CLINICAL TRIALS PROFILE FOR TACRINE HYDROCHLORIDE

All Clinical Trials for TACRINE HYDROCHLORIDE

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00551161 ↗	Magnetic Resonance Spectroscopy Study of Memantine in Alzheimer's Disease	Completed	Forest Laboratories	Phase 4	2007-08-01	We are studying subjects with mild to moderate Alzheimer's disease who have been on a stable dose of any cholinesterase inhibitor [donepezil (Aricept), rivastigmine (Exelon), or galantamine (Razadyne)] for at least 3 months, and have not previously taken memantine (Namenda). This is an open-label study, with magnetic resonance spectroscopy (MRS) as the primary outcome measure, along with neuropsychological testing, and optional lumbar puncture, evaluating patients on their stable dose of a cholinesterase inhibitor over 24 weeks, followed by another 24 weeks on memantine in combination with stable dose of cholinesterase inhibitor. The purpose of this study is to characterize the progression of disease using MRS, cerebrospinal fluid (CSF) biomarkers, and cognitive outcome measures, and to determine whether changes in cognitive function on neuropsychological testing are correlated to changes in MR spectroscopic and/or CSF biomarkers.
NCT00006187 ↗	The Safety and Efficacy of an Investigational Drug in Delaying the Progression of Alzheimer's Disease	Terminated	Merck Sharp & Dohme Corp.	Phase 3	1969-12-31	This is a 15-month study with two phases. During the first 12-month phase of this study, patients will be randomly assigned to receive either active study drug or placebo (approximately half of all patients will be on active study drug, the other half on placebo). The second phase is a 3-month randomized withdrawal period. For this phase approximately 10% of the patients will remain on the active drug.
NCT00190021 ↗	Donepezil Treatment of Psychotic Symptoms in Dementia Patients	Unknown status	Beersheva Mental Health Center	Phase 3	1969-12-31	Conventional psychotropic medications may be used to treat behavioral disturbances and psychotic symptoms in patients with dementia and they are the drugs of choice for treating delusions and hallucinations. However the sensitivity to side effects in these patients often restricts the use of these agents (2, 3). Although, atypical antipsychotics have some advantages compared with conventional neuroleptics, they also are associated with side effects (5, 6). Cholinesterase inhibitors (ChEIs) enhance neuronal transmission by increasing the availability of acetylcholine in muscarinic and nicotinic receptors. According to findings of some researchers ChEIs have psychotropic effects and may play an important role in controlling neuropsychiatric and behavioral disturbances in patients with Alzheimer's disease (7-10). These agents may also contribute to the management of other disorders with cholinergic system abnormalities and neuropsychiatric symptoms such as visual hallucinations (11). Donepezil is a piperidine-based reversible, noncompetitive ChEI, which is indicated in the management of patients with Alzheimer's disease of mild to moderate severity (12-14). Preliminary observations suggest the possible value of ChEIs in the amelioration of psychotic symptoms in patients with dementia of the Alzheimer's type (DAT), dementia with Lewy bodies and patients suffering from Parkinson's disease (11-18). The results of our study (18) indicate that the addition of donepezil to perphenazine resulted in qualitatively superior clinical gains compared to higher doses of neuroleptic therapy without donepezil. The finding of the pilot study although impressive, stem from data regarding a rather small sample. The present (second) phase of the study will include a larger sample of patients. We now intend to examine 80 inpatients, aged 65-90 years old, suffering from DAT.

Clinical Trial Conditions for TACRINE HYDROCHLORIDE

Condition Name

Condition Name for TACRINE HYDROCHLORIDE
Intervention	Trials
Alzheimer Disease	2
Cocaine Dependence	1
Cocaine Use Disorders	1

Condition MeSH

Condition MeSH for TACRINE HYDROCHLORIDE
Intervention	Trials
Alzheimer Disease	3
Dementia	1
Cocaine-Related Disorders	1

Clinical Trial Locations for TACRINE HYDROCHLORIDE

Trials by Country

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−

Trials by Country for TACRINE HYDROCHLORIDE
Location	Trials
United States	19
Israel	1

Trials by US State

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−

Trials by US State for TACRINE HYDROCHLORIDE
Location	Trials
Missouri	2
New York	2
California	1
Arizona	1
Wisconsin	1

Clinical Trial Progress for TACRINE HYDROCHLORIDE

Clinical Trial Phase

Clinical Trial Phase for TACRINE HYDROCHLORIDE
Clinical Trial Phase	Trials
Phase 4	1
Phase 3	2
Phase 2	2

Clinical Trial Status

Clinical Trial Status for TACRINE HYDROCHLORIDE
Clinical Trial Phase	Trials
Completed	2
Terminated	1
Unknown status	1

Clinical Trial Sponsors for TACRINE HYDROCHLORIDE

Sponsor Name

Sponsor Name for TACRINE HYDROCHLORIDE
Sponsor	Trials
Midwest Biomedical Research Foundation	2
Merck Sharp & Dohme Corp.	1
Beersheva Mental Health Center	1

Sponsor Type

Sponsor Type for TACRINE HYDROCHLORIDE
Sponsor	Trials
Other	4
Industry	2
NIH	1

Tacrine Hydrochloride: A Comprehensive Review of Clinical Trials, Market Analysis, and Projections

Introduction

Tacrine hydrochloride, a centrally active cholinesterase inhibitor, was once a promising treatment for Alzheimer's disease and other central nervous system disorders. However, its use has been significantly impacted by adverse reactions, particularly hepatotoxicity. Here, we delve into the clinical trials, market analysis, and projections for tacrine hydrochloride.

