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A Phase 3, Open-label, Non-controlled Study to Evaluate the Pharmacokinetics, Safety and Tolerability, and Efficacy of TAK-771 in Japanese Subjects with Primary Immunodeficiency Diseases (PID)

A Study of TAK-771 in Japanese People With Primary Immunodeficiency Diseases (PID)

16

A total of 16 subjects were enrolled in the study; all (100.0%) of 16 subjects were determined to be eligible for this study and treated throughout the study. All subject completed the study.

- The median age was 21.0 years (range: 5-62 years). Subjects aged >=12 years were 12 (75.0%) subjects and those aged >=18 years were 11 (68.8%) subjects. Ten (62.5%) subjects were males and 6 (37.5%) subjects were females. With regards to prior treatment, the majority of subjects (10 [62.5%] subjects) were on cSCIG treatment prior to TAK-771. - The most common primary immunodeficiency diagnosis was common variable deficiency (CVID) (10 [62.5%] subjects), followed by X-linked agammaglobulinemia (XLA) 21 (3 [18.8%] subjects).

The analysis of the safety results in this study indicated that treatment with TAK-771 administered every 3 or 4 weeks was safe and well tolerated in Japanese subjects aged 2 years or older with PID, in terms of AEs, tolerability events, laboratory values, vital signs, body weight, and physical examinations. Overall, the safety profile observed in Japanese subjects in this study was generally consistent with the existing safety profile of TAK-771. - A total number of infusions administered to all subjects in the overall treatment period was 147 infusions: 45 infusions in Epoch 1 and 102 infusions in Epoch 2. The median maximum infusion rate per site in Epoch 2 was 240.0 mL/h. The median duration of the individual infusions in Epoch 2 was 74.0 minutes. No subject required a dose adjustment to maintain the minimum serum trough level of IgG >=5 g/L, as predefined in the protocol. - The median numbers of infusions per month per subject and infusion sites per infusion in Epoch 2 were 1.09 and 2.00, respectively. The median number of infusion sites per month per subject in Epoch 2 was 2.17. - No deaths or TEAEs leading to discontinuation of TAK-771 occurred during the study. - A total of 3 serious TEAEs (adrenal insufficiency, gastroenteritis [1 event each in Epoch 1], and upper respiratory tract inflammation [1 event in Epoch 2]) were reported in 2 subjects. In severity, upper respiratory tract inflammation was severe, adrenal insufficiency and gastroenteritis were moderate, and all were resolved and considered not related to TAK-771 by the investigator. - One severe TEAE (upper respiratory tract inflammation) was reported in 1 (6.3%) subject in Epoch 2, which was considered not related to TAK-771. Except for this event, none of TEAEs were severe and the majority of TEAEs were mild in severity. - In total, 181 TEAEs were reported in 15 (93.8%) subjects and the most common TEAEs by PT in the overall treatment period were pyrexia (6 [37.5%] subjects) and nasopharyngitis (4 [25.0%] subjects). In Epoch 1, 57 TEAEs were reported in 13 (81.3%) subjects, and 124 TEAEs were reported in 15 (93.8%) subjects in Epoch 2. The most common TEAEs by PT in Epoch 1 were pyrexia (5 [31.3%] subjects), followed by nasopharyngitis (3 [18.5%] subjects), and in Epoch 2 were pyrexia (5 [31.3%] subjects), followed by nasopharyngitis (3 [18.8%] subjects). Most TEAEs reported in this study were resolved/resolving by the EOS visit. - A total of 104 TEAEs in 11 (68.8%) subjects were considered related to TAK-771 by the investigator, and the most common related TEAEs by PT in the overall