Tacrolimus Formulations for Tremors in Liver Transplant Patients

(LCP-TAC Trial)

Overseen By Trana Hussaini

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of British Columbia

Must be taking: Tacrolimus

Must not be taking: Dopamine blockers

Disqualifiers: Prior transplant, Hemodialysis, Hyperthyroidism, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 8 weeks

124 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This is a randomized open label study in de novo liver transplant recipients that aims to compare the risk of tacrolimus induced tremors with once daily extended-release formulation, Envarsus, versus the twice daily immediate-release formulation. Both formulations of tacrolimus are currently approved for the prevention of rejection in liver transplant patients.

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 participate if you are taking medications known to cause tremors, like dopamine blocking agents.

Is tacrolimus safe for humans?

Tacrolimus is generally safe for humans, but it can cause side effects like tremors, which are linked to the drug's concentration in the blood. Adjusting the formulation or dosage can help reduce these side effects, as seen in studies with kidney and liver transplant patients. ^{1 2 3 4 5}

How does the drug tacrolimus differ from other treatments for tremors in liver transplant patients?

Tacrolimus is unique because it is an immunosuppressant drug used after organ transplants, and its extended-release formulations can help manage tremors by reducing peak drug concentration, which is often linked to tremor severity. This approach may require a lower dose compared to immediate-release versions, potentially improving tremor symptoms and quality of life. ^{1 2 4 6 7}

Who Is on the Research Team?

Trana Hussaini, Pharm D

Principal Investigator

University of British Columbia

Jo-Ann Ford, RN

Principal Investigator

University of British Columbia

Are You a Good Fit for This Trial?

This trial is for adults over 18 who've just had their first liver transplant and have a kidney function (eGFR) above 30 ml/min. They should be starting on Tacrolimus within 7 days after the transplant and must give informed consent to participate.

Inclusion Criteria

You understand and agree to participate in the study after learning about it.

I can start Tacrolimus within a week after my liver transplant.

Your kidney function is good, with an eGFR of more than 30 ml/min, when starting tacrolimus.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either LCPT or IR-TAC in combination with mycophenolate and short-term corticosteroids

8 weeks

Regular visits for monitoring tremor severity using wearable sensors

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of diabetes onset and kidney function

12 months

Visits at 6 and 12 months post-transplant

Long-term Follow-up

Continued monitoring of immunosuppression medication adherence and incidence of acute cellular rejection

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Tacrolimus

Trial Overview The study compares two forms of Tacrolimus in new liver transplant recipients: Envarsus, an extended-release tablet taken once daily, versus a twice-daily immediate-release version. The goal is to see which causes fewer tremors.

How Is the Trial Designed?

Group I: LCPT Experimental Treatment 1 Intervention

Group II: IR-TAC Active Control 1 Intervention

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

Approved in European Union as Prograf for:

• Prevention of organ rejection in liver, kidney, and heart transplant patients

Approved in United States as Prograf for:

• Prevention of organ rejection in liver, kidney, and heart transplant patients

Approved in Canada as Advagraf for:

• Prevention of organ rejection in liver, kidney, and heart transplant patients

Approved in Japan as Prograf for:

• Prevention of organ rejection in liver, kidney, and heart transplant patients

Approved in Switzerland as Prograf for:

• Prevention of organ rejection in liver, kidney, and heart transplant patients

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Paladin Labs Inc.

Collaborator

Trials

4

Recruited

360+

Published Research Related to This Trial

In a study of 35 patients with severe liver disease, it was found that postural hand tremor severity significantly increased after liver transplantation (LTX) and immunosuppression with cyclosporin A (CsA) or tacrolimus (FK 506), indicating a potential side effect of these treatments.

The study revealed that higher plasma levels of CsA were associated with greater tremor amplitude, suggesting that the tremor may be influenced by the medication dosage, and that applying a weight load reduced the dominant tremor frequency in both patients and normal controls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postural hand tremor before and following liver transplantation and immunosuppression with cyclosporine or tacrolimus in patients without clinical signs of hepatic encephalopathy. Paul, F., Müller, J., Christe, W., et al.[2013]

In a phase 3b study involving 38 kidney transplant recipients, switching from immediate-release tacrolimus to the novel extended-release formulation LCPT led to significant improvements in hand tremor, as measured by the Fahn-Tolosa-Marin scale and accelerometry.

