Clinical Trial For Early SARS-CoV-2 (COVID-19) Treatment

Efficacy and Safety of the Use of Hydroxychloroquine, Favipiravir or Hydroxychloroquine + Favipiravir in Early SARS-CoV-2 (COVID-19) Treatment

This study is a randomized, double-blinded, and placebo controlled phase III clinical trial which aims to investigate the superiority of hydroxychloroquine, favipiravir or hydroxychloroquine + favipiravir treatment, initiated especially in the early period in the treatment of COVID-19, over the patients being followed up with placebo in adults aged 18~59 Years.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Favipiravir + Hydroxychloroquine; Drug: Favipiravir; Drug: Hydroxychloroquine; Drug: Placebo

Detailed Description

This study is a randomized, double-blinded, and placebo controlled phase III clinical trial in in adults aged 18~59 Years. The study was planned as a multicenter, randomized controlled, double-blind, parallel-arm drug study. The purpose of this study is to evaluate the efficacy and safety of hydroxychloroquine, favipiravir, or hydroxychloroquine + favipiravir treatments that were initiated early in patients who were caught during filiation or who were decided to be outpatient due to mild disease findings during hospital admission, after the diagnosis of COVID-19 against patients with placebo. It is planned that the study will be conducted with two separate arms. Study arms are planned as 2:2:2:1 for 320:320:320:160 patients as follows. The dose of Favipiravir has been determined as the standard dose. Hydroxychloroquine will also be given without a loading dose.

• Study Type: Interventional
• Enrollment (Actual): 1120
• Phase: Phase 3

Contacts and Locations

Study Locations

• Turkey
  • Ankara, Turkey
    • Ankara City Hospital
  • Istanbul, Turkey
    • Basaksehir Cam ve Sakura City Hospital
  • Istanbul, Turkey
    • Istanbul Bakirkoy Dr. Sadi Konuk Training and Research Hospital
  • Istanbul, Turkey
    • Istanbul University Istanbul Medicine Faculty
  • Istanbul, Turkey
    • Kartal Dr. Lütfi Kırdar City Hospital
  • Istanbul, Turkey
    • Sancaktepe Sehit Prof. Dr. Ilhan Varank Training and Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Volunteers who have understood all the procedures to be applied within the scope of the study protocol and gave their consent.
2. Patients between 18-60 years old.
3. Patients whose symptoms and complaints associated with COVID-19 started within 48 hours.

4. Mild cases whose treatment to be given as outpatient.

   1. Although asymptomatic, patients with high CRP (> 20 mg/L) and/or lymphopenia (<1000/mm3)
   2. Patients with symptoms such as fever, muscle/joint pain, cough, sore throat, nasal congestion, loss of smell.
   3. Patients without serious underlying diseases (cardiovascular diseases, diabetes mellitus, hypertension, cancer, chronic lung diseases, immunosuppressive conditions)
   4. Patients with normal chest x-ray and / or chest tomography (no sign of pneumonia)
5. Patients who accept oropharyngeal sample and venous blood collection at regular intervals within the scope of the protocol.
6. Patients who were not involved in any other interventional study.

Exclusion Criteria:

1. Patients who do not give their consent in writing after informing.
2. Being under the age of 18 and over the age of 60.
3. Patients with a known history of allergy to one of the study drugs (hydroxychloroquine, favipiravir).
4. Volunteers who the researcher thinks may have problems with adherence to treatment.
5. Volunteers who will have trouble taking medication by mouth due to resistant nausea, vomiting or chronic diarrhea.
6. Patients with chronic liver disease and transaminase (ALT or AST) levels 5 times the higher than the normal level.
7. Patients with heart disease or arrhythmia history.
8. Patients with gout or hyperuricemia.
9. Patients with signs of pneumonia in their lungs.
10. Patients with chronic renal failure (glomerular filtration rate <30).
11. Pregnant or breastfeeding patients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydroxychloroquine + Favipiravir; Hydroxychloroquine 2x200 mg 5 days and favipiravir 2 x 1600 mg loading, then 4 days 2 x 600 mg maintenance (5 days)	Drug: Favipiravir + Hydroxychloroquine; Favipiravir (1600 mg), as two tablet per day at the first day and then Favipiravir (600 mg) as two tablet per day for the remaining 4-day interval + Hydroxychloroquine (200 mg), as two tablets per day for 5-day interval.; Other Names: Favicovir Film Tablet + Hydroxychloroquine sulfate
Active Comparator: Favipiravir + Placebo (Hydroxychloroquine); Favipiravir 2 x 1600 mg loading, then 4 days 2 x 600 mg maintenance (5 days) + Placebo (Hydroxychloroquine ) 2x200 mg (5 days)	Drug: Favipiravir; Favipiravir (1600 mg), as two tablet per day at the first day and then Favipiravir (600 mg) as two tablet per day for the remaining 4-day interval + Placebo [Hydroxychloroquine (200 mg)], as two tablets per day for 5-day interval.; Other Names: Favicovir Film Tablet
Active Comparator: Hydroxychloroquine + Placebo (Favipiravir); Hydroxychloroquine 2x200 mg (for 5 days) + placebo (favipiravir) 2 x 1600 mg loading, then 4 days 2 x 600 mg maintenance (5 days)	Drug: Hydroxychloroquine; Hydroxychloroquine (200 mg), as two tablets per day for 5-day interval + Placebo [Favipiravir (1600 mg)], as two tablet per day at the first day and then Favipiravir (600 mg) as two tablet per day for the remaining 4-day interval.; Other Names: Hydroxychloroquine sulfate
Placebo Comparator: Placebo (Favipiravir) + Placebo (Hydroxychloroquine); Placebo (favipiravir) 2 x 1600 mg loading, then 4 days 2 x 600 mg maintenance (5 days) + Placebo (Hydroxychloroquine) 2x200 mg (5 days)	Drug: Placebo; Placebo [Favipiravir (1600 mg)], as two tablet per day at the first day and then Placebo Favipiravir (600 mg) as two tablet per day for the remaining 4-day interval + Hydroxychloroquine (200 mg), as two tablets per day for 5-day interval.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Worsening of clinical findings	Worsening of clinical findings such as respiratory distress or persistence of fever, which require hospital admission to begin another treatment (for example, remdesivir, dexamethasone, anti-cytokines, etc.)	During the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete resolution of symptoms and signs	Complete resolution of symptoms and signs	Fifth day after examination
Complete resolution of symptoms and signs	Complete resolution of symptoms and signs	Tenth day after examination
Negative RT-PCR test for SARS-CoV-2	Negative RT-PCR test for SARS-CoV-2 virus	Tenth day after examination
Determination of IgM, IgG levels for SARS-CoV-2	Determination of IgM, IgG levels for SARS-CoV-2 virus	Tenth day after examination
Negative RT-PCR test for SARS-CoV-2	Negative RT-PCR test for SARS-CoV-2 on the 30th day visit	Thirtieth day after examination
Determination of IgM, IgG antibodies	Determination of IgM, IgG antibodies against SARS-CoV-2	Thirtieth day after examination
Development of signs of pneumonia	Development of signs of pneumonia	During the study
Requirement of respiratory support with oxygen mask	Requirement of respiratory support with oxygen mask	During the study
Requirement of respiratory support with high flow oxygen	Requirement of respiratory support with high flow oxygen	During the study
Requirement of mechanical ventilation	Requirement of mechanical ventilation	During the study
Death	Death	During the study
The rate of discontinuation of treatments due to side effects	The rate of discontinuation of treatments due to side effects (gastrointestinal, allergic skin rash, arrhythmia, other cardiac reasons)	During the study
Time to improvement of symptoms after the initiation of study drugs	Time to improvement of symptoms after the initiation of study drugs	During the study

