Zoledronic Acid for Parkinson's Disease

(TOPAZ Trial)

Recruiting at 75 trial locations

Overseen By Mustafa Siddiqui, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: California Pacific Medical Center Research Institute

Must not be taking: Bisphosphonates, SERMs, Denosumab

Disqualifiers: Hip fracture, Non-ambulatory, Kidney dialysis, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 1 day

2650 Participants Needed

Trial Summary

What is the purpose of this trial?

This home-based study is a randomized (1:1) placebo-controlled trial of a single infusion of zoledronic acid-5 mg (ZA) for the prevention of fractures in men and women aged 60 years and older with Parkinson's disease and parkinsonism with at least 2 years of follow-up. A total of 2650 participants will be enrolled and randomized in the United States. Participants, follow-up outcome assessors, and study investigators will be blinded to assigned study treatment. This trial is funded by the National Institute of Aging.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have used bisphosphonate drugs in the last 12 months or other osteoporosis treatments in the last 6 months.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have used bisphosphonate drugs in the last 12 months or other osteoporosis treatments in the last 6 months.

What data supports the idea that Zoledronic Acid for Parkinson's Disease is an effective drug?

The available research does not provide any data supporting the effectiveness of Zoledronic Acid for treating Parkinson's Disease. The studies focus on other treatments and conditions related to Parkinson's, such as surgical interventions and joint replacements, but do not mention Zoledronic Acid as a treatment for Parkinson's Disease. ^{1 2 3 4 5}

What safety data exists for Zoledronic Acid in treating Parkinson's Disease?

The provided research does not contain specific safety data for Zoledronic Acid (also known as Zometa or Reclast) in the treatment of Parkinson's Disease. The studies focus on other drugs like istradefylline, safinamide, and zonisamide for Parkinson's Disease, but none mention Zoledronic Acid. Therefore, no relevant safety data for Zoledronic Acid in this context is available from the provided research. ^{6 7 8 9 10}

Is the drug Zoledronic Acid a promising treatment for Parkinson's Disease?

The information provided does not mention Zoledronic Acid as a treatment for Parkinson's Disease. Instead, it focuses on Zonisamide, which is shown to improve motor function in Parkinson's patients. Therefore, there is no evidence here to suggest that Zoledronic Acid is a promising treatment for Parkinson's Disease. ^{11 12 13 14 15}

How does the drug Zoledronic Acid differ from other treatments for Parkinson's disease?

Zoledronic Acid is unique for Parkinson's disease as it is primarily used for bone-related conditions like osteoporosis and not typically associated with neurological treatments. This makes its use in Parkinson's disease novel, as it may offer a different mechanism of action compared to traditional dopaminergic therapies. ^{5 14 16 17 18}

Research Team

Steve Cummings, MD

Principal Investigator

CPMC Research Institute

Eligibility Criteria

This trial is for men and women aged 60 or older with Parkinson's disease or parkinsonism, who can follow the study for at least 2 years. They must be able to consent and have a neurologist-confirmed diagnosis. People using bisphosphonates in the last year, those with recent or planned dental procedures, on osteoporosis treatments within 6 months, undergoing dialysis, non-ambulatory individuals, or with certain other diseases are excluded.

Inclusion Criteria

I am 60 years old or older.

I have been diagnosed with Parkinson's Disease or parkinsonism by a neurologist.

Willing and able to continue in follow-up for at least 2 years

Exclusion Criteria

I need someone's help to walk.

I haven't had nor plan to have any tooth extractions or major dental work soon.

The study staff decides that you are not suitable for the study, for example, if you have an uncontrolled drug or alcohol addiction.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

eConsent, screening questionnaire, baseline questionnaire, Telemedicine assessment, Nurse Home Visit

Treatment

Participants receive a single intravenous infusion of Zoledronic acid (5 mg) or placebo

1 day

1 Nurse Home Visit for drug administration

Follow-up

Participants are monitored for fractures and mortality every 4 months

2 years

Contact every 4 months

Long-term follow-up

Participants are monitored for clinical and hip fractures

5 years

Treatment Details

Interventions

• Zoledronic Acid

Trial Overview The study tests if a single infusion of Zoledronic Acid (ZA) can prevent fractures compared to a placebo in patients with Parkinson's-related conditions. It's randomized and blinded—meaning neither participants nor researchers know who gets ZA or placebo—and involves over three thousand participants across the U.S.

