NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial

ABSTRACT

Objective

The optimal treatment and timing for sudden sensorineural hearing loss (SSNHL) remain debated. This study aimed to determine if the hearing improvement and recovery time were better in the NAD+ group as compared to the control group.

Methods

There was a randomized, double‐blind, controlled clinical trial conducted between June 2022 and June 2024. SSNHL patients were randomly divided into two groups: the NAD+ group (NAD+ plus standard treatment, n = 18) and the control group (standard treatment, n = 20). The primary outcomes were PTA improvement, recovery rate per Siegel's criteria, and average recovery time, measured from baseline to 3‐month follow‐ups.

Results

The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group (F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months. Higher pre‐treatment tinnitus and aural fullness scores were linked to better outcomes with NAD+ for SSNHL.

Conclusions

NAD+ was more effective in improving hearing and reducing recovery time in SSNHL patients and also benefited tinnitus and aural fullness management.

Level of Evidence

2

This 2‐year, single‐center, double‐blind study with a small sample size compared NAD+ and control groups in a randomized controlled trial for sudden sensorineural hearing loss (SSNHL). Results showed that NAD+ led to better hearing improvement from 7 days to 3 months and a shorter average recovery time compared to the control group. Additionally, NAD+ significantly improved symptoms like tinnitus and aural fullness, especially after 3 months. Pre‐treatment tinnitus scores above 30 and aural fullness scores above 5.3 were linked to better outcomes with NAD+ for SSNHL.

1. Introduction

Sudden sensorineural hearing loss (SSNHL) occurs rapidly within 72 h, with a hearing loss of at least 30 dB over three frequencies. It often includes tinnitus (90% of cases), aural fullness (50% of cases), dizziness, or other ear‐related symptoms. SSNHL affects 5–27 per 100,000 individuals annually in the United States, 60.9 per 100,000 in Japan, and 0.59% in China [1, 2, 3]. Its causes are mostly unknown but may involve vascular issues, inner ear problems, or viral infections [4].

The 2019 SSNHL guideline recommended standard treatments for enhancing ear microcirculation and nerve recovery [5]. Our previous research demonstrated that nerve growth factor (NGF) combined with standard treatment improved hearing recovery rates compared to the control group (70.5% vs. 42.1%) [6]. Wang reported that high‐concentration intratympanic dexamethasone injections achieved an overall efficacy rate of 70.6%, while Yu found oral steroids to be effective at rates of 50% for single doses and 44% for divided doses after 3 months [7, 8]. Additionally, Batroxobin has superior overall hearing improvement of 41.6% in profound cases (> 100 dB HL) after two weeks [9].

Previous studies have shown mixed results; the recovery time for hearing loss has been largely ignored, and the effectiveness of SSNHL treatments is debated. Unsuccessful recovery from SSNHL can seriously affect long‐term hearing and quality of life, often causing anxiety and depression [10, 11].

Nicotinamide adenine dinucleotide (NAD+), or Coenzyme I, is crucial for energy metabolism and immune regulation. H.‐J. Kim demonstrated that increasing NAD+ levels through activation of NQO1 and salvage pathways protected hearing in mice [12, 13]. Our study supported this, showing that increasing NAD+ through both de novo and salvage pathways protected hair cells in zebrafish and mice, reducing cell death and improving hearing thresholds [14]. Notably, each 1 μM rise in blood NAD+ levels reduced the risk of SNHL by 0.9 times [15].

Driven by the contentious nature of effective treatments and the limited time window for hearing recovery in SSNHL, as well as the correlation between blood NAD+ levels and the progression of hearing loss, we have initiated a single‐center, small‐sample, double‐blind, randomized controlled trial to evaluate the safety and efficacy of NAD+ injections in SSNHL over a 2‐year period. It was hypothesized that the NAD+ group would exhibit superior hearing improvement within a shorter recovery timeframe, alongside enhanced amelioration of associated otologic symptoms.

2. Materials and Methods

2.1. Study Design and Participants

This study is a single‐center, 2‐year, randomized controlled trial (RCT) with a small sample size, employing a double‐blind design and comprising two parallel groups (NAD+ and control group). Recruitment occurred from June 2022 to June 2024 in the Department of Otolaryngology‐Head and Neck Surgery at Sun Yat‐Sen Memorial Hospital, China.

