A Phase I, Double-Blind, Two-Part, Sequential Study to Evaluate the Pharmacokinetics of Gepotidacin Tablets in Healthy Adult and Adolescent Participants

Part 1- Period 1: Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Time of the Last Quantifiable Concentration (AUC[0-t]) After Single Dose Administration of Gepotidacin 1500 mg

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 1: Area Under the Concentration-time Curve From Time 0 (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) After Single Dose Administration of Gepotidacin 1500 mg

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 1: Area Under the Concentration-time Curve From Time 0 (Pre-dose) to 24 Hours Post-dose (AUC[0-24]) After Single Dose Administration of Gepotidacin 1500 mg

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 3: RoAUC Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18, 24, 36, 48 and 60 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis. Accumulation ratio was calculated as AUC(0-tau) after the second dose, where 0 is the timepoint prior to second dose, divided by AUC(0-tau) after the first dose, where 0 is the predose timepoint prior to the first dose.

Part 1- Period 2: Cmax Following Two Doses of Gepotidacin 3000 mg Administered at 12 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 18, 20, 24, 36, 48 and 60 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 2: AUC(0-t) Following Two Doses of Gepotidacin 3000 mg Administered at 12 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 18, 20, 24, 36, 48 and 60 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 2: Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Time Tau (Tau=12) (AUC[0-tau]) Following Two Doses of Gepotidacin 3000 mg Administered at 12 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 2: AUC(0-24) Following Two Doses of Gepotidacin 3000 mg Administered at 12 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 18, 20 and 24 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 3: AUC(0-24) Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18 and 24 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 3: AUC(0-48) Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 2: Accumulation Ratio for AUC (RoAUC) Following Two Doses of Gepotidacin 3000 mg Administered at 12 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 18, 20, 24, 36, 48 and 60 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis. Accumulation ratio was calculated as AUC(0-tau) after the second dose, where 0 is the timepoint prior to second dose, divided by AUC(0-tau) after the first dose, where 0 is the predose timepoint prior to the first dose.

Part 1: Number of Participants With Urinalysis Toxicities of Grade 3 or Higher

Time Frame: Up to Day 19

Urine samples were collected for the analysis of urine parameters including specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase. Toxicities were graded using the Division of Microbiology and Infectious Diseases toxicity grading where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe and Grade 4=Life-threatening. Number of participants with a grade 3 or higher toxicity for any of the urine parameter is presented

Part 1- Period 1: Area Under the Concentration-time Curve From Time 0 (Pre-dose) to 48 Hours Post-dose (AUC[0-48]) After Single Dose Administration of Gepotidacin 1500 mg

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 1: Maximum Observed Concentration (Cmax) After Single Dose Administration of Gepotidacin 1500 mg

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 3: AUC(0-t) Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18, 24, 36, 48 and 60 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 3: AUC(0-tau) (Tau=6) Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4 and 6 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin.PK parameters were analyzed using standard non-compartmental analysis.

Part 1- Period 2: AUC(0-48) Following Two Doses of Gepotidacin 3000 mg Administered at 12 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 18, 20, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 2: Period 1: Number of Participants With Abnormal 12-lead ECG Findings

Time Frame: Predose, predose 2, predose 3, 0.5. 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours on Day 1, 24, 36 hours on Day 2 and 48 hours on Day 3

A 12-lead ECG was recorded with the participant in a semi-supine position after a rest of at least 10 minutes. Twelve lead ECGs were obtained by using an automated ECG machine that measured PR, QRS, QT, and QTc intervals and calculated heart rate. Data for abnormal NCS and CS were presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

Part 1- Period 2: Accumulation Ratio for Cmax (RoCmax) Following Two Doses of Gepotidacin 3000 mg Administered at 12 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 18, 20, 24, 36, 48 and 60 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis. Accumulation ratio was calculated as Cmax after the second dose divided by Cmax after the first dose.

Part 1- Period 3: RoCmax Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18, 24, 36, 48 and 60 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis. Accumulation ratio was calculated as Cmax after the second dose divided by Cmax after the first dose.

Part 1- Period 3: Cmax Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Dosing Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18, 24, 36, 48 and 60 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 2- Period 1: AUC(0-24) After Single Dose Administration of Gepotidacin 1500 mg

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 2- Period 1: Cmax After Single Dose Administration of Gepotidacin 1500 mg

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 2- Period 1: AUC(0-t) After Single Dose Administration of Gepotidacin 1500 mg

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 2- Period 1: AUC(0-infinity) After Single Dose Administration of Gepotidacin 1500 mg

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 2- Period 2: AUC(0-24) Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18 and 24 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis

Part 2- Period 2: Cmax Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 1: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time Frame: Up to Day 19

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Number of participants with common (\>=5%) non-serious AEs and SAEs is presented.

Part 2: Number of Participants With Non-serious AEs and SAEs

Time Frame: Up to Day 21

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Number of participants with common (\>=5%) non-serious AEs and SAEs are presented.

Part 2- Period 1: AUC(0-48) After Single Dose Administration of Gepotidacin 1500 mg

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 2- Period 2: AUC(0-t) Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 2- Period 2: AUC(0-tau) (Tau=6) Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4 and 6 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

Part 2- Period 2: AUC(0-48) Following Two Doses of Gepotidacin 3000 mg Administered at 6 Hour Interval

Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18, 24, 36 and 48 hours post-dose

Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis

Part 1: Number of Participants With Hematology Toxicities of Grade 3 or Higher

Time Frame: Up to Day 19

Blood samples were collected for the analysis of following hematology parameters: platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), white blood cell (WBC) count, neutrophils, lymphocytes, monocytes, eosinophils and basophils. The hematology abnormalities were graded using the Division of Microbiology and Infectious Diseases toxicity grading where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe and Grade 4=Life-threatening. Number of participants with a grade 3 or higher toxicity for any of the hematology parameter is presented.

