Evaluation of Rotigotine and Rivastigmine Combination Therapy on Cognitive Function in Mild to Moderate Alzheimer's Disease: A Phase III Randomized Controlled Trial
- Trial ID
- 2023-504602-11-00
- Protocol
- DOPAD-3
- Sponsor
- Fondazione Santa Lucia
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of **rotigotine** in combination with **rivastigmine** on frontal lobe cognitive functions in patients with mild to moderate **Alzheimer's disease**. This is assessed by comparing the change from baseline to Week 24 in the Frontal Assessment Battery (FAB) score between the treatment group receiving rotigotine and rivastigmine and the control group receiving rivastigmine and placebo. The clinical relevance of this objective lies in its potential to enhance cognitive function management in Alzheimer's disease, which could improve patient outcomes and quality of life.
Secondary objectives include evaluating the efficacy of rotigotine in combination with rivastigmine on activities of daily living, as compared to rivastigmine in combination with placebo. This is measured by the change from baseline to Week 24 in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score. This objective is clinically significant as it addresses the impact of treatment on the functional abilities of patients, which is crucial for maintaining independence and reducing caregiver burden.
Participants
The clinical trial involves participants diagnosed with **mild to moderate Alzheimer's disease**. The study population includes both male and female subjects, aged between 50 and 85 years. Participants are required to have a general health status that is acceptable for a six-month clinical trial, with stable pharmacological treatment of any other chronic condition for at least one month prior to screening. The trial does not include a vulnerable population. The selection criteria necessitate that participants have a formal education of eight or more years and exhibit evidence of frontal lobe dysfunctions. Additionally, participants must have a caregiver available and living in the same household or interacting with the patient to ensure the administration of the drug. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **rotigotine** in combination with **rivastigmine** in patients with mild to moderate **Alzheimer's disease**. The trial is structured as a parallel group, international, multi-center phase III study, with an estimated duration of 24 weeks. Participants will be randomly assigned to receive either the active treatment or a placebo, ensuring that neither the participants nor the investigators know which treatment is being administered, thus maintaining the integrity of the study's blinding process.
The trial will commence with an inclusion (screening) visit, where potential participants will be assessed against the inclusion criteria, such as age between 50-85 years, a diagnosis of Alzheimer's disease according to IWG criteria, and evidence of frontal lobe dysfunctions. Following successful screening, eligible participants will be enrolled in the study. The study involves multiple follow-up visits to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. These visits are crucial for collecting data on the primary endpoint, which is the change in frontal lobe cognitive functions from baseline to week 24, as measured by the Frontal Assessment Battery (FAB).
The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the overall impact of the treatment. The expected length of participant involvement is approximately six months, aligning with the trial's duration. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial's design and procedures are meticulously planned to ensure the collection of robust and reliable data, contributing to the understanding of the therapeutic potential of rotigotine in combination with rivastigmine for Alzheimer's disease.
Treatment
The clinical trial involves the administration of **Neupro 4mg/24h transdermal patch**, which contains the active substance **rotigotine**. This pharmaceutical form is a transdermal patch designed for continuous delivery of the medication over a 24-hour period. The patch is applied via the **transdermal route**, ensuring a steady release of 4 mg of rotigotine per day. The maximum treatment period for this dosage is 6 weeks. The patches are not imprinted, and participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
Another experimental treatment in the study is the **Neupro 2 mg/24 h transdermal patch**, also containing **rotigotine**. This patch is similarly designed for transdermal use, delivering 2 mg of the active substance over 24 hours. The maximum total dose for this treatment is 8 mg, with a treatment period extending up to 24 weeks. As with the 4 mg patch, these patches are not imprinted, and compliance is monitored to maintain the integrity of the study results.
The study also includes a **placebo** treatment, which is identical in appearance to the active medication patches but does not contain any active substance. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo patches are applied in the same manner as the active patches, and compliance is similarly monitored to ensure consistency across all study groups.
Efficacy
The efficacy of the investigational treatment in this clinical trial will be assessed by evaluating the impact of **rotigotine** in combination with rivastigmine on frontal lobe cognitive functions in patients with mild to moderate Alzheimer's disease. The primary endpoint for efficacy evaluation is the change from baseline to Week 24 in the Frontal Assessment Battery (FAB) score. This endpoint will compare the effects of the combination therapy against rivastigmine in combination with a placebo. The FAB is a validated tool used to assess frontal lobe cognitive functions, and it will be administered at specified timepoints throughout the study to measure changes in cognitive performance.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Men and women (non-childbearing potential, as defined in Appendix 2) with a diagnosis of AD according to IWG criteria 2. Age 50-85 years 3. MRI or computerized tomography (CT) assessment within twelve months before baseline, corroborating the clinical diagnosis of AD and excluding other potential causes of dementia, especially cerebrovascular lesions (see exclusion criteria, number 3) 4. Patients who show CSF biomarker data supporting the diagnosis of AD measured within the last 3 years, or patients with a positive Amyloid Pet Scan within the last 3 years will qualify for the study 5. Mild to moderate stage of AD according to MMSE ≥18 and ≤26 6. Clinical Dementia Rating (CDR) total score of 0.5 or 1 (mild) 7. Evidence of frontal lobe dysfunctions as assessed by FAB ≤14 8. Absence of major depressive disease according to GDS of < 5 9. Formal education for eight or more years 10. Previous decline in cognition for more than six months as documented in patient medical records 11. A caregiver available and living in the same household or interacting with the patient and available if necessary to assure administration of drug 12. Patients living at home or nursing home setting without continuous nursing care 13. General health status acceptable for a participation in a 6-month clinical trial 14. Stable pharmacological treatment of any other chronic condition for at least one month prior to screening 15. No regular intake of prohibited medications. 16. Signed informed consent by the patient, prior to the initiation of any study specific procedure and signed consent of the caregiver
Exclusion Criteria
- Failure to perform screening or baseline examinations 2. Hospitalization or change of chronic concomitant medication one month prior to screening or during screening period 3. Clinical, laboratory or neuro-imaging findings consistent with: • other primary degenerative dementia (dementia with Lewy bodies, fronto-temporal dementia, Huntington’s disease, Creutzfeldt-Jakob Disease, Down’s syndrome, etc.); • other neurodegenerative condition (Parkinson’s disease, amyotrophic lateral sclerosis, etc.); • orthostatic hypotension and autonomic disorders • cerebrovascular disease (major infarct, one strategic or multiple lacunar infarcts, extensive white matter lesions > one quarter of the total white matter); • other central nervous system diseases (severe head trauma, tumors, subdural hematoma or other space occupying processes, etc.); • seizure disorder; • other infectious, metabolic, or systemic diseases affecting the central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, serum electrolytes out of normal range, juvenile onset diabetes mellitus, etc.). 4. A current DSM-V diagnosis of active major depression, schizophrenia, or bipolar disorder 5. Clinically significant, advanced, or unstable disease that may interfere with primary or secondary variable evaluations, and which may bias the assessment of the clinical or mental status of the patient or put the patient at special risk, such as: • chronic liver disease, liver function test abnormalities or other signs of hepatic insufficiency (ALT, AST, Gamma GT, alkaline phosphatase > 2.5 ULN); • respiratory insufficiency; • renal insufficiency (serum creatinine >2 mg/dl) or creatinine clearance ≤ 30 mL/min according to Cockcroft-Gault formula). In case of creatinine clearance ≤30 mL/min, an alternative verification of the renal function must be completed using Cystatin C analysis. In case of normal level of Cystatin C, the patient can be included; • heart disease (myocardial infarction, unstable angina, heart failure, Cardiomyopathy within six months before screening); • bradycardia (heart beat <50/min.) or tachycardia (heart beat >95/min); • hypertension (>180/95) or hypotension (<90/60) requiring treatment with more than three drugs; •AV block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcB-interval (males >450 and females >470 msec); • uncontrolled diabetes defined by HbA1c >8.5;
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 24 Jul 2023 | 40 |
 Germany | Recruiting | 24 Jul 2023 | 30 |
 Italy | Recruiting | 24 Jul 2023 | 278 |
 Spain | Not Yet Recruiting | 24 Jul 2023 | 30 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Neupro 4mg/24h transdermal patch | Test | TRANSDERMAL PATCH | TRANSDERMAL USE | 4 | 6 | PRD5478782 |
Identical with the MP patches but without the active substance | Placebo | N/A | — | — | — | N/A |
Neupro 2 mg/24 h transdermal patch | Test | TRANSDERMAL PATCH | TRANSDERMAL USE | 2 | 24 | PRD5476459 |