Participants met SSNHL criteria based on 2019 SSNHL clinical guideline: (i) age ≥ 18, (ii) unilateral SSNHL with a 30‐dB SNHL at three consecutive frequencies, (iii) no severe neurological, psychological, systemic, or hereditary diseases. Exclusions included diagnosed acoustic neuroma, NAD+ intolerance, pregnancy, and any condition affecting study conduct.

All participants provided written informed consent, and the study procedures received approval from the Ethical and Scientific Committee of Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University. The study was reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines, conducted in alignment with the Declaration of Helsinki, and registered on ClinicalTrials.gov as NCT05849519.

2.2. Randomization and Masking

This study employed block randomization with a block size of 4, assigning two participants per group. Six allocation orders (AABB, ABAB, ABBA, BABA, BAAB, BBAA) were possible, and an external statistician generated the randomization table by selecting numbers 1–6. The table and block size remained confidential. The treatment allocations were then placed in sealed, opaque, sequentially numbered envelopes, which were opened by independent individuals during enrollment, ensuring that the research team was blind to the allocations. To prevent information leaks, participants were randomly assigned to different wards, maintaining a double‐blind setup. Thus, this study used a fixed block length and a randomized treatment sequence to ensure population balance and prevent predictable allocations [16].

2.3. Procedure

The intervention commenced with inpatient treatment, lasting a median of 7 days (range: 4–13 days), and was subsequently followed by 7 days of outpatient treatment for both groups.

During inpatient treatment, participants in the NAD+ group received an injection of coenzyme I in conjunction with standard therapies, specifically a daily intramuscular injection of NAD+ (5 mg, Kaifeng Knature Pharmaceutical Co. Ltd., Henan, China; national drug approval number: H41024721) administered in 2 mL of saline. In contrast, the control group received only standard treatment. Standard therapies interventions comprised the following components: (i) Corticosteroids: Methylprednisolone sodium succinate (Solu Medrol, 1 mg/kg, Pfizer Manufacturing Belgium NV) was administered via intravenous infusion, diluted in 100 mL of 0.9% sodium chloride solution (NS), once daily. (ii) Ginkgo biloba : An extract of Ginkgo biloba leaves (Ginaton, 20 mL) was infused intravenously after dilution in 250 mL of 0.9% NS once daily. (iii) Batroxobin: Batroxobin injection (1 mL) was administered intravenously every other day, diluted in 250 mL of 0.9% NS. (iv) Neurotrophic agents: Mecobalamin was administered both intravenously, diluted in 100 mL of 0.9% NS, and via acupoint injection, once daily.

Preclinical safety data affirm the tolerability of NAD+ at this specified dosage. Median lethal dose of NAD+ is determined to be 4.333 mg/kg, with no evidence of repeat‐dose toxicity reported [17]. Adverse reactions have been documented only at significantly higher doses, typically around 1000 mg/kg/day, and may manifest as dry mouth, nausea, dizziness, and palpitations; however, the occurrence rate of such side effects is exceedingly low, reported at less than 0.01% [18]. Importantly, Hekimian et al. demonstrated that intramuscular administration of 100 mg NAD+ was well tolerated and did not result in significant adverse effects, indicating that the 5 mg dose used in this study falls within a safe and conservative range [19].

2.4. Outcomes

The primary outcome was hearing improvement, measured by change in pure tone average (PTA) from baseline to endpoint follow‐up hearing thresholds. Hearing improvement was classified according to Siegel's criteria into four categories: complete recovery (final PTA < 25 dB HL), partial recovery (PTA improvement > 15 dB HL and final PTA between 25 and 45 dB HL), slight recovery (PTA improvement > 15 dB HL and final PTA > 45 dB HL), and no recovery (PTA improvement < 15 dB HL and final PTA > 75 dB HL) [20]. The total markedly effective rate = (cases of complete + partial recovery)/total cases, and the total effective rate = (cases of complete + partial + slight recovery)/total cases. The average time to complete recovery was determined using the Kaplan–Meier (K–M) survival analysis, defining an “event” as the first follow‐up visit where the affected ear achieved complete recovery (final PTA < 25 dB HL). Patients who did not fully recover by the end of the follow‐up period or who were lost to follow‐up were censored at their last audiological assessment. Additionally, this study examined prognostic factors associated with hearing improvement and the average time to complete recovery as primary outcomes. The evaluation of hearing outcomes also incorporated the assessment of the word recognition score (WRS) and maximum speech recognition score (SRS_max) following treatment.

Secondary outcomes focused on improvements and prognostic factors in tinnitus handicap inventory (THI), tinnitus visual analogue scale (VAS), and aural fullness VAS. The severity of tinnitus was evaluated by THI and tinnitus VAS, while the severity of aural fullness was quantified by aural fullness VAS. THI scores span from 0 to 100, while VAS scores range from 0 to 10, with elevated scores reflecting increased symptom severity. Improvements were categorized as strong improvement (THI > 20 points, tinnitus VAS ≥ 3 points, aural fullness VAS ≥ 5 points), modest improvement (THI 7–19 points, tinnitus VAS 1–2 points, aural fullness VAS 2–4 points), or no improvement (THI < 7 points, tinnitus VAS ≤ 0 points, aural fullness VAS ≤ 1 point). The total strong improvement rate of tinnitus THI, tinnitus VAS, and aural fullness VAS = cases of strong improvement/total cases. Degree of SSNHL was defined as mild (PTA = 26–40 dB HL); moderate (PTA = 41–55 dB HL); moderate–severe (PTA = 56–70 dB HL); Severe or above (PTA > 70 dB HL).

All outcomes were measured at baseline and followed up at 3, 7, and 14 days, as well as at 1 and 3 months, including PTA, tinnitus THI, tinnitus VAS, and aural fullness VAS. Safety outcomes included predefined toxic reactions like dry mouth, nausea, dizziness, palpitations, or other minor symptoms.

2.5. Statistical Analysis

Sample size estimation was based on primary outcome variables of PTA using a two‐sample means test. Due to high correlation among primary outcome variables, each was tested at α = 0.025. The study employed a superiority design with a clinical superiority margin of 15 dB HL, adhering to the 2019 guidelines and Siegel's criteria, which recommend using a PTA improvement of ≥ 15 dB HL as the effective threshold for the treatment of SSNHL. Previous RCTs on SSNHL have reported a pooled standard deviation (SD) for PTA improvement ranging from approximately 14.6 to 15.4 dB HL [21, 22]. Based on these data, Cohen's d was calculated to be approximately 0.97–1.03. Consequently, this study adopted a standardized effect size σ = 1.0 for the purpose of estimating the sample size. With a power of 0.8 (1−β = 0.8) and a significance level of α = 0.025, the sample size calculation, accounting for a 20% attrition rate, determined that 36 participants were required, with 18 per group. In this study, p < 0.05 was statistically significant.

Statistical analysis and visualization were performed in R (ver. 4.4.2). The primary analysis included participants who received at least one dose of the study drug and attended at least two follow‐up visits. PTA improvement between NAD+ and control groups was assessed using an independent samples t‐test. Mann–Whitney U tests were used to evaluate differences in hearing success, WRS, SRS_max, tinnitus THI, tinnitus VAS, and aural fullness VAS, considering the sample size and the similarity in distributional shapes.

Linear regression analyzed how baseline outcomes predicted improvement, and a linear mixed‐effects model examined outcomes over time, accounting for group, time point, and their interactions, while addressing missing data. The Bonferroni correction was applied to multiple comparisons to adjust the significance level. K‐M curves compared average recovery times between groups. Safety analysis included all participants and reported adverse reactions as a proportion in each group.

3. Results

Between July 6, 2022 and May 9, 2024, 52 participants were screened, with 45 randomized into NAD+ or control groups. These participants were monitored from July 9, 2022, to October 10, 2024, at specified intervals of 3, 7, and 14 days, as well as at 1 and 3 months. During this period, 2 from the NAD+ group and 5 from the control group were lost to follow‐up, leaving 38 participants who completed the trial. Of these, 18 (47.37%) were from the NAD+ group and 20 (52.63%) from the control group. The trial concluded after reaching the required sample size and completing all follow‐ups (Figure 1).

