Post Hoc Analysis of Solriamfetol Efficacy in Obstructive Sleep Apnea Patients with Excessive Daytime Sleepiness Stratified by Disease Severity

Abstract

Introduction

Solriamfetol, a dopamine and norepinephrine reuptake inhibitor, is indicated for the treatment of excessive daytime sleepiness (EDS) associated with obstructive sleep apnea (OSA). This study aims to evaluate the efficacy and safety profiles of solriamfetol across different severity levels of OSA via the post hoc analysis of a randomized clinical trial in a Chinese population.

Methods

Participants were assigned in a 1:1 ratio to either the placebo group or solriamfetol group (dose titrated up to 150 mg/day) for 12 consecutive weeks, with randomization stratified by adherence status to primary OSA therapy. The co-primary endpoints were defined as the changes of mean sleep latency measured by the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) scores from baseline to week 12 in the full analysis set. The efficacy and safety profiles of solriamfetol were analyzed across subgroups stratified by baseline apnea hypopnea index (AHI).

Results

Among eligible patients for subgroup analysis, 42.5%, 34.5%, and 23% had baseline AHI < 5, 5 ≤ AHI < 30, and AHI ≥ 30, respectively. At week 12, solriamfetol treatment significantly prolonged MWT sleep latency relative to placebo across all AHI subgroups. The least squares (LS) mean differences (standard error) versus placebo were 12.133 (2.2239) min for the AHI < 5 subgroup (P < 0.0001), 12.676 (2.5363) min for the 5 ≤ AHI < 30 subgroup (P < 0.0001), and 10.935 (2.6023) min for the AHI ≥ 30 subgroup (P = 0.0001). In subgroups with baseline AHI < 5 and 5 ≤ AHI < 30, solriamfetol significantly reduced ESS scores vs. placebo (LS mean difference [SE] versus placebo, − 2.0 [0.95] and − 2.1 [1.01], P = 0.0404 and P = 0.0394, respectively). In the baseline AHI ≥ 30 subgroup, solriamfetol showed a tendency toward reduction in ESS scores compared with placebo, although the difference was not statistically significant (P = 0.2497). Meanwhile, solriamfetol was well tolerated, with the most common treatment-emergent adverse events (> 10% incidence in any treatment group) including upper respiratory tract infection, hyperuricemia, dizziness, and hypertension.

Conclusion

Solriamfetol showed good efficacy and tolerability regardless of OSA severity among Chinese OSA participants with EDS.

Trial Registration

The parent study was registered at www.chinadrugtrials.org.cn with the trial number CTR20231397 on May 15, 2023.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s12325-026-03690-5.

Key Summary Points

Why carry out this study?

Excessive daytime sleepiness (EDS) is a core symptom of obstructive sleep apnea (OSA), and solriamfetol, as a dual dopamine and norepinephrine reuptake inhibitor, has been approved for treating EDS in patients with OSA across the USA, Europe, and China.

Patients with OSA and different baseline disease severity need individualized management, and this post hoc analysis of a randomized clinical trial aimed to clarify whether baseline apnea hypopnea index (AHI) levels affect the efficacy and safety of solriamfetol.

What was learned from the study?

This subgroup analysis of a randomized clinical trial in Chinese patients with OSA-EDS shows that solriamfetol maintains consistent efficacy and favorable tolerability across OSA severity subgroups stratified by baseline AHI levels.

The results enable clinicians to use solriamfetol reliably across all OSA severity subgroups and lay a foundation for future stratified treatment and precision medicine research.

Introduction

Obstructive sleep apnea (OSA) is a highly prevalent, chronic sleep disorder with significant burden of disease and health consequences [1]. On the basis of the number of apneas and hypopneas per hour of sleep, i.e., the apnea hypopnea index (AHI), persons with an AHI of 5–15, 16–30, or more than 30 were considered to have mild, moderate, or severe OSA [2]. OSA is highly prevalent in the general population, especially in its mild and moderate forms, with the prevalence ranging from 9.4% to 45.7% and from 5.4% to 15.7%, respectively, whereas severe OSA is less prevalent [3–5].

