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 studies the safety and efficacy of asfotase alfa in infants and young children with infantile onset HPP.
Detailed description
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.
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
No minimum to 36 Months
Healthy volunteers
No
Inclusion criteria
* Legal guardian(s) must provide informed consent prior to any study procedures * Documented diagnosis of severe HPP as indicated by: * Total serum alkaline phosphatase at least 3 standard deviations (SD) below the mean for age * Plasma pyridoxal 5'-phosphate (PLP) at least 4 times the upper limit of normal * Radiographic evidence of HPP (hypophosphatasia), characterized by: * Flared and frayed metaphyses * Severe, generalized osteopenia * Widened growth plates * One or more HPP-related findings: * History or presence of: * Non-traumatic post-natal fracture * Delayed fracture healing * History of elevated serum calcium * Functional craniosynostosis with decreased head circumference growth * Nephrocalcinosis * Respiratory compromise * Rachitic chest deformity and/or vitamin B6 dependent seizures * Failure to thrive * Onset of symptoms prior to 6 months of age * Age ≤ 36 months * Otherwise medically stable (patient may be on ventilatory support) * Legal guardian(s) must be willing to comply with the study
Exclusion criteria
* History of sensitivity to any of the constituents of the study drug * Current or prior clinically significant cardiovascular, endocrinologic, hematologic, hepatic, immunologic, metabolic, infectious, urologic, pulmonary, neurologic, dermatologic, renal condition and/or other major disease which, in the opinion of the investigator, precludes study participation * Treatment with an investigational drug within 1 month prior to the start of study drug administration * Current enrollment in any other study involving an investigational new drug, device or treatment for HPP (e.g., bone marrow transplantation) * Low serum calcium, phosphate or 25(OH) vitamin D * Current evidence of a treatable form of rickets * Prior treatment with bisphosphonate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Rickets Severity From Baseline to Week 24, Based on Assessment of Skeletal Radiographs Using Radiologic Global Impression of Change (RGI-C) | 24 weeks | A 7-point RGI-C (Radiographic Global Impression of Change) score was used to rate change in rickets severity. Scores ranged from -3 (severe worsening of rickets) to +3 (complete healing of rickets). 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. Average scores were derived for each patient at each assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Serum Concentration of Asfotase Alfa (Cmax) | Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose) | Maximum serum concentration observed during intensive PK sampling interval. |
| Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) | Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose). | Time at maximum serum concentration observed during intensive PK sampling interval. |
| Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose). | Area under serum concentration-time curve to last measurable concentration during intensive PK sampling interval. |
Countries
Canada, United Arab Emirates, United Kingdom, United States
Participant flow
Recruitment details
The trial was posted on clinicaltrials.gov. Physicians managing the care of infants and young children with a confirmed diagnosis of HPP contacted existing sites or requested assistance with site set up from the sponsor.
Pre-assignment details
All screened patients met eligibility criteria and were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Asfotase Alfa All enrolled patients receive a single IV (intravenous) dose of Asfotase Alfa of 2 mg/kg followed by 7 days of observation. Following an assessment of safety data by an independent Data Safety Monitoring Board (DSMB), patients begin thrice weekly SC (subcutaneous) injections of Asfotase Alfa at a dose of 1 mg/kg for the remaining 23 weeks of the study. | 11 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Asfotase Alfa |
|---|---|
| Age, Categorical <=18 years | 11 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 1.11 years STANDARD_DEVIATION 1.13 |
| Region of Enrollment Canada | 1 participants |
| Region of Enrollment United Arab Emirates | 1 participants |
| Region of Enrollment United Kingdom | 2 participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 7 / 11 |
Outcome results
Primary
Change in Rickets Severity From Baseline to Week 24, Based on Assessment of Skeletal Radiographs Using Radiologic Global Impression of Change (RGI-C)
A 7-point RGI-C (Radiographic Global Impression of Change) score was used to rate change in rickets severity. Scores ranged from -3 (severe worsening of rickets) to +3 (complete healing of rickets). 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. Average scores were derived for each patient at each assessment.
Time frame: 24 weeks
Population: ITT (intention to treat)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Asfotase Alfa | Change in Rickets Severity From Baseline to Week 24, Based on Assessment of Skeletal Radiographs Using Radiologic Global Impression of Change (RGI-C) | 2.00 Units on a scale |
Comparison: One treatment groupp-value: 0.0039Wilcoxon signed-rank test
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 during intensive PK sampling interval.
Time frame: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose).
Population: ITT population. N=number of patients who received a full dose of asfotase alfa and had sufficient data for non-compartmental analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asfotase Alfa | Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | 79800 h*U/L | Standard Deviation 21700 |
| Study Week 2 Subcutaneous Dose (1 mg/kg 3x/Week) | Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | 14700 h*U/L | Standard Deviation 9730 |
| Study Week 3 Subcutaneous Dose (1 mg/kg 3x/Week) | Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt) | 33700 h*U/L | Standard Deviation 19700 |
Secondary
Maximum Serum Concentration of Asfotase Alfa (Cmax)
Maximum serum concentration observed during intensive PK sampling interval.
Time frame: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose)
Population: ITT population. N=number of patients who received a full dose of asfotase alfa and had sufficient data for non-compartmental analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asfotase Alfa | Maximum Serum Concentration of Asfotase Alfa (Cmax) | 2230 U/L | Standard Deviation 1100 |
| Study Week 2 Subcutaneous Dose (1 mg/kg 3x/Week) | Maximum Serum Concentration of Asfotase Alfa (Cmax) | 376 U/L | Standard Deviation 226 |
| Study Week 3 Subcutaneous Dose (1 mg/kg 3x/Week) | Maximum Serum Concentration of Asfotase Alfa (Cmax) | 897 U/L | Standard Deviation 491 |
Secondary
Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)
Time at maximum serum concentration observed during intensive PK sampling interval.
Time frame: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose).
Population: ITT population. N=number of patients who received a full dose of asfotase alfa and had sufficient data for non-compartmental analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asfotase Alfa | Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) | 4.3 hour | Standard Deviation 4.3 |
| Study Week 2 Subcutaneous Dose (1 mg/kg 3x/Week) | Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) | 29.7 hour | Standard Deviation 13.2 |
| Study Week 3 Subcutaneous Dose (1 mg/kg 3x/Week) | Time at Maximum Serum Concentration of Asfotase Alfa (Tmax) | 12.0 hour | Standard Deviation 7.7 |