Phase 3 Study of ALXN1850 versus Placebo in Adolescent and Adult Participants with HPP who have not previously been treated with Asfotase Alfa

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alexion Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

5 Aug 2024 → ongoing

Decision date (initial)

2024-04-01

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

To assess the efficacy of ALXN1850 versus placebo on functional outcomes in adolescent and adult participants with HPP who have not previously been treated with asfotase alfa

Secondary objectives 13

1. To evaluate the efficacy of ALXN1850 versus placebo on functional outcomes in adolescent and adult participants with HPP who have not previously been treated with asfotase alfa
2. To evaluate the efficacy of ALXN1850 versus placebo on functional outcomes in adult participants with HPP who have not previously been treated with asfotase alfa
3. To evaluate the effect of treatment with ALXN1850 versus placebo on pain in adult 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 in adult participants with HPP who have not previously been treated with asfotase alfa
5. To assess the efficacy of ALXN1850 versus placebo on functional outcomes in adolescent and adult participants with HPP who have not previously been treated with asfotase alfa
6. To assess the treatment effect of ALXN1850 versus placebo on radiographic outcomes in adolescent participants with HPP who have not previously been treated with asfotase alfa
7. To evaluate the effect of treatment with ALXN1850 versus placebo on health-related quality of life outcomes in adult and adolescent participants with HPP who have not previously been treated with asfotase alfa
8. To evaluate the effect of treatment with ALXN1850 versus placebo on pain in adult participants with HPP who have not previously been treated with asfotase alfa
9. To evaluate the effect of treatment with ALXN1850 versus placebo on fatigue, pain, and health-related quality of life outcomes in adolescent participants with HPP who have not previously been treated with asfotase alfa
10. To assess treatment satisfaction with ALXN1850 in adolescent and adult participants with HPP who have not previously been treated with asfotase alfa
11. To assess the safety and tolerability of ALXN1850 in adolescent and adult participants with HPP who have not previously been treated with asfotase alfa
12. To evaluate the PK/PD of ALXN1850 in adolescent and adult participants with HPP who have not previously been treated with asfotase alfa
13. To assess the immunogenicity to ALXN1850 in adolescent and adult 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, European Medicines Agency, Food And Drug Administration

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 8

1. Participant must be ≥ 12 years of age at Day 1
2. Diagnosis of HPP documented in the medical records
3. Must meet 1 of the following criteria: a. Documented ALPL gene variant (pathogenic, likely pathogenic, or variant of unknown significance) from a Clinical Laboratory Improvement Amendments (CLIA) or ISO 15189 certified laboratory b. PLP above the upper limit of normal (ULN) during the Screening Period (central or local laboratory results allowed per local regulations)
4. Must meet 1 of the following criteria without a probable cause other than HPP: a. Serum ALP activity below the age- and sex-adjusted normal range during the Screening Period, as measured by the Central Laboratory b. Two 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 CLIA or ISO 15189 certified, or have other local equivalent laboratory certification with Alexion’s approval.
5. Two separate 6MWTs at below 85% of the predicted distance (for age, sex, weight, and height) during the Screening Period without a probable cause other than HPP (Note: participants who require assistive walking devices may be included)
6. Female participants of childbearing potential and male participants must follow protocol specified contraception requirements and guidance
7. The participant or their legal representative must be capable of giving signed informed consent as described in the protocol. For adolescent participants, 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 this protocol.
8. Not willing or able to receive asfotase alfa for any reason, including not willing or able to comply with the injection schedule for asfotase alfa.

Exclusion criteria 25

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 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 agonist/antagonist/inhibitor within 2 months before Day 1 unless used as contraception or for treatment of dysmenorrhea
17. Received a RANKL inhibitor within 6 months before Day 1
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. Serum 25-hydroxy (25-OH) vitamin D below 20 ng/mL during Screening
22. PTH > ULN of the laboratory reference range during Screening
23. Participants who are unwilling to undergo genetic testing for the ALPL gene.
24. Participants who are pregnant, planning to become pregnant, or breastfeeding during the course of the study.
25. 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. Change from baseline in 6MWT at the end of the Randomized Evaluation Period (Day 169)

Secondary endpoints 18

1. Change from baseline in 30-second STS test at the end of the Randomized Evaluation Period (Day 169)
2. Change from baseline in LEFS at the end of the Randomized Evaluation Period (Day 169)
3. Change from baseline in BPI-SF pain severity score at the end of the Randomized Evaluation Period (Day 169)
4. Change from baseline in FACIT-Fatigue score at the end of the Randomized Evaluation Period (Day 169)
5. Change from baseline in Timed Up-and-Go (TUG) at the end of the Randomized Evaluation Period (Day 169)
6. Change from baseline in % Predicted 6MWT at the end of the Randomized Evaluation Period (Day 169)
7. RGI-C Score at the end of the Randomized Evaluation Period (Day 169)
8. RGI-C responder at the end of the Randomized Evaluation Period (Day 169)
9. Change from baseline in RSS at the end of the Randomized Evaluation Period (Day 169)
10. Change from baseline at the end of the Randomized Evaluation Period (Day 169) in: - EuroQoL 5 Dimensions 5 Level (EQ-5D-5L) scale - SF-36v2 PCS score
11. Change from baseline in BPI-SF pain interference score at the end of the Randomized Evaluation Period (Day 169)
12. Change from baseline at the end of the Randomized Evaluation Period (Day 169) in: - PODCI Adolescent – Self-reported - APPT score - Pediatric FACIT-Fatigue score
13. TSQM-9 score at the end of the Randomized Evaluation Period (Day 169)
14. Incidence of TEAEs, TESAEs, AESIs, and AEs leading to study intervention discontinuation or interruption
15. Plasma ALXN1850 Ctrough over time through the end of the Randomized Evaluation Period (Day 169)
16. Plasma ALXN1850 PK parameters in adolescent participants during the Randomized Evaluation Period
17. Observed, change from baseline, and percent change from baseline in plasma concentration of PPi, PLP, PA, and PLP/PL ratio over time through the end of the Randomized Evaluation Period (Day 169)
18. ADA incidence, ADA response categories, and ADA titer, as well as NAb incidence and NAb titer

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 · 27 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Corrective measures 1 · Art. 77 CTR

Results and documents

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

Documents 140 files

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

Application history

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