Effectiveness and Safety of Quinine Sulfate as add-on Therapy for COVID-19 in Hospitalized Adults in Indonesia ( DEAL-COVID19 )

This is an adaptive, multicenter, randomized, open-label, controlled trial to evaluate the effectiveness and safety of quinine sulfate in mild to moderate COVID-19 hospitalized adults with confirmed positive Rapid Test or PCR.

The study is a multi-center trial that will be conducted in up to approximately 2 sites nationally. New sites may be added as needed after appropriate assessment. Interim monitoring will be conducted to evaluate the arms and for effectiveness and safety. Any change would be accompanied by an updated sample size.

Eligible patients are male and female patients aged ≥ 18 years to < 60 years old who are hospitalized with Covid-19 based on clinical symptoms determined by physician and confirmed by Rapid Test or PCR test with mild to moderate symptoms that fulfill the inclusion and exclusion criteria stated in the protocol. Total Subjects: 100

Subjects with any of these conditions will be excluded:

• Received quinine sulfate, hydroxychloroquine, chloroquine, lumefantrine, or mefloquine within 30 days prior to this research;
• Having receive any treatment for COVID-19 prior to this research;
• Any contraindication to quinine sulfate
• Inability to swallow pills or any other reason that compliance with the medical regimen is not likely;
• Pregnant and breastfeeding;
• Severe underlying disease where treatment and follow up is not likely to be beneficial to the patient based on physician judgement (e.g. retinopathy, cardiovascular disease (QTc > 500 mdet (narrow QRS); QTc ≥ 550 mdet (wide QRS)), heart arrythmia, uncontrolled diabetes mellitus, hypertension, chronic pulmonary disease, asthma, chronic kidney disease (Creatinine > 2x normal value), liver disease (SGOT/SGPT > 2x normal value), chronic neurological disease, or etc.). This includes people requiring care in designated supported living facilities and severe dementia;
• Platelet count less than 150,000 and more than 450,000 cells/μL;
• Possibility of being transferred to a non-study-hospital within 72 hours.

Any suspected serious adverse event reaction is reported to CRO/Sponsor and EC within 24 hours, using patient's study ID.

During the study conduct, the study team shall keep all the relevant source documents and transcribe the data in case report form (CRF). The study team should also update study essential document (e.g. subject log, investigational product accountability log, etc.) and keep the copy captured by scan/camera for monitoring/audit/inspection purpose.

The study is expected to be finished in 1,5 years.

Standard of Care (SoC) treatment is based on COVID-19 Treatment Protocol (4th edition, 2020) published by Medical Associations (PDPI, PERKI, PAPDI,PERDATIN, IDAI).

MILD CASE:

Arm 1 = SoC alone Arm 2 = SoC + Quinine Sulfate (2 tablets of Quinine Sulfate 200 mg administered orally once daily for 5 days).

MODERATE CASE:

Arm 1 = SoC alone Arm 2 = SoC + Quinine Sulfate (2 tablets of Quinine Sulfate 200 mg administered orally every 12 hours in Day 1, followed with 2 tablets of Quinine Sulfate 200 mg administered once daily for 5-7 days).

It is anticipated that patients with COVID-19 will present to participating hospitals, and that no external recruitment efforts towards potential subjects are needed. Recruitment efforts may also include dissemination of information about this trial to other medical professionals/hospitals.

The Ethics Committee will approve the recruitment process and all materials prior to any recruitment to prospective subjects directly.

Screening will begin with a brief discussion with study staff. Some will be excluded based on demographic data and medical history (i.e., pregnant, < 18 years of age, renal failure, etc.). Information about the study will be presented to potential subjects (or legally authorized representative) and questions will be asked to determine potential eligibility. Screening procedures can begin only after informed consent is obtained.

To evaluate the effectiveness of Quinine Sulfate in the therapy of mild to moderate hospitalized adults with confirmed COVID-19 based on subject's clinical condition assessed using a 7-point ordinal scale. Secondary parameters will be Incidence and duration of Oxygenation (days of oxygenation), incidence is defined as number of days from randomization until the subject received oxygenation, duration is defined as total days of the use of oxygenation; incidence of Ventilation (days to receiving ventilation) and length of stay in hospital (after subject received randomization code until subject discharge/death/recovered).

To evaluate the safety of quinine sulfate on laboratory parameters, serious adverse events and QT interval based on ECG result.

• Change in CBC, SGOT, SGPT, Ureum and Creatinine;
• Number of reported Serious Adverse Event (SAE);
• Change in QT interval based on ECG result.

Analyses relate outcome to the randomly allocated treatment (e.g. intent-to-treat). The primary analyses assess any effects of treatment allocation on all-cause in-hospital mortality, analyzing separately people who already at mild and moderate level at entry and those who did not. Interim analysis will be carried out after 50% subject enrolled. A Data Safety Monitoring Board (DSMB) will monitor ongoing results to ensure subject well-being and safety as well as study integrity. The DSMB will evaluate the study safety parameter after 50% subject enrolled in the study.

The main secondary analyses assess any effects of treatment allocation on:

• Duration of hospitalization (time from randomization to discharge) (days);
• Incidence and duration of Oxygenation;
• Incidence and duration of Ventilation;
• Clinical outcome from baseline at day 10 or if discharged earlier

Study related data will be recorded in electronically. All the data in the source documents shall be collected by the study team to be transcribed in the electronic case report form (eCRF) and other study documents are stored in the electronic trial master file (eTMF). Once the document recorded, the electronic data will be automatically available for monitoring/audit/inspection purpose. All the electronic system used and data recording in the study must be conducted in compliance to Good Clinical Practice.

The investigator must assure that subjects' anonymity will be maintained and that their identities are protected from unauthorized parties. On CRFs or other documents submitted to the funder, subjects should not be identified by their names, but by an identification code. The investigator should keep a subject enrolment log showing codes, names and addresses. The investigator should maintain documents not for submission to funder, e.g. subjects' written consent forms, in strict confidence.

The investigator shall ensure the quality control and quality assurance of the data generated during the study and how the data will be handled, including providing access to monitoring activities, audit and inspection and source documents which will be used in the study. Investigator will permit monitoring, audits and inspections by funder/CRO, EC, and regulatory bodies.

All source records including electronic data (if any) will be stored in secured systems in accordance with institutional policies and locally applicable regulation. All the essential documents should be retained until at least 5 years after the study ended or based on the applicable regulatory requirements or based on the agreement with the funder.

The Drug Safety Monitoring Board (DSMB) is an Independent Data Monitoring Committee consisting of doctors who are experienced in clinical trials, statisticians, and other members who do not direct involvement with this study. The DSMB responsible for the ongoing review of a clinical trial and for making recommendations to the sponsor concerning the continuation, modification, and termination of the trial as it is being conducted. The DSMB will be the only committee that is allowed to review the confidential data in the study. The statistician will analyze the subject's security data and report to DSMB to be evaluated more closely. The key responsibilities of the DSMB are to ensure patient safety by routine review of overall safety data including all SAEs, SUSARs, all severe AEs and AEs leading to drug or study discontinuation and, where applicable, literature cases and information from Competent Authorities(CAs) and by judging the relevance of the events for patients' safety. The DSMB will review the results of data that has been analyzed in accordance with SAP and consider other evidence arising from other studies and will provide advice to the Trial Steering Committee (TSC) (the research committee and national coordinator) regarding the sustainability of this study. The DSMB may recommend the TSC to the recruitment or study termination or provide recommendations related to alternatives treatment (if any)