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

• ClinicalTrials.gov Identifier: NCT02882477
• Recruitment Status: Unknown
• First Posted: August 29, 2016
• Last Update Posted: August 29, 2016
• Sponsor: Hadassah Medical Organization
• Information provided by (Responsible Party): David Zangen, Hadassah Medical Organization

Study Description

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) .

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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 ]

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

Contact: David Zangen, Professor; 0097507874488; zangend@hadassah.org.il

Contact: Ulla Najwa Abdulhag, MD; 0097505172866; najwa.ped@gmail.com

Locations

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

• Principal Investigator: David Zangen, Professor; Head of pediatric endocrinology department

More Information

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
• 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:

Peptic Ulcer; Hearing Loss; Hearing Loss, Sensorineural; Wolfram Syndrome; Optic Atrophy; Metabolic Diseases; Iron Metabolism Disorders; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Deafness; Optic Nerve Diseases; Cranial Nerve Diseases; Eye Diseases; Deaf-Blind Disorders; Optic Atrophies, Hereditary; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Blindness; Vision Disorders; Eye Diseases, Hereditary; Diabetes Insipidus; Kidney Diseases; Urologic Diseases; Abnormalities, Multiple; Congenital Abnormalities; Genetic Diseases, Inborn