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Pharmacokinetic and Dose Response Study of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia (HPP)

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ClinicalTrials.gov Identifier: NCT02797821
Recruitment Status : Completed
First Posted : June 14, 2016
Results First Posted : July 10, 2018
Last Update Posted : August 24, 2018
Sponsor:
Information provided by (Responsible Party):
Alexion Pharmaceuticals

Brief Summary:
The purpose of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of asfotase alfa in adult participants with pediatric-onset HPP.

Condition or disease Intervention/treatment Phase
Hypophosphatasia Drug: Asfotase alfa Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2a, Randomized, Multicenter, Open-Label, Pharmacokinetic, and Dose Response Study of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia
Actual Study Start Date : June 6, 2016
Actual Primary Completion Date : June 21, 2017
Actual Study Completion Date : June 21, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Asfotase Alfa 0.5 mg/kg Dose
Participants received 0.5 milligrams (mg) per kilogram (kg) of asfotase alfa administered subcutaneously (SC) 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.
Drug: Asfotase alfa
Other Name: Strensiq

Experimental: Asfotase Alfa 2.0 mg/kg Dose
Participants received 2.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.
Drug: Asfotase alfa
Other Name: Strensiq

Experimental: Asfotase Alfa 3.0 mg/kg Dose
Participants received 3.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1.
Drug: Asfotase alfa
Other Name: Strensiq




Primary Outcome Measures :
  1. Change In Plasma PPi From Baseline To Pre-3rd Dose At Week 9 [ Time Frame: Baseline to Week 9 ]

    Plasma PPi concentrations were determined using a specific enzyme-catalyzed reaction with a radiolabelled marker in a 3-step process. Baseline plasma PPi values were calculated by averaging pre-dose values from samples collected during the Run-in Period at -168, -156, -24, -12, and 0 hours before Baseline. Week 9 plasma PPi values were calculated using blood samples collected before administration of the 3rd dose. The analysis was a restricted maximum likelihood (REML)-based repeated measures mixed model with treatment, visit, sex, Baseline PPi, Baseline weight group (≥ median versus < median), and study drug lot assignment as factors, and an unstructured covariance structure for within-participant correlation.

    Per inclusion criteria, participants had to have had a Screening PPi concentration of ≥3.9 micromolar (μM). Three participants (1 in each group) had Screening PPi concentrations of ≥3.9 μM, but Baseline PPi values ranged between 3.5 to 3.8 μM.



Secondary Outcome Measures :
  1. Change In Plasma PLP From Baseline To Pre-3rd Dose At Week 9 [ Time Frame: Baseline to Week 9 ]
    Plasma PLP was quantified using liquid chromatography/mass spectrometry. Baseline plasma PLP values were calculated by averaging the pre-dose PLP values from blood samples collected during the Run-in Period at -168, -156, -24, -12, and 0 hours before Baseline. Week 9 PLP values were calculated using blood samples collected before the administration of the 3rd dose. The analysis was a REML-based repeated measures mixed model with treatment, visit, sex, Baseline PPi, Baseline weight group (≥ median versus < median) and study drug lot assignment as factors, and an unstructured covariance structure for within-participant correlation.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participants or their legal representative(s) provided written informed consent prior to undergoing any study-related procedures.
  2. Participants were ≥18 years of age at Screening.
  3. Participant had pediatric-onset hypophosphatasia (HPP), defined as onset of first sign(s)/symptom (s) of HPP prior to 18 years of age.
  4. Participants had a documented diagnosis of HPP as indicated by a documented history of HPP-related skeletal abnormalities and 1 or more of the following:

    • Documented tissue-nonspecific alkaline phosphatase (TNSALP) gene mutation(s) from a certified laboratory.
    • Serum alkaline phosphatase (ALP) level below the age-adjusted normal range AND plasma pyridoxal-5'-phosphate (PLP) above the upper limit of normal at Screening.
  5. Participants had a plasma inorganic pyrophosphate (PPi) level of ≥3.9 micromolar (µM) at Screening.
  6. Female participants of childbearing potential had a negative pregnancy test at the time of enrollment.
  7. Sexually active male and female participants of childbearing potential agreed to use a highly effective method of birth control during the study.
  8. Female participants not of child-bearing potential due to 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. Participants were willing to comply with study procedures and the visit schedule.

Exclusion Criteria:

  1. Investigational site personnel directly affiliated with this study and/or their immediate families. Immediate family was 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 non-approved use of a drug or device.
  4. Participated, within the last 30 days, in a clinical study involving a study drug (other than the study drug used in this study).
  5. Completed or withdrawn from this study or any other study investigating asfotase alfa in the previous 3 years.
  6. Women who were pregnant, planning to become pregnant, or breastfeeding.
  7. Serum 25-hydroxy Vitamin D levels below 20 nanogram (ng) per milliliter (mL) at Screening.
  8. Screening serum creatinine or parathyroid hormone (PTH) levels ≥1.5 times the upper limit of normal.
  9. Any medical condition, serious concurrent illness and/or injury, recent orthopedic surgery, or other extenuating circumstance that, in the opinion of the Investigator, may have significantly interfered with study compliance or study endpoints.
  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 participants directly recorded data.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02797821


Locations
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United States, Missouri
Shriners Hospitals for Children
Saint Louis, Missouri, United States, 63110
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Tennessee
Vanderbilt Medical Center Endocrinology
Nashville, Tennessee, United States, 37232
Germany
University of Würzburg
Würzburg, Germany, 97074
Sponsors and Collaborators
Alexion Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Alexion Pharmaceuticals:
Study Protocol  [PDF] November 16, 2015
Statistical Analysis Plan  [PDF] June 28, 2017


Additional Information:
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Responsible Party: Alexion Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02797821     History of Changes
Other Study ID Numbers: AA-HPP-208
First Posted: June 14, 2016    Key Record Dates
Results First Posted: July 10, 2018
Last Update Posted: August 24, 2018
Last Verified: July 2018

Keywords provided by Alexion Pharmaceuticals:
HPP
asfotase alfa

Additional relevant MeSH terms:
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Hypophosphatasia
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Immunoglobulin G
Immunologic Factors
Physiological Effects of Drugs