Efficacy and Safety of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The ONSET-2 Phase 3 Randomized Trial.

PURPOSE: To evaluate the efficacy and safety of OC-01 (varenicline solution) nasal spray for treatment of patients with dry eye disease. DESIGN: Randomized, multicenter, double-masked, vehicle-controlled, phase 3 study. PARTICIPANTS: Adults 22 years of age or older with a diagnosis of dry eye disease, artificial tear use, Ocular Surface Disease Index score of 23 or more, and Schirmer test score (STS) of 10 mm or less. Eligibility was not restricted by eye dryness score (EDS). METHODS: Patients (N = 758) were randomized in a 1:1:1 ratio to twice-daily treatment with 50-µl intranasal spray in each nostril of OC-01 0.03 mg (n = 260), OC-01 0.06 mg (n = 246), or vehicle (control; n = 252) for 4 weeks (ClinicalTrials.gov identifier, NCT04036292). MAIN OUTCOME MEASURES: The primary efficacy end point was the percentage of patients achieving a 10-mm improvement or more in STS at week 4. Secondary end points included change from baseline to week 4 in STS and EDS in a controlled adverse environment (CAE) chamber and in the clinic. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: A statistically significantly greater percentage of patients achieved the primary end point in both OC-01 treatment groups compared with the vehicle group (OC-01 0.03 mg, 47.3%; OC-01 0.06 mg, 49.2%; vehicle, 27.8%; P < 0.0001 for both doses). Change from baseline in STS at week 4 was statistically significantly greater for patients receiving OC-01 than vehicle (P < 0.0001 for both doses). Eye dryness score assessed at week 4 improved with OC-01 treatment compared with vehicle, although the difference was not significant for EDS measured in the CAE chamber and showed (nominal) significance in the clinic. Overall, 86.5% of patients (654/756) reported at least 1 TEAE during the treatment period; most were mild, nonocular (sneezing, cough, throat irritation, and instillation site irritation) and were reported by fewer patients in the vehicle group than in the OC-01 treatment groups (OC-01 0.03 mg, 97.3%; OC-01 0.06 mg, 99.2%; vehicle, 57%). CONCLUSIONS: OC-01 nasal spray was well tolerated and showed a clinically meaningful effect on signs and symptoms of dry eye disease.

A phase II randomized trial to evaluate the long-term (12-week) efficacy and safety of OC-01 (varenicline solution) nasal spray for dry eye disease: The MYSTIC study.

PURPOSE: Dry eye disease is characterized by loss of tear film stability. OC-01 (varenicline solution) is a small-molecule nicotinic acetylcholine receptor agonist administered as a nasal spray that stimulates tear production. METHODS: In MYSTIC (NCT03873246) patients aged ≥22 years with dry eye disease were randomized 1:1:1 to OC-01 0.03 mg, OC-01 0.06 mg, or vehicle (n = 41 per group), administered twice daily via intranasal spray, for 12 weeks (84 days). Primary efficacy endpoint was mean change from baseline in anesthetized Schirmer's test score (STS) in study eye at day (D) 84. RESULTS: Patients receiving OC-01 0.03 and 0.06 mg had statistically significantly increased tear production at D84 versus vehicle; least squares mean changes from baseline in STS were 10.8 mm and 11.0 mm for OC-01 0.03 and 0.06 mg, respectively. A trend toward a higher proportion of patients experiencing ≥10-mm improvement in STS from baseline was observed with OC-01 0.03 mg (36.6%; p > 0.05), and was significant for OC-01 0.06 mg (48.8%; p = 0.024), versus vehicle (24.4%). Non-ocular treatment-emergent adverse events (TEAEs) were reported by 21 patients; the most common was sneezing (OC-01 0.03 mg, 2 [4.9%]; OC-01 0.06 mg, 3 [7.3%]), with similar frequencies between treatment groups. No severe or serious TEAEs were reported. CONCLUSIONS: OC-01 (varenicline solution) nasal spray improved tear production in patients with dry eye disease over a long-term (12-week) period, and represents a receptor neuro-activator with a nasal route of administration that spares the ocular surface to stimulate tear production.

Maternal Cardiovascular Dysregulation During Early Pregnancy After In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.

