UMIN-CTR Clinical Trial

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

Hypophosphatasia

Classification by specialty

Pediatrics

Classification by malignancy

Others

Genomic information

YES

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

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

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

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

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

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

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

Institute

Shimane University School of Medicine

Institute

Department

Personal name

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

Co-sponsor

National Institute of Advanced Industrial Science and Technology

Name of secondary funder(s)

Organization

Address

Tel

Email

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

島根大学医学部附属病院

Date of disclosure of the study information

2010

Year

07

Month

01

Day

URL releasing protocol

Publication of results

Published

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

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 related information

Registered date

2010

Year

06

Month

27

Day

Last modified on

2018

Year

01

Month

04

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000004613