Bioequivalence Study to Evaluate the Impact of Varying Cr... | NCT02723630

Label	Type	Description	Intervention Names
Sequence A:	Experimental	Participants will receive one dose of Treatment 1 followed by one dose of Treatment 2, then one dose of Treatment 3	Drug: Lenvatinib 10 mg
Sequence B	Experimental	Participants will receive one dose of Treatment 2, followed by one dose of Treatment 3, then one dose of Treatment 1	Drug: Lenvatinib 10 mg
Sequence C	Experimental	Participants will receive one dose of Treatment 3, followed by one dose of Treatment 1, then one dose of Treatment 2	Drug: Lenvatinib 10 mg
Sequence D	Experimental	Participants will receive one dose of Treatment 3, followed by one dose of Treatment 2, then one dose of Treatment 1	Drug: Lenvatinib 10 mg
Sequence E	Experimental	Participants will receive one dose of Treatment 1, followed by one dose of Treatment 3, then one dose of Treatment 2	Drug: Lenvatinib 10 mg
Sequence F

Name	Type	Description	Arm Group Labels	Other Names
Lenvatinib 10 mg	Drug	Treatment 1: low Type-C crystal level <12% Treatment 2: reference* Type-C crystal level 12% to 26% Treatment 3: high Type-C crystal level >26%	Sequence A:

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Area Under the Plasma Concentration-Time Curve From Zero Time (Predose) to Time of Last Quantifiable Concentration (AUC(0-t))	Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methodology using a previously validated assay. The lower limit of quantitation (LLOQ) for the assay was 0.25 ng/mL. AUC(0-t) was calculated by the linear-up log-down trapezoidal method. No concentration estimates were provided for missing sample values. Any sample with a missing value was treated as if the sample had not been scheduled for collection.	Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose
Area Under the Concentration-Time Curve From Zero Time (Predose) Extrapolated to Infinite Time (AUC(0-inf))	Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL. AUC(0-t) was calculated by the linear-up log-down trapezoidal method. AUC(0-inf) was calculate as follows; (AUC(0-inf)) = (AUC(0-t)) + (Ct/Kel), where Ct is the last measurable drug concentration and Kel is the elimination rate constant. The apparent first-order Kel was estimated, when possible, from the slope of the regression line for the terminal ln-linear concentration-time values.	Periods 1, 2, and 3; 0 (Predose), 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose.
Area Under the Concentration-Time Curve From Zero Time (Predose) to 24 Hours (AUC(0-24))	Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.

Secondary Outcomes

Measure	Description	Time Frame
Area Under the Concentration-Time Curve From Zero Time (Predose) to 72 Hours (AUC(0-72))	Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Healthy male and female participants age greater than or equal to 18 years and less than or equal to 55 years old
Nonsmokers or smokers who smoke no more than 10 cigarettes per day
BMI greater than or equal to 18 and less than or equal to 32 kg/m2 at Screening
Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin)
All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing)
Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the participant must agree to use a double-barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.
Male participants must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation.
Provide written informed consent

Exclusion Criteria:

