Product information and disease description Place of product in therapy Approaches to treatment

Heterogeneity of treatment effect

19 evidence topics · 17 sources

Tavapadon: predefined subgroups in the fixed-dose monotherapy trial

“In addition to the consistent efficacy outcomes in the overall tavapadon group, subgroup analyses of participants treated with both 5-mg and 15-mg doses of tavapadon demonstrated motor improvement across predefined subgroups, although greatest consistency in improvements was seen in the 15-mg group, which suggests a higher dose of tavapadon may be necessary for specific populations.” (opens the source at this quote in a new tab)
“Further study may be needed to confirm these findings.” (opens the source at this quote in a new tab)
“Most participants (514 of 529 [97.2%]) were White, which may impact generalizability.” (opens the source at this quote in a new tab)

Tavapadon: predefined subgroups in the flexible-dose monotherapy trial

“The effect of tavapadon versus placebo on MDS-UPDRS Parts II and III combined scores was consistent at week 26 across subgroups by age (<65 years vs ≥65 years), sex, mH&Y staging at screening, baseline MDS-UPDRS Part II and III individual scores, concomitant use of an MAO-B inhibitor, disease duration (<1 year, 1 year to <2 years), and geographical region (appendix p 5).” (opens the source at this quote in a new tab)
“More than half of the participants were male (169 [56%] of 304) and most were White (268 [88%] of 304)” (opens the source at this quote in a new tab)

Tavapadon: representativeness of the adjunctive trial population

“This study was not designed to compare tavapadon with D2/D3 DAs or other adjunctive therapies for PD.” (opens the source at this quote in a new tab)
“The study population was predominantly White (96.8%), and further study of tavapadon in underrepresented populations may be needed.” (opens the source at this quote in a new tab)

Patient characteristics that modify the risk of dyskinesia and impulse control disorders

“Patient and disease characteristics influence the risk of adverse effects related to the use of levodopa and dopamine agonists and may affect initial treatment choices.” (opens the source at this quote in a new tab)
“Predisposing patient characteristics for ICDs are male sex, younger age, history of ICDs, history of mood disorders (particularly depression), the presence of apathy, and a family history of ICDs and addiction.” (opens the source at this quote in a new tab)
“Older patients are at greater risk for cognitive and behavioral adverse effects of dopamine agonists.” (opens the source at this quote in a new tab)

Predisposing factors for dyskinesia and dopamine agonist adverse effects in early disease

“Younger age at disease onset, lower body weight, female sex, and increased disease severity are all predisposing factors for the development of levodopa-induced dyskinesia.” (opens the source at this quote in a new tab)
“DAs are associated with a greater risk of excessive daytime somnolence and sleep attacks; therefore, patients whose employment requires driving or operating heavy machinery may face greater impairment from these adverse effects.” (opens the source at this quote in a new tab)
“The trend demonstrates that although DAs are more likely than levodopa to cause hallucinations at some time points, the difference between treatments for this outcome is small in early PD for the first 5 years of treatment.” (opens the source at this quote in a new tab)
“This may be related to the inclusion of younger patients without cognitive impairment in early PD trials.” (opens the source at this quote in a new tab)

Clinical and demographic correlates of impulse control disorders

“Additional variables independently associated with ICDs were levodopa use, living in the United States, younger age, being unmarried, current cigarette smoking, and a family history of gambling problems.” (opens the source at this quote in a new tab)

Impulse control disorders across dopaminergic therapies and disease stages

“Recognise that impulse control disorders can develop in a person with Parkinson's disease who is on any dopaminergic therapy at any stage in the disease course.” (opens the source at this quote in a new tab)
“A history of previous impulsive behaviours.” (opens the source at this quote in a new tab)
“A history of alcohol consumption and/or smoking.” (opens the source at this quote in a new tab)

