Biological Availability
Conditions
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.
Interventions
DRUGZavegepant 100mg non-enteric coated soft gel capsule
Zavegepant (PF-07930207/BHV3500) 100mg non-enteric coated soft gel capsule
DRUGZavegepant 100mg immediate release tablet
Zavegepant (PF-07930207/BHV3500) 100mg dodecylmaltoside dosage form immediate release tablet
DRUGZavegepant 2 x 100mg immediate release tablets
2 x Zavegepant (PF-07930207/BHV3500) 100mg dodecylmaltoside dosage form immediate release tablets - total dose 200mg
DRUGZavegepant 4 x 25mg enteric coated soft gel capsule
Zavegepant (PF-07930207/BHV3500) 25 mg enteric coated soft gel capsules - total dose 100mg
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
All investigators, Sponsor personnel, clinical monitors, independent PK analyst, and participants in the study will be unblinded to the treatment allocation as the primary and secondary endpoints are based on objective criteria of laboratory findings.
Intervention model description
Randomized, open-label, single dose, 4-period cross-over, comparative bioavailability study in healthy volunteer participants.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
A total of 52 participants were assigned to study interventions.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants were assigned to 1 of the 4 sequences, and each sequence consisted of 4 periods. The 4 sequences were ACBD, CDAB, BADC, and DBCA. There was a washout period of at least 7 days between doses. A=1×100-mg zavegepant non-enteric coated SGC administered under fasting condition. B=1×100-mg zavegepant IR tablet + DDM dosage form administered under fasting condition. C=1×200-mg zavegepant IR tablet (total dose of 200 mg) + DDM dosage form administered under fasting condition. D=4×25-mg zavegepant enteric coated SGC (total dose of 100 mg) administered under fasting condition. | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 |
| Overall Study | Other | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Customized 18-65 years of age | 37.0 Years |
| Race/Ethnicity, Customized American Indian | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black | 11 Participants |
| Race/Ethnicity, Customized Hawaiian | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 51 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants |
| Race/Ethnicity, Customized White | 41 Participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 51 | 0 / 50 | 0 / 50 |
| other Total, other adverse events | 3 / 51 | 2 / 51 | 4 / 50 | 3 / 50 |
| serious Total, serious adverse events | 1 / 51 | 0 / 51 | 0 / 50 | 0 / 50 |
Outcome results
Primary
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Zavegepant
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.
Time frame: 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
Population: Included all participants who received at least 1 dose of zavegepant, and for whom the pharmacokinetic (PK) profile had been adequately characterized.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Zavegepant | 83.65 Hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 52 |
| Treatment B: Zavegepant 100 mg IR+DDM | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Zavegepant | 102.5 Hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 66 |
| Treatment C: Zavegepant 200 mg IR+DDM | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Zavegepant | 184.4 Hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 73 |
| Treatment D: Zavegepant 4*25 mg SGC | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Zavegepant | 47.29 Hours*nanograms per milliliter (h*ng/mL) | Geometric Coefficient of Variation 51 |
Primary
AUClast of Zavegepant
AUClast was calculated using linear/log trapezoidal method.
Time frame: 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
Population: Included all participants who received at least 1 dose of zavegepant, and for whom the PK profile had been adequately characterized.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | AUClast of Zavegepant | 82.13 h*ng/mL | Geometric Coefficient of Variation 54 |
| Treatment B: Zavegepant 100 mg IR+DDM | AUClast of Zavegepant | 96.25 h*ng/mL | Geometric Coefficient of Variation 66 |
| Treatment C: Zavegepant 200 mg IR+DDM | AUClast of Zavegepant | 175.5 h*ng/mL | Geometric Coefficient of Variation 72 |
| Treatment D: Zavegepant 4*25 mg SGC | AUClast of Zavegepant | 42.25 h*ng/mL | Geometric Coefficient of Variation 54 |
Primary
Maximum Observed Concentration (Cmax) of Zavegepant
Cmax was observed directly from data.