Commonly used in vitro fertilization protocols produce pregnancies without a corpus luteum (CL), a major source of reproductive hormones. In vitro fertilization pregnancies without a CL showed deficient gestational increases of central (aortic) arterial compliance during the first trimester and were at increased risk for developing preeclampsia. Here, we investigated whether there was generalized impairment of cardiovascular adaptation in in vitro fertilization pregnancies without a CL compared with pregnancies conceived spontaneously or through ovarian stimulation, which lead to 1 and >1 CL, respectively (n=19-26 participants per cohort). Prototypical maternal cardiovascular adaptations of gestation were serially evaluated noninvasively, initially during the follicular phase before conception, 6× in pregnancy, and then, on average, 1.6 years post-partum. The expected increases of cardiac output, left atrial dimension, peak left ventricular filling velocity in early diastole (E wave velocity), peripheral/central arterial pulse pressure ratio, and global AC, as well as decrease in augmentation index were significantly attenuated or absent during the first trimester in women who conceived without a CL, when compared with the 1 and >1 CL cohorts, which were comparable. Thereafter, these cardiovascular measures showed recovery in the 0 CL group except for E wave velocity, which remained depressed. These results provided strong support for a critical role of CL factor(s) in the transformation of the maternal cardiovascular system in early gestation. Regimens that lead to the development of a CL or replacement of missing CL factor(s) may be indicated to improve cardiovascular function and reduce preeclampsia risk in in vitro fertilization pregnancies.

Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.

In vitro fertilization involving frozen embryo transfer and donor oocytes increases preeclampsia risk. These in vitro fertilization protocols typically yield pregnancies without a corpus luteum (CL), which secretes vasoactive hormones. We investigated whether in vitro fertilization pregnancies without a CL disrupt maternal circulatory adaptations and increase preeclampsia risk. Women with 0 (n=26), 1 (n=23), or >1 (n=22) CL were serially evaluated before, during, and after pregnancy. Because increasing arterial compliance is a major physiological adaptation in pregnancy, we assessed carotid-femoral pulse wave velocity and transit time. In a parallel prospective cohort study, obstetric outcomes for singleton livebirths achieved with autologous oocytes were compared between groups by CL number (n=683). The expected decline in carotid-femoral pulse wave velocity and rise in carotid-femoral transit time during the first trimester were attenuated in the 0-CL compared with combined single/multiple-CL cohorts, which were similar (group-time interaction: P=0.06 and 0.03, respectively). The blunted changes of carotid-femoral pulse wave velocity and carotid-femoral transit time from prepregnancy in the 0-CL cohort were most striking at 10 to 12 weeks of gestation ( P=0.01 and 0.006, respectively, versus 1 and >1 CL). Zero CL was predictive of preeclampsia (adjusted odds ratio, 2.73; 95% CI, 1.14-6.49) and preeclampsia with severe features (6.45; 95% CI, 1.94-25.09) compared with 1 CL. Programmed frozen embryo transfer cycles (0 CL) were associated with higher rates of preeclampsia (12.8% versus 3.9%; P=0.02) and preeclampsia with severe features (9.6% versus 0.8%; P=0.002) compared with modified natural frozen embryo transfer cycles (1 CL). In common in vitro fertilization protocols, absence of the CL perturbed the maternal circulation in early pregnancy and increased the incidence of preeclampsia.

Wave reflections and global arterial compliance during normal human pregnancy.

Profound changes occur in the maternal circulation during pregnancy. Routine measures of arterial function - central systolic pressure (CSP) and augmentation index (AIx) - decline during normal human pregnancy. The objectives of this study were twofold: (1) explore wave reflection indices besides CSP and AIx that are not routinely reported, if at all, during normal human pregnancy; and (2) compare wave reflection indices and global arterial compliance (gAC) obtained from carotid artery pressure waveforms (CAPW) as a surrogate for aortic pressure waveforms (AOPW) versus AOPW synthesized from radial artery pressure waveforms (RAPW) using a generalized transfer function. To our knowledge, a comparison of these two methods has not been previously evaluated in the context of pregnancy. Ten healthy women with normal singleton pregnancies were studied using applanation tonometry (SphygmoCor) at pre-conception, and then during 10-12 and 33-35 gestational weeks. CSP and AIx declined, and gAC increased during pregnancy as previously reported. As a consequence of the rise in gAC, the return of reflected waves of lesser magnitude from peripheral reflection sites to the aorta was delayed that, in turn, reduced systolic duration of reflected waves, augmentation index, central systolic pressure, LV wasted energy due to reflected waves, and increased brachial-central pulse pressure. For several wave reflection indices, those derived from CAPW as a surrogate for AOPW versus RAPW using a generalized transfer function registered greater gestational increases of arterial compliance. This discordance may reflect imprecision of the generalized transfer function for some waveform parameters, though potential divergence of carotid artery and aortic pressure waveforms during pregnancy cannot be excluded.