A Study of Soticlestat With Itraconazole and Mefenamic Acid in Healthy Adults

A Phase 1, Open-Label Study to Evaluate the Effect of Itraconazole and Mefenamic Acid on the Single-Dose Pharmacokinetic Profile of Soticlestat in Healthy Participants

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05064449

Enrollment

Registered

2021-10-01

Start date

2021-10-14

Completion date

2021-11-30

Last updated

2023-10-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy Volunteers

Keywords

Drug Therapy

Brief summary

The main aim of this study is to check how itraconazole and mefenamic acid affect the way soticlestat is processed by the body. The study will have 2 parts. Participants can only participate in one study part. Part 1: Participants will check into the study clinic to receive soticlestat, four days later they will begin receiving itraconazole and will stay in the clinic for 11 more days, receiving soticlestat in combination with itraconazole on one of those days. Participants will be contacted about 8 days after leaving the clinic for follow-up. Part 2: Participants will check into the study clinic to receive soticlestat, four days later they will begin receiving mefenamic acid and will stay in the clinic for 7 more days, receiving soticlestat in combination with mefenamic acid on one of those days.. Participants will be contacted about 9 days after leaving the clinic for follow-up.

Detailed description

The drug being tested in this study is called soticlestat (TAK-935). The study will evaluate the safety and tolerability of soticlestat when co-administered with either itraconazole or mefenamic acid in healthy participants. The study will be conducted in 2 parts: Part 1 (drug-drug interaction \[DDI\] with itraconazole), Part 2 (DDI with mefenamic acid). The study will enroll approximately 28 participants. Participants will be enrolled into two parts (Part 1 and Part 2) to receive soticlestat along with adjunctive therapy itraconazole and mefenamic acid as: * Part 1: Soticlestat 300 mg + Itraconazole 200 mg * Part 2: Soticlestat 300 mg + Mefenamic Acid 500 mg (first dose only) and 250 mg (subsequent doses) Both Parts 1 and 2 will have two period (Periods 1 and 2). In Period 1, participants will receive only soticlestat (study drug) and in Period 2, participants will receive study drug along with either itraconazole or mefenamic acid depending upon in which part they are in. The data will be collected and stored in electronic case report form (eCRF). This single-center trial will be conducted in the United States. The overall duration of the study is approximately 52 days for participants in Part 1 (includes screening and follow-up), but 48 days for participants in Part 2 (including screening and follow-up). There will be follow up for all participants approximately 15 days after the last dose of soticlestat in each study part.

Interventions

DRUGSoticlestat

Soticlestat tablets.

DRUGItraconazole

Itraconazole oral solution.

DRUGMefenamic acid

Mefenamic acid capsule.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

19 Years to 55 Years

Healthy volunteers

Yes

Inclusion criteria

1. Has body mass index (BMI) greater than or equal to (\>=) 18.0 and less than or equal to (\<=) 32.0 kilogram per meter square (kg/m\^2) at screening. 2. Continuous non-smoker who has not used nicotine-containing products for at least 90 days prior to the first dosing. 3. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or electrocardiograms (ECGs), as deemed by the Investigator or designee. * Supine blood pressure is \>=90/40 millimeter of mercury (mmHg) and \<=140/90 mmHg at screening; * Supine pulse rate is \>=45 beats per minute (bpm) and \<=100 bpm at screening; * QT interval corrected for pulse rate using Fridericia's formula (QTcF) is \<=450 millisecond (msec) (males) or \<=470 msec (females) and ECG findings considered normal or not clinically significant by the Investigator or designee at screening; * Estimated creatinine clearance \>=80 milliliter per minute (mL/min) at screening; * Liver function tests including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \<=1.5\*the upper limit of normal (ULN) at screening and check-in. 4. Able to swallow multiple tablets.