Clinically significant illness that requires medical treatment within 8 weeks of Screening or a clinically significant infection that requires medical treatment within 4 weeks of dosing
Evidence of disease that may influence the outcome of the study within 4 weeks prior to dosing, e.g., psychiatric disorders and disorders of the gastrointestinal tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or participants who have a congenital abnormality in metabolism
Any history of GI surgery that may affect pharmacokinetic profiles of lenvatinib e.g., hepatectomy, nephrotomy, digestive organ resection known at Screening or Baseline
Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, ECG findings, or laboratory test results that require medical treatment at Screening or Baseline
Blood pressure measurements of greater than 150/90 mm Hg. Confirmation should be obtained by performing three measurements (at least 5 minutes apart) to yield a mean value. Participants may be enrolled if they are on a stable dose of a single antihypertensive drug at least 30 days prior to the first dose of study drug and do not intend to change the dose or drug during the study.
A prolonged QTcF interval (QTcF greater than 450 ms) demonstrated on ECG at Screening or Baseline
Known history of clinically significant drug allergy at Screening or Baseline
Known history of food allergies or presently experiencing significant seasonal or perennial allergy at Screening or Baseline or with a known history of sensitivity to any of the components of the test products
Known to be human immunodeficiency virus positive at Screening
Active viral hepatitis (A, B, or C) as demonstrated by positive serology at Screening
History of drug or alcohol dependency or abuse within the 2 years prior to Screening or a positive urine drug test at Screening or Baseline
Intake of grapefruit or grapefruit-containing beverages or food within 72 hours prior to dosing
Intake of medications known to be strong inhibitors or inducers of CYP450 3A4 metabolizing enzymes within 2 weeks prior to dosing
Currently enrolled in another clinical trial or used any investigational drug or device within 30 days preceding informed consent
Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or donation of plasma within 1 week of dosing
Engagement in strenuous exercise within 2 weeks prior to check-in (e.g., marathon runners, weight lifters)
Any condition that would make the participant, in the opinion of the investigator or sponsor unsuitable for the study or not likely to complete the study for any reason

ID	Title	Description
FG000	Sequence A	The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence A were administered lenvatinib with 240 mL of water in the following sequence; Treatment 1 (low Crystal form Type-C level <4%), Treatment 2 (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches), and Treatment 3 (high Crystal form Type-C level 38%) on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals.

Arm/Group Information

ID	Title	Description
BG000	Sequence A	The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence A were administered lenvatinib with 240 mL of water in the following sequence; Treatment 1 (low Crystal form Type-C level <4%), Treatment 2 (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches), and Treatment 3 (high Crystal form Type-C level 38%) on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals.
BG001	Sequence B	The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence B were administered lenvatinib with 240 mL of water in the following sequence; Treatment 2 (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches), Treatment 3 (high Crystal form Type-C level 38%), and Treatment 1 (low Crystal form Type-C level <4%), on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals.
BG002	Sequence C	The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence C were administered lenvatinib with 240 mL of water in the following sequence; Treatment 3 (high Crystal form Type-C level 38%), Treatment 1 (low Crystal form Type-C level <4%), and Treatment 2 (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches), on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals.
BG003	Sequence D	The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence D were administered lenvatinib with 240 mL of water in the following sequence; Treatment 3 (high Crystal form Type-C level 38%), Treatment 2 (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches), and Treatment 1 (low Crystal form Type-C level <4%), on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals.
BG004	Sequence E	The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence E were administered lenvatinib with 240 mL of water in the following sequence; Treatment 1 (low Crystal form Type-C level <4%), Treatment 3 (high Crystal form Type-C level 38%), and Treatment 2 (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches), on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals.
BG005	Sequence F	The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence F were administered lenvatinib with 240 mL of water in the following sequence; Treatment 2 (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches), Treatment 1 (low Crystal form Type-C level <4%), and Treatment 3 (high Crystal form Type-C level 38%), on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals.
BG006	Total	Total of all reporting groups

Units	Counts
Participants	BG00010 BG00110 BG00210 BG00310 BG00410 BG00510 BG00660

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Area Under the Plasma Concentration-Time Curve From Zero Time (Predose) to Time of Last Quantifiable Concentration (AUC(0-t))

Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methodology using a previously validated assay. The lower limit of quantitation (LLOQ) for the assay was 0.25 ng/mL. AUC(0-t) was calculated by the linear-up log-down trapezoidal method. No concentration estimates were provided for missing sample values. Any sample with a missing value was treated as if the sample had not been scheduled for collection.

