UMIN-CTR Clinical Trial

Basic information
Official scientific title of the study	Allogeneic Bone Marrow and Mesenchymal Stem Cell Transplantation for patients with severe Hypophosphatasia
Title of the study (Brief title)	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	Takeshi Taketani
Organization	Shimane University Hospital
Division name	Division of Blood Transfusion
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	Takeshi Taketani
Organization	Shimane University Hospital
Division name	Division of Blood Transfusion
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)

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

Progress
Recruitment status	Completed
Date of protocol fixation	2010 Year 06 Month 21 Day
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

Related information
URL releasing protocol
Publication of results	Published
URL releasing results
Results
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/icdr_e/ctr_view.cgi?recptno=R000004613