The study found that 78.9% of patients reported improvement in tremor after the switch to LCPT, suggesting it may be a beneficial alternative for managing tremor without further reducing tacrolimus dosage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study. Langone, A., Steinberg, SM., Gedaly, R., et al.[2021]

In a study of 689 solid organ transplant recipients, 41.7% reported experiencing mild to severe tremor, which significantly impacted their daily activities and health-related quality of life (HRQoL).

Higher blood levels of tacrolimus, a common immunosuppressant used in transplant patients, were found to be an independent factor associated with the severity of tremor, suggesting a need for further research on its effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremor, Daily Functioning, and Health-Related Quality of Life in Solid Organ Transplant Recipients. Riemersma, NL., Kremer, D., Knobbe, TJ., et al.[2023]

Converting stable liver transplant patients from once-daily prolonged-release tacrolimus to once-daily extended-release tacrolimus is safe, with only two patients experiencing adverse effects that resolved after returning to the original medication.

This conversion not only reduced the mean daily cost of tacrolimus therapy from 5.54 to 4.11 Euros per patient but also required careful monitoring and dose adjustments to maintain effective serum levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conversion From Once-Daily Prolonged-Release Tacrolimus to Once-Daily Extended-Release Tacrolimus in Stable Liver Transplant Recipients. Altieri, M., Delaval, G., Kimmoun, E., et al.[2018]

In a case study of a 42-year-old male liver transplant recipient, the addition of deoxyschisandrin significantly increased the blood concentration of tacrolimus (Tac) from 2.3 ng/mL to 17.7 ng/mL within three days, indicating a potential interaction that enhances Tac levels.

This case highlights the importance of closely monitoring tacrolimus levels when deoxyschisandrin is used concurrently, as it may lead to increased risk of toxicity and necessitate adjustments in immunosuppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of deoxyschisandrin on blood tacrolimus levels: a case report. Jiang, W., Wang, X., Kong, L.[2017]

In a study of four kidney transplant patients on tacrolimus, a common immunosuppressant, postural and kinetic tremors were observed, primarily affecting their hands and impacting daily activities.

Limb cooling was found to temporarily reduce the amplitude of these tremors, suggesting it could be a potential therapeutic option for managing tacrolimus-induced tremors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenomenology and Physiology of Tacrolimus Induced Tremor. Wagle Shukla, A., Lunny, C., Hisham, I., et al.[2023]

Calcineurin inhibitors like tacrolimus can cause severe tremors in up to 50% of solid organ transplant recipients, which can significantly impact their daily lives.

In a case study of a lung transplant recipient, traditional treatments for tremors were ineffective, but she experienced significant improvement after undergoing magnetic resonance-guided focused ultrasound thalamotomy, suggesting this procedure may be a promising option for managing tremors in similar patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnetic Resonance Guided Focused Ultrasound Thalamotomy for Treatment of Severe Essential Tremor in a Lung Transplant Recipient-A Case Report. Modi, P., Qiu, L., Fallah, T., et al.[2023]

Citations

1. Denmark pubmed.ncbi.nlm.nih.gov

Postural hand tremor before and following liver transplantation and immunosuppression with cyclosporine or tacrolimus in patients without clinical signs of hepatic encephalopathy. [2013]

2. Denmark pubmed.ncbi.nlm.nih.gov

Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Tremor, Daily Functioning, and Health-Related Quality of Life in Solid Organ Transplant Recipients. [2023]

4. Turkey pubmed.ncbi.nlm.nih.gov

Conversion From Once-Daily Prolonged-Release Tacrolimus to Once-Daily Extended-Release Tacrolimus in Stable Liver Transplant Recipients. [2018]

5. England pubmed.ncbi.nlm.nih.gov

The effect of deoxyschisandrin on blood tacrolimus levels: a case report. [2017]

6. England pubmed.ncbi.nlm.nih.gov

Phenomenology and Physiology of Tacrolimus Induced Tremor. [2023]

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

Magnetic Resonance Guided Focused Ultrasound Thalamotomy for Treatment of Severe Essential Tremor in a Lung Transplant Recipient-A Case Report. [2023]