FIGURE 1.

CONSORT trial flow diagram. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

There were 38 participants, with a mean age of 41.74 ± 14.97 years, 30 male (30/38, 78.95%) and 8 female (8/38, 21.05%), 16 right ear (16/38, 42.11%) and 22 left ear (22/38, 57.89%), the average onset of SSNHL was 6.58 ± 4.90 days, the average hospital length of stay was 7.63 ± 1.73 days, the mean 4‐frequency PTA was 76.88 ± 21.19 dB HL, WRS was 54.87% ± 40.28%, SRS_max was 90.53 ± 18.88 dB HL, two were mild SSNHL (2/38, 5.26%), five were moderate (5/38, 13.16%), 6 were moderate–severe (6/38, 15.79%), and 25 were severe or above (25/38, 65.79%). Demographic and clinical characteristics between NAD+ and the control group were presented (Table 1). The scattergram illustrated the PTA and WRS for both the NAD+ and control groups prior to treatment (Figure 2). The NAD+ group showed a significantly shorter hospital length of stay than the control group (Z = −2.286, p = 0.022).

TABLE 1.

Demographic and clinical characteristics between NAD+ and control group [mean ± SD or n (%)].

Characteristics	Total (n = 38)	NAD+ (n = 18)	Control (n = 20)	p
Age, years	41.74 (14.97)	40.06 (13.20)	43.25 (16.60)	0.609
Gender
Male	30 (78.95)	14 (77.78)	16 (80.00)	0.867
Female	8 (21.05)	4 (22.22)	4 (20.00)
Onset of SSNHL, days	6.58 (4.90)	5.33 (2.99)	7.70 (5.99)	0.249
Hospital length of stay, days	7.63 (1.73)	7.17 (1.65)	8.05 (1.73)	0.022*
Pre‐affected PTA, dB HL	76.88 (21.19)	74.03 (20.97)	79.44 (21.60)	0.440
Pre‐affected WRS, %	54.87 (40.28)	66.11 (38.98)	44.75 (39.65)	0.133
Pre‐affected SRSmax, dB HL	90.53 (18.88)	85.56 (22.55)	95.00 (13.95)	0.093
Unaffected PTA, dB HL	14.31 (7.93)	12.57 (6.83)	15.88 (8.67)	0.203
Unaffected WRS, %	100.00 (0)	100.00 (0)	100.00 (0)	1.000
Unaffected SRSmax, dB HL	18.29 (11.87)	16.67 (11.38)	19.75 (12.40)	0.432
Pre‐tinnitus THI (n = 36)	41.00 (24.75) (n = 36)	45.89 (28.49) (n = 18)	36.11 (19.97) (n = 18)	0.242
Pre‐tinnitus VAS (n = 36)	5.69 (2.12)	6.17 (2.20)	5.22 (1.99)	0.186
Pre‐aural fullness VAS (n = 32)	5.50 (2.23)	6.06 (1.95)	4.94 (2.41)	0.157
Degree of SSNHL
Mild	2 (5.26)	1 (5.55)	1 (5.00)	0.846
Moderate	5 (13.16)	3 (16.67)	2 (10.00)
Moderate–severe	6 (15.79)	2 (11.11)	4 (20.00)
Severe or above	25 (65.79)	12 (66.67)	13 (65.00)

Note: *p < 0.05. Pre‐affected PTA/WRS/SRS_max/Pre‐tinnitus THI/Pre‐aural fullness VAS was defined to the baseline PTA/WRS/SRS_max/THI/VAS. Unaffected PTA/WRS/SRS_max were defined as the PTA/WRS/SRS_max of the contralateral (healthy) ear.

Abbreviations: PTA, pure tone average; SRS_max, maximum speech recognition score; THI, tinnitus handicap inventory; VAS, visual analogue scale; WRS, word recognition score.

FIGURE 2.

