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Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy

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ClinicalTrials.gov Identifier: NCT02882477
Recruitment Status : Unknown
Verified August 2016 by David Zangen, Hadassah Medical Organization.
Recruitment status was:  Not yet recruiting
First Posted : August 29, 2016
Last Update Posted : August 29, 2016
Sponsor:
Information provided by (Responsible Party):
David Zangen, Hadassah Medical Organization

Brief Summary:
Patients who are genetically diagnosed with the recently reported and rare Wolfram syndrome type 2 ( WFS2) and have the degenerative and symptomatic disease including signs such as diabetes, platelet aggregation defect or visual problems will be asked to participate in this study. Knowing the pathomechanism of WFS2 with rapid cell death, after doing baseline investigations to asses the severity of their disease, the participants will be offered a chelator therapy with in addition to the antioxidant Acetylcystein, in diabetic patients an Incertin (GLP-1 ) therapy will be offered as well. The baseline investigations will be repeated after 2 months and after 5 months of therapy in order to asses the progression of the disease and to show if the chelator and anti oxidant therapy and in diabetic patients the GLP-1 therapy could stop the progression of the disease.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus Iron Metabolism Disorders Gastroduodenal Ulcer Optic Atrophy Sensorineural Hearing Loss Platelet Dysfunction Drug: Deferiprone Drug: Acetylcysteine Drug: Sitagliptin and Metformin Phase 2 Phase 3

Detailed Description:

In WFS2 mutation the protein nutrient-deprivation autophagy factor-1(NAF-1) is affected.

Given the known result of NAF-1 protein dysfunction in animal and cultured cell line models namely a toxic accumulation of iron in the mitochondria,leading to mitochondrial destruction and oxidative stress we aim to obtain fibroblast samples from the patients and (use laboratory fibroblasts from healthy subjects as controls) These cell cultures will initially be studied for intracellular iron accumulation and then re-evaluated following treatment by Deferiprone and/or Glucagon-like peptide 1 (GLP-1) ex-vivo in the laboratory .

If repeated (n>=3) histological evidence confirms the beneficial effect of Deferiprone and/or GLP-1(incertin based therapy) in the patient's cultured fibroblasts by reversing the toxic iron accumulation in the patient's mitochondria to a normal level, he/she will be offered "in vivo" therapy using the oral chelating agent - with or without dipeptidylpeptidase-4 inhibitor (DPP-4) inhibitors or GLP-1 receptor agonists. Adding GLP-1 based therapy will depend on the diabetic status of the patient.

Prior and following 60 and 150 days of Chelator and/or GLP-1 therapy they will go through the following clinical and laboratory evaluations which will establish the baseline and post therapeutic parameters (outcome) to be compared:

detailed medical history and physical examination complete blood count (CBC) and iron levels platelet aggregation studies Fundoscopy and visual evoked potentials (VEP) Hearing evaluation Oral glucose Tolerance Test optional Intra venous glucose tolerance test (IVGTT) /glucagon/arginine test HBA1C Daily profile of blood glucose Optional CGMS ( continuous glucose monitoring system) Gastroscopy and gastric biopsy if the patient suffers from abdominal pain, hematemesis, melena or iron deficiency anemia or if peptic ulcer disease is clinically suspected.

Based on the routine use of the iron chelator, FDA approved, Deferiprone for Thalassemia (with detailed official guidelines of the Israel association for Pediatric Hematology) and for a similar subcellular iron accumulating disease - e.g. Friedreich Ataxia, we will initially use a dose of 20 mg per kilogram body weight (BW) daily divided in two equal doses. N-Acetylcystein an over the counter drug which also is an anti-oxidant will be given orally in the dose of 200mg twice daily to have a synergistic effect with Deferiprone.

In addition if they suffer from diabetes they will receive Januet (Sitagliptin/metformin) .

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone, and Incretin Based Therapy
Study Start Date : December 2016
Estimated Primary Completion Date : May 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: Deferiprone and Acetylcystein
PO Deferiprone 20 mg/kg divided in 2 doses PO Acetylcysteine 200 mg divided in 2 doses 5 months duration
Drug: Deferiprone
Other Name: Ferriprox

Drug: Acetylcysteine
Other Name: Reolin

Experimental: Deferiprone and Acetylcystein with Sitagliptin and Metformin
PO Deferiprone 20 mg/kg divided in 2 doses PO Acetylcysteine 200mg divided in 2 doses PO Januet 50/500 if BW < 30kg and 50/850 if BW> 30kg *2/D 5 months duration
Drug: Deferiprone
Other Name: Ferriprox

Drug: Acetylcysteine
Other Name: Reolin

Drug: Sitagliptin and Metformin
Other Name: Januet




Primary Outcome Measures :
  1. Insulin levels in blood in response to Glucose Challenge - Oral Glucose tolerance test (OGTT ) and Intra venous glucose tolerance test (IVGTT) [ Time Frame: 5 months ]
  2. Platelet aggregation to Adenosine diphosphate (ADP) and Collagen - blood test for Platelet function test [ Time Frame: 5 months ]
  3. Nerve conduction velocity in VEP [ Time Frame: 5 months ]
  4. HBA1C level [ Time Frame: 5 months ]
  5. daily glucose level measurement in the blood using Glucometer two to 5 times daily [ Time Frame: 5 months ]
  6. C-Peptide levels in blood in response to Glucose Challenge - Oral Glucose tolerance test ( OGTT ) and Intra venous glucose tolerance test IVGTT [ Time Frame: 5 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   3 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female patients, of any age genetically and clinically diagnosed with Wolfram syndrome type 2.

Exclusion Criteria:

  • Patients who are non-cooperative.
  • Patients with bone marrow disease or neutropenia.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02882477


Contacts
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Contact: David Zangen, Professor 0097507874488 zangend@hadassah.org.il
Contact: Ulla Najwa Abdulhag, MD 0097505172866 najwa.ped@gmail.com

Locations
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Israel
Hadassah medical center
Jerusalem, Israel
Contact: David Zangen, Professor    0097507874488    zanegnd@hadassah.org.il   
Contact: Ulla Najwa Abdulhag, MD    0097505172866    najwa.ped@gmail.com   
Sponsors and Collaborators
Hadassah Medical Organization
Investigators
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Principal Investigator: David Zangen, Professor Head of pediatric endocrinology department

Publications:

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Responsible Party: David Zangen, Professor, Hadassah Medical Organization
ClinicalTrials.gov Identifier: NCT02882477    
Other Study ID Numbers: 0003-16-HMO
First Posted: August 29, 2016    Key Record Dates
Last Update Posted: August 29, 2016
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Peptic Ulcer
Hearing Loss
Hearing Loss, Sensorineural
Wolfram Syndrome
Optic Atrophy
Metabolic Diseases
Iron Metabolism Disorders
Atrophy
Pathological Conditions, Anatomical
Hearing Disorders
Ear Diseases
Otorhinolaryngologic Diseases
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Deafness
Optic Nerve Diseases
Cranial Nerve Diseases
Eye Diseases
Duodenal Diseases
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Stomach Diseases
Deaf-Blind Disorders
Optic Atrophies, Hereditary
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Blindness