UMIN-CTR Clinical Trial

Public title

SEARCH FOR CLINICAL MARKERS REFLECTING DISEASE BURDEN OF PERINATAL AND INFANTILE HYPOPHOSPHATASIA

Acronym

Marker study in patients with HPP

Scientific Title

SEARCH FOR CLINICAL MARKERS REFLECTING DISEASE BURDEN OF PERINATAL AND INFANTILE HYPOPHOSPHATASIA

Scientific Title:Acronym

Marker study in patients with HPP

Region

Japan

Condition

hypophosphatasia

Classification by specialty

Endocrinology and Metabolism

Pediatrics

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

The primary objectives of this study are to investigate the following matters in perinatal lethal/non-lethal and infantile HPP in clinical course:
>To identify candidate predictive markers that could correlate with the disease burden of bone manifestation in HPP
>To investigate bone calcification and bone quality by BMD, BMC and bone metabolism markers other than RSS and RGI-C, regardless of therapeutic intervention including Asfotase alfa treatment

Basic objectives2

Others

Basic objectives -Others

The secondary objectives of this study are to investigate the following matters in perinatal lethal/non-lethal HPP and infantile HPP in clinical course:
>To search for candidate factors to affect motor functions development
>To investigate association of the extent of whole body bone calcification with dental manifestations
>To investigate disease burden of developmental/mental delay, and to search for the factors associated with developmental/mental delay

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

>Evaluation of bone based on radiographs using Rickets Severity Scale (RSS) and modified Radiographic global impression of change(mRGI-C) as a validated scale of HPP(0, 12, 24, 48, 72, 96week)
>Time until intervention with artificial respiratory therapy becomes necessary in the patients who have not received artificial respiratory therapy at the beginning of the observation period (0, 12, 24, 48, 72, 96week)
>In the patients who have necessitated artificial respiratory therapy at the beginning of the observation period or during the observation period, evaluation will be made based on the status of artificial respirator, respiratory support time (including the duration of the use of artificial respirator or the duration of oxygen inhalation), frequency of ventilation with artificial respirator or oxygen flow rate, pressure of artificial respirator, and fraction of inspiratory oxygen (FiO2). (0, 12, 24, 48, 72, 96week)
>Body weight, height, arm span, head circumference and chest circumference will be determined and physical development will be examined and evaluated. (0, 12, 24, 48, 72, 96week)
>Intellectual and motor development will be evaluated using Kyoto Scale of Psychological Development (K scale). (48, 96week)
>The clinical course of HPP in teeth will be examined and evaluated on the basis of the clinical findings such as the number, time and site of teeth lost, depth of the periodontal pockets, periodontal bleeding, tooth mobility and dental formula, and imaging evaluation of morphological abnormalities of teeth and dental age on radiographs. (48, 72, 96week)
>Gross motor function test will be conducted using Denver IIgross motor development scale. (24, 48, 72, 96week)
>Hearing test will be conducted using the auditory brain stem response (ABR) to evaluate the status of impaired hearing. (0, 24week)

Key secondary outcomes

Health Outcomes
>ADL will be evaluated using PedsQL and CHAQ. (96week)
Biomarkers
>PLP, PL (0 or cord blood sample, 12, 24, 48, 72, 96week) and metabolites detected by metabolome technology in plasma 0 or cord blood, 12, 48week will be determined to evaluate the usefulness as metabolic markers
>P1NP, CTX, Sclerostin, FGF23 and factors related with bone metabolism tested by multi-plex analysisin serum will be determined as bone metabolism markers to investigate the usefulness as markers reflecting bone quality (0 or cord blood, 12, 48week)
>Bone mineral content and bone mineral density will be determined as the markers for ossification using dual-energy X-ray absorptiometry, and the bone mass in the process of ossification in HPP patients will be quantified. Moreover, Lean Body Mass will be determined by DXA as a quantitative marker for muscle mass (48, 96week)