treatment period were pyrexia (5 [31.3%] subjects), followed by infusion site erythema, injection site erythema, infusion site swelling, infusion site pain, and headache (2 [12.5%] subjects each). In Epoch 1, 37 related TEAEs were reported in 9 (56.3%) subjects, and 67 related TEAEs were reported in 11 (68.8%) subjects in Epoch 2. The most common related TEAEs by PT in Epoch 1 were pyrexia (4 [25.0%] subjects), followed by infusion site erythema, injection site erythema, infusion site swelling, infusion site pain, and headache (2 [12.5%] subjects each), and in Epoch 2 were pyrexia (5 [31.3%] subjects), followed by infusion site erythema and injection site erythema (2 [12.5%] subjects each). - The rate of TEAEs per subject-years was 19.859, and that of related TEAEs per subject-years was 11.411. - In total, 58 local TEAEs were reported in 8 (50.0%) subjects. Of them, 18 events were reported in 7 (43.8%) subjects in Epoch 1, and 40 events were reported in 7 (43.8%) subjects in Epoch 2. None of the local TEAEs were severe or serious, and the majority of the local TEAEs were mild and all were resolved. A total of 49 related local TEAEs were reported in 7 (43.8%) subjects. Of them, 16 events were reported in 6 (37.5%) subjects in Epoch 1, and 33 events were reported in 6 (37.5%) subjects in Epoch 2. The rate of local TEAEs per subject-years was 6.364, and that of related local TEAEs per subject-years was 5.376. - A total of 123 systemic TEAEs were reported in 14 (87.5%) subjects. Of them, 39 events were reported in 12 (75.0%) subjects in Epoch 1, and 84 events were reported in 14 (87.5%) subjects in Epoch 2. One severe systemic TEAE (upper respiratory tract inflammation) was reported in Epoch 2, which was considered not related to TAK-771 by the investigator. The majority of the events were mild and mostly resolved/resolving. A total of 55 related systemic TEAEs were reported in 7 (43.8%) subjects. Of them, 21 events were reported in 6 (37.5%) subjects in Epoch 1, and 34 events were reported in 6 (37.5%) subjects in Epoch 2. The rate of systemic TEAEs per subject-years was 13.495 and that of related systemic TEAEs per subject-years was 6.034. - By age group, the reported TEAEs were comparable between the age groups 17 years or younger and 18 years or older. - No severe or serious infusion-associated TEAEs were reported. In total, 64 infusion-associated TEAEs were reported in 8 (50.0%) subjects. Of them, 21 events were reported in 6 (37.5%) subjects in Epoch 1, and 43 events were reported in 8 (50.0%) subjects in Epoch 2. The majority of these events were mild, and all were resolved during the study. A total of 55 related infusion-associated TEAEs were reported in 7 (43.8%) subjects. Of them, 19 events were reported in 5 (31.3%) subjects in Epoch 1, and 36 events were reported in 7 (43.8%) subjects in Epoch 2. The rate of infusion-associated TEAEs per subject-years was 7.022, and that of related infusion-associated TEAEs per subject-years was 6.034. - The median percentage of infusions completed as planned was 100% (range: 100.0-100.0%) in the overall treatment period. No subject experienced a tolerability event (reduction of infusion rate, interruption or discontinuation of TAK-771 due to TEAEs related to TAK-771) in this study. - The median number of weeks to reach the final dose interval in Epoch 1 was 6.00 weeks. All subjects achieved and maintained a treatment interval of 3 or 4 weeks in Epoch 2. - There were no subjects who developed a titer of >=1:160 for binding antibodies against rHuPH20. - No clinically significant changes in laboratory values, vital signs, and body weights were observed.

