Clinical trial NCT04981379: Clinical Trial For Early SARS-CoV-2 (COVID-19) Treatment
Official title: Efficacy and Safety of the Use of Hydroxychloroquine, Favipiravir or Hydroxychloroquine + Favipiravir in Early SARS-CoV-2 (COVID-19) Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Covid19
Keywords: COVID-19
Hydroxychloroquine
Favipiravir
Lead sponsor: Health Institutes of Turkey
Sponsor class: OTHER_GOV
First posted: 2021-07-29
Enrollment: 1120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Worsening of clinical findings
timeFrame: During the study
Secondary outcomes:
measure: Complete resolution of symptoms and signs
timeFrame: Fifth day after examination
measure: Complete resolution of symptoms and signs
timeFrame: Tenth day after examination
measure: Negative RT-PCR test for SARS-CoV-2
timeFrame: Tenth day after examination
measure: Determination of IgM, IgG levels for SARS-CoV-2
timeFrame: Tenth day after examination
measure: Negative RT-PCR test for SARS-CoV-2
timeFrame: Thirtieth day after examination
measure: Determination of IgM, IgG antibodies
timeFrame: Thirtieth day after examination
measure: Development of signs of pneumonia
timeFrame: During the study
measure: Requirement of respiratory support with oxygen mask
timeFrame: During the study
measure: Requirement of respiratory support with high flow oxygen
timeFrame: During the study
measure: Requirement of mechanical ventilation
timeFrame: During the study
measure: Death
timeFrame: During the study
measure: The rate of discontinuation of treatments due to side effects
timeFrame: During the study
measure: Time to improvement of symptoms after the initiation of study drugs
timeFrame: During the study
Other outcomes:
Locations:
city: Ankara
country: Turkey
facility: Ankara City Hospital
city: Istanbul
country: Turkey
facility: Başakşehir Çam ve Sakura City Hospital
city: Istanbul
country: Turkey
facility: Istanbul Bakirkoy Dr. Sadi Konuk Training and Research Hospital
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul Medicine Faculty
city: Istanbul
country: Turkey
facility: Kartal Dr. Lütfi Kırdar City Hospital
city: Istanbul
country: Turkey
facility: Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital
Study officials:
affiliation: Faculty Member
name: Ahmet Gül, Prof.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.