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Recruitment status Completed
Unique ID issued by UMIN UMIN000003828
Receipt No. R000004613
Scientific Title Allogeneic Bone Marrow and Mesenchymal Stem Cell Transplantation for patients with severe Hypophosphatasia
Date of disclosure of the study information 2010/07/01
Last modified on 2018/01/04

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Basic information
Public title Allogeneic Bone Marrow and Mesenchymal Stem Cell Transplantation for patients with severe Hypophosphatasia
Acronym Allogeneic Bone Marrow and Mesenchymal Stem Cell Transplantation for patients with severe Hypophosphatasia
Scientific Title Allogeneic Bone Marrow and Mesenchymal Stem Cell Transplantation for patients with severe Hypophosphatasia
Scientific Title:Acronym Allogeneic Bone Marrow and Mesenchymal Stem Cell Transplantation for patients with severe Hypophosphatasia
Region
Japan

Condition
Condition Hypophosphatasia
Classification by specialty
Pediatrics
Classification by malignancy Others
Genomic information YES

Objectives
Narrative objectives1 Hypophosphatasia (HPP), which occurred with mutations of the liver/bone/kidney alkaline phosphatase (ALPL) gene cording tissue-nonspecific alkaline phosphatase (ALP), is one of the bone metabolic disorders. ALPL mutations result in the disturbance of bone and tooth mineralization and low levels of serum ALP activity. Clinical characteristics of HPP depend on age of onset. Especially, perinatal and infantile patients have a poor prognosis due to respiratory impairment. Phenotype in patients with HPP also is closely related to residual enzymatic activities defined by ALPL mutations. Nowadays, no curative treatment exists for HPP. Recently, two patients with infantile HPP underwent allogeneic BM transplantation (BMT) and subsequently one received mesenchymal stem cell transplantation (MSCT) and the other did bone fragments and osteoblast-like cells. We also performed allogeneic BMT, MSCT, osteoblast and osteogenic constructs implantation. These 3 patients clinically improved to some extent.
We, Shimane University and National Institute of Advanced Industrial Science and Technology, proceed with new therapeutic development of genetically-engineered MSCT for severe congenital bone metabolism disorders, which is one of the project for realization of regenerative medicine sponsored by Ministry of Education, Culture, Sports, Science and Technology. Specifically, we plan to transfect a normal ALP gene in MSCs harvested from patients with HPP and to transplant genetically-engineered autologous MSCs for the patients after safety of a gene-insertion site is confirmed. As preliminary steps for the project, we perform an allogeneic BMT and MSCT for the purpose of rescuing the patients with severe HPP.
Basic objectives2 Efficacy
Basic objectives -Others
Trial characteristics_1 Confirmatory
Trial characteristics_2 Explanatory
Developmental phase Phase II,III

Assessment
Primary outcomes rescuing the patients with severe hypophospatasia
Key secondary outcomes Height, Weight, alkaline phosphatase(ALP), bone-type ALP, Ca, P, substrates of ALP(phosphoethanolamine, pyridoxal 5-phosphate), Neutrohpil ALP score, X-ray of bone and chest, bone density, ability of bone formation

Base
Study type Interventional

Study design
Basic design Single arm
Randomization Non-randomized
Randomization unit
Blinding Open -no one is blinded
Control Uncontrolled
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms 1
Purpose of intervention Treatment
Type of intervention
Maneuver
Interventions/Control_1 1. BM harvest
1)Agreement about Harvesting BM
2)Harvest volume; 100-120ml
3)Anesthetic protocol; discuss by donor
2.BMT and MSCT
First, we perform allogeneic BMT, and then allogeneic MSCT from same BM donor. Only MSCT is repeatedly performed if the patient deteriorates symptoms after BMT and MSCT.
1)BMT
-Timing of BMT
as soon as possible after diagnosis
-Conditioning
Buslfan 0.9-1mg/kg/dose every 6 hours,
4days
Cyclophosphamide 50mg/kg/dose, 4days
Antithymocyte globulin 1.25mg/kg/dose,
4days
-Prophylaxis of GVHD
Methotrexate 10-15mg/m2/dose, 4days
Taclolimus, 0.02-0.04mg/kg/day, about
6 months
2)MSCT
-Cultured-Expansion of MSCs from BM
-Preservation of MSCs
-Timing of MSCT
About 14 to 21 days After BMT
-Administration route and volume
More than 106/kg is intravenously
injected.
-Administration of immunosuppressant drugs
-Taclolimus 0.02-0.04mg/kg/day, about 6 months
3. Examination period
From July 1, 2010 to March 31, 2013
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