Exclusion criteria

1. Has history of any illness that, in the opinion of the Investigator or designee, might confound the results of the study or poses an additional risk to the participants by their participation in the study. 2. Has history or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing. 3. Has history or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds. 4. Unable to refrain from or anticipates the use of: • Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements within 14 days prior to the first dosing. Thyroid hormone replacement medication may be permitted if the participant has been on the same stable dose for the immediate 3 months prior to first dosing. 5. Has history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is approximately equivalent to the following: beer 354 milliliter (mL)/12 Ounce \[oz\], wine \[118 mL/4 oz\], or distilled spirits \[29.5 mL/1 oz\] per day). 6. Consumes excessive amounts, defined as greater than 4 servings (1 serving is approximately equivalent to 120 mg of caffeine), of coffee, tea, cola, energy drinks, or other caffeinated beverages per day. 7. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 30 days prior to the first dosing and throughout the study. 8. Donation of blood or significant blood loss within 56 days prior to the first dosing. 9. Plasma donation within 7 days prior to the first dosing. 10. Has participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. The 30-day window or 5 half-lives will be derived from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of Period 1 of the current study.

Design outcomes

Primary

Measure	Time frame
Part 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Soticlestat When Administered Alone and With Mefenamic Acid	Soticlestat alone: Period 1, Day 1 pre-dose and at multiple timepoints (up to 96 hours) post-dose; Soticlestat with mefenamic acid: Period 2, Day 2 pre-dose and at multiple timepoints (up to 144 hours) post-dose
Part 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Soticlestat When Administered Alone and With Itraconazole	Soticlestat alone: Period 1, Day 1 pre-dose and at multiple timepoints (up to 96 hours) post-dose; Soticlestat with itraconazole: Period 2, Day 5 pre-dose and at multiple timepoints (up to 168 hours) post-dose
Part 2, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Soticlestat When Administered Alone and With Mefenamic Acid	Soticlestat alone: Period 1, Day 1 pre-dose and at multiple timepoints (up to 96 hours) post-dose; Soticlestat with mefenamic acid: Period 2, Day 2 pre-dose and at multiple timepoints (up to 144 hours) post-dose
Part 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Soticlestat When Administered Alone and With Itraconazole	Soticlestat alone: Period 1, Day 1 pre-dose and at multiple timepoints (up to 96 hours) post-dose; Soticlestat with itraconazole: Period 2, Day 5 pre-dose and at multiple timepoints (up to 168 hours) post-dose
Part 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Soticlestat When Administered Alone and With Mefenamic Acid	Soticlestat alone: Period 1, Day 1 pre-dose and at multiple timepoints (up to 96 hours) post-dose; Soticlestat with mefenamic acid: Period 2, Day 2 pre-dose and at multiple timepoints (up to 144 hours) post-dose
Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Soticlestat When Administered Alone and With Itraconazole	Soticlestat alone: Period 1, Day 1 pre-dose and at multiple timepoints (up to 96 hours) post-dose; Soticlestat with itraconazole: Period 2, Day 5 pre-dose and at multiple timepoints (up to 168 hours) post-dose
Part 1, Cmax: Maximum Observed Plasma Concentration for Soticlestat When Administered Alone and With Itraconazole	Soticlestat alone: Period 1, Day 1 pre-dose and at multiple timepoints (up to 96 hours) post-dose; Soticlestat with itraconazole: Period 2, Day 5 pre-dose and at multiple timepoints (up to 168 hours) post-dose
Part 2, Cmax: Maximum Observed Plasma Concentration for Soticlestat When Administered Alone and With Mefenamic Acid	Soticlestat alone: Period 1, Day 1 pre-dose and at multiple timepoints (up to 96 hours) post-dose; Soticlestat with mefenamic acid: Period 2, Day 2 pre-dose and at multiple timepoints (up to 144 hours) post-dose

