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TerminatedNCT00668564Updated Dec 28, 2017Results posted

Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism

A Phase 2 interventional study of Stem Cell Transplantation and Cyclophosphamide in Hurler's Syndrome, Maroteaux-Lamy Syndrome and Sly Syndrome, sponsored by Masonic Cancer Center, University of Minnesota. Terminated at 1 site in United States. Open to participants aged Up to 21 Years. Per ClinicalTrials.gov, last updated 2017-12-28.

Sponsored by Masonic Cancer Center, University of Minnesota · Phase 2, Interventional, and Treatment

Why this study was terminated
Replaced by another study
Phase
Phase 2
Study type
Interventional
Enrollment
18
Allocation
Not applicable
Ages
Up to 21 Years
Sex
All
01

Study summary

The primary objective of this clinical trial is to evaluate the ability to achieve and sustain donor engraftment in patients with lysosomal and peroxisomal inborn errors of metabolism undergoing hematopoietic stem cell transplantation (HCT).

Read the detailed description

This has been an ongoing area of interest by our group at the Univ. of Minnesota, but this is a new protocol to take the place of several older protocols. While survival has been very good on the prior protocols over the past decade, incomplete engraftment has remained somewhat problematic. Therefore, we have modified the preparative regimen somewhat to increase engraftment by replacing anti-thymocyte globulin (ATG) with Campath-1H, a drug that is more immune suppressive. In addition, we have modified the supportive care regimen. Based on this, we will monitor levels of an anti-oxidant therapy (N-acetylcysteine) and biomarkers of inflammation and oxidative stress for the families that consent to these research studies.

02

Conditions studied

  • Hurler's Syndrome
  • Maroteaux-Lamy Syndrome
  • Sly Syndrome
  • Alpha Mannosidosis
  • Fucosidosis
  • Aspartylglucosaminuria
  • Sphingolipidoses
  • Krabbe Disease
  • Wolman's Disease
  • Niemann-Pick Disease Type B
  • Niemann-Pick Disease, Type C

Keywords

  • Inborn errors of metabolism
  • Sphingolipidoses
  • Recessive Leukodystrophies- GLD, Krabbe disease, MLD
  • Peroxisomal Disorders
  • Wolman syndrome
  • Niemann-Pick B patients
  • Niemann-Pick C subtype 2
03

Who can participate

Ages eligible
Up to 21 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Mucopolysaccharidosis (MPS) Disorders:

    • MPS IH (Hurler syndrome)
    • MPS-VI (Maroteaux-Lamy syndrome)
    • MPS VII (Sly syndrome).
  • Glycoprotein metabolic disorders:

    • Alpha mannosidosis
    • Fucosidosis
    • Aspartylglucosaminuria
  • Sphingolipidoses and Recessive Leukodystrophies: Presymptomatic patients with globoid cell leukodystrophy (GLD, also known as Krabbe disease) and metachromatic leukodystrophy (MLD) will be eligible for treatment on this protocol. White matter disease by magnetic resonance imaging (MRI) alone is not an exclusion if the patient is asymptomatic.
  • Peroxisomal Disorders: Presymptomatic patients with inherited peroxisomal disorders associated with of very long chain fatty acids (VLCFA) elevation, identified by family history or laboratory testing (including neonatal screening), are eligible for this protocol. White matter disease by MRI alone is not an exclusion if the patient is asymptomatic.
  • Other Inherited Diseases of Metabolism:

    • Wolman syndrome (acid lipase deficiency)
    • Niemann-Pick B patients (sphingomyelin deficiency)
    • Niemann-Pick C subtype 2
  • Donor Availability: Patients considered for transplantation must have a sufficient graft as based on current criteria of the University of Minnesota Blood and Marrow Transplantation Program: Priority will be as follows, although in circumstances in which timing is of the essence, cord blood grafts may be chosen over an unrelated graft, despite the priority listed above.
  • Multidisciplinary Evaluation: Patients will be eligible for transplantation only after they are seen and evaluated by members of the Inherited Metabolic and Storage Disease Program (IMSD) team, and the team has offered transplantation to the patient/family.

Exclusion criteria

Exclusion Criteria:

  • Symptomatic patients with peroxisomal or lysosomal disorders are excluded but may be considered for other treatment protocols.
  • Major organ dysfunction. Evidence of major organ impairment, including:

    • Cardiac: left ventricular ejection fraction \<40%
    • Renal: serum creatinine >2.5 x normal for age
    • Hepatic: total bilirubin >3 x normal, or Alanine transaminase (ALT) > 3 x normal
    • Pulmonary: requirement for continuous oxygen supplementation
  • Pregnancy
  • Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology
  • Patients >21 years of age.
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
18 participants (actual)

Study arms

  • Experimental
    Intent-to-Treat

    All patients treated with study regimen.