Excessive daytime sleepiness (EDS) is one of the core symptoms and complaints of OSA, causing increased risks of car accidents, mood disorders, adverse cardiovascular outcomes, and impairment of quality of life [6–9]. Even though EDS is reported to normally occur in around one-third of patients with OSA [6, 7], some studies indicate that there is no or only a weakly significant relationship between prevalence of EDS and severity of OSA [7, 10, 11]. Notably, research on EDS management in patients with OSA has increased significantly in recent years. However, the complexity of OSA increases the difficulty of managing EDS, necessitating special attention.

Patients with OSA and different severity require different management strategies and face different challenges. Continuous positive airway pressure (CPAP) is recognized as the first-line treatment for OSA. However, a meta-analysis indicated that CPAP significantly reduced subjective daytime sleepiness but had no effect on objective daytime sleepiness in patients with mild OSA [12]. Moreover, CPAP therapy did not improve cardiovascular morbidity or mortality in patients with mild OSA [13]. Notably, adherence to CPAP is generally lower in patients with mild OSA than in those with more severe OSA, and many patients with mild OSA refuse CPAP treatment. For these reasons, CPAP is not universally recommended for mild OSA [14]. In clinical practice, real-world overall acceptance and adherence to CPAP remains suboptimal, further complicating the management of OSA and associated EDS [7, 15–17]. Additionally, residual EDS is highly prevalent even in patients who receive adequate primary OSA therapy. Together, these findings highlight substantial unmet medical needs for treating patients with OSA and EDS, especially given the heterogeneity in OSA severity and corresponding primary management strategies.

In recent years, several wake-promoting agents have become available for the treatment of OSA-EDS, such as modafinil, pitolisant, and solriamfetol [18]. Solriamfetol, as a dual reuptake inhibitor of dopamine and noradrenaline, was recently been approved for the treatment of patients with OSA and EDS in the USA, Europe, and China [18, 19]. A recently published 12-week, randomized, placebo-controlled clinical trial (Chinadrugtrials.org.cn identifier CTR20231397) showed substantial efficacy and acceptable safety profiles of solriamfetol among Chinese patients with OSA and EDS [20]. Specifically, the profile of participants in that trial could be divided into three cohorts, namely participants who were adherent, non-adherent, or not on primary OSA therapy, which could reflect the real-world clinical practice pattern. A subgroup analysis of this randomized clinical trial further indicated that the efficacy and safety of solriamfetol was not affected by the adherence to primary OSA therapy, which is also consistent with two previous studies conducted in western countries [19, 21, 22]. Thus, this evidence supports the use of solriamfetol as a novel option for patients with OSA and EDS.

Heterogenous baseline AHI levels could be found in the study by Shen et al. [21], which is also in line with the real-world pattern that physicians may face in patients with OSA and a wide range of disease severity. However, little is known that whether the efficacy and safety of solriamfetol is affected by different baseline AHI levels. Thus, the current post hoc study aimed to evaluate the efficacy and safety of solriamfetol among subgroups with different baseline AHI level.

Methods

Study Design

This study was a post hoc analysis of a 12-week, double-blind, placebo-controlled, randomized, parallel-group, multicenter clinical trial (Chinadrugtrials.org.cn identifier CTR20231397). The original trial evaluated the efficacy and safety of solriamfetol for EDS in Chinese adult participants with OSA. The parent randomized clinical trial was approved by the institutional review board of Peking University Sixth Hospital ([2023] Ethics Review No. 22-1) and by the 25 independent ethics committees at all other participating sites. The ethical approval numbers for each study site are summarized in Table S1. The trial was conducted in strict compliance with the principles of the Declaration of Helsinki, as well as the 2020 Good Clinical Practice (GCP) guidelines issued by the National Medical Products Administration of China. All participants gave written informed consent before undergoing any study-related screening assessments.

