E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypophosphatasia is a rare inborn error of bone metabolism caused by inactivating mutations in the gene encoding the Tissue-nonspecific alkaline phosphatase isoenzyme.
With deficiency of Tissue-nonspecific alkaline phosphatase, there is a buildup of extracellular inorganic pyrophosphate, which inhibits mineralization of bone matrix. |
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E.1.1.1 | Medical condition in easily understood language |
Hypophosphatasia a bone disorder caused by genetic changes called mutations. These gene mutations result in low levels of an enzyme needed to harden children's bones. |
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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 | 20.0 |
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 evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of asfotase alfa following administration of a range of dose regimens that encompasses the dose proven to be effective in children ( in adult patients with pediatric-onset HPP. |
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E.2.2 | Secondary objectives of the trial |
to evaluate the safety and tolerability of asfotase alfa in adult patients with pediatric-onset HPP |
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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:
1. Patients or their legal representative(s) must provide written informed consent prior to undergoing any study-related procedures
2. Patient has pediatric-onset HPP, defined as onset of first sign(s)/symptom(s) of HPP prior to 18 years of age
3. Documented diagnosis of HPP as indicated by a documented history of HPP-related skeletal abnormalities and 1 or more of the following:
− Documented TNSALP gene mutation(s) from a certified laboratory
− Serum ALP level below the age-adjusted normal range AND plasma PLP above the upper limit of normal at Screening.
4. Patients must have a plasma PPi level of ≥3.9 μM at Screening
5. Patients must be ≥18 years of age at Screening
6. Sexually active male and female patients of childbearing potential must agree to use a highly effective method of birth control during the study and for 3 months following the last dose of study drug. Male patients must also not donate sperm during the Screening and treatment periods and for at least 3 months after the last dose of asfotase alfa. Highly effective contraceptive methods are as follows:
a. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation− Oral
b. Progestogen-only hormonal contraception associated with inhibition of ovulation− Oral
c. Intrauterine device
d. Intrauterine hormone-releasing system
e. Bilateral tubal occlusion
f. Vasectomy with documented medical assessment of surgical success
g. Condom and spermicide
7. Female patients of childbearing potential must have a negative pregnancy test at the time of enrollment
8. Female patients not of child-bearing potential due to surgical sterilization (at least 6 weeks after surgical bilateral oophorectomy with or without hysterectomy or at least 6 weeks after tubal ligation) confirmed by medical history, or menopause
9. Patients must be willing to comply with study procedures and the visit schedule |
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E.4 | Principal exclusion criteria |
Patients will be excluded from participation in this study if they meet any of the following exclusion criteria:
1. Investigational site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
2. Employees of Alexion Pharmaceuticals
3. Currently enrolled in a clinical study involving another study drug or nonapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study (excluding the HPP registry, in which concurrent enrollment is allowed).
4. Participated, within the last 30 days, in a clinical study involving a study drug (other than the study drug used in this study). If the previous study drug has a long half-life, 3 months or 5 half-lives (whichever is longer) should have passed.
5. Have completed or withdrawn from this study or any other study investigating asfotase alfa in the previous 3 years. This exclusion criterion does not apply to patients who are re-screened prior to randomization or patients enrolled in the HPP registry.
6. Women who are pregnant, planning to become pregnant, or breastfeeding
7. Serum 25-OH Vitamin D below 20 ng/mL at Screening
8. Screening serum creatinine or parathyroid hormone (PTH) levels 1.5 times the upper limit of normal
9. Medical condition, serious concurrent illness and/or injury, recent orthopedic surgery, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance or study endpoints, including all prescribed evaluations and follow-up activities
10. Prior treatment with bisphosphonates within 2 years of study entry for any length of time or for more than 2 consecutive years at any prior timepoint
11. Treatment with PTH, strontium, or sclerostin inhibitors within 6 months prior to the first dose of study drug
12. Unwilling or unable to comply with the use of a data collection device on which study patients will directly record data |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week -12 to -2, -1, 1, 2, 3-5, 7-8, 9, 10-12, 13 |
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E.5.2 | Secondary end point(s) |
Change of PLP, assessment of PK parameters and assessment of safety |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Change of PLP: Week -12 to -2, -1, 1, 2, 3-5, 7-8, 9, 10-12, 13
PK parameters: Week 1, 2, 3-5, 7-8, 9, 10-12, 13
Safety: study duration |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | Yes |
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.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 10 |