Trial Outcomes & Findings for Bioequivalence Study of Esomeprazole 20 Milligram (mg) Delayed-Release Capsules in Healthy Adult Participants (NCT NCT05265247)

Last Updated: 2024-02-05

Results Overview

Cmax is defined as maximum observed post-dose concentration; obtained without interpolation. Blood samples were collected at the indicated time points for the analysis of Cmax. Pharmacokinetic (PK) parameters were calculated by standard non-compartmental analysis.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

61 participants

Primary outcome timeframe

Pre-dose (within 1 hour prior to dosing), 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8,10, 12, 16, and 24 hours post dose in each treatment period (each period is of 2 days)

Results posted on

2024-02-05

Participant Flow

The study was conducted at single center in Canada.

A total of 61 participants were enrolled, of which 55 participants were randomized and dosed (6 enrolled participants were not randomized).

Participant milestones

Participant milestones
Measure	Esomeprazole CG (Test)/Esomeprazole AZ (Reference) Participants received Esomeprazole 20 milligram (mg) delayed-release from Catalent, Guayama (CG) (Test product) one capsule once daily as an oral administration on day 1 of period 1. Participants received Esomeprazole 20 mg delayed-release (Nexium 24 hour \[HR\]) from AstraZeneca (AZ) (Reference product) one capsule once daily as an oral administration on day 1 of period 2. Participants received the investigational products in the fasted state with approximately 240 milliliters (mL) of entire amount of ambient temperature water. There was a washout period of at least 7 days between each dosing.	Esomeprazole AZ (Reference)/Esomeprazole CG (Test) Participants received Esomeprazole 20 mg delayed-release (Nexium 24 hour \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1. Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 2. Participants received the investigational products in the fasted state with approximately 240 mL of entire amount of ambient temperature water. There was a washout period of at least 7 days between each dosing.
Period 1 (2 Days) STARTED	26	29
Period 1 (2 Days) COMPLETED	26	29
Period 1 (2 Days) NOT COMPLETED	0	0
Washout Period (7 Days) STARTED	26	29
Washout Period (7 Days) COMPLETED	22	22
Washout Period (7 Days) NOT COMPLETED	4	7
Period 2 (2 Days) STARTED	22	22
Period 2 (2 Days) COMPLETED	22	22
Period 2 (2 Days) NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Esomeprazole CG (Test)/Esomeprazole AZ (Reference) Participants received Esomeprazole 20 milligram (mg) delayed-release from Catalent, Guayama (CG) (Test product) one capsule once daily as an oral administration on day 1 of period 1. Participants received Esomeprazole 20 mg delayed-release (Nexium 24 hour \[HR\]) from AstraZeneca (AZ) (Reference product) one capsule once daily as an oral administration on day 1 of period 2. Participants received the investigational products in the fasted state with approximately 240 milliliters (mL) of entire amount of ambient temperature water. There was a washout period of at least 7 days between each dosing.	Esomeprazole AZ (Reference)/Esomeprazole CG (Test) Participants received Esomeprazole 20 mg delayed-release (Nexium 24 hour \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1. Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 2. Participants received the investigational products in the fasted state with approximately 240 mL of entire amount of ambient temperature water. There was a washout period of at least 7 days between each dosing.
Washout Period (7 Days) Positive Result for Coronavirus (COVID)-19	1	3
Washout Period (7 Days) Withdrawal by Subject	0	1
Washout Period (7 Days) Non-compliance with study requirements	3	3

Baseline Characteristics

Bioequivalence Study of Esomeprazole 20 Milligram (mg) Delayed-Release Capsules in Healthy Adult Participants

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Esomeprazole CG (Test)/Esomeprazole AZ (Reference) n=26 Participants Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 1. Participants received Esomeprazole 20 mg delayed-release (Nexium 24 \[HR\]) from AZ (Reference product) one capsule once daily as an oral administration on day 1 of period 2. Participants received the investigational products in the fasted state with approximately 240 mL of entire amount of ambient temperature water. There was a washout period of at least 7 days between each dosing.	Esomeprazole AZ (Reference)/Esomeprazole CG (Test) n=29 Participants Participants received Esomeprazole 20 mg delayed-release (Nexium 24 \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1. Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 2. Participants received the investigational products in the fasted state with approximately 240 mL of entire amount of ambient temperature water. There was a washout period of at least 7 days between each dosing.	Total n=55 Participants Total of all reporting groups
Age, Continuous	39.4 years STANDARD_DEVIATION 9.63 • n=5 Participants	37.0 years STANDARD_DEVIATION 10.90 • n=7 Participants	38.1 years STANDARD_DEVIATION 10.30 • n=5 Participants
Sex: Female, Male Female	18 Participants n=5 Participants	21 Participants n=7 Participants	39 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	8 Participants n=7 Participants	16 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	22 Participants n=5 Participants	24 Participants n=7 Participants	46 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	25 Participants n=5 Participants	29 Participants n=7 Participants	54 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose (within 1 hour prior to dosing), 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8,10, 12, 16, and 24 hours post dose in each treatment period (each period is of 2 days)

