Hypophosphatasia (HPP)
Conditions
Keywords
Hypophosphatasia, HPP, Bone Disease, Soft Bones, Low Alkaline Phosphatase, genetic metabolic disorder, alkaline phosphatase, tissue non-specific alkaline phosphatase, rickets, osteomalacia
Brief summary
This clinical trial studied the safety and efficacy of asfotase alfa in children with HPP compared to a historical control group.
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 no approved disease-modifying treatments for patients with this disease. There is also limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form. Efficacy analyses were prospectively defined in the protocol with a comparison to historical controls. The historical control group came from patients whose characteristics matched as closely as possible the entry criteria for the trial. The control group included all patients who had x-rays within the age range defined by the inclusion criteria of this study (5 to 12 years of age, inclusive, with open growth plates). The pre-specified plan for analysis was to combine the two asfotase alfa treated groups (asfotase alfa 2 mg/kg subcutaneous (SC) injection three times per week or 3 mg/kg subcutaneous (SC) injection three times per week) and compare them to historical controls.
Interventions
BIOLOGICALasfotase alfa
2 mg/kg subcutaneous injection three times per week for 6 months.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent from parent or legal guardian prior to participation 2. Patients \> 5 and \< 12 years of age with open growth plates at time of enrollment 3. Tanner stage of 2 or less indicating pre-pubescence 4. Documented history of HPP, as evidenced by: * Presence of HPP-related rickets on skeletal radiographs of the wrist and knee * Serum alkaline phosphatase (ALP) below age-adjusted normal range * Plasma PLP at least twice the upper limit of normal 5. 25(OH) vitamin D level \> 20 ng/mL 6. Ability of patient and parent/guardian to comply with study requirements
Exclusion criteria
1. Serum calcium or phosphorus below age-adjusted normal range 2. History of sensitivity to any study drug constituent 3. 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 4. Treatment with an investigational drug within 1 month before start of study drug 5. Current enrollment in any other study involving an investigational new drug, device, or treatment for HPP (e.g., bone marrow transplantation) 6. Current evidence of a treatable form of rickets 7. Prior treatment with bisphosphonates 8. Bone fracture or orthopedic surgery within the past 12 months that, in the opinion of the Investigator would interfere with the ability of study patient to comply with study protocol 9. Major congenital abnormality other than those associated with HPP
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale | Baseline and Week 24 | A 7-point RGI-C (radiographic global impression of change) score was used to rate change in rickets severity. Only those patients with a minimum score of +2 indicating substantial healing of rickets) were considered responders. Three pediatric radiologists not affiliated with the conduct of the study performed the ratings. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy) | Baseline and Week 24 | Change from Baseline to Week 24 in osteoid volume/bone volume (%), calculated as the absolute difference of the Baseline and Week 24 percentages. |
| Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy) | Baseline and Week 24 | Change from Baseline to Week 24 in mineralization lag time. |
| Change in Height (Z-scores) | Baseline and Week 24 | Change from Baseline to Week 24 in Height Z-Score. Height Z-Scores assigned based on Centers for Disease Control (CDC) growth charts and methodology. |
| Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi) | Baseline and Week 24 | Change from Baseline to Week 24 in Plasma PPi |
| Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy) | Baseline and Week 24 | Change from Baseline to Week 24 in osteoid thickness. |
| Maximum Serum Concentration of Asfotase Alfa (Cmax). | Study Week 1 (0 to 48 hours post-dose) | Maximum serum concentration observed following single dose of asfotase alfa. |
| Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) | Study Week 1 (0 to 48 hours post-dose) | Maximum serum concentration observed following single dose of asfotase alfa. |
| Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | Study Week 1 (0 to 48 hours post-dose) | Area under serum concentration-time curve to last measurable concentration following single dose of asfotase alfa. |
| Time at Maximum Serum Concentration of Asfotase Alfa (Tmax). | Study Week 6 (0 to 48 hours post-dose) | Time at maximum serum concentration observed following multiple doses of asfotase alfa. |
| Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP) | Baseline and Week 24 | Change from Baseline to Week 24 in Plasma PLP |
Countries
Canada, United States
Participant flow
Recruitment details
Patients were recruited to participate in the study from September to December 2009 at investigational sites via posting in clinicaltrials.gov and contact with physicians experienced in the diagnosis and management of HPP. De-identified historical controls were also selected from a natural history database of patients with HPP.
Pre-assignment details
Patients meeting eligibility criteria were randomly assigned to receive 2mg/kg or 3mg/kg of asfotase alfa SC 3 times weekly for 24 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Asfotase Alfa 2 mg/kg 2 mg/kg thrice weekly administered as a subcutaneous (SC) injection | 6 |
| Asfotase Alfa 3 mg/kg 3 mg/kg administered thrice weekly as a subcutaneous (SC) injection | 7 |
| Historical Control De-identified historical controls selected from a natural history database of patients with HPP. | 16 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Asfotase Alfa 2 mg/kg | Asfotase Alfa 3 mg/kg | Historical Control | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 7 Participants | 16 Participants | 29 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 8.4 years STANDARD_DEVIATION 2.2 | 9.1 years STANDARD_DEVIATION 2.3 | 6.0 years STANDARD_DEVIATION 1.78 | 7.3 years STANDARD_DEVIATION 2.4 |
| Region of Enrollment Canada | 2 participants | 2 participants | 0 participants | 4 participants |
| Region of Enrollment United States | 4 participants | 5 participants | 16 participants | 25 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 11 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 7 / 7 |
| serious Total, serious adverse events | 0 / 6 | 0 / 7 |
Outcome results
Primary
Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale
A 7-point RGI-C (radiographic global impression of change) score was used to rate change in rickets severity. Only those patients with a minimum score of +2 indicating substantial healing of rickets) were considered responders. Three pediatric radiologists not affiliated with the conduct of the study performed the ratings.
