Hypophosphatasia
Conditions
Keywords
Enzyme replacement therapy
Brief summary
The goal of this clinical trial is to compare the effectiveness of two doses of ilofotase alfa, an enzyme replacement treatment, in patients with hypophosphatasia (HPP). The main question it aims to answer is if the harmful accumulating levels of extracellular inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP) can be reduced with ilofotase alfa. Researchers will compare the two doses of ilofotase alfa to see if treatment effects differ between the doses.
Detailed description
Recombinant human alkaline phosphatase (ilofotase alfa) is a full-length human chimeric alkaline phosphatase (ALP) that could benefit patients with hypophosphatasia (HPP), which is characterized by low activity of tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). This is a pilot trial for a potential future trial aimed at identifying whether treatment with ilofotase alfa can normalize circulating levels of PPi, PLP and other biochemical markers of TNSALP deficiency along with the safety/tolerability of different doses of ilofotase alfa. The trial is designed as a single-center, open-label, randomized, parallel group clinical trial in adult patients with HPP. Two different dose levels (0.8 mg/kg and 3.2 mg/kg) of ilofotase alfa will be assessed. Participants will receive a single dose of ilofotase alfa, administered as a 1-hour intravenous infusion on Study Day 1. Participants will stay at the research center for a total of 12 days; from 2 days before study drug administration (run-in) to 10 days after treatment. An additional follow-up assessment is scheduled 14 days after administration of ilofotase alfa. Blood and urine samples will be taken daily for drug concentration and laboratory measurements assessing safety and effectiveness of treatment. In addition physical examinations will be performed on Day 1 and as needed afterwards.
Interventions
BIOLOGICALIlofotase Alfa, 0.8 mg/kg
Biological: single 1-hour intravenous infusion of 0.8 mg/kg ilofotase alfa
BIOLOGICALIlofotase Alfa, 3.2 mg/kg
Biological: single 1-hour intravenous infusion of 3.2 mg/kg ilofotase alfa
Sponsors
AM-Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Trial is masked for received dose; type of drug received is open-label
Intervention model description
2 doses will be compared
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Genetically confirmed variant in the tissue-nonspecific isozyme alkaline phosphatase (ALPL)-Gene. * Clinical symptoms of HPP. * Medical history with 1) at least two independent measures of Alkaline Phosphatase (ALP) below lower level of normal (LLN) and 2) at least one measurement of either PPi or PLP above upper level of normal (ULN). * Provision of signed and dated informed consent form (ICF) in accordance with local regulations at screening. * Patients must agree not to get pregnant/not to get their partner pregnant, during the trial. Consequently, patients must agree to use adequate contraception as detailed in study protocol.
Exclusion criteria
* Participant is unable or unwilling to participate in all scheduled visits and perform all protocol-mandated assessments. * Has a known or suspected hypersensitivity to ilofotase alfa or any components of the formulation used. * Body weight \< 40 kilogram and \> 120 kilogram. * Patient has a history of clinically significant abnormalities or of any illness that, in the opinion of the trial investigator, might confound the results of the trial or pose an additional risk to the patient by their participation in the trial. * NSAID use in the past 2 weeks. * Use of corticosteroids in the past 4 weeks. * Use of compounds intended to interfere with bone metabolism (e.g. Denosumab, Teriparatide, Romosozumab, Raloxifene) in the past 3 months. * Use of bisphosphonates in the past 2 years. * Participation in a drug trial within 60 days, or five times the half-life of the drug, whichever is longer, prior to administration of ilofotase alfa. * Use of asfotase alfa in the previous 3 months. Patients will not be withheld from approved asfotase alfa if medically indicated. * A patient who is currently pregnant or lactating. * Use of supplements including Vitamin B6.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Percent Change From Baseline in Extracellular Inorganic Pyrophosphate (PPi) | Day 1 to Day 10 | Percent Change from BaseLine (PCBL) in PPi serum concentration is calculated for all post-dose PPi measures recorded from Day 1 to Day 10. Per patient, 12 measurements were done: 3 at Day 1 and 1 each day from Day 2 to Day 10. The Percent Change from BaseLine for measurement x (x=1,…12) is calculated: PCBL(x)= \[(PPi( x)-PPi(baseline))/PPi(baseline)\]\*100. The subject's maximum percent change from baseline is defined as the Max (PCBL(1), …, PCBL(12)). |
