Hypophosphatasia
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 long term safety and efficacy of asfotase alfa in infants and young children with infantile onset HPP who completed study ENB-002-08 (NCT00744042). Partial funding for this study was provided by the Office of Orphan Product Development (OOPD).
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.
Interventions
BIOLOGICALasfotase alfa
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
24 Weeks to 42 Months
Healthy volunteers
No
Inclusion criteria
* Patient completed participation in ENB-002-08 (NCT00744042) * Written informed consent by parent or other legal guardian prior to any study procedures being performed * Parent or other legal guardian willing to comply with study requirements
Exclusion criteria
* History of sensitivity to any of the constituents of the study drug * Clinically significant disease that precludes study participation * Enrollment in any study (other than ENB-002-08) involving an investigational drug, device, or treatment for HPP (e.g., bone marrow transplantation)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Long-term Tolerability of Subcutaneous (SC) Asfotase Alfa | 84 months | Outcome measure is the number of patients with 1 or more treatment-emergent adverse event. The time period is from Baseline in the ENB-003-08 study to the end of the ENB-003-08 study. |
| Long-term Efficacy of Asfotase Alfa in Treating Rickets in Infants and Young Children With Hypophosphatasia (HPP). | Up to 90 Months | Outcome measure is the evaluation of radiographic change in rickets severity using a qualitative Radiographic Global Impression of Change (RGI-C) Scale. Skeletal radiographs obtained at the patient's last assessment were compared with skeletal radiographs obtained before initiation of treatment (Baseline in Study ENB-002-08 \[NCT00744042\]). The RGI-C is a 7-point rating scale that ranges from -3 (indicative of severe worsening of HPP-associated rickets) to +3 (indicative of complete or near complete healing of HPP-associated rickets). The time period is pre-dose (Baseline from ENB-002-08 study) to the last assessment for each patient in the ENB-003-08 study, which represents up to 90 months of exposure for the combined studies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of SC Asfotase Alfa on Growth: Weight Z-scores | Up to 90 Months | Outcome measure is the change from Baseline in Z-scores for weight. The time period is pre-dose (Baseline from the ENB-002-08 study \[NCT00744042\]) to the last assessment in the ENB-003-08 study, which represents up to 90 months of exposure in the combined studies. |
| Long-term Pharmacodynamics (PD) of SC Asfotase Alfa: Plasma Inorganic Pyrophosphate (PPi) Levels | Up to 90 Months | Outcome measure is the change from Baseline in plasma inorganic pyrophosphate (PPi) levels. The time period is pre-dose (Baseline from the ENB-002-08 study \[NCT00744042\]) to the last assessment for each patient in the ENB-003-08 study, which represents up to 90 months of exposure for the combined studies. |
| Effect of SC Asfotase Alfa on Respiratory Function | Up to 90 Months | Outcome measure is the shift in the proportion of patients requiring respiratory support at their last assessment in Study ENB-003-08 compared with Baseline. The time period is pre-dose (Baseline from the ENB-002-08 study \[NCT00744042\]) to the last assessment in the ENB-003-08 study, which represents up to 90 months of exposure in the combined studies. |
| Effect of SC Asfotase Alfa on Growth: Height/Length Z-scores | Up to 90 Months | Outcome measure is the change from Baseline in Z-scores for height/length. The time period is pre-dose (Baseline from the ENB-002-08 study \[NCT00744042\]) to the last assessment in the ENB-003-08 study, which represents up to 90 months of exposure in the combined studies. |
| Long-term Pharmacodynamics (PD) of SC Asfotase Alfa: Pyridoxal-5-phosphate (PLP) Levels | Up to 90 Months | Outcome measure is the change from Baseline in pyridoxal-5-phosphate (PLP) levels. The time period is pre-dose (Baseline from the ENB-002-08 study \[NCT00744042\]) to the last assessment for each patient in the ENB-003-08 study, which represents up to 90 months of exposure for the combined studies. |
Countries
United Arab Emirates, United Kingdom, United States
Participant flow
Recruitment details
The main criteria for inclusion in Study ENB-002-08 were male and female patients \</= 36 months of age, with severe infantile-onset HPP (symptom onset before 6 months of age) who were medically stable (ventilator support was allowed). To enter extension Study ENB-003-08, parent/guardian had to consent and patient had to complete Study ENB-002-08.
