Treatment of COVID-19 Cases and Chemoprophylaxis of Contacts as Prevention (HCQ4COV19)

• ClinicalTrials.gov Identifier: NCT04304053
• Recruitment Status: Completed
• First Posted: March 11, 2020
• Last Update Posted: June 30, 2020
• Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Collaborators: Germans Trias i Pujol Hospital; Department of Health, Generalitat de Catalunya; Laboratorios Gebro Pharma SA; Laboratorios Rubió; Institut Catala de Salut
• Information provided by (Responsible Party): Oriol Mitja, Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

Tracking Information

• First Submitted Date: March 5, 2020
• First Posted Date: March 11, 2020
• Last Update Posted Date: June 30, 2020
• Actual Study Start Date: March 18, 2020
• Actual Primary Completion Date: June 15, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 26, 2020)

• Study 1- Clinical and virological outcome in exposed contacts [ Time Frame: Up to 14 days after start of treatment ]
  Incidence of secondary PCR confirmed symptomatic Covid-19 episodes among contacts after high risk PCR+ exposure
• Study 1- Transmission of SARS-CoV-2 in exposed contacts [ Time Frame: Up to 14 days after start of treatment ]
  Incidence of symptomatically compatible or a PCR-positive result regardless of symptoms
• Study 2- Virological outcome in index cases [ Time Frame: Up to 7 days after start of treatment ]
  Reduction of viral RNA load in nasopharyngeal swabs at days 3, and 7 after treatment start.
• Study 2- Clinical outcome in index cases [ Time Frame: Up to 28 days after start of treatment ]
  Time from randomization to complete resolution of symptoms at an extended 28-days follow-

Original Primary Outcome Measures (submitted: March 7, 2020)

Effectiveness of chemoprophylaxis assessed by incidence of secondary COVID-19 cases [ Time Frame: Up to 14 days after start of treatment ]

Incidence of secondary cases among contacts of a case and contacts of contacts

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: March 7, 2020)

• The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at days 3 [ Time Frame: 3 days after start of treatment ]
• The mortality rate of subjects at weeks 2 [ Time Frame: Up to 14 days after start of treatment ]
• Proportion of participants that drop out of study [ Time Frame: Up to 14 days after start of treatment ]
• Proportion of participants that show non-compliance with study drug [ Time Frame: Up to 14 days after start of treatment ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Treatment of COVID-19 Cases and Chemoprophylaxis of Contacts as Prevention
• Official Title: Treatment of Non-severe Confirmed Cases of COVID-19 and Chemoprophylaxis of Their Contacts as Prevention Strategy: a Cluster Randomized Clinical Trial (PEP CoV-2 Study)
• Brief Summary: This study is a research project to evaluate the efficacy of hydroxychloroquine for post-exposure prophylaxis and early treatment of Covid-19. The intervention entails administering prophylactic hydroxychloroquine to all contacts (Study 1) and treating non severe confirmed cases with hydroxychloroquine (Study 2).

Detailed Description

Hydroxychloroquine (HCQ) is a drug that has been extensively used for the prevention of malaria. HCQ showed excellent in vitro results and strong antiviral effects on SARS-CoV-2 infection of primate cells at low concentration. Empirical data for the efficacy of HCQ in hospitalized Covid-19 patients became available after the start of this study; HCQ administration did not result in a significantly higher PCR negative conversion in a RCT including 150 patients and there was no reduction in the risk of death/intubation in two large observational studies.

Study 1 -We investigated the efficacy and safety of HCQ to prevent secondary SARS-CoV-2 infection and Covid-19 disease in contacts exposed to a PCR-positive Covid-19 case during.

Study 2- We also conducted a study to test the hypothesis that HCQ treatment would be more efficacious than no-treatment for patients with mild Covid-19.

Initially, the protocol included the use of combined treatment with a HIV protease inhibidor (cobicistat-boosted darunavir) for cases (study 2), but it was adapted to HCQ alone after the recommendation of the pharmaceutical company not to use DRVc for the treatment of Covid-19 due to lack of activity in-vitro.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Primary study: Cluster-randomized clinical trial of Covid-19 contacts

Secondary study: Randomized clinical trial of Covid-19 cases

Masking: None (Open Label)
Masking Description:

Open label

Primary Purpose: Prevention

• Condition: COVID-19

Intervention

• Drug: Treatment and prophylaxis

  Cases will be offered a therapeutic regimen hydroxychloroquine (200mg tablets) 800mg on day 1, and 400mg on days 2-7

  Contacts will be offered a prophylactic regimen of hydroxychloroquine (200mg tablets) 800mg on day 1, and 400mg on days 2-7.

• Other: Standard Public Health measures
  Isolation of patient and contact tracing as per national guidelines.

Study Arms

• Active Comparator: No Intervention- SARS-CoV-2 surveillance

  Study 1- Contacts will complete a survey collecting demographic, epidemiological and clinical data and provides a swab for RT-PCR testing at baseline and day 14.

  Study 2- Index case completes a survey collecting demographic, epidemiological and clinical data and provides a swab for RT-PCR testing at baseline and on days 3 and 7.

  Isolation of patient and contact tracing as per national guidelines.

  Intervention: Other: Standard Public Health measures
• Experimental: Testing, treatment and prophylaxis of SARS-CoV-2

  Study 1- Contacts receive Hydroxychloroquine prophylaxis. Contacts will complete a survey collecting demographic, epidemiological and clinical and provides a swab for RT-PCR testing at baseline and day 14.

