A Study to Learn About the Study Medication, Zavegepant, in Healthy Volunteers

Phase 1

Completed

Conditions: Biological Availability

Interventions: Drug: Zavegepant 100mg non-enteric coated soft gel capsule
Drug: Zavegepant 100mg immediate release tablet
Drug: Zavegepant 2 x 100mg immediate release tablets
Drug: Zavegepant 4 x 25mg enteric coated soft gel capsule

Registration Number: NCT06137703

Lead Sponsor: Pfizer

Brief Summary: This trial is designed to compare the rate and extent of absorption of four different formulations of zavegepant. 52 healthy male and female volunteers will receive a single dose of each formulation at least 7 days apart over a period of about 7 weeks and the amount of drug in their blood will be assessed over the 24 hour period after each dose.

Detailed Description: This is a Phase 1, single centre, open-label, single dose, 4-period, crossover study designed to compare the pharmacokinetics (PK) of zavegepant from three Test products and a Reference product (treatment D).

52 male and female healthy volunteers will be randomly assigned to one of 4 treatment sequences: ACBD, CDAB, BADC, and DBCA.

In each period, subjects will receive one of the following: Treatment A, B, C, or D on Day 1, followed by 24 hours of PK and safety assessments. On Day 2 subjects will be discharged from the clinical site and instructed to return after at least a 7 day washout time has passed for subsequent periods of treatment.

The study will include a screening visit from Day -28 to Day -2. Eligible subjects will be admitted to the clinical site on Day -1 and will be confined until completion of the assessments on Day 2. There will be a washout period of at least 7 days between doses. Study Exit procedures will be performed after the last assessment on the morning of Day 2 of Period 4. Study Exit procedures will be performed as soon as possible in case of Early Termination.

The total duration of study participation for each subject from Screening through Study Exit is anticipated to be approximately 6.5 weeks.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

Inclusion Criteria

Participants must provide Informed Consent Form (ICF) obtained prior to the conduct of any study activities.
Healthy Male or female participants at least 18 and less than 56 years of age,
Participants must be Non-smokers and not have used any nicotine-containing products for 3 months prior to screening.
Body Mass Index (BMI) >18.5 and <30.0kg/m2 and body weight ≥ 50.0kg for males and ≥ 45.0kg for females.
All females participants must not be breastfeeding and have a negative urine pregnancy test at Screening.
Females of childbearing potential must be willing to use acceptable contraceptive methods throughout the study and for 30 days after the last study drug administration.
Male participants with a female partner of childbearing potential must be willing to use acceptable contraceptive methods from the first study drug administration until at least 90 days after the last study drug administration.

Exclusion Criteria

Current diagnosis of viral hepatitis or a history of liver disease.
Any history of seizure disorder (e.g., epilepsy) other than a single childhood febrile seizure.
Current or recent (within 3 months of the first study drug administration) gastrointestinal disease that may interfere with drug absorption.
Prior gastrointestinal surgery that interferes with absorption and motility (e.g., gastric bypass, duodenectomy or gastric banding).
History of drug or alcohol abuse.
History of anaphylaxis, a documented hypersensitivity reaction, or a clinically significant reaction to any drug or to any of the excipient supporting the zavegepant formulations.
Donation of plasma within 7 days prior to dosing, or donation or loss of blood (excluding volume drawn at Screening) of 50 mL to 499 mL of blood within 30 days, or more than 499 mL within 56 days prior to dosing.
Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to the dosing, extended to 90 days for biological products.
Inability or difficulty to swallow tablets or capsules.
Subjects with any clinically significant abnormality or significant abnormal laboratory test results found during medical screening or Day-1. Positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody during screening.
Inadequate renal function - estimated glomerular filtration rate (eGFR) according to the Modification of Diet in Renal Disease (MDRD) study equation ≤ 60 mL/min/1.73 m2 at Screening.
Any of the following laboratory parameters greater than the upper limit of normal (ULN) values at Screening or Baseline (Day -1): alkaline phosphatase (ALP) aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, direct bilirubin, and indirect bilirubin, and alkaline phosphatase.
Any clinically significant abnormalities on 12-lead ECG or blood pressure (BP) at Screening or Baseline (Day -1) visits.
Any clinically significant abnormal haematological laboratory test values at Screening or Baseline (Day -1) visits.
Positive test for COVID-19 performed on Day -1 of each period.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sequence 2	Zavegepant 4 x 25mg enteric coated soft gel capsule	Period 1 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 2 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg immediate release tablet (Treatment B).
Sequence 1	Zavegepant 100mg immediate release tablet	Period 1 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 2 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 4 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D).
Sequence 2	Zavegepant 2 x 100mg immediate release tablets	Period 1 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 2 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg immediate release tablet (Treatment B).
Sequence 1	Zavegepant 100mg non-enteric coated soft gel capsule	Period 1 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 2 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 4 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D).
Sequence 1	Zavegepant 2 x 100mg immediate release tablets	Period 1 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 2 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 4 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D).
Sequence 1	Zavegepant 4 x 25mg enteric coated soft gel capsule	Period 1 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 2 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 4 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D).
Sequence 3	Zavegepant 100mg non-enteric coated soft gel capsule	Period 1 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 3 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 4 - Two zavegepant 100mg immediate release tablets (Treatment C).
Sequence 4	Zavegepant 4 x 25mg enteric coated soft gel capsule	Period 1 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 3 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A).
Sequence 3	Zavegepant 100mg immediate release tablet	Period 1 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 3 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 4 - Two zavegepant 100mg immediate release tablets (Treatment C).
Sequence 3	Zavegepant 2 x 100mg immediate release tablets	Period 1 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 3 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 4 - Two zavegepant 100mg immediate release tablets (Treatment C).
Sequence 4	Zavegepant 100mg non-enteric coated soft gel capsule	Period 1 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 3 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A).
Sequence 3	Zavegepant 4 x 25mg enteric coated soft gel capsule	Period 1 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 3 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 4 - Two zavegepant 100mg immediate release tablets (Treatment C).
Sequence 4	Zavegepant 100mg immediate release tablet	Period 1 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 3 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A).
Sequence 4	Zavegepant 2 x 100mg immediate release tablets	Period 1 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 2 - Single zavegepant 100mg immediate release tablet (Treatment B) followed by at least 7 days washout; Period 3 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A).
Sequence 2	Zavegepant 100mg non-enteric coated soft gel capsule	Period 1 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 2 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg immediate release tablet (Treatment B).
Sequence 2	Zavegepant 100mg immediate release tablet	Period 1 - Two zavegepant 100mg immediate release tablets (Treatment C) followed by at least 7 days washout; Period 2 - Four zavegepant 25mg enteric coated soft gel capsule (Treatment D) followed by at least 7 days washout; Period 3 - Single zavegepant 100mg non-enteric coated soft gel capsule (Treatment A) followed by at least 7 days washout; Period 4 - Single zavegepant 100mg immediate release tablet (Treatment B).

