STRENSIQ® Immunogenicity Study

Phase 1

Conditions: HYPOPHOSPHATASIA
MedDRA version: 20.1Level: PTClassification code: 10049933Term: Hypophosphatasia Class: 100000004850
Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Registration Number: CTIS2022-502793-17-00

Lead Sponsor: Alexion Pharmaceuticals Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 8

Inclusion Criteria

Participants must be = 2 years of age and < 18 years with open epiphyseal growth plates at the time of signing the informed assent/consent by the participant or their legal guardian., Reoccurrence or worsening of rickets for at least the past 3 months in participants who showed an initial efficacy response to asfotase alfa after at least 6 months of continuous treatment and currently receiving asfotase alfa. RSS will be used to determine severity at Baseline., Presence of ADAs, with or without NAbs, irrespective of their titers, Confirmation by the Treatment Monitoring Board (TMB) that both the clinical evidence and immunogenicity-mediated association noted above are present., Male or female, Female participants of childbearing potential and male participants with partners of childbearing potential must follow protocol-specified contraception guidance, Participant, or participant’s legal guardian, is capable of signing informed consent or assent, which includes compliance with the requirements and restrictions listed in the informed consent or assent form and in this protocol.

Exclusion Criteria

Non-immune-mediated LoE. Potential causes of non-immune-mediated LoE could include poor treatment adherence, inappropriate injection technique, vitamin D deficiency (vitamin D level should be > 20 ng/mL. If < 20 ng/mL at Screening, rescreening is allowed after vitamin D supplementation), undernutrition, or concomitant diseases, and should be ruled out when assessing participants for a suspected LoE of asfotase alfa., Female participants who have a positive pregnancy test at Screening or Day 1., Inability of the participant, or the participant’s legal guardian, to provide informed consent, Pregnant, breastfeeding, or intending to conceive during the course of the study., Inability to travel to the clinic for specified visits during the Treatment Period caused by disease per se or logistics (does not apply to external travel restrictions)., The participant is at risk of reactivation or has an active significant viral infection such as hepatitis B, cytomegalovirus, herpes simplex, human polyomavirus (also known as John Cunningham [JC] virus), parvovirus, or Epstein Barr virus., The participant is at risk of reactivation of tuberculosis or has regular contact (eg, in the household) with individuals who are being actively treated for tuberculosis., The participant has had or is required to have any live vaccination within 1 month prior to enrollment., Any medical condition (eg, cardiac, pulmonary, renal, hepatic, hematologic, oncologic,or psychiatric) that, in the opinion of the Investigator, might interfere with participation in the study (such as any interference with rituximab, methotrexate, and bortezomib), pose any added risk to the participant, or confound the assessment of the participant., Known history of human immunodeficiency virus (HIV) infection (evidenced by HIV type 1 or type 2 [HIV 1, HIV 2] antibody) or hepatitis B or C viral infection., History of hypersensitivity to any ingredient contained in any of the study interventions., Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to Screening., Evidence of severe hepatic or renal impairment or any other medical conditions that are contraindications for use of any of the components of the IST regimens according to the Reference Safety Information (RSI) or local approved product labeling., History of malignancy within 5 years of Screening that has been treated with no evidence of recurrence., Any concomitant medications contraindicated for rituximab, methotrexate, and bortezomib (including, but not limited to, those listed in the RSI for each IST)., Participation in another investigational drug or investigational device study within 30 days before the first dose administered in this study. Participants currently enrolled in the HPP Global Registry and/or HPP Registry Substudy should be discontinued prior to the Baseline of this study

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To Evaluate the effect of Immunosuppressive therapies (IST) in participants treated with asfotase alfa who demonstrate immune-mediated loss of effectiveness (LoE);Secondary Objective: To assess impact of immunogenicity in participants treated with IST undergoing asfotase alfa treatment for the duration of the study., Evaluate the effect of IST on PK/PD biomarkers of HPP, Evaluate the safety of IST use in participants with immune-mediated LoE, Assess impact of IST on B cells with rituximab treatment;Primary end point(s): Number and percentage of participants who achieve IST complete response at Week 100. The definition of IST complete response at Week 100 is defined as follows: ADA or NAb titer is decreased from Baseline by at least 2 titer steps or becomes negative, and Radiographic evidence of improvement on RSS by a score of at least 1 or more points from Baseline

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s):ADA incidence, ADA response categories, ADA titer, NAb incidence and NAb titer in participants treated with IST undergoing asfotase alfa treatment through the duration of the study;Secondary end point(s):Plasma concentrations of TNSALP as measured by asfotase alfa enzyme activity (PK), PLP, and PPi, at prespecified time points;Secondary end point(s):Incidence of TEAEs and TESAEs, clinical safety laboratory test results, vital signs, 12-lead ECGs, physical examination findings, and for bortezomib treated participants echocardiography, and pediatric-modified Total Neuropathy Scale;Secondary end point(s):Enumeration of CD19 B cells in participants treated with IST undergoing asfotase alfa treatment for the duration of the study