复发性尿崩症成年人的发酵诺丽多糖和免疫相关生物标志物：一项随机、双盲、安慰剂对照试验

摘要(中文译文)

来源于诺丽（noni）的发酵多糖被认为可调节先天免疫反应，但临床证据仍然有限。本随机、双盲、安慰剂对照试验评估了发酵诺丽多糖对反复上呼吸道感染（URTIs）成人自然杀伤（NK）细胞活性及免疫相关生物标志物的影响。共纳入100名年龄40至<75岁、有既往12个月内上呼吸道感染≥2次记录史的成人，随机分配接受发酵诺丽多糖（487.5 mg/片，每次两片，每日一次；FNP提取物975 mg/日）或匹配安慰剂，为期8周。主要终点为效靶比（E:T）50:1、25:1和12.5:1时NK细胞活性的变化，采用K562 NK敏感靶细胞评估。次要终点包括循环细胞因子（IFN-γ、TNF-α、IL-2、IL-6、IL-10、IL-12、IL-1β）和免疫球蛋白G（IgG）。84名参与者（治疗组43名，安慰剂组41名）纳入改良意向治疗/全分析集（mITT/FAS）；81名参与者（41/40）构成符合方案集（PPS）。主要疗效在mITT/FAS中分析。本试验在试验完成后于CRiS回顾性注册（KCT0011316）；经IRB批准的方案在入组前已定稿，此后未再更改。治疗组NK细胞活性在所有三个E:T比值下均较基线升高，而安慰剂组则略有下降。调整后的组间LS均值差异（95% CI）在E:T 50:1时为+8.94（-0.61，18.50；= 0.066），25:1时为+7.68（-1.14，16.50；= 0.087），12.5:1时为+3.29（-2.95，9.54；= 0.145），均有利于治疗组，但在mITT/FAS中未达到常规显著性阈值。预设的PPS敏感性分析在E:T 50:1（+11.03；= 0.025）和25:1（+9.94；= 0.028）达到显著性。部分细胞因子（IFN-γ、IL-2、IL-6、IL-10、IL-1β）在治疗组的升高幅度大于安慰剂组，而TNF-α、IL-12和IgG无变化。第4周、第8周及累积URTI发生率组间无显著差异。干预耐受良好，无严重不良事件，无因治疗相关原因停药。与安慰剂相比，发酵诺丽多糖补充剂在主要mITT/FAS分析中于所有三个E:T比值（50:1、25:1和12.5:1）下显示NK细胞活性数值上更大的升高，尽管这些组间差异未达到统计学显著性。预设的符合方案集（PPS）敏感性分析显示，在E:T比值50:1和25:1时组间差异显著。治疗组部分细胞因子（IFN-γ、IL-2、IL-6、IL-10）相对安慰剂的升高幅度也更大。URTI发生率、IgG、GARS、WBC或白细胞亚群比例均未观察到显著的组间差异。这些探索性生物标志物发现，在无安全性信号的情况下，提示可能存在免疫调节特征，但并未确立临床疗效。需要在更大规模、前瞻性注册、采用临床裁定感染相关终点的试验中予以确认。

Abstract

Fermented polysaccharides derived from (noni) have been suggested to modulate innate immune responses, but clinical evidence remains limited. This randomized, double-blind, placebo-controlled trial evaluated the effects of fermented noni polysaccharides on natural killer (NK) cell activity and immune-related biomarkers in adults with recurrent upper respiratory tract infections (URTIs). A total of 100 adults aged 40 to <75 years with a documented history of ≥2 episodes of upper respiratory tract infection in the prior 12 months were randomly assigned to receive fermented noni polysaccharides (487.5 mg/tablet, two tablets once daily; 975 mg/day of FNP extract) or a matched placebo for 8 weeks. The primary endpoint was the change in NK cell activity at effector-to-target (E:T) ratios of 50:1, 25:1, and 12.5:1, assessed using K562 NK-sensitive target cells. Secondary endpoints included circulating cytokines (IFN-γ, TNF-α, IL-2, IL-6, IL-10, IL-12, IL-1β) and immunoglobulin G (IgG). Eighty-four participants (43 treatment, 41 placebo) were included in the modified intention-to-treat/full analysis set (mITT/FAS); 81 participants (41/40) constituted the per-protocol set (PPS). Primary efficacy was analyzed in the mITT/FAS. This trial was retrospectively registered at CRiS (KCT0011316) after trial completion; the IRB-approved protocol was finalised before enrolment and remained unchanged thereafter. NK cell activity in the treatment group increased from baseline at all three E:T ratios, whereas it slightly decreased in the placebo group. Adjusted between-group LS mean differences (95% CI) were +8.94 (-0.61, 18.50; = 0.066) at E:T 50:1, +7.68 (-1.14, 16.50; = 0.087) at 25:1, and +3.29 (-2.95, 9.54; = 0.145) at 12.5:1, all favouring treatment but not reaching the conventional threshold for significance in the mITT/FAS. Prespecified PPS sensitivity analyses reached significance at E:T 50:1 (+11.03; = 0.025) and 25:1 (+9.94; = 0.028). Selected cytokines (IFN-γ, IL-2, IL-6, IL-10, IL-1β) increased to a greater extent in the treatment group than in the placebo group, whereas TNF-α, IL-12, and IgG were unchanged. URTI incidence at week 4, week 8, and cumulatively did not differ significantly between groups. The intervention was well tolerated, with no serious adverse events and no treatment-related discontinuations. Compared with placebo, fermented noni polysaccharide supplementation showed numerically greater increases in NK cell activity at all three E:T ratios (50:1, 25:1, and 12.5:1) in the primary mITT/FAS analysis, although these between-group differences did not reach statistical significance. Prespecified per-protocol set (PPS) sensitivity analyses showed significant between-group differences at E:T ratios of 50:1 and 25:1. The treatment group also showed greater increases in selected cytokines (IFN-γ, IL-2, IL-6, IL-10) relative to placebo. No significant between-group differences were observed in URTI incidence, IgG, GARS, WBC, or leukocyte subset proportions. These exploratory biomarker findings, in the absence of safety signals, suggest a possible immunomodulatory profile but do not establish clinical efficacy. Confirmation in larger, prospectively registered trials with clinically adjudicated infection-related endpoints is warranted.

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