| Maximum Percent Change From Baseline in Pyridoxal 5'-Phosphate (PLP) | Day 1 to Day 10 | Percent Change from BaseLine (PCBL) in PLP serum concentration is calculated for all post-dose PLP measures recorded from Day 1 to Day 10. Per patient, 12 measurements were done: 3 at Day 1 and 1 each day from Day 2 to Day 10. The Percent Change from BaseLine for measurement x (x=1,…12) is calculated: PCBL(x)= \[(PLP( x)-PLP(baseline))/PLP(baseline)\]\*100. The subject's maximum percent change from baseline is defined as the Max (PCBL(1), …, PCBL(12)). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Maximum Percent Change From Baseline in Pyridoxal (PL). | Day 1 to Day 10 | Percent Change from BaseLine (PCBL) in PL serum concentration is calculated for all post-dose PL measures recorded from Day 1 to Day 10. Per patient, 12 measurements were done: 3 at Day 1 and 1 each day from Day 2 to Day 10. The Percent Change from BaseLine for measurement x (x=1,…12) is calculated: PCBL(x)= \[(PL( x)-PL(baseline))/PL(baseline)\]\*100. The subject's maximum percent change from baseline is defined as the Max (PCBL(1), …, PCBL(12)). |
| Maximum Percent Change From Baseline in Alkaline Phosphatase (ALP) Activity | Day 1 to Day 10 | Percent Change from BaseLine (PCBL) in ALP Activity is calculated for all post-dose ALP measures recorded from Day 2 to Day 10. Per patient, 9 measurements were done: 1 each day from Day 2 to Day 10. The Percent Change from BaseLine for measurement x (x=1,…9) is calculated: PCBL(x)= (ALP(x)-ALP(baseline))/ALP(baseline)\*100, \[x=1,...,9\]. The subject's maximum percent change from baseline is defined as the Max (PCBL(1), …, PCBL(9)) |
| Treatment-emergent Adverse Events (TEAEs) | Day 1 to Day 15 | Any untoward medical occurrence in a patient enrolled and treated in the clinical trial regardless of its causal relationship to the trial medication. |
| Maximum Fold Change From Baseline in PL/PLP Ratio | Day 1 to Day 10 | Fold Change from BaseLine (FCBL) in PL/PLP ratio is calculated for all post-dose PL/PLP ratio measures recorded from Day 1 to Day 10. Per patient, 12 measurements were done: 3 at Day 1 and 1 each day from Day 2 to Day 10. The Fold Change from BaseLine for measurement x (x=1,…12) is calculated: FCBL(x)= (PL/PLPratio( x) / PL/PLPratio(baseline)). The subject's maximum fold change from baseline is defined as the Max (FCBL(1), …, FCBL(12)). |
| Maximum Percent Change From Baseline in Urine Phosphoethanolamine (PEA) | Day 1 to Day 10 | Percent Change from BaseLine (PCBL) in PEA concentration is calculated for all post-dose PEA measures recorded from Day 2 to Day 10. Per patient, 9 measurements were done: 1 each day from Day 2 to Day 10. The Percent Change from BaseLine for measurement x (x=1,…9) is calculated: PCBL(x)= \[(PEA( x)-PEA(baseline))/PEA(baseline)\]\*100. The subject's maximum percent change from baseline is defined as the Max (PCBL(1), …, PCBL(9)). |
Countries
Germany
Participant flow
Pre-assignment details
12 patients were enrolled, screened and randomized (6 to the 0.8 mg ilofotase alfa dose group, 6 to the 3.2 mg ilofotase alfa dose group)
Participants by arm
| Arm | Count |
|---|---|
| 0.8 mg/kg Ilofotase Alfa Single, 1-hour intravenous infusion of 0.8 mg/kg ilofotase alfa | 6 |
| 3.2 mg/kg Ilofotase Alfa Single, 1-hour intravenous infusion of 3.2 mg/kg ilofotase alfa | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | 0.8 mg/kg Ilofotase Alfa | 3.2 mg/kg Ilofotase Alfa | Total |
|---|---|---|---|
| Age, Continuous | 49.5 years | 51.0 years | 51.0 years |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 12 |
| other Total, other adverse events | 1 / 6 | 3 / 6 | 4 / 12 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 12 |
Outcome results
Primary
Maximum Percent Change From Baseline in Extracellular Inorganic Pyrophosphate (PPi)
Percent Change from BaseLine (PCBL) in PPi serum concentration is calculated for all post-dose PPi measures recorded from Day 1 to Day 10. Per patient, 12 measurements were done: 3 at Day 1 and 1 each day from Day 2 to Day 10. The Percent Change from BaseLine for measurement x (x=1,…12) is calculated: PCBL(x)= \[(PPi( x)-PPi(baseline))/PPi(baseline)\]\*100. The subject's maximum percent change from baseline is defined as the Max (PCBL(1), …, PCBL(12)).