Clinical Trials Overview

Clinical trials of tacrine hydrochloride were extensive, but they revealed both efficacy and significant limitations.

Methodology and Results

A systematic review of clinical trials conducted between 1981 and 1997 identified 49 trials, including 21 randomized controlled trials. These trials involved 3555 patients with mild to moderate Alzheimer's disease, with tacrine dosages ranging from 25 to 200 mg/day over 3-36 weeks[2].

Efficacy

The trials showed that tacrine had a modest degree of efficacy, with about 20% of patients experiencing improvements in cognitive function and functional ability at 3-6 months of treatment. However, these improvements were generally small, with patients showing a 3-4 point improvement on the Alzheimer's Disease Assessment Scale cognitive subscale and a 2-3 point improvement on the Mini-Mental State Examination[2].

Adverse Effects

Despite its efficacy, tacrine was associated with significant adverse effects. Over 80% of patient withdrawals were due to tacrine-related adverse events, primarily cholinergic manifestations and transaminase elevations. These adverse effects were more frequent at higher doses (>100 mg/day) and typically resolved upon discontinuation of the treatment[2].

Economic Impact and Cost Savings

The economic analysis of tacrine use in Alzheimer's disease treatment revealed some positive outcomes despite the clinical limitations.

Cost Savings

A cost analysis based on a decision-analytic model indicated that the use of tacrine could result in significant cost savings. Patients who continued higher doses of tacrine experienced a cost saving of more than $36,500 over 5 years, primarily due to reduced time in nursing homes. Even when averaged over all patients, including those who discontinued or took only low doses, tacrine use was associated with a cost saving of $9,250 over the patient's lifetime[1].

Market Analysis

Approval and Withdrawal

Tacrine hydrochloride was approved by the FDA in 1993 for the treatment of Alzheimer's disease. However, due to its severe adverse reactions, particularly hepatotoxicity, it was later withdrawn from the U.S. market[3][4].

Market Impact

The withdrawal of tacrine from the market significantly impacted the treatment landscape for Alzheimer's disease. Other acetylcholinesterase inhibitors like donepezil, galantamine, and rivastigmine have since become the standard treatments, offering better safety profiles and comparable efficacy[4].

Projections and Future Directions

Given the discontinuation of tacrine due to its adverse effects, the future of this drug is limited.

Alternative Treatments

The focus has shifted to other acetylcholinesterase inhibitors and newer therapeutic approaches such as monoclonal antibodies, which have been approved for Alzheimer's disease treatment. These alternatives offer improved safety and efficacy profiles, making them more viable options for patients[4].

Lessons Learned

The experience with tacrine highlights the importance of thorough safety and efficacy evaluations in clinical trials. It also underscores the need for continuous monitoring of adverse effects post-marketing to ensure patient safety.

Conclusion

Tacrine hydrochloride, while showing some promise in early clinical trials, ultimately failed to become a sustainable treatment option for Alzheimer's disease due to its significant adverse effects. The economic benefits it offered were overshadowed by the clinical risks, leading to its withdrawal from the market.

Key Takeaways

• Efficacy: Tacrine showed modest improvements in cognitive function and functional ability in a small proportion of patients.
• Adverse Effects: Significant adverse reactions, including hepatotoxicity and cholinergic manifestations, limited its clinical usefulness.
• Economic Impact: Despite clinical limitations, tacrine use was associated with cost savings due to reduced nursing home time.
• Market Analysis: Withdrawn from the U.S. market due to adverse effects, replaced by safer alternatives like donepezil and galantamine.
• Future Directions: Focus on safer and more effective treatments such as other acetylcholinesterase inhibitors and monoclonal antibodies.

FAQs

Q: What was the primary reason for the withdrawal of tacrine from the market?

A: The primary reason for the withdrawal of tacrine from the market was its severe adverse reactions, particularly hepatotoxicity[3][4].

Q: Did tacrine show any economic benefits in the treatment of Alzheimer's disease?

A: Yes, tacrine use was associated with significant cost savings, primarily due to reduced time in nursing homes[1].

Q: What are the current alternatives to tacrine for treating Alzheimer's disease?

A: Current alternatives include other acetylcholinesterase inhibitors like donepezil, galantamine, and rivastigmine, as well as newer treatments such as monoclonal antibodies[4].

Q: How did the adverse effects of tacrine manifest in clinical trials?

A: Adverse effects included cholinergic manifestations and transaminase elevations, which were more frequent at higher doses and resolved upon discontinuation of the treatment[2].

Q: What was the impact of tacrine on cognitive function in patients with Alzheimer's disease?

A: Tacrine resulted in modest improvements in cognitive function and functional ability in about 20% of patients, as measured by the Alzheimer's Disease Assessment Scale and the Mini-Mental State Examination[2].

Sources

1. The economic impact of the tacrine in the treatment of Alzheimer's ... - PubMed
2. Methodology, results and quality of clinical trials of tacrine in the ... - PubMed
3. Tacrine Hydrochloride | DrugBank Online - DrugBank
4. Advances in Clinical and Experimental Medicine - Advances in Clinical and Experimental Medicine
5. tacrine - Drug Central - Drug Central