Participants by arm
| Arm | Count |
|---|---|
| Asfotase Alfa An initial single intravenous (IV) infusion of 2 mg/kg asfotase alfa, followed by subcutaneous (SC) injections of 1 mg/kg asfotase alfa 3 times per week | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | Asfotase Alfa |
|---|---|
| Age, Continuous | 56.44 weeks STANDARD_DEVIATION 61.888 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 9 / 10 |
Outcome results
Primary
Long-term Efficacy of Asfotase Alfa in Treating Rickets in Infants and Young Children With Hypophosphatasia (HPP).
Outcome measure is the evaluation of radiographic change in rickets severity using a qualitative Radiographic Global Impression of Change (RGI-C) Scale. Skeletal radiographs obtained at the patient's last assessment were compared with skeletal radiographs obtained before initiation of treatment (Baseline in Study ENB-002-08 \[NCT00744042\]). The RGI-C is a 7-point rating scale that ranges from -3 (indicative of severe worsening of HPP-associated rickets) to +3 (indicative of complete or near complete healing of HPP-associated rickets). The time period is pre-dose (Baseline from ENB-002-08 study) to the last assessment for each patient in the ENB-003-08 study, which represents up to 90 months of exposure for the combined studies.
Time frame: Up to 90 Months
Population: Full Analysis Set (All 10 patients enrolled in Study ENB-003-08)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Asfotase Alfa | Long-term Efficacy of Asfotase Alfa in Treating Rickets in Infants and Young Children With Hypophosphatasia (HPP). | 2.00 scores on a scale |
Comparison: Change is relative to Baseline in Study ENB-002-08 (NCT00744042). The RGI-C score represents evaluation of skeletal X-rays at each post-treatment study timepoint compared with pre-treatment X-rays from Study ENB-002-08 using an ordinal scale. Therefore, an RGI-C score is not applicable for radiographs obtained at Baseline.p-value: 0.002Wilcoxon signed-rank test
Primary
Long-term Tolerability of Subcutaneous (SC) Asfotase Alfa
Outcome measure is the number of patients with 1 or more treatment-emergent adverse event. The time period is from Baseline in the ENB-003-08 study to the end of the ENB-003-08 study.
Time frame: 84 months
Population: Full Analysis Set (All 10 patients enrolled in Study ENB-003-08)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Asfotase Alfa | Long-term Tolerability of Subcutaneous (SC) Asfotase Alfa | 10 Participants |
Secondary
Effect of SC Asfotase Alfa on Growth: Height/Length Z-scores
Outcome measure is the change from Baseline in Z-scores for height/length. The time period is pre-dose (Baseline from the ENB-002-08 study \[NCT00744042\]) to the last assessment in the ENB-003-08 study, which represents up to 90 months of exposure in the combined studies.
Time frame: Up to 90 Months
Population: Full Analysis Set (All 10 patients enrolled in Study ENB-003-08)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Asfotase Alfa | Effect of SC Asfotase Alfa on Growth: Height/Length Z-scores | 1.93 Z-score |
Secondary
Effect of SC Asfotase Alfa on Growth: Weight Z-scores
Outcome measure is the change from Baseline in Z-scores for weight. The time period is pre-dose (Baseline from the ENB-002-08 study \[NCT00744042\]) to the last assessment in the ENB-003-08 study, which represents up to 90 months of exposure in the combined studies.