Pharmacokinetic (PK) analysis set included participants who had sufficient PK data to derive at least one PK parameter. Participants with a predose concentration >5% Cmax and participants who experienced emesis at or before two times median tmax were excluded from the data analysis.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng·hr/mL

Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose

ID	Title	Description
OG000	Treatment 1: Low Crystal Form	Treatment 1: low Crystal form Type-C level < 4%
OG001	Treatment 2: Reference Crystal Form	Treatment 2: reference (reference range determined from clinical batches) Crystal form Type-C level 15%
OG002	Treatment 3: High Crystal Form	Treatment 3: high Crystal form Type-C level 38%

Units	Counts
Participants	OG00059 OG00159 OG00259

Title

Denominators

Categories

Title	Measurements
	OG0001010± 40.4 OG0011010± 36.9 OG002965± 39.3

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.	Mixed Models Analysis		0.8826	P-value for the formulation	Geometric Least Square Mean Ratio	100.52			2-Sided	90	94.84	106.53			Geometric LS Mean ratio was back-transformed least squares mean and mean treatment difference.

Primary

Area Under the Concentration-Time Curve From Zero Time (Predose) Extrapolated to Infinite Time (AUC(0-inf))

Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for >24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL. AUC(0-t) was calculated by the linear-up log-down trapezoidal method. AUC(0-inf) was calculate as follows; (AUC(0-inf)) = (AUC(0-t)) + (Ct/Kel), where Ct is the last measurable drug concentration and Kel is the elimination rate constant. The apparent first-order Kel was estimated, when possible, from the slope of the regression line for the terminal ln-linear concentration-time values.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng·hr/mL

Periods 1, 2, and 3; 0 (Predose), 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose.

ID	Title	Description
OG000	Treatment 1: Low Crystal Form	Treatment 1: low Crystal form Type-C level <4%
OG001	Treatment 2: Reference Crystal Form	Treatment 2: reference* Crystal form Type-C level 15%, *reference range determined from clinical batches

Primary

Area Under the Concentration-Time Curve From Zero Time (Predose) to 24 Hours (AUC(0-24))

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng·hr/mL

Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, and 24 hours postdose

ID	Title	Description
OG000	Treatment 1: Low Crystal Form	Treatment 1: (low Crystal form Type-C level <4%)
OG001	Treatment 2: Reference Crystal Form	Treatment 2: (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches)
OG002	Treatment 3: High Crystal Form	Treatment 3: (high Crystal form Type-C level 38%)

Secondary

Area Under the Concentration-Time Curve From Zero Time (Predose) to 72 Hours (AUC(0-72))

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng·hr/mL

Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours postdose

ID	Title	Description
OG000	Treatment 1: Low Crystal Form	Treatment 1: (low Crystal form Type-C level <4%)
OG001	Treatment 2: Reference Crystal Form	Treatment 2: (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches)
OG002	Treatment 3: High Crystal Form	Treatment 3: (high Crystal form Type-C level 38%)

Secondary

Maximum Observed Concentration (Cmax) of Lenvatinib in Plasma

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose

ID	Title	Description
OG000	Treatment 1: Low Crystal Form	Treatment 1: (low Crystal form Type-C level <4%)
OG001	Treatment 2: Reference Crystal Form	Treatment 2: (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches)
OG002	Treatment 3: High Crystal Form	Treatment 3: (high Crystal form Type-C level 38%)

Secondary

Time to Cmax (Tmax) for Lenvatinib

PK analysis set

Posted

Median

Full Range

Hours

Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose

ID	Title	Description
OG000	Treatment 1: Low Crystal Form	Treatment 1: (low Crystal form Type-C level <4%)
OG001	Treatment 2: Reference Crystal Form	Treatment 2: (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches)
OG002	Treatment 3: High Crystal Form	Treatment 3: (high Crystal form Type-C level 38%)

Secondary

Terminal Elimination Phase Half-life (t1/2)

PK analysis set

Posted

Mean

Standard Deviation

Hours

Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose

ID	Title	Description
OG000	Treatment 1: Low Crystal Form	Treatment 1: (low Crystal form Type-C level <4%)
OG001	Treatment 2: Reference Crystal Form	Treatment 2: (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches)
OG002	Treatment 3: High Crystal Form	Treatment 3: (high Crystal form Type-C level 38%)