Participant Groups

Group I: Zoledronic acid (ZA) Active Control 1 Intervention

A single intravenous infusion of Zoledronic acid (5 mg) infused over 45 minutes

Group II: Placebo Placebo Group 1 Intervention

A single intravenous infusion of placebo infused over 45 minutes

Zoledronic Acid is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Zometa for:

• Prevention of skeletal events in patients with bone metastases from solid tumors
• Treatment of tumor-induced hypercalcemia

Approved in United States as Reclast for:

• Treatment and prevention of osteoporosis in postmenopausal women
• Treatment and prevention of glucocorticoid-induced osteoporosis
• Treatment of Paget's disease of bone

Approved in Canada as Zometa for:

• Prevention of skeletal events in patients with bone metastases from solid tumors
• Treatment of tumor-induced hypercalcemia
• Treatment of osteoporosis in postmenopausal women

Approved in Japan as Zometa for:

• Treatment of bone metastases from solid tumors
• Treatment of tumor-induced hypercalcemia
• Treatment of osteoporosis

Who Is Running the Clinical Trial?

California Pacific Medical Center Research Institute

Lead Sponsor

Trials

44

Recruited

10,600+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Duke University

Collaborator

Trials

2,495

Recruited

5,912,000+

University of Pittsburgh

Collaborator

Trials

1,820

Recruited

16,360,000+

Parkinson's Foundation

Collaborator

Trials

13

Recruited

1,030,000+

Findings from Research

In a study of 41 patients with Parkinson's syndrome who underwent hip fracture surgery, those treated with endoprosthesis showed significantly better walking recovery compared to those treated with internal fixation, with 62.5% of endoprosthesis patients able to walk independently after rehabilitation.

Overall, Parkinson's disease negatively impacts walking recovery after hip fractures, as 21.9% of patients were unable to walk at the end of rehabilitation, highlighting the challenges faced by this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Gait in patients with Parkinson's disease after surgically treated hip fracture]. Gialanella, B.[2014]

Parkinson's disease patients face higher risks of falls and osteoporosis, complicating their treatment for hip fractures, particularly regarding surgical approaches and post-operative care.

There is uncertainty about whether Parkinson's patients have a worse prognosis after hip fractures compared to age-matched individuals, indicating a need for more research to clarify their outcomes and improve care strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parkinson's disease patients who fracture their neck of femur: a review of outcome data. Clubb, VJ., Clubb, SE., Buckley, S.[2008]

In a case study of a 75-year-old woman with Parkinson's disease and psychosis, intramuscular botulinum toxin injections were successfully used to aid in the immobilization of her fractured arm after surgery, helping to protect the surgical site during recovery.

Three months post-surgery, the patient showed signs of successful fracture healing, indicating that botulinum toxin could be a safe and effective option for patients who struggle with immobilization due to psychiatric conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Botulinum Toxin as an Adjunctive Therapy for Immobilization of a Distal Humerus Fracture in Parkinson's Disease-Associated Psychosis: A Case Report. Lapow, J., Hirth, J., Agarwalla, A., et al.[2023]

In a study of 10 patients with Parkinson's disease undergoing unicompartmental knee arthroplasty (UKA), there were no perioperative complications, and patients experienced significant improvements in knee pain and physical function as measured by the Knee Society Scores and SF-36 Physical Component Scores.

Despite the improvements in pain and some functional scores, the surgery did not lead to better range of motion or overall knee function, as many patients still had unchanged flexion contractures and only a few were able to ambulate independently at follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unicompartmental knee arthroplasty in patients with Parkinson's disease. Goh, GS., Zeng, GJ., Thever, Y., et al.[2021]

Surgical interventions like thalamotomy, thalamic stimulation, and pallidotomy can be effective for Parkinson's disease patients who do not respond to medication or have severe motor complications, with the choice of procedure tailored to the patient's specific symptoms.