Detailed description of the trial has been published previously [20]. In brief, eligible participants were randomly allocated in a 1:1 ratio under double-blind conditions to receive either solriamfetol or placebo. Randomization was stratified according to adherence status toward primary OSA therapy, categorized as adherent, non-adherent, or no use of primary OSA treatment. All subjects completed a screening and baseline phase of up to 60 days, followed by a 12-week therapeutic intervention period. Dosing of solriamfetol was titrated up to 150 mg once daily from the first day to the second week of the treatment period on the basis of clinical response and tolerability. Investigators could adjust the dose downward once during the titration phase, while maintaining each participant’s maximum tolerable dosage (75 mg or 150 mg once daily). This stable dose was sustained starting from day 4 of the second treatment week through the completion of the study intervention. After the 12-week therapeutic period, all participants proceeded to a 2-week safety follow-up phase.

Participants

Inclusion and exclusion criteria for participants were previously described [20]. The main inclusion criteria for eligible participants were (1) adults aged 18–75 years, (2) diagnosed with OSA according to International Classification of Sleep Disorders-3 criteria [23], (3) had a baseline mean sleep onset latency < 30 min on the Multiple Sleep Latency Test (MWT), calculated as the average of the first four trials out of five 40-min assessments, (4) an Epworth Sleepiness Scale (ESS) score ≥ 10 at baseline, and (5) a usual nightly sleep duration of ≥ 6 h.

To enhance the generalizability of the study findings, participants qualified if they met one of the following criteria: (1) current use of primary OSA therapy (defined as positive airway pressure, oral pressure therapy, oral appliances or upper airway stimulator) at least once weekly; (2) prior surgical intervention targeting underlying upper airway obstruction; (3) past use of primary OSA therapy for ≥ 1 month with at least one documented therapeutic adjustment (i.e., change in positive airway pressure or mask), despite no current use; (4) no prior use of primary OSA therapy and refusal to initiate such treatment (a small subset of participants). The combined proportion of participants meeting criteria 3 and 4 was restricted to below 30%, ensuring the study population representative of Chinese patients with OSA in clinical practice.

Participants were excluded if they met any of the following: (1) clinically significant medical, behavioral, or psychiatric conditions (other than OSA) known to induce EDS; (2) use of medications that could interfere with EDS assessment—either within a period equivalent to at least 5 half-lives of the medication prior to the baseline visit or throughout the study duration; (3) habitual bedtime later than 1:00 a.m.; (4) occupation involving nighttime or rotating shift work; (5) current or past (within the preceding 2 years) diagnosis of moderate-to-severe substance use disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria; or (6) excessive caffeine consumption (defined as > 600 mg/day) in the week prior to baseline or anticipated during the study.

Outcomes

The parent clinical trial adopted two co-primary efficacy endpoints: (1) alterations from baseline to week 12 in mean sleep latency, which was calculated using the first four tests of five 40-min MWT sessions; (2) shifts in ESS total scores from baseline through week 12 endpoint. In addition to the baseline visit, the MWT measurements were also performed at weeks 2, 5, and 12, while the ESS and PGI-C evaluations were conducted at the weeks 2, 5, 8, and 12. Safety and tolerability profiles were evaluated via treatment-emergent adverse events (TEAEs), vital signs, laboratory tests, 12-lead electrocardiogram, 24-h ambulatory blood pressure monitoring, and physical examination.

Subgroup by Baseline AHI

Leveraging data from patients with OSA-EDS enrolled in the parent study, who exhibited variability in primary OSA therapy receipt and adherence to such therapy, the present subgroup analysis aimed to investigate the efficacy and safety of solriamfetol in patients stratified by OSA severity at enrollment. According to the baseline AHI level, eligible participants were divided into three subgroups, namely patients with OSA-EDS and AHI < 5, 5 ≤ AHI < 30, and AHI ≥ 30, referring to treatment responsive, mild-to-moderate OSA (mmOSA), and severe OSA subgroups.

