Trial Outcomes & Findings for Safety and Tolerability Study of SHP465 in Children Aged 4 to 12 Years Diagnosed With Attention-deficit/Hyperactivity Disorder (ADHD) (NCT NCT03325894)

NCT ID: NCT03325894

Last Updated: 2021-06-03

Results Overview

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs was defined as AEs that start or deteriorate on or after the date of the first dose of investigational product and no later than 3 days following the last dose of investigational product.

• Recruitment status: TERMINATED
• Study phase: PHASE3
• Target enrollment: 141 participants
• Primary outcome timeframe: From start of study drug administration up to follow-up (approximately up to 367 days)
• Results posted on: 2021-06-03

Participant Flow

The study was conducted at 33 centers in the United States between 02 January 2018 (first participant first visit) and 19 January 2019 (last participant last visit).

Overall, 141 participants enrolled and received the treatment in two groups (Group A and B). Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in Group A and participants who were directly enrolled into this study were in Group B.

Participant milestones

Measure	Group A (Antecedent Studies) Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Overall Study STARTED	64	77
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	64	77

Reasons for withdrawal

Measure	Group A (Antecedent Studies) Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Overall Study Adverse Event	2	3
Overall Study Protocol Violation	1	2
Overall Study Withdrawal by Subject	10	6
Overall Study Lost to Follow-up	4	9
Overall Study Lack of Efficacy	8	14
Overall Study Study Terminated by Sponsor	38	43
Overall Study Other (Not received Treatment)	1	0

Baseline Characteristics

Safety and Tolerability Study of SHP465 in Children Aged 4 to 12 Years Diagnosed With Attention-deficit/Hyperactivity Disorder (ADHD)

Baseline characteristics by cohort

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.	Total n=140 Participants Total of all reporting groups
Age, Continuous	7.5 years STANDARD_DEVIATION 2.61 • n=5 Participants	6.1 years STANDARD_DEVIATION 2.33 • n=7 Participants	6.8 years STANDARD_DEVIATION 2.56 • n=5 Participants
Sex: Female, Male Female	22 Participants n=5 Participants	28 Participants n=7 Participants	50 Participants n=5 Participants
Sex: Female, Male Male	41 Participants n=5 Participants	49 Participants n=7 Participants	90 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	16 Participants n=5 Participants	26 Participants n=7 Participants	42 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	46 Participants n=5 Participants	51 Participants n=7 Participants	97 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	19 Participants n=5 Participants	17 Participants n=7 Participants	36 Participants n=5 Participants
Race (NIH/OMB) White	37 Participants n=5 Participants	57 Participants n=7 Participants	94 Participants n=5 Participants
Race (NIH/OMB) More than one race	6 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: From start of study drug administration up to follow-up (approximately up to 367 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs was defined as AEs that start or deteriorate on or after the date of the first dose of investigational product and no later than 3 days following the last dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	29 Participants	38 Participants

PRIMARY outcome

Timeframe: Baseline, FoTA (up to 330 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.

Change from baseline in pulse rate at FoTA was reported. FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product in the current study.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Pulse Rate at Final On-Treatment Assessment (FoTA)	1.5 beats per minute Standard Deviation 9.82	0.1 beats per minute Standard Deviation 10.31

PRIMARY outcome

Timeframe: Baseline, FoTA (up to 330 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.

Change from baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at FoTA was reported. FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product in the current study.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Blood Pressure at Final On-Treatment Assessment (FoTA) SBP: Change at FoTA	0.6 Millimeters of mercury Standard Deviation 7.17	0.6 Millimeters of mercury Standard Deviation 7.36
Change From Baseline in Blood Pressure at Final On-Treatment Assessment (FoTA) DBP: Change at FoTA	2.3 Millimeters of mercury Standard Deviation 7.76	1.7 Millimeters of mercury Standard Deviation 6.03

PRIMARY outcome

Timeframe: Baseline, FoTA (up to 330 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.