Scattergram of pre‐treatment PTA and WRS for all SSNHL patients. WRS was plotted on the x‐axis, while PTA was plotted on the y‐axis. The numerals within the plot indicated the number of patients whose audiometric data correspond to specific coordinates on the graph. Abbreviations: SSNHL, sudden sensorineural hearing loss; PTA, pure tone average; WRS, word recognition score.

3.1. Primary Outcomes

In the primary outcome analysis, the NAD+ group showed a significant hearing improvement of 40.21 ± 17.65 dB HL compared to 23.06 ± 20.83 dB HL in the control group (t = 2.722, 95% confidence interval [CI] = [4.37, 29.92], p = 0.010) (Figure 3). Following treatment, the WRS in the NAD+ group reached 100%, which was significantly superior to the 82.50% in the control group (Z = −2.953, p = 0.035). Additionally, the NAD+ group had a better SRS_max of 43.89 ± 32.38 dB HL compared to 81.50 ± 26.41 dB HL in the control group (Z = −3.605, p < 0.001). The NAD+ group showed approximately 17 dB HL better PTA improvement, 17.50% better WRS, and 37 dB HL better SRS_max than the control group. The scattergram depicted the variation in PTA and WRS among SSNHL patients from baseline to the endpoint of follow‐up (Figure 4).

FIGURE 3.

The (A) initial PTA and (B) hearing improvement between NAD+ and control groups. Improvement of PTA was measured by the change in PTA from baseline to endpoint follow‐up. Abbreviation: PTA, pure tone average; *p < 0.05. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

FIGURE 4.

Scattergram of the change in PTA and WRS for SSNHL patients from baseline to follow‐up endpoint, with absolute WRS change on the x‐axis and PTA change on the y‐axis, and no change at the center of both axes. The numerals within the plot represent the number of patients whose changes in audiometric data correspond to specific coordinates on the graph. Abbreviations: SSNHL, sudden sensorineural hearing loss; PTA, pure tone average; WRS, word recognition score.

The NAD+ group had a total effective rate of 94.44% (17/18) versus 60.00% (12/20) in the control group, a markedly effective rate of 66.67% (12/18) compared to 25.00% (5/20), and a complete recovery rate of 44.44% (8/18) against 10.00% (2/20) (Z = −3.014, p = 0.003) (Table S1). The effective rates for the NAD+ group were 34.44% to 41.67% higher than those of the control group. Our findings indicated that NAD+ may lead to greater hearing improvement compared to the control group, as indicated by the following regression analyses: NAD+ group (r = 0.475, Adjusted R² = 0.177, F (1, 16) = 4.660, p = 0.046, y = 0.400x + 10.624) and control group (r = 0.397, Adjusted R² = 0.111, F (1, 18) = 3.368, p = 0.083, y = 0.383x−7.342) (Figure 5A).

FIGURE 5.

Scatter plot and line graphs of (A) PTA: PrePTA (dB HL) and PTA improvement (dB HL), (B) tinnitus THI: PreTHI and THI improvement, (C) aural fullness VAS: PreVAS and VAS improvement. Improvement of PTA/THI/VAS was measured by the change in PTA/THI/VAS from baseline to endpoint follow‐up. PrePTA/THI/VAS was defined to the baseline PTA/THI/VAS. Abbreviations: PTA, pure tone average; THI, tinnitus handicap inventory; VAS, visual analogue scale. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

PTA improved over time in both NAD+ and control groups (F = 57.632, p < 0.001), with significant group × time interactions (F = 2.867, p = 0.030). The NAD+ group showed significantly greater hearing improvement than the control group from 7 days to 3 months, with differences of −18.07 dB HL at 7 days (p = 0.016, 95% CI = [−32.631, −3.508]), −20.68 dB HL at 14 days (p = 0.007, 95% CI = [−35.452, −5.907]), −18.11 dB HL at 1 month (p = 0.021, 95% CI = [−33.343, −2.880]), and −20.25 dB HL at 3 months (p = 0.011, 95% CI = [−35.647, −4.844]) (Figure 6A). K–M survival analysis indicated the NAD+ group had a shorter average recovery time of 62.97 days compared to 175.98 days in the control group (p = 0.028) (Figure 7). No adverse events (AEs) were reported in the NAD+ group.