These surgeries are performed under local anesthesia and involve precise targeting based on anatomical and physiological techniques, but are contraindicated in patients with cognitive dysfunction, severe gait issues, or other health risks that could complicate surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Neurosurgical stereotactic treatment in Parkinson's disease]. Schuurman, PR., Speelman, JD., de Bie, RM., et al.[2017]

A review of 402 drug-related adverse events linked to movement disorders revealed that calcium-entry blockers (31%) and benzamides (27%) were the most commonly implicated drugs.

The study found that serious adverse events occurred in nearly 80% of cases, predominantly affecting females and individuals aged 11-30 and 60-80 years, highlighting the need for caution when prescribing these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Drug-induced extrapyramidal disorders]. Horga, JF., Navarro, M., Peiró, V., et al.[2022]

Istradefylline, when used alongside levodopa, significantly reduces the time patients with Parkinson's Disease spend in the OFF state and improves motor function as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) Part III.

The study found that istradefylline is safe, with no significant differences in adverse events compared to placebo, although it was associated with a higher risk of dyskinesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Istradefylline, an adenosine A₂A receptor antagonist, for patients with Parkinson's Disease: a meta-analysis. Chen, W., Wang, H., Wei, H., et al.[2014]

In a study of 511 Spanish patients with Parkinson's Disease, safinamide demonstrated a favorable safety profile and led to significant improvements in motor function, with 57.4% of patients showing clinically meaningful benefits when used as an add-on to levodopa.

Motor complications decreased from 83.2% to 63.3% over the study period, indicating safinamide's efficacy in managing symptoms, although caution is advised for patients with cognitive impairment due to a slightly higher frequency of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SYNAPSES. A European observational study to evaluate the safety and the effectiveness of safinamide in routine clinical practice: post-hoc analysis of the Spanish study population. Kulisevsky, J., Esquivel, A., Freire-Álvarez, E., et al.[2023]

Zonisamide significantly improves motor function in patients with Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), as evidenced by a reduction in the UPDRS III total score in a study of 1749 patients.

While zonisamide shows promise as a treatment option, it may increase the risk of adverse effects such as contusions and reduced appetite in DLB patients, and somnolence in PD patients, indicating the need for further safety evaluations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zonisamide's Efficacy and Safety on Parkinson's Disease and Dementia with Lewy Bodies: A Meta-Analysis and Systematic Review. Kong, L., Xi, J., Jiang, Z., et al.[2022]

Safinamide, when used as an add-on therapy for Parkinson's disease, significantly reduces 'off-time' and increases 'on time without troublesome dyskinesia', showing its efficacy in managing motor complications associated with anti-Parkinson's medications.

The study found no significant difference in adverse events between the safinamide and placebo groups, suggesting that safinamide is a safe option for patients, although further research is needed due to some studies having a high risk of bias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of safety and efficacy of safinamide for motor fluctuations in patients with Parkinson's disease. Abdelalem Aziz Ahmed, M.[2020]

In two 12-week clinical trials involving adult patients with Parkinson's disease, zonisamide (25 mg once daily) significantly improved motor function compared to placebo, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) Part III.

Zonisamide was generally well tolerated, with no significant difference in the incidence of adverse events between the zonisamide and placebo groups, indicating a favorable safety profile as an adjunctive therapy with levodopa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zonisamide: in Parkinson's disease. Yang, LP., Perry, CM.[2021]

Zonisamide (ZNS) has been found to significantly improve motor function in advanced Parkinson's disease patients at a low dose of 25 mg per day, with effects lasting for at least one year, leading to its approval as an anti-parkinsonian agent in Japan in 2009.

The mechanism of ZNS's benefits includes increasing dopamine levels in the brain by enhancing the synthesis of dopamine and inhibiting monoamine oxidase activity, along with neuroprotective effects that may help in managing Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The discovery of an antiparkinsonian drug, zonisamide]. Murata, M.[2019]

Zonisamide enhances the effects of levodopa in treating motor symptoms of Parkinson's disease, but it also increases levodopa-induced abnormal involuntary movements, indicating a complex interaction between the two drugs.

