Trial Outcomes & Findings for Long-term Safety of SPD422 in Japanese Adults With Essential Thrombocythaemia (NCT NCT01467661)

NCT ID: NCT01467661

Last Updated: 2021-06-09

Results Overview

Baseline considered from study SPD422-308 (NCT01214915). Final assessment was defined as the last non-missing data (End of study visit in SPD422-309 \[NCT01467661\], or early termination visit either in SPD422-308 \[NCT01214915\] or SPD422-309 \[NCT01467661\], or last available study visit).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 41 participants
• Primary outcome timeframe: Baseline and final assessment (within 5 days of the last dose of investigational product)
• Results posted on: 2021-06-09

Participant Flow

The study was conducted in 15 centers in the Japan between 27 October 2010 and 01 May 2015.

Overall 53 participants were enrolled in study SPD422-308 (NCT01214915), 42 of them completed the study. Of these 42 participants, 41 entered in to the current extension study SPD422-309 (NCT01467661) with 33 of 41 participants entered the post marketing trial and 32 participants completed the study (after marketing approval was granted).

Participant milestones

Measure	SPD422 (Anagrelide Hydrochloride) Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Overall Study STARTED	53
Overall Study Completed SPD422-308 (NCT01214915)	42
Overall Study Started SPD422-309 (NCT01467661)	41
Overall Study Started Post Marketing Trial	33
Overall Study COMPLETED	32
Overall Study NOT COMPLETED	21

Reasons for withdrawal

Measure	SPD422 (Anagrelide Hydrochloride) Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Overall Study Adverse Event	16
Overall Study Withdrawal by Subject	1
Overall Study Lack of Efficacy	3
Overall Study Not enrolled to SPD422-309 (NCT01467661)	1

Baseline Characteristics

Long-term Safety of SPD422 in Japanese Adults With Essential Thrombocythaemia

Baseline characteristics by cohort

Measure	SPD422 (Anagrelide Hydrochloride) n=53 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Age, Continuous	61.6 years STANDARD_DEVIATION 13.10 • n=5 Participants
Sex: Female, Male Female	30 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and final assessment (within 5 days of the last dose of investigational product)

Population: Safety analysis set included all enrolled participants who had taken at least 1 dose of SPD422 since enrolment into Study SPD422-308 (NCT01214915).

Baseline considered from study SPD422-308 (NCT01214915). Final assessment was defined as the last non-missing data (End of study visit in SPD422-309 [NCT01467661], or early termination visit either in SPD422-308 [NCT01214915] or SPD422-309 [NCT01467661], or last available study visit).

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=53 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Change From Baseline in Platelet Count at Final Assessment Baseline	1021.6 10^9 platelets per liter (10^9/L) Standard Deviation 433.14
Change From Baseline in Platelet Count at Final Assessment Change at final assessment	-346.2 10^9 platelets per liter (10^9/L) Standard Deviation 638.35

PRIMARY outcome

Timeframe: Baseline and final assessment (within 5 days of the last dose of investigational product)

Population: Post-marketing trial safety analysis set included all participants in the safety analysis set who continued into the post-marketing part of study SPD422-309 (NCT01467661). Here, n = number of participants analysed at specific time point.

Baseline considered from study SPD422-308 (NCT01214915). Final assessment was defined as the last non-missing data (End of study visit in SPD422-309 [NCT01467661], or early termination visit either in SPD422-308 [NCT01214915] or SPD422-309 [NCT01467661], or last available study visit).

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=33 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Change From Baseline in Platelet Count During Post-marketing Trial at Final Assessment Baseline	1088.3 10^9 platelets per liter (10^9/L) Standard Deviation 486.33
Change From Baseline in Platelet Count During Post-marketing Trial at Final Assessment Change at final assessment	-647.9 10^9 platelets per liter (10^9/L) Standard Deviation 514.89

PRIMARY outcome

Timeframe: Baseline, Week 1, Month 1-12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, and final assessment (within 5 days of the last dose of investigational product)

Population: Safety analysis set included all enrolled participants who had taken at least 1 dose of SPD422 since enrolment into Study SPD422-308 (NCT01214915). Here, n = number of participants analysed at specific time point.

Baseline considered from study SPD422-308 (NCT01214915). Final assessment was defined as the last non-missing data (End of study visit in SPD422-309 [NCT01467661], or early termination visit either in SPD422-308 [NCT01214915] or SPD422-309 [NCT01467661], or last available study visit). Participants who achieved platelet count <600 x 10^9 platelets per liter at each visit were reported.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=53 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Baseline (n = 53)	11.3 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Week 1 (n = 53 )	17.0 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 1 (n = 49)	42.9 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 2 (n = 48)	50.0 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 3 (n = 46)	54.3 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 4 (n = 45)	60.0 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 5 (n = 45)	66.7 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 6 (n = 44)	65.9 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 7 (n = 43)	67.4 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 8 (n = 43)	72.1 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 9 (n = 43)	69.8 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 10 (n = 43)	69.8 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 11 (n = 42)	69.0 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 12 (n = 42)	69.0 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 15 (n = 41)	75.6 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 18 (n = 41)	78.0 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 21 (n = 40)	77.5 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 24 (n = 38)	78.9 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 27 (n = 38)	81.6 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 30 (n = 37)	75.7 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 33 (n = 36)	72.2 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 36 (n = 36)	83.3 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 39 (n = 33)	81.8 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 42 (n = 26)	73.1 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 45 (n = 16)	68.8 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Month 48 (n = 11)	81.8 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 Final assessment (n = 53)	60.4 percentage of participants

PRIMARY outcome

Timeframe: Baseline and final assessment (within 5 days of the last dose of investigational product)

Population: Post-marketing trial safety analysis set included all participants in the safety analysis set who continued into the post-marketing part of study SPD422-309 (NCT01467661). Here, n = number of participants analysed at specific time point.

Baseline considered from study SPD422-308 (NCT01214915). Final assessment was defined as the last non-missing data (End of study visit in SPD422-309 [NCT01467661], or early termination visit either in SPD422-308 [NCT01214915] or SPD422-309 [NCT01467661], or last available study visit). Participants who achieved platelet count <600 x 10^9 platelets per liter during the post-marketing trial were reported.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=33 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 During Post-marketing Trial Baseline (n = 33)	12.1 percentage of participants
Percentage of Participants Who Achieved Platelet Count Less Than (<) 600 During Post-marketing Trial Final assessment(n = 31)	80.6 percentage of participants

PRIMARY outcome

Timeframe: Baseline and final assessment (within 5 days of the last dose of investigational product)

Population: Safety analysis set included all enrolled participants who had taken at least 1 dose of SPD422 since enrolment into Study SPD422-308 (NCT01214915). Here, n = number for participants evaluable at the specific category.

Baseline considered from study SPD422-308 (NCT01214915). Final assessment (FA) was defined as the last nonmissing data (End of study visit in SPD422-309 [NCT01467661], or early termination visit either in SPD422-308 [NCT01214915] or SPD422-309 [NCT01467661], or last available study visit). Participants who had platelet count <600 x 10^9 platelet per liter and greater than equal (>=) 600 x 10^9 platelet per liter at the final assessment as a shift from baseline was reported. Percentage of participants with shift = number of participants with shift / Safety analysis set (53 participants) * 100.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=53 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Percentage of Participants Who Achieved Shift From Baseline in Platelet Count FA: Platelet count <600 to <600 (n = 6)	9.4 percentage of participants
Percentage of Participants Who Achieved Shift From Baseline in Platelet Count FA: Platelet count <600 to >=600 (n = 6)	1.9 percentage of participants
Percentage of Participants Who Achieved Shift From Baseline in Platelet Count FA: Platelet count >=600 to <600 (n = 47)	50.9 percentage of participants
Percentage of Participants Who Achieved Shift From Baseline in Platelet Count FA: Platelet count >=600 to >=600 (n = 47)	37.7 percentage of participants

PRIMARY outcome

Timeframe: Baseline and final assessment (within 5 days of the last dose of investigational product)

Population: Post-marketing trial safety analysis set included all participants in the safety analysis set who continued into the post-marketing part of study SPD422-309 (NCT01467661). Here, n = number for participants evaluable at the specific category.