Height was measured in centimeters (cm) without shoes and with light clothing using a stadiometer. FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product in the current study.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Height at Final On-Treatment Assessment (FoTA)	3.7 centimeter Standard Deviation 4.60	2.9 centimeter Standard Deviation 2.49

PRIMARY outcome

Timeframe: Baseline, FoTA (up to 330 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.

Weight was measured in kilograms (kg) without shoes and with light clothing using a calibrated scale. FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product in the current study.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Weight at Final On-Treatment Assessment (FoTA)	1.4 kilograms Standard Deviation 2.93	1.1 kilograms Standard Deviation 2.41

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specific categories.

Change from baseline in hematology parameter basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils band form, segmented neutrophils, neutrophils/total cells and platelets were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Hematology Parameters at Early Termination/Day 360 Lymphocytes	0.14 10^9 cells per liter Standard Deviation 0.948	-0.12 10^9 cells per liter Standard Deviation 0.685
Change From Baseline in Hematology Parameters at Early Termination/Day 360 Basophils	-0.01 10^9 cells per liter Standard Deviation 0.040	0.01 10^9 cells per liter Standard Deviation 0.051
Change From Baseline in Hematology Parameters at Early Termination/Day 360 Eosinophils	0.02 10^9 cells per liter Standard Deviation 0.389	0.04 10^9 cells per liter Standard Deviation 0.240
Change From Baseline in Hematology Parameters at Early Termination/Day 360 Leukocytes	-0.25 10^9 cells per liter Standard Deviation 1.519	-0.09 10^9 cells per liter Standard Deviation 2.107
Change From Baseline in Hematology Parameters at Early Termination/Day 360 Monocytes	-0.12 10^9 cells per liter Standard Deviation 0.282	0.01 10^9 cells per liter Standard Deviation 0.217
Change From Baseline in Hematology Parameters at Early Termination/Day 360 Neutrophils Band Form	0.00 10^9 cells per liter Standard Deviation 0.00	0.00 10^9 cells per liter Standard Deviation 0.049
Change From Baseline in Hematology Parameters at Early Termination/Day 360 Segmented Neutrophils	-0.40 10^9 cells per liter Standard Deviation 1.296	-0.02 10^9 cells per liter Standard Deviation 2.139
Change From Baseline in Hematology Parameters at Early Termination/Day 360 Neutrophils/Total Cells	-0.32 10^9 cells per liter Standard Deviation 1.349	0.00 10^9 cells per liter Standard Deviation 1.915
Change From Baseline in Hematology Parameters at Early Termination/Day 360 Platelets	8.0 10^9 cells per liter Standard Deviation 46.76	4.6 10^9 cells per liter Standard Deviation 60.19

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specific categories.

Change from baseline in hematology leukocytes parameter: basophils, eosinophils, lymphocytes, monocytes and neutrophil were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Leukocytes at Early Termination/Day 360 Basophils/Leukocytes	-0.17 percentage of leukocytes Standard Deviation 0.631	0.04 percentage of leukocytes Standard Deviation 0.589
Change From Baseline in Leukocytes at Early Termination/Day 360 Eosinophils/Leukocytes	0.38 percentage of leukocytes Standard Deviation 4.288	0.30 percentage of leukocytes Standard Deviation 3.222
Change From Baseline in Leukocytes at Early Termination/Day 360 Lymphocytes/Leukocytes	4.42 percentage of leukocytes Standard Deviation 12.140	-0.97 percentage of leukocytes Standard Deviation 11.517
Change From Baseline in Leukocytes at Early Termination/Day 360 Monocytes/Leukocytes	-1.02 percentage of leukocytes Standard Deviation 3.982	0.52 percentage of leukocytes Standard Deviation 2.650
Change From Baseline in Leukocytes at Early Termination/Day 360 Neutrophils Band Form/Leukocytes	0.0 percentage of leukocytes Standard Deviation 0.00	0.0 percentage of leukocytes Standard Deviation 0.62
Change From Baseline in Leukocytes at Early Termination/Day 360 Neutrophils, Segmented/Leukocytes	-3.8 percentage of leukocytes Standard Deviation 12.39	-0.6 percentage of leukocytes Standard Deviation 13.15
Change From Baseline in Leukocytes at Early Termination/Day 360 Neutrophils/Leukocytes	-3.62 percentage of leukocytes Standard Deviation 13.359	0.35 percentage of leukocytes Standard Deviation 11.756

