Participant flow:
A total of 92 participants were enrolled and randomized, comprising 40 participants
with PD and 52 with T2DM. All randomized participants were included in the intention-to
treat population. Following attrition and loss to follow-up, data from 38 participants in
the EDC-HHA01 group (20 with T2DM and 18 with PD) and 37 participants in the placebo
group (21 with T2DM and 16 with PD) were available for analysis of the primary outcome.
Study adherence, assessed through capsule count, exceeded 94% across all groups, and no
protocol deviations affecting the primary outcome analyses were identified.
Baseline characteristics:
Baseline demographic characteristics showed no significant between-group differences p > 0.05Baseline metabolic parameters, including HbA1c, fasting glucose, insulin, and indices of insulin resistance, did not differ significantly between the intervention and placebo groups within diagnostic strata. Baseline symptom scores and quality‑of‑life measures were likewise comparable across groups.
Outcome measures:
PrimaryOutcome:GlycemicControl(HbA1c); In participants with prediabetes (PD), EDC‑HHA01 supplementation produced a statistically and clinically significant reduction in HbA1c from baseline compared with placebo (median change −1.15%, p < 0.001, Wilcoxon signed‑rank test), resulting in a meaningful between‑group difference at study end (∆ median = −0.55%, p = 0.007, Mann–Whitney U test). Effect size analysis confirmed a large treatment effect (Cliff’s δ = −0.64). In participants with type 2 diabetes (T2DM), HbA1c reductions were modest (∆ median = −1.00%), and between‑group differences did not reach statistical significance (∆ median = −0.70%, p = 0.223, Mann–Whitney U test). Placebo groups exhibited only small reductions in HbA1c across strata, consistent with lifestyle‑related effects. The treatment effect was most pronounced in PD, particularly among participants not receiving metformin.
Secondary glycemic outcomes showed no significant between‑group differences in fasting glucose, with high variability, and postprandial glucose responses demonstrated favorable but non‑significant trends in the intervention group, particularly in PD. Endotoxemia analyses revealed opposing median shifts in PD, with placebo participants showing increased endotoxemia and EDC‑HHA01 recipients showing reductions, including a statistically significant decrease in circulating LPS (p < 0.05; moderate effect size). In T2DM, endotoxemia changes were modest and non‑significant. Indices of insulin resistance demonstrated significant between‑group superiority in PD (∆ HOMA‑IR p = 0.042, Mann–Whitney U test), with reductions in fasting insulin consistent with glycemic improvements, while no significant differences were observed in T2DM. Renal and lipid parameters showed modest within‑group changes but remained within clinically acceptable ranges throughout the 6‑month intervention.
Adverse events:
Safety and tolerability over the six‑month intervention were favorable, with no serious adverse events and adherence exceeding 94%. EDC‑HHA01 was well tolerated, showing modest improvements in gastrointestinal symptoms compared with placebo (gas/bloating, diarrhea, constipation; p < 0.05), with small‑to‑moderate effect sizes (Cliff’s δ = 0.32–0.47). Additional differences favored the intervention for headache frequency and sleep disturbance, while no significant differences were observed for dermatologic, respiratory, or other non‑gastrointestinal symptoms. Exploratory patient‑reported outcomes indicated perceived benefits, including reduced intestinal gas (p = 0.03), improved bowel habits (p = 0.02), improved stool consistency (p = 0.04), better hunger regulation and digestive comfort, higher perceived physical energy (p = 0.02), and lower anxiety (p = 0.03), with moderate‑to‑large effect sizes (Cliff’s δ = 0.45–0.68). These findings support a favorable tolerability and acceptability profile rather than confirmatory efficacy signals.
Summary study:
A total of 92 participants were enrolled and randomized (40 with prediabetes [PD] and 52 with type 2 diabetes [T2DM]), all included in the intention‑to‑treat population. Following attrition, primary outcome data were available for 75 participants (38 intervention, 37 placebo), with adherence exceeding 94% and no protocol deviations. Baseline demographic and metabolic parameters, including HbA1c, fasting glucose, insulin, and indices of insulin resistance, showed no significant between‑group differences.
For the primary outcome, participants with PD receiving EDC‑HHA01 demonstrated a significant reduction in HbA1c compared with placebo (median change −1.15%, p < 0.001), resulting in a clinically meaningful between‑group difference (∆ median = −0.55%, p = 0.007; large effect size, Cliff’s δ = −0.64). In T2DM, HbA1c reductions were modest (∆ median = −1.00%) and not statistically significant (∆ median = −0.70%, p = 0.223). Secondary outcomes showed favorable but non‑significant trends in fasting and postprandial glucose, and significant reductions in endotoxemia markers in PD (LPS, p < 0.05; moderate effect size), with attenuated effects in T2DM. Insulin resistance indices improved significantly in PD (∆ HOMA‑IR p = 0.042), but not in T2DM. Renal and lipid parameters remained within clinically acceptable ranges.
Safety and tolerability were favorable, with no serious adverse events and >94% adherence. EDC‑HHA01 was associated with modest improvements in gastrointestinal symptoms compared with placebo (p < 0.05; Cliff’s δ = 0.32–0.47), and exploratory patient‑reported outcomes indicated perceived benefits in gastrointestinal comfort, stool consistency, hunger regulation, physical energy (p = 0.02), and anxiety reduction (p = 0.03), with moderate‑to‑large effect sizes (Cliff’s δ = 0.45–0.68). Overall, findings support good tolerability and stage‑dependent efficacy signals, particularly in PD.
Url for Results File:
https://doi.org/10.3390/microorganisms14040749
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