Time frame: 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
Population: Included all participants who received at least 1 dose of zavegepant, and for whom the PK profile had been adequately characterized.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Maximum Observed Concentration (Cmax) of Zavegepant | 36.28 ng/mL | Geometric Coefficient of Variation 68 |
| Treatment B: Zavegepant 100 mg IR+DDM | Maximum Observed Concentration (Cmax) of Zavegepant | 41.20 ng/mL | Geometric Coefficient of Variation 80 |
| Treatment C: Zavegepant 200 mg IR+DDM | Maximum Observed Concentration (Cmax) of Zavegepant | 76.93 ng/mL | Geometric Coefficient of Variation 77 |
| Treatment D: Zavegepant 4*25 mg SGC | Maximum Observed Concentration (Cmax) of Zavegepant | 12.78 ng/mL | Geometric Coefficient of Variation 82 |
Secondary
Apparent Clearance (CL/F) of Zavegepant From Plasma
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.
Time frame: 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
Population: Included all participants who received at least 1 dose of zavegepant, and for whom the PK profile had been adequately characterized.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Apparent Clearance (CL/F) of Zavegepant From Plasma | 1195 liters per hour (L/h) | Geometric Coefficient of Variation 52 |
| Treatment B: Zavegepant 100 mg IR+DDM | Apparent Clearance (CL/F) of Zavegepant From Plasma | 975.5 liters per hour (L/h) | Geometric Coefficient of Variation 66 |
| Treatment C: Zavegepant 200 mg IR+DDM | Apparent Clearance (CL/F) of Zavegepant From Plasma | 1085 liters per hour (L/h) | Geometric Coefficient of Variation 73 |
| Treatment D: Zavegepant 4*25 mg SGC | Apparent Clearance (CL/F) of Zavegepant From Plasma | 2115 liters per hour (L/h) | Geometric Coefficient of Variation 51 |
Secondary
Apparent Volume of Distribution (Vz/F) of Zavegepant
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.
Time frame: 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
Population: Included all participants who received at least 1 dose of zavegepant, and for whom the PK profile had been adequately characterized.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Apparent Volume of Distribution (Vz/F) of Zavegepant | 14230 L | Geometric Coefficient of Variation 60 |
| Treatment B: Zavegepant 100 mg IR+DDM | Apparent Volume of Distribution (Vz/F) of Zavegepant | 12250 L | Geometric Coefficient of Variation 79 |
| Treatment C: Zavegepant 200 mg IR+DDM | Apparent Volume of Distribution (Vz/F) of Zavegepant | 12740 L | Geometric Coefficient of Variation 85 |
| Treatment D: Zavegepant 4*25 mg SGC | Apparent Volume of Distribution (Vz/F) of Zavegepant | 27530 L | Geometric Coefficient of Variation 59 |
Secondary
Blood Pressure at 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.
Time frame: Screening and study exit
Population: Safety analysis set included all participants who received at least 1 dose of any study intervention. Number of Participants Analyzed represents the total number of participants in the safety analysis set. Number Analyzed in each row represents the number of participants with observations at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Blood Pressure at Screening and Study Exit | SBP at Screening | 121.5 mm Hg |
| Treatment A: Zavegepant 100 mg SGC | Blood Pressure at Screening and Study Exit | SBP at study exit | 114.0 mm Hg |
| Treatment A: Zavegepant 100 mg SGC | Blood Pressure at Screening and Study Exit | DBP at Screening | 82.0 mm Hg |
| Treatment A: Zavegepant 100 mg SGC | Blood Pressure at Screening and Study Exit | DBP at study exit | 76.0 mm Hg |
Secondary
Blood Pressure on Day -1 and 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.
Time frame: Day -1, pre-dose and 2 hours post dose on Day 1 of each period
Population: Safety analysis set included all participants who received at least 1 dose of any study intervention. Number of Participants Analyzed represents the total number of participants in the safety analysis set. Number Analyzed in each row represents the number of participants with observations at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | SBP on Day -1 | 115.0 millimeter of mercury (mm Hg) |
| Treatment A: Zavegepant 100 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | Pre-dose SBP on Day 1 of each period | 113.0 millimeter of mercury (mm Hg) |
| Treatment A: Zavegepant 100 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | SBP at 2 hours post dose on Day 1 of each period | 113.0 millimeter of mercury (mm Hg) |
| Treatment A: Zavegepant 100 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | DBP at Day -1 | 75.0 millimeter of mercury (mm Hg) |
| Treatment A: Zavegepant 100 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | Pre-dose DBP on Day 1 of each period | 75.0 millimeter of mercury (mm Hg) |
| Treatment A: Zavegepant 100 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | DBP at 2 hours post dose on Day 1 of each period | 75.0 millimeter of mercury (mm Hg) |
| Treatment B: Zavegepant 100 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | DBP at 2 hours post dose on Day 1 of each period | 76.0 millimeter of mercury (mm Hg) |
| Treatment B: Zavegepant 100 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | DBP at Day -1 | 77.0 millimeter of mercury (mm Hg) |
| Treatment B: Zavegepant 100 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | SBP on Day -1 | 115.0 millimeter of mercury (mm Hg) |
| Treatment B: Zavegepant 100 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | SBP at 2 hours post dose on Day 1 of each period | 114.0 millimeter of mercury (mm Hg) |
| Treatment B: Zavegepant 100 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | Pre-dose SBP on Day 1 of each period | 113.0 millimeter of mercury (mm Hg) |
| Treatment B: Zavegepant 100 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | Pre-dose DBP on Day 1 of each period | 76.0 millimeter of mercury (mm Hg) |
| Treatment C: Zavegepant 200 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | Pre-dose SBP on Day 1 of each period | 114.0 millimeter of mercury (mm Hg) |
| Treatment C: Zavegepant 200 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | SBP at 2 hours post dose on Day 1 of each period | 113.5 millimeter of mercury (mm Hg) |
| Treatment C: Zavegepant 200 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | DBP at Day -1 | 76.0 millimeter of mercury (mm Hg) |
| Treatment C: Zavegepant 200 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | DBP at 2 hours post dose on Day 1 of each period | 77.0 millimeter of mercury (mm Hg) |
| Treatment C: Zavegepant 200 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | Pre-dose DBP on Day 1 of each period | 74.0 millimeter of mercury (mm Hg) |
| Treatment C: Zavegepant 200 mg IR+DDM | Blood Pressure on Day -1 and Day 1 of Each Period | SBP on Day -1 | 116.5 millimeter of mercury (mm Hg) |
| Treatment D: Zavegepant 4*25 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | Pre-dose DBP on Day 1 of each period | 76.0 millimeter of mercury (mm Hg) |
| Treatment D: Zavegepant 4*25 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | DBP at 2 hours post dose on Day 1 of each period | 75.0 millimeter of mercury (mm Hg) |
| Treatment D: Zavegepant 4*25 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | Pre-dose SBP on Day 1 of each period | 114.5 millimeter of mercury (mm Hg) |
| Treatment D: Zavegepant 4*25 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | DBP at Day -1 | 76.0 millimeter of mercury (mm Hg) |
| Treatment D: Zavegepant 4*25 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | SBP on Day -1 | 116.5 millimeter of mercury (mm Hg) |
| Treatment D: Zavegepant 4*25 mg SGC | Blood Pressure on Day -1 and Day 1 of Each Period | SBP at 2 hours post dose on Day 1 of each period | 113.0 millimeter of mercury (mm Hg) |
Secondary
Heart Rate (HR) on Day -1 and 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.