Population: PK analysis set included all participants of the PK population who completed both treatment periods, and for which the relevant PK parameters (at least at least Area Under the Plasma Concentration Versus Time Curve Calculated from Time 0 to the Last Measurable Sampling Time Point \[AUC0-t\] or Cmax) could be derived. Participants with baseline concentration greater than (\>) 5 percent (%) of the individual Cmax for either period were to be excluded from the PK analysis set.

Outcome measures

Outcome measures
Measure	Esomeprazole CG (Test) n=44 Participants Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.	Esomeprazole AZ (Reference) n=44 Participants Participants received Esomeprazole 20 mg delayed-release (Nexium 24 \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.
Maximum Observed Post Dose Concentration (Cmax)	483 Nanograms per milliliter Geometric Coefficient of Variation 51.1	514 Nanograms per milliliter Geometric Coefficient of Variation 46.2

PRIMARY outcome

Population: PK analysis set.

AUC(0-t) is defined as area under the plasma concentration versus time curve calculated from time 0 to the last measurable sampling time point t, computed using the linear trapezoidal rule. Blood samples were collected at the indicated time points for the analysis of AUC0-t. PK parameters were calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Esomeprazole CG (Test) n=44 Participants Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.	Esomeprazole AZ (Reference) n=44 Participants Participants received Esomeprazole 20 mg delayed-release (Nexium 24 \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.
Area Under the Plasma Concentration Versus Time Curve Calculated From Time 0 to the Last Measurable Sampling Time Point	772.10 Hour*nanograms per milliliter Geometric Coefficient of Variation 74.0	815.55 Hour*nanograms per milliliter Geometric Coefficient of Variation 68.6

SECONDARY outcome

Population: PK analysis set. Only those participants having adjusted coefficient of determination greater than equal to 0.80 for the derived parameter AUC0-inf were included for summary statistics and statistical modelling.

AUC(0-inf) is defined as area under the plasma concentration versus time curve calculated from time 0 to infinity. AUC0-inf is equal to (=) AUC0-t plus (+) concentration at the last measurable sampling time point \[C(t)\]/terminal elimination rate constant (λz). Blood samples were collected at the indicated time points for the analysis of AUC0-inf. PK parameters were calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Esomeprazole CG (Test) n=42 Participants Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.	Esomeprazole AZ (Reference) n=43 Participants Participants received Esomeprazole 20 mg delayed-release (Nexium 24 \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.
Area Under the Plasma Concentration Versus Time Curve Calculated From Time 0 to Infinity (AUC0-inf)	792.72 Hour*nanograms per milliliter Geometric Coefficient of Variation 73.5	800.94 Hour*nanograms per milliliter Geometric Coefficient of Variation 68.8

SECONDARY outcome

Population: PK analysis set. Only those participants having adjusted coefficient of determination greater than equal to 0.80 for the derived parameter %AUCex were included for summary statistics and statistical modelling.

%AUCex is defined as percentage of AUC(0-inf) obtained by extrapolation, calculated as (1-\[AUC{0-t}/AUC{0-inf}\]) ×100. Blood samples were collected at the indicated time points for the analysis of %AUCex. PK parameters were calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Esomeprazole CG (Test) n=42 Participants Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.	Esomeprazole AZ (Reference) n=43 Participants Participants received Esomeprazole 20 mg delayed-release (Nexium 24 \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.
Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex)	0.34 Percentage of AUC Extrapolated Geometric Coefficient of Variation 109.1	0.35 Percentage of AUC Extrapolated Geometric Coefficient of Variation 74.6

SECONDARY outcome

Population: PK analysis set. Only those participants having adjusted coefficient of determination greater than equal to 0.80 for the derived parameter λz were included for summary statistics and statistical modelling.