Time frame: Baseline and Week 24
Population: ITT population, which included randomized patients that received treatment with asfotase alfa, even if discontinued or lost to follow-up. The last assessment prior to Week 24 is used for missing Week 24 data; patients with no post-baseline assessments imputed as having no change. A historical control group is used for comparison.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Historical Controls | Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale | 0 units on a scale |
| Asfotase Alfa Combined | Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale | 2.00 units on a scale |
p-value: 0.0007Wilcoxon (Mann-Whitney)
Secondary
Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)
Area under serum concentration-time curve to last measurable concentration following single dose of asfotase alfa.
Time frame: Study Week 1 (0 to 48 hours post-dose)
Population: ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | 19700 h*U/L | Standard Deviation 5720 |
| Asfotase Alfa Combined | Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | 45200 h*U/L | Standard Deviation 15100 |
Secondary
Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)
Area under serum concentration-time curve to last measurable concentration following multiple doses of asfotase alfa.
Time frame: Study Week 6 (0 to 48 hours post-dose).
Population: ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | 76000 h*U/L | Standard Deviation 28100 |
| Asfotase Alfa Combined | Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | 94200 h*U/L | Standard Deviation 44400 |
Secondary
Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi)
Change from Baseline to Week 24 in Plasma PPi
Time frame: Baseline and Week 24
Population: ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi) | -1.883 uM | Standard Deviation 0.7285 |
p-value: <0.0001t-test, 2 sided
Secondary
Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP)
Change from Baseline to Week 24 in Plasma PLP
Time frame: Baseline and Week 24
Population: ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP) | -164.533 ng/mL | Standard Deviation 121.484 |
p-value: 0.0007t-test, 2 sided
Secondary
Change in Height (Z-scores)
Change from Baseline to Week 24 in Height Z-Score. Height Z-Scores assigned based on Centers for Disease Control (CDC) growth charts and methodology.
Time frame: Baseline and Week 24
Population: ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Change in Height (Z-scores) | 0.01 Height Z score | Standard Deviation 0.141 |
p-value: 0.757Wilcoxon Signed-Rank
Secondary
Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy)
Change from Baseline to Week 24 in mineralization lag time.
Time frame: Baseline and Week 24
Population: ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy) | 20.392 days | Standard Deviation 208.9814 |
p-value: 0.7417t-test, 2 sided
Secondary
Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy)
Change from Baseline to Week 24 in osteoid thickness.
Time frame: Baseline and Week 24
Population: ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy) | -3.858 um | Standard Deviation 4.2784 |
p-value: 0.0097t-test, 2 sided
Secondary
Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy)
Change from Baseline to Week 24 in osteoid volume/bone volume (%), calculated as the absolute difference of the Baseline and Week 24 percentages.
Time frame: Baseline and Week 24
Population: ITT population, which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly), even if they discontinued or were lost to follow-up during the conduct of the clinical trial. Data imputation was not performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy) | -4.225 percentage points | Standard Deviation 7.5582 |
p-value: 0.0789t-test, 2 sided
Secondary
Maximum Serum Concentration of Asfotase Alfa (Cmax).
Maximum serum concentration observed following single dose of asfotase alfa.
Time frame: Study Week 1 (0 to 48 hours post-dose)
Population: ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Maximum Serum Concentration of Asfotase Alfa (Cmax). | 566 U/L | Standard Deviation 120 |
| Asfotase Alfa Combined | Maximum Serum Concentration of Asfotase Alfa (Cmax). | 1260 U/L | Standard Deviation 439 |
Secondary
Maximum Serum Concentration of Asfotase Alfa (Cmax).
Maximum serum concentration observed following multiple doses of asfotase alfa.
Time frame: Study Week 6 (0 to 48 hours post-dose)
Population: ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Maximum Serum Concentration of Asfotase Alfa (Cmax). | 1780 U/L | Standard Deviation 666 |
| Asfotase Alfa Combined | Maximum Serum Concentration of Asfotase Alfa (Cmax). | 2280 U/L | Standard Deviation 875 |
Secondary
Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)
Maximum serum concentration observed following single dose of asfotase alfa.
Time frame: Study Week 1 (0 to 48 hours post-dose)
Population: ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) | 37.2 hours | Standard Deviation 8.1 |
| Asfotase Alfa Combined | Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) | 34.3 hours | Standard Deviation 6 |
Secondary
Time at Maximum Serum Concentration of Asfotase Alfa (Tmax).
Time at maximum serum concentration observed following multiple doses of asfotase alfa.
Time frame: Study Week 6 (0 to 48 hours post-dose)
Population: ITT population which included all randomized patients that received any treatment with asfotase alfa (2 mg/kg or 3 mg/kg thrice weekly).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Historical Controls | Time at Maximum Serum Concentration of Asfotase Alfa (Tmax). | 20.8 hours | Standard Deviation 10 |
| Asfotase Alfa Combined | Time at Maximum Serum Concentration of Asfotase Alfa (Tmax). | 17.3 hours | Standard Deviation 8.6 |