Time frame: Day -1, pre-dose and 2 hours post dose on Day 1 of each period
Population: Safety analysis set included all participants who received at least 1 dose of any study intervention. Number of Participants Analyzed represents the total number of participants in the safety analysis set. Number Analyzed in each row represents the number of participants with observations at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Heart Rate (HR) on Day -1 and Day 1 of Each Period | HR on Day -1 | 71.0 Beats per minute (beats/min) |
| Treatment A: Zavegepant 100 mg SGC | Heart Rate (HR) on Day -1 and Day 1 of Each Period | HR at 2 hours post dose on Day 1 of each period | 71.0 Beats per minute (beats/min) |
| Treatment A: Zavegepant 100 mg SGC | Heart Rate (HR) on Day -1 and Day 1 of Each Period | Pre-dose HR on Day 1 of each period | 73.0 Beats per minute (beats/min) |
| Treatment B: Zavegepant 100 mg IR+DDM | Heart Rate (HR) on Day -1 and Day 1 of Each Period | HR on Day -1 | 72.0 Beats per minute (beats/min) |
| Treatment B: Zavegepant 100 mg IR+DDM | Heart Rate (HR) on Day -1 and Day 1 of Each Period | HR at 2 hours post dose on Day 1 of each period | 70.0 Beats per minute (beats/min) |
| Treatment B: Zavegepant 100 mg IR+DDM | Heart Rate (HR) on Day -1 and Day 1 of Each Period | Pre-dose HR on Day 1 of each period | 74.0 Beats per minute (beats/min) |
| Treatment C: Zavegepant 200 mg IR+DDM | Heart Rate (HR) on Day -1 and Day 1 of Each Period | Pre-dose HR on Day 1 of each period | 73.5 Beats per minute (beats/min) |
| Treatment C: Zavegepant 200 mg IR+DDM | Heart Rate (HR) on Day -1 and Day 1 of Each Period | HR on Day -1 | 73.0 Beats per minute (beats/min) |
| Treatment C: Zavegepant 200 mg IR+DDM | Heart Rate (HR) on Day -1 and Day 1 of Each Period | HR at 2 hours post dose on Day 1 of each period | 71.0 Beats per minute (beats/min) |
| Treatment D: Zavegepant 4*25 mg SGC | Heart Rate (HR) on Day -1 and Day 1 of Each Period | HR on Day -1 | 73.0 Beats per minute (beats/min) |
| Treatment D: Zavegepant 4*25 mg SGC | Heart Rate (HR) on Day -1 and Day 1 of Each Period | HR at 2 hours post dose on Day 1 of each period | 70.0 Beats per minute (beats/min) |
| Treatment D: Zavegepant 4*25 mg SGC | Heart Rate (HR) on Day -1 and Day 1 of Each Period | Pre-dose HR on Day 1 of each period | 73.5 Beats per minute (beats/min) |
Secondary
HR at 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.
Time frame: Screening and study exit
Population: Safety analysis set included all participants who received at least 1 dose of any study intervention. Number of Participants Analyzed represents the total number of participants in the safety analysis set. Number Analyzed in each row represents the number of participants with observations at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | HR at Screening and Study Exit | HR at Screening | 65.0 beats/min |
| Treatment A: Zavegepant 100 mg SGC | HR at Screening and Study Exit | HR at study exit | 74.0 beats/min |
Secondary
Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG)
ECG was measured after the participants had been resting for at least 5 minutes in a seated position.
Time frame: Screening up to study exit (approximately 6.5 weeks)
Population: Included all participants who received at least 1 dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) | ECG Mean Heart Rate | 0 Participants |
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) | PR Interval, Aggregate | 0 Participants |
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) | QRS Duration, Aggregate | 0 Participants |
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) | QT Interval, Aggregate | 0 Participants |
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) | QTc corrected using Bazett's formula (QTcB) Interval, Aggregate | 0 Participants |
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) | QTc corrected using Fridericia's formula (QTcF) Interval, Aggregate | 0 Participants |
Secondary
Number of Participants With Clinically Significant Laboratory Abnormalities
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.