Secondary

Measure	Time frame	Description
Parts 1 and 2: Number of Participants With Clinically Significant Abnormal Values for Laboratory Evaluations	Part 1: Day 1 of Period 1 up to Day 12 of Period 2; Part 2: Day 1 of Period 1 up to Day 8 of Period 2	—
Parts 1 and 2: Number of Participants With Clinically Significant Abnormal Values for Vital Signs	Part 1: Day 1 of Period 1 up to Day 12 of Period 2; Part 2: Day 1 of Period 1 up to Day 8 of Period 2	—
Parts 1 and 2: Number of Participants With Clinically Significant Abnormal Values for Electrocardiogram (ECG)	Part 1: Day 1 of Period 1 up to Day 12 of Period 2; Part 2: Day 1 of Period 1 up to Day 8 of Period 2	—
Parts 1 and 2: Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS)	Part 1: Day 1 of Period 1 up to Day 12 of Period 2; Part 2: Day 1 of Period 1 up to Day 8 of Period 2	The C-SSRS is an interview-based rating scale to systematically assess any suicidality, suicidal behavior, or suicidal ideation. Any suicidality is emergence of any suicidal ideation or suicidal behavior. Any suicidal behavior was indicated when response was yes for any these questions- actual attempted to suicide, engaged in non-suicidal self-injurious behavior, interrupted attempt, aborted attempt, preparatory acts. Any suicidal ideation was indicated when response was yes for any of these questions- wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intended to act, without specific plan or with specific plan and intended to suicide.
Parts 1 and 2: Number of Participants Reported One or More Treatment-emergent Adverse Event (TEAE)	Part 1: from Day 1 of Period 1 up to 15 days after the last dose of soticlestat in Period 2 (up to Day 20 in Period 2); Part 2: from Day 1 of Period 1 up to 15 days after the last dose of soticlestat in Period 2 (up to Day 17 in Period 2)	—

Countries

United States

Participant flow

Recruitment details

Participants took part in the study at 1 investigative site in the United States from 14 October 2021 to 30 November 2021.

Pre-assignment details

Healthy participants were enrolled in this 2-part study to receive soticlestat tablets alone in Period 1 and soticlestat tablets and itraconazole solution in Period 2 of Part 1; and soticlestat tablets alone in Period 1 and soticlestat tablets and mefenamic acid capsules in Period 2 of Part 2. Both study parts (Parts 1 and 2) were conducted independently from one another, no crossover happened between both parts.

Participants by arm

Arm	Count
Part 1: Soticlestat 300 mg + Itraconazole 200 mg Soticlestat 300 mg administered as 3\100 mg tablets, orally, once on Day 1 of Period 1, followed by 4 days washout period, further followed by itraconazole 200 mg administered as 20 mL of 10 mg/ml solution, orally, once daily from Day 1 up to Day 11 of Period 2 and soticlestat 300 mg administered as 3\100 mg tablets, orally, once on Day 5 of Period 2.	14
Part 2: Soticlestat 300 mg + Mefenamic Acid 500 mg and 250 mg Soticlestat 300 mg administered as 3\100 mg tablets, orally, once on Day 1 of Period 1, followed by 4 days washout period, further followed by initial single dose of mefenamic acid 500 mg administered as 2\250 mg capsules, orally on the morning of Day 1 and 250 mg subsequent doses at every six hours from Day 1 up to Day 7 of Period 2, and soticlestat 300 mg administered as 3\*100 mg tablets, orally, once on Day 2 of Period 2.	14
Total	28

Baseline characteristics

Characteristic	Part 1: Soticlestat 300 mg + Itraconazole 200 mg	Part 2: Soticlestat 300 mg + Mefenamic Acid 500 mg and 250 mg	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	14 Participants	14 Participants	28 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	2 Participants	4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	12 Participants	12 Participants	24 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Asian	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized Black or African American	4 Participants	5 Participants	9 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized White	8 Participants	5 Participants	13 Participants
Race/Ethnicity, Customized White, American Indian or Alaska Native	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized White, Black or African American	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized White, Native Hawaiian or Other Pacific Islander	1 Participants	0 Participants	1 Participants
Region of Enrollment United States of America	14 Participants	14 Participants	28 Participants
Sex: Female, Male Female	3 Participants	2 Participants	5 Participants
Sex: Female, Male Male	11 Participants	12 Participants	23 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 14	0 / 14	0 / 14	0 / 14	0 / 14	0 / 14
other Total, other adverse events	1 / 14	2 / 14	3 / 14	1 / 14	0 / 14	3 / 14
serious Total, serious adverse events	0 / 14	0 / 14	0 / 14	0 / 14	0 / 14	0 / 14