Secondary

Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib

Safety assessments consisted of monitoring and recording all adverse events (AEs) (serious and non-serious); regular monitoring of hematology, blood chemistry and urine values; periodic measurement of vital signs and electrocardiograms, performance of physical examinations. A TEAE was defined as an AE that emerges during treatment, having been absent at pretreatment (Baseline), or reemerges during treatment, having been present at pretreatment but stopped before treatment, or worsens in severity during treatment relative to the pretreatment state, when the AE is continuous. TEAEs considered by the investigator to be possibly or probably related to study drug, or TEAEs with missing causality, were included.

Safety analysis set (SAS) included the group of participants who received at least one dose of study drug and had at least one postdose safety assessment.

Posted

Number

Percentage of participants

From date of first dose up to 30 days after the last dose of study treatment, up to approximately 2 months

ID	Title	Description
OG000	Treatment 1: Low Crystal Form	Treatment 1: (low Crystal form Type-C level <4%)
OG001	Treatment 2: Reference Crystal Form	Treatment 2: (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches)

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal pain	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0010 affected59 at risk EG0021 affected59 at risk
Constipation	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Dry mouth	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0010 affected59 at risk EG0021 affected59 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Flatulence	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Nausea	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0010 affected59 at risk EG0021 affected59 at risk
Vomiting	Gastrointestinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0010 affected59 at risk EG0021 affected59 at risk
Oedema peripheral	General disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0010 affected59 at risk EG0021 affected59 at risk
Pain	General disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Nasopharyngitis	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Rash pustular	Infections and infestations	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Blood bilirubin increased	Investigations	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0021 affected59 at risk
Blood cholesterol increased	Investigations	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Blood phosphorus increased	Investigations	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Blood pressure increased	Investigations	MedDRA 16.0	Systematic Assessment	EG0002 affected59 at risk EG0012 affected59 at risk EG0021 affected59 at risk
Blood triglycerides increased	Investigations	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Haematocrit decreased	Investigations	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Haemoglobin decreased	Investigations	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Increased appetite	Metabolism and nutrition disorders	MedDRA 16.0	Systematic Assessment	EG0002 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0010 affected59 at risk EG0021 affected59 at risk
Burning sensation	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0002 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Dizziness	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Headache	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0002 affected59 at risk EG0014 affected59 at risk EG0026 affected59 at risk
Lethargy	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Restless legs syndrome	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Syncope	Nervous system disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Abortion spontaneous	Pregnancy, puerperium and perinatal conditions	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Hypervigilance	Psychiatric disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Insomnia	Psychiatric disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Pollakiuria	Renal and urinary disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0010 affected59 at risk EG0021 affected59 at risk
Vaginal haemorrhage	Reproductive system and breast disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 16.0	Systematic Assessment	EG0002 affected59 at risk EG0010 affected59 at risk EG0022 affected59 at risk
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0012 affected59 at risk EG0020 affected59 at risk
Erythema	Skin and subcutaneous tissue disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0021 affected59 at risk
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA 16.0	Systematic Assessment	EG0000 affected59 at risk EG0011 affected59 at risk EG0020 affected59 at risk
Papule	Skin and subcutaneous tissue disorders	MedDRA 16.0	Systematic Assessment	EG0002 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA 16.0	Systematic Assessment	EG0002 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA 16.0	Systematic Assessment	EG0001 affected59 at risk EG0010 affected59 at risk EG0020 affected59 at risk

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Treatment 1: Low Crystal Form	Treatment 1: (low Crystal form Type-C level <4%)	59	1	59	14	59
EG001	Treatment 2: Reference Crystal Form	Treatment 2: (reference* Crystal form Type-C level 15%, *reference range determined from clinical batches)	59	0	59	14	59
EG002	Treatment 3: High Crystal Form	Treatment 3: (high Crystal form Type-C level 38%)	59	0	59	12	59