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In a study, PRODUODOPA provided a significant improvement (increase) in average daily normalised ‘On’ time without troublesome dyskinesia and a significant reduction (decrease) in average daily normalised ‘Off’ time vs oral IR LD/CD at 12 weeks. 1
A pivotal, Phase 3, randomised, double-blind, double-dummy, active-controlled study evaluating the efficacy, safety and tolerability of 24- hour daily continuous subcutaneous infusion of PRODUODOPA (n=74) compared with oral IR levodopa/carbidopa (n=67) for the treatment of motor fluctuations in patients with advanced PD (N=141) at 12 weeks. 1
- Of the 74 patients randomised to receive PRODUODOPA, 48 completed the study and 26 discontinued treatment.
- Of the 67 patients receiving optimised oral IR levodopa/carbidopa (LD/CD), 62 completed treatment and 5 discontinued.
- Primary reasons for drug discontinuation in both groups were adverse events, withdrawn consent, and difficulty with the drug delivery system. The incidence of adverse events leading to study drug discontinuation was higher in the PRODUODOPA group with infusion site adverse events (cellulitis 4/74 [5%]), pain (3/74 [4%]), bruising, haemmorrhage and oedema (2/74 [3%]) being most common.1
Change from baseline to Week 12 in average daily normalised ‘On’ time without troublesome dyskinesia was the primary endpoint. ‘On’ time without troublesome dyskinesia is the sum of normalised ‘On’ time without dyskinesia and normalised ‘On’ time with non-troublesome dyskinesia. 1
Key secondary endpoints included change from baseline to Week 12 in average daily normalised ‘Off’ time, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II score and presence of morning akinesia at Week 12. Morning akinesia is defined as reporting ‘Off’ status as the first morning symptom on waking. 1
- Secondary efficacy endpoints were tested in a hierarchical order:1
- Hierarchical testing for significance was terminated at the first secondary endpoint, change in MDS-UPDRS Part II, as this did not reach statistical significance.1
- As the secondary endpoints following MDS-UPDRS Part II weren’t tested for significance, no p values are available in the referenced publication and no clinical conclusions can be drawn from these endpoints.1
‘On’ and ‘Off’ times and morning akinesia were assessed using a 24-hour Parkinson’s disease diary and normalised to a 16-hour waking day. 1
Average daily normalised ‘On’ time without troublesome dyskinesia and normalised ‘Off’ time at 12 weeks1
‘On’ time without troublesome dyskinesia is the sum of normalised ‘On’ time without dyskinesia and normalised ‘On’ time with non-troublesome dyskinesia. Assessed using a 24-hour PD Diary and normalised to a 16-hour waking day. The mean daily normalised ‘On’ time without troublesome dyskinesia for patients on PRODUODOPA was 9.20 hours (SE 2.42) at baseline and 9.49 hours (SE 2.62) for patients taking optimised oral IR LD/CD. The mean daily normalised ‘Off’ time for patients on PRODUODOPA was 6.34 hours (SE 2.27) at baseline and 5.91 hours (SE 1.88) for patients taking optimised oral IR LD/CD.
Adverse events (AEs) were reported in 63 (85%) of 74 patients treated with PRODUODOPA and 42 (63%) of 67 patients treated with oral IR LD/CD at Week 12.1
Overview of treatment-emergent AEs (safety analysis set)1
| At 12 weeks | PRODUODOPA (n=74) | Oral LD/CD (n=67) |
Adverse events, n (%) | 63 (85) | 42 (63) |
Deaths, n (%) | 0 | 1 (1) |
Serious adverse events, n (%) | 6 (8) | 4 (6) |
Severe adverse events, n (%) | 7 (9) | 1 (1) |
Any adverse event leading to death, n (%) | 0 | 1 (1)* |
Any adverse event leading to premature study drug discontinuation,† n (%) | 16 (22) | 1 (1) |
Any adverse event considered related to study drug, n (%) | 52 (70) | 15 (22) |
Adapted from Soileau MJ, et al. 2022.
Preferred terms classified according to the Medical Dictionary for Regulatory Activities version 24.0.
*Considered by the investigator to have no reasonable possibility of being related to study drug. †Adverse events were one of the reasons for discontinuation, irrespective of whether it was the primary reason.
