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Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin (Dysferlin)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01863004
Recruitment Status : Terminated (insufficient enrollment rate)
First Posted : May 27, 2013
Last Update Posted : September 21, 2017
Sponsor:
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland

Tracking Information
First Submitted Date  ICMJE April 29, 2013
First Posted Date  ICMJE May 27, 2013
Last Update Posted Date September 21, 2017
Study Start Date  ICMJE December 2012
Actual Primary Completion Date September 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 22, 2013)
Dysferlin protein expression levels change from baseline over 5 days assessed by repeated biopsies and blood draws in skeletal muscle and in blood monocytes following administration of a single dose of Bortezomib. [ Time Frame: repeated needle muscle biopsies over a five day period ]
Repeated needle muscle biopsies and blood draws will be performed after administration of a single dose of Bortezomib (Velcade) to assess dysferlin protein expression in skeletal muscle and in blood monocytes over a five day period.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin
Official Title  ICMJE Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin
Brief Summary Dysferlin is a protein with an important role in the repair of muscle surface membranes. Mutations in dysferlin cause different forms of muscular dystrophies. Dysferlinopathies are inherited in an autosomal recessive manner, and many patients with this disease harbor mis-sense mutations in at least one of their two pathogenic DYSF alleles. These patients have significantly reduced or absent dysferlin levels in skeletal muscle, suggesting that dysferlin encoded by mis-sense alleles is rapidly degraded by the cell's quality-control system. In a series of in-vitro experiments we showed that mis-sense mutated dysferlin can be salvaged from degradation by proteasomal inhibition. This resulted in an increase of functional dysferlin protein and a subsequent repair of plasma membranes of cultured patient-derived muscle cells. In this proof-of-concept study we would like to test wether proteasomal inhibition can salvage mis-sense mutated dysferlin in patients harboring certain dysferlin mis-sense mutations.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Dysferlinopathy
Intervention  ICMJE Drug: Bortezomib
Other Name: Velcade®
Study Arms  ICMJE Experimental: Bortezomib (Velcade®)

This study tests whether salvage of mis-sense mutated dysferlin through proteasomal inhibition seen in cultured muscle cells can be translated into patients harboring dysferlin mis-sense mutations. The proteasomal inhibitor Bortezomib (Velcade®) is already approved as a medication for the treatment of multiple myeloma in Switzerland and in other countries.

Following an administration of a single dose of Bortezomib repeated needle muscle biopsies and blood draws will be performed to assess dysferlin levels in skeletal muscle and blood monocytes over a five day period.

Intervention: Drug: Bortezomib
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 20, 2017)
3
Original Estimated Enrollment  ICMJE
 (submitted: May 22, 2013)
5
Actual Study Completion Date  ICMJE September 15, 2017
Actual Primary Completion Date September 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • must carry at least one allele of a salvageable mis-sense mutation of dysferlin
  • Age ≥ 18 years
  • Written informed consent

Exclusion Criteria:

  • Bleeding disorder
  • Acute or chronic kidney failure (CCL <50 ml/min)
  • Advanced liver disease or active hepatitis
  • Congestive heart failure NYHA III and IV
  • Pregnancy or nursing
  • Immunosuppression (prednisolone doses below 20 mg/d are allowed)
  • Therapy with strong inhibitors of cytochrome P450 3A4
  • HCV or HIV infection
  • Regular alcohol consumption (>14 drinks a week)
  • Drug addiction
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01863004
Other Study ID Numbers  ICMJE DYSF001A1
2011DR1148 ( Registry Identifier: Swissmedic Referenznummer 2011DR1148 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University Hospital, Basel, Switzerland
Study Sponsor  ICMJE University Hospital, Basel, Switzerland
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Michael Sinnreich, Prof. Dr. MD Sponsor-Investigator, Neuromuscular Center, Neurology Clinic, University Hospital Basel, Switzerland
PRS Account University Hospital, Basel, Switzerland
Verification Date September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP