E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10049933 |
E.1.2 | Term | Hypophosphatasia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the following:
• Effect of asfotase alfa treatment on skeletal manifestations of HPP as measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale for all treated patients
• Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa for all treated patients |
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E.2.2 | Secondary objectives of the trial |
To evaluate the following:
-Effect of asfotase alfa treatment on skeletal manifestations of HPP as measured by radiographs using a Rickets Severity Scale score
-For patients who are not mechanically ventilated at the time of enrollment, the percentage who are alive and ventilator-free after receiving asfotase alfa as compared to an age-matched historical control group
-Effect of asfotase alfa treatment on respiratoy function as measure by ventilator status, time on respiratory support, ventilator rate or oxygen volume, ventilator pressures, and fraction of inspired oxygen
-Effect of asfotase alfa treatment on physical growth as measured by body weight, length, arm span, head circumference, and chest circumference for all treated patients
-Effect of asfotase alfa treatment on tooth loss for all treated patients
-PK properties of asfotase alfa
-Effect of asfotase alfa on plasma inorganic pyrophosphate (PPi) and plasma pyridoxal-5'-phosphate (PLP)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria for enrollment in this study:
- Parent or legal guardian(s) must provide written informed consent prior to any study procedures being performed and must be willing to comply with all study required procedures.
- Documented diagnosis of HPP as indicated by:
o Total serum alkaline phosphatase (ALP) below the lower limit of normal for age.
o Plasma PLP above the upper limit of normal (unless patient is receiving pyridoxine for seizures).
o Radiographic evidence of HPP at screening, characterized by:
* Flared and frayed metaphyses and
* Severe, generalized osteopenia and
* Widened growth plates and
* Areas of radiolucency or sclerosis
o Two or more of the following HPP-related findings:
* History or presence of:
+ Nontraumatic post-natal fracture
+ Delayed fracture healing
* Nephrocalcinosis or history of elevated serum calcium
* Functional craniosynostosis
* Respiratory compromise or rachitic chest deformity
* Vitamin B6-dependent seizures
* Failure to thrive
- Onset of symptoms prior to 6 months of age
- Chronological age of ≤ 5 years or adjusted age for premature infants born ≤ 37 weeks gestation
- Otherwise medically stable in the opinion of the Investigator and/or Sponsor |
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E.4 | Principal exclusion criteria |
Patients will be excluded from enrollment in this study if they meet any of the following exclusion criteria:
- Clinically significant disease, such as, but not limited to, hepatitis C virus / human immunodeficiency virus / hepatitis B virus, that precludes study participation, in the opinion of the Investigator and/or Sponsor
- Serum calcium or phosphate levels below the normal range.
- Current evidence of treatable form of rickets
- Prior treatment with bisphosphonates.
- Treatment with an investigational drug within 1 month prior to the start of asfotase alfa treatment
- Current enrollment in any other study involving an investigational new drug, device, or treatment for HPP (eg, bone marrow transplantation)
- Intolerance to the IP or any of its excipients
- Previous participation in the same study
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E.5 End points |
E.5.1 | Primary end point(s) |
• Effect of asfotase alfa treatment on skeletal manifestations of HPP as measured by radiographs using a qualitative Radiographic Global Impression of Change (RGI-C) scale for all treated patients
• Safety and tolerability of repeated subcutaneous (SC) injections of asfotase alfa for all treated patients |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoint: screening visit, month 3, month 6, month 9, month 12, month 18, month 24, month 30, month 36, month 42, month 48;
Safety endpoint: continuous monitoring |
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E.5.2 | Secondary end point(s) |
-Effect of asfotase alfa treatment on skeletal manifestations of HPP as measured by radiographs using a Rickets Severity Scale score
-For patients who are not mechanically ventilated at the time of enrollment, the percentage who are alive and ventilator-free after receiving asfotase alfa as compared to an age-matched historical control group
-Effect of asfotase alfa treatment on respiratory function as measured by ventilator status, time on respiratory support, ventilator rate or oxygen volume, ventilator pressures, and fraction of inspired oxygen for all treated patients
- Effect of treatment on physical growth as measured by body weight, length, arm span, head circumference, and chest circumference for all treated patients
- Effect of treatment on tooth loss for all treated patients
- PK properties of asfotase alfa
- Effect of asfotase alfa on plasma inorganic pyrophosphate (PPi)and plasma pyridoxal-5'-phosphate (PLP) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
week-4 to day -8, day -1, day 1, day 2, day 3, week 3, week 6 day 1, week 6 day 3, month 3, month 6, month 9, month 12, month 15, month 18, month 24, month 30, month 36, month 42, month 48.
Not all secondary endpoints are measured on the same day. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
France |
Germany |
Italy |
Japan |
Russian Federation |
Saudi Arabia |
Spain |
Taiwan |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |