Trial Outcomes & Findings for Pharmacokinetics of SSP-004184 in the Treatment of Chronic Iron Overload Requiring Chelation Therapy (NCT NCT01604941)

NCT ID: NCT01604941

Last Updated: 2021-06-29

Results Overview

The efficacy of SPD602 was assessed by determining LIC. Abdominal MRI data were collected by using FerriScan R2 standard procedures and used to determine LIC. A negative change from baseline indicates that LIC decreased. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 32 participants
• Primary outcome timeframe: Baseline, 12 and 24 weeks
• Results posted on: 2021-06-29

Participant Flow

The study started as a double-arm study with once daily (QD) dosing but was amended first to a double-arm study with twice daily (BID) dosing and then to a single-arm study after removing the higher dose. Some participants were enrolled directly to BID dosing, some to QD dosing and then re-enrolled to BID dosing, some completed with QD dosing.

Participant milestones

Measure	SPD602 50mg/mg/Day Twice Daily Dosing (BID) Participants were randomly assigned to 50 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation.	SPD602 75mg/kg/Day Twice Daily Dosing (BID) Participants were randomly assigned to 75 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation.	SPD602 50mg/kg/Day Once (QD) Then Twice Daily Dosing (BID) Participants were randomly assigned to QD dosing then re-enrolled to 50 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation.	SPD602 75mg/kg/Day Once (QD) Then Twice Daily Dosing (BID) Participants were randomly assigned to QD dosing then re-enrolled to 75 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation.	SPD602 50mg/kg/Day Once Daily Dosing (QD) Participants were randomly assigned to 50 mg/kg/day oral QD dosing and continued QD dosing until the end of study (24 weeks) or early discontinuation.	SPD602 75mg/kg/Day Once Daily Dosing (QD) Participants were randomly assigned to 75 mg/kg/day oral QD dosing and continued QD dosing until the end of study (24 weeks) or early discontinuation.
Overall Study STARTED	11	4	3	3	4	7
Overall Study COMPLETED	0	0	0	0	3	0
Overall Study NOT COMPLETED	11	4	3	3	1	7

Reasons for withdrawal

Measure	SPD602 50mg/mg/Day Twice Daily Dosing (BID) Participants were randomly assigned to 50 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation.	SPD602 75mg/kg/Day Twice Daily Dosing (BID) Participants were randomly assigned to 75 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation.	SPD602 50mg/kg/Day Once (QD) Then Twice Daily Dosing (BID) Participants were randomly assigned to QD dosing then re-enrolled to 50 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation.	SPD602 75mg/kg/Day Once (QD) Then Twice Daily Dosing (BID) Participants were randomly assigned to QD dosing then re-enrolled to 75 mg/kg/day oral BID dosing and continued BID dosing until the end of study (24 weeks) or early discontinuation.	SPD602 50mg/kg/Day Once Daily Dosing (QD) Participants were randomly assigned to 50 mg/kg/day oral QD dosing and continued QD dosing until the end of study (24 weeks) or early discontinuation.	SPD602 75mg/kg/Day Once Daily Dosing (QD) Participants were randomly assigned to 75 mg/kg/day oral QD dosing and continued QD dosing until the end of study (24 weeks) or early discontinuation.
Overall Study Adverse Event	1	2	0	0	1	5
Overall Study Non-compliance	1	0	0	0	0	0
Overall Study Participant Decision	0	0	0	0	0	2
Overall Study Early Study Termination	9	2	3	3	0	0

Baseline Characteristics

Pharmacokinetics of SSP-004184 in the Treatment of Chronic Iron Overload Requiring Chelation Therapy

Baseline characteristics by cohort

Measure	SPD602 50mg/kg/Day n=12 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	SPD602 75mg/kg/Day n=7 Participants Participants received SPD602 75mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	Total n=19 Participants Total of all reporting groups
Age, Continuous	28.3 years STANDARD_DEVIATION 5.79 • n=5 Participants	24.4 years STANDARD_DEVIATION 5.80 • n=7 Participants	26.8 years STANDARD_DEVIATION 5.94 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	5 Participants n=7 Participants	13 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 12 and 24 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

