Zambon SUCCESS Parkinson Disease Study Protocol V.2.0
Research type
Research Study
Full title
AN OBSERVATIONAL, PROSPECTIVE, MULTINATIONAL, MULTICENTRE STUDY COMPARING THE EFFECTIVENESS OF SAFINAMIDE, RASAGILINE AND OTHER “STANDARD OF CARE” AS ADD-ON THERAPY TO LEVODOPA (L-DOPA) IN PARKINSON’S DISEASE (PD) FLUCTUATING PATIENTS
IRAS ID
271577
Contact name
Nicola Pavese
Contact email
Sponsor organisation
Zambon S.p.A.
Duration of Study in the UK
2 years, 1 months, 31 days
Research summary
Research Summary
The Study is an observational, prospective, multinational, multicentre study comparing the effectiveness of safinamide, rasagiline and other “standard of care” as add-on therapy to levodopa (L-dopa) in Parkinson’s disease (pd) fluctuating patients.
The aim of this observational study is to evaluate the effectiveness of safinamide, rasagiline and other standard of care drugs when prescribed in clinical routine as add-on to L-dopa in terms of quality of life, improvement of chronic pain, change in Anti-Parkinson treatment (modification of doses, addition or withdrawal or other Anti-Parkinson drugs, etc.), use of concomitant pain-killer medications, hospitalisations and use of other healthcare resources, and number of lost working days.
Approximately, 1235 patients will be enrolled within 5 countries (UK, Belgium, Germany, Italy, Spain) and spitted into 3 groups according to the received treatment: safinamide, rasagiline and other “standard of care” as add-on therapy to levodopa (L-dopa).
The enrolled period will be approximately 9 month and all patient will be followed for approximately 12 month.
The current study will collect data from 3 clinical visits: a baseline visit at the start of the observation period, a second visit approximately 6-months later, and a final visit at the end of the observation period (approximately 12-months). Visits will be scheduled per standard clinical practice.Summary of results
Study population In total, 1133 patients with PD were enrolled (ENR analysis set), of whom 506 patients (44.7%) received safinamide, 430 patients (38.0%) received rasagiline, and 197 patients (17.4%) received Other SoC. The majority of the safinamide patients were enrolled between Q3 2020 and Q2 2021, whereas 50% of the patients who received rasagiline were enrolled from Q4 2021 and Q1 2022. A low proportion of patients withdrew, with the majority of patients (87.7%) completing the study. All the 1133 enrolled patients (ENR) are included in the SAF and 1050 patients (92.7%) are included in the EAS.
In the ENR, the mean (standard deviation [SD]) age of the patients was 69.2 (9.62) years in the safinamide group; 69.8 (9.14) years in the rasagiline group, and 70.0 (8.38) years in the Other SoC group. Overall, more than half of the patients were male: 55.1% in the safinamide group, 62.3% in the rasagiline group and 55.3% in the Other SoC group. Majority of the patients were Not Hispanic or Latino: 52.6% in the safinamide group, 56.5% in the rasagiline group and 60.9% in the Other SoC group. The mean (SD) delay from symptom onset to diagnosis was 12.2 (10.57) months in the safinamide group; 11.5 (19.52) months in the rasagiline group and 12.1 (10.63) months in the Other SoC group. The mean (SD) disease duration at baseline was 6.0 (5.60) years in the safinamide group, 4.6 (4.31) years in the rasagiline group and 6.5 (5.32) years in the Other SoC group. The mean (SD) time from treatment start to baseline was 3.1 (2.65) weeks in the safinamide group, 2.6 (2.48) weeks in the rasagiline group and 2.9 (4.65) weeks in the Other SoC group. Functional disability of Stage 2 (by Hoehn and Yahr scale) was the most common, reported in 41.5% of patients in the safinamide group, 42.3% of patients in the rasagiline group and 42.6% of patients in the Other SoC group. Bradykinesia was the most common motor symptom, reported in 92.1% of patients in the safinamide group, 92.1% of patients in the rasagiline group and 94.4% of patients in the Other SoC group.
In the SAF, the mean (SD) duration for treatment was 359.6 (111.43) days in the safinamide group, 344.1 (116.14) days in the rasagiline group, and 343.6 (116.86) days for Other SoC group. Among the patients in the safinamide group, 2 patients (0.4%) switched to rasagiline, 10 patients (2.0%) switched to Other SoC, 14 patients (2.8%) had a temporary interruption, and 63 patients (12.5%) had a permanent discontinuation. Among the patients in the rasagiline group, 6 patients (1.4%) switched to safinamide and 11 patients (2.6%) switched to Other SoC, 1 patient (0.2%) had a temporary interruption, and 51 patients (11.9%) had a permanent discontinuation. Among the patients in the Other SoC group, 2 patients (1.0% each) switched to safinamide and rasagiline, respectively, 1 patient (0.5%) had a temporary interruption, and 30 patients (15.2%) had a permanent discontinuation.