Pharmacokinetics Results: The primary endpoint: - The serum trough levels of total IgG measured during Epoch 2 were stable and all over 5 g/L. - The serum total IgG levels before starting TAK-771 dose (at 2 pre-doses) and after receiving TAK-771 over 6 months (at last 3 doses) were maintained regardless of dosing intervals and age groups, with Geo mean of 9.624 g/L (95% CI of Geo mean: 8.421-11.00, median: 9.68) and 9.494 g/L (95% CI of Geo mean: 8.286-10.88, median: 9.24), respectively. The Geo means of serum total IgG levels before starting TAK-771 dose and after receiving TAK-771 over 6 months were 7.804 g/L (95% CI of Geo mean: 6.224-9.786, median: 8.23) and 8.822 g/L (95% CI of Geo mean: 5.236-14.87, median: 8.56) for subjects aged <12 years old, and 10.32 g/L (95% CI of Geo mean: 8.846-12.04, median: 10.1) and 9.686 g/L (95% CI of Geo mean: 8.201-11.44, median: 9.32) for subjects aged >12 years old, respectively. The secondary endpoints: - The serum trough levels of IgG subclasses in the trough evaluation period of Epoch 2 were stable. Meanwhile, the serum levels of IgG subclasses before starting TAK-771 dose (at 2 pre-doses) and after receiving TAK-771 over 6 months (at last 3 doses) were also comparable regardless of dosing intervals and age groups. - Pharmacokinetic parameters of serum IgG levels were evaluated in 4 subjects aged 12 years or older during Epoch 2. The Geo mean of AUC0-tau was 327.9 g*day/L (95% CI of Geo mean: 212.7-505.7, median: 339). The Geo mean of AUC0-tau/Dose was 767.9 (g*day/L)/(g/kg) (95% CI of Geo mean: 294.9-1999). The Geo mean of Cmax of total IgG was 12.72 g/L (95% CI of Geo mean: 8.805-18.37) with the median tmax of 6.94 days (range: 2.94-8.85). The t1/2z was estimated for total IgG with the value of 112 days, but it should be noted this result was obtained from only one subject. - The trough levels of specific antibodies against Clostridium tetani toxoid, HIB, and HBV showed no substantial difference at Epoch 1 Week 1 visit and at EOS visit. Efficacy Results: - There were no validated ASBIs reported in this study. - The Poisson estimates of the annual rate of all infections were 3.56 (95% CI: 1.44-7.12) in Epoch 1 and 2.74 (95% CI: 1.40-4.74) in the overall treatment period. The most frequently reported infections (categorized by system organ class [SOC] infections and infestations occurring in >10% subjects) by preferred term (PT) included nasopharyngitis, chronic sinusitis, oral herpes, and COVID-19. - The mean and median number of days not able to attend school/work or to perform normal daily activities due to illness/infection per year were 2.72 days and 0.00 day (range: 0.0-43.5 days) in Epoch 1, 7.13 days and 0.00 day (range: 0.0-30.3 days) in Epoch 2, and 6.75 days and 0.00 day (range: 0.0-26.8 days) in the overall treatment period, respectively. The mean and median number of days on antibiotics per year were 2.17 days and 0.00 day (range: 0.0-34.8 days) in Epoch 1, 5.67 days and 0.00 day (range: 0.0-51.9 days) in Epoch 2, and 5.68 days and 0.00 day (range: 0.0-40.2 days) in the overall treatment period, respectively. - The mean and median number of hospitalizations due to illness/infection per year were 0.54 and 0.00 (range: 0.0-8.7) in Epoch 1, 0.14 and 0.00 (range: 0.0-2.2) in Epoch 2, and 0.22 and 0.00 (range: 0.0-1.7) in the overall treatment period, respectively. The mean and median number of hospitalization days per subject per year were 1.63 days and 0.00 day (range: 0.0-26.1 days) in Epoch 1, 0.81 days and 0.00 day (range: 0.0-13.0 days) in Epoch 2, and 0.98 days and 0.00 day (range: 0.0-10.5 days) in the overall treatment period, respectively. Two subjects were hospitalized due to AEs. - The mean and median number of acute physician visits due to illness/infection per subject per year were 4.35 visits and 0.00 visit (range: 0.0-34.8 visits) in Epoch 1, 2.53 visits and 0.00 visit (range: 0.0-15.1 visits) in Epoch 2, and 3.23 visits and 1.74 visits (range: 0.0-11.7 visits) in the overall treatment period, respectively. - Overall, scores of HRQoL (PEDS-QL, SF-36, and EQ-5D-3L questionnaires) and treatment satisfaction (TSQM-9 questionnaire) appeared to be similar at baseline, at Week16/Week19, and EOS visit. - Most of the subjects liked the frequency of administration and the number of needlesticks per month. As for an overall treatment preference, the majority of subjects showed their preference to continue receiving TAK-771. Safety Results: Refer to 'Adverse events' Brief summary (continued): Efficacy of TAK-771 administration was demonstrated by no occurrence of validated ASBIs and the low annual rate of all infections, with the maintenances of protective trough levels for total IgG and specific antibodies. Stable and protective total IgG levels were maintained throughout Epoch 2. The safety and tolerability of TAK-771 were demonstrated by the analyses of AEs and tolerability events. Health-related QoL assessments and patient outcomes of treatment satisfaction and preference showed that subjects appreciated the treatment flexibility and convenience offered by the 3- or 4- week dosing interval of SCIG, TAK-771.

