Safety and Pharmacokinetics Study of Oral Lithium in Patients With Chronic Spinal Cord Injury

Spinal Cord Injuries Clinical Trial

Official title:

A Three Month, Open-label, Single-arm Trial Evaluating the Safety and Pharmacokinetics of Oral Lithium in Patients Diagnosed With Chronic Spinal Cord Injury

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00431171
• Other study ID #: CN101
• Status: Completed
• Phase: Phase 1
• First received: February 1, 2007
• Last updated: January 13, 2012
• Start date: September 2007
• Est. completion date: January 2010

Study information

• Verified date: January 2012
• Source: The University of Hong Kong
• Contact: n/a
• Is FDA regulated: No
• Health authority: Hong Kong: Department of Health
• Study type: Interventional

Clinical Trial Summary

The current study is a phase I open-label clinical trial to examine plasma levels after oral lithium treatments in 20 subjects with chronic spinal cord injury. The subjects will receive standard doses of oral lithium used in treatment of manic depression. The goal of the trial is to show feasibility and safety of maintaining plasma levels of 0.6 mmol/L to 1.2 mmol/L for six weeks in subjects with chronic spinal cord injury.

Description:

Patients with spinal cord injury (SCI) usually have permanent and often devastating neurological deficits and disability. There has been successful research in a number of fields that may someday help people with spinal cord injuries.

The planned treatment trials will focus on the effects of oral lithium on neurological function in people with chronic spinal cord injury and those that have received umbilical cord blood mononuclear cell transplants to the spinal cord. The interest in these two treatments derives from recent reports indicating that umbilical cord blood stem cells may be beneficial for spinal cord injury and that lithium may promote regeneration and recovery of function after spinal cord injury. Both lithium and umbilical cord blood are widely available therapies that have long been used to treat diseases in humans.

The current study is a phase I open-label clinical trial to examine plasma levels after oral lithium treatments in 20 subjects with chronic spinal cord injury. The subjects will receive standard doses of oral lithium used in treatment of manic depression. The goal of the trial is to show feasibility and safety of maintaining plasma levels of 0.6 mmol/L to 1.2 mmol/L for six weeks in subjects with chronic spinal cord injury.

Lithium attracted much attention as a potential neuroregenerative therapy based on experiments in animal models of SCI in 2004. However, toxic levels of lithium (>1.5 mmol/L) are close to the effective levels (0.6 - 1.2 mmol/L). At toxic levels, patients may become confused and lethargic, have diarrhea, upset stomach, and develop tremors, ataxia, dysarthria, and nystagmus. Lithium toxicity may be compounded by sodium depletion or diuretics (thiazides) that inhibit kidney sodium upgrade and ACE inhibitors. Plasma levels also depend on fluid input/output. Therefore, care will be taken to titrate the dose and to test plasma levels of the drug at the beginning, at day 2, 7, and week 6 during the treatment period.

Acute toxicity usually produces relatively mild symptoms. Chronic lithium toxicity may lead to more severe neurotoxic symptoms. However, these symptoms usually develop after 3-5 years of treatment.

Data obtained from this study will be used to develop future chronic spinal cord injury clinical studies: (1) randomized controlled trials with lithium versus placebo; and (2) randomized controlled trials comparing effects of lithium and placebo on subjects who have received umbilical cord blood mononuclear cell transplants to the spinal cord.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: January 2010
• Est. primary completion date: January 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Subjects of either gender and 18 - 60 years of age (preferably 10 males and females each)

• Subjects with chronic spinal cord injury (defined as 12 months or more post spinal cord injury), as confirmed by a MRI

• Subjects with neurological status: ASIA A, B or C

• Subjects must be able to read, understand, and complete the VAS

• Subjects who have voluntarily signed* and dated* an informed consent form, approved by an IEC/IRB, prior to any study-specific procedures *If a subject consents to participation but is not in a position to personally sign and date the informed consent form because of his or her physical condition, the consent must be confirmed at the time of consent orally, signed on behalf by the subject's relative, and by an impartial witness who is present throughout the whole informed consent process.

Exclusion Criteria: Subjects are excluded if they have

• a history of hypersensitivity to lithium

• significant renal, cardiovascular, hepatic and psychiatric diseases

• significant medical diseases or infection

• brain injury

• Addison's disease

• debilitation or dehydration

• recently taken or are taking diuretics or other drugs with known interaction with lithium, such as tricyclic antidepressants, NSAIDs and tetracycline

• a history of alcohol abuse or drug abuse, or if they are

• pregnant or lactating women;

• female of childbearing potential and are unwilling to use an effective contraceptive method while enrolled in the study;

• subjects who are currently participating in another investigational study or have been taking any investigational drug within the last 4 weeks prior to screening of this study (Visit 1); and finally,

• any criteria, which, in the opinion of the investigator, suggest that the subject would not be compliant with the study protocol.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Spinal Cord Injuries

Intervention

Drug:
• Lithium carbonate

Locations

Country	Name	City	State
China	MacLehose Medical Rehabilitation Centre	Pokfulam	Hong Kong SAR

Sponsors (2)