FIGURE 6.

Data distribution and change in (A) PTA, (B) tinnitus THI, (C) tinnitus VAS, (D) aural fullness VAS between NAD+ and control groups based on linear mixed‐effects model from baseline to 3 months. Abbreviations: PTA, pure tone average; THI, tinnitus handicap inventory; VAS, visual analogue scale; *p < 0.05. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

FIGURE 7.

Kaplan–Meier survival analysis was performed on SSNHL between NAD+ and control groups. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com]

3.2. Secondary Outcomes

In the secondary outcomes, the control group had one participant without tinnitus and aural fullness, one without tinnitus, and three without aural fullness, while the NAD+ group had two without aural fullness at baseline. The NAD+ group showed a significantly higher strong improvement rate for tinnitus THI at 61.11% (11/18) compared to 27.78% (5/18) in the control group, and for aural fullness VAS at 50.00% (8/16) compared to 37.50% (6/16) in the control group (Z = −3.096, p = 0.002). However, there was no significant difference between the groups for tinnitus VAS strong improvement (p > 0.05) (Table S1).

Both groups experienced improvements in tinnitus THI and VAS scores over the trial (Tinnitus THI: F = 15.885, p < 0.001; Tinnitus VAS: F = 8.128, p < 0.001). The NAD+ group improved by 27.42 in THI (p < 0.001, 95% CI = [13.614, 41.222]) and 3.50 in VAS (p = 0.001, 95% CI = [0.953, 6.047]), while the control group improved by 14.75 in THI (p = 0.022, 95% CI = [1.148, 28.347]) and 2.30 in VAS (p = 0.097, 95% CI = [−0.193, 4.793]) at post 3 months compared to baseline. Aural fullness VAS also improved in both groups (F = 16.486, p < 0.001), with the NAD+ group showing a 4.12 improvement (p < 0.001, 95% CI = [1.794, 6.450]) and the control group a 3.15 improvement (p < 0.001, 95% CI = [0.916, 5.384]) at post 3 months compared to baseline. Significant group × time interactions were observed for tinnitus THI (F = 2.867, p = 0.030), although this was evident only from baseline to Day 3, with a mean difference of 17.70 (p = 0.026, 95% CI = [−33.189, −2.211]). There were no significant interactions for tinnitus VAS and aural fullness VAS (p > 0.05). (Figure 6B–D).

Our findings indicated that NAD+ may significantly improve tinnitus in participants with pre‐tinnitus THI scores over 30 [r = 0.760, adjusted R ² = 0.551, F (1, 16) = 17.126, p < 0.001, y = 0.732x −9.057] and be more beneficial for aural fullness in those with VAS scores over 5.3 [r = 0.809, adjusted R ² = 0.630, F (1, 14) = 26.558, p < 0.001, y = 1.114 × −2.192]. (Figure 5B,C).

4. Discussion

To the best of our knowledge, this study represented the first 2‐year RCT to investigate the safety and efficacy of NAD+ in the treatment of SSNHL, showing that the NAD+ group had significantly better short‐term hearing improvement compared to traditional treatments.

In this study, 65.79% (25/38) of participants had severe or profound cases, with an average baseline PTA of 76.88 dB HL. The NAD+ group experienced a significant hearing improvement of 40.21 dB HL after treatment, surpassing the control group's improvement of 23.06 dB HL and reaching mild SNHL levels (~30 dB HL). In contrast, the control group remained at moderate to moderate–severe SNHL levels (50–55 dB HL). This PTA improvement for the NAD+ group surpassed previous studies that reported hearing improvements of 19.03–23.94 dB with conventional treatments, 28.1 dB with hyperbaric oxygen therapy (HBO), 26.5 dB with intratympanic steroid (ITS) treatment, and 22.19 dB with systemic steroid (SS) treatment [23, 24, 25, 26]. In conclusion, PTA improvement in the NAD+ group significantly exceeded that of the control group and previous studies, greatly surpassing the minimum clinically significant difference in the treatment of SSNHL, and highlighting its significant therapeutic effect.