Administrations of TAK-771 were effective, safe, and tolerated in Japanese subjects with PID aged 2 years or older.

Feb. 20, 2024

Yes

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210457

Nishizawa Atsushi

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

smb.Japanclinicalstudydisclosure@takeda.com

Contact for Clinical Trial Information

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

+81-6-6204-2111

smb.Japanclinicalstudydisclosure@takeda.com

Complete

Jan. 24, 2022

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Be a Japanese person.
2. Participant must have a documented diagnosis of a form of primary humoral immunodeficiency involving antibody formation and requiring gammaglobulin replacement, as defined according to the International Union of Immunological Societies(IUIS) Committee 2017. The diagnosis must be confirmed by the Medical Director prior to TAK-771 treatment.
3. Participant has been receiving a stable clinical dose of intravenous immunoglobulin (IVIG) or conventional subcutaneous immunoglobulin (cSCIG), which is equivalent to approximately 200 to 600 mg/kg body weight per 3 to 4 week period for IVIG and approximately 50 to 200 mg/kg body weight per week for cSCIG based on the description in the package insert, consistently over a period of at least 3 months prior to screening, or Participant has been receiving of TAK-664 with fixed dose and dosing frequency at least 3 months prior to enrollment. That is, participant is about to complete Study TAK-664-3001 or participating in Study TAK-664-3002.
4. Participant who has been receiving IVIG or cSCIG had all serum trough levels of total immunoglobulin G (IgG) >=5 g/L within 1 month prior to the screening/enrollment.
5. Serum trough levels at screening/enrollment meet one of the following:
a. IVIG-treated or cSCIG-treated participants
Participant who had serum trough levels of IgG >=5 g/L at the last 2 points in screening procedure before the first administration of TAK-771.
b. TAK-664-treated participants
Participant who had serum trough levels of IgG >=5 g/L at the last 2 points in TAK-664 studies before the first administration of TAK-771.
6. Participant is willing and able to comply with use of digital tools and applications.

