4006-776-356 出国就医服务电话

免费获得国外相关药品，最快 1 个工作日回馈药物信息

出境医 / 临床实验 / Niacin Supplementation in Healthy Controls and Mitochondrial Myopathy Patients (NiaMIT)

Niacin Supplementation in Healthy Controls and Mitochondrial Myopathy Patients (NiaMIT)

Study Description
Brief Summary:

The most frequent form of adult-onset mitochondrial disorders is mitochondrial myopathy, often manifesting with progressive external ophthalmoplegia (PEO), progressive muscle weakness and exercise intolerance. Mitochondrial myopathy is often caused by single heteroplasmic mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions, the former being sporadic and latter caused by mutations in nuclear-encoded proteins of mtDNA maintenance. Currently, no curative treatment exists for this disease. The investigators have previously observed that supplementation with an NAD+ precursor vitamin B3, nicotinamide riboside, prevented and delayed disease symptoms by increasing mitochondrial biogenesis in a mouse model for mitochondrial myopathy. Vitamin B3 exists in several forms: nicotinic acid (niacin), nicotinamide, and nicotinamide riboside, and it has been demonstrated to give power to diseased mitochondria in animal studies by increasing intracellular levels of NAD+, the important cofactor required for the cellular energy metabolism.

In this study, the form of vitamin B3, niacin, was used to activate dysfunctional mitochondria and to rescue signs of mitochondrial myopathy. Of the vitamin B3 forms, niacin, is employed, because it has been used in large doses to treat hypercholesterolemia patients, and has a proven safety record in humans. Phenotypically similar mitochondrial myopathy patients are studied, as the investigator's previous expertise indicates that similar presenting phenotypes predict uniform physiological and clinical responses to interventions, despite varying genetic backgrounds. Patients either with sporadic single mtDNA deletions or a mutation in a Twinkle gene causing multiple mtDNA deletions were recruited. In addition, for every patient, two gender- and age-matched healthy controls are recruited. Clinical examinations and collection of muscle biopsies are performed at the time points 0, 4 and 10 months (patients) or at 0 and 4 months (controls). Fasting blood samples are collected every second week until 4 months and thereafter every six weeks until the end of the study. The effects of niacin on disease markers, muscle mitochondrial biogenesis, muscle strength and the metabolism of the whole body are studied in patients and healthy controls.

The hypothesis is that an NAD+ precursor, niacin, will increase intracellular NAD+ levels, improve mitochondrial biogenesis and alleviate the symptoms of mitochondrial myopathy in humans.


Condition or disease Intervention/treatment Phase
Mitochondrial Myopathies Dietary Supplement: Niacin Not Applicable

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: All participants (healthy controls and mitochondrial myopathy patients) receive orally administered a slow-released form of niacin.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Effect of Niacin Supplementation on Systemic Nicotinamide Adenine Dinucleotide (NAD+) Metabolism, Physiology and Muscle Performance in Healthy Controls and Mitochondrial Myopathy Patients
Actual Study Start Date : June 1, 2014
Actual Primary Completion Date : December 31, 2017
Actual Study Completion Date : December 31, 2018
Arms and Interventions
Arm Intervention/treatment
Experimental: Niacin in controls
The arm includes healthy controls supplemented with niacin.
 Dietary Supplement: Niacin
The dose for a slow-released form of niacin will be 750-1000 mg/day. The daily niacin dose, 250 mg/day, is gradually escalated by 250 mg/month so that the full dose is reached after 3 months. The intervention time with the full niacin dose is 1 and 7 months for controls and patients, respectively, and subsequently total intervention time 4 and 10 months, respectively. At the end of the study, the daily dose will be decreased by 250 mg/month rate.
Other Name: Nicotinic acid
Experimental: Niacin in mitochondrial myopathy patients
The arm includes mitochondrial myopathy patients supplemented with niacin.
 Dietary Supplement: Niacin
The dose for a slow-released form of niacin will be 750-1000 mg/day. The daily niacin dose, 250 mg/day, is gradually escalated by 250 mg/month so that the full dose is reached after 3 months. The intervention time with the full niacin dose is 1 and 7 months for controls and patients, respectively, and subsequently total intervention time 4 and 10 months, respectively. At the end of the study, the daily dose will be decreased by 250 mg/month rate.
Other Name: Nicotinic acid
Outcome Measures
Primary Outcome Measures :
  1. NAD+ and related metabolite levels in blood and muscle [ Time Frame: Baseline, 4 months and 10 months ]
    Change in concentrations of NAD+ and related metabolites such as: nicotinamide adenine dinucleotide phosphate, nicotinic acid adenine dinucleotide, nicotinamide, and nicotinamide mononucleotide measured using high performance liquid chromatography-mass spectrometry


