HypophosphatasiaPhase 2NCT01163149
Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP)
A Phase 2 study testing asfotase alfa in people with Hypophosphatasia, run by Alexion Pharmaceuticals, Inc. at 3 sites in 2 countries.
Trial summary
This clinical trial was conducted to study hypophosphatasia (HPP), a bone disorder caused by gene mutations or changes. These gene mutations cause low levels of an enzyme needed to harden bone. Read more about this study
- Who is it for?
- Ages 13 to 65 years
- Conditions the study is for
- Hypophosphatasia
- What is being tested?
- asfotase alfa
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 19 participants
- Where
- 3 sitesin 2 countries
- Study dates
- Jun 2010to Jun 2016
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 13 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patients must meet all of the following inclusion criteria to be eligible for participation in this study:
- Patients or their legal representative(s) must provide written informed consent prior to undergoing any study-related procedures
- Patients must be ≥ 13 and ≤ 65 years of age at the time of study enrollment
- Female patients of childbearing potential and sexually mature males must agree to use a medically acceptable form of birth control; for the purposes of this study, females are considered of non-childbearing potential if they are surgically sterile (i.e., have undergone a total hysterectomy, bilateral salpingo-oophorectomy or tubal ligation) or are post-menopausal, defined as having complete cessation of menstruation for at least 1 year after 45 years of age
- Patients must have a pre-established clinical diagnosis of HPP as indicated by:
- Serum alkaline phosphatase (ALP) below the age-adjusted normal range
Show all 10Show fewer
- Plasma PLP at least twice the upper limit of normal (no vitamin B6 administered for at least 1 week prior to determination)
- Evidence of osteopenia or osteomalacia on skeletal radiographs
- Patients must have osteomalacia on bone biopsy, characterized by an MLT z-score of +2 or more (results from ENB-001-08 may be used)
- Patients must be willing to comply with study procedures and the visit schedule
Who cannot join
- Patients will be excluded from participation in this study if they meet any of the following exclusion criteria:
- Women who are pregnant or lactating
- History of sensitivity to tetracycline
- Serum calcium or phosphate levels below the normal range
- Serum 25(OH) vitamin D below 20 ng/mL
- Serum creatinine or parathyroid hormone (PTH) levels above the upper limit of normal
Show all 11Show fewer
- Medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities
- Orthopedic surgery within 12 months prior to study entry that may interfere with the ability to perform functional assessments for the study
- Prior treatment with bisphosphonates within 2 years of study entry for any length of time or for more than 2 years at any time point; for patients with prior bisphosphonate use that is allowed, the bone resorption markers serum C-telopeptide and urine N-telopeptide or urine deoxypyridinoline must also be within the normal range or elevated to be eligible for study participation
- Treatment with PTH within 6 months prior to the start of asfotase alfa administration
- Participation in an interventional or investigational drug study within 30 days prior to study participation
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
United States2 sites
Duke University Medical Center
Durham, North Carolina, 27710
Shriner's Hospital for Children
St Louis, Missouri, 63131
Canada1 site
Health Sciences Centre Winnipeg, University of Manitoba
Winnipeg, Manitoba, R3A 1S1
About this study
Official title: A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Concurrent Control Study of the Safety, Efficacy, Pharmacokinetic of ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Adolescents and Adults With Hypophosphatasia (HPP)
This clinical trial was conducted to study hypophosphatasia (HPP), a bone disorder caused by gene mutations or changes. These gene mutations cause low levels of an enzyme needed to harden bone. The purpose of this study was to test the safety and efficacy of two doses of the study drug called asfotase alfa as compared to a control group to see effects on adolescents and adults with HPP.
Read the detailed description
Asfotase alfa was formerly referred to as ENB-0040
Hypophosphatasia (HPP) is a life-threatening, genetic, and ultra-rare metabolic disease characterized by defective bone mineralization and impaired phosphate and calcium regulation that can lead to progressive damage to multiple vital organs, including destruction and deformity of bones, profound muscle weakness, seizures, impaired renal function, and respiratory failure. There are limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.
