Background

Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia.

Objective

The aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD).

Methods

A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18–64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT^®) and the single-staircase Snap & Sniff^® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance.

Results

Of 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT^® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose–response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings.

Conclusion

Findings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16–100 weeks) studies.

Clinical trial registration

TRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.

中文翻译：

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艾氯胺酮鼻喷雾剂对难治性抑郁症患者嗅觉功能和鼻腔耐受性的影响：来自四项多中心、随机、双盲、安慰剂对照、III 期研究的结果

背景

鼻内给药为患者和医生提供了一种无创且方便的给药选择，特别是对于需要长期/重复治疗给药的疾病。然而，在某些情况下，这种递送可能对鼻和嗅上皮细胞有害。

客观的

本研究的目的是评估长期间歇性使用艾氯胺酮鼻喷雾剂与口服抗抑郁药 (AD) 联合治疗对难治性抑郁症 (TRD) 患者的嗅觉功能和鼻腔耐受性的潜在影响。

方法

共有 1142 名 TRD 患者参与了四项多中心、随机、双盲、III 期研究：三项短期研究（两项针对 18-64 岁的患者，一项针对 65 岁以上的患者）和一项长期研究艾氯胺酮鼻喷雾剂 + AD 与安慰剂鼻喷雾剂 + AD 的维持研究。在这四项研究中，在 21 个国家的 208 个地点进行了评估。嗅觉功能使用 40 项宾夕法尼亚大学气味识别测试 (UPSIT ^® ) 和单楼梯 Snap & Sniff ^®气味检测阈值测试 (S&S-T) 进行测量。还评估了鼻部耐受性，包括鼻部检查和定量、自我管理的鼻部症状问卷 (NSQ)。使用协方差分析分析数据。

结果

在 1142 名参与者中，734 名是女性（64.3%）。所有参与者的平均年龄在 45.7 至 70.0 岁之间。总体而言，855 名患者接受了 esketamine 鼻喷雾 + AD，432 名患者接受了安慰剂鼻喷雾 + AD。鼻功能的客观评估显示没有证据表明艾氯胺酮给药后有不良影响。基于 UPSIT ^®和 S&S-T 结果，与安慰剂鼻喷雾剂 + 口服 AD 相比，艾氯胺酮鼻内给药对气味识别或阈值测试分数没有影响。同样，重复使用艾氯胺酮鼻喷雾剂对鼻功能的评估没有有意义的影响。在艾氯胺酮剂量和嗅觉测试分数之间未观察到剂量反应关系。Esketamine 鼻喷雾剂耐受性良好，如对 NSQ 的反应和阴性鼻腔检查结果所示。

结论

该分析的结果表明，在短期（4 周）或长期（16-100周）学习。

临床试验注册

TRANSFORM-1：NCT02417064，注册日期：15/04/2015；TRANSFORM-2：NCT02418585，注册日期：16/04/2015；TRANSFORM-3：NCT02422186，注册日期：21/04/2015；SUSTAIN-1：NCT02493868，注册日期：10/07/2015。