Secondary Outcome Measures :
  1. Number of diseased muscle fibers [ Time Frame: Baseline, 4 months and 10 months ]
    Change in number of abnormal muscle fibers (frozen sections, in situ histochemical activity analysis of cytochrome c oxidase negative / succinate-dehydrogenase positive muscle fibers; and immunohistochemistry of complex I negative muscle fibers

  2. Mitochondrial biogenesis [ Time Frame: Baseline, 4 months and 10 months ]
    Change in mitochondria immunohistochemical staining intensity

  3. Muscle mitochondrial oxidative capacity [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle histochemical activity of mitochondrial cytochrome c oxidase

  4. Muscle metabolomic profile [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle metabolite concentrations measured with mass spectrometry

  5. Core muscle strength [ Time Frame: Baseline, 4 months and 10 months ]
    Change in core muscle strength measured by static and dynamic back and abdominal strength tests (number of repeats)

  6. Circulating levels of disease biomarkers, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15) [ Time Frame: Baseline, 4 months and 10 months ]
    Change in circulating FGF21 and GDF15 concentrations measured using ELISA kits

  7. Muscle mitochondrial DNA deletions [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification

  8. Muscle transcriptomic profile [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle gene expression determined using RNA sequencing approach


Other Outcome Measures:
  1. Body weight and body composition [ Time Frame: Baseline, 4 months and 10 months ]
    Change in body weight as well as fat mass and fat free mass measured with bioimpedance

  2. Ectopic lipid accumulation, i.e. liver and muscle lipid content [ Time Frame: Baseline, 4 months and 10 months ]
    Change in liver and muscle fat content measured with proton magnetic resonance spectroscopy

  3. Circulating lipid profiles [ Time Frame: Baseline, 4 months and 10 months ]
    Change in circulating HDL, LDL and triglyceride concentrations measured using standard photometric enzymatic assay


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   17 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Manifestation of pure mitochondrial myopathy, with no major other symptoms or manifestations, caused by single or multiple deletions of mtDNA
  2. Age and gender matched healthy controls for every patient
  3. Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 forms 14 days prior to the enrollment and during the study
  4. Written, informed consent to participate in the study

Exclusion Criteria:

  1. Inability to follow study protocol
  2. Pregnancy or breast-feeding at any time of the trial
  3. Malignancy that requires continuous treatment
  4. Unstable heart disease
  5. Severe kidney disease requiring treatment
  6. Severe encephalopathy
  7. Regular usage of intoxicants
Contacts and Locations

Sponsors and Collaborators
University of Helsinki
Helsinki University Central Hospital
Institute for Molecular Medicine
University of Iowa
Investigators
Layout table for investigator information
Principal Investigator: Anu Suomalainen Wartiovaara, MD,PhD Research Programs Unit, University of Helsinki, Helsinki, Finland
Tracking Information
First Submitted Date  ICMJE May 24, 2019
First Posted Date  ICMJE June 4, 2019
Last Update Posted Date June 4, 2019
Actual Study Start Date  ICMJE June 1, 2014
Actual Primary Completion Date December 31, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 31, 2019) 		NAD+ and related metabolite levels in blood and muscle [ Time Frame: Baseline, 4 months and 10 months ]
Change in concentrations of NAD+ and related metabolites such as: nicotinamide adenine dinucleotide phosphate, nicotinic acid adenine dinucleotide, nicotinamide, and nicotinamide mononucleotide measured using high performance liquid chromatography-mass spectrometry
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: May 31, 2019)
  • Number of diseased muscle fibers [ Time Frame: Baseline, 4 months and 10 months ]
    Change in number of abnormal muscle fibers (frozen sections, in situ histochemical activity analysis of cytochrome c oxidase negative / succinate-dehydrogenase positive muscle fibers; and immunohistochemistry of complex I negative muscle fibers
  • Mitochondrial biogenesis [ Time Frame: Baseline, 4 months and 10 months ]
    Change in mitochondria immunohistochemical staining intensity
  • Muscle mitochondrial oxidative capacity [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle histochemical activity of mitochondrial cytochrome c oxidase
  • Muscle metabolomic profile [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle metabolite concentrations measured with mass spectrometry
  • Core muscle strength [ Time Frame: Baseline, 4 months and 10 months ]
    Change in core muscle strength measured by static and dynamic back and abdominal strength tests (number of repeats)
  • Circulating levels of disease biomarkers, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15) [ Time Frame: Baseline, 4 months and 10 months ]
    Change in circulating FGF21 and GDF15 concentrations measured using ELISA kits
  • Muscle mitochondrial DNA deletions [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification
  • Muscle transcriptomic profile [ Time Frame: Baseline, 4 months and 10 months ]
    Change in muscle gene expression determined using RNA sequencing approach
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: May 31, 2019)
  • Body weight and body composition [ Time Frame: Baseline, 4 months and 10 months ]
    Change in body weight as well as fat mass and fat free mass measured with bioimpedance
  • Ectopic lipid accumulation, i.e. liver and muscle lipid content [ Time Frame: Baseline, 4 months and 10 months ]
    Change in liver and muscle fat content measured with proton magnetic resonance spectroscopy
  • Circulating lipid profiles [ Time Frame: Baseline, 4 months and 10 months ]
    Change in circulating HDL, LDL and triglyceride concentrations measured using standard photometric enzymatic assay
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Niacin Supplementation in Healthy Controls and Mitochondrial Myopathy Patients
Official Title  ICMJE The Effect of Niacin Supplementation on Systemic Nicotinamide Adenine Dinucleotide (NAD+) Metabolism, Physiology and Muscle Performance in Healthy Controls and Mitochondrial Myopathy Patients
Brief Summary