Primary analysis: Change in PDQ-39 SI score (imputed values; EAS) From Baseline to Visit 3, there was a minimal increase in the PDQ-39 SI score in the safinamide (mean change: 0.2) and rasagiline (mean change: 0.3) groups, and a small decrease in the Other SoC group (mean change: -0.6).
When comparing the patients who received safinamide with rasagiline, there were no significant differences in change in PDQ-39 SI scores from Baseline to Visit 3, after adjusting for confounding using an inverse probability of treatment weighting method (AIPW method) (ATE: 0.85; 95% CI: -0.68, 2.48). Similarly, there was no difference in the change in PDQ-39 SI from Baseline to Visit 3 when comparing safinamide or rasagiline to Other SoC (AIPW adjustment: safinamide vs Other SoC: ATE=1.37; 95% CI: -0.76, 3.59; rasagiline vs Other SoC: ATE=0.39; 95% CI: -2.82, 3.92).
Secondary analysis results
• PDQ-39 domains scores (imputed values; EAS) The stigma domain of the PDQ-39 had the largest reduction between Baseline and Visit 3 in the safinamide group (mean [SD] change: -2.1 [21.0]), followed by bodily pain (mean [SD] change: -1.3 [21.2]). The cognition and communication domains had significantly greater reductions between Baseline and Visit 2 in the safinamide group compared with rasagiline after adjusting for confounding (cognition domain ATE: -2.53 [AIPW method]; 95% CI -4.70, -0.40; communication domain ATE: -2.38 [AIPW method]; 95% CI -4.52, -0.21); there were no significant differences between the groups between Baseline and Visit 3. Similarly, social support domain score had significantly greater reductions between Baseline and Visit 2 in the safinamide group compared with Other SoC after adjusting for confounding (ATE: -2.55 [AIPW method]; 95% CI -4.94, -0.16).
• UPDRS (imputed values; EAS)
The mean (SD) UPDRS-III at baseline was 24.4 (11.85) in the safinamide group, 23.0 (11.17) in the rasagiline group, and 25.4 (12.69) in the Other SoC group. The score did not change over follow-up for the safinamide and rasagiline groups. However, in the Other SoC group, the mean (SD) change in UPDRS-III score (from baseline) at Visit 2 and Visit 3, were 0.3 (8.62) and 1.1 (9.13), respectively.
In adjusted analysis, there were no significant differences between safinamide and rasagiline groups in terms of change in UPDRS-III between Baseline and Visit 2 (ATE: -0.02 [AIPW method]; 95% CI -1.23, 1.19) and Visit 3 (ATE: -0.01 [AIPW method]; 95% CI -1.22, 1.23). However, there was a significant difference between safinamide and Other SoC in terms of change in UPDRS-III between Baseline and Visit 2 (ATE: -1.59 [AIPW method]; 95% CI -3.10, -0.15) and Visit 3 (ATE: -1.68 [AIPW method]; 95% CI -3.28, -0.13).
• NRS (imputed values; EAS)
The pain NRS score did not change over follow-up in the safinamide group (mean [SD] Baseline: 3.1 [2.90]; mean [SD] change from Baseline to Visit 3: 0.4 [2.94]). There were also no differences between safinamide and rasagiline group in terms of change in NRS between Baseline and Visit 2 (ATE: 0.08 [AIPW method]; 95% CI -0.27, 0.43) and Visit 3 (ATE: 0.03 [AIPW method]; 95% CI -0.32, 0.36).
Also, there were no differences between the safinamide and Other SoC groups at either visit (Visit 2 – ATE: 0.03 [AIPW method]; 95% CI -0.39, 0.45; Visit 3 – ATE: 0.07 [AIPW method]; 95% CI -0.39, 0.50), or between the rasagiline and Other SoC groups at either visit (Visit 2 – ATE: 0.09 [AIPW method]; 95% CI -0.55, 0.94; Visit 3 – ATE: 0.06 [AIPW method]; 95% CI -1.02, 0.63).
• Anti-Parkinson medications (EAS)
At baseline, the mean (SD) number of anti-PD medications was 1.5 (0.80) in the safinamide group, 1.4 (0.70; N=151) in the rasagiline group, and 1.3 (0.51; N=86) in the Other SoC group. At Visit 2, the mean (SD) change from baseline in the number of anti-PD drugs was 0.0 (0.23) for safinamide group, -0.1 (0.25) for rasagiline group, 0.1 (0.45) for Other SoC group. At Visit 3, the mean (SD) change from baseline in the number of anti-PD drugs was 0.0 (0.34) for the safinamide group, 0.0 (0.34) for rasagiline group, and 0.2 (0.56) for Other SoC group.