Concomitant dopamine agonists and dyskinesia with levodopa/carbidopa/entacapone

“These effects were more pronounced in patients receiving dopamine agonists at baseline.” (opens the source at this quote in a new tab)
“In patients receiving dopamine agonists, LCE-treated patients had a greater risk of dyskinesia (hazard ration, 1.55; p = 0.006), and a greater frequency of dyskinesia (41.9% vs 31.3%).” (opens the source at this quote in a new tab)
“However, there was no difference in the time to onset (hazard ratio, 0.99; 95% CI, 0.68–1.45; p = 0.96) or frequency (34% vs 35.5%) of dyskinesia between patients in the LCE and LC groups for those not receiving dopamine agonists.” (opens the source at this quote in a new tab)
“Kaplan-Meier survival curves show that among patients who were receiving dopamine agonists at baseline, those randomized to L-dopa/carbidopa/entacapone (LCE) had greater risk of developing dyskinesia than those receiving L-dopa/carbidopa (LC) (Cox proportional hazard ratio, 1.55; 95% confidence interval [CI], 1.13–2.13; p = 0.006).” (opens the source at this quote in a new tab)
“The estimated first quartile time to onset of dyskinesia was 78.9 weeks for the LCE group and 117.4 weeks for LC.” (opens the source at this quote in a new tab)
“The adjusted mean difference in change from baseline to final visit in UPDRS score between the LCE and LC groups was greater in those receiving concomitant dopamine agonists (difference, 1.8; p = 0.08) than in those who were not (difference, −0.1; p = 0.95).” (opens the source at this quote in a new tab)
“Patients on dopamine agonists were younger (58.7±8.6 vs 62.3±7.8 years; p < 0.001), had longer disease duration (2.5±1.6 vs 1.3±1.5 years; p < 0.001)” (opens the source at this quote in a new tab)
“Patients receiving dopamine agonists had a higher frequency of dyskinesias, and LCE was significantly more prone than LC to induce dyskinesias in this subpopulation.” (opens the source at this quote in a new tab)
“This is likely because patients on dopamine agonists were younger at baseline, were about 5 years younger at disease onset, had longer disease duration, and probably had greater disease severity as they had comparable baseline UPDRS scores despite receiving dopamine agonists.” (opens the source at this quote in a new tab)
“It is interesting that LCE did not increase the frequency or shorten the time to onset of dyskinesia in patients not on dopamine agonists, despite higher L-dopa dose equivalents, similar to what was observed in the FIRST-STEP study.” (opens the source at this quote in a new tab)

Dyskinesia frequency by age, sex, body weight, disease duration, and MAO-B inhibitor use with levodopa/carbidopa with or without entacapone

Subgroup	Levodopa/carbidopa/entacapone, no./total (%)	Levodopa/carbidopa, no./total (%)	P value
Age <65 years	“102/223 (45.7)”	“95/253 (37.5)”	“0.021”
Age ≥65 years	“42/150 (28.0)”	“28/119 (23.5)”	“0.162”
Men	“90/245 (36.7)”	“65/222 (29.3)”	“0.043”
Women	“54/128 (42.2)”	“58/150 (38.7)”	“0.191”
Body weight <75 kg	“61/142 (43.0)”	“67/164 (40.9)”	“0.374”
Body weight ≥75 kg	“83/231 (35.9)”	“56/208 (26.9)”	“0.018”
Disease duration <2 years	“75/157 (47.8)”	“50/168 (29.8)”	“<0.001”
Disease duration ≥2 years	“69/216 (31.9)”	“73/204 (35.8)”	“0.514”
Without MAO-B inhibitor	“123/335 (36.7)”	“115/343 (33.5)”	“0.170”
With MAO-B inhibitor	“21/38 (55.3)”	“8/29 (27.6)”	“0.005”

“Dyskinesias were more common in patients younger than 65 years, and LCE was associated with an increased risk of dyskinesia in younger, but not older, patients.” (opens the source at this quote in a new tab)
“Patients with lower body weight (<75kg) had more dyskinesia, but LCE was more likely to induce dyskinesia in heavier patients.” (opens the source at this quote in a new tab)
“Dyskinesias were more common in those with disease duration <2 years, and LCE was more likely to cause dyskinesia in those with a shorter duration of disease (p < 0.01).” (opens the source at this quote in a new tab)
“Finally, patients receiving monoamine oxidase type B inhibitors were more likely to have dyskinesia than those who were not, and although numbers were small, had a much greater chance of having dyskinesia if they were receiving LCE (p = 0.005).” (opens the source at this quote in a new tab)
“p values are post hoc, are not corrected, and are for descriptive purposes only.” (opens the source at this quote in a new tab)

Dopamine agonist subgroup in early versus delayed levodopa

“Nonetheless, on subgroup analysis of dopamine agonists, rate of dyskinesias was smaller in the delayed-start group (OR 1.82; 95% CI: 1.08-3.07; P = 0.03).” (opens the source at this quote in a new tab)

Age and the comparison of initial levodopa with levodopa-sparing therapy

“Patients assigned only between dopamine agonists and MAOBI had less severe disease and were younger, with a mean age of 62 years compared with 71 years in the other two randomisation options.” (opens the source at this quote in a new tab)
“Treatment efficacy, as measured by PDQ-39 mobility subscale, did not differ according to baseline stratification variables (age, Hoehn and Yahr stage, and duration of Parkinson’s disease symptoms).” (opens the source at this quote in a new tab)
“Subgroup comparisons in PD MED noted no difference in treatment efficacy in those younger than and older than 70 years and hence do not support age-specific treatment recommendations.” (opens the source at this quote in a new tab)
“few participants (12%) were younger than 60 years at randomisation, particularly in the levodopa versus levodopa-sparing comparison” (opens the source at this quote in a new tab)
“the trial provides little direct evidence for how such patients should be treated.” (opens the source at this quote in a new tab)