Statistical Analysis

Post hoc analyses of the co-primary efficacy endpoints (MWT and ESS) in subgroups by baseline AHI levels were performed using a mixed-effects repeated measures model with fixed effects for treatment, visit, treatment-by-visit interaction, and baseline value of the efficacy end point as a covariate. Results were presented as least squares mean change from baseline and standard error (SE), with least squares mean differences from placebo and 95% confidence intervals for the co-primary end points of MWT and ESS. The efficacy analysis above was based on the adjusted full analysis set (FAS), which was defined as participants who were randomized, received at least one dose of the study drug, underwent evaluation at baseline, at least one post-dose efficacy data, and had baseline AHI data.

Safety related parameters (adverse events, heart rate, and blood pressure) were summarized for the adjusted safety set by baseline AHI levels. Likewise, the adjusted safety set comprised participants who not only received at least one dose of the study drug but also had baseline AHI data. All analyses were performed using SAS 9.4.

Results

Demographic and Clinical Characteristics

Among the 204 randomized participants, 3 patients were excluded from the FAS because of invalid post-treatment efficacy evaluation data, yielding 101 patients in the solriamfetol group and 100 patients in the placebo group (Fig. 1). Notably, a participant in the placebo group was further excluded from the current post hoc analysis because of missing baseline AHI data. On the basis of the adjusted FAS, demographic features were very similar between placebo and solriamfetol groups, including age, gender, and BMI, indicating good comparability between them.

Fig. 1.

Enrollment and disposition of participants

Of note, the majority of patients in the solriamfetol group (42.57%, N = 43) and placebo group (42.42%, N = 42) had an AHI less than 5, which can be attributed to the high proportion of patients receiving primary OSA therapy, particularly 97.67% (42/43) and 90.48% (38/42) in the solriamfetol and placebo groups, respectively. Besides, comparable proportions of patients (51.49% and 51.52%, respectively) in each group were adherent to the primary therapy. Detailed baseline characteristics of each subgroup across treatment groups are summarized in Table 1.

Table 1.

Baseline demographics and clinical characteristics by baseline AHI levels (full analysis set)

Variable	Placebo			Solriamfetol
	Baseline AHI < 5 (N = 42)	Baseline 5 ≤ AHI < 30 (N = 34)	Baseline AHI ≥ 30 (N = 23)	Baseline AHI < 5 (N = 43)	Baseline 5 ≤ AHI < 30 (N = 35)	Baseline AHI ≥ 30 (N = 23)
Baseline demographics
Age, years	45.55 (10.84)	45.29 (14.73)	45.35 (12.89)	45.81 (12.38)	45.46 (11.61)	46.57 (11.59)
Male, %	37 (88.10)	30 (88.24)	21 (91.30)	40 (93.02)	31 (88.57)	22 (95.65)
Female, %	5 (11.90)	4 (11.76)	2 (8.70)	3 (6.98)	4 (11.43)	1 (4.35)
BMI, kg/m2	27.15 (3.81)	27.83 (4.21)	26.43 (3.41)	28.40 (3.65)	27.31 (3.46)	27.17 (2.61)
Baseline clinical characteristics
MSL on MWT, min	12.25 (5.41)	12.72 (7.53)	9.93 (6.85)	12.13 (7.42)	11.39 (7.60)	9.58 (5.90)
ESS score	15.43 (2.67)	13.35 (3.02)	13.91 (2.58)	15.07 (3.45)	14.91 (3.97)	14.09 (2.35)
AHI	1.53 (1.27)	15.14 (7.33)	50.49 (17.10)	1.58 (1.33)	14.07 (7.67)	57.08 (16.97)
Primary therapy adherence
Adherent, %	33 (78.57)	14 (41.18)	4 (17.39)	35 (81.4)	15 (42.86)	2 (8.70)
PAP	33	13	2	35	15	1
Oral appliance	0	0	0	0	1	0
Surgery	0	1	2	5	0	1
Non-adherent, %	5 (11.90)	11 (32.35)	3 (13.04)	7 (16.28)	9 (25.71)	4 (17.39)
PAP	5	11	3	7	9	4
Oral appliance	0	0	0	0	0	0
Surgery	0	0	0	0	0	0
No primary therapy, %	4 (9.52)	9 (26.47)	16 (69.57)	1 (2.33)	11 (31.43)	17 (73.91)