The study suggests that zonisamide's antiparkinsonian effects are primarily due to its modulation of levodopa-dopamine metabolism in the striatum, rather than through direct dopaminergic pathways, as it did not affect key dopamine-related proteins in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zonisamide Enhances Motor Effects of Levodopa, Not of Apomorphine, in a Rat Model of Parkinson's Disease. Nishijima, H., Miki, Y., Ueno, S., et al.[2020]

Current research is advancing in three main therapy categories for Parkinson's disease: symptomatic treatments, neuroprotective strategies, and neurorestorative approaches, with several promising therapies in clinical trials.

Gene therapy techniques, particularly those using viral vectors to deliver therapeutic genes into the brain, have shown modest benefits in early trials, including a method that encodes for glutamic acid decarboxylase, which may help improve symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upcoming treatments in Parkinson's disease, including gene therapy. Rodnitzky, RL.[2012]

In a phase 3 trial involving 351 patients with dementia with Lewy bodies (DLB), zonisamide significantly improved motor function compared to placebo, with a notable reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) scores at 12 weeks.

Both 25 mg and 50 mg doses of zonisamide were found to be safe and well tolerated, with adverse events occurring in about 47% to 55% of patients, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of zonisamide on parkinsonism in patients with dementia with Lewy bodies: A phase 3 randomized clinical trial. Murata, M., Odawara, T., Hasegawa, K., et al.[2021]

COMT inhibitors have been shown to effectively prolong the action of levodopa in Parkinson's disease patients experiencing the 'wearing off' phenomenon, providing a new treatment option for those with fluctuating responses to standard therapy.

Clozapine not only alleviates levodopa-induced psychosis but also helps reduce tremors and dyskinesias, highlighting its dual role in managing symptoms of Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New medical and surgical treatments for Parkinson's disease. Klockgether, T., Löschmann, PA., Wüllner, U.[2019]

References

1. Italy pubmed.ncbi.nlm.nih.gov

[Gait in patients with Parkinson's disease after surgically treated hip fracture]. [2014]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Parkinson's disease patients who fracture their neck of femur: a review of outcome data. [2008]

3. United States pubmed.ncbi.nlm.nih.gov

Botulinum Toxin as an Adjunctive Therapy for Immobilization of a Distal Humerus Fracture in Parkinson's Disease-Associated Psychosis: A Case Report. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Unicompartmental knee arthroplasty in patients with Parkinson's disease. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

[Neurosurgical stereotactic treatment in Parkinson's disease]. [2017]

6. Spain pubmed.ncbi.nlm.nih.gov

[Drug-induced extrapyramidal disorders]. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Istradefylline, an adenosine A₂A receptor antagonist, for patients with Parkinson's Disease: a meta-analysis. [2014]

8. Spain pubmed.ncbi.nlm.nih.gov

SYNAPSES. A European observational study to evaluate the safety and the effectiveness of safinamide in routine clinical practice: post-hoc analysis of the Spanish study population. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Zonisamide's Efficacy and Safety on Parkinson's Disease and Dementia with Lewy Bodies: A Meta-Analysis and Systematic Review. [2022]

10. England pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of safety and efficacy of safinamide for motor fluctuations in patients with Parkinson's disease. [2020]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Zonisamide: in Parkinson's disease. [2021]

12. Japan pubmed.ncbi.nlm.nih.gov

[The discovery of an antiparkinsonian drug, zonisamide]. [2019]

13. United States pubmed.ncbi.nlm.nih.gov

Zonisamide Enhances Motor Effects of Levodopa, Not of Apomorphine, in a Rat Model of Parkinson's Disease. [2020]

14. England pubmed.ncbi.nlm.nih.gov

Upcoming treatments in Parkinson's disease, including gene therapy. [2012]

15. England pubmed.ncbi.nlm.nih.gov

Effect of zonisamide on parkinsonism in patients with dementia with Lewy bodies: A phase 3 randomized clinical trial. [2021]

16. England pubmed.ncbi.nlm.nih.gov

New medical and surgical treatments for Parkinson's disease. [2019]

17. United States pubmed.ncbi.nlm.nih.gov

Spheramine for treatment of Parkinson's disease. [2021]

18. England pubmed.ncbi.nlm.nih.gov

Targets and Mechanisms in Prevention of Parkinson's Disease through Immunomodulatory Treatments. [2017]