Disease-modifying effect, effect on motor symptoms, and safety of levodopa/DCI in combination with selegiline or zonisamide will be evaluated in patients with Parkinson’s disease who are currently treated with levodopa/DCI.
Multicenter, prospective, randomized, parallel-group, open-label study.
The primary endpoint is the percent change of SBR of DAT-SPECT from the first evaluation to the final evaluation at 1 year. The first DAT-SPECT will be conducted between 14 and 42 days after randomization, and the second will be conducted between 365 and 393 days (Figure 1).
The method of SBR measurement is as follows: (1) [123I] FP-CIT 167MBq (DaTSCAN; Nihon Medi-Physics, Tokyo, Japan) will be intravenously administered under a resting state with patient’s eyes closed. (2) Continuous repetitive rotation acquisition will be performed for 20 to 30 min after 180 min of [123I] FP-CIT administration. The scan range will be adjusted to cover the entire brain, including the vertex and cerebellum. (3) Reconstruction of DAT-SPECT will be performed in accordance with the method used by the institution. (4) Neither scatter correction nor attenuation correction will be performed. (5) SBR, the specific binding capacity of striatum, will be calculated using the SBR analysis software DaTView (Aze corporation, Kanagawa, Japan) [19, 20].
Secondary endpoints are the percent change of UPDRS Part II and Part III scores and Parkinson's Disease Questionnaire (PDQ)-39 scores from baseline to post-treatment. UPDRS is a widely-used standard for comprehensive evaluation of severity of Parkinson’s disease. Assessment of mental state, ADL, motor function, and treatment-related complications is made on a scale of 5. UPDRS Part II and Part III will be used in this study. PDQ-39 is a Parkinson’s disease-specific tool for quality of life assessment based on 8 aspects (mobility, ADL, emotional well-being, stigma, social support, cognitions, communication, and bodily discomfort).
The primary objective of this study is to select a candidate arm to elucidate the additive effect of selegiline or zonisamide to levodopa/DCI. A screening design will therefore be used. When this study is conducted as a phase II randomized controlled study using a significance level α of 0.20 (one sided) to take into account indeterminate results, Bonferroni’s multiple comparison adjustment will provide a p-value of 0.10 (0.20/2) in 2 inter-group comparisons with levodopa/DCI. By using the reported minimum SBR reduction rate in DAT-SPECT for levodopa/DCI alone (4%) , the reported maximum SBR reduction rate in combination therapy (7.5%), and standard deviation of 10% (common value), the minimum required sample size to make the power (1-β) 0.70 or higher will be 54. Expecting around 10% of participants to be ineligible or withdraw from the study, one treatment arm should include 60 patients (180 in total).
Patients with early stage of Parkinson’s disease (within 3 years of onset) will be eligible to participate in the study. Participants will be recruited from the Neurology experts of 13 general hospitals specialized in Parkinson’s disease treatment.
Patients with Parkinson’s disease diagnosed based on the UK Brain Bank criteria and treated with levodopa/DCI at the participating institutions at the time of registration and those who fulfil the following inclusion criteria will be included in the study:
(1) Aged ≥55 and <80 at the time of registration
(2) Within 3 years of onset of motor symptoms
(3) Within 3 months after starting levodopa/DCI and having been treated with levodopa/DCI alone for at least 28 days immediately before starting the study treatment
(4) Receiving levodopa/DCI at a daily dose between 150 and 300 mg
(5) Mini-Mental State Examination score of 24 or higher
(6) Eligibility determined by the physician
(7) Capable of providing written consent to participate in this study
Patients who meet any of the following criteria will be excluded from this study:
(1) Treated with drugs other than levodopa/DCI for Parkinson’s disease for 1 month or longer
(2) Confirmed or possible pregnancy, breastfeeding
(3) Currently being treated with antidepressant(s) or antipsychotic(s)
(4) Past or current infarction or cerebrovascular disease in the basal ganglia
(not including asymptomatic lacunar infarction)
(5) History of epilepsy or currently under treatment for epilepsy
(6) Under treatment for alcohol poisoning
(7) Serious complication(s) (e.g., hepatic damage, renal damage, endocrine disease)
(8) Family history of Parkinson’s disease
(9) Hypersensitivity to 123I-ioflupane
Sampling and recruitment strategies
Potential study participants who consulted the participating institutions will be continuously sampled. The target sample size will be achieved because many patients with Parkinson’s disease are treated at the participating institutions. The cost of DAT-SPECT is covered by research funds.