In the NAD+ group, WRS reached 100% after treatment, which was significantly higher than the 82.50% in the control group. This post‐treatment WRS in the NAD+ group surpassed previous studies that reported WRS improvements ranging from 23.3% to 33.4% with different frequencies of ITS treatment [27]. However, a poorer WRS (< 52%) was significantly associated with the poor prognosis of SSNHL (OR = 1.05, 95% CI = [1.01, 1.10]) [28]. The pre‐treatment WRS in the NAD+ group was above 52%, possibly leading to overestimated improvements. Future research with larger sample sizes is needed to verify the efficacy of NAD+ in improving WRS.

NAD+ group exhibited a total effective rate of 94.44%, significantly higher than 60.00% observed in the control group. However, to accurately assess the true therapeutic benefits of NAD+, it is essential to consider potential factors such as spontaneous recovery, placebo effects, and baseline symptom variability. Meta‐analysis estimated that pooled spontaneous recovery of SSNHL at 60.28% (95% CI = [38.88%, 79.94%]), with higher heterogeneity (I ² = 86.0%, 95% CI = [69.4%, 93.6%]), which indicated that spontaneous recovery in SSNHL should not be underestimated [29]. Notably, the placebo effect, which includes positive treatment expectations among SSNHL patients, can result in notable improvements, as evidenced by a 14.3 dB recovery, but active treatment showed significantly better results (OR = 2.18, 95% CI = [1.06, 4.46]) [30]. The NAD+ group demonstrated effectiveness that surpassed expected spontaneous recovery and placebo effects, suggesting that potential therapeutic advantages exist beyond natural recovery and psychological effects.

NAD+ treatment had a total markedly effective rate of 66.67%, much higher than the control group's 25.00%, and similar to previous treatments at 57.3% and 24.5% for SSNHL [31]. The complete recovery rate for NAD+ was 44.44%, surpassing control's 10.00% and outperforming 18.4% recovery from tympanotomy and labyrinthine window sealing in severe or profound SSNHL cases unresponsive to corticosteroids [32]. Overall, NAD+ led to superior hearing improvement, indicating its potential in protecting and repairing cochlear hair cells (HCs) and spiral ganglion neurons (SGNs), thus enhancing auditory recovery.

In the study, the NAD+ group showed an average hearing improvement of 20 dB HL (range 18.07–20.68 dB HL) compared to the control group over 7 days to 3 months, indicating significant early recovery. Meta‐analysis revealed that ITS+HBO resulted in the largest hearing improvement of 14.5 dB [95% CI = 4.2, 25.0], followed by post auricle steroid injection (PSI) at 11.1 dB [95% CI = 4.4, 17.9], and ITS at 7.7 dB [95% CI = 4.8, 10.7], compared to the control group for refractory SSNHL [33]. Additionally, intratympanic steroid delivery via an indwelling catheter improved PTA by about 17 dB compared to standard treatment after 1 month, but caused some adverse effects like a slight burning sensation, bleeding, and persistent perforation [34]. There findings indicated that the combination of NAD+ with standard treatment may exhibit an interactive and synergistic effect, leading to accelerated hearing recovery. Building upon the inherent anti‐inflammatory and microcirculation‐enhancing properties of the standard treatment, NAD+ further expedited the recovery of cochlear hair cell function by augmenting cellular energy metabolism and mitigating oxidative stress. This ultimately resulted in a more pronounced and rapid improvement in hearing.

Our study found that NAD+ supplementation reduced hearing recovery time to 62.97 days, compared to 175.98 days in the control group, suggesting a reduction of about 3 months. To the best of our knowledge, this is the first study to report on NAD+ treatment recovery times for SSNHL. Additionally, an RCT indicated that Ginkgo biloba extract (EGb761) led to complete hearing recovery in mild SSNHL patients after 8 weeks [35]. In contrast, conventional treatment in moderate to severe SSNHL patients resulted in hearing thresholds of 35.6 to 53.19 dB across frequencies after 6 months, failing to achieve normal hearing levels [36].