After adjustment, there was a small decrease in the mean number of anti-PD medications received in the safinamide group compared to patients in the rasagiline group between Baseline and Visit 3 (ATE: -0.06 [AIPW method]; 95% CI -0.1197, -0.0100). There was also a significant increase in the number of anti-PD medications in the Other SoC group compared to the safinamide group (Visit 2 - ATE: -0.06 [AIPW method]; 95% CI -0.1271, -0.0020; Visit 3 - ATE: -0.11 [AIPW method]; 95% CI -0.1946, -0.0411).
• “Pain-killer” medications (EAS)
Between Baseline and Visit 3, 231 patients (49.1%) in the safinamide group, 130 patients (33.2%) in the rasagiline group and 72 patients (38.1%) in the Other SoC group received pain-killer medications. Patients in the safinamide group used more new pain-killer medications between Baseline and Visit 2 than patients in the Other SoC group (ATE: 0.066 [AIPW method]; 95% CI 0.0015, 0.1347).
Healthcare resource utilisation (HCRU) and lost working days (EAS) Due to the COVID-19 pandemic, which was characterized by lockdowns and social isolation, many patients were not able to attend visits, most data for healthcare resource utilisation were represented by zeros.
After adjustment the following differences were observed in EAS:
- The number of ER visits between Baseline and Visit 3 was higher in the rasagiline group than in the SoC group (RR: 2.53; 95% CI 1.18, 5.45).
- The number of PD visits between Baseline and Visit 2 was higher in the safinamide group than in the rasagiline group (RR: 1.34; 95% CI 1.09, 1.65) and was lower in the rasagiline group than in the Other SoC group (RR: 0.77; 95% CI 0.62, 0.95). Between Baseline and Visit 3, the number of PD visits were lower in the safinamide group than in the rasagiline (RR: 0.82; 95% CI: 0.68, 0.99) or Other SoC groups (RR: 0.66; 95% CI 0.53, 0.80). Lower number of PD visits were also reported in the rasagiline group than in the Other SoC group (RR: 0.65; 95% CI 0.52, 0.82).
- The number of diagnostic examinations visits between Baseline and Visit 2 was higher in the safinamide group than in the SoC group (RR: 1.54; 95% CI 1.22, 1.96). Between Baseline and Visit 3, number of diagnostic examinations visits was higher in the safinamide group than in the rasagiline group (RR: 1.39; 95% CI 1.11, 1.75). Lower number of diagnostic examinations visits were also reported in the rasagiline group than in the Other SoC group (RR: 0.60; 95% CI 0.44, 0.81).
- The number of rehabilitation visits between Baseline and Visit 2 was higher in patients who in the safinamide group than in the rasagiline group (RR: 1.64; 95% CI 1.52, 1.77) or Other SoC (RR: 1.34; 95% CI 1.22, 1.48). A similar result was also observed between Baseline and Visit 3: the number of rehabilitation visits was higher in the safinamide group than in the rasagiline group (RR: 1.15; 95% CI: 1.08, 1.22). The safinamide group has also shown a higher number of rehabilitation visits between baseline and V3 compared to Other SoC (RR: 1.76; 95% CI: 1.60, 1.94). The number of rehabilitation visits was also higher in the rasagiline group than in the Other SoC group (RR: 1.78; 95% CI: 1.62, 1.95).
- The number of lost working days, between Baseline and Visit 2, was higher in the safinamide group than in the rasagiline group (RR: 2.47; 95% CI 2.24, 2.73) or Other SoC (RR: 29.15; 95% CI 20.66, 41.13) and was higher in the rasagiline group than in the Other SoC group (RR: 2.19; 95% CI 1.66, 2.89). Between Baseline and Visit 3, the number of lost working days was lower in the safinamide group than in the rasagiline group (RR: 0.28; 95% CI 0.24, 0.31).
Safety analysis results
Over one-third of patients in the safinamide experienced a TEAE (36.2%) during the follow-up period, similar to rasagiline (38.6%) and Other SoC (32.0%). Likewise, similar proportions of patients in the safinamide, rasagiline and Other SoC groups experienced serious TEAEs (11.5% vs 11.4% vs 12.2%) and TEAEs leading to treatment discontinuation (8.9% vs 8.1% vs 9.1%). The proportion of patients who experienced at least one TEAE considered causally related to study treatment was also similar between the safinamide and rasagiline groups (8.3% vs 8.6%); 12.7% of patients in the Other SoC group experienced at least one TEAE considered causally related to study treatment.