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in hematology parameter erythrocytes were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=31 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=31 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Erythrocytes at Early Termination/Day 360	0.017 10^12 cells per liter Standard Deviation 0.3368	-0.007 10^12 cells per liter Standard Deviation 0.2889

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in hematology parameter erythrocytes mean corpuscular hemoglobin concentration were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=31 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=31 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin Concentration at Early Termination/Day 360	-0.09 gram per deciliter Standard Deviation 0.664	-0.16 gram per deciliter Standard Deviation 1.018

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in hematology parameter erythrocytes mean corpuscular hemoglobin were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=31 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=31 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Erythrocytes Mean Corpuscular Hemoglobin at Early Termination/Day 360	0.42 picogram Standard Deviation 0.642	0.38 picogram Standard Deviation 1.259

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in hematology parameter hematocrit were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=31 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=31 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Hematocrit at Early Termination/Day 360	0.86 percentage of hematocrit Standard Deviation 2.784	0.59 percentage of hematocrit Standard Deviation 2.901

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in hematology parameter hemoglobin were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=31 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=31 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Hemoglobin at Early Termination/Day 360	2.5 gram per liter Standard Deviation 8.68	1.5 gram per liter Standard Deviation 9.82

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specific categories.

Change from baseline in hematology parameter erythrocytes mean corpuscular volume and mean platelet volume were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Hematology Parameters (Erythrocytes Mean Corpuscular Volume and Mean Platelet Volume) at Early Termination/ Day 360 Mean Platelet Volume	-0.1 femtoliters Standard Deviation 0.77	0.2 femtoliters Standard Deviation 0.96
Change From Baseline in Hematology Parameters (Erythrocytes Mean Corpuscular Volume and Mean Platelet Volume) at Early Termination/ Day 360 Erythrocytes Mean Corpuscular Volume	1.48 femtoliters Standard Deviation 1.438	1.46 femtoliters Standard Deviation 2.565

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specific categories

Change from baseline in chemistry parameter alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma glutamyl transferase, and lactate dehydrogenase were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Chemistry Parameters at Early Termination/Day 360 Alkaline Phosphatase	-18.2 Unit per liter Standard Deviation 62.28	-32.6 Unit per liter Standard Deviation 68.15
Change From Baseline in Chemistry Parameters at Early Termination/Day 360 Aspartate Aminotransferase	-1.9 Unit per liter Standard Deviation 5.27	21.4 Unit per liter Standard Deviation 129.48
Change From Baseline in Chemistry Parameters at Early Termination/Day 360 Gamma Glutamyl Transferase	-0.4 Unit per liter Standard Deviation 2.20	1.3 Unit per liter Standard Deviation 5.06
Change From Baseline in Chemistry Parameters at Early Termination/Day 360 Lactate Dehydrogenase	-9.0 Unit per liter Standard Deviation 24.24	26.2 Unit per liter Standard Deviation 185.52
Change From Baseline in Chemistry Parameters at Early Termination/Day 360 Alanine Aminotransferase	-2.3 Unit per liter Standard Deviation 4.18	9.6 Unit per liter Standard Deviation 52.75

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in chemistry parameters albumin and protein were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=32 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=30 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Chemistry Parameters (Albumin and Protein) at Early Termination/Day 360 Albumin	-0.2 gram per liter Standard Deviation 2.82	-0.1 gram per liter Standard Deviation 2.45
Change From Baseline in Chemistry Parameters (Albumin and Protein) at Early Termination/Day 360 Protein	0.7 gram per liter Standard Deviation 4.27	1.0 gram per liter Standard Deviation 3.55

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specific categories.

Change from baseline in chemistry parameters blood urea nitrogen, cholesterol, glucose, phosphate, potassium, sodium and urate were studies. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Chemistry Parameters (Blood Urea Nitrogen, Cholesterol, Glucose, Phosphate, Potassium, Sodium and Urate) at Early Termination/Day 360 Blood Urea Nitrogen	-0.235 millimoles per liter Standard Deviation 1.0664	-0.036 millimoles per liter Standard Deviation 1.4248
Change From Baseline in Chemistry Parameters (Blood Urea Nitrogen, Cholesterol, Glucose, Phosphate, Potassium, Sodium and Urate) at Early Termination/Day 360 Calcium	0.035 millimoles per liter Standard Deviation 0.1101	0.004 millimoles per liter Standard Deviation 0.0977
Change From Baseline in Chemistry Parameters (Blood Urea Nitrogen, Cholesterol, Glucose, Phosphate, Potassium, Sodium and Urate) at Early Termination/Day 360 Cholesterol	-0.082 millimoles per liter Standard Deviation 0.4592	-0.295 millimoles per liter Standard Deviation 0.8294
Change From Baseline in Chemistry Parameters (Blood Urea Nitrogen, Cholesterol, Glucose, Phosphate, Potassium, Sodium and Urate) at Early Termination/Day 360 Glucose	-0.183 millimoles per liter Standard Deviation 0.9841	0.138 millimoles per liter Standard Deviation 0.9205
Change From Baseline in Chemistry Parameters (Blood Urea Nitrogen, Cholesterol, Glucose, Phosphate, Potassium, Sodium and Urate) at Early Termination/Day 360 Phosphate	-0.045 millimoles per liter Standard Deviation 0.1940	-0.153 millimoles per liter Standard Deviation 0.2056
Change From Baseline in Chemistry Parameters (Blood Urea Nitrogen, Cholesterol, Glucose, Phosphate, Potassium, Sodium and Urate) at Early Termination/Day 360 Potassium	-0.02 millimoles per liter Standard Deviation 0.569	-0.01 millimoles per liter Standard Deviation 0.367
Change From Baseline in Chemistry Parameters (Blood Urea Nitrogen, Cholesterol, Glucose, Phosphate, Potassium, Sodium and Urate) at Early Termination/Day 360 Sodium	0.8 millimoles per liter Standard Deviation 2.57	0.3 millimoles per liter Standard Deviation 2.48
Change From Baseline in Chemistry Parameters (Blood Urea Nitrogen, Cholesterol, Glucose, Phosphate, Potassium, Sodium and Urate) at Early Termination/Day 360 Urate	-0.0073 millimoles per liter Standard Deviation 0.04488	0.0142 millimoles per liter Standard Deviation 0.07180

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specific categories.

Change from baseline in chemistry parameters bilirubin and creatinine were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Chemistry Parameters (Bilirubin and Creatinine) at Early Termination/Day 360 Bilirubin	0.90 micromoles per liter Standard Deviation 3.644	-0.14 micromoles per liter Standard Deviation 2.994
Change From Baseline in Chemistry Parameters (Bilirubin and Creatinine) at Early Termination/Day 360 Creatinine	3.3 micromoles per liter Standard Deviation 8.20	6.7 micromoles per liter Standard Deviation 17.15

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in thyrotropin were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=30 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=25 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Thyrotropin at Early Termination/ Day 360	0.2576 milli-international units per litre Standard Deviation 0.98862	0.2392 milli-international units per litre Standard Deviation 0.90169

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in thyroxine,free were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=21 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=25 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Thyroxine,Free at Early Termination/Day 360	0.61 picomole per liter Standard Deviation 1.851	-0.46 picomole per liter Standard Deviation 2.632

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in urine specific gravity were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=30 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=35 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Urinalysis (Specific Gravity) at Early Termination/Day 360	0.0029 Ratio Standard Deviation 0.00762	0.0010 Ratio Standard Deviation 0.00923

PRIMARY outcome

Timeframe: Baseline, Early termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in urobilinogen were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=21 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=34 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Urobilinogen at Early Termination/Day 360	0.09 milligrams per deciliter Standard Deviation 0.393	0.05 milligrams per deciliter Standard Deviation 0.309

PRIMARY outcome

Timeframe: Baseline, Early Termination/Day 360

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specified time point.