Study type

Observational

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

Purpose of intervention

Type of intervention

Interventions/Control_1

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

1

days-old

<=

Age-upper limit

183

days-old

>=

Gender

Male and Female

Key inclusion criteria

1.Patients who have not been treated with asfotase alfa
2.Patients aged younger than 6 months at the time of enrollment
3.Patients diagnosed as hypophosphatasia
4.Patients who fall under any of the following items (1) to (6), and who are judged by the physicians to be likely to have HPP
(1)The serum total ALP level is lower than the standard value for the age and gender.
(2)Fetal ultrasound findings
1)Markedly short extremities (femur length (FL) of -4SD or less in the second and third pregnancy trimesters)
2)Fraying of metaphysis
3)Craniotabes (deformation of the cranial bone by mild compression by a probe)
4)Thoracic hypoplasia
(3)Fetal CT findings
1)Marked ossification insufficiency in the whole body
2)Shortening of long bones
3)Metaphyseal cupping
4)Thoracic hypoplasia
(4)Following radiographic findings unique to HPP
1)Metaphyseal flaring and fraying
2)Systemic osteopenia
3)Enlargement of growth cartilage area
4)Findings of the metaphyseal radiolucent tongue-like protrusion or sclerosis
(5)Two or more items in the following HPP-related findings are satisfied.
1)Past or present history of the following conditions
1.Prenatal or postnatal non-traumatic fracture
2.Delay in fracture healing
2)Past history of nephrocalcinosis and hypercalcemia
3)Craniosynostosis
4)Respiratory dysfunction or rickets-like thoracic deformation
5)Vitamin B6-dependent convulsive seizures
6)Failure to thrive
(6)Mutation in the ALPL gene encoding tissue-nonspecific alkaline phosphatase has been identified.
5.Patients for whom informed consent can be obtained in writing from their legally authorized representatives

Key exclusion criteria

1.Patients diagnosed as having rickets from causes other than HPP, such as vitamin D deficient rickets
2.Patients diagnosed as skeletal dysplasia other than HPP, such as osteogenesis imperfecta and campomelic dysplasia
3.Patients with serum calcium concentrations or phosphorus concentrations lower than the lower limit of the institutional standard values of the study sites
4.The serum total ALP level is not lower than the lower limit of the standard values for corresponding age and gender.
5.Patients participating in clinical trials using the drugs, medical devices or treatment methods that are not approved in Japan or at study sites
6.Patients having clinically significant diseases, who is judged by investigators not to be able to participate in this study

Target sample size

20

Name of lead principal investigator

1st name	Takuo
Middle name
Last name	Kubota

Organization

Osaka University

Division name

Dept. of Pediatrics, Graduate School of Medicine

Zip code

565-0871

Address

2-2 Yamadaoka, Suita, Osaka, Japan

TEL

06-6879-3932

Email

tkubota@ped.med.osaka-u.ac.jp

Name of contact person

1st name	Takuo
Middle name
Last name	Kubota

Organization

Osaka University

Division name

Dept. of Pediatrics, Graduate School of Medicine

Zip code

565-0871

Address

2-2 Yamadaoka, Suita, Osaka, Japan

TEL

06-6879-3932

Homepage URL

Email

tkubota@ped.med.osaka-u.ac.jp

Institute

Osaka University

Institute

Department

Personal name

Organization

Alexion Pharma GK

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Osaka University

Address

2-2 Yamadaoka, Suita, Osaka, Japan

Tel

06-6210-8296

Email

rinri@hp-crc.med.osaka-u.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

大阪大学医学部附属病院（大阪府）、岡山大学病院（岡山県）、島根大学医学部附属病院（島根県）、新潟大学医歯学総合病院（新潟県）、地域医療機能推進機構（JCHO）大阪病院（大阪府）、名古屋大学医学部附属病院（愛知県）、東北大学病院（宮城県）、大阪母子医療センター（大阪府）、宮城県立こども病院（宮城県）、埼玉県立小児医療センター（埼玉県）、安城更生病院（愛知県）、金沢大学附属病院（石川県）、奈良県立医科大学附属病院（奈良県）、兵庫県立こども病院（兵庫県）、千葉県こども病院（千葉県）、函館五稜郭病院（北海道）、久留米大学病院（福岡県）、順天堂大学医学部附属静岡病院（静岡県）、鳥取大学医学部附属病院（鳥取県）、大阪発達総合医療センター（大阪府）、あいち小児保健医療総合センター（愛知県）、北海道医療大学（北海道）、埼玉医科大学病院（埼玉県）、長野県立こども病院（長野県）、大分大学医学部附属病院（大分県）、筑波大学附属病院（茨城県）、豊橋市民病院（愛知県），名古屋第一日赤医療センター（愛知県）

Date of disclosure of the study information

2018

Year

09

Month

18

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

Results

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

No longer recruiting

Date of protocol fixation

2018

Year

05

Month

08

Day

Date of IRB

2018

Year

05

Month

08

Day

Anticipated trial start date

2018

Year

05

Month

08

Day

Last follow-up date

2022

Year

12

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Observational study of perinatal and infantile hypophosphatasia

Registered date

2018

Year

09

Month

14

Day

Last modified on

2022

Year

03

Month

18

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000037950