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The Safety and Tolerability of Kinetin, in Patients With Familial Dysautonomia

Primary Purpose

Familial Dysautonomia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Kinetin
Sponsored by
NYU Langone Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Familial Dysautonomia

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male of female patients aged 16 and older
  2. Confirmed diagnosis of familial dysautonomia by genetic testing
  3. Written informed consent to participate in the trial and understanding that they can withdraw consent at anytime without affecting their future care.
  4. Ability to comply with the requirements of the study procedures.

Exclusion Criteria:

  1. Patients who have taken other nutritional supplements that may affect IKAP mRNA splicing within the last 30 days
  2. Patients with a known hypersensitivity to any component of the nutritional supplement kinetin
  3. Patients with atrial fibrillation, angina or an electrocardiogram documenting significant abnormality that may jeopardize the patient's health.
  4. Patients with significant pulmonary, liver, renal (creatinine >2.5 mg/ml) or cardiac illness
  5. Women who are pregnant or lactating
  6. Women of childbearing potential who are not using medically accepted methods of contraception.
  7. Patients who have a significant abnormality on clinical examination that may, in the investigator's opinion, jeopardize their healthy participating in this pilot trial.
  8. Patients taking allopurinol, other xanthine oxidase inhibitors or other compounds that may interfere with the metabolism of kinetin including oral calcium supplements.

Sites / Locations

  • NYU Langone Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Kinetin

Arm Description

Kinetin titration phase to 30mg/kg dose or individual max dose taken once daily. Patients will then proceed to steady state long-term phase at maximum individual dose of kinetin over a 3 year period.

Outcomes

Primary Outcome Measures

Change in Safety blood labs
safety blood labs (CBC, metabolic panel)
Change in vital signs
Sitting and standing blood pressure measurements and heart rate
Change in ECG
12 lead ECG measures
Number of participants with adverse events
Number of adverse events

Secondary Outcome Measures

Full Information

First Posted
October 21, 2014
Last Updated
June 14, 2019
Sponsor
NYU Langone Health
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1. Study Identification

Unique Protocol Identification Number
NCT02274051
Brief Title
The Safety and Tolerability of Kinetin, in Patients With Familial Dysautonomia
Official Title
The Safety and Tolerability of Kinetin, a Nutritional Supplement That Corrects the Splicing Defect, in Patients With Familial Dysautonomia
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Completed
Study Start Date
November 2009 (undefined)
Primary Completion Date
May 4, 2019 (Actual)
Study Completion Date
May 4, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
NYU Langone Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a study of kinetin, a nutritional supplement that corrects the mRNA splicing defect in patients with familial dysautonomia (FD, also known as Riley Day syndrome or hereditary sensory and autonomic neuropathy type III). FD is a rare fatal autosomal recessive disease in which the growth and development of selective neuronal populations is impaired. The disease is the result of a point mutation in the gene sequence that encodes for kinase complex associated protein (IKAP) in chromosome 9q31. The mutation, at the start of the non-encoding intron 20, weakens the splice site, causing the spliceosome to wrongly join together exons 19 and 21 when transcribing the mRNA strand and miss out exon 20. The mutated mRNA produces a short unstable IKAP protein that is quickly degraded. Interestingly, the mutation does not lead to a complete loss of function. Instead, it results in a tissue specific deficiency in splicing efficiency with both normal (wild type) and mutant IKAP mRNA being expressed in different ratios in different tissues. Some cells, like fibroblasts, produce mostly normal mRNA and protein, where as others, like neurons, produce mostly mutant mRNA and almost no functional protein product.
Detailed Description
Familial dysautonomia (FD, also called Riley Day syndrome or hereditary sensory and autonomic neuropathy type III) is an autosomal recessive disease caused by a point mutation in the kinase complex associated protein (IKAP) gene sequence (1, 2). This leads to a tissue specific splicing defect with variable "skipping" of exon 20 (1, 3, 4). The consequence is a devastating congenital sensory neuropathy, affecting pain and temperature perception (5) as well as afferent information from the viscera (6). As a result, patients suffer recurrent aspiration pneumonias, respiratory insufficiency, proprioceptive ataxia, scoliosis and the long-term consequences of volatile blood pressure including renal failure (7) and left ventricular hypertrophy (8). In-vitro studies have shown that the plant hormone kinetin corrects the splicing defect and increases the production of normal IKAP protein levels in FD derived cell lines (9, 10). Preliminary studies in heterozygous carriers of the IKAP mutation showed that dietary supplementation with kinetin increased the production of correctly spliced IKAP mRNA, in white blood cells (11). Preliminary studies in patients with FD have demonstrated that kinetin also increases the expression of correctly spliced IKAP mRNA extracted from white blood cells. However, the effect of kinetin on mRNA levels in neuronal tissue is unknown. The overall objective of this study is to assess the safety and tolerability of administering kinetin in patients with FD. The specific aim of this proposal is to determine the safety of a once daily dose of kinetin in patients with FD using a dose ascending titration and to determine the long-term safety and tolerability during 3-years of receiving a maximum tolerated steady state dose of kinetin. The investigators hope to also demonstrate early proof of concept that kinetin enhances the ability of neuronal tissue to correctly splice IKAP mRNA.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Familial Dysautonomia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Kinetin
Arm Type
Experimental
Arm Description
Kinetin titration phase to 30mg/kg dose or individual max dose taken once daily. Patients will then proceed to steady state long-term phase at maximum individual dose of kinetin over a 3 year period.
Intervention Type
Dietary Supplement
Intervention Name(s)
Kinetin
Intervention Description
Titration of Kinetin to maximum individualized dose, then steady state over a 3 year period once daily dose.
Primary Outcome Measure Information:
Title
Change in Safety blood labs
Description
safety blood labs (CBC, metabolic panel)
Time Frame
At baseline and after each 6 months period and at 36 months
Title
Change in vital signs
Description
Sitting and standing blood pressure measurements and heart rate
Time Frame
At baseline and after each 6 months period and at 36 months
Title
Change in ECG
Description
12 lead ECG measures
Time Frame
At baseline and after each 6 months period and at 36 months
Title
Number of participants with adverse events
Description
Number of adverse events
Time Frame
At baseline and after each 6 months period and at 36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male of female patients aged 16 and older Confirmed diagnosis of familial dysautonomia by genetic testing Written informed consent to participate in the trial and understanding that they can withdraw consent at anytime without affecting their future care. Ability to comply with the requirements of the study procedures. Exclusion Criteria: Patients who have taken other nutritional supplements that may affect IKAP mRNA splicing within the last 30 days Patients with a known hypersensitivity to any component of the nutritional supplement kinetin Patients with atrial fibrillation, angina or an electrocardiogram documenting significant abnormality that may jeopardize the patient's health. Patients with significant pulmonary, liver, renal (creatinine >2.5 mg/ml) or cardiac illness Women who are pregnant or lactating Women of childbearing potential who are not using medically accepted methods of contraception. Patients who have a significant abnormality on clinical examination that may, in the investigator's opinion, jeopardize their healthy participating in this pilot trial. Patients taking allopurinol, other xanthine oxidase inhibitors or other compounds that may interfere with the metabolism of kinetin including oral calcium supplements.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Horacio Kaufmann, MD
Organizational Affiliation
NYU School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
NYU Langone Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States

12. IPD Sharing Statement

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The Safety and Tolerability of Kinetin, in Patients With Familial Dysautonomia

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