Phase 3 Study of ALXN1850 in Treatment-Naïve Pediatric Participants with HPP

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alexion Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

26 Apr 2024 → ongoing

Decision date (initial)

2024-02-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the efficacy of ALXN1850 versus placebo on radiographic outcomes in pediatric participants with HPP who have not previously been treated with asfotase alfa

Secondary objectives 9

1. To assess the efficacy of ALXN1850 versus placebo on radiographic outcomes in pediatric participants with HPP who have not previously been treated with asfotase alfa
2. To assess the efficacy of ALXN1850 versus placebo on functional outcomes in pediatric participants with HPP who have not previously been treated with asfotase alfa
3. To assess the treatment effect of ALXN1850 versus placebo on radiographic outcomes in pediatric participants with HPP who have not previously been treated with asfotase alfa
4. To evaluate the effect of treatment with ALXN1850 versus placebo on fatigue, pain, and health-related quality of life outcomes in pediatric participants with HPP who have not previously been treated with asfotase alfa
5. To assess treatment satisfaction with ALXN1850 in pediatric participants with HPP who have not previously been treated with asfotase alfa
6. To evaluate the safety and tolerability of ALXN1850 administered for up to 24 weeks in pediatric participants with HPP who have not previously been treated with asfotase alfa
7. To evaluate PK of ALXN1850 administered for 24 weeks in pediatric participants with HPP who have not previously been treated with asfotase alfa
8. To evaluate PD of ALXN1850 administered for 24 weeks in pediatric participants with HPP who have not previously been treated with asfotase alfa
9. To assess immunogenicity to ALXN1850 through the duration of the study in pediatric participants with HPP who have not previously been treated with asfotase alfa

Conditions and MedDRA coding

hypophosphatasia

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Pharmaceuticals And Medical Devices Agency, Food And Drug Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003343-PIP01-22

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Participant must be ≥ 2 and < 12 years of age at Day 1
2. Diagnosis of HPP documented in the medical records, and the following criteria fulfilled without other probable cause than HPP: a. Presence of HPP-related rickets on skeletal X-rays during the Screening Period, with a minimum Rickets Severity Score (RSS) of 1.0 AND b. Serum ALP activity below the age- and sex-adjusted normal range during the Screening Period as measured by the Central Laboratory OR 2 documented serum ALP activity results, at least 15 days apart, below the age- and sex-adjusted local laboratory normal range during the 24 months before the Day 1 Visit. Note: Local laboratories need to be Clinical Laboratory Improvement Amendments (CLIA) or ISO 15189 certified, or have other local equivalent laboratory certification with Alexion’s approval.
3. Must meet 1 of the following criteria: a. Documented ALPL gene variant (pathogenic, likely pathogenic, or variant of unknown significance) from a CLIA or ISO 15189 certified laboratory (Section 8.7) b. PLP above the upper limit of normal (ULN) during the Screening Period (central or local laboratory results allowed per local regulations)
4. Tanner stage 2 or less during the Screening Period
5. Female participants of childbearing potential and male participants must follow contraception requirements and guidance as defined in the protocol.
6. The participant’s legal guardian must be willing and able to provide written informed consent (as defined in the protocol) and the participant must be willing to give written informed assent (if applicable as determined by the central or local Institutional Review Board [IRB]/Institutional [or independent] Ethics Committee [IEC]). Written informed consent/assent includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.

