Simvastatin Nasal Rinses for the Treatment of COVID-19 Mediated Dysomsia
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Safety and feasibility of simvastatin nasal wash
研究概览
简要总结
Olfactory dysfunction (OD) or changes in smell and/or taste is one of the cardinal presenting symptoms of COVID-19. Despite the prevalence of COVID and resultant OD, the pathophysiology of COVID-mediated OD is not fully understood, but recent evidence indicates that local inflammatory and oxidative injury play a major role.
This phase 1 safety trial evaluates the use of simvastatin nasal irrigations for the management of COVID-mediated OD. We will determine the maximum tolerable dose and evaluate the safety and tolerability of high-volume simvastatin nasal irrigations in subjects with persistent COVID-mediated OD.
Each subject will complete bloodwork at baseline and then at the completion of their participation in the study. During this trial, we will observe olfactory function for each participant at baseline and completion of this study via the University of Pennsylvania Smell Identification Test (UPSIT). Investigational product will be shipped directly to the subject for daily irrigation each day for 4 weeks. Weekly throughout the study for a total of 4 weeks, subjects will complete the Sino-Nasal Outcome Test-22.
The current study would provide the support for Phase II and III clinical trials. Additionally, the study has applications for other disease processes affecting the sinonasal cavities.
详细描述
Olfactory dysfunction (OD) is one of the hallmark symptoms of SARS-CoV-2, the virus which has caused the COVID-19 pandemic. There is increasing evidence of the role of local inflammation and oxidative damage in COVID-mediated OD. To date, the only recommended therapy for patients with COVID-19 mediated OD is olfactory training, which has not been shown to result in a dramatic improvement in olfaction. Thus, it is essential that other effective management strategies are identified for the rapidly growing COVID-mediated dysosmic population.
Statins are utilized primarily for the reduction of cholesterol. However, statins also have pleiotropic effects on cellular inflammation, oxidative stress, and neuroprotection. Multiple studies have evaluated the anti-inflammatory effects of topical statins within the airway and shown that topical application can reduce inflammatory mediators such as IL-4, IL-6, IL-6, IL-8, CCL-11 and inflammatory cells. The anti-inflammatory effect of statins has also been demonstrated for neuroinflammation. One study evaluated the anti-inflammatory effects of 10 uM simvastatin suspensions on human monocyte-derived macrophages THP-1 as a surrogate for microglial cells and noted a significant reduction in lipopolysaccharide-induced IL-6 secretion. Another study evaluated the impact of nasally administered polymerosomes impregnated with simvastatin (doses 0-20 ug/mL) and brain-derived neurotrophic factor on neuroinflammation in mice and noted reduced IL-6 and IL-1b within brain homogenate after 3 days of exposure.
The safety of topical simvastatin has also been explored in vitro. The effect of topical simvastatin on nasal ciliary function was evaluated by applying 1x10-6 M to nasal cell brushings for 30 minutes. The resulting ciliary beat frequency was evaluated and demonstrated no adverse effects compared to control. Transepithelial electrical resistance was also evaluated 4 hours after exposure of bronchial epithelial cells aerosolized simvastatin and did not demonstrate any significant changes in transepithelial cell resistance between control cells and those treated with aerosolized simvastatin short term. However, after 14 days, a significant reduction in transepithelial resistance was noted, indicating a significant increase in cellular permeability. It is important to note, however, that this change incellular permeability did not associate with any change in cell viability. Manickavasagam et al. also evaluated the safety of simvastatin nanoparticles up to 20 uM on mouse hippocampal neuronal cells and did not note toxicity, indicating that our test concentration (maximum 10 uM) should not result in toxicity to the neural tissue.
Wang et al. evaluated the toxicity and anti-inflammatory effects of statin suspensions applied to human nasal epithelial cells and showed a reduction in CCL5, CCL11, IL-5, and IL-13 after 24 hr drug exposure without significant impacts of cell viability.
Statins also aid in nerve regeneration. Multiple studies have demonstrated neuroprotective effects after spinal cord injury, traumatic brain injury, and peripheral nerve injury. Studies of peripheral nerve injury have demonstrated that early administration of statins can accelerate nerve regeneration through increased neurite growth. Multiple mouse studies have shown that oral statin administration can improve proliferation and neuroregenesis of the olfactory epithelium in mice who have undergone chemical injury to the olfactory mucosa.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Males and females age 18-70 years old
- •Diagnosis of COVID-19 at least 3 months prior to study enrollment, but no greater than 12 months prior to study.