Eligibility
Age-lower limit

Not applicable
Age-upper limit
6 months-old >=
Gender Male and Female
Key inclusion criteria 1. Criteria for patient (severe-type HPP) inclusion
1)Age at onset is less than 6-month old
2)ALP activity less than the normal range
3)Bone symptoms including hypomineralization, fracture, long-bone deformity
4)Respiratory impairment
5)ALPL mutations bringing down low ALP activity
6)Reduced activity of bone formation in MSCs
2.Criteria for BM donor
We need to select BM donor because this clinical trial uses BM and BM-derived MSC. Criteria for BM donor are as follows;
1)Second-degree family of the patient
2)No symptom of hypomineralization
3)Normal activity of ALP
4)ALPL gene
-Wild type
-ALPL mutations with normal activity of ALP
5)HLA
-Identical donor
-If HLA is mismatched, severe
treatment-related complication and
graft failure are less likely to
occur.
6)Negative infections including HIV, HBV, HCV, and HTLV1
7)Age preference
-Adult
-If a child becomes a BM donor, we must confirm the following.
#Adult-donor candidates have bone
symptoms with ALPL mutations and are
HLA mismatched donors from who the
patient is likely to develop severe
complications such as graft failure
or GVHD.
#Minor human rights
#Minor informed consent
#Deliberation in a local ethical
committee
#Explanation from doctor, medical
social worker, and transplantation
coordinator
Key exclusion criteria 1. Objective
Patients with non-severe HPP
Patients wothuout inclusion criteria
2. BM donor
Patients wothuout inclusion criteria
Target sample size 5

Research contact person
Name of lead principal investigator
1st name
Middle name
Last name Takeshi Taketani
Organization Shimane University Hospital
Division name Division of Blood Transfusion
Zip code
Address 89-1, Enya, Izumo, Shimane, 693-8501, Japan
TEL 0853-20-2409
Email ttaketani@med.shimane-u.ac.jp

Public contact
Name of contact person
1st name
Middle name
Last name Takeshi Taketani
Organization Shimane University Hospital
Division name Division of Blood Transfusion
Zip code
Address 89-1, Enya, Izumo, Shimane, 693-8501, Japan
TEL 0853-20-2409
Homepage URL
Email ttaketani@med.shimane-u.ac.jp

Sponsor
Institute Shimane University School of Medicine
Institute
Department

Funding Source
Organization Research on Regenerative Medicine for Clinical Application, Ministry of Health, Labour and Welfare
Organization
Division
Category of Funding Organization Japanese Governmental office
Nationality of Funding Organization

Other related organizations
Co-sponsor National Institute of Advanced Industrial Science and Technology
Name of secondary funder(s)

IRB Contact (For public release)
Organization
Address
Tel
Email

Secondary IDs
Secondary IDs NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions 島根大学医学部附属病院

Other administrative information
Date of disclosure of the study information
2010 Year 07 Month 01 Day

Related information
URL releasing protocol
Publication of results Published

Result
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

Progress
Recruitment status Completed
Date of protocol fixation
2010 Year 06 Month 21 Day
Date of IRB
Anticipated trial start date
2010 Year 07 Month 01 Day
Last follow-up date
2016 Year 03 Month 31 Day
Date of closure to data entry
2017 Year 09 Month 30 Day
Date trial data considered complete
2017 Year 11 Month 30 Day
Date analysis concluded
2017 Year 12 Month 31 Day

Other
Other related information

Management information
Registered date
2010 Year 06 Month 27 Day
Last modified on
2018 Year 01 Month 04 Day


Link to view the page
URL(English) https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000004613

Research Plan
Registered date File name

Research case data specifications
Registered date File name

Research case data
Registered date File name


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