Change from baseline in urine pH were reported. Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=30 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=35 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Urine Potential of Hydrogen (pH) at Early Termination/Day 360	0.1 pH Standard Deviation 0.83	0.1 pH Standard Deviation 1.07

PRIMARY outcome

Timeframe: Baseline, FoTA (up to 330 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Heart rate was measured by Electrocardiogram (ECG). ECG was performed using the central ECG provider's equipment and was send to the central ECG provider electronically. Change from baseline in heart rate at FoTA were reported. FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the average of all valid ECG measurements as the last assessment obtained before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=61 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=75 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Heart Rate at Final On-Treatment Assessment (FoTA)	1.78 beats per minute Standard Deviation 7.618	-0.12 beats per minute Standard Deviation 10.973

PRIMARY outcome

Timeframe: Baseline, FoTA (up to 330 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

ECG was performed using the central ECG provider's equipment and was sent to the central ECG provider electronically to measure PR, RR, QRS , QT, QTcB and QTcF intervals. FoTA was defined as the last valid assessment obtained after Baseline and whilst on investigational product (on or before 2 days after the last dose date).Group A baseline was the baseline of the antecedent studies. Group B baseline was the average of all valid ECG measurements as the last assessment obtained before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=61 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=75 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Electrocardiogram Parameters at Final On-Treatment Assessment (FoTA) FoTA: PR Interval	-1.77 milliseconds Standard Deviation 10.129	0.14 milliseconds Standard Deviation 8.539
Change From Baseline in Electrocardiogram Parameters at Final On-Treatment Assessment (FoTA) FoTA: RR Interval	-18.05 milliseconds Standard Deviation 71.382	-1.77 milliseconds Standard Deviation 88.658
Change From Baseline in Electrocardiogram Parameters at Final On-Treatment Assessment (FoTA) FoTA: QRS Interval	0.93 milliseconds Standard Deviation 4.419	1.62 milliseconds Standard Deviation 5.688
Change From Baseline in Electrocardiogram Parameters at Final On-Treatment Assessment (FoTA) FoTA: QT Interval	-4.74 milliseconds Standard Deviation 17.826	-1.49 milliseconds Standard Deviation 18.616
Change From Baseline in Electrocardiogram Parameters at Final On-Treatment Assessment (FoTA) FoTA: QTcB Interval	-0.52 milliseconds Standard Deviation 14.145	-1.39 milliseconds Standard Deviation 14.796
Change From Baseline in Electrocardiogram Parameters at Final On-Treatment Assessment (FoTA) FoTA: QTcF Interval	-1.97 milliseconds Standard Deviation 13.126	-1.37 milliseconds Standard Deviation 11.808

PRIMARY outcome

Timeframe: FoTA (up to 330 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specific categories.