The efficacy of SPD602 was assessed by determining LIC. Abdominal MRI data were collected by using FerriScan R2 standard procedures and used to determine LIC. A negative change from baseline indicates that LIC decreased. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Change From Baseline in Liver Iron Concentration (LIC) as Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI) Week 12, n=5,10	-3.4 mg Fe/g*dw Standard Deviation 6.4	-3.8 mg Fe/g*dw Standard Deviation 5.0
Change From Baseline in Liver Iron Concentration (LIC) as Assessed by FerriScan R2 Magnetic Resonance Imaging (MRI) Week 24, n=1,2	-5.3 mg Fe/g*dw Standard Deviation NA Only 1 participant was analyzed	-2.1 mg Fe/g*dw Standard Deviation 4.5

PRIMARY outcome

Timeframe: Baseline, 12 and 24 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

The efficacy of SPD602 was assessed by determining LIC and adjusting for transfusional iron intake. Abdominal MRI data were collected by using FerriScan R2 standard procedures and used to determine LIC. A negative change from baseline indicates that LIC decreased. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI Week 12, n=5,10	-6.3 mg Fe/g*dw Standard Deviation 8.4	-6.6 mg Fe/g*dw Standard Deviation 6.7
Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by FerriScan R2 MRI Week 24, n=1,2	-12.8 mg Fe/g*dw Standard Deviation NA Only 1 participant was analyzed	-9.3 mg Fe/g*dw Standard Deviation 5.0

SECONDARY outcome

Timeframe: Baseline, 12 and 24 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

The efficacy of SPD602 was assessed by determining LIC. Abdominal MRI data were collected by using R2* standard procedures (liver and pancreas) and used to determine LIC. A negative change from baseline indicates that LIC decreased. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Change From Baseline in LIC as Assessed by R2* MRI Week 12, n=5,9	-3.2 mg Fe/g*dw Standard Deviation 2.3	-3.2 mg Fe/g*dw Standard Deviation 2.1
Change From Baseline in LIC as Assessed by R2* MRI Week 24, n=1,2	-2.4 mg Fe/g*dw Standard Deviation NA Only 1 participant was analyzed	-3.3 mg Fe/g*dw Standard Deviation 1.3

SECONDARY outcome

Timeframe: Baseline, 12 and 24 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

The efficacy of SPD602 was assessed by determining LIC and adjusting for transfusional iron intake. Abdominal MRI data were collected by using R2* standard procedures (liver and pancreas) and used to determine LIC. A negative change from baseline indicates that LIC decreased. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI Week 12, n=5,9	-6.0 mg Fe/g*dw Standard Deviation 4.5	-6.2 mg Fe/g*dw Standard Deviation 3.2
Change From Baseline in LIC Adjusted by Transfusional Iron Intake And Assessed by R2* MRI Week 24, n=1,2	-9.9 mg Fe/g*dw Standard Deviation NA Only 1 participant was analyzed	-10.5 mg Fe/g*dw Standard Deviation 0.8

SECONDARY outcome

Timeframe: Baseline, 12 and 24 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

The efficacy of SPD602 was assessed by estimating cardiac iron load. T2* data from cardiac MRI were collected by using standard procedures and used as an estimate of cardiac iron load. T2* is an MR relaxation parameter that is reported in milliseconds. Iron within a tissue decreases homogeneity of the magnetic field and shortens the T2* relaxation rate (Anderson, 2001). Low cardiac T2* values are associated with increased risk of heart failure (Kirk, 2009). A negative change from baseline in the T2* relaxation rate indicates that iron load increased. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Change From Baseline in Cardiac T2* Relaxation Rate, an MRI Parameter Used to Estimate Cardiac Iron Load Week 12, n=5,7	-0.64 milliseconds Standard Deviation 3.080	-0.24 milliseconds Standard Deviation 3.910
Change From Baseline in Cardiac T2* Relaxation Rate, an MRI Parameter Used to Estimate Cardiac Iron Load Week 24, n=1,2	-4.10 milliseconds Standard Deviation NA Only 1 participant was analyzed	-2.60 milliseconds Standard Deviation 2.121

SECONDARY outcome

Timeframe: Baseline, 8 and 16 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