Collaborators and Investigators

• Sponsor: Health Institutes of Turkey
• Investigators: Study Director: Ahmet Gül, Prof., faculty member

Publications and helpful links

General Publications

• McCullough PA. Favipiravir and the Need for Early Ambulatory Treatment of SARS-CoV-2 Infection (COVID-19). Antimicrob Agents Chemother. 2020 Nov 17;64(12):e02017-20. doi: 10.1128/AAC.02017-20. Print 2020 Nov 17.
• Shrestha DB, Budhathoki P, Khadka S, Shah PB, Pokharel N, Rashmi P. Favipiravir versus other antiviral or standard of care for COVID-19 treatment: a rapid systematic review and meta-analysis. Virol J. 2020 Sep 24;17(1):141. doi: 10.1186/s12985-020-01412-z.
• Doi Y, Hibino M, Hase R, Yamamoto M, Kasamatsu Y, Hirose M, Mutoh Y, Homma Y, Terada M, Ogawa T, Kashizaki F, Yokoyama T, Koba H, Kasahara H, Yokota K, Kato H, Yoshida J, Kita T, Kato Y, Kamio T, Kodama N, Uchida Y, Ikeda N, Shinoda M, Nakagawa A, Nakatsumi H, Horiguchi T, Iwata M, Matsuyama A, Banno S, Koseki T, Teramachi M, Miyata M, Tajima S, Maeki T, Nakayama E, Taniguchi S, Lim CK, Saijo M, Imai T, Yoshida H, Kabata D, Shintani A, Yuzawa Y, Kondo M. A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01897-20. doi: 10.1128/AAC.01897-20. Print 2020 Nov 17.
• Hu TY, Frieman M, Wolfram J. Insights from nanomedicine into chloroquine efficacy against COVID-19. Nat Nanotechnol. 2020 Apr;15(4):247-249. doi: 10.1038/s41565-020-0674-9.
• Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, Skipper CP, Nascene AA, Nicol MR, Abassi M, Engen NW, Cheng MP, LaBar D, Lother SA, MacKenzie LJ, Drobot G, Marten N, Zarychanski R, Kelly LE, Schwartz IS, McDonald EG, Rajasingham R, Lee TC, Hullsiek KH. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020 Aug 6;383(6):517-525. doi: 10.1056/NEJMoa2016638. Epub 2020 Jun 3.
• Kaptein SJF, Jacobs S, Langendries L, Seldeslachts L, Ter Horst S, Liesenborghs L, Hens B, Vergote V, Heylen E, Barthelemy K, Maas E, De Keyzer C, Bervoets L, Rymenants J, Van Buyten T, Zhang X, Abdelnabi R, Pang J, Williams R, Thibaut HJ, Dallmeier K, Boudewijns R, Wouters J, Augustijns P, Verougstraete N, Cawthorne C, Breuer J, Solas C, Weynand B, Annaert P, Spriet I, Vande Velde G, Neyts J, Rocha-Pereira J, Delang L. Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity. Proc Natl Acad Sci U S A. 2020 Oct 27;117(43):26955-26965. doi: 10.1073/pnas.2014441117. Epub 2020 Oct 9.

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2020
• Primary Completion (Actual): January 31, 2021
• Study Completion (Actual): February 16, 2021

Study Registration Dates

• First Submitted: July 26, 2021
• First Submitted That Met QC Criteria: July 26, 2021
• First Posted (Actual): July 29, 2021

Study Record Updates

• Last Update Posted (Actual): July 29, 2021
• Last Update Submitted That Met QC Criteria: July 26, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; Favipiravir; Hydroxychloroquine
• 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; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Favipiravir; Hydroxychloroquine
• Other Study ID Numbers: COVID-19-FAV-HQ

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

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