Time frame: Day 1 to Day 10
Population: All randomized patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.8 mg/kg Ilofotase Alfa | Maximum Percent Change From Baseline in Extracellular Inorganic Pyrophosphate (PPi) | -36.46 percent change | Standard Deviation 11.502 |
| 3.2 mg/kg Ilofotase Alfa | Maximum Percent Change From Baseline in Extracellular Inorganic Pyrophosphate (PPi) | -77.31 percent change | Standard Deviation 16.113 |
| Overall | Maximum Percent Change From Baseline in Extracellular Inorganic Pyrophosphate (PPi) | -56.88 percent change | Standard Deviation 25.165 |
Comparison: Analysis of the difference in relative maximum change from baseline between dose groups of ilofotase alfa by a 2-sided t-test for PPi.p-value: 0.000595% CI: [22.842, 58.858]t-test, 2 sided
Comparison: Analysis of the difference in relative maximum change from baseline (LS Means) between dose groups of ilofotase alfa by a mixed model repeated measures (MMRM) analysis for PPi.p-value: <0.000195% CI: [-16.52, -5.82]Mixed Models Analysis
Primary
Maximum Percent Change From Baseline in Pyridoxal 5'-Phosphate (PLP)
Percent Change from BaseLine (PCBL) in PLP serum concentration is calculated for all post-dose PLP measures recorded from Day 1 to Day 10. Per patient, 12 measurements were done: 3 at Day 1 and 1 each day from Day 2 to Day 10. The Percent Change from BaseLine for measurement x (x=1,…12) is calculated: PCBL(x)= \[(PLP( x)-PLP(baseline))/PLP(baseline)\]\*100. The subject's maximum percent change from baseline is defined as the Max (PCBL(1), …, PCBL(12)).
Time frame: Day 1 to Day 10
Population: All randomized patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.8 mg/kg Ilofotase Alfa | Maximum Percent Change From Baseline in Pyridoxal 5'-Phosphate (PLP) | -34.68 percent change | Standard Deviation 8.898 |
| 3.2 mg/kg Ilofotase Alfa | Maximum Percent Change From Baseline in Pyridoxal 5'-Phosphate (PLP) | -65.56 percent change | Standard Deviation 6.559 |
| Overall | Maximum Percent Change From Baseline in Pyridoxal 5'-Phosphate (PLP) | -50.12 percent change | Standard Deviation 17.768 |
Comparison: Analysis of the difference in relative maximum change from baseline between dose groups of ilofotase alfa by a 2-sided t-test for PLP.p-value: <0.000195% CI: [20.831, 40.941]t-test, 2 sided
Comparison: Analysis of the difference in relative maximum change from baseline (LS Means) between dose groups of ilofotase alfa by an MMRM analysis for PLP.p-value: 0.002495% CI: [-35.81, -9.2]Mixed Models Analysis
Other Pre-specified
Maximum Fold Change From Baseline in PL/PLP Ratio
Fold Change from BaseLine (FCBL) in PL/PLP ratio is calculated for all post-dose PL/PLP ratio measures recorded from Day 1 to Day 10. Per patient, 12 measurements were done: 3 at Day 1 and 1 each day from Day 2 to Day 10. The Fold Change from BaseLine for measurement x (x=1,…12) is calculated: FCBL(x)= (PL/PLPratio( x) / PL/PLPratio(baseline)). The subject's maximum fold change from baseline is defined as the Max (FCBL(1), …, FCBL(12)).
Time frame: Day 1 to Day 10
Population: All randomized patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.8 mg/kg Ilofotase Alfa | Maximum Fold Change From Baseline in PL/PLP Ratio | 6.9145 fold change | Standard Deviation 1.83957 |
| 3.2 mg/kg Ilofotase Alfa | Maximum Fold Change From Baseline in PL/PLP Ratio | 7.8062 fold change | Standard Deviation 2.70554 |
| Overall | Maximum Fold Change From Baseline in PL/PLP Ratio | 7.3604 fold change | Standard Deviation 2.2544 |
Comparison: Analysis of the difference in fold change from baseline between dose groups of ilofotase alfa by a 2-sided t-test for PL/PLP ratio.p-value: 0.519595% CI: [-3.868, 2.084]t-test, 2 sided
Comparison: Analysis of the difference in fold change form baseline (LS Means) between dose levels of ilofotase alfa by an MMRM analysis for PL/PLP ratio.p-value: <0.000195% CI: [0.69, 1.33]Mixed Models Analysis
Other Pre-specified
Maximum Percent Change From Baseline in Alkaline Phosphatase (ALP) Activity
Percent Change from BaseLine (PCBL) in ALP Activity is calculated for all post-dose ALP measures recorded from Day 2 to Day 10. Per patient, 9 measurements were done: 1 each day from Day 2 to Day 10. The Percent Change from BaseLine for measurement x (x=1,…9) is calculated: PCBL(x)= (ALP(x)-ALP(baseline))/ALP(baseline)\*100, \[x=1,...,9\]. The subject's maximum percent change from baseline is defined as the Max (PCBL(1), …, PCBL(9))
Time frame: Day 1 to Day 10
Population: All randomized patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.8 mg/kg Ilofotase Alfa | Maximum Percent Change From Baseline in Alkaline Phosphatase (ALP) Activity | 2685.57 percent change | Standard Deviation 1492.991 |
| 3.2 mg/kg Ilofotase Alfa | Maximum Percent Change From Baseline in Alkaline Phosphatase (ALP) Activity | 7021.23 percent change | Standard Deviation 2063.878 |
| Overall | Maximum Percent Change From Baseline in Alkaline Phosphatase (ALP) Activity | 4853.40 percent change | Standard Deviation 2841.847 |
Comparison: Analysis of the difference in relative maximum change from baseline between dose groups of ilofotase alfa by a 2-sided t-test for ALP activity.p-value: 0.001995% CI: [-6652.753, -2018.576]t-test, 2 sided
Other Pre-specified
Maximum Percent Change From Baseline in Pyridoxal (PL).