Serum ferritin levels were determined from serum biochemistry analyses. A negative change from baseline indicates that serum ferritin decreased.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Change From Baseline in Serum Ferritin Week 8, n=5,11	-762.63 ng/mL Standard Deviation 2100.683	-568.08 ng/mL Standard Deviation 1426.687
Change From Baseline in Serum Ferritin Week 16, n=1,4	586.47 ng/mL Standard Deviation NA Only 1 participant was analyzed	137.63 ng/mL Standard Deviation 972.970

SECONDARY outcome

Timeframe: 12 and 24 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the FerriScan R2 according to standard procedures. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC Week 12, n=5,10	4 participants	8 participants
Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC Week 24, n=1,2	1 participants	1 participants

SECONDARY outcome

Timeframe: 12 and 24 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the FerriScan R2 according to standard procedures, and the results were adjusted for transfusional iron intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC Adjusted For Transfusional Iron Intake Week 12, n=5,10	4 participants	8 participants
Number of Participants Classified as a Responder by FerriScan R2 MRI Analysis of LIC Adjusted For Transfusional Iron Intake Week 24, n=1,2	1 participants	1 participants

SECONDARY outcome

Timeframe: 12 and 24 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the R2* according to standard procedures (liver and pancreas). Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Number of Participants Classified as a Responder by R2* MRI Analysis of LIC Week 12, n=5,9	5 participants	9 participants
Number of Participants Classified as a Responder by R2* MRI Analysis of LIC Week 24, n=1,2	1 participants	2 participants

SECONDARY outcome

Timeframe: 12 and 24 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

A responder was defined as a participant whose observed liver iron concentration (LIC) at the measured time point was less than the baseline value. LIC was assessed by abdominal MRI with the R2* according to standard procedures (liver and pancreas), and the results were adjusted for transfusional iron intake. Early Termination was within the protocol defined visit date +/- 14 days window and was mapped to next scheduled MRI visit for 3 participants. For participants who had a blood transfusion on the MRI exam date, the blood transfusion done immediately prior to the MRI exam date was included in the calculation of daily transfusion intake.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Number of Participants Classified as a Responder by R2* MRI Analysis of LIC Adjusted For Transfusional Iron Intake Week 12, n=5,9	5 participants	9 participants
Number of Participants Classified as a Responder by R2* MRI Analysis of LIC Adjusted For Transfusional Iron Intake Week 24, n=1,2	1 participants	2 participants

SECONDARY outcome

Timeframe: 8 and 16 weeks

Population: The Full Analysis Set, defined as all participants in the Safety Set who had at least 1 post-baseline primary efficacy assessment. The Safety Set was defined as all participants who had taken at least 1 BID dose of investigational product.

A responder was defined as a participant whose observed serum ferritin level at the measured time point was less than the baseline value. Serum ferritin levels were determined from serum biochemistry analyses.

Outcome measures

Measure	SPD602 50 mg/kg/d n=5 Participants Participants received SPD602 50mg/kg/day oral dosing either twice daily (BID) or once daily (QD), then BID.	All Participants With BID Dosing n=11 Participants Of the 21 participants randomly assigned to BID dosing (including re-enrolled participants), 10 were excluded from the Full Analysis Set. Data for this arm were analyzed to verify that the protocol, as finally amended, was not impacted by using only the lower dose.
Number of Participants Classified as a Responder by Serum Ferritin Week 16, n=1,4	0 participants	1 participants
Number of Participants Classified as a Responder by Serum Ferritin Week 8, n=5,11	3 participants	8 participants

Adverse Events

SPD602 50mg/kg/Day

Serious events: 2 serious events

Other events: 9 other events

Deaths: 0 deaths

SPD602 75mg/kg/Day

Serious events: 2 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Measure	SPD602 50mg/kg/Day n=12 participants at risk Participants received SPD602 50mg/kg/day oral dosing BID either as originally randomized or as a re-enrolled participant.	SPD602 75mg/kg/Day n=7 participants at risk Participants received SPD602 75mg/kg/day oral dosing BID either as originally randomized or as a re-enrolled participant.
General disorders Chest pain	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
General disorders Pain	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Congenital, familial and genetic disorders Sickle cell anaemia with crisis	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Hepatobiliary disorders Cholelithiasis	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Musculoskeletal and connective tissue disorders Flank pain	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Nervous system disorders Neuropathy peripheral	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.