Data are presented as mean (SD), unless otherwise indicated

AHI apnea–hypopnea index, BMI body mass index, PAP positive airway pressure, ESS Epworth Sleepiness Scale, MSL mean sleep latency, MWT Maintenance of Wakefulness Test

Efficacy of Solriamfetol Among Patients with Different Baseline AHI level

The magnitude of change in mean MWT sleep latency from baseline to week 12 was consistent among three subgroups stratified by baseline AHI. In all three subgroups, solriamfetol treatment was associated with significantly increased MWT sleep latency compared to placebo at week 12 (LS mean difference [SE] vs. placebo, 12.133 [2.2239] min, 12.676 [2.5363] min, and 10.935 [2.6023] min, P < 0.0001, P < 0.0001, and P = 0.0001 in AHI < 5, 5 ≤ AHI < 30, and AHI ≥ 30 subgroup, respectively). Of note, a significantly prolonged MWT sleep latency was observed in the solriamfetol group as early as week 2 across all subgroups (Fig. 2).

Fig. 2.

Subgroup analysis by baseline AHI on LS mean changes of MWT sleep latency from baseline to week 2, week 5, and week 12. At week 12, solriamfetol significantly prolonged MWT sleep latency compared with placebo with the least squares (LS) mean differences (standard error, SE) versus placebo of 12.133 (2.2239) min in the AHI < 5 subgroup, 12.676 (2.5363) min in the 5 ≤ AHI < 30 subgroup, and 10.935 (2.6023) min in the AHI ≥ 30 subgroup. AHI, apnea hypopnea index; LS, least square; MWT, maintenance of wakefulness test. **P < 0.01; ***P < 0.001

Patterns of change in ESS from baseline to week 12 among the three subgroups were generally in line with those in the overall population. In subgroups of AHI < 5 and 5 ≤ AHI < 30, solriamfetol treatment was associated with significantly decreased ESS scores (LS mean difference [SE] vs. placebo, − 2.0 [0.95] and − 2.1 [1.01], P = 0.0404 and P = 0.0394, respectively). Notably, a significantly decreased ESS score was found as early as week 8 in subgroup of AHI < 5. In the subgroup of AHI ≥ 30, numerically greater reductions in ESS scores were observed in the solriamfetol group than in the placebo group, though statistical significance was not achieved (LS mean difference vs. placebo, − 1.3 [1.10], P = 0.2497) (Fig. 3).

Fig. 3.

Subgroup analysis by baseline AHI on LS mean changes of ESS scores from baseline to week 2, week 5, week 8, and week 12. At week 12, solriamfetol treatment significantly decreased ESS scores with LS mean difference (SE) vs. placebo of − 2.0 (0.95) in AHI < 5 subgroup and − 2.1 (1.01) in 5 ≤ AHI < 30 subgroup, respectively. AHI, apnea hypopnea index; LS, least square; ESS, Epworth Sleepiness Scale. *P < 0.05

Safety of Solriamfetol Among Patients with Different Baseline AHI Level

Generally, a higher percentage of participants in the solriamfetol group experienced ≥ 1 TEAEs than those in the placebo group across all three subgroups stratified by baseline AHI. Per the Common Terminology Criteria for Adverse Events, the severity of most TEAEs was classified as grade < 2. Specifically, one participant (2.38%) with AHI < 5 in the placebo group and one participant (2.88%) with 5 ≤ AHI < 30 in the solriamfetol group developed a serious TEAE, respectively. No death occurred. The most common TEAEs (> 10% in any treatment groups) included upper respiratory tract infection, hyperuricemia, dizziness, and hypertension (Table 2).

Table 2.