Levodopa response in participants without a dopaminergic deficit on baseline imaging

“nor did subjects with such scans in the group receiving the highest dose of levodopa have an improvement in the scores on the UPDRS (i.e., a change between the score at baseline and at week 40 of 3.38±4.25 units, as compared with a change of −4.95±10.4 units in the subjects receiving levodopa at 600 mg daily whose baseline SPECT scans showed abnormalities; P=0.002).” (opens the source at this quote in a new tab)
“Whether the subjects with no evidence of dopaminergic deficit on scanning do or do not have classic Parkinson’s disease remains uncertain.” (opens the source at this quote in a new tab)
“The fact that scans of some patients with early Parkinson’s disease do not have evidence of a dopaminergic deficit needs to be taken into consideration in the planning of future trials to test drugs for neuroprotective effects.” (opens the source at this quote in a new tab)

Young-onset disease, disease duration, and the frequency of levodopa motor complications

“Most notably, we did not include papers where the motor complication rate was assessed specifically among young-onset (< 40 years) PD patients.” (opens the source at this quote in a new tab)
“The literature suggests that this subgroup of PD patients is at a very high risk for developing both dyskinesias and motor fluctuations relatively early in the course of treatment.” (opens the source at this quote in a new tab)
“One might infer from this study that a typical PD patient (excluding young-onset) has about a 40% likelihood of developing motor fluctuations after 5 years of levodopa therapy.” (opens the source at this quote in a new tab)
“The differences in dyskinesia frequencies between pre-levodopa era versus modern era patients may relate to clinical disease durations prior to starting levodopa therapy.” (opens the source at this quote in a new tab)

Patient characteristics associated with deep brain stimulation outcomes

“Characteristics associated with worse deep brain stimulation outcomes include older age (≥75 years), cognitive impairment (particularly dementia), and the presence of levodopa-unresponsive symptoms (eg, gait, balance disturbance).” (opens the source at this quote in a new tab)

Duration of motor fluctuations and response to opicapone

“A pooled post-hoc analysis of these trials showed similar effect sizes in subjects with a short (≤ 1 year) or longer (> 2 years) history of motor fluctuations at trial start” (opens the source at this quote in a new tab)

Patient profile and disease stage in adjunct selection

“Similarly, in clinical practice, consideration must be given to the patient profile and disease stage.” (opens the source at this quote in a new tab)
“In addition to the varying degree of certainty of the efficacy of an intervention, its safety and individual tolerability must be taken into account, together with each patient's preference.” (opens the source at this quote in a new tab)

D1/D5 agonism in late-stage disease: pilot crossover study

“Neither traditional scales nor clinician impression of change detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients.” (opens the source at this quote in a new tab)

Fixed-dose versus flexible-dose comparison of the monotherapy trials in a meta-analysis

“Because each dosing strategy is represented by exactly one trial, this comparison is equivalent to the between-trial contrast of the primary analysis: fixed-dose TEMPO-1 gave − 11.73 (95% CI − 13.74 to − 9.72) and flexible-dose TEMPO-2 gave − 9.10 (95% CI − 11.70 to − 6.50), a difference of 2.63 points that was not statistically significant (Q(1) = 2.46, p = 0.117). With one trial per stratum this comparison has negligible power and is confounded with every other difference between the two trials; it should not be read as evidence that dosing strategy does not moderate the treatment effect.” (opens the source at this quote in a new tab)

Heterogeneity of pooled adverse event estimates between monotherapy and adjunctive trials

“Overall incidence of AEs was significantly higher in the treatment group (RR 1.36; 95% CI 1.09 to 1.71) with substantial between-study heterogeneity (I² = 72.3%, p = 0.005). The heterogeneity is explained by the adjunctive trials: in B7601003, where 20 of 23 placebo participants (87.0%) reported an adverse event on a background of levodopa, tavapadon added essentially no relative risk (RR 0.97; 95% CI 0.79 to 1.19), whereas in the early-stage monotherapy trials, with placebo event rates of 41% to 55%, risk ratios ranged from 1.39 to 1.72.” (opens the source at this quote in a new tab)
“Discontinuation due to adverse events was also elevated (RR 2.72; 95% CI 1.07 to 6.96), again with substantial heterogeneity (I² = 65.2%, p = 0.015), reflecting variable titration schedules and tolerability management across trials” (opens the source at this quote in a new tab)