Time frame: Baseline up to study exit (approximately 6.5 weeks)
Population: Included all participants who received at least 1 dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Clinically Significant Laboratory Abnormalities | Hematology - Hemoglobin<lower limit of normal | 1 Participants |
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis - Abnormal Urine Leukocytes | 0 Participants |
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis - Abnormal Leukocyte Esterase | 0 Participants |
| Treatment B: Zavegepant 100 mg IR+DDM | Number of Participants With Clinically Significant Laboratory Abnormalities | Hematology - Hemoglobin<lower limit of normal | 0 Participants |
| Treatment B: Zavegepant 100 mg IR+DDM | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis - Abnormal Urine Leukocytes | 0 Participants |
| Treatment B: Zavegepant 100 mg IR+DDM | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis - Abnormal Leukocyte Esterase | 0 Participants |
| Treatment C: Zavegepant 200 mg IR+DDM | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis - Abnormal Leukocyte Esterase | 0 Participants |
| Treatment C: Zavegepant 200 mg IR+DDM | Number of Participants With Clinically Significant Laboratory Abnormalities | Hematology - Hemoglobin<lower limit of normal | 1 Participants |
| Treatment C: Zavegepant 200 mg IR+DDM | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis - Abnormal Urine Leukocytes | 0 Participants |
| Treatment D: Zavegepant 4*25 mg SGC | Number of Participants With Clinically Significant Laboratory Abnormalities | Hematology - Hemoglobin<lower limit of normal | 0 Participants |
| Treatment D: Zavegepant 4*25 mg SGC | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis - Abnormal Urine Leukocytes | 1 Participants |
| Treatment D: Zavegepant 4*25 mg SGC | Number of Participants With Clinically Significant Laboratory Abnormalities | Urinalysis - Abnormal Leukocyte Esterase | 1 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
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.
Time frame: Baseline up to study exit (approximately 6.5 weeks)
Population: Included all participants who received at least 1 dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 TEAE | 3 Participants |
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 treatment-related TEAE | 1 Participants |
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 Severe TEAEs | 1 Participants |
| Treatment A: Zavegepant 100 mg SGC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 Serious TEAEs | 1 Participants |
| Treatment B: Zavegepant 100 mg IR+DDM | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 treatment-related TEAE | 0 Participants |
| Treatment B: Zavegepant 100 mg IR+DDM | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 Severe TEAEs | 0 Participants |
| Treatment B: Zavegepant 100 mg IR+DDM | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 Serious TEAEs | 0 Participants |
| Treatment B: Zavegepant 100 mg IR+DDM | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 TEAE | 2 Participants |
| Treatment C: Zavegepant 200 mg IR+DDM | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 Severe TEAEs | 0 Participants |
| Treatment C: Zavegepant 200 mg IR+DDM | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 treatment-related TEAE | 1 Participants |
| Treatment C: Zavegepant 200 mg IR+DDM | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 Serious TEAEs | 0 Participants |
| Treatment C: Zavegepant 200 mg IR+DDM | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 TEAE | 4 Participants |
| Treatment D: Zavegepant 4*25 mg SGC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 Serious TEAEs | 0 Participants |
| Treatment D: Zavegepant 4*25 mg SGC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 treatment-related TEAE | 0 Participants |
| Treatment D: Zavegepant 4*25 mg SGC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 TEAE | 3 Participants |
| Treatment D: Zavegepant 4*25 mg SGC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Participants with at least 1 Severe TEAEs | 1 Participants |
Secondary
Respiratory Rate (RR) on 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.
