Kumaresan Kala, Bengtsson Sara, Sami Saber, Clark Allan, Hummel Thomas, Boardman James, High Juliet, Sobhan Rashed, Philpott Carl
Norwich Medical School, University of East Anglia, Norwich, UK.
Norfolk & Waveney ENT Service, James Paget University Hospital NHS Foundation Trust, Great Yarmouth, UK.
Pilot Feasibility Stud. 2023 Oct 12;9(1):174. doi: 10.1186/s40814-023-01402-2.
Smell loss is a common problem with an estimated 5% of the population having no functioning sense of smell. Viral causes of smell loss are the second most common cause and the coronavirus (COVID-19) pandemic is estimated to have caused 20,000 more people this year to have a lasting loss of smell. Isolation, depression, anxiety, and risk of danger from hazards such as toxic gas and spoiled food are all negative impacts. It also affects appetite with weight loss/gain in two-thirds of those affected. Phantosmia or smell distortion can also occur making most foods seem unpalatable. Smell training has been tried with good results in the immediate post-viral phase. Evidence behind treatment with steroids has not shown to have proven effectiveness. With this, a key problem for patients and their clinicians is the lack of proven effective therapeutic treatment options. Based on previous studies, there is some evidence supporting the regenerative potential of retinoic acid, the metabolically active form of vitamin A in the regeneration of olfactory receptor neurons. It is based on this concept that we have chosen vitamin A as our study comparator.
To undertake a two-arm randomised trial of intranasally delivered vitamin A vs no intervention to determine proof of concept.
METHODS/DESIGN: The study will compare 10,000 IU once daily Vitamin A self-administered intranasal drops versus peanut oil drops (placebo) delivered over 12 weeks in patients with post-viral olfactory loss. Potentially eligible patients will be recruited from the Smell & Taste Clinic and via the charity Fifth Sense. They will be invited to attend the Brain Imaging Centre at the University of East Anglia on two occasions, 3 months apart. If they meet the eligibility criteria, they will be consented to enter the study and randomised to receive vitamin A drops or no treatment in a 2:1 ratio. MRI scanning will enable volumetric measurement of the OB and ROS; fMRI will then be conducted using an olfactometer to deliver pulsed odours-phenethylalcohol (rose-like) and hydrogen sulphide (rotten eggs). Participants will also perform a standard smell test at both visits as well as complete a quality-of-life questionnaire. Change in OB volume will be the primary outcome measure.
We expect the outputs of this study to enable a subsequent randomised controlled trial of Vitamin A versus placebo. With PPI input we will make the outputs publicly available using journals, conferences, and social media via Fifth Sense. We have already prepared a draft RCT proposal in partnership with the Norwich Clinical Trials Unit and plan to develop this further in light of the findings.
ISRCTN registry 39523. Date of registration in the primary registry: 23rd February 2021.
嗅觉丧失是一个常见问题，估计有5%的人口嗅觉功能丧失。嗅觉丧失的病毒病因是第二大常见病因，据估计，今年冠状病毒（COVID-19）大流行导致多2万人长期嗅觉丧失。隔离、抑郁、焦虑以及来自有毒气体和变质食物等危险的危险风险都是负面影响。它还会影响三分之二受影响者的食欲，导致体重减轻或增加。幻嗅或嗅觉扭曲也可能发生，使大多数食物看起来难以下咽。嗅觉训练已在病毒感染后的急性期进行尝试，效果良好。使用类固醇治疗的证据尚未证明其有效性。因此，患者及其临床医生面临的一个关键问题是缺乏经证实有效的治疗选择。根据先前的研究，有一些证据支持视黄酸（维生素A的代谢活性形式）在嗅觉受体神经元再生中的再生潜力。基于这一概念，我们选择维生素A作为我们的研究对照物。
进行一项双臂随机试验，比较经鼻给予维生素A与不干预，以确定概念验证。
方法/设计：该研究将比较10000国际单位的每日一次自我经鼻滴注维生素A与花生油滴注（安慰剂），在病毒感染后嗅觉丧失的患者中进行12周的治疗。潜在符合条件的患者将从嗅觉与味觉诊所及通过慈善机构“第五感”招募。他们将被邀请两次前往东英吉利大学脑成像中心，间隔3个月。如果他们符合资格标准，将同意进入研究，并以2:1的比例随机接受维生素A滴剂或不接受治疗。MRI扫描将能够对嗅球（OB）和嗅上皮（ROS）进行体积测量；然后使用嗅觉计进行功能磁共振成像（fMRI），以输送脉冲气味——苯乙醇（玫瑰味）和硫化氢（臭鸡蛋味）。参与者在两次就诊时还将进行标准嗅觉测试，并完成一份生活质量问卷。嗅球体积的变化将是主要结局指标。
我们预计本研究的结果将有助于随后进行维生素A与安慰剂的随机对照试验。在公众参与和信息平台（PPI）的投入下，我们将通过“第五感”利用期刊、会议和社交媒体将研究结果公开。我们已经与诺维奇临床试验单位合作编写了一份随机对照试验提案草案，并计划根据研究结果进一步完善。
国际标准随机对照试验编号（ISRCTN）39523。在主要注册机构的注册日期：2021年2月23日。