Exclusion criteria 26

1. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, neurological disorders, or any other disorders that are capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data as determined by the Investigator
2. Diagnosis of primary or secondary hyperparathyroidism
3. Hypoparathyroidism, unless secondary to HPP
4. Any new fracture within 12 weeks before Day 1 (excluding pseudofractures)
5. Planned surgical intervention which may impact the results of study assessments (in the opinion of the Investigator) during the Randomized Evaluation Period
6. History of allergy or hypersensitivity to any ingredient contained in ALXN1850 or the placebo comparator
7. Body weight < 10 kg during the Screening Period
8. Received asfotase alfa or ALXN1850 at any time before Day 1
9. Received vitamin B6 (including vitamin supplements that contain vitamin B6) within 6 weeks before Day 1
10. Received oral bisphosphonate within 6 months before Day 1
11. Received IV bisphosphonate within 12 months before Day 1
12. Received a parathyroid hormone (PTH)-related protein analog (eg, abaloparatide) or PTH analog (eg, teriparatide) within 2 weeks before Day 1
13. Received strontium within 6 months before Day 1
14. Received sclerostin inhibitors within 6 months before Day 1
15. Received growth hormone therapy within 6 months before Day 1
16. Received estrogen or estrogen agonist/antagonist/inhibitor within 2 months before Day 1 unless used as contraception or for treatment of dysmenorrhea
17. Received a receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor within 6 months before Day 11
18. Participation in any other clinical study involving an investigational study intervention within 30 days before initiation of the first dose of study intervention. Participants involved in interventional studies are not eligible unless the time since last treatment has exceeded 30 days or 5 half-lives of the study intervention, whichever is longer.
19. Corrected calcium levels (adjusted for albumin) below age-adjusted normal range during Screening
20. Serum phosphorus levels below the age-adjusted normal range during Screening
21. Evidence of a treatable form of rickets (eg, vitamin D deficiency) other than HPP during Screening
22. Serum 25-hydroxy (25-OH) vitamin D below 20 ng/mL during Screening
23. PTH > ULN of the laboratory reference range during Screening
24. Participants who are unwilling to undergo genetic testing for the ALPL gene
25. Participants who are pregnant, planning to become pregnant, or breastfeeding during the course of the study
26. Investigational site personnel involved directly in the study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. RGI-C score at the end of the Randomized Evaluation Period (Day 169)

Secondary endpoints 10

1. Change from baseline in RSS at the end of the Randomized Evaluation Period (Day 169)
2. "Change from baseline at the end of the Randomized Evaluation Period (Day 169) in the following: - 6MWT (≥ 5 years of age) - % Predicted 6MWT (≥ 5 years of age) - BOT-2 (≥ 4 years of age) - PDMS-3 (< 4 years of age)"
3. RGI-C responder at the end of the Randomized Evaluation Period (Day 169)
4. Change from baseline at the end of the Randomized Evaluation Period (Day 169) in the following: - EQ-5D-Y health state score (≥ 8 years of age) - EQ-5D-Y-Proxy Version 1 health state score (≥ 4 to < 8 years of age) - PODCI-Parent global function score - APPT score (≥ 8 years of age) - Pediatric FACIT-Fatigue score (≥ 8 years of age) -Pediatric FACIT-Fatigue Proxy score (≥ 2 to < 8 years of age)
5. TSQM-9 score at the end of the Randomized Evaluation Period (Day 169)
6. Incidence of TEAEs, TESAEs, AESIs, and AEs leading to study intervention discontinuation or interruption
7. "Estimation of PK parameters and accumulation ratios - ALXN1850 PK: AUC(0-24h) at Day 1, AUC(0-24h) and C(trough) at D85; accumulation ratio of D85 to Day 1 based on AUC(0-24h)"
8. Plasma ALXN1850 C(trough) over time through the end of the Randomized Evaluation Period (Day 169)
9. "Estimation of PD parameters - Observed, change, and percent changes in plasma concentration of PPi, PLP, PA, and PLP/PL ratio from baseline through the end of the Randomized Evaluation Period (Day 169)"
10. ADA incidence, ADA response categories, and ADA titer, as well as NAb incidence and NAb titers

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alexion Pharmaceuticals Inc.

Sponsor organisation

Alexion Pharmaceuticals Inc.

Address

121 Seaport Boulevard

City

Boston

Postcode

02210-2050

Country

United States

Scientific contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Public contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Locations

8 EU/EEA countries · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 155 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

12 submissions — initial application plus substantial / non-substantial modifications