Clinical trial NCT00744042: Safety and Efficacy Study of Asfotase Alfa in Severely Affected Infants With Hypophosphatasia (HPP)
Official title: A Multicenter, Open-Label Study of the Safety, Tolerability and Pharmacology of Asfotase Alfa in up to 10 Severely Affected Patients With for the Treatment of Severely Affected Patients With Infantile Hypophosphatasia (HPP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hypophosphatasia (HPP)
Keywords: Hypophosphatasia
HPP
Bone Disease
Soft Bones
Low Alkaline Phosphatase
genetic metabolic disorder
alkaline phosphatase
tissue non-specific alkaline phosphatase
rickets
osteomalacia
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2008-08-29
Enrollment: 11
Sex: ALL
Maximum age (years): 36
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This clinical trial studies the safety and efficacy of asfotase alfa in infants and young children with infantile onset HPP.

Detailed description: Hypophosphatasia (HPP) is a life-threatening, genetic, and ultra-rare metabolic disease characterized by defective bone mineralization and impaired phosphate and calcium regulation that can lead to progressive damage to multiple vital organs, including destruction and deformity of bones, profound muscle weakness, seizures, impaired renal function, and respiratory failure. There are no approved disease-modifying treatments for patients with this disease. There is also limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.

Eligibility criteria: Inclusion Criteria:

* Legal guardian(s) must provide informed consent prior to any study procedures
* Documented diagnosis of severe HPP as indicated by:

  * Total serum alkaline phosphatase at least 3 standard deviations (SD) below the mean for age
  * Plasma pyridoxal 5'-phosphate (PLP) at least 4 times the upper limit of normal
  * Radiographic evidence of HPP (hypophosphatasia), characterized by:

    * Flared and frayed metaphyses
    * Severe, generalized osteopenia
    * Widened growth plates
  * One or more HPP-related findings:

    * History or presence of:

      * Non-traumatic post-natal fracture
      * Delayed fracture healing
    * History of elevated serum calcium
    * Functional craniosynostosis with decreased head circumference growth
    * Nephrocalcinosis
    * Respiratory compromise
  * Rachitic chest deformity and/or vitamin B6 dependent seizures
  * Failure to thrive
* Onset of symptoms prior to 6 months of age
* Age ≤ 36 months
* Otherwise medically stable (patient may be on ventilatory support)
* Legal guardian(s) must be willing to comply with the study

Exclusion Criteria:

* History of sensitivity to any of the constituents of the study drug
* Current or prior clinically significant cardiovascular, endocrinologic, hematologic, hepatic, immunologic, metabolic, infectious, urologic, pulmonary, neurologic, dermatologic, renal condition and/or other major disease which, in the opinion of the investigator, precludes study participation
* Treatment with an investigational drug within 1 month prior to the start of study drug administration
* Current enrollment in any other study involving an investigational new drug, device or treatment for HPP (e.g., bone marrow transplantation)
* Low serum calcium, phosphate or 25(OH) vitamin D
* Current evidence of a treatable form of rickets
* Prior treatment with bisphosphonate

Primary outcomes:
measure: Change in Rickets Severity From Baseline to Week 24, Based on Assessment of Skeletal Radiographs Using Radiologic Global Impression of Change (RGI-C)
timeFrame: 24 weeks
Secondary outcomes:
measure: Maximum Serum Concentration of Asfotase Alfa (Cmax)
timeFrame: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose)
measure: Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)
timeFrame: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose).
measure: Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)
timeFrame: Study Week 1 (0 to 168 hours post-dose). Study Week 2 and Study Week 3 (0 to 48 hours post-dose).
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Wilmington
country: United States
facility: Alfred I. duPont Hospital for Children
state: Delaware
city: Springfield
country: United States
facility: St. John's Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center, Munroe-Meyer Institute
state: Nebraska
city: Nashville
country: United States
facility: Vanderbilt Children's Hospital
state: Tennessee
city: Green Bay
country: United States
facility: St. Vincent Hospital
state: Wisconsin
city: Winnipeg
country: Canada
facility: The University of Manitoba Health Sciences Centre
state: Manitoba
city: Al Ain
country: United Arab Emirates
facility: Tawam-John Hopkins Hospital
state: Abu-Dhabi
city: Sheffield
country: United Kingdom
facility: Sheffield Children's Hospital
state: England
city: Belfast
country: United Kingdom
facility: Royal Belfast Hospital for Sick Children
state: Northern Ireland
Study officials:
References:
citation: Millan JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP. Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res. 2008 Jun;23(6):777-87. doi: 10.1359/jbmr.071213.
citation: Drake MT, Khosla S. Bone-targeted replacement therapy for hypophosphatasia. J Bone Miner Res. 2008 Jun;23(6):775-6. doi: 10.1359/jbmr.080305. No abstract available.
citation: Padidela R, Yates R, Benscoter D, McPhail G, Chan E, Nichani J, Mughal MZ, Myer C 4th, Narayan O, Nissenbaum C, Wilkinson S, Zhou S, Saal HM. Characterization of tracheobronchomalacia in infants with hypophosphatasia. Orphanet J Rare Dis. 2020 Aug 6;15(1):204. doi: 10.1186/s13023-020-01483-9.
citation: Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2016 Jan;101(1):334-42. doi: 10.1210/jc.2015-3462. Epub 2015 Nov 3.
citation: Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012 Mar 8;366(10):904-13. doi: 10.1056/NEJMoa1106173.