PSQ was a 7-item questionnaire typically used to assess sleep quality with pharmacologic treatment. The questionnaire collects data on average time to sleep, sleep latency, frequency of interrupted sleep, duration of interrupted sleep, total sleep time and sleep quality over the last week. The assessment was done by the nature of the responses, not by a numbered scale. Participants analyzed for number of times woke up per night category were only the participants who responded as yes for the woke up during the night category in this outcome measure. FoTA was defined as the last valid assessment obtained after Baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Overall quality - Better than usual	1 Participants	0 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Woke up during the night - Yes	17 Participants	13 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Woke up during the night - No	46 Participants	64 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Number of times woke up per night = 0	0 Participants	2 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Number of times woke up per night = 1	12 Participants	10 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Number of times woke up per night = 2	4 Participants	2 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Number of times woke up per night = 3	1 Participants	0 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Number of times woke up per night = 4	0 Participants	0 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Number of times woke up per night >= 5	0 Participants	0 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Overall quality of sleep - Very Poor	0 Participants	0 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Overall quality of sleep - Poor	6 Participants	1 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Overall quality of sleep - Average	23 Participants	20 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Overall quality of sleep - Good	24 Participants	29 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Overall quality of sleep - Very Good	10 Participants	27 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Past week a typical week - Yes	48 Participants	66 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Past week a typical week - No	15 Participants	11 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Past week was not typical - Vacation	4 Participants	1 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Past week was not typical - School break	7 Participants	7 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Past week was not typical - Friend house	0 Participants	0 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Past week was not typical - ill	0 Participants	2 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Past week was not typical - other	4 Participants	1 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Overall quality - Same as usual	13 Participants	8 Participants
Number of Participants With Quality of Sleep Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) FoTA: Overall quality - Worse than usual	5 Participants	4 Participants

PRIMARY outcome

Timeframe: FoTA (up to 330 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, the number of participants analyzed refer to the participants evaluable for this outcome at specific categories.

PSQ was a 7-item questionnaire typically used to assess sleep quality with pharmacologic treatment. The questionnaire collects data on average time to sleep, sleep latency, frequency of interrupted sleep, duration of interrupted sleep, total sleep time and sleep quality over the last week. FoTA was defined as the last valid assessment obtained after Baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. Length of time awake per night and length of time to fall asleep per night was assessed at FoTA.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Length of Time Awake Per Night and Length of Time to Fall Asleep Per Night Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) Length of Time to Fall Asleep per Night	20.2 minutes Standard Deviation 17.12	22.3 minutes Standard Deviation 24.74
Length of Time Awake Per Night and Length of Time to Fall Asleep Per Night Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA) Length of Time Awake per Night	8.8 minutes Standard Deviation 4.14	14.4 minutes Standard Deviation 23.10

PRIMARY outcome

Timeframe: FoTA (up to 330 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.

PSQ was a 7-item questionnaire typically used to assess sleep quality with pharmacologic treatment. The questionnaire collects data on average time to sleep, sleep latency, frequency of interrupted sleep, duration of interrupted sleep, total sleep time and sleep quality over the last week. FoTA was defined as the last valid assessment obtained after Baseline and whilst on investigational product (on or before 2 days after the last dose date). Group A baseline was the baseline of the antecedent studies. Group B baseline was the last value collected before the first dose of investigational product. Length of time sleeping per night was assessed at FoTA.

Outcome measures

Measure	Group A (Antecedent Studies) n=63 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Length of Time Sleeping Per Night Assessed by Post Sleep Questionnaire (PSQ) at Final On-Treatment Assessment (FoTA)	9.1 hours Standard Deviation 1.40	9.6 hours Standard Deviation 1.21

PRIMARY outcome

Timeframe: FoTA (up to 330 days)

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

CSHQ was a tool designed to screen for the most common sleep problems in children and consisted of 33 items for scoring and several extra items intended to provide administrators with other potentially useful information about respondents. The instrument evaluates the 8 different subscales: bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep disordered breathing, and daytime sleepiness. A 3-point scale was used for rating: "usually" if the sleep behavior occurs 5 to 7 times per week, "sometimes" for 2 to 4 times per week, and "rarely" for once or not at all during the week. The TSD score, which is the sum of all responses, included all items of the 8 subscales, but consisted of only 33 items because two on the bedtime resistance and sleep anxiety subscales were identical (range: 0, 99). A negative value indicates less sleep disturbance.

Outcome measures

Measure	Group A (Antecedent Studies) n=62 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Total Sleep Disturbance Score of Children's Sleep Habits Questionnaire (CSHQ ) at Final On-Treatment Assessment (FoTA)	42.2 Units on scale Standard Deviation 8.44	39.3 Units on scale Standard Deviation 5.85

PRIMARY outcome

Timeframe: Day 330

Population: Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The number of participants with postive response in suicidal ideation and suicidal behavior were reported.

