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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 0.8 mg/kg ilofotase alfa | Experimental | Single dose administered intravenously over 1 hour |
|
| 3.2 mg/kg ilofotase alfa | Experimental | Single dose administered intravenously over 1 hour |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ilofotase Alfa, 0.8 mg/kg | Biological | Biological: single 1-hour intravenous infusion of 0.8 mg/kg ilofotase alfa |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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)). | Day 1 to Day 10 |
| 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)). | Day 1 to Day 10 |
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| Measure | Description | Time Frame |
|---|---|---|
| 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)) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Dr Seefried | Osteologie / Klinische Studieneinheit, Orthopädische Klinik - KLH, Würzburg, Germany | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Osteologie / Klinische Studieneinheit, Orthopädische Klinik - KLH | Würzburg | 97074 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41378916 | Derived | Seefried L, Bernholz J, Kraan M, Nitschke Y, Rutsch F, Mallek M, Kleinert S, Genest F. A randomized Phase 1b trial evaluating the pharmacodynamics of ilofotase alfa in adults with hypophosphatasia. J Bone Miner Res. 2026 Mar 2;41(3):231-241. doi: 10.1093/jbmr/zjaf185. |
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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)
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| ID | Title | Description |
|---|---|---|
| FG000 | 0.8 mg/kg Ilofotase Alfa | Single, 1-hour intravenous infusion of 0.8 mg/kg ilofotase alfa |
| FG001 | 3.2 mg/kg Ilofotase Alfa | Single, 1-hour intravenous infusion of 3.2 mg/kg ilofotase alfa |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Intention-to-treat population = all randomized patients
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| ID | Title | Description |
|---|---|---|
| BG000 | 0.8 mg/kg Ilofotase Alfa | Single, 1-hour intravenous infusion of 0.8 mg/kg ilofotase alfa |
| BG001 | 3.2 mg/kg Ilofotase Alfa | Single, 1-hour intravenous infusion of 3.2 mg/kg ilofotase alfa |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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)). | All randomized patients. | Posted | Mean | Standard Deviation | percent change | Day 1 to Day 10 |
|
Day 1 to Day 15
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 0.8 mg/kg Ilofotase Alfa | Single dose administered intravenously over 1 hour Ilofotase Alfa, 0.8 mg/kg: Biological: single 1-hour intravenous infusion of 0.8 mg/kg ilofotase alfa |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dysgeusia | Nervous system disorders | MedDRA 26.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| AM-Pharma Office | AM-Pharma | 31 (0)30 228 92 22 | office@am-pharma.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 30, 2023 | Sep 9, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jun 5, 2023 | Sep 9, 2024 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D007014 | Hypophosphatasia |
| ID | Term |
|---|---|
| D008664 | Metal Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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2 doses will be compared
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Trial is masked for received dose; type of drug received is open-label
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| Ilofotase Alfa, 3.2 mg/kg | Biological | Biological: single 1-hour intravenous infusion of 3.2 mg/kg ilofotase alfa |
|
|
| Day 1 to Day 10 |
| 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)). | Day 1 to Day 10 |
| 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)). | Day 1 to Day 10 |
| 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)). | Day 1 to Day 10 |
| 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. | Day 1 to Day 15 |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| 3.2 mg/kg Ilofotase Alfa |
Single, 1-hour intravenous infusion of 3.2 mg/kg ilofotase alfa |
| OG002 | Overall | Single, 1-hour intravenous infusion of 0.8 mg/kg or 3.2 mg/kg ilofotase alfa |
|
|
|
| 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)). | All randomized patients. | Posted | Mean | Standard Deviation | percent change | Day 1 to Day 10 |
|
|
|
|
| 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)) | All randomized patients. | Posted | Mean | Standard Deviation | percent change | Day 1 to Day 10 |
|
|
|
|