Time frame: Day -1 of each period
Population: Safety analysis set included all participants who received at least 1 dose of any study intervention. Number of Participants Analyzed represents the total number of participants in the safety analysis set who had at least 1 observation of RR on Day -1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Respiratory Rate (RR) on Day -1 of Each Period | 14.0 Breaths per minute (breaths/min) |
| Treatment B: Zavegepant 100 mg IR+DDM | Respiratory Rate (RR) on Day -1 of Each Period | 14.0 Breaths per minute (breaths/min) |
| Treatment C: Zavegepant 200 mg IR+DDM | Respiratory Rate (RR) on Day -1 of Each Period | 14.0 Breaths per minute (breaths/min) |
| Treatment D: Zavegepant 4*25 mg SGC | Respiratory Rate (RR) on Day -1 of Each Period | 14.0 Breaths per minute (breaths/min) |
Secondary
RR at 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.
Time frame: Screening and study exit
Population: Safety analysis set included all participants who received at least 1 dose of any study intervention. Number of Participants Analyzed represents the total number of participants in the safety analysis set. Number Analyzed in each row represents the number of participants with observations at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | RR at Screening and Study Exit | RR at Screening | 14.0 breaths/min |
| Treatment A: Zavegepant 100 mg SGC | RR at Screening and Study Exit | RR at study exit | 14.0 breaths/min |
Secondary
Temperature at 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 ℃.
Time frame: Screening and study exit
Population: Included all participants who received at least 1 dose of any study intervention.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Temperature at Screening and Study Exit | Temperature at Screening | 36.40 ℃ |
| Treatment A: Zavegepant 100 mg SGC | Temperature at Screening and Study Exit | Temperature at study exit | 36.60 ℃ |
Secondary
Temperature on 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 ℃.
Time frame: Day -1 of each period
Population: Safety analysis set included all participants who received at least 1 dose of any study intervention. Number of Participants Analyzed represents the total number of participants in the safety analysis set who had at least 1 observation of temperature on Day -1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Temperature on Day -1 of Each Period | 36.60 Degree Celsius (℃) |
| Treatment B: Zavegepant 100 mg IR+DDM | Temperature on Day -1 of Each Period | 36.40 Degree Celsius (℃) |
| Treatment C: Zavegepant 200 mg IR+DDM | Temperature on Day -1 of Each Period | 36.50 Degree Celsius (℃) |
| Treatment D: Zavegepant 4*25 mg SGC | Temperature on Day -1 of Each Period | 36.50 Degree Celsius (℃) |
Secondary
Terminal Phase Half-Life (t1/2) of Zavegepant
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.
Time frame: 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
Population: Included all participants who received at least 1 dose of zavegepant, and for whom the PK profile had been adequately characterized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Terminal Phase Half-Life (t1/2) of Zavegepant | 8.346 Hours | Standard Deviation 1.3101 |
| Treatment B: Zavegepant 100 mg IR+DDM | Terminal Phase Half-Life (t1/2) of Zavegepant | 8.907 Hours | Standard Deviation 2.3611 |
| Treatment C: Zavegepant 200 mg IR+DDM | Terminal Phase Half-Life (t1/2) of Zavegepant | 8.243 Hours | Standard Deviation 1.3004 |
| Treatment D: Zavegepant 4*25 mg SGC | Terminal Phase Half-Life (t1/2) of Zavegepant | 9.149 Hours | Standard Deviation 1.5552 |
Secondary
Time to Reach Cmax (Tmax) of Zavegepant
Tmax was observed directly from data as time of first occurrence.
Time frame: 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
Population: Included all participants who received at least 1 dose of zavegepant, and for whom the PK profile had been adequately characterized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A: Zavegepant 100 mg SGC | Time to Reach Cmax (Tmax) of Zavegepant | 0.9830 Hours |
| Treatment B: Zavegepant 100 mg IR+DDM | Time to Reach Cmax (Tmax) of Zavegepant | 0.5000 Hours |
| Treatment C: Zavegepant 200 mg IR+DDM | Time to Reach Cmax (Tmax) of Zavegepant | 0.5000 Hours |
| Treatment D: Zavegepant 4*25 mg SGC | Time to Reach Cmax (Tmax) of Zavegepant | 2.000 Hours |