1. Participant has a known history of or is positive at screening/enrollment for one or more of the following: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) Type 1/2
For participants who are switching from TAK-664 studies, the eligibility will be reconfirmed after result of the specialty test conducted at Week 1 become available.
2. Abnormal laboratory values at screening/enrollment meeting any one of the following criteria (abnormal tests may be repeated once to determine if they are persistent):
- Persistent alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >2.5 times the upper limit of normal (ULN) for the testing laboratory
- Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] =<500/mm^3)
3. Participant has presence of renal function impairment defined by eGFR <60 mL/min/1.73m^2.
4. Participant has been diagnosed with, or had a malignancy (other than adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the disease-free period prior to screening exceeds 5 years.
5. Participant is receiving anti-coagulation therapy or has a history of thrombotic episodes (including deep vein thrombosis, myocardial infarction, cerebrovascular accident, pulmonary embolism) within 12 months prior to screening/enrollment or a history of thrombophilia.
6. Participant has abnormal protein loss (protein losing enteropathy, nephrotic syndrome)
7. Participant has anemia that would preclude phlebotomy for laboratory studies according to standard practice at the site.
8. Participant has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IVIG, subcutaneous immunoglobulin (SCIG), and/or Immune Serum Globulin infusions
9. Participant has immunoglobulin A (IgA) deficiency (serum IgA less than 0.07g/L) and history of hypersensitivity, or history of confirmed anti-IgA antibodies, or both.
10. Participant is on preventative (prophylactic) systemic antibacterial antibiotics at doses sufficient to treat or prevent bacterial infections, and cannot stop these antibiotics at the time of screening/enrollment.
11. Participant has active infection and is receiving antibiotic therapy for the treatment of infection at the time of screening/enrollment or had a serious bacterial infection within the 3 months prior to screening/enrollment
12. Participant has a bleeding disorder, or a platelet count less than 20,000/microL, or in the opinion of the investigator, would be at significant risk of increased bleeding or bruising as a result of subcutaneous (SC) therapy.
13. Participant has total protein >9 g/dL or myeloma, or macroglobulinemia (IgM) or paraproteinemia.
14. Participant has a known allergy to hyaluronidase
15. Participant has severe dermatitis that would preclude adequate sites for safe product administration.

Both

Primary Immunodeficiency Diseases (PID)

Epoch 1: TAK-771 Ramp up Period
TAK-771 includes Immune Globulin Infusion (IGI) 10% and Recombinant Human Hyaluronidase (rHuPH20). Participants will receive SC infusion of rHuPH20 solution at a dose of 80 U/g IgG first, followed by SC infusion of 10% IGI within 10 minutes of completion of the infusion of rHuPH20 solution. The dose of 10% IGI will be increased from 1/3 of full dose to full dose in 3 weeks for participants who will receive TAK-771 once every 3 week, or from 1/4 of full dose to full dose in 6 weeks for participants who will receive TAK-771 once every 4 week.

Epoch 2: TAK-771 Full Dose Treatment Period
TAK-771 includes Immune Globulin Infusion (IGI) 10% and Recombinant Human Hyaluronidase (rHuPH20). Participants will receive subcutaneous infusion of rHuPH20 solution at a dose of 80 U/g IgG first, followed by SC infusion of 10% IGI within 10 minutes of completion of the infusion of rHuPH20 solution, every 3, or 4 weeks for up to Week 24.

1. Epoch 2: Serum Trough Levels of Total IgG Antibodies after Administration of TAK-771
Time Frame: Up to Week 31 for Participants with 4-Week Dosing Interval or Up to Week 28 for Participants with 3-Week Dosing Interval
The data was reported at Week 7, 11, 15, 19, 23, 27, and 31 for 4-Week interval and at Week 4, 7, 10, 13, 16, 19, 22, 25 and 28 for 3-Week interval.

1.-7. Epoch 2: Maximum Concentration (Cmax), Time to Maximum Concentration (Tmax), Area Under the Curve (AUC), Half-life, Apparent Total Clearance (CL/F), Apparent Volume of Distribution (Vz/F) and Minimum Concentration (Cmin) of Total Serum Levels of IgG and IgG Subclasses (IgG1, IgG2, IgG3, and IgG4)
Time Frame: Pre-infusion at the last dose of TAK-771 (Week 27 for participants with 4-Week dosing interval or Week 25 for participants with 3-Week dosing interval) and post infusion at multiple time points up to Week 31 for participants with 4-Week dosing interval and up to Week 28 for participants with 3-Week dosing interval

