Amantadine for COVID-19: A Randomized, Placebo Controlled, Double-blinded, Clinical Trial
试验速览
- 阶段
- 3 期
- 发起方
- 入组人数
- 226
- 试验地点
- 1
- 主要终点
- Clinical status on day 14
研究概览
简要总结
Introduction:
Corona virus disease 19 (COVID-19) is a devastating pandemic. By early February 2021, more than 102 million people were infected globally with more than 2.2 million reported deaths. Current treatments are approved for hospitalized patients with severe COVID-19 only. No treatment is approved to prevent progression to severe COVID-19 in the early stages of disease. Previous studies have indicated that amantadine is effective against severe acute respiratory syndrome corona virus 1 (SARS-CoV-1). Trials are needed to determine if this translates to a beneficial effect in patients with COVID-19. We hypothesize that preemptive therapy with amantadine of non-hospitalized high-risk adults with SARS-CoV-2 infection disease will prevent disease progression and hospitalization.
Methods and analysis:
The study is a randomized, double-blinded, placebo-controlled, single center study with two treatment arms; oral amantadine or placebo. Individuals with confirmed SARS-CoV-2 infection and one of following; i) age ≥ 40 years or ii) ≥ 18 years of age with at least one comorbidity or iii) ≥ 18 years of age with a body mass index (BMI) above 30 will be enrolled in the study. We plan to enroll 121 persons in each arm, with a total of 242 participants. Follow up period is 90 days. The primary outcome is disease severity on day 14 assessed by the 8-point COVID outcome scale proposed by the world health organization.
Ethics and dissemination:
Approvals by the Ethics Committee and National Competent Authorities will be obtained prior to study initiation. Results will be submitted for publication in a peer-reviewed journal and presented at international conferences.
Impact:
The results of the study will contribute with important knowledge on the efficacy and safety of oral amantadine in the treatment of non-hospitalized high-risk individuals with SARS-CoV-2 infection.
详细描述
BACKGROUND
Globally, Corona virus disease 19 (COVID-19) has caused more than 2.2 million deaths.
Most infected cases present with mild respiratory symptoms and fever, and spontaneously recover within two weeks. However, for approximately 20% of the cases, the disease will progress to pneumonia and in the most severe cases respiratory failure, multiple organ dysfunction, and death. Individuals aged ≥ 50 years of age and adults with known comorbidity or obesity are at particular risk of a severe course of the disease.
Within the past year treatments have proven to be beneficial for severe COVID-19 in randomized controlled trials. However, no treatment has been proven to inhibit progression from mild to severe COVID-19. Such a treatment could potentially have major impact on long-term morbidity and mortality especially in areas with limited access to vaccines. The fastest way of identifying such a treatment may be repurposed drugs. Other benefits of repurposed drugs include affordable prices and known safety profiles.
Amantadine is a potential treatment candidate that for years has been employed in the clinic for treatment of influenza virus A infection and for treatment of dyskinesia associated with Parkinson's disease. Furthermore, a potential repurposing of amantadine for the prevention and treatment of severe acute respiratory syndrome corona virus(SARS CoV-2) infection has been suggested. Two viroporins have been identified in the genome of SARS-CoV-2, Protein E and Protein 3a, with strong similarities to the viroporins in the deadly coronavirus SARS-CoV-1. The expression of both Protein E and 3a has been shown to promote SARS-CoV-1 replication and virulence, and the deletion of SARS CoV-1 protein E gene attenuates the virus. Amantadine has previously been shown to bind and inhibit protein E. Knocking down E protein ion channel activity in SARS CoV-1 decreases edema accumulation, which is the major determinant of acute respiratory distress syndrome (ARDS). Furthermore, levels of inflammasome-activated interleukin-1b, tumor necrosis factor (TNF) and interleukin-6 were reduced in the lung airways of the animals infected with viruses lacking E protein ion channel activity, indicating that E protein ion channel function is required for inflammasome activation. All these key cytokines promote the progression of lung damage and ARDS pathology. As such, by potentially blocking protein E ion channel activity, amantadine may prevent severe progression of SARS-CoV-2. Thus, we hypothesize that amantadine can ameliorate disease progression in persons with SARS-CoV-2 infection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Unblinded personnel will perform randomization into one of two arms (ratio 1:1). The randomization list will be generated centrally in random blocks. Blinded personnel will not have access to the randomization key. Unblinded staff will deliver sealed envelopes containing treatment allocation to blinded study personnel to use for emergency unblinding.
All investigators, outcome assessors, and study participants will be blinded to the treatment allocation.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Population at risk of developing severe COVID-19, defined as either:
- •Age ≥ 40 years
- •Age ≥ 18 years and at least one of the following comorbidities: Chronic heart disease without heart failure or proarrhythmic conditions or ventricular arrythmias, diabetes, chronic lung disease, hypertension, chronic kidney disease estimated glomerula filtration rate (GFR)<60 ml/minute, BMI
- •COVID-19 disease confirmed by the presence of SARS-CoV-2 nucleic acid by polymerase chain reaction (PCR) within 5 days prior to inclusion.
- •For women of childbearing age (defined as non-sterile premenopausal women):
- •Negative pregnancy test and willingness to use contraceptive during the study period (90 days)
- •● Provision of informed consent.
排除标准
- •Current hospitalization
- •Allergy to amantadine hydrochloride, rimantadine or inactive ingredients.
- •Known history of:
- •Untreated narrow-angle glaucoma
- •Kidney disease with eGFR < 35 ml/min
- •Heart failure, proarrhythmic conditions, ventricular arrhythmias.
- •Parkinson's disease
- •Gastric ulcer
- •Liver Disease
- •Hereditary galactose intolerance, lactose intolerance or glucose/galactose malabsorption
- •Current use of:
- •Neuroleptics/antipsychotics/ levodopa
- •Anticholinergics
- •Thiazides
- •Concurrent malignancy requiring chemotherapy
- •Pregnancy and breastfeeding
研究组 & 干预措施
Amantadine
The intervention group will receive a dose at day 1 of amantadine 100 mg followed by 100 mg amantadine after 6 hours. The following 4 consecutive days, study participants will receive a daily dose of 200mg amantadine, 100 mg (1 capsule) morning and 100 mg (1 capsule) evening, yielding 5 days of treatment in total (10 capsules in total).
干预措施: Amantadine (Drug)
Placebo
The control group will receive placebo treatment with lactose monohydrate; 1 capsule, followed by 1 capsule after 6 hours on day 1. The following 4 consecutive days, study participants will receive 1 capsule morning and 1 capsule evening, yielding 5 days of treatment in total (10 capsules in total).
干预措施: Lactose monohydrate (Drug)
结局指标
主要结局
Clinical status on day 14
时间窗: 14 days
Clinical status on day 14 according to 8 point ordinal scale for clinical improvement. No limitations to activities=1, Limitations to activities=2, Hospitalized no oxygen therapy=3, Oxygen by mask or nasal prongs=4, Non-invasive ventilation or high flow oxygen=5, Intubation and mechanical ventilation=6, Ventilation + additional organ support, ECMO=7, Death=8.
次要结局
- Duration of hospitalization(90 days)
- Severe adverse events(90 days)
- Mortality(Day 7, 14, 28 and 90)
- PCR SARS-CoV-2(Day 7)
- Mechanical ventilation(Day 7, 14, 28 and 90)
- Hospitalization(Day 7, 14, 28 and 90)
- Adverse events(90 days)
研究者
Nina Weis
Professor
Copenhagen University Hospital, Hvidovre