Table 2.

Objectives and endpoints.

Primary objective	Endpoint
To demonstrate that tirzepatide QW at the MTD (10 or 15 mg) is superior to placebo for mean decrease in AHI	Change in AHI from baseline to week 52 (events/hour)
Key secondary objectives (controlled for type I error)	Endpoints
To demonstrate that tirzepatide QW at the MTD (10 or 15 mg) is superior to placebo for: • Change in AHI • A hierarchical assessment of PROs • Clinically meaningful change in AHI • Achieving OSA remission or mild non-symptomatic OSA • Change in body weight • Change in inflammatory status • Change in SBP	From baseline to week 52: • Percent change in AHI • A hierarchical combination of change in:  ○ FOSQ-10 score  ○ FOSQ-30 vigilance subscale score  ○ FOSQ-30 activity level subscale score • Percent of participants with ≥50% AHI reduction • Percent of participants with  ○ AHI <5 events/hour or  ○ AHI 5–14 events/hour with ESS score ≤10 • Percent change in body weight • Change in hsCRP concentration From baseline to week 48a: • Change in SBP
Other secondary objectives	Endpoints
To demonstrate that tirzepatide QW at the MTD (10 or 15 mg) is superior to placebo for: • Change in excessive daytime sleepiness • Change in patient-reported functional status as assessed by FOSQ (30-item) • Change in body weight • Change in lipid parameters • Change in PROs • Insulin • Hypoxic burden • Change in DBP	From baseline to week 52: • Change in ESS score • Change in all other FOSQ domain scores • Percent of participants who achieve  ○ ≥10% body weight reduction  ○ ≥15% body weight reduction  ○ ≥20% body weight reduction • Change in  ○ HDL cholesterol  ○ Non-HDL cholesterol  ○ Triglycerides • Change in  ○ PROMIS sleep-related impairment short form 8a score  ○ PROMIS sleep disturbance short form 8b score  ○ SF-36v2 acute form domain scores • Percent of participants with improved categorical shift in PGIS score for  ○ OSA sleepiness  ○ OSA fatigue  ○ OSA snoring • Change in fasting insulin • Change in SASHB (% min/hour) From baseline to week 48a: • Change in DBP
Exploratory objectives	Endpoints
To demonstrate that tirzepatide QW at the MTD (10 or 15 mg) is superior to placebo for: • Change in PROs • To evaluate the effect of tirzepatide on sleep parameters as measured by actigraphy (Axivity AX6 accelerometer)	From baseline to week 52: • Change in  ○ EQ-5D-5L utility index  ○ EQ-VAS scores • Percent of participants with improved categorical shift in PGIC score for:  ○ OSA sleepiness  ○ OSA fatigue  ○ OSA sleep quality  ○ OSA snoring • Mean change from baseline to endpoint assessment in:  ○ Daytime sleep duration  ○ Daily step counts  ○ Average acceleration

Abbreviations: AHI, apnea-hypopnea index; BP, blood pressure; DBP, diastolic blood pressure; EQ-5D-5L, EuroQol 5-Dimension 5-Level; EQ-VAS, EuroQol visual analogue scale; ESS, Epworth Sleepiness Scale; FOSQ-10, Functional Outcomes of Sleep Questionnaire short version; FOSQ-30, Functional Outcomes of Sleep Questionnaire long version; HDL, high -density lipoprotein; hsCRP, high -sensitivity C-reactive protein; MTD, maximum tolerated dose; OSA, obstructive sleep apnea; PGIC, Patient Global Impression of Change; PGIS, Patient Global Impression of Severity; PROs, patient -reported outcomes; PROMIS, Patient -Reported Outcomes Measurement Information System; QW, once weekly; SASHB, sleep apnea-specific hypoxic burden; SBP, systolic blood pressure; SF-36v2, Short-Form 36 Health Survey version 2.

^aBP will be assessed at week 48 because positive airway pressure suspension at week 52 may confound BP assessment.