Baseline considered from study SPD422-308 (NCT01214915). Final assessment (FA) was defined as the last non-missing data (End of study visit in SPD422-309 [NCT01467661], or early termination visit either in SPD422-308 [NCT01214915] or SPD422-309 [NCT01467661], or last available study visit). Participants who had platelet count <600 x 10^9 platelet per liter and greater than equal (>=) 600 x 10^9 platelet per liter at the final assessment as a shift from baseline during the post marketing trial was reported. Percentage of participants with shift = number of participants with shift / post-marketing safety analysis set (33 participants) * 100.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=33 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Percentage of Participants Who Achieved Shift From Baseline in Platelet Count During Post-marketing Trial FA: Platelet count <600 to <600 (n = 3)	9.7 percentage of participants
Percentage of Participants Who Achieved Shift From Baseline in Platelet Count During Post-marketing Trial FA: Platelet count <600 to >=600 (n = 3)	0.0 percentage of participants
Percentage of Participants Who Achieved Shift From Baseline in Platelet Count During Post-marketing Trial FA: Platelet count >=600 to <600 (n = 28)	71.0 percentage of participants
Percentage of Participants Who Achieved Shift From Baseline in Platelet Count During Post-marketing Trial FA: Platelet count >=600 to >=600 (n = 28)	19.4 percentage of participants

PRIMARY outcome

Timeframe: From start of study treatment (SPD422-308) up to 12 days after the last dose of investigational product

Population: Safety analysis set included all enrolled participants who had taken at least 1 dose of SPD422 since enrolment into Study SPD422-308 (NCT01214915).

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse event was defined as the onset of any AE or if the severity of a pre-existing AE worsened any time on or after the date of first dose of investigational product in Study SPD422-308 (NCT01214915) and up to and including 12 days after the last dose is taken.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=53 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Participants with TEAEs	100 percentage of participants
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Participants with TESAEs	39.6 percentage of participants

PRIMARY outcome

Timeframe: From start of study treatment (SPD422-308) up to 12 days after the last dose of investigational product

Population: Post-marketing trial safety analysis set included all participants in the safety analysis set who continued into the post-marketing part of study SPD422-309 (NCT01467661).

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse event was defined as the onset of any AE or if the severity of a pre-existing AE worsened any time on or after the date of first dose of investigational product in Study SPD422-308 (NCT01214915) and up to and including 12 days after the last dose is taken.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=33 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Percentage of Participants With TEAEs and TESAEs During Post-marketing Trial Participants with TEAEs	39.4 percentage of participants
Percentage of Participants With TEAEs and TESAEs During Post-marketing Trial Participants with TESAEs	3.0 percentage of participants

PRIMARY outcome

Timeframe: From start of study treatment (SPD422-308) up to 12 days after the last dose of investigational product

Population: Safety analysis set included all enrolled participants who had taken at least 1 dose of SPD422 since enrolment into Study SPD422-308 (NCT01214915).

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse event was defined as the onset of any AE or if the severity of a pre-existing AE worsened any time on or after the date of first dose of investigational product in Study SPD422-308 (NCT01214915) and up to and including 12 days after the last dose is taken. Clinical Laboratory analysis included hematology, biochemistry, and urinalysis.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=53 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Percentage of Participants With TEAEs and TESAEs Related to Clinical Laboratory Result Participants with TEAEs	73.6 percentage of participants
Percentage of Participants With TEAEs and TESAEs Related to Clinical Laboratory Result Participants with TESAEs	1.9 percentage of participants

PRIMARY outcome

Timeframe: From start of study treatment (SPD422-308) up to 12 days after the last dose of investigational product

Population: Post-marketing trial safety analysis set included all participants in the safety analysis set who continued into the post-marketing part of study SPD422-309 (NCT01467661).

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse event was defined as the onset of any AE or if the severity of a pre-existing AE worsened any time on or after the date of first dose of investigational product in Study SPD422-308 (NCT01214915) and up to and including 12 days after the last dose is taken. Clinical Laboratory analysis included hematology, biochemistry, and urinalysis.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=33 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Percentage of Participants With TEAEs and TESAEs Related to Clinical Laboratory Result During Post-marketing Trial Participants with TEAEs	0 percentage of participants
Percentage of Participants With TEAEs and TESAEs Related to Clinical Laboratory Result During Post-marketing Trial Participants with TESAEs	0 percentage of participants

PRIMARY outcome

Timeframe: From start of study treatment (SPD422-308) up to 12 days after the last dose of investigational product

Population: Safety analysis set included all enrolled participants who had taken at least 1 dose of SPD422 since enrolment into Study SPD422-308 (NCT01214915).