The most frequent form of adult-onset mitochondrial disorders is mitochondrial myopathy, often manifesting with progressive external ophthalmoplegia (PEO), progressive muscle weakness and exercise intolerance. Mitochondrial myopathy is often caused by single heteroplasmic mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions, the former being sporadic and latter caused by mutations in nuclear-encoded proteins of mtDNA maintenance. Currently, no curative treatment exists for this disease. The investigators have previously observed that supplementation with an NAD+ precursor vitamin B3, nicotinamide riboside, prevented and delayed disease symptoms by increasing mitochondrial biogenesis in a mouse model for mitochondrial myopathy. Vitamin B3 exists in several forms: nicotinic acid (niacin), nicotinamide, and nicotinamide riboside, and it has been demonstrated to give power to diseased mitochondria in animal studies by increasing intracellular levels of NAD+, the important cofactor required for the cellular energy metabolism.

In this study, the form of vitamin B3, niacin, was used to activate dysfunctional mitochondria and to rescue signs of mitochondrial myopathy. Of the vitamin B3 forms, niacin, is employed, because it has been used in large doses to treat hypercholesterolemia patients, and has a proven safety record in humans. Phenotypically similar mitochondrial myopathy patients are studied, as the investigator's previous expertise indicates that similar presenting phenotypes predict uniform physiological and clinical responses to interventions, despite varying genetic backgrounds. Patients either with sporadic single mtDNA deletions or a mutation in a Twinkle gene causing multiple mtDNA deletions were recruited. In addition, for every patient, two gender- and age-matched healthy controls are recruited. Clinical examinations and collection of muscle biopsies are performed at the time points 0, 4 and 10 months (patients) or at 0 and 4 months (controls). Fasting blood samples are collected every second week until 4 months and thereafter every six weeks until the end of the study. The effects of niacin on disease markers, muscle mitochondrial biogenesis, muscle strength and the metabolism of the whole body are studied in patients and healthy controls.