  Study 2- Index case receives Hydroxychloroquine. Index case completes a survey collecting demographic, epidemiological and clinical data and provides a swab for RT-PCR testing at baseline and on days 3, and 7.

  Isolation of patient and contact tracing as per national guidelines.

  Interventions:

  • Drug: Treatment and prophylaxis
  • Other: Standard Public Health measures

Publications *

• Akhtar S, Das JK, Ismail T, Wahid M, Saeed W, Bhutta ZA. Nutritional perspectives for the prevention and mitigation of COVID-19. Nutr Rev. 2021 Feb 11;79(3):289-300. doi: 10.1093/nutrit/nuaa063.
• Mitjà O, Corbacho-Monné M, Ubals M, Alemany A, Suñer C, Tebé C, Tobias A, Peñafiel J, Ballana E, Pérez CA, Admella P, Riera-Martí N, Laporte P, Mitjà J, Clua M, Bertran L, Sarquella M, Gavilán S, Ara J, Argimon JM, Cuatrecasas G, Cañadas P, Elizalde-Torrent A, Fabregat R, Farré M, Forcada A, Flores-Mateo G, López C, Muntada E, Nadal N, Narejos S, Nieto A, Prat N, Puig J, Quiñones C, Ramírez-Viaplana F, Reyes-Urueña J, Riveira-Muñoz E, Ruiz L, Sanz S, Sentís A, Sierra A, Velasco C, Vivanco-Hidalgo RM, Zamora J, Casabona J, Vall-Mayans M, González-Beiras C, Clotet B; BCN-PEP-CoV2 Research Group. A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. N Engl J Med. 2021 Feb 4;384(5):417-427. doi: 10.1056/NEJMoa2021801. Epub 2020 Nov 24.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 26, 2020): 2300
• Original Estimated Enrollment (submitted: March 7, 2020): 2900
• Actual Study Completion Date: June 15, 2020
• Actual Primary Completion Date: June 15, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Study 1:

Inclusion Criteria for a contact:

1. Asymptomatic individuals exposed to a PCR confirmed COVID19 case within 7 days as either a healthcare worker or household contact
2. Aged ≥18 years male or female;
3. In women of childbearing potential, negative pregnancy test and commitment to use contraceptive method throughout the study.
4. Willing to take study medication;
5. Willing to comply with all study procedures;
6. Able to provide oral, informed consent and/or assent.

Exclusion Criteria for a contact:

1. With known history of cardiac arrhythmia (or QT prolongation syndrome);
2. Unable to take drugs by mouth;
3. With significantly abnormal liver function (Child Pugh C)
4. Need of dialysis treatment, or GFR≤30 mL/min/1.73 m2;
5. Participants with psoriasis, myasthenia, haematopoietic and retinal diseases,CNS-related hearing loss or glucose-6-phosphate dehydrogenase deficit;
6. Persons already treated with any of the study drugs during the last 30 days;
7. Pregnant or lactating women;
8. Any contraindications as per the Data Sheet of Hydroxychloroquine.

Study 2:

Inclusion Criteria for a case:

1. Patients who meet the requirements of the New Coronavirus Infection Diagnosis (Acute <5 days respiratory infection symptoms, or fever alone, or acute cough alone and positive PCR)
2. Aged ≥18 years male or female;
3. In women of childbearing potential, negative pregnancy test and commitment to use contraceptive method throughout the study.
4. Willing to take study medication
5. Willing to comply with all study procedures, including repeat nasal swab at day 3
6. Able to provide oral and written informed consent

Exclusion Criteria for a case:

1. Hospital admission
2. Serious condition meeting one of the following: (1) respiratory distress with respiratory rate >=30 breaths/min; (2) oxygen saturation<=93% on quiet status; (3) Arterial partial pressure of oxygen (PaO2)/oxygen concentration<=300mmHg;
3. Critically ill patients meeting one of the following: (1) Experience respiratory failure and need to receive mechanical ventilation; (2) Experience shock; (3) Complicated with other organs failure and need intensive care and therapy in ICU;
4. Participants under treatment with medications likely to interfere with experimental drugs
5. Unable to take drugs by mouth;
6. With significantly abnormal liver function (Child Pugh C)
7. Need of dialysis treatment, or GFR≤30 mL/min/1.73 m2;
8. Participants with psoriasis, myasthenia, haematopoietic and retinal diseases,CNS-related hearing loss or glucose-6-phosphate dehydrogenase deficit
9. Participants with severe neurological and mental illness;
10. Pregnant or lactating women;
11. Inability to consent and/or comply with study protocol;
12. Individuals with known hypersensitivity to the study drugs.
13. Persons already treated with any of the study drugs during the last 30 days.
14. Any contraindications as per the Data Sheet of Hydroxychloroquine.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Spain

Administrative Information

• NCT Number: NCT04304053
• Other Study ID Numbers: HCQ4COV19; 2020-001031-27 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Open access
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• Time Frame: 30 days after start of treatment
• Access Criteria: Open access for everybody
• URL: http://www.estudicovid19.org

• Current Responsible Party: Oriol Mitja, Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Original Responsible Party: Oriol Mitja, Germans Trias i Pujol Hospital, Prof (Ass) Infectious Disease and Global Health
• Current Study Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Original Study Sponsor: Lihir Medical Centre

Collaborators

• Germans Trias i Pujol Hospital
• Department of Health, Generalitat de Catalunya
• Laboratorios Gebro Pharma SA
• Laboratorios Rubió
• Institut Catala de Salut

• Investigators: Not Provided
• PRS Account: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Verification Date: June 2020