AEs of special interest1
| At 12 weeks | PRODUODOPA (n=74) | Oral LD/CD (n=67) |
Infusion site events, n (%) | 53 (72) | 8 (12) |
Hallucinations or psychosis, n (%) | 11 (15) | 2 (3) |
Falls and associated injuries, n (%) | 13 (18) | 17 (25) |
Somnolence, n (%) | 1 (1) | 1 (1) |
Polyneuropathy, n (%) | 2 (3) | 2 (3) |
Weight loss, n (%) | 1 (1) | 1 (1) |
Adapted from Soileau MJ, et al. 2022.
Most frequent (≥5%) AEs1
| At 12 weeks | PRODUODOPA (n=74) | Oral LD/CD (n=67) |
Infusion site erythema, n (%) | 20 (27) | 1 (1) |
Infusion site pain, n (%) | 19 (26) | 1 (1) |
Infusion site cellulitis, n (%) | 14 (19) | 0 |
Infusion site oedema, n (%) | 9 (12) | 0 |
Dyskinesia, n (%) | 8 (11) | 4 (6) |
Fall, n (%) | 6 (8) | 12 (18) |
Infusion site bruising, n (%) | 6 (8) | 2 (3) |
Infusion site haemorrhage, n (%) | 6 (8) | 0 |
Infusion site nodule, n (%) | 6 (8) | 0 |
‘On’ and ‘Off’ phenomena, n (%) | 6 (8) | 0 |
Hallucination, n (%) | 5 (7) | 1 (1) |
Balance disorder, n (%) | 4 (5) | 0 |
Constipation, n (%) | 4 (5) | 0 |
Hallucination visual, n (%) | 4 (5) | 0 |
Infusion site induration, n (%) | 4 (5) | 0 |
Infusion site infection, n (%) | 4 (5) | 0 |
Infusion site pruritus, n (%) | 4 (5) | 0 |
Peripheral swelling, n (%) | 4 (5) | 0 |
Adapted from Soileau MJ, et al. 2022.
AE: Adverse Event
References
- Soileau MJ, et al. Lancet Neurol. 2022;21:1099–1109.
IL-PRODD-240009. Date of preparation: July 2024.
Study design1
Duration: 12 weeks.
Study type: Pivotal, Phase 3, randomised, double-blind, double-dummy, active-controlled study conducted at 65 academic and community study centres in the USA and Australia.
Patient population: Patients aged at ≥30 years with a diagnosis of idiopathic and levodopa-responsive Parkinson’s disease (PD). Patients were required to be on a minimum of 400 mg/day levodopa equivalents (from levodopa-containing medications and catechol-O-methyl transferase (COMT) inhibitors), and have inadequately controlled motor fluctuations with an average off time of at least 2.5 hours/day over 3 consecutive days.
Aim: To assess the efficacy and safety of 24-hour/day continuous subcutaneous infusion of PRODUODOPA compared with oral immediate-release (IR) levodopa/carbidopa (LD/CD) for the treatment of motor fluctuations in patients with advanced Parkinson’s disease.
Methods: The study included a screening period (6–60 days), an oral LD/CD stabilisation period (2–3 weeks), and a double-blind treatment period (12 weeks) for a total of 13 scheduled visits. 141 patients were randomised 1:1 to either 24-hour/day CSCI of PROUDODOPA plus oral placebo or 24-hour/day CSCI of placebo solution plus oral LD/CD:
- Of the 74 patients randomised to receive PRODUODOPA, 48 completed the study and 26 discontinued treatment (14 from adverse event, 5 withdrew consent, 1 from lack of efficacy, 4 had difficulty with drug delivery system and 2 others)
- Of the 67 patients receiving optimised oral IR LD/CD, 62 completed treatment and 5 discontinued (1 from adverse event, 3 withdrew consent and 1 had difficulty with drug delivery system)
- Primary reasons for drug discontinuation in both groups were adverse events, withdrawn consent, and difficulty with the drug delivery system. The incidence of adverse events leading to study drug discontinuation was higher in the PRODUODOPA group with infusion site adverse events (cellulitis 4/74 [5%]), pain (3/74 [4%]), bruising, haemmorrhage and oedema (2/74 [3%]) being most common