- Conditions
- Hypophosphatasia
- Being tested
- asfotase alfa
- Keywords
- Hypophosphatasia, HPP, Bone Disease, Soft Bones, Low Alkaline Phosphatase, genetic metabolic disorder, alkaline phosphatase, tissue-specific alkaline phosphatase (TNSALP), rickets, osteomalacia
- Medical subject headings
- Hypophosphatasia, Bone Diseases, Rickets, Osteomalacia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
asfotase alfaDrug
Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (total of 2.1 mg/kg/week)
asfotase alfaDrug
Cohort 2: Daily SC injections of 0.5 mg/kg Asfotase Alfa (3.5 mg/kg/week total)
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 | Experimental | Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total) Receives: Drug: asfotase alfa |
| Cohort 2 | Experimental | Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total) Receives: Drug: asfotase alfa |
| Concurrent Control | No intervention | Following completion of the Week 24 visit, all patients (including those randomized to the concurrent control cohort) may be eligible to participate in an open-label extension treatment period. In this extension period, all patients will be treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects will receive 1 mg/kg/day 6 days/week for an additional 48 weeks or until regulatory approval of the drug. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change From Baseline to Week 24 for Plasma Pyridoxal-5' Phosphate (PLP)
Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma pyridoxal-5' phosphate (PLP)
Measured: Baseline, Week 24
Change From Baseline to Week 24 for Plasma Inorganic Pyrophosphate (PPi)
Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma inorganic pyrophosphate (PPi)
Measured: Baseline, Week 24
Safety and Tolerability of Asfotase Alfa
The safety and tolerability of daily subcutaneous (SC) injections of asfotase alfa was assessed by routine monitoring of patients for treatment-emergent adverse events (TEAEs) and injection-associated reactions (IARs).
Measured: Up to 288 weeks exposure to asfotase alfa
Secondary outcomes (6)
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA)
A DXA scan was performed to evaluate bone mineral content (BMC) of the spine, hip, and whole body during the primary (first 24 weeks) and extension treatment periods (up to 288 weeks).
Measured: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288.
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA)
A DXA scan was performed to evaluate bone bone mineral density (BMD) of the spine, hip, and whole body during the primary (first 24 weeks) and extension treatment periods (up to 288 weeks).
Measured: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288.
Change in Walking Ability as Measured by the Six-Minute Walk Test (6MWT)
The patient was instructed to walk the length of a pre-measured hallway for 6 minutes. The primary measurement was distance walked (in meters).
Measured: Baseline, Week 24 (primary treatment period) and up to 288 weeks of asfotase alfa exposure
Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Volume/Bone Volume
A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Volume/Bone Volume (%). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.
Measured: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).
Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Thickness
A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Thickness (um). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.
Measured: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).
Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Mineralization Lag Time
A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Mineralization Lag Time (days). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.
Measured: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jul 2010 (estimated)
- Study startJun 2010
- Primary completionJun 2016
- Study completionJun 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HypophosphatasiaStudies of the same condition, open and under way.
- More trials run by Alexion Pharmaceuticals, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- Alexion Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01163149
- Sponsor's protocol ID
- ENB-009-10
- Status last verified
- Mar 2019
- First submitted
- 24 Jun 2010
- Last updated
- 13 Mar 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Millan JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP. Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res. 2008 Jun;23(6):777-87. doi: 10.1359/jbmr.071213.
PubMed 18086009Simmons JH, Rush ET, Petryk A, Zhou S, Martos-Moreno GA. Dual X-ray absorptiometry has limited utility in detecting bone pathology in children with hypophosphatasia: A pooled post hoc analysis of asfotase alfa clinical trial data. Bone. 2020 Aug;137:115413. doi: 10.1016/j.bone.2020.115413. Epub 2020 May 14.
PubMed 32417537Gospe SM 3rd, Santiago-Turla C, DeArmey SM, Cummings TJ, Kishnani PS, Bhatti MT. Ectopic Ocular Surface Calcification in Patients With Hypophosphatasia Treated With Asfotase Alfa. Cornea. 2019 Jul;38(7):896-900. doi: 10.1097/ICO.0000000000001947.
PubMed 30969260
Study at a glance
From the registry record, last updated by the sponsor on 13 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Concurrent Control Study of the Safety, Efficacy, Pharmacokinetic of ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Adolescents and Adults With Hypophosphatasia (HPP)
- ClinicalTrials.gov ID
- NCT01163149
- Acronym / sponsor ID
- ENB-009-10
- Conditions
- Hypophosphatasia
- Keywords
- Hypophosphatasia, HPP, Bone Disease, Soft Bones, Low Alkaline Phosphatase, genetic metabolic disorder, alkaline phosphatase, tissue-specific alkaline phosphatase (TNSALP)
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- Alexion Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- Jun 2010
- Primary completion
- Jun 2016 (actual)
- Study completion
- Jun 2016 (actual)
- First posted
- 15 Jul 2010 (estimated)
- Results
- Posted 18 Sep 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This clinical trial was conducted to study hypophosphatasia (HPP), a bone disorder caused by gene mutations or changes. These gene mutations cause low levels of an enzyme needed to harden bone. The purpose of this study was to test the safety and efficacy of two doses of the study drug called asfotase alfa as compared to a control group to see effects on adolescents and adults with HPP.