Discussion and Conclusions: The SUCCESS study enrolled 1133 patients with PD, including 506 patients in the safinamide group, 430 patients in the rasagiline group, and 197 patients in the Other SoC group.
The observed changes in patients’ QoL (PDQ-39 SI score) over the study period were 0.2 points for safinamide, 0.3 points for rasagiline and -0.5 points for Other SoC, none exceeding the minimal clinically important difference threshold (-1.6 units), indicating that the QoL of patients in all three treatment groups did not meaningfully change over the follow-up period, and thus the QoL remained stable during the study by all treatment groups. Patients in the safinamide group tended to have more severe disease at baseline when compared with patients in the rasagiline group, including QoL, concomitant medications, disease duration, and comorbidities. Patients in the safinamide group had similar baseline QoL and disease duration to the Other SoC group but received more concomitant medications. In order to balance these potential confounding factors between the groups, a propensity score-based analysis was used when comparing the three treatment groups in terms of QoL over follow-up. This analysis showed no difference in change in PDQ-39 SI score over the study period. Similarly to QoL, other endpoints including disability (UPDRS) and pain (NRS) did not change above the minimal clinically important difference over follow-up. Whilst the confounding effect of baseline imbalances in characteristics between the groups was addressed through the propensity score analysis, other factors could be influencing these comparisons. The first is the COVID-19 pandemic. The pandemic had a profound effect on the majority of the world’s population, leading to increased social isolation and anxiety. Therefore, the pandemic likely affected the QoL of the patients included in this study. More patients in the safinamide group were recruited mainly during the pandemic (Q3 2020-Q2 2021) compared with the other two groups. These periods of the pandemic were generally characterised by stricter lockdown rules and more uncertainty, potentially influencing QoL to a greater extent. Therefore, this differential in time-period of recruitment between the treatment groups likely resulted in bias within the analysis. Furthermore, the pandemic influenced the ability to complete routine clinic visits, potentially influencing the level of care patients received, further exacerbating the bias caused by the pandemic on this analysis. This is illustrated by the low number of visits for PD and other healthcare utilisations over the study period. The results of HCRU were also influenced by a high number of zeros in the data, which led to challenging interpretation of the results, with no clear trend.
Regarding safety, approximately one-third of patients in all treatment groups experienced a TEAE during the follow-up period (safinamide: 36.2%; rasagiline: 38.6%; Other SoC: 32.0%).
Likewise, the proportions of patients who had serious TEAEs and TEAEs leading to discontinuation were similar across the treatment groups, indicating the comparative safety profile of the three groups. A higher proportion of patients in the Other SoC group experienced at least one AE considered causally related to study treatment. However, given the caveats above regarding potential differences in patient characteristics at baseline and the effect of the pandemic on standard of care, interpretations of these unadjusted comparisons should be made with caution. Overall, the safety profile of the safinamide appears satisfactory and in line with what included in its approved label.
Limitations of the study include the fact that patients could have had up to 2 months of treatment prior to baseline, potentially leading to treatment influencing baseline data and thus attenuating any observed changes over follow--up. However, most patients were recruited within 4 weeks of treatment start, and there was only half a week difference between the safinamide and rasagiline groups, and therefore bias was likely minimal. Pain NRS scores in this study at baseline were low (indicating mild pain). This meant there was limited opportunity for pain NRS scores to improve over the study period, making it difficult to assess the effectiveness of the treatments on pain levels.
In conclusion, SUCCESS is a large cohort of patients with PD receiving safinamide, rasagiline or Other SoC treatments. These patients typically maintained their QoL, pain, and disability over the course of the study. Adjusted analyses illustrated mostly no differences between the three treatment groups regarding QoL or other outcomes over time. However, these comparative effectiveness analyses are likely influenced by the COVID-19 pandemic. In terms of safety, patients who received safinamide in SUCCESS had a similar safety profile compared with the rasagiline and Other SoC groups.
Ethical and Regulatory Considerations: To ensure the quality and integrity of research, this study was conducted in compliance with the last version of the Declaration of Helsinki. The study was also conducted in compliance with the Guidelines for Good Clinical Practice (GCP) where applicable, the Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the International Society for Pharmacoepidemiology (ISPE), and the European Medicines Agency (EMA) Good Pharmacovigilance Practices (GVP) Guidelines (Module VI and VIII), with the applicable regulatory requirements of the participating countries, and with the Zambon and Contract research organization (CRO) Standard Operating Procedures (SOPs).
This study was undertaken only after written and dated approval from the Ethics committee (EC) and Regulatory Authorities (RA) where applicable had been received by the Investigator and by the Sponsor/CRO for the study protocol, all its appendices, and the ICF.REC name
HSC REC A
REC reference
19/NI/0209
Date of REC Opinion
11 Dec 2019
REC opinion
Further Information Favourable Opinion