Other adverse events

Measure	SPD602 50mg/kg/Day n=12 participants at risk Participants received SPD602 50mg/kg/day oral dosing BID either as originally randomized or as a re-enrolled participant.	SPD602 75mg/kg/Day n=7 participants at risk Participants received SPD602 75mg/kg/day oral dosing BID either as originally randomized or as a re-enrolled participant.
Nervous system disorders Paraesthesia	16.7% 2/12 • Number of events 3 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	57.1% 4/7 • Number of events 5 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Renal and urinary disorders Chromaturia	16.7% 2/12 • Number of events 2 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	28.6% 2/7 • Number of events 2 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Constipation	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	42.9% 3/7 • Number of events 4 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Nervous system disorders Headache	16.7% 2/12 • Number of events 4 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	28.6% 2/7 • Number of events 2 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Nervous system disorders Hypoaesthesia	16.7% 2/12 • Number of events 4 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	28.6% 2/7 • Number of events 3 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
General disorders Pyrexia	25.0% 3/12 • Number of events 7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Vomiting	25.0% 3/12 • Number of events 4 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Musculoskeletal and connective tissue disorders Back pain	16.7% 2/12 • Number of events 8 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	16.7% 2/12 • Number of events 3 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Musculoskeletal and connective tissue disorders Pain in extremity	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	28.6% 2/7 • Number of events 4 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Abdominal pain	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Musculoskeletal and connective tissue disorders Arthralgia	16.7% 2/12 • Number of events 2 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations Blood urea increased	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Faeces discoloured	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Infections and infestations Influenza	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations International normalised ratio increased	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Renal and urinary disorders Leukocyturia	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations Anion gap increased	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Musculoskeletal and connective tissue disorders Limb discomfort	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Nausea	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 2 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
General disorders Oedema peripheral	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Musculoskeletal and connective tissue disorders Sensation of heaviness	16.7% 2/12 • Number of events 2 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Infections and infestations Tonsillitis	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations Activated partial thromboplastin time prolonged	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Injury, poisoning and procedural complications Allergic transfusion reaction	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
General disorders Asthenia	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations Blood bicarbonate decreased	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations Blood creatinine increased	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Diarrhoea	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Eructation	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Metabolism and nutrition disorders Folate deficiency	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Gastrooesophageal reflux disease	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Renal and urinary disorders Glycosuria	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Hiatus hernia	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Immune system disorders Hypersensitivity	8.3% 1/12 • Number of events 2 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
General disorders Influenza like illness	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Musculoskeletal and connective tissue disorders Myalgia	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Nasal congestion	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Infections and infestations Nasopharyngitis	8.3% 1/12 • Number of events 2 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Musculoskeletal and connective tissue disorders Neck pain	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations Nitrite urine present	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Renal and urinary disorders Polyuria	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Renal and urinary disorders Proteinuria	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations Red blood cells urine positive	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Regurgitation	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Infections and infestations Rhinitis	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Infections and infestations Upper respiratory tract infection	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations Urine protein/creatinine ratio increased	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 2 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
General disorders Axillary pain	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Nervous system disorders Dizziness	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Dyspepsia	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Gastrointestinal disorders Frequent bowel movements	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Throat irritation	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Infections and infestations Bacteriuria	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Infections and infestations Gastroenteritis	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations Electrocardiogram T wave abnormal	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Investigations pH urine increased	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Skin and subcutaneous tissue disorders Erythema	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Skin and subcutaneous tissue disorders Pruritus allergic	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Psychiatric disorders Insomnia	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Vascular disorders Hypotension	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Vascular disorders Pallor	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
General disorders Fatigue	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Congenital, familial and genetic disorders Sickle cell anaemia with crisis	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 5 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Musculoskeletal and connective tissue disorders Flank pain	8.3% 1/12 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	0.00% 0/7 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.
Nervous system disorders Neuropathy peripheral	0.00% 0/12 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.	14.3% 1/7 • Number of events 1 All safety analyses, including analyses of AEs, were based on the Safety Set, which included participants in the 50mg/kg/day BID and 75mg/kg/day BID dosing groups who had taken at least 1 BID dose of investigational product. Participants in the QD only dosing groups were not included in the Safety Set.

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