Safety and tolerability (safety analysis set)

Variable	Placebo			Solriamfetol
	Baseline AHI < 5 (N = 43)	Baseline 5 ≤ AHI < 30 (N = 34)	Baseline AHI ≥ 30 (N = 24)	Baseline AHI < 5 (N = 43)	Baseline 5 ≤ AHI < 30 (N = 35)	Baseline AHI ≥ 30 (N = 24)
Overall
Any TEAEs	27 (62.8)	23 (67.6)	16 (66.7)	35 (81.4)	29 (82.9)	20 (83.3)
TEAEs related to trial drug	12 (27.9)	13 (38.2)	5 (20.8)	15 (34.9)	13 (37.1)	8 (33.3)
Serious TEAEs	1 (2.3)	0	0	0	1 (2.9)	0
TEAEs leading to early withdrawal from the study	0	0	0	1 (2.3)	1 (2.9)	0
TEAEs leading to discontinuation of study drug	0	0	0	1 (2.3)	1 (2.9)	0
TEAEs with CTCAE ≥ 3	1 (2.3)	3 (8.8)	1 (4.2)	2 (4.7)	2 (5.7)	1 (4.2)
Most common TEAEs (> 10%)
Upper respiratory tract infection	4 (9.3)	4 (11.8)	3 (12.5)	7 (16.3)	7 (20.0)	5 (20.8)
Hyperuricemia	0	5 (14.7)	3 (12.5)	2 (4.7)	4 (11.4)	2 (8.3)
Dizziness	0	1 (2.9)	0	7 (16.3)	2 (5.7)	2 (8.3)
Hypertension	1 (2.3)	4 (11.8)	0	2 (4.7)	4 (11.4)	1 (4.2)

Data are presented as no. (%)

TEAE treatment-emergent adverse event, CTCAE Common Terminology Criteria for Adverse Events, AHI apnea–hypopnea index

Of note, across three OSA severity subgroups stratified by baseline AHI, the solriamfetol group showed small and similar mean elevations in heart rate, systolic blood pressure, and diastolic blood pressure from baseline at week 12 compared to the placebo group (Table 3).

Table 3.

Change from baseline to week 12 in vital signs (safety analysis set)

Vital sign	Placebo			Solriamfetol
	Baseline AHI < 5 (N = 43)	Baseline 5 ≤ AHI < 30 (N = 34)	Baseline AHI ≥ 30 (N = 24)	Baseline AHI < 5 (N = 43)	Baseline 5 ≤ AHI < 30 (N = 35)	Baseline AHI ≥ 30 (N = 24)
No.	38	33	22	41	30	23
Heart rate, beats/min	− 0.03 (4.79)	− 0.94 (4.78)	− 0.20 (10.35)	2.03 (7.99)	0.76 (6.63)	6.26 (6.45)
BP, mmHg
Systolic	− 0.21 (6.30)	− 2.53 (5.81)	− 1.72 (6.60)	1.70 (5.30)	2.74 (6.78)	1.77 (6.59)
Diastolic	− 0.96 (5.11)	− 0.33 (5.34)	− 1.86 (4.04)	0.25 (4.71)	1.26 (4.83)	− 0.20 (5.06)

Data are presented as mean (SD), unless otherwise indicated. Change from baseline is averaged across all time points on 12 MWT day

AHI apnea–hypopnea index, BP blood pressure

Discussion

In the current subgroup analysis of a randomized clinical trial among Chinese patients with OSA-EDS, solriamfetol treatment displayed robust efficacy in managing OSA-EDS, as evidenced by the consistent prolonged MWT sleep latency and decreased ESS scores among three subgroups stratified by baseline AHI. Moreover, similar safety profiles were detected among subgroups after solriamfetol administration, which supports the conclusion that solriamfetol demonstrates reliable efficacy and a well-tolerated safety profile in patients across different baseline AHI levels.

Of note, among the available wake-promoting agents for addressing residual EDS in patients with OSA, a network meta-analysis based on 18 studies showed that solriamfetol achieved the greatest improvement in ESS scores and sleep latency compared with pitolisant, modafinil, and armodafinil [18]. Findings from the study by Cheng et al. further indicated good efficacy and acceptable safety profile among Chinese patients with OSA and EDS [20]. Our study group recently conducted a subgroup analysis based on different adherence levels to primary OSA therapy, showing that solriamfetol efficacy and safety was not affected by usage of primary OSA therapy [21], which is quite important considering the real-world complexity of OSA management. Further, our current study provides evidence to solve another clinical question regarding the complexity of disease severity.