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse event was defined as the onset of any AE or if the severity of a pre-existing AE worsened any time on or after the date of first dose of investigational product in Study SPD422-308 (NCT01214915) and up to and including 12 days after the last dose is taken. Vital signs included pulse rate, systolic and diastolic blood pressure, and weight.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=53 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Percentage of Participants With TEAEs and TESAEs Related to Vital Signs Participants with TEAEs	5.7 percentage of participants
Percentage of Participants With TEAEs and TESAEs Related to Vital Signs Participants with TESAEs	0 percentage of participants

PRIMARY outcome

Timeframe: From start of study treatment (SPD422-308) up to 12 days after the last dose of investigational product

Population: Post-marketing trial safety analysis set included all participants in the safety analysis set who continued into the post-marketing part of study SPD422-309 (NCT01467661).

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse event was defined as the onset of any AE or if the severity of a pre-existing AE worsened any time on or after the date of first dose of investigational product in Study SPD422-308 (NCT01214915) and up to and including 12 days after the last dose is taken. Vital signs included pulse rate, systolic and diastolic blood pressure, and weight.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=33 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Percentage of Participants With TEAEs and TESAEs Related to Vital Signs During Post-marketing Trial Participants with TEAEs	3.0 percentage of participants
Percentage of Participants With TEAEs and TESAEs Related to Vital Signs During Post-marketing Trial Participants with TESAEs	0 percentage of participants

PRIMARY outcome

Timeframe: From start of study treatment (SPD422-308) up to 12 days after the last dose of investigational product

Population: Safety analysis set included all enrolled participants who had taken at least 1 dose of SPD422 since enrolment into Study SPD422-308 (NCT01214915).

Standard 12-Lead ECG analysis was performed to identify the ECG abnormalities. Clinically significant abnormalities like QT prolongation, atrial fibrillation, were decided by the investigator during the study.

Outcome measures

Measure	SPD422 (Anagrelide Hydrochloride) n=53 Participants Participants received anagrelide hydrochloride (SPD422) tablet orally at a dose of 1.0 milligram (mg) per day and titrated as necessary with a maximum single dose of 2.5 mg, total daily dose not more than 10 mg and total dosage increment should not exceed 0.5 mg per day in any week of treatment.
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities	11 participants

Adverse Events

SPD422: Safety Analysis Set

Serious events: 21 serious events

Other events: 53 other events

Deaths: 0 deaths

SPD422: Post-marketing Trial Safety Analysis Set

Serious events: 1 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Measure	SPD422: Safety Analysis Set n=53 participants at risk Included all enrolled participants who had taken at least 1 dose of SPD422 since enrolment into Study SPD422-308 (NCT01214915).	SPD422: Post-marketing Trial Safety Analysis Set n=33 participants at risk Included all subjects in the safety analysis set who continued into the post-marketing part of study SPD422-309 (NCT01467661).
Blood and lymphatic system disorders Leukocytosis	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders SPLENOMEGALY	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders ANGINA PECTORIS	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders CARDIAC FAILURE	1.9% 1/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders CARDIAC FAILURE CONGESTIVE	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders Palpitations	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders PRINZMETAL ANGINA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Congenital, familial and genetic disorders CYTOGENETIC ABNORMALITY	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders VISUAL IMPAIRMENT	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders COLONIC POLYP	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders GASTRIC ULCER	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders GASTROINTESTINAL HAEMORRHAGE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders LOWER GASTROINTESTINAL HAEMORRHAGE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders MELAENA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders OEDEMA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders PYREXIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations PNEUMONIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations PYELONEPHRITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications LACERATION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Neoplasms benign, malignant and unspecified (incl cysts and polyps) ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Neoplasms benign, malignant and unspecified (incl cysts and polyps) PROSTATE CANCER	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders ALTERED STATE OF CONSCIOUSNESS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders CEREBRAL HAEMORRHAGE	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders HEADACHE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders TRANSIENT ISCHAEMIC ATTACK	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders HAEMATURIA	1.9% 1/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders INTERSTITIAL LUNG DISEASE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders PNEUMOTHORAX	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders BASILAR ARTERY THROMBOSIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders CEREBRAL INFARCTION	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders LACUNAR INFARCTION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders PERIPHERAL ARTERIAL OCCLUSIVE DISEASE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product

