National CounterACT Initiative

Mitochondrial Alteration Clinical Trial

Official title:

Mitochondrial Targeted Biofuels as Countermeasures Against Chemical Threats

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03597438
• Other study ID #: 18-015056
• Secondary ID: 1R21NS103826-01
• Status: Completed
• Start date: May 7, 2018
• Est. completion date: February 22, 2024

Study information

• Verified date: February 2024
• Source: Children's Hospital of Philadelphia
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The purpose of the study is to determine in vitro effects on mitochondrial function of selected chemical agents in human cells, and assess the capability of a cell-permeable succinate prodrug to attenuate toxic effects The project aims at repurposing this recent pharmaceutical discovery, currently being developed for treatment of toxic exposure, for an expanded indication to treat chemically induced mitochondrial toxicity.

Description:

The study duration per subject will be approximately 15 minutes to complete the one time blood collection.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 236
• Est. completion date: February 22, 2024
• Est. primary completion date: April 18, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

Patient Inclusion Criteria:

1. Males or females age greater or equal 2 years of age

2. Weight greater or equal to 10 kg

3. Parental/guardian permission (informed consent) and if appropriate, child assent.

Patient Exclusion Criteria:

1. Known primary mitochondrial disorder.

2. Use of an investigational drug within 30 days prior to enrollment.

3. Parents/guardians or subjects who in the opinion of the Investigator, may be non-compliant with study schedules or procedures.

Volunteer Inclusion Criteria

1. Males or females > 18 years of age

2. Employee, trainee, or student informed consent

Volunteer Exclusion Criteria:

1. Prior enrollment in this study.

2. Known primary mitochondrial disorder.

3. Use of an investigational drug within 30 days prior to enrollment.

Related Conditions & MeSH terms

• Mitochondrial Alteration

Locations

Country	Name	City	State
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Children's Hospital of Philadelphia	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (14)

Bus JS, Gibson JE. Paraquat: model for oxidant-initiated toxicity. Environ Health Perspect. 1984 Apr;55:37-46. doi: 10.1289/ehp.845537. — View Citation

Degli Esposti M. Inhibitors of NADH-ubiquinone reductase: an overview. Biochim Biophys Acta. 1998 May 6;1364(2):222-35. doi: 10.1016/s0005-2728(98)00029-2. — View Citation

Eckerman I. THE BHOPAL SAGA: Universities Press (India); 2005.

Ehinger JK, Piel S, Ford R, Karlsson M, Sjovall F, Frostner EA, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, Elmer E. Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency. Nat Commun. 2016 Aug 9;7:12317. doi: 10.1038/ncomms12317. — View Citation

Friedrich T, van Heek P, Leif H, Ohnishi T, Forche E, Kunze B, Jansen R, Trowitzsch-Kienast W, Hofle G, Reichenbach H, et al. Two binding sites of inhibitors in NADH: ubiquinone oxidoreductase (complex I). Relationship of one site with the ubiquinone-binding site of bacterial glucose:ubiquinone oxidoreductase. Eur J Biochem. 1994 Jan 15;219(1-2):691-8. doi: 10.1111/j.1432-1033.1994.tb19985.x. — View Citation

Gassner B, Wuthrich A, Scholtysik G, Solioz M. The pyrethroids permethrin and cyhalothrin are potent inhibitors of the mitochondrial complex I. J Pharmacol Exp Ther. 1997 May;281(2):855-60. — View Citation

Gunnell D, Eddleston M, Phillips MR, Konradsen F. The global distribution of fatal pesticide self-poisoning: systematic review. BMC Public Health. 2007 Dec 21;7:357. doi: 10.1186/1471-2458-7-357. — View Citation

Hase Y, Tatsuno M, Nishi T, Kataoka K, Kabe Y, Yamaguchi Y, Ozawa N, Natori M, Handa H, Watanabe H. Atrazine binds to F1F0-ATP synthase and inhibits mitochondrial function in sperm. Biochem Biophys Res Commun. 2008 Feb 1;366(1):66-72. doi: 10.1016/j.bbrc.2007.11.107. Epub 2007 Dec 4. — View Citation

Hollingworth RM, Ahammadsahib KI, Gadelhak G, McLaughlin JL. New inhibitors of complex I of the mitochondrial electron transport chain with activity as pesticides. Biochem Soc Trans. 1994 Feb;22(1):230-3. doi: 10.1042/bst0220230. No abstract available. — View Citation

Jeevaratnam K, Vidya S, Vaidyanathan CS. In vitro and in vivo effect of methyl isocyanate on rat liver mitochondrial respiration. Toxicol Appl Pharmacol. 1992 Dec;117(2):172-9. doi: 10.1016/0041-008x(92)90234-j. — View Citation

Lim S, Ahn SY, Song IC, Chung MH, Jang HC, Park KS, Lee KU, Pak YK, Lee HK. Chronic exposure to the herbicide, atrazine, causes mitochondrial dysfunction and insulin resistance. PLoS One. 2009;4(4):e5186. doi: 10.1371/journal.pone.0005186. Epub 2009 Apr 13. — View Citation

Mesnage R, Arno M, Costanzo M, Malatesta M, Seralini GE, Antoniou MN. Transcriptome profile analysis reflects rat liver and kidney damage following chronic ultra-low dose Roundup exposure. Environ Health. 2015 Aug 25;14:70. doi: 10.1186/s12940-015-0056-1. Erratum In: Environ Health. 2017 Mar 23;16(1):28. — View Citation

Satoh T, Miyoshi H, Sakamoto K, Iwamura H. Comparison of the inhibitory action of synthetic capsaicin analogues with various NADH-ubiquinone oxidoreductases. Biochim Biophys Acta. 1996 Jan 11;1273(1):21-30. doi: 10.1016/0005-2728(95)00131-x. — View Citation

Tawara T, Fukushima T, Hojo N, Isobe A, Shiwaku K, Setogawa T, Yamane Y. Effects of paraquat on mitochondrial electron transport system and catecholamine contents in rat brain. Arch Toxicol. 1996;70(9):585-9. doi: 10.1007/s002040050316. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Attenuation by the succinate prodrug of toxin-induced decrease in mitochondrial respiration.	Data will be assessed using 2-tailed Student's t-test. Dose-response curves for respiration will be made for each toxin and IC50 calculated. In case of difficulties in demonstrating acute toxicity of chemical agents, dose-titration experiments and long-term incubation (up to 24 hours) will be performed	by end of 2018
Secondary	Attenuation of toxin-induced decrease in mitochondrial membrane potential and attenuate lactate production by the succinate prodrug.	Data will be assessed using 2-tailed Student's t-test. Dose-response curves for respiration will be made for each toxin and IC50 calculated. In case of difficulties in demonstrating acute toxicity of chemical agents, dose-titration experiments and long-term incubation (up to 24 h) will be performed	by end of 2018