The baseline AHI-based stratification in this study may not fully reflect the complex pathophysiology and intrinsic severity of OSA [24], owing to confounding factors including CPAP adherence, nocturnal variability, and scoring bias. Nonetheless, it retains practical reference value for guiding the clinical identification of treatment responses across distinct patient subgroups. Besides, findings from another post hoc analysis of the solriamfetol clinical trial showed consistent AHI levels across the 12-week study duration [25], which, to some extent, indicates that stratification by baseline AHI adequately captures the variability in disease severity during the randomized controlled trial, thus supporting the validity of subgroup analyses assessing treatment efficacy across different OSA severity levels.

Most of the patients with baseline AHI < 5 had well-controlled OSA symptoms with CPAP yet still experienced residual sleepiness, which reflects the wide range of real-world patients with residual EDS. A recently conducted prospective study reported that as high as 28.2% patients with OSA still had EDS even after a medium duration of 5 months treatment with CPAP [26]. Consistent with previous studies [27, 28], solriamfetol demonstrated efficacy in reducing EDS in this subgroup cohort by significantly improving MWT sleep latency and decreasing ESS scores, suggesting its potential as an adjunctive therapy to CPAP and highlighting its prominent value in managing patients with post-treatment residual symptoms.

Of note, patients with OSA and AHI levels ranging from 5 to 30 are highly prevalent and account for about 5.4–45.7% of the general OSA population [29]. In the parent randomized controlled trial, a notable proportion of patients with mmOSA (N = 69, 34.5% of total cohort) were included for efficacy and safety evaluation, of which around 60% patients had poor or no adherence on any primary OSA therapy. This is consistent with findings that CPAP is not universally recommended, well accepted, or adherent among patients with OSA of milder severity. Notably, although mmOSA is reported to be associated with increased risk of incident hypertension in a previous study [5], it was found that conventional therapy such as CPAP is not always successful with mmOSA, especially in the presence of non-anatomical traits for patients [30]. The absence of compelling evidence for cardiovascular morbidity and mortality improvement by CPAP in patients with mild OSA [13] also contributed to the poor adherence of CPAP primary therapy. It was once reported that up to 47% of the CPAP-treated patients with OSA quit treatment by 3 years [31]. Solriamfetol was found to be effective and well tolerated for patients with OSA and baseline 5 ≤ AHI < 30 in the current analysis, as evidenced by a significant prolongation in MWT duration and a reduction in ESS scores. Given the poor adherence to CPAP therapy among patients with milder severity of OSA, wake-promoting agents such as solriamfetol might also serve as a possible supportive therapeutic option for sleepy patients with OSA and low AHI levels to improve their quality of life [24].

The current analysis included around 23% of patients who had baseline AHI ≥ 30, most of whom were not on any primary OSA therapy. Such patients were included to better reflect real-world practice in the management of OSA [20]. Similar trends in efficacy and safety of solriamfetol were also found in this subgroup. Specifically, small numerically increases in heart rate and blood pressure compared to placebo were observed in this subgroup, which is also consistent with previous results from other subgroups. Taken together, these findings suggest that solriamfetol may serve as a symptomatic supportive treatment for OSA-EDS with different baseline AHI levels. It is important to note that solriamfetol should not be considered as a substitute for therapy targeting airway problems. Especially for patients had AHI higher than 30, the use of primary OSA therapy should be highly recommended. Physicians should accordingly reinforce the critical role of primary OSA interventions and encourage consistent patient adherence.

