NiaMIT Continuation With Early-stage Mitochondrial Myopathy Patients

Mitochondrial Myopathies Clinical Trial

Official title:

NiaMIT (NiaMIT_0001) Continuation for Early-stage Mitochondrial Myopathy Patients to Investigate the Effect of Niacin Supplementation on Systemic Nicotinamide Adenine Dinucleotide (NAD+) Metabolism, Physiology and Muscle Performance

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04538521
• Other study ID #: NiaMIT_002
• Status: Completed
• Phase: N/A
• Start date: February 11, 2019
• Est. completion date: September 18, 2020

Study information

• Verified date: January 2021
• Source: University of Helsinki
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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. However, an NAD+ precursor vitamin B3 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. Vitamin B3 exists in several forms: nicotinic acid (niacin), nicotinamide, and nicotinamide riboside. Nicotinamide riboside has been shown to prevent and improve disease symptoms in several mouse models of mitochondrial myopathy. In addition, the investigators have previously observed that treatment with another form of vitamin B3, niacin, improved NAD+ deficiency and muscle performance in mitochondrial myopathy patients.

In this study, the form of vitamin B3, niacin, is used to activate dysfunctional mitochondria and to rescue signs of mitochondrial myopathy in early-stage patients. 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 with mitochondrial myopathy, typically harboring a sporadic single mtDNA deletion or a mutation in nuclear mtDNA maintenance gene causing multiple mtDNA deletions, are recruited. In addition, data from healthy controls from the primary NiaMIT study (ClinicalTrials.gov Identifier: NCT03973203) are utilized to analyse the collected data. Clinical examinations and collection of muscle biopsies are performed at the time points 0 and 10 months. Fasting blood samples are collected every second week until 1.5 months, every fourth 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 already in early stages of the disease.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: September 18, 2020
• Est. primary completion date: September 18, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 17 Years and older

Eligibility

Inclusion Criteria:

1. Early-stage, genetically diagnosed mitochondrial myopathy, with no major other symptoms or manifestations, caused by single or multiple deletions of mtDNA

2. Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 forms 14 days prior to the enrollment and during the study

3. 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

Related Conditions & MeSH terms

• Mitochondrial Myopathies
• Muscular Diseases

Intervention

Dietary Supplement:
• Niacin
The dose for a slow-released form of niacin will be 500-1000 mg/day. The daily niacin dose, 250 mg/day, is gradually escalated by 250 mg/month so that the full dose is reached after 2 months. The intervention time with the full niacin dose is 8 months and subsequently total intervention time 10 months.

Locations

Country	Name	City	State
Finland	University of Helsinki	Helsinki

Sponsors (3)

Lead Sponsor	Collaborator
University of Helsinki	Helsinki University Central Hospital, Institute for Molecular Medicine

Country where clinical trial is conducted

Finland, 

References & Publications (12)

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. — View Citation

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. — View Citation

Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol. 2007 Mar 19;99(6A):22C-31C. Epub 2006 Nov 28. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Body weight	Change in body weight	Baseline and 10 months
Other	Body composition	Change in fat mass and fat free mass measured with bioimpedance	Baseline and 10 months
Other	Ectopic lipid accumulation, i.e. liver and muscle lipid content	Change in liver and muscle fat content measured with proton magnetic resonance spectroscopy	Baseline and 10 months
Other	Circulating lipid profiles	Change in circulating HDL, LDL and triglyceride concentrations measured using standard photometric enzymatic assay	Baseline, 4 months and 10 months
Primary	NAD+ and related metabolite levels in blood and muscle	Change in concentrations of NAD+ and related metabolites such as: nicotinamide adenine dinucleotide phosphate, nicotinic acid adenine dinucleotide, nicotinamide, and nicotinamide mononucleotide measured using a quantitative colorimetric assay.	Baseline, 4 months and 10 months
Secondary	Number of diseased muscle fibers	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	Baseline and 10 months
Secondary	Mitochondrial biogenesis	Change in mitochondria immunohistochemical staining intensity	Baseline and 10 months
Secondary	Muscle mitochondrial oxidative capacity	Change in muscle histochemical activity of mitochondrial cytochrome c oxidase	Baseline and 10 months
Secondary	Muscle and blood metabolomic profiles	Change in muscle or serum/plasma metabolite concentrations measured with mass spectrometry	Baseline and 10 months
Secondary	Core muscle strength	Change in core muscle strength measured by static and dynamic back and abdominal strength tests (number of repeats)	Baseline and 10 months
Secondary	Circulating levels of disease biomarkers, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15)	Change in circulating FGF21 and GDF15 concentrations measured using ELISA kits	Baseline and 10 months
Secondary	Muscle mitochondrial DNA deletions	Change in muscle mtDNA deletion load detected using polymerase chain reaction amplification	Baseline and 10 months
Secondary	Muscle transcriptomic profile	Change in muscle gene expression determined using RNA sequencing approach	Baseline and 10 months