Primary Outcome Measures

Name	Time	Method
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Zavegepant	Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose	AUCinf was calculated as AUClast+(Clast\/kel), where AUClast is the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast\ is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. AUClast was calculated using Linear/Log trapezoidal method.
Maximum Observed Concentration (Cmax) of Zavegepant	Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose	Cmax was observed directly from data.
AUClast of Zavegepant	Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose	AUClast was calculated using linear/log trapezoidal method.

Secondary Outcome Measures

Name	Time	Method
Time to Reach Cmax (Tmax) of Zavegepant	Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose	Tmax was observed directly from data as time of first occurrence.
Terminal Phase Half-Life (t1/2) of Zavegepant	Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose	t1/2 was calculated as Log e(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Apparent Clearance (CL/F) of Zavegepant From Plasma	Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post-dose	CL/F was calculated as dose/AUCinf. AUCinf was calucalted as AUClast+(Clast\/kel), where Clast\ is the predicted plasma concentration at the last quantifiable time point estimated, and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. AUClast was calculated using linear/log trapezoidal method.
Apparent Volume of Distribution (Vz/F) of Zavegepant	Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose	Vz/F was calculated by Dose/(AUCinf×kel). AUCinf was calculated by AUClast+(Clast\/kel), where Clast\ is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. AUClast was calculated using the linear/log trapezoidal method.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Baseline up to study exit (approximately 6.5 weeks)	Adverse evetn (AE)=any untoward medical occurrence in a patient or clinical trial participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. TEAEs=AEs between first dose of study treatment and up to the end of study participation that were absent before treatment or that worsened relative to pretreatment state. A serious TEAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related was classified based on medical judgement. Severe=Incapacitating with inability to carry out usual activities or significantly affects clinical status, and requires specific action and/or medical attention.
Number of Participants With Clinically Significant Laboratory Abnormalities	Baseline up to study exit (approximately 6.5 weeks)	Clinically significant laboratory abnormalities were identified as Grade 3 to 4 laboratory test results graded according to numeric laboratory test criteria in the latest version of Common Technical Criteria for Adverse Events (CTCAE) if available, otherwise according to the latest version of Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version. Clinically significant laboratory abnormalities with occurrence in at least 1 participant are reported for this outcome measure. Baseline was defined as the last results (scheduled or unscheduled) obtained prior to the first drug administration.
Blood Pressure on Day -1 and Day 1 of Each Period	Day -1, pre-dose and 2 hours post dose on Day 1 of each period	Blood pressure was measured after the participants had been resting for at least 5 minutes in a seated position. Normal range for systolic blood pressure (SBP)=90-140 mm Hg; normal range for diastolic blood pressure (DBP)=50-90 mm Hg.
Heart Rate (HR) on Day -1 and Day 1 of Each Period	Day -1, pre-dose and 2 hours post dose on Day 1 of each period	HR was measured after the participants had been resting for at least 5 minutes in a seated position. Normal range for heart rate=50-100 beats/min.
HR at Screening and Study Exit	Screening and study exit	HR was measured after the participants had been resting for at least 5 minutes in a seated position. Normal range for heart rate=50-100 beats/min.
Blood Pressure at Screening and Study Exit	Screening and study exit	Blood pressure was measured after the participants had been resting for at least 5 minutes in a seated position. Normal range for SBP=90-140 mm Hg; normal range for DBP=50-90 mm Hg.
Respiratory Rate (RR) on Day -1 of Each Period	Day -1 of each period	RR was measured after the participants had been resting for at least 5 minutes in a sitting position. Normal range for RR=8-20 breaths/min.
RR at Screening and Study Exit	Screening and study exit	RR was measured after the participants had been resting for at least 5 minutes in a sitting position. Normal range for RR=8-20 breaths/min.
Temperature on Day -1 of Each Period	Day -1 of each period	Temperature was measured after the participants had been resting for at least 5 minutes in a seated position. Normal range for temperature=35.8-37.6 ℃.
Temperature at Screening and Study Exit	Screening and study exit	Temperature was measured after the participants had been resting for at least 5 minutes in a seated position. Normal range for temperature=35.8-37.6 ℃.
Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG)	Screening up to study exit (approximately 6.5 weeks)	ECG was measured after the participants had been resting for at least 5 minutes in a seated position.