The hypothesis is that an NAD+ precursor, niacin, will increase intracellular NAD+ levels, improve mitochondrial biogenesis and alleviate the symptoms of mitochondrial myopathy in humans.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
All participants (healthy controls and mitochondrial myopathy patients) receive orally administered a slow-released form of niacin.
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Mitochondrial Myopathies
Intervention  ICMJE Dietary Supplement: Niacin
The dose for a slow-released form of niacin will be 750-1000 mg/day. The daily niacin dose, 250 mg/day, is gradually escalated by 250 mg/month so that the full dose is reached after 3 months. The intervention time with the full niacin dose is 1 and 7 months for controls and patients, respectively, and subsequently total intervention time 4 and 10 months, respectively. At the end of the study, the daily dose will be decreased by 250 mg/month rate.
Other Name: Nicotinic acid
Study Arms  ICMJE
  • Experimental: Niacin in controls
    The arm includes healthy controls supplemented with niacin.
    Intervention: Dietary Supplement: Niacin
  • Experimental: Niacin in mitochondrial myopathy patients
    The arm includes mitochondrial myopathy patients supplemented with niacin.
    Intervention: Dietary Supplement: Niacin
Publications *
  • Suomalainen A, Battersby BJ. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat Rev Mol Cell Biol. 2018 Feb;19(2):77-92. doi: 10.1038/nrm.2017.66. Epub 2017 Aug 9. Review.
  • Ylikallio E, Suomalainen A. Mechanisms of mitochondrial diseases. Ann Med. 2012 Feb;44(1):41-59. doi: 10.3109/07853890.2011.598547. Epub 2011 Aug 2.
  • Rajman L, Chwalek K, Sinclair DA. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab. 2018 Mar 6;27(3):529-547. doi: 10.1016/j.cmet.2018.02.011. Review.
  • Khan NA, Auranen M, Paetau I, Pirinen E, Euro L, Forsström S, Pasila L, Velagapudi V, Carroll CJ, Auwerx J, Suomalainen A. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol Med. 2014 Jun;6(6):721-31. doi: 10.1002/emmm.201403943.
  • Cerutti R, Pirinen E, Lamperti C, Marchet S, Sauve AA, Li W, Leoni V, Schon EA, Dantzer F, Auwerx J, Viscomi C, Zeviani M. NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. Cell Metab. 2014 Jun 3;19(6):1042-9. doi: 10.1016/j.cmet.2014.04.001. Epub 2014 May 8.
  • Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol. 2007 Mar 19;99(6A):22C-31C. Epub 2006 Nov 28. Review.
  • Vosper H. Niacin: a re-emerging pharmaceutical for the treatment of dyslipidaemia. Br J Pharmacol. 2009 Sep;158(2):429-41. doi: 10.1111/j.1476-5381.2009.00349.x. Epub 2009 Jul 20. Review.
  • Ahola S, Auranen M, Isohanni P, Niemisalo S, Urho N, Buzkova J, Velagapudi V, Lundbom N, Hakkarainen A, Muurinen T, Piirilä P, Pietiläinen KH, Suomalainen A. Modified Atkins diet induces subacute selective ragged-red-fiber lysis in mitochondrial myopathy patients. EMBO Mol Med. 2016 Nov 2;8(11):1234-1247. doi: 10.15252/emmm.201606592. Print 2016 Nov.
  • Suomalainen A, Elo JM, Pietiläinen KH, Hakonen AH, Sevastianova K, Korpela M, Isohanni P, Marjavaara SK, Tyni T, Kiuru-Enari S, Pihko H, Darin N, Õunap K, Kluijtmans LA, Paetau A, Buzkova J, Bindoff LA, Annunen-Rasila J, Uusimaa J, Rissanen A, Yki-Järvinen H, Hirano M, Tulinius M, Smeitink J, Tyynismaa H. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol. 2011 Sep;10(9):806-18. doi: 10.1016/S1474-4422(11)70155-7. Epub 2011 Aug 3.
  • Nikkanen J, Forsström S, Euro L, Paetau I, Kohnz RA, Wang L, Chilov D, Viinamäki J, Roivainen A, Marjamäki P, Liljenbäck H, Ahola S, Buzkova J, Terzioglu M, Khan NA, Pirnes-Karhu S, Paetau A, Lönnqvist T, Sajantila A, Isohanni P, Tyynismaa H, Nomura DK, Battersby BJ, Velagapudi V, Carroll CJ, Suomalainen A. Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism. Cell Metab. 2016 Apr 12;23(4):635-48. doi: 10.1016/j.cmet.2016.01.019. Epub 2016 Feb 25.
  • Khan NA, Nikkanen J, Yatsuga S, Jackson C, Wang L, Pradhan S, Kivelä R, Pessia A, Velagapudi V, Suomalainen A. mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression. Cell Metab. 2017 Aug 1;26(2):419-428.e5. doi: 10.1016/j.cmet.2017.07.007.
  • Pirinen E, Auranen M, Khan NA, Brilhante V, Urho N, Pessia A, Hakkarainen A, Kuula J, Heinonen U, Schmidt MS, Haimilahti K, Piirilä P, Lundbom N, Taskinen MR, Brenner C, Velagapudi V, Pietiläinen KH, Suomalainen A. Niacin Cures Systemic NAD(+) Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Cell Metab. 2020 Jun 2;31(6):1078-1090.e5. doi: 10.1016/j.cmet.2020.04.008. Epub 2020 May 7. Erratum in: Cell Metab. 2020 Jul 7;32(1):144.

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: May 31, 2019) 		15
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 31, 2018
Actual Primary Completion Date December 31, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Manifestation of pure mitochondrial myopathy, with no major other symptoms or manifestations, caused by single or multiple deletions of mtDNA
  2. Age and gender matched healthy controls for every patient
  3. Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 forms 14 days prior to the enrollment and during the study
  4. Written, informed consent to participate in the study

Exclusion Criteria:

  1. Inability to follow study protocol
  2. Pregnancy or breast-feeding at any time of the trial
  3. Malignancy that requires continuous treatment
  4. Unstable heart disease
  5. Severe kidney disease requiring treatment
  6. Severe encephalopathy
  7. Regular usage of intoxicants
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 17 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03973203
Other Study ID Numbers  ICMJE NiaMIT_0001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Anu Wartiovaara, University of Helsinki
Study Sponsor  ICMJE University of Helsinki
Collaborators  ICMJE
  • Helsinki University Central Hospital
  • Institute for Molecular Medicine
  • University of Iowa
Investigators  ICMJE
Principal Investigator: Anu Suomalainen Wartiovaara, MD,PhD Research Programs Unit, University of Helsinki, Helsinki, Finland
PRS Account University of Helsinki
Verification Date May 2019

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

治疗医院

新药特效药

前沿医讯