Lead Sponsor	Collaborator
The University of Hong Kong	China Spinal Cord Injury Network

Country where clinical trial is conducted

China, 

References & Publications (23)

Angelucci F, Mathé AA, Aloe L. Neurotrophic factors and CNS disorders: findings in rodent models of depression and schizophrenia. Prog Brain Res. 2004;146:151-65. Review. — View Citation

Aubert J, Dunstan H, Chambers I, Smith A. Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat Biotechnol. 2002 Dec;20(12):1240-5. Epub 2002 Nov 25. — View Citation

Chen KP, Shen WW, Lu ML. Implication of serum concentration monitoring in patients with lithium intoxication. Psychiatry Clin Neurosci. 2004 Feb;58(1):25-9. — View Citation

de Boer J, Siddappa R, Gaspar C, van Apeldoorn A, Fodde R, van Blitterswijk C. Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells. Bone. 2004 May;34(5):818-26. — View Citation

De Boer J, Wang HJ, Van Blitterswijk C. Effects of Wnt signaling on proliferation and differentiation of human mesenchymal stem cells. Tissue Eng. 2004 Mar-Apr;10(3-4):393-401. — View Citation

Etheridge SL, Spencer GJ, Heath DJ, Genever PG. Expression profiling and functional analysis of wnt signaling mechanisms in mesenchymal stem cells. Stem Cells. 2004;22(5):849-60. — View Citation

Gitlin M. Lithium and the kidney: an updated review. Drug Saf. 1999 Mar;20(3):231-43. Review. — View Citation

Grignon S, Bruguerolle B. Cerebellar lithium toxicity: a review of recent literature and tentative pathophysiology. Therapie. 1996 Mar-Apr;51(2):101-6. Review. — View Citation

Hashimoto R, Senatorov V, Kanai H, Leeds P, Chuang DM. Lithium stimulates progenitor proliferation in cultured brain neurons. Neuroscience. 2003;117(1):55-61. — View Citation

Hellweg R, Lang UE, Nagel M, Baumgartner A. Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats. Mol Psychiatry. 2002;7(6):604-8. — View Citation

Karch FE, Lasagna L. Adverse drug reactions. A critical review. JAMA. 1975 Dec 22;234(12):1236-41. — View Citation

Kilts CD. The ups and downs of oral lithium dosing. J Clin Psychiatry. 1998;59 Suppl 6:21-6; discussion 27. Review. — View Citation

Kim JS, Chang MY, Yu IT, Kim JH, Lee SH, Lee YS, Son H. Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo. J Neurochem. 2004 Apr;89(2):324-36. — View Citation

Merendino RA, Arena A, Gangemi S, Ruello A, Losi E, Bene A, D'Ambrosio FP. In vitro interleukin-8 production by monocytes treated with lithium chloride from breast cancer patients. Tumori. 2000 Mar-Apr;86(2):149-52. — View Citation

Merendino RA, Arena A, Gangemi S, Ruello A, Losi E, Bene A, Valenti A, D'Ambrosio FP. In vitro effect of lithium chloride on interleukin-15 production by monocytes from IL-breast cancer patients. J Chemother. 2000 Jun;12(3):252-7. — View Citation

Merendino RA, Mancuso G, Tomasello F, Gazzara D, Cusumano V, Chillemi S, Spadaro P, Mesiti M. Effects of lithium carbonate on cytokine production in patients affected by breast cancer. J Biol Regul Homeost Agents. 1994 Jul-Sep;8(3):88-91. — View Citation

Mignat C, Unger T. ACE inhibitors. Drug interactions of clinical significance. Drug Saf. 1995 May;12(5):334-47. Review. — View Citation

Oakley PW, Whyte IM, Carter GL. Lithium toxicity: an iatrogenic problem in susceptible individuals. Aust N Z J Psychiatry. 2001 Dec;35(6):833-40. — View Citation

Ohteki T, Parsons M, Zakarian A, Jones RG, Nguyen LT, Woodgett JR, Ohashi PS. Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3. J Exp Med. 2000 Jul 3;192(1):99-104. — View Citation

Phiel CJ, Klein PS. Molecular targets of lithium action. Annu Rev Pharmacol Toxicol. 2001;41:789-813. Review. — View Citation

Shimomura A, Nomura R, Senda T. Lithium inhibits apoptosis of mouse neural progenitor cells. Neuroreport. 2003 Oct 6;14(14):1779-82. — View Citation

Willing AE, Zigova T, Milliken M, Poulos S, Saporta S, McGrogan M, Snable G, Sanberg PR. Lithium exposure enhances survival of NT2N cells (hNT neurons) in the hemiparkinsonian rat. Eur J Neurosci. 2002 Dec;16(12):2271-8. — View Citation

Yick LW, So KF, Cheung PT, Wu WT. Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury. J Neurotrauma. 2004 Jul;21(7):932-43. Erratum in: J Neurotrauma. 2007 Aug;24(8):1415. Dosage error in article text. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of clinical adverse events including known and unknown adverse events, and changes from baseline in vital signs, ECGs and laboratory parameters
Secondary	Plasma lithium level

External Links

•   The results of the the captioned study was published in Spinal Cord (2011) ,49 issue