8. Epoch 2: Serum Trough Levels of IgG subclasses (IgG1, IgG2, IgG3, and IgG4) after Administration of TAK-771
Time Frame: 4-Week dosing interval (Week 7, Week 11, Week 15, Week 19, Week 23, Week 27, and Week 31); 3-Week dosing interval (Week 4, Week 7, Week 10, Week 16, Week 19, Week 22, Week 25, and Week 28)

9.-11. Epoch 1 and 2: Trough Levels of Anti-Clostridium Tetani Toxoid Antibody, Anti-HBV Antibody and Anti-HIB Antibody After Administration of TAK-771
Time Frame: From Week 1, up to end of trial (EOS: Week 31 for participants with 4-Week dosing interval or Week 28 for participants with 3-Week dosing interval)

12. Percentage of Participants with Treatment-Emergent Adverse Events (TEAEs)
Time Frame: From Week 1, up to Week 31 for Participants with 4-Week Dosing or up to Week 28 for Participants with 3-Week Dosing Interval

13. Percentage of Participants with TAK-771-Related and TAK-771-Non-Related TEAEs
Time Frame: From Week 1, up to Week 31 for Participants with 4-Week Dosing Interval or up to Week 28 for Participants with 3-Week Dosing Interval

14. Percentage of Participants with Serious and Non-serious TEAEs
Time Frame: From Week 1, up to Week 31 for Participants with 4-Week Dosing Interval or up to Week 28 for Participants with 3-Week Dosing Interval

15.-18. Percentage of Participants with Severe TEAEs, Local and Systemic TEAEs, TEAEs Leading to Premature Discontinuation from Study and Infusion-associated TEAEs
Time Frame: From Week 1, up to Week 31 for Participants with 4-Week Dosing Interval or up to Week 28 for Participants with 3-Week Dosing Interval

19.-20. Percentage of Participants with Clinically Significant Changes in Clinical Laboratory Parameters, Vital Signs and Body Weight Recorded as TEAEs
Time Frame: From Week 1, up to Week 31 for Participants with 4-Week Dosing Interval or up to Week 28 for Participants with 3-Week Dosing Interval

21.-22. Epoch 2: Percentage of Participants who Develop Anti-rHuPH20 Binding Antibody Titers of Greater Than or Equal to 1:160 and who Develop Neutralizing Antibodies to rHuPH20
Time Frame: 4-Week dosing interval (Week 7, Week 19, and Week 31); 3-Week dosing interval (Week 4, Week 16, and Week 28)

23. Percentage of Participants who Experienced Tolerability Events Related to the Infusion of TAK-771
Time Frame: From Week 1, up to Week 31 for Participants with 4-Week Dosing Interval or up to Week 28 for Participants with 3-Week Dosing Interval
Tolerability events is defined as a case that the infusion rate is reduced, or that the infusion is interrupted or stopped, due to a TEAE related to TAK-771 infusion.

24. Epoch 1: Number of Weeks to Reach Final Dose Interval (3 Weeks or 4 Weeks)
Time Frame: Up to Week 4 for Participants with 4-Week Dosing Interval or Up to Week 3 for Participants with 3-Week Dosing Interval
The number of weeks to reach final dose interval is defined as treatment duration of Epoch 1.

25.-26. Epoch 2: Percentage of Participants who Achieve a Treatment Interval of 3 or 4 Weeks and who Maintain a Treatment Interval of 3 or 4 Weeks
Time Frame: Up to Week 31 for Participants with 4-Week Dosing Interval or Up to Week 28 for Participants with 3-Week Dosing Interval

27. Annual Rate of Validated Acute Serious Bacterial Infections (ASBIs)
Time Frame: From Week 1, up to Week 31 for Participants with 4-Week Dosing Interval or up to Week 28 for Participants with 3-Week Dosing Interval
The annual rate of validated ASBIs is calculated as the mean number of ASBIs per participant per year. The data was collected using poisson estimate. Point-estimate and 99% confidence bound (i.e., the upper bound of two-sided 98% confidence interval) were calculated using a Poisson model with subject-year in study as the offset variable.