Time frame: Up to 90 Months
Population: Full Analysis Set (All 10 patients enrolled in Study ENB-003-08)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Asfotase Alfa | Effect of SC Asfotase Alfa on Growth: Weight Z-scores | 2.43 Z-score |
Secondary
Effect of SC Asfotase Alfa on Respiratory Function
Outcome measure is the shift in the proportion of patients requiring respiratory support at their last assessment in Study ENB-003-08 compared with Baseline. The time period is pre-dose (Baseline from the ENB-002-08 study \[NCT00744042\]) to the last assessment in the ENB-003-08 study, which represents up to 90 months of exposure in the combined studies.
Time frame: Up to 90 Months
Population: Full Analysis Set (All 10 patients enrolled in Study ENB-003-08)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Asfotase Alfa | Effect of SC Asfotase Alfa on Respiratory Function | Supplemental oxygen | 0 Participants |
| Asfotase Alfa | Effect of SC Asfotase Alfa on Respiratory Function | Mechanical ventilation | 3 Participants |
| Asfotase Alfa | Effect of SC Asfotase Alfa on Respiratory Function | No respiratory support | 6 Participants |
| Asfotase Alfa | Effect of SC Asfotase Alfa on Respiratory Function | Continuous positive airway pressure | 1 Participants |
| Asfotase Alfa | Effect of SC Asfotase Alfa on Respiratory Function | Other | 1 Participants |
| Asfotase Alfa | Effect of SC Asfotase Alfa on Respiratory Function | Biphasic positive airway pressure | 0 Participants |
| Asfotase Alfa (Last Assessment) | Effect of SC Asfotase Alfa on Respiratory Function | Other | 0 Participants |
| Asfotase Alfa (Last Assessment) | Effect of SC Asfotase Alfa on Respiratory Function | No respiratory support | 9 Participants |
| Asfotase Alfa (Last Assessment) | Effect of SC Asfotase Alfa on Respiratory Function | Supplemental oxygen | 0 Participants |
| Asfotase Alfa (Last Assessment) | Effect of SC Asfotase Alfa on Respiratory Function | Continuous positive airway pressure | 0 Participants |
| Asfotase Alfa (Last Assessment) | Effect of SC Asfotase Alfa on Respiratory Function | Mechanical ventilation | 1 Participants |
| Asfotase Alfa (Last Assessment) | Effect of SC Asfotase Alfa on Respiratory Function | Biphasic positive airway pressure | 0 Participants |
Secondary
Long-term Pharmacodynamics (PD) of SC Asfotase Alfa: Plasma Inorganic Pyrophosphate (PPi) Levels
Outcome measure is the change from Baseline in plasma inorganic pyrophosphate (PPi) levels. The time period is pre-dose (Baseline from the ENB-002-08 study \[NCT00744042\]) to the last assessment for each patient in the ENB-003-08 study, which represents up to 90 months of exposure for the combined studies.
Time frame: Up to 90 Months
Population: Full Analysis Set (All 10 patients enrolled in Study ENB-003-08). Change from Baseline could not be calculated for 3 patients due to non-evaluable samples at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Asfotase Alfa | Long-term Pharmacodynamics (PD) of SC Asfotase Alfa: Plasma Inorganic Pyrophosphate (PPi) Levels | -2.460 uM |
Secondary
Long-term Pharmacodynamics (PD) of SC Asfotase Alfa: Pyridoxal-5-phosphate (PLP) Levels
Outcome measure is the change from Baseline in pyridoxal-5-phosphate (PLP) levels. The time period is pre-dose (Baseline from the ENB-002-08 study \[NCT00744042\]) to the last assessment for each patient in the ENB-003-08 study, which represents up to 90 months of exposure for the combined studies.
Time frame: Up to 90 Months
Population: Full Analysis Set (All 10 patients enrolled in Study ENB-003-08). Change from Baseline could not be calculated for 2 patients because of non-evaluable samples at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Asfotase Alfa | Long-term Pharmacodynamics (PD) of SC Asfotase Alfa: Pyridoxal-5-phosphate (PLP) Levels | -266.200 ng/mL |