Open-Label, Single-Center, Randomized, 2-way Crossover Study Evaluating Relative Bioavailability of OC-01 (Varenicline) Nasal Spray as Compared to Orally Administered Varenicline (the ZEN Study)

Molecule Varenicline solution nasal spray (formerly known as OC-01)
Therapeutic focus Dry eye disease2
Phase 1
Status Completed
Participants 22
Completion Date November 15, 2019

Note: This clinical trial was not included in the submission which resulted in Tyrvaya® approval.
1. https://clinicaltrials.gov/study/NCT04072146; 2. Nau J. et al. Clinical Therapeutics. 2021;43:1595–1607.

Trial Design1

The study objective was to compare the systemic bioavailability of varenicline nasal spray with that of varenicline administered orally1

Note: The FDA-approved dosage of varenicline solution nasal spray is 0.03 mg BID.2 *Delivered as one 50-μL spray of varenicline 1.2 mg/mL into each nostril; †Delivered as a single oral tablet.1
OD, once daily; FDA, Food and Drug Administration.
1. Nau J. et al. Clinical Therapeutics. 2021;43:1595–607; 2. TYRVAYA®(varenicline solution) nasal spray. Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213978s005lbl.pdf.

Inclusion Criteria

  • ≥18 and ≤65 years old at screening1
  • Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2 1
  • Healthy as determined by an experienced physician within 28 days before study entry, based on medical history, vital signs, physical examination, 12-lead electrocardiogram (ECG), intranasal examination, and laboratory tests (serology, hematology, clinical chemistry, and urinalysis)2
  • A negative urine pregnancy test at screening visit if female and of childbearing potential without use an acceptable means of birth control*1
*Acceptable methods of contraception include hormonal (oral, implantable, injectable, or transdermal contraceptives) or mechanical (spermicide in conjunction with a barrier such as a diaphragm or condom, intrauterine device, or surgical sterilization of partner).1
1. https://clinicaltrials.gov/study/NCT04072146; 2. Nau J. et al. Clinical Therapeutics. 2021;43:1595–1607.

Exclusion Criteria

  • Nasal or sinus surgery (including history of application of nasal cautery) or significant trauma to these areas1
  • Vascularized polyp, severely deviated septum, chronic recurrent nosebleeds, or severe nasal airway obstruction as confirmed by intranasal examination1
  • Active nasal infection at screening visit2
  • Current use of nasal continuous positive airway pressure (CPAP) therapy2
  • Any contraindication to varenicline according to the applicable label1
  • Severe renal impairment (estimated creatinine clearance less than 30 mL/min1)
  • Concomitant use of snuff, chewing tobacco, e-cigarettes or cigarettes/cigars1
  • Concomitant use of nicotinic acetylcholine receptor (nAChR) agonists (nicotine/cytisine/varenicline)2
  • Any condition or history that, in the opinion of the investigator, may interfere with study compliance, outcome measures, safety parameters, and/or the general medical condition of the subject1
  • Female who is pregnant, nursing an infant, or planning a pregnancy at screening1
  • Female of childbearing potential who is not using an acceptable means of birth control (see inclusion criteria for acceptable methods of contraception)1
  • Currently enrolled in an investigational drug or device study or used an investigational drug or device within 30 days prior to screening1
1. https://clinicaltrials.gov/study/NCT04072146; 2. Nau J. et al. Clinical Therapeutics. 2021;43:1595–1607.

Primary Endpoint

  • Relative systemic bioavailability of intranasal vs oral varenicline, at highest intended single dose, using estimates of AUC0–t, AUC0–∞, Cmax and Tmax
    • Nau J. et al. Clinical Therapeutics. 2021;43:1595–1607.

Safety Endpoints

  • Clinical and laboratory tolerability of intranasal and oral varenicline, assessed through vital signs, physical and intranasal examinations, 12-lead ECG, and laboratory tests (hematology, clinical chemistry, and urinalysis)*
  • Adverse events (AEs)†
*Performed before the patient received intranasal or oral varenicline on days 1 and 15, 2 hours after each dose, and/or at the final study visit; †AEs were monitored throughout the study period and coded using Medical Dictionary for Regulatory Activities, version 22.0.
ECG, electrocardiogram.
Nau J. et al. Clinical Therapeutics. 2021;43:1595–1607.

Baseline Characteristics

*Data presented as mean (SD), unless otherwise specified.
BMI, body mass index.
Nau J. et al.Clinical Therapeutics. 2021;43:1595–1607.

Efficacy Outcome Measures – Primary Endpoint

Mean change in systemic exposure over time (n=16)1

Note: The FDA-approved dosage of varenicline solution nasal spray is 0.03 mg BID.2
AUC, area under the curve; Cmax, maximum observed concentration; LLOQ, lower limit of quantification.

1. Nau J. et al.Clinical Therapeutics. 2021;43:1595–1607; 2. TYRVAYA®(varenicline solution) nasal spray. Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213978s005lbl.pdf.

Safety Outcome Measures*1

Note: The FDA-approved dosage of varenicline solution nasal spray is 0.03 mg BID.2 *Data presented as n (%); †One participant completed treatment period 1 with oral varenicline but was discontinued from the study before dosing in treatment period 2 due to adverse events unrelated to study treatment (headache and increased blood pressure); ‡Serious TEAEs were defined as those resulting in death, a life-threatening adverse event, inpatient hospitalization or prolonged hospitalization, persistent or significant incapacity or substantial disruption to normal life functions, a congenital anomaly or birth defect in an offspring, or any other medically important event that could jeopardize the participant and require medical intervention to prevent such an outcome.1
TEAE, treatment-emergent adverse event.
1. Nau J. et al.Clinical Therapeutics.2021;43:1595–1607; 2. TYRVAYA®(varenicline solution) nasal spray. Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213978s005lbl.pdf.