Outcome results

Primary

Part 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Soticlestat When Administered Alone and With Itraconazole

Time frame: Soticlestat alone: Period 1, Day 1 pre-dose and at multiple timepoints (up to 96 hours) post-dose; Soticlestat with itraconazole: Period 2, Day 5 pre-dose and at multiple timepoints (up to 168 hours) post-dose

Population: All participants who complied sufficiently with the protocol and display an evaluable PK profile (example, exposure to treatment, availability of measurements and absence of major protocol violations) were included in the PK analysis set. Here, overall number of participants analyzed signified those who were evaluable for this outcome measure.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1: Soticlestat 300 mg Alone	Part 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Soticlestat When Administered Alone and With Itraconazole	1483 nanogramhours per milliliter(nghr/mL)	Geometric Coefficient of Variation 56.1
Part 1: Soticlestat 300 mg + Itraconazole 200 mg	Part 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Soticlestat When Administered Alone and With Itraconazole	1914 nanogramhours per milliliter(nghr/mL)	Geometric Coefficient of Variation 42.8

Comparison: Linear mixed-effects model was used for analysis, using fixed-effect (treatment), random-effect (participants). The point estimates and the 90% CIs for the GMR of AUC∞ for soticlestat with versus without itraconazole were calculated by exponentiation of the point estimates of the differences between treatments and the corresponding 90% CIs from the analyses on the ln-transformed AUC∞.90% CI: [106.21, 144.68]

Primary

Part 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Soticlestat When Administered Alone and With Itraconazole

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1: Soticlestat 300 mg Alone	Part 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Soticlestat When Administered Alone and With Itraconazole	1391 ng*hr/mL	Geometric Coefficient of Variation 54.9
Part 1: Soticlestat 300 mg + Itraconazole 200 mg	Part 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Soticlestat When Administered Alone and With Itraconazole	1697 ng*hr/mL	Geometric Coefficient of Variation 45.3

Comparison: Linear mixed-effects model was used for analysis, using fixed-effect (treatment), random-effect (participants). The point estimates and the 90% CIs for the GMR of AUClast for soticlestat with versus without itraconazole were calculated by exponentiation of the point estimates of the differences between treatments and the corresponding 90% CIs from the analyses on the ln-transformed AUClast.90% CI: [103.47, 143.79]

Primary

Part 1, Cmax: Maximum Observed Plasma Concentration for Soticlestat When Administered Alone and With Itraconazole

Population: All participants who complied sufficiently with the protocol and display an evaluable pharmacokinetic (PK) profile (example, exposure to treatment, availability of measurements and absence of major protocol violations) were included in the PK analysis set.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1: Soticlestat 300 mg Alone	Part 1, Cmax: Maximum Observed Plasma Concentration for Soticlestat When Administered Alone and With Itraconazole	1310 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 80.2
Part 1: Soticlestat 300 mg + Itraconazole 200 mg	Part 1, Cmax: Maximum Observed Plasma Concentration for Soticlestat When Administered Alone and With Itraconazole	1527 nanogram per milliliter (ng/mL)	Geometric Coefficient of Variation 65.5

Comparison: Linear mixed-effects model was used for analysis, using fixed-effect (treatment), random-effect (participants). The point estimates and the 90 percent (%) confidence intervals (CIs) for the geometric mean ratio (GMR) of Cmax for soticlestat with versus without itraconazole were calculated by exponentiation of the point estimates of the differences between treatments and the corresponding 90% CIs from the analyses on the ln-transformed Cmax.90% CI: [91.3, 148.9]

Primary

Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Soticlestat When Administered Alone and With Itraconazole

Arm	Measure	Value (MEDIAN)
Part 1: Soticlestat 300 mg Alone	Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Soticlestat When Administered Alone and With Itraconazole	0.500 hour
Part 1: Soticlestat 300 mg + Itraconazole 200 mg	Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Soticlestat When Administered Alone and With Itraconazole	0.503 hour

p-value: =0.230590% CI: [-0.001, 0.126]Wilcoxon Signed Rank Test

Primary

Part 2, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Soticlestat When Administered Alone and With Mefenamic Acid