Part 2: Number of Participants With Hematology Toxicities of Grade 3 or Higher

Time Frame: Up to Day 21

Blood samples were collected for the analysis of following hematology parameters: platelet count, RBC count, hemoglobin, hematocrit, MCV, MCH, WBC count, neutrophils, lymphocytes, monocytes, eosinophils and basophils. The hematology abnormalities were graded using the Division of Microbiology and Infectious Diseases toxicity grading where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe and Grade 4=Life-threatening. Number of participants with a grade 3 or higher toxicity for any of the hematology parameter is presented.

Part 1: Number of Participants With Clinical Chemistry Toxicities of Grade 3 or Higher

Time Frame: Up to Day 19

Blood samples were collected for the analysis of following clinical chemistry parameters: blood urea nitrogen (BUN), creatinine, glucose (fasting), potassium, sodium, magnesium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total and direct bilirubin, creatine phosphokinase, calcium, chloride, carbon dioxide, total protein and albumin. The clinical chemistry abnormalities were graded using the Division of Microbiology and Infectious Diseases toxicity grading where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe and Grade 4=Life-threatening. Number of participants with a grade 3 or higher toxicity for any of the clinical chemistry parameter is presented

Part 2: Number of Participants With Clinical Chemistry Toxicities of Grade 3 or Higher

Time Frame: Up to Day 21

Blood samples were collected for the analysis of following clinical chemistry parameters: BUN, creatinine, glucose (fasting), potassium, sodium, magnesium, AST, ALT, alkaline phosphatase, total and direct bilirubin, creatine phosphokinase, calcium, chloride, carbon dioxide, total protein and albumin. The clinical chemistry abnormalities were graded using the Division of Microbiology and Infectious Diseases toxicity grading where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe and Grade 4=Life-threatening. Number of participants with a grade 3 or higher toxicity for any of the clinical chemistry parameter is presented

Part 2: Number of Participants With Urinalysis Toxicities of Grade 3 or Higher

Time Frame: Up to Day 21

Urine samples were collected for the analysis of urine parameters including specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase. Toxicities were graded using the Division of Microbiology and Infectious Diseases toxicity grading where Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe and Grade 4=Life-threatening. Number of participants with a grade 3 or higher toxicity for any of the urine parameter is presented

Part 1: Number of Participants With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) of Potential Clinical Importance

Time Frame: Up to Day 19

SBP and DBP were measured in a semi-supine position after 5 minutes of rest. The potential clinically important range for vital signs were: SBP (lower: \<85 and upper: \>160 millimeters of mercury \[mmHg\]) and DBP (lower: \<45 and upper: \>100 mmHg).

Part 2: Number of Participants With SBP and DBP of Potential Clinical Importance

Time Frame: Up to Day 21

SBP and DBP were measured in a semi-supine position after 5 minutes of rest. The potential clinically important range for vital signs were: SBP (lower: \<85 and upper: \>160 mmHg) and DBP (lower: \<45 and upper: \>100 mmHg).

Part 1: Number of Participants With Abnormal Heart Rate of Potential Clinical Importance

Time Frame: Up to Day 19

Heart rate was measured in a semi-supine position after 5 minutes of rest. The potential clinically important range for heart rate was (lower:\<40 and upper: \>110 beats per minute).

Part 2: Number of Participants With Abnormal Heart Rate of Potential Clinical Importance

Time Frame: Up to Day 21

Heart rate was measured in a semi-supine position after 5 minutes of rest. The potential clinically important range for heart rate was (lower:\<40 and upper: \>110 beats per minute).

Part 1: Period 1: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings

Time Frame: Predose, predose 2, predose 3, 0.5. 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hours on Day 1, 24, 36 hours on Day 2 and 48 hours on Day 3.

A 12-lead ECG was recorded with the participant in a semi-supine position after a rest of at least 10 minutes. Twelve lead ECGs were obtained by using an automated ECG machine that measured PR, QRS, QT, and corrected QT (QTc) intervals and calculated heart rate. Data for abnormal not clinically significant (NCS) and clinically significant (CS) ECG findings are presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

Part 1: Period 2: Number of Participants With Abnormal 12-lead ECG Findings

Time Frame: Predose, predose 2, predose 3, 0.5. 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 18, 20 hours on Day 1, 24, 36 hours on Day 2, 48 and 60 hours on Day 3

A 12-lead ECG was recorded with the participant in a semi-supine position after a rest of at least 10 minutes. Twelve lead ECGs were obtained by using an automated ECG machine that measured PR, QRS, QT, and QTc intervals and calculated heart rate. Data for abnormal NCS and CS ECG findings are presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

Part 1: Period 3: Number of Participants With Abnormal 12-lead ECG Findings

Time Frame: Predose, predose 2, predose 3, 0.5. 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18 hours on Day 1, 24, 36 hours on Day 2, 48 and 60 hours on Day 3

A 12-lead ECG was recorded with the participant in a semi-supine position after a rest of at least 10 minutes. Twelve lead ECGs were obtained by using an automated ECG machine that measured PR, QRS, QT, and QTc intervals and calculated heart rate. Data for abnormal NCS and CS ECG findings are presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

Part 2: Period 2: Number of Participants With Abnormal 12-lead ECG Findings

Time Frame: Predose, predose 2, predose 3, 0.5. 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 18 hours on Day 1, 24, 36 hours on Day 2 and 48 hours on Day 3

A 12-lead ECG was recorded with the participant in a semi-supine position after a rest of at least 10 minutes. Twelve lead ECGs were obtained by using an automated ECG machine that measured PR, QRS, QT, and QTc intervals and calculated heart rate. Data for abnormal NCS and CS were presented CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.