    Procedure: Stem Cell Transplantation · Drug: Cyclophosphamide · Drug: Campath-1H · Drug: Busulfan

Interventions

  • ProcedureStem Cell Transplantation

    The purpose of hematopoietic stem cell transplantation is to introduce blood producing cells from a normal donor. These cells can either provide what is missing in the body to the other cells, or can change the body's immune response to the substances that have accumulated in the body. These normal hematopoietic stem cells can come from bone marrow, peripheral blood (i.e., the blood circulating in our body's blood vessels) or umbilical cord blood (i.e., blood taken from the umbilical cord after a baby is born and umbilical cord is cut). The new donor cells repopulate the blood and bone marrow system and enter the organs of the body, including the brain. Wherever these cells go, they will produce the needed enzyme.

    Also known as: Bone Marrow Transplant, cord blood transplant

  • DrugCyclophosphamide

    Days before Transplant Drug Frequency * 4 Cyclophosphamide Once, given over 2 hours * 3 Cyclophosphamide Once, given over 2 hours * 2 Cyclophosphamide Once, given over 2 hours * 1 Cyclophosphamide Once, given over 2 hours

    Also known as: Cytoxan

  • DrugCampath-1H

    Days before Transplant Drug Frequency 12 Campath-1H Once, given over 2 hours 11 Campath-1H Once, given over 2 hours 10 Campath-1H Once, given over 2 hours

    Also known as: Alemtuzamab

  • DrugBusulfan

    Days before Transplant Drug Frequency 9 Busulfan Four times per day 8 Busulfan Four times per day 7 Busulfan Four times per day 6 Busulfan Four times per day

    Also known as: Busulfex

05

What researchers measure

Primary outcomes

  1. Number of Patients Achieving Engraftment

    Rate of successful engraftment - patients who achieved and sustained donor engraftment; donor chimerism by day 100 of at least 90% after undergoing hematopoietic stem cell transplantation.

    Time frame: Day 100

Secondary outcomes

  1. Overall Survival

    Number of patients alive at timepoints.

    Time frame: Day 100, 1 Year, 3 Years

06

Results

Posted Jul 13, 2011
Limitations and caveats
Other secondary objectives outlined in study protocol were not analyzed; number of patients were too few to be relevant.

Participant flow

Participant flow — Overall Study
MilestoneIntent-to-Treat
Started18
Completed18
Not completed0

Outcome measures

PrimaryNumber of Patients Achieving Engraftment

Rate of successful engraftment - patients who achieved and sustained donor engraftment; donor chimerism by day 100 of at least 90% after undergoing hematopoietic stem cell transplantation.

Time frame:
Day 100
Reported as:
Number · Participants
Number of Patients Achieving Engraftment
ParticipantsIntent-to-Treat
Number of Patients Achieving Engraftment14
SecondaryOverall Survival

Number of patients alive at timepoints.

Time frame:
Day 100, 1 Year, 3 Years
Reported as:
Number · Participants
Overall Survival
ParticipantsIntent-to-Treat
Day 10014
1 Year12

Adverse events

Collected over Day 1 through Day 100 post-transplant.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Intent-to-Treat—8/18 (44.4%)0/18 (0%)
Most frequent serious events
Most frequent serious events
EventIntent-to-Treat
DeathGeneral disorders6/18
Graft failureBlood and lymphatic system disorders2/18
Auto recoveryGeneral disorders2/18

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Intent-to-Treat
<=18 years18
Between 18 and 65 years0
>=65 years0
Age, Continuous
Age, Continuous(years)Intent-to-Treat
Mean4.7 ± 4.3
Sex: Female, Male
Sex: Female, Male(Participants)Intent-to-Treat
Female7
Male11
Region of Enrollment
Region of Enrollment(participants)Intent-to-Treat
United States18
07

Study locations

1 site
  • University of Minnesota, Fairview
    Minneapolis, Minnesota 55455, United States
08

References and documents

Publications

  • Miller WP, Rothman SM, Nascene D, Kivisto T, DeFor TE, Ziegler RS, Eisengart J, Leiser K, Raymond G, Lund TC, Tolar J, Orchard PJ. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011 Aug 18;118(7):1971-8. doi: 10.1182/blood-2011-01-329235. Epub 2011 May 17. PubMed 21586746 ↗
09

Registry details

Key details

Study ID
NCT00668564
Lead sponsor
Masonic Cancer Center, University of Minnesota
Responsible party
Sponsor
First posted
Apr 29, 2008
Start date
Mar 2008
Primary completion
Feb 2010
Completion
Feb 2010
Results posted
Jul 13, 2011
Last update
Dec 28, 2017

Study contacts

Paul Orchard, MD
principal investigator · University of Minnesota Medical Center

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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