liver with ALT/AST increased 5 times higher than the upper limit of normal or with Child Pugh C
  3. Creatinine clearance (Cockcroft-Gault Equation) < 30 ml/min or having hemodialysis/peritoneal dialysis
  4. Known allergy or hypersensitivity to Favipiravir
  5. Gout or history of gout or hyperuricemia two times the upper limit of normal
  6. If using Remdesivir, Lopinavir-ritonavir, Hydroxychloroquine or any other antiviral drug with potential effect against SARS-CoV-2 virus
  7. Lactating female
  8. Asymptomatic COVID-19 cases
  9. Mild COVID-19 cases not meeting the inclusion criteria symptoms
  10. Moderate COVID-19 cases not meeting the inclusion criteria symptoms

(*All female patients age 18 - 50 years will be screened for pregnancy by urine test & any pregnant patient will be excluded. Also, the patient must be consented to take contraception or practice celibacy during the study period & until 7 days after treatment. Since the expected wash out period of the study drug Favipiravir is 10hrs minimum to 27.5hrs maximum (half life is 2-5.5hrs), it is a safe practice to avoid conception for 1 week after stopping the drug of interest)


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): NCT04694612


Contacts
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Contact: Prabhat Adhikari, MD +977-9843003527 prabhatadhikari@gmail.com
Contact: Janak Koirala, MD +977 9818762117 jkoirala2002@gmail.com

Locations
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Nepal
Armed Police Force Hospital Recruiting
Kathmandu, Bagmati, Nepal, 44600
Contact: Roshan Jha, MD    +977-9851260182    dr.roshankumarjha395@gmail.com   
Charak Memorial Hospital Recruiting
Pokhara, Gandaki, Nepal, 33800
Contact: Klara Paudel, MD    +9779802823456      
Sponsors and Collaborators
Nepal Health Research Council
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Responsible Party: Dr. Prabhat Adhikari, MD, Nepal Health Research Council
ClinicalTrials.gov Identifier: NCT04694612    
Other Study ID Numbers: 683-2020
First Posted: January 5, 2021    Key Record Dates
Last Update Posted: January 5, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Infection