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Mitigate Immune-Mediated Loss of Therapeutic Response to Asfotase Alfa (STRENSIQ®) for Hypophosphatasia (RESTORE)

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ClinicalTrials.gov Identifier: NCT06015750
Recruitment Status : Not yet recruiting
First Posted : August 29, 2023
Last Update Posted : April 8, 2024
Sponsor:
Information provided by (Responsible Party):
Alexion Pharmaceuticals, Inc.

Study Description
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Brief Summary:
The primary objective of this study is to evaluate the effect of immunosuppressive therapy (IST) in participants treated with asfotase alfa who demonstrate immune-mediated loss of effectiveness (LoE).

Condition or disease Intervention/treatment Phase
Hypophosphatasia Drug: methotrexate Drug: rituximab Drug: bortezomib Drug: IVIg Drug: Folic Acid Phase 4

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 8 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Interventional, Prospective Open-Label Study of Immunosuppressive Therapies to Mitigate Immune-Mediated Loss of Therapeutic Response to Asfotase Alfa (STRENSIQ®) for Hypophosphatasia (RESTORE)
Estimated Study Start Date : April 30, 2024
Estimated Primary Completion Date : April 28, 2028
Estimated Study Completion Date : April 28, 2028

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Pediatric participants with HPP
Pediatric participants who have been receiving asfotase alfa treatment for their HPP, and who demonstrate immune-mediated LoE.
 Drug: methotrexate
Methotrexate will be administered SC or orally weekly for 104 weeks.

Drug: rituximab
Rituximab will be administered intravenously (IV) continuously weekly, for up to 74 weeks.

Drug: bortezomib
Bortezomib will be administered via IV bolus or SC, as needed.

Drug: IVIg
IVIg will be administered via IV monthly through initial 74 weeks.

Drug: Folic Acid
Folic acid will be given orally as long as methotrexate is being dosed.


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants Who Achieve Immunosuppressive Therapy (IST) Complete Response at Week 100 [ Time Frame: Week 100 ]

Secondary Outcome Measures :
  1. Number Participants with Antidrug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) [ Time Frame: Baseline Through Week 100 ]
  2. ADA and NAb Titer Levels [ Time Frame: Baseline Through Week 100 ]
  3. Serum Concentration of Asofatase Alfa (Measured as Enzyme Activity) [ Time Frame: Baseline Through Week 100 ]
  4. Plasma Concentration of Pyridoxal-5ˈ-Phosphate (PLP) [ Time Frame: Baseline Through Week 100 ]
  5. Plasma Concentration of Inorganic Pyrophosphates (PPi) [ Time Frame: Baseline Through Week 100 ]
  6. Number of Participants with Treatment-emergent Adverse Events and Treatment-emergent Serious Adverse Events [ Time Frame: Baseline Through Week 104 ]

Eligibility Criteria
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Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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 TMB that both the clinical evidence and immunogenicity-mediated association noted above are present.
  • Female participants of childbearing potential and male participants with partners of childbearing potential must follow protocol-specified contraception guidance as described in Section 10.5.
  • Participant, or participant's legal guardian, is capable of signing informed consent or assent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the informed consent or assent form and in this protocol.

Exclusion Criteria:

  • 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.
  • Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to Screening.
  • 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.
Contacts and Locations
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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06015750


Contacts
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Contact: Alexion Pharmaceuticals, Inc. (Sponsor) 1-855-752-2356 clinicaltrials@alexion.com

Sponsors and Collaborators
Alexion Pharmaceuticals, Inc.
More Information
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Responsible Party: Alexion Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT06015750    
Other Study ID Numbers: D8400C00001
AA-HPP-407 ( Other Identifier: Alexion )
2022-502793-17 ( EudraCT Number )
First Posted: August 29, 2023    Key Record Dates
Last Update Posted: April 8, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Alexion has a public commitment to allow requests for access to study data and will be supplying a protocol, CSR, and plain language summaries.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alexion Pharmaceuticals, Inc.:
Hypophosphatasia
HPP
Asfotase alfa
Strensiq
Additional relevant MeSH terms:
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Hypophosphatasia
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Folic Acid
Rituximab
Methotrexate
Bortezomib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
 Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Nucleic Acid Synthesis Inhibitors
Hematinics
Vitamin B Complex
Vitamins
Micronutrients