Percent Change from BaseLine (PCBL) in PL serum concentration is calculated for all post-dose PL measures recorded from Day 1 to Day 10. Per patient, 12 measurements were done: 3 at Day 1 and 1 each day from Day 2 to Day 10. The Percent Change from BaseLine for measurement x (x=1,…12) is calculated: PCBL(x)= \[(PL( x)-PL(baseline))/PL(baseline)\]\*100. The subject's maximum percent change from baseline is defined as the Max (PCBL(1), …, PCBL(12)).
Time frame: Day 1 to Day 10
Population: All randomized patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.8 mg/kg Ilofotase Alfa | Maximum Percent Change From Baseline in Pyridoxal (PL). | 409.76 percent change | Standard Deviation 138.504 |
| 3.2 mg/kg Ilofotase Alfa | Maximum Percent Change From Baseline in Pyridoxal (PL). | 222.33 percent change | Standard Deviation 91.332 |
| Overall | Maximum Percent Change From Baseline in Pyridoxal (PL). | 316.05 percent change | Standard Deviation 148.635 |
Comparison: Analysis of the difference in relative maximum change from baseline between dose groups of ilofotase alfa by a 2-sided t-test for PL.p-value: 0.019995% CI: [36.516, 338.344]t-test, 2 sided
Comparison: Analysis of the difference in relative maximum change from baseline (LS Means) between dose groups of ilofotase alfa by an MMRM analysis for PL.p-value: 0.203495% CI: [-31.92, 6.89]Mixed Models Analysis
Other Pre-specified
Maximum Percent Change From Baseline in Urine Phosphoethanolamine (PEA)
Percent Change from BaseLine (PCBL) in PEA concentration is calculated for all post-dose PEA measures recorded from Day 2 to Day 10. Per patient, 9 measurements were done: 1 each day from Day 2 to Day 10. The Percent Change from BaseLine for measurement x (x=1,…9) is calculated: PCBL(x)= \[(PEA( x)-PEA(baseline))/PEA(baseline)\]\*100. The subject's maximum percent change from baseline is defined as the Max (PCBL(1), …, PCBL(9)).
Time frame: Day 1 to Day 10
Population: All randomized patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.8 mg/kg Ilofotase Alfa | Maximum Percent Change From Baseline in Urine Phosphoethanolamine (PEA) | -28.58 percent change | Standard Deviation 15.161 |
| 3.2 mg/kg Ilofotase Alfa | Maximum Percent Change From Baseline in Urine Phosphoethanolamine (PEA) | -51.82 percent change | Standard Deviation 19.614 |
| Overall | Maximum Percent Change From Baseline in Urine Phosphoethanolamine (PEA) | -40.20 percent change | Standard Deviation 20.573 |
Comparison: Analysis of the difference in relative maximum change from baseline between dose groups of ilofotase alfa by a 2-sided t-test for urine PEA.p-value: 0.069395% CI: [-2.319, 48.812]t-test, 2 sided
Comparison: Analysis of the difference in relative maximum change from baseline (LS Means) between dose groups of ilofotase alfa by an MMRM analysis for urine PEA.p-value: 0.708695% CI: [-57.88, 40.35]Mixed Models Analysis
Other Pre-specified
Treatment-emergent Adverse Events (TEAEs)
Any untoward medical occurrence in a patient enrolled and treated in the clinical trial regardless of its causal relationship to the trial medication.
Time frame: Day 1 to Day 15
Population: All patients who received trial medication were included in the population for the safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 0.8 mg/kg Ilofotase Alfa | Treatment-emergent Adverse Events (TEAEs) | 1 Participants |
| 3.2 mg/kg Ilofotase Alfa | Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Overall | Treatment-emergent Adverse Events (TEAEs) | 4 Participants |