- •Objective olfactory dysfunction, believed to be due to COVID-19, that has persisted despite viral recovery otherwise (initial score on the UPSIT consistent with decreased olfactory function (<= 34 in women, <=33 in men)
- •Not currently using concomitant therapies specifically for the treamtment of OD, or willing to discontinue other therapies for the treatment of OD for the duration of the trial
- •Ability to read, write, and understand English
排除标准
- •Olfactory loss prior to COVID-19 infection
- •History of conditions that impact olfactory function
- •Chronic rhinosinusitis
- •History of prior sinonasal or skullbase surgery
- •Neurodegenerative disorders (Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Lewy body dementia, frontotemporal dementia)
- •Current or recent (within 8 weeks of study enrollment) oral statin use
- •History of conditions that increase risks of statin intolerance
- •Untreated hypothyroidism
- •History of chronic kidney disease or abnormal renal function at the time of enrollment
- •Personal or family history of myositis or elevated creatine kinase at the time of enrollment
- •Alcohol consumption greater than 7 drinks per week (female) or 14 drinks per week (male)
- •History of liver disease or elevated liver enzymes at the time of enrollment
- •History of statin intolerance
- •Human immunodeficiency virus
- •Viral hepatitis
- •History indicating that the subject should receive oral statins
- •Myocardialinfarction
- •Cardiac surgery in the last 2 years
- •Elevated total cholesterol at baseline
- •History of malignancy
- •History of statin intolerance
- •Currently pregnant or nursing
- •Use of any medications contraindicated with statins
- •Antiviral protease inhibitors
- •Antifungals
- •Cyclosporine
- •Calcium channel blockers
- •Gemfibrozil
- •Ingestion of >1 quart of grapefruit juice per day
研究组 & 干预措施
topical nasal simvastatin - 0.1 mg dose
topical nasal simvastatin - 0.1 mg dose
Subjects are entered into the study in groups of 3. This first cohort will receive the lowest dose of simvastatin (0.1mg) via nasal irrigation for 4 weeks. If none of the 3 subjects report toxicity, the next group of 3 subjects enrolled will receive the consecutive higher dose of simvastatin for 1 month. If >2 of the 3 subjects enrolled in the first group report toxicity then the dose is considered toxic or "MTD is exceeded." If 1 of the first 3 reports toxicity, then the next group of 3 enrolled subjects will receive the same dose as group 1. When 6 subjects receive the same dose, and <1 of them report toxicity, the consecutive group of 3 subjects will receive the successive higher dose. If >2 of the 6 subjects on the same dose report toxicities, then MTD is exceeded. Intra-patient dose escalation will not be performed.
干预措施: Simvastatin (Drug)
topical nasal simvastatin - 0.25 mg dose
topical nasal simvastatin - 0.25 mg dose
Subjects are entered into the study in groups of 3. This 2nd cohort will receive the 0.25mg simvastatin via nasal irrigation for 4 weeks. If none of the 3 subjects report toxicity, the next group of 3 subjects enrolled will receive the consecutive higher dose of simvastatin for 1 month. If >2 of the 3 subjects enrolled in the first group report toxicity then the dose is considered toxic or "MTD is exceeded." If 1 of the first 3 reports toxicity, then the next group of 3 enrolled subjects will receive the same dose as group 1. When 6 subjects receive the same dose, and <1 of them report toxicity, the consecutive group of 3 subjects will receive the successive higher dose. If >2 of the 6 subjects on the same dose report toxicities, then MTD is exceeded. Intra-patient dose escalation will not be performed.
干预措施: Simvastatin (Drug)
topical nasal simvastatin - 0.5 mg dose
topical nasal simvastatin - 0.5 mg dose
Subjects are entered into the study in groups of 3. This 3rd cohort will receive the 0.5mg simvastatin via nasal irrigation for 4 weeks. If none of the 3 subjects report toxicity, the next group of 3 subjects enrolled will receive the consecutive higher dose of simvastatin for 1 month. If >2 of the 3 subjects enrolled in the first group report toxicity then the dose is considered toxic or "MTD is exceeded." If 1 of the first 3 reports toxicity, then the next group of 3 enrolled subjects will receive the same dose as group 1. When 6 subjects receive the same dose, and <1 of them report toxicity, the consecutive group of 3 subjects will receive the successive higher dose. If >2 of the 6 subjects on the same dose report toxicities, then MTD is exceeded. Intra-patient dose escalation will not be performed.
干预措施: Simvastatin (Drug)
topical nasal simvastatin - 1 mg dose
topical nasal simvastatin - 1 mg dose
Subjects are entered into the study in groups of 3. This 4th cohort will receive the 1mg simvastatin via nasal irrigation for 4 weeks. If none of the 3 subjects report toxicity, then the drug will be considered tolerated at the maximum tested dose. If >2 of the 3 subjects enrolled in the first group report toxicity then the dose is considered toxic or "MTD is exceeded." If 1 of the first 3 reports toxicity, then the next group of 3 enrolled subjects will receive the same dose as group 1. When 6 subjects receive the same dose, and <1 of them report toxicity, then this maximum dose is considered tolerable. If >2 of the 6 subjects on the same dose report toxicities, then MTD is exceeded. Intra-patient dose escalation will not be performed.
干预措施: Simvastatin (Drug)
结局指标
主要结局
Safety and feasibility of simvastatin nasal wash
时间窗: 4 weeks
Primary objective is to evaluate safety and feasibility of simvastatin nasal wash. * Successive cohorts of 3 subjects will be enrolled until dose-limiting toxicities (DLT; defined as the development of statin intolerance with liver toxivity or muscle toxicity as determined by elevated AST, ALT, or CK or the development of significant systemic or sinonasal symptoms requiring drug discontinuation) are observed in greater than 33% of the enrolled subjects. We will monitor for signs or symptoms of toxicity. * Weekly throughout the study, subjects will complete the SNOT-22. The absolute change in SNOT-22 scores from baseline will be utilized to describe any adverse effects of simvastatin rinses on sinonasal function and quality of life. * Nasal endoscopy will be performed at the time of enrollment and at study completion to ensure no local tissue effects of topical simvastatin rinses. A Lund-Kennedy score reflecting sinonasal disease severity will be noted at the time of nasal endoscopy.
次要结局
- Maximum tolerable dose of simvastatin nasal rinses via a dose escalation trial.(4 weeks)
研究者
Nyssa Farrell
Assistant Professor of Otolaryngology
Washington University School of Medicine