λz is defined as terminal elimination rate constant computed as the slope of the regression line of ln (C\[t\]) on time. The regression should generally involve at least 3 consecutive measurable concentrations that decrease over time. Blood samples were collected at the indicated time points for the analysis of λz. PK parameters were calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Esomeprazole CG (Test) n=42 Participants Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.	Esomeprazole AZ (Reference) n=43 Participants Participants received Esomeprazole 20 mg delayed-release (Nexium 24 \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.
Terminal Elimination Rate Constant	0.8839 1 per hour Interval 0.3528 to 1.4328	0.8504 1 per hour Interval 0.3524 to 1.5184

SECONDARY outcome

Population: PK analysis set.

Tmax is defined as the time of the maximum observed post-dose concentration. Blood samples were collected at the indicated time points for the analysis of Tmax. PK parameters were calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Esomeprazole CG (Test) n=44 Participants Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.	Esomeprazole AZ (Reference) n=44 Participants Participants received Esomeprazole 20 mg delayed-release (Nexium 24 \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.
Time of the Maximum Observed Post-Dose Concentration (Tmax)	1.983 Hour Interval 0.733 to 5.983	1.983 Hour Interval 0.983 to 4.483

SECONDARY outcome

Population: PK analysis set. Only those participants having adjusted coefficient of determination greater than equal to 0.80 for the derived parameter T1/2 were included for summary statistics and statistical modelling.

T1/2 is defined as elimination half-life computed as T1/2 = ln(2)/ λz. Blood samples were collected at the indicated time points for the analysis of T1/2. PK parameters were calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Esomeprazole CG (Test) n=42 Participants Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.	Esomeprazole AZ (Reference) n=43 Participants Participants received Esomeprazole 20 mg delayed-release (Nexium 24 \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.
Elimination Half-Life (T1/2)	0.78 Hour Interval 0.48 to 1.96	0.82 Hour Interval 0.46 to 1.97

Adverse Events

Esomeprazole CG (Test)

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Esomeprazole AZ (Reference)

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Haleon Response Center

HALEON

Phone: +4407880182593

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee HALEON agreements may vary with individual investigators but will not prohibit any investigator from publishing. HALEON supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	Esomeprazole CG (Test) n=48 participants at risk Participants received Esomeprazole 20 mg delayed-release from CG (Test product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.	Esomeprazole AZ (Reference) n=51 participants at risk Participants received Esomeprazole 20 mg delayed-release (Nexium 24 \[HR\]) from AZ (Reference Product) one capsule once daily as an oral administration on day 1 of period 1 or period 2 as per randomization schedule. Participants received the investigational product in the fasted state with approximately 240 mL of entire amount of ambient temperature water.
Infections and infestations Covid-19	2.1% 1/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	7.8% 4/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Infections and infestations Urinary tract infection	2.1% 1/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	0.00% 0/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Nervous system disorders Headache	2.1% 1/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	5.9% 3/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Nervous system disorders Dizziness	2.1% 1/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	0.00% 0/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Nervous system disorders Hypoaesthesia	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Nervous system disorders Somnolence	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Investigations Red blood cells urine	2.1% 1/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Investigations Blood creatine phosphokinase increased	2.1% 1/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	0.00% 0/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Gastrointestinal disorders Abdominal pain	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Gastrointestinal disorders Faeces soft	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Gastrointestinal disorders Nausea	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Gastrointestinal disorders Vomiting	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Musculoskeletal and connective tissue disorders Muscle spasms	2.1% 1/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	0.00% 0/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Eye disorders Vision blurred	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
General disorders Vessel puncture site pain	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Metabolism and nutrition disorders Decreased appetite	2.1% 1/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	0.00% 0/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Psychiatric disorders Insomnia	2.1% 1/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	0.00% 0/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Reproductive system and breast disorders Dysmenorrhoea	2.1% 1/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	0.00% 0/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	0.00% 0/48 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.	2.0% 1/51 • Adverse Events (AEs) were collected from the signing of informed consent until 5 days after last administration of study product (up to 41 days). An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study product including any washout or lead-in product (or medical device), whether or not considered related to the study product, including any washout or lead-in product (or medical device). A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse outcome is serious. AEs were presented treatment wise.