Outcome measures

Measure	Group A (Antecedent Studies) n=2 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=2 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Number of Participants With a Positive Response in Columbia-Suicide Severity Rating Scale (C-SSRS) at Day 330 Suicidal Ideation	0 Participants	0 Participants
Number of Participants With a Positive Response in Columbia-Suicide Severity Rating Scale (C-SSRS) at Day 330 Suicidal Behavior	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, FoTA (up to 330 days)

Population: Full analysis set (FAS) consisted of all participants in the safety set who have completed at least 1 post-dose efficacy assessment using ADHD-RS-5 Total Score. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Clinician administered ADHD-RS-5, child, home version total score were analyzed. ADHD-RS-5 consists of 18 items designed to reflect current symptomatology of ADHD based on diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) criteria. Each item is scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54. The 18 items may be grouped into 2 subscales: hyperactivity/impulsivity (9 items) and inattentiveness (9 items). Higher total scores indicated higher impairment and lower scores indicated no impairment. FoTA was defined as the last valid assessment obtained after Baseline and whilst on investigational product (on or before 2 days after the last dose date).

Outcome measures

Measure	Group A (Antecedent Studies) n=62 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Change From Baseline in Clinician-administered Attention-Deficit/Hyperactivity Disorder Rating Scale-5 (ADHD-RS-5) Total Score at Final On-Treatment Assessment (FoTA)	-19.2 Score on a scale Standard Error 1.88	-19.3 Score on a scale Standard Error 1.69

SECONDARY outcome

Timeframe: FoTA (up to 330 days)

Population: FAS consisted of all participants in the safety set who have completed at least 1 post-dose efficacy assessment using ADHD-RS-5 Total Score. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

CGI-I scale was performed to rate the improvement of a participant's condition on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). FoTA was defined as the last valid assessment obtained after baseline and whilst on investigational product (on or before 2 days after the last dose date).

Outcome measures

Measure	Group A (Antecedent Studies) n=62 Participants Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 Participants Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Clinical Global Impression of Improvement (CGI-I) at Final On-Treatment Assessment (FoTA)	2.7 Score on a scale Standard Error 0.16	2.9 Score on a scale Standard Error 0.15

Adverse Events

Group A (Antecedent Studies)

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Group B (Direct Enrollment)

Serious events: 1 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Measure	Group A (Antecedent Studies) n=63 participants at risk Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 participants at risk Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.00% 0/63 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.	1.3% 1/77 • Number of events 1 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.

Other adverse events

Measure	Group A (Antecedent Studies) n=63 participants at risk Participants who completed antecedent studies SHP465-112 (NCT03327402) or SHP465-309 (NCT03325881) were in group A and received 6.25 milligram (mg) SHP465 capsule orally once daily for up to 330 days.	Group B (Direct Enrollment) n=77 participants at risk Participants who directly enrolled in this study were in group B and received 6.25 mg SHP465 capsule orally once daily for up to 330 days.
Gastrointestinal disorders Diarrhoea	0.00% 0/63 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.	9.1% 7/77 • Number of events 12 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.
Gastrointestinal disorders Vomiting	0.00% 0/63 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.	6.5% 5/77 • Number of events 5 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.
Investigations Weight decreased	4.8% 3/63 • Number of events 4 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.	7.8% 6/77 • Number of events 7 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.
Metabolism and nutrition disorders Decreased appetite	1.6% 1/63 • Number of events 1 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.	7.8% 6/77 • Number of events 7 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.
Nervous system disorders Headache	7.9% 5/63 • Number of events 5 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.	3.9% 3/77 • Number of events 4 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.
Psychiatric disorders Irritability	6.3% 4/63 • Number of events 5 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.	1.3% 1/77 • Number of events 1 • From start of study drug administration up to follow-up (approximately up to 367 days) Safety set consisted of all participants who had taken at least 1 dose of investigational product in this current study.

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