Time frame: Soticlestat alone: Period 1, Day 1 pre-dose and at multiple timepoints (up to 96 hours) post-dose; Soticlestat with mefenamic acid: Period 2, Day 2 pre-dose and at multiple timepoints (up to 144 hours) post-dose

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1: Soticlestat 300 mg Alone	Part 2, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Soticlestat When Administered Alone and With Mefenamic Acid	1533 ng*hr/mL	Geometric Coefficient of Variation 42.2
Part 1: Soticlestat 300 mg + Itraconazole 200 mg	Part 2, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Soticlestat When Administered Alone and With Mefenamic Acid	1594 ng*hr/mL	Geometric Coefficient of Variation 45.6

Comparison: Linear mixed-effects model was used for analysis, using fixed-effect (treatment), random-effect (participants). The point estimates and the 90% CIs for the GMR of AUC∞ for soticlestat with versus without mefenamic acid were calculated by exponentiation of the point estimates of the differences between treatments and the corresponding 90% CIs from the analyses on the ln-transformed AUC∞.90% CI: [86.17, 117.38]

Primary

Part 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Soticlestat When Administered Alone and With Mefenamic Acid

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1: Soticlestat 300 mg Alone	Part 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Soticlestat When Administered Alone and With Mefenamic Acid	1423 ng*hr/mL	Geometric Coefficient of Variation 41.6
Part 1: Soticlestat 300 mg + Itraconazole 200 mg	Part 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Soticlestat When Administered Alone and With Mefenamic Acid	1528 ng*hr/mL	Geometric Coefficient of Variation 46.2

Comparison: Linear mixed-effects model was used for analysis, using fixed-effect (treatment), random-effect (participants). The point estimates and the 90% CIs for the GMR of AUClast for soticlestat with versus without mefenamic acid were calculated by exponentiation of the point estimates of the differences between treatments and the corresponding 90% CIs from the analyses on the ln-transformed AUClast.90% CI: [91.68, 125.77]

Primary

Part 2, Cmax: Maximum Observed Plasma Concentration for Soticlestat When Administered Alone and With Mefenamic Acid

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1: Soticlestat 300 mg Alone	Part 2, Cmax: Maximum Observed Plasma Concentration for Soticlestat When Administered Alone and With Mefenamic Acid	1414 ng/mL	Geometric Coefficient of Variation 58.4
Part 1: Soticlestat 300 mg + Itraconazole 200 mg	Part 2, Cmax: Maximum Observed Plasma Concentration for Soticlestat When Administered Alone and With Mefenamic Acid	1517 ng/mL	Geometric Coefficient of Variation 55.8

Comparison: Linear mixed-effects model was used for analysis, using fixed-effect (treatment), random-effect (participants). The point estimates and the 90% CIs for the GMR of Cmax for soticlestat with versus without mefenamic acid were calculated by exponentiation of the point estimates of the differences between treatments and the corresponding 90% CIs from the analyses on the ln-transformed Cmax.90% CI: [88.02, 130.83]

Primary

Part 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Soticlestat When Administered Alone and With Mefenamic Acid

Arm	Measure	Value (MEDIAN)
Part 1: Soticlestat 300 mg Alone	Part 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Soticlestat When Administered Alone and With Mefenamic Acid	0.505 hour
Part 1: Soticlestat 300 mg + Itraconazole 200 mg	Part 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Soticlestat When Administered Alone and With Mefenamic Acid	0.522 hour

p-value: =0.58390% CI: [-0.128, 0.018]Wilcoxon Signed Rank Test

Secondary

Parts 1 and 2: Number of Participants Reported One or More Treatment-emergent Adverse Event (TEAE)

Time frame: Part 1: from Day 1 of Period 1 up to 15 days after the last dose of soticlestat in Period 2 (up to Day 20 in Period 2); Part 2: from Day 1 of Period 1 up to 15 days after the last dose of soticlestat in Period 2 (up to Day 17 in Period 2)