Detailed description
Asfotase alfa was formerly referred to as ENB-0040
Hypophosphatasia (HPP) is a life-threatening, genetic, and ultra-rare metabolic disease characterized by defective bone mineralization and impaired phosphate and calcium regulation that can lead to progressive damage to multiple vital organs, including destruction and deformity of bones, profound muscle weakness, seizures, impaired renal function, and respiratory failure. There are limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Drug: asfotase alfaCohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total) |
| Cohort 2 | Experimental | Drug: asfotase alfaCohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total) |
| Concurrent Control | No intervention | –Following completion of the Week 24 visit, all patients (including those randomized to the concurrent control cohort) may be eligible to participate in an open-label extension treatment period. In this extension period, all patients will be treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects will receive 1 mg/kg/day 6 days/week for an additional 48 weeks or until regulatory approval of the drug. |
Who may qualify
- Ages
- 13 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (10 listed)
- Patients must meet all of the following inclusion criteria to be eligible for participation in this study:
- Patients or their legal representative(s) must provide written informed consent prior to undergoing any study-related procedures
- Patients must be ≥ 13 and ≤ 65 years of age at the time of study enrollment
- Female patients of childbearing potential and sexually mature males must agree to use a medically acceptable form of birth control; for the purposes of this study, females are considered of non-childbearing potential if they are surgically sterile (i.e., have undergone a total hysterectomy, bilateral salpingo-oophorectomy or tubal ligation) or are post-menopausal, defined as having complete cessation of menstruation for at least 1 year after 45 years of age
- Patients must have a pre-established clinical diagnosis of HPP as indicated by:
Key exclusion criteria (11 listed)
- Patients will be excluded from participation in this study if they meet any of the following exclusion criteria:
- Women who are pregnant or lactating
- History of sensitivity to tetracycline
- Serum calcium or phosphate levels below the normal range
- Serum 25(OH) vitamin D below 20 ng/mL
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| asfotase alfaCohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (total of 2.1 mg/kg/week) | Drug | Cohort 1 |
| asfotase alfaCohort 2: Daily SC injections of 0.5 mg/kg Asfotase Alfa (3.5 mg/kg/week total) | Drug | Cohort 2 |
Primary outcome
Change From Baseline to Week 24 for Plasma Pyridoxal-5' Phosphate (PLP)
Time frame: Baseline, Week 24
Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma pyridoxal-5' phosphate (PLP)
Change From Baseline to Week 24 for Plasma Inorganic Pyrophosphate (PPi)
Time frame: Baseline, Week 24
Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma inorganic pyrophosphate (PPi)
Safety and Tolerability of Asfotase Alfa
Time frame: Up to 288 weeks exposure to asfotase alfa
The safety and tolerability of daily subcutaneous (SC) injections of asfotase alfa was assessed by routine monitoring of patients for treatment-emergent adverse events (TEAEs) and injection-associated reactions (IARs).
6 secondary outcomes
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA)
Time frame: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288.
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA)
Time frame: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288.
Change in Walking Ability as Measured by the Six-Minute Walk Test (6MWT)
Time frame: Baseline, Week 24 (primary treatment period) and up to 288 weeks of asfotase alfa exposure
Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Volume/Bone Volume
Time frame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).
Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Thickness
Time frame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).
Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Mineralization Lag Time
Time frame: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Mar 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 18086009Millan JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP. Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res. 2008 Jun;23(6):777-87. doi: 10.1359/jbmr.071213.
- Derived from this study: PubMed 32417537Simmons JH, Rush ET, Petryk A, Zhou S, Martos-Moreno GA. Dual X-ray absorptiometry has limited utility in detecting bone pathology in children with hypophosphatasia: A pooled post hoc analysis of asfotase alfa clinical trial data. Bone. 2020 Aug;137:115413. doi: 10.1016/j.bone.2020.115413. Epub 2020 May 14.
- Derived from this study: PubMed 30969260Gospe SM 3rd, Santiago-Turla C, DeArmey SM, Cummings TJ, Kishnani PS, Bhatti MT. Ectopic Ocular Surface Calcification in Patients With Hypophosphatasia Treated With Asfotase Alfa. Cornea. 2019 Jul;38(7):896-900. doi: 10.1097/ICO.0000000000001947.
- HPP support groupLink provided by the sponsor.
- US Hypophosphatasia Group (Soft Bones)Link provided by the sponsor.
- Hypophosphatasia WebsiteLink provided by the sponsor.
- Hypophosphatasia Website for Healthcare ProvidersLink provided by the sponsor.
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Hypophosphatasia
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing asfotase alfa in people with Hypophosphatasia, run by Alexion Pharmaceuticals, Inc. at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Sep 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline to Week 24 for Plasma Pyridoxal-5' Phosphate (PLP) (time frame: Baseline, Week 24). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01163149, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Mar 2019.