Similar to prior subgroup analyses of other factors [19, 21, 22], the efficacy and safety profile of solriamfetol was also consistently observed in subgroups of OSA severity stratified by baseline AHI. The improvement in MWT sleep latency exceeded the clinically meaningful threshold of 4 min in all subgroups [32]. Meanwhile, the magnitude of improvement in ESS scores with solriamfetol vs. placebo was relatively smaller and statistically non-significant in the subgroup with an AHI ≥ 30. This finding may be attributable to the limited sample size and a stronger placebo effect observed for this subjective outcome measure compared with objective indices. However, caution should be exercised regarding potential cardiovascular risks (e.g., mild pulse rate elevation), and routine monitoring of blood pressure and heart rate is recommended for patients with severe OSA-EDS receiving solriamfetol. Notably, solriamfetol represents a valuable adjunct to CPAP therapy in this patient population, thereby optimizing the comprehensive management of OSA-EDS.

A key strength of this study lies in its simulation of real-world clinical scenarios commonly encountered by clinicians in the management of patients with OSA-EDS, including patient subgroups stratified by primary therapy receipt, treatment adherence status, and the extent of therapeutic improvement achieved. In addition to AHI, a recent study indicated that elevated arousal threshold may contribute to EDS by prolonging respiratory events, exacerbating intermittent hypoxia, increasing sleep pressure, and disrupting architecture [33]. One potential future research direction would be stratified analysis of solriamfetol based on the baseline arousal index.

This study has several limitations. First, the baseline AHI levels of the current study may not reflect the original disease severity because of confounding by different adherence to primary OSA therapy. The mild (5 ≤ AHI < 15) and moderate (15 ≤ AHI < 30) OSA subgroups contained inadequate sample sizes for independent testing; we therefore merged these two strata for pooled statistical analyses in the present study. Further comparison is warranted in future large-scale studies. In addition, as a result of the small sample size in each subgroup, a further sensitivity analysis by adherence to primary therapy was difficult to perform and is therefore highly encouraged in future studies. Second, the exploratory nature of this post hoc analysis and enrollment of a relatively small sample size in each subgroup, all of whom were of Chinese ethnicity, limited the robustness of the study findings to some extent. Further validation is warranted in larger cohorts and across diverse ethnic populations in real-world settings. Besides, the accuracy of ESS for measuring daytime sleepiness may not be really relevant for Asian population since some questions are not suitable for the Asian population who usually do nap after lunch and use a motorcycle but not a car. Finally, the behavioral impacts of solriamfetol on patients remain unexplored, specifically its potential effects on occupational injury and motor vehicle crash risk in OSA-EDS cohorts. The real-world clinical impact of solriamfetol thus merits further investigation.

Conclusions

In a subgroup analysis of a randomized clinical trial involving Chinese patients with OSA-EDS, solriamfetol demonstrated consistent efficacy and good tolerability across all subgroups of OSA severity stratified by baseline AHI.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Rui Chen and Changjun Sun contributed to the conceptualization, formal analysis, methodology, project administration, supervision, validation, visualization, and writing—review and editing of this study. Jiucheng Shen participated in the conceptualization and data curation. Kaida Guo, Jing Wang, Zhijun Wang, Shiyuan Gao, Qiaojun Wang, and Fei Han assisted with data curation and critically revised the manuscript. Weijia Zhang, Hui Ye, and Xiang Li contributed to the conceptualization and methodology. Ruolin Zhang was involved in the formal analysis and critically revised the manuscript. All authors have approved and reviewed the final manuscript in line with ICMJE guidelines.

Funding

Sponsorship for this study and Rapid service Fee and Open Access Fee were funded by the Ignis Therapeutics (Suzhou) Limited, China but will be paid by the authors.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Weijia Zhang, Hui Ye, Xiang Li, and Ruolin Zhang are employees of Ignis Therapeutics (Shanghai) Limited. All other authors; Changjun Su, Jiucheng Shen, Kaida Guo, Jing Wang, Zhijun Wang, Shiyuan Gao, Qiaojun Wang, Fei Han and Rui Chen declare no conflicts of interest.

Ethical Approval

The parent randomized clinical trial was approved by the institutional review board of Peking University Sixth Hospital ([2023] Ethics Review No. 22-1) and by the 25 independent ethics committees at all other participating sites. The ethical approval numbers for each study site are summarized in Table S1.