The study found that NAD+ aids in significant auditory recovery within 7 days, normalizing in about 2 months. This may be due to acute inner ear injury affecting NAD+ homeostasis and increasing oxidative stress in hair cells, resulting in cellular damage. NAD+ treatment boosted cochlear NAD+ levels, activated SIRT1, and enhanced mitochondrial antioxidant capacity, protecting hair cells. Our prior animal studies have also demonstrated that modulating NAD+ de novo and salvage synthesis pathways can promote SIRT1 expression, increase p53 deacetylation, reduce cochlear hair cell loss, and improve hearing thresholds.

Reactive oxygen species (ROS) induced oxidative stress, which contributed to mitochondrial DNA (mtDNA) mutations and subsequent mitochondrial dysfunction. The concentration of plasma circulating cell‐free mtDNA was significantly elevated in SSNHL patients compared to controls, suggesting that mitochondrial dysfunction is a risk factor for SSNHL [37]. SIRT3 and SIRT5, members of the sirtuin family, are highly conserved NAD+‐dependent deacetylases located in the mitochondria. SIRT3 enhanced the levels of NADPH and glutathione (GSH) in mitochondria through the deacetylation and activation of isocitrate dehydrogenase 2 (IDH2). Additionally, SIRT3 prevented the degeneration of SCNs by activating the NAD+‐SIRT3 pathway, thereby protecting auditory function. SIRT5 played a role in mitigating oxidative stress and maintaining ROS homeostasis by deacetylating FOXO3A and IDH2, thereby contributing to improve auditory function [38]. Consequently, upregulation of NAD+ levels enhanced mitochondrial function, protected cochlear HCs and SGNs, and facilitated hearing recovery in SSNHL.

In this study, the NAD+ group demonstrated a significantly higher rate of substantial improvement in tinnitus THI (61.11% vs. 27.78%) and in aural fullness VAS (50.00% vs. 37.50%) compared to the control group. Previous studies reported a 38.7% effectiveness for intratympanic dexamethasone (ITD) and 15.63% for HBO in similar cases [39]. Notably, the NAD+ group exhibited superior improvements in tinnitus THI/VAS scores (THI: 27.42 vs. 14.75; VAS: 3.5 vs. 2.3) and aural fullness VAS scores (4.12 vs. 3.15) compared to the control group. Improved hearing outcomes in the NAD+ group were linked to a better prognosis for tinnitus and aural fullness, aligning with previous findings that better hearing improvements were associated with improved THI and aural fullness VAS scores [40, 41, 42]. Thus, symptom scores in the NAD+ group were significantly higher than those in the control group and previous studies, substantially surpassing the minimum clinically significant difference in SSNHL treatment, thereby underscoring its notable therapeutic efficacy.

This study has limitations, including a small sample size and being a single‐center RCT, which may affect the generalizability of the results. Larger, multicenter RCTs are needed to confirm NAD+'s efficacy in treating SSNHL and to ensure external validity. The Mann–Whitney U test was used due to the limited sample size, but methods like permutation tests or bootstrapping might offer more robust inferences with heteroscedasticity or unequal sample sizes. Although balanced baseline characteristics, the NAD+ group initially had higher tinnitus and aural fullness scores, potentially causing residual confounding. Their severe initial symptoms might have exaggerated perceived improvements. Nevertheless, it demonstrated superior efficacy, suggesting potential benefits in reducing tinnitus and aural fullness, warranting further investigation. This study only reported outcomes over a 3‐month follow‐up period; future research should include longer follow‐up periods to assess the sustained recovery or relapse rates of the NAD+ group.

5. Conclusion

The NAD+ group demonstrated superior hearing improvement and a shorter recovery time for SSNHL, with associated otologic symptoms such as tinnitus and aural fullness also showing greater improvement. Furthermore, NAD+ exhibited a more favorable safety profile for SSNHL. To ensure the external validity of these findings and assess the long‐term efficacy of NAD+ treatment, large‐scale, long‐term, multicenter RCTs are warranted in the future.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: The degree of hearing recovery and improvement for tinnitus and aural fullness between NAD+ and control group [n (%)].

Gao M., Guan Y., Yue X., et al., “ NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial,” The Laryngoscope 136, no. 3 (2026): 1204–1214, 10.1002/lary.70173.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.