Other adverse events

Measure	SPD422: Safety Analysis Set n=53 participants at risk Included all enrolled participants who had taken at least 1 dose of SPD422 since enrolment into Study SPD422-308 (NCT01214915).	SPD422: Post-marketing Trial Safety Analysis Set n=33 participants at risk Included all subjects in the safety analysis set who continued into the post-marketing part of study SPD422-309 (NCT01467661).
Cardiac disorders ANGINA PECTORIS	3.8% 2/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders AORTIC VALVE INCOMPETENCE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders ARRHYTHMIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders ATRIAL FIBRILLATION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders BUNDLE BRANCH BLOCK RIGHT	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders CARDIAC FAILURE	3.8% 2/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders CARDIAC FAILURE CONGESTIVE	5.7% 3/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders CARDIOMEGALY	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders CORONARY ARTERY STENOSIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders CYANOSIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders LONG QT SYNDROME	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders MITRAL VALVE INCOMPETENCE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders PALPITATIONS	39.6% 21/53 • Number of events 27 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders PERICARDIAL EFFUSION	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders PRINZMETAL ANGINA	3.8% 2/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders SINUS TACHYCARDIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders SUPRAVENTRICULAR EXTRASYSTOLES	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders SUPRAVENTRICULAR TACHYCARDIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders TACHYCARDIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Cardiac disorders VENTRICULAR EXTRASYSTOLES	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Congenital, familial and genetic disorders CYTOGENETIC ABNORMALITY	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders ANAEMIA	54.7% 29/53 • Number of events 32 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders EOSINOPHILIA	7.5% 4/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders IRON DEFICIENCY ANAEMIA	11.3% 6/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders LEUKOCYTOSIS	1.9% 1/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders LEUKOPENIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders LYMPHADENITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders LYMPHADENOPATHY	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders LYMPHOPENIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders NEUTROPENIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders RED BLOOD CELL ABNORMALITY	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders SPLENOMEGALY	3.8% 2/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Blood and lymphatic system disorders THROMBOCYTOPENIA	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Ear and labyrinth disorders EUSTACHIAN TUBE DYSFUNCTION	1.9% 1/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Ear and labyrinth disorders TINNITUS	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Ear and labyrinth disorders VERTIGO	13.2% 7/53 • Number of events 10 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Endocrine disorders HYPOTHYROIDISM	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders AGE-RELATED MACULAR DEGENERATION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders CATARACT	7.5% 4/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders CONJUNCTIVAL HAEMORRHAGE	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders CONJUNCTIVITIS	5.7% 3/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders DRY EYE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders EYE SWELLING	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders OCULAR HYPERAEMIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders PTERYGIUM	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders RETINAL HAEMORRHAGE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders VISUAL ACUITY REDUCED	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Eye disorders VISUAL IMPAIRMENT	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders ABDOMINAL DISCOMFORT	7.5% 4/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders ABDOMINAL DISTENSION	7.5% 4/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders ABDOMINAL PAIN	5.7% 3/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders ABDOMINAL PAIN UPPER	15.1% 8/53 • Number of events 10 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders ABDOMINAL TENDERNESS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders APHTHOUS STOMATITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders CHEILITIS	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders COLITIS ISCHAEMIC	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders COLONIC POLYP	3.8% 2/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders CONSTIPATION	13.2% 7/53 • Number of events 7 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders DENTAL CARIES	11.3% 6/53 • Number of events 7 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders DIARRHOEA	35.8% 19/53 • Number of events 25 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders DIVERTICULUM INTESTINAL	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders DRY MOUTH	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders DYSPEPSIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders ENTEROCOLITIS	3.8% 2/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders EPIGASTRIC DISCOMFORT	5.7% 3/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders FAECAL INCONTINENCE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders GASTRIC POLYPS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders GASTRIC ULCER	1.9% 1/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders GASTRITIS	7.5% 4/53 • Number of events 8 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders GASTROINTESTINAL HAEMORRHAGE	1.9% 1/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders GASTROOESOPHAGEAL REFLUX DISEASE	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders GINGIVAL BLEEDING	15.1% 8/53 • Number of events 10 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders GINGIVAL HYPERTROPHY	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders HAEMATOCHEZIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders HAEMORRHOIDS	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders LOWER GASTROINTESTINAL HAEMORRHAGE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders MELAENA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders NAUSEA	11.3% 6/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders OESOPHAGITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders PERIODONTAL DISEASE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders POLYP COLORECTAL	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders STOMATITIS	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Gastrointestinal disorders VOMITING	9.4% 5/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders ASTHENIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders CHEST DISCOMFORT	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders CHEST PAIN	7.5% 4/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders CHILLS	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders FACE OEDEMA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders FATIGUE	20.8% 11/53 • Number of events 14 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders GAIT DISTURBANCE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders MALAISE	9.4% 5/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders OEDEMA	9.4% 5/53 • Number of events 7 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders OEDEMA PERIPHERAL	30.2% 16/53 • Number of events 21 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders PYREXIA	20.8% 11/53 • Number of events 16 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
General disorders TENDERNESS	3.8% 2/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Hepatobiliary disorders CHOLESTASIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Hepatobiliary disorders GALLBLADDER POLYP	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Hepatobiliary disorders HEPATIC FUNCTION ABNORMAL	9.4% 5/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Hepatobiliary disorders HEPATIC STEATOSIS	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations BRONCHITIS	15.1% 8/53 • Number of events 11 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations CELLULITIS	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations CHRONIC SINUSITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations CYSTITIS	9.4% 5/53 • Number of events 9 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations DERMATOPHYTOSIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations DIARRHOEA INFECTIOUS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations EAR INFECTION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations ENTERITIS INFECTIOUS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations FOLLICULITIS	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations GASTROENTERITIS	13.2% 7/53 • Number of events 7 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations GASTROENTERITIS VIRAL	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations GASTROINTESTINAL INFECTION	3.8% 2/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations HAEMOPHILUS INFECTION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations HERPES ZOSTER	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations INFECTED SKIN ULCER	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations INFLUENZA	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations LIP INFECTION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations NASOPHARYNGITIS	41.5% 22/53 • Number of events 48 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	6.1% 2/33 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations OESOPHAGEAL CANDIDIASIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations ONYCHOMYCOSIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations ORAL HERPES	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations OTITIS EXTERNA	1.9% 1/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations OTITIS MEDIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations PARONYCHIA	1.9% 1/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations PERICORONITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations PERIODONTITIS	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations PHARYNGITIS	7.5% 4/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations PHARYNGITIS MYCOPLASMAL	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations PNEUMONIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations PYELONEPHRITIS	1.9% 1/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations RHINITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations TINEA PEDIS	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	13.2% 7/53 • Number of events 11 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations URETHRITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations URINARY TRACT INFECTION	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Infections and infestations VAGINAL INFECTION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications ABDOMEN CRUSHING	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications CONTUSION	17.0% 9/53 • Number of events 10 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications DEAFNESS TRAUMATIC	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications EPICONDYLITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications EXCORIATION	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications FALL	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications FOOT FRACTURE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications FRACTURE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications FROSTBITE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications HEAD INJURY	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications LACERATION	1.9% 1/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications LIGAMENT SPRAIN	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications POST PROCEDURAL HAEMORRHAGE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications RIB FRACTURE	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications SUBCUTANEOUS HAEMATOMA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications THERMAL BURN	1.9% 1/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications TOOTH FRACTURE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications TRAUMATIC HAEMATOMA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Injury, poisoning and procedural complications WRIST FRACTURE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations ALANINE AMINOTRANSFERASE INCREASED	3.8% 2/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations ASPARTATE AMINOTRANSFERASE INCREASED	1.9% 1/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations BLOOD ALKALINE PHOSPHATASE INCREASED	11.3% 6/53 • Number of events 7 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations BLOOD CREATININE INCREASED	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations BLOOD GLUCOSE INCREASED	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations BLOOD POTASSIUM DECREASED	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations BLOOD PRESSURE INCREASED	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations BLOOD URIC ACID INCREASED	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations BLOOD URINE PRESENT	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations C-REACTIVE PROTEIN INCREASED	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations CRYSTAL URINE PRESENT	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations DIFFERENTIAL WHITE BLOOD CELL COUNT ABNORMAL	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations ELECTROCARDIOGRAM QT PROLONGED	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations GAMMA-GLUTAMYLTRANSFERASE INCREASED	13.2% 7/53 • Number of events 9 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations GLUCOSE URINE PRESENT	3.8% 2/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations HAEMOGLOBIN DECREASED	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations HAPTOGLOBIN DECREASED	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations HEPATIC ENZYME INCREASED	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations METAMYELOCYTE COUNT INCREASED	1.9% 1/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations MYELOCYTE COUNT INCREASED	1.9% 1/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations PROSTATIC SPECIFIC ANTIGEN INCREASED	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations PROTEIN URINE PRESENT	5.7% 3/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations RED BLOOD CELL NUCLEATED MORPHOLOGY PRESENT	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations WEIGHT DECREASED	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations WHITE BLOOD CELL COUNT DECREASED	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Investigations WHITE BLOOD CELL COUNT INCREASED	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders DECREASED APPETITE	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders DEHYDRATION	11.3% 6/53 • Number of events 7 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders FLUID RETENTION	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders GLUCOSE TOLERANCE IMPAIRED	7.5% 4/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders HYPERGLYCAEMIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders HYPERKALAEMIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders HYPERLIPIDAEMIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders HYPERURICAEMIA	15.1% 8/53 • Number of events 10 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders HYPOALBUMINAEMIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders HYPOGLYCAEMIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Metabolism and nutrition disorders METABOLIC DISORDER	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders ARTHRALGIA	15.1% 8/53 • Number of events 9 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders BACK PAIN	15.1% 8/53 • Number of events 8 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders FLANK PAIN	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders INTERVERTEBRAL DISC PROTRUSION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders MUSCLE SPASMS	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders MUSCLE TIGHTNESS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders MUSCULOSKELETAL PAIN	3.8% 2/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders MUSCULOSKELETAL STIFFNESS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders MYALGIA	9.4% 5/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders OSTEOARTHRITIS	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders OSTEOPOROSIS	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders PAIN IN EXTREMITY	18.9% 10/53 • Number of events 10 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	6.1% 2/33 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders PERIARTHRITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders PERIOSTITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders RHEUMATOID ARTHRITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders SPINAL OSTEOARTHRITIS	3.8% 2/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders TENDON CALCIFICATION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Musculoskeletal and connective tissue disorders TENDONITIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Neoplasms benign, malignant and unspecified (incl cysts and polyps) ACOUSTIC NEUROMA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Neoplasms benign, malignant and unspecified (incl cysts and polyps) ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Neoplasms benign, malignant and unspecified (incl cysts and polyps) LUNG NEOPLASM	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Neoplasms benign, malignant and unspecified (incl cysts and polyps) MYELOFIBROSIS	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Neoplasms benign, malignant and unspecified (incl cysts and polyps) NEOPLASM	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Neoplasms benign, malignant and unspecified (incl cysts and polyps) PROSTATE CANCER	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Neoplasms benign, malignant and unspecified (incl cysts and polyps) SEBORRHOEIC KERATOSIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Neoplasms benign, malignant and unspecified (incl cysts and polyps) UTERINE LEIOMYOMA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders NEURALGIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders TRANSIENT ISCHAEMIC ATTACK	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders ALTERED STATE OF CONSCIOUSNESS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders AMNESIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders CEREBRAL HAEMORRHAGE	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders DIZZINESS	7.5% 4/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders DIZZINESS POSTURAL	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders DYSAESTHESIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders DYSGEUSIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders HEADACHE	49.1% 26/53 • Number of events 36 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders HYPERAESTHESIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders HYPOAESTHESIA	11.3% 6/53 • Number of events 9 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders NEUROPATHY PERIPHERAL	3.8% 2/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders PALATAL PALSY	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders PARAESTHESIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders SOMNOLENCE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders SUBARACHNOID HAEMORRHAGE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders SYNCOPE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Nervous system disorders TREMOR	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Psychiatric disorders ANXIETY	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Psychiatric disorders INSOMNIA	7.5% 4/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Psychiatric disorders RESTLESSNESS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders CYSTITIS NONINFECTIVE	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders DYSURIA	1.9% 1/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders HAEMATURIA	1.9% 1/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders HAEMORRHAGE URINARY TRACT	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders HYDRONEPHROSIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders HYDROURETER	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders HYPERTONIC BLADDER	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders NEPHROLITHIASIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders NOCTURIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders POLLAKIURIA	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders PROTEINURIA	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders RENAL IMPAIRMENT	13.2% 7/53 • Number of events 8 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders RENAL TUBULAR DISORDER	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Renal and urinary disorders URINARY INCONTINENCE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Reproductive system and breast disorders BENIGN PROSTATIC HYPERPLASIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Reproductive system and breast disorders CERVICAL DYSPLASIA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Reproductive system and breast disorders CYSTOCELE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Reproductive system and breast disorders ERECTILE DYSFUNCTION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Reproductive system and breast disorders GENITAL HAEMORRHAGE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Reproductive system and breast disorders VAGINAL HAEMORRHAGE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders ASTHMA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders COUGH	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders DYSPNOEA	15.1% 8/53 • Number of events 9 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders EPISTAXIS	15.1% 8/53 • Number of events 13 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders HAEMOPTYSIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders INTERSTITIAL LUNG DISEASE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders OROPHARYNGEAL PAIN	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders PLEURAL EFFUSION	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders PNEUMONIA ASPIRATION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders PNEUMOTHORAX	1.9% 1/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders PULMONARY SARCOIDOSIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders SPUTUM INCREASED	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Respiratory, thoracic and mediastinal disorders UPPER RESPIRATORY TRACT INFLAMMATION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders ASTEATOSIS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders CHRONIC PIGMENTED PURPURA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders DERMAL CYST	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders DERMATITIS CONTACT	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders DRY SKIN	9.4% 5/53 • Number of events 6 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders ECZEMA	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders ECZEMA ASTEATOTIC	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders ECZEMA NUMMULAR	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders ERYTHEMA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders HAEMORRHAGE SUBCUTANEOUS	7.5% 4/53 • Number of events 4 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders SEBORRHOEIC DERMATITIS	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders RASH	13.2% 7/53 • Number of events 9 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders HEAT RASH	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders INGROWING NAIL	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders NIGHT SWEATS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders PIGMENTATION DISORDER	5.7% 3/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders PRURITUS	7.5% 4/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders PURPURA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders RASH ERYTHEMATOUS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders ROSACEA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Skin and subcutaneous tissue disorders URTICARIA	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Surgical and medical procedures SKIN LESION EXCISION	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders ARTERIOSCLEROSIS	3.8% 2/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders BASILAR ARTERY THROMBOSIS	1.9% 1/53 • Number of events 2 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders CEREBRAL INFARCTION	13.2% 7/53 • Number of events 7 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders ERYTHROMELALGIA	3.8% 2/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders HAEMATOMA	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders HYPERTENSION	26.4% 14/53 • Number of events 15 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	3.0% 1/33 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders LACUNAR INFARCTION	3.8% 2/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders ORTHOSTATIC HYPOTENSION	3.8% 2/53 • Number of events 5 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders PERIPHERAL ARTERIAL OCCLUSIVE DISEASE	3.8% 2/53 • Number of events 3 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders PERIPHERAL CIRCULATORY FAILURE	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders PERIPHERAL COLDNESS	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product
Vascular disorders RAYNAUD'S PHENOMENON	1.9% 1/53 • Number of events 1 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product	0.00% 0/33 • From start of study treatment (SPD422308) up to 12 days after the last dose of investigational product

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
• Publication restrictions are in place

Restriction type: OTHER