28. Annual Rate of All Infections per Participant
Time Frame: From Week 1, up to Week 31 for Participants with 4-Week Dosing Interval or up to Week 28 for Participants with 3-Week Dosing Interval
The annual rate of all infections is calculated as the mean number of infections per participant per year.

29.-33. Healthcare Resource Utilization: Days Not Able To Attend School/Work or To Perform Normal Daily Activities Due to Illness/Infection, Days on Antibiotics, Number of Hospitalizations Due to Illness/Infection, Length of Stay in Days of Hospitalizations Due to Illness/Infection and Number of Acute (Urgent or Unscheduled) Physician Visits Due to Illness/Infection
Time Frame: From Week 1, up to Week 31 for Participants with 4-Week Dosing Interval or up to Week 28 for Participants with 3-Week Dosing Interval

34. Infusion Parameters in Epoch 2: Number of Infusion Sites per Infusion
Time Frame: From Week 7, up to Week 31 for Participants with 4-Week Dosing Interval or From Week 4, up to Week 28 for Participants with 3-Week Dosing Interval
Total number of infusion sites injected in Epoch 2 / Total number of infusions administered in Epoch 2.

35. Infusion Parameters in Epoch 2: Number of Infusion Sites per Month
Time Frame: From Week 7, up to Week 31 for Participants with 4-Week Dosing Interval or From Week 4, up to Week 28 for Participants with 3-Week Dosing Interval
Total number of infusion sites injected in Epoch 2 / (duration of Epoch 2 / 30.4375), where duration of Epoch 2 is calculated as the end date of the Epoch 2 - the start date of the Epoch 2 + 1.

36. Infusion Parameters in Epoch 2: Duration of Individual Infusions
Time Frame: From Week 7, up to Week 31 for Participants with 4-Week Dosing Interval or From Week 4, up to Week 28 for Participants with 3-Week Dosing Interval
End date and time of infusion in Epoch 2-Start date and time of infusion in Epoch 2, for each infusion per participant.

37. Infusion Parameters in Epoch 2: Maximum Infusion Rate per Site
Time Frame: From Week 7, up to Week 31 for Participants with 4-Week Dosing Interval or From Week 4, up to Week 28 for Participants with 3-Week Dosing Interval
Maximum Infusion Rate results from CRF / number of infusion sites/body.

38. Infusion Parameters in Epoch 2: Infusion Volume per Site
Time Frame: From Week 7, up to Week 31 for Participants with 4-Week Dosing Interval or From Week 4, up to Week 28 for Participants with 3-Week Dosing Interval
Infusion Volume per Site is scheduled Dose results from CRF / number of infusion sites/body.

39. Quality of Life (QOL): Pediatric Quality of Life Inventory (PEDS-QL)
Time Frame: 4-Week dosing interval (Week 1, Week 19, and Week 31); 3-Week dosing interval (Week 1, Week 16, and Week 28)

40. QOL: Short Form-36 Health Survey Version 2 (SF-36 v2)
Time Frame: 4-Week dosing interval (Week 1, Week 19, and Week 31); 3-Week dosing interval (Week 1, Week 16, and Week 28)

41. QOL: EuroQoL (Quality of Life)-5 Dimensions 3 Levels (EQ-5D-3L) Health Questionnaire
Time Frame: 4-Week dosing interval (Week 1, Week 19, and Week 31); 3-Week dosing interval (Week 1, Week 16, and Week 28)

42. Treatment Preference
Time Frame: Up to Week 31 for Participants with 4-Week Dosing Interval or Up to Week 28 for Participants with 3-Week Dosing Interval

43. Treatment Satisfaction: Questionnaire for Medication-9 (TSQM-9)
Time Frame: 4-Week dosing interval (Week 1, Week 19, and Week 31); 3-Week dosing interval (Week 1, Week 16, and Week 28)

+81-3-5803-5612

Oct. 26, 2021

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