| 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)). | All randomized patients. | Posted | Mean | Standard Deviation | percent change | Day 1 to Day 10 |
|
|
|
|
| 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)). | All randomized patients. | Posted | Mean | Standard Deviation | percent change | Day 1 to Day 10 |
|
|
|
|
| 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)). | All randomized patients. | Posted | Mean | Standard Deviation | fold change | Day 1 to Day 10 |
|
|
|
|
| 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. | All patients who received trial medication were included in the population for the safety analysis. | Posted | Count of Participants | Participants | Day 1 to Day 15 |
|
|
|
| 0 |
| 6 |
| 0 |
| 6 |
| 1 |
| 6 |
| EG001 | 3.2 mg/kg Ilofotase Alfa | Single dose administered intravenously over 1 hour Ilofotase Alfa, 3.2 mg/kg: Biological: single 1-hour intravenous infusion of 3.2 mg/kg ilofotase alfa | 0 | 6 | 0 | 6 | 3 | 6 |
| EG002 | Overall | Single dose administered intravenously over 1 hour Ilofotase Alfa, 0.8 or 3.2 mg/kg: Biological: single 1-hour intravenous infusion of 0.8 or 3.2 mg/kg ilofotase alfa | 0 | 12 | 0 | 12 | 4 | 12 |
| Headache | Nervous system disorders | MedDRA 26.0 | Non-systematic Assessment |
|
| Restless arm syndrome | Nervous system disorders | MedDRA 26.0 | Non-systematic Assessment |
|
| Restless legs syndrome | Nervous system disorders | MedDRA 26.0 | Non-systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 26.0 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 26.0 | Non-systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 26.0 | Non-systematic Assessment |
|
The PI may publish the study results but must submit the publication to the sponsor for review at least 60 days prior to publication. The sponsor may request changes/removals of sponsor information. The PI should remove such information if the correct presentation of the results is still ensured. The PI must consider the sponsor's other comments but must not adopt them. If publication could affect the patentability of the invention, the sponsor may request an additional period of up to 120 days.
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| Analysis of the difference in relative maximum change from baseline (LS Means) between dose groups of ilofotase alfa by an MMRM analysis for PLP. | Mixed Models Analysis | 0.0024 | Significant test: two-sided; significance level 5%. | Difference in LS Means | -22.51 | Standard Error of the Mean | 6.289 | 2-Sided | 95 | -35.81 | -9.20 | Other | The difference between LS Means of change from baseline between dose groups was calculated. The analysis was performed using an MMRM model with fixed effects for baseline value, dose group, timepoint, interaction between dose group and timepoint, as well as random effects for patient and error. |
| 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. | Mixed Models Analysis | 0.7086 | Significant test: 2-sided; significance level 5%. | Difference in LS Means | -8.76 | Standard Error of the Mean | 22.986 | 2-Sided | 95 | -57.88 | 40.35 | Other | The difference between LS Means of change from baseline between dose groups was calculated. The analysis was performed using an MMRM model with fixed effects for baseline value, dose group, timepoint, interaction between dose group and timepoint, as well as random effects for patient and error. |
| Analysis of the difference in relative maximum change from baseline (LS Means) between dose groups of ilofotase alfa by an MMRM analysis for PL. | Mixed Models Analysis | 0.2034 | Significant test: 2-sided; significance level 5% | Difference in LS Means | -12.51 | Standard Error of the Mean | 9.767 | 2-Sided | 95 | -31.92 | 6.89 | Other | The difference between LS Means of change from baseline between dose groups was calculated. The analysis was performed using an MMRM model with fixed effects for baseline value, dose group, timepoint, interaction between dose group and timepoint, as well as random effects for patient and error. |
| 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. | Mixed Models Analysis | <0.0001 | Significant test: 2-sided; significance level 5%. | Difference in LS Means | 1.01 | Standard Error of the Mean | 0.161 | 2-Sided | 95 | 0.69 | 1.33 | Other | The difference between LS Means of fold change from baseline between dose groups was calculated. The analysis was performed using an MMRM model with fixed effects for baseline value, dose group, timepoint, interaction between dose group and timepoint, as well as random effects for patient and error. |