Eligible patients with Parkinson’s disease will be randomly assigned to three arms; (1) levodopa/DCI alone, (2) levodopa/DCI + selegiline, or (3) levodopa/DCI + zonisamide. The minimization method will be used for randomization. Institution and age will be the adjustment factors for medication assignment. The study dose will be levodopa/DCI 150–300 mg/day, selegiline 5 mg/day, and zonisamide 25 mg/day.
The investigators will screen potential participants, provide information on this study to eligible patients based on the information documents, obtain written consent from them, and interview them to obtain demographic and background information. All primary and secondary outcome data will be collected at baseline and 1 year. All evaluations will be made when the motor symptoms are in “on” state. The participating patients will be instructed to avoid taking anti-Parkinson drugs other than the study drugs, and all the drugs known to affect DAT-SPECT (Figure 2). The subject will be withdrawn from the study when there is (1) the subject’s request, (2) occurrence of severe adverse events, (3) worsening of the subject’s medical condition, and (4) eligibility criteria violation. The Data Center (Clinical Study Support Center, Wakayama Medical University) is responsible for data management, central monitoring, and statistical analysis. The audit will be conducted by quality assurance room (Clinical Study Support Center, Wakayama Medical University) independently from investigators and the sponsor.
Primary analysis and evaluation criteria
Percent change of SBR [(SBRpre – SBRpost)/SBRpre] will be calculated based on SBR of DAT-SPECT for the initial evaluation (SBRpre) and SBR at the time of final evaluation at 1 year (SBRpost) for each patient in the full analysis set. The one-sided alternative hypothesis “the reduction rate in the levodopa/DCI alone arm is higher than that in the levodopa/DCI + selegiline arm or the levodopa/DCI + zonisamide arm” will be tested against the null hypothesis “the mean reduction rate is comparable between the levodopa/DCI alone arm and levodopa/DCI + selegiline arm and between the levodopa/DCI alone arm and the levodopa/DCI + zonisamide arm” using the two-sample t-test. The Bonferroni adjustment will be used while considering multiple comparisons. The combination therapy will be considered more effective than levodopa/DCI alone if p-value from the test is less than 0.10 and the reduction rate in the combination therapy arm is lower than that in the levodopa/DCI alone arm. If levodopa/DCI + selegiline and levodopa/DCI + zonisamide are both effective, the treatment arm with lower SBR reduction rate will be considered a candidate treatment.
Evaluation of primary endpoint
In addition to evaluation based on the primary analysis and evaluation criteria, 95% confidence interval (CI) for the sample mean of percent change of SBR and population mean will be calculated for each arm. Two-sample t-test will be performed for the mean percent change of SBR in the levodopa/DCI + selegiline arm and levodopa/DCI + zonisamide arm. A subgroup analysis will be performed to compare the patient background and adjustment factors for treatment assignment among the treatment arms. If a bias is found in the adjustment factors for treatment assignment or patient background (p = 0.20), a multiple regression analysis will be performed using the biased factor and the treatment arm (the levodopa/DCI alone group as control) as independent variables.
Evaluation of secondary efficacy endpoints
UPDRS scores and PDQ-39 scores will be compared between the levodopa/DCI alone arm and levodopa/DCI + selegiline arm and between the levodopa/DCI alone arm and levodopa/DCI + zonisamide arm using two-sample t-test with Bonferroni adjustment. 95% CI will be calculated for sample mean and population mean in each treatment arm.
autonomy, privacy, and confidentiality
The protocol of this study was approved by the Ethical Review Board of Wakayama Medical University in January 2016 and registered at the University Hospital Medical Information Network (UMIN) clinical trials registry in May 2016 (UMIN000022533). Potential participants will be provided thorough information on this study based on the information document to help them for making a decision about their participation in this study. Voluntary written consent for study participation will be obtained from them. Request for withdrawal of consent from participants will be accepted anytime. If any matters affecting the decision of participants to continue their participation in this study arise, the information document will be revised, the study participants will be provided study information based on the revised information document, and written consent to continue their participation will be obtained. Personal information will be anonymized and maintained in a securely locked database. The protocol of this study will be carried out in accordance with the Declaration of Helsinki.
Risks and safety
Levodopa/DCI, selegiline, zonisamide, and 123I-ioflupane to be used in this study are already in clinical use. The study dosage will be within the scope of the approved clinical dosage; therefore, the treatment will be highly safe. However, the participants will be exposed to low-dose radiation more frequently than regular clinical practice because of DAT-SPECT that will be performed twice within a year. The candidate participants will be thoroughly informed of the additional irradiation.