Orodispersible sublingual piribedil to abort OFF episodes: A single dose placebo‐controlled, randomized, double‐blind, cross‐over study

Rascol, Olivier; Azulay, Jean‐Philippe; Blin, Olivier; Bonnet, Anne‐Marie; Brefel‐Courbon, Christine; Césaro, P.; Damier, Philippe; Debilly, Bérengère; Durif, F.; Galitzky, Monique; Grouin, Jean‐Marie; Pennaforte, S.; Villafane, Gabriel; Yaici, Sadek; Agid, Yves

doi:10.1002/mds.22922

Cited by 22 publications

(18 citation statements)

References 24 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The present controlled study reinforces this treatment strategy with piribedil, another dopamine agonist. Although not marketed in several countries, piribedil was chosen in this study because of its broad use in France over several decades with well known safety profile and relatively low cost compared with more recent dopamine agonists, the fact that it is a non-ergot drug, its known efficacy on motor symptoms in Parkinson's disease but also based on early studies indicating a benefit on depression (Post et al, 1978;Castro-Caldas et al, 2006;Rascol et al, 2006Rascol et al, , 2010. Most importantly, in a previous study (Thobois et al, 2010) we had shown that dopamine withdrawal syndrome is related to mesolimbic dopaminergic denervation and we hypothesized that a D2/D3 agonist should be beneficial on non-motor psychic symptoms that we have classified as hypodopaminergic (Ardouin et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil

Thobois

Lhommée

Klinger

et al. 2013

Brain

225

177

View full text Add to dashboard Cite

Apathy is one of the most common symptoms encountered in Parkinson's disease, and is defined as a lack of motivation accompanied by reduced goal-directed cognition, behaviour and emotional involvement. In a previous study we have described a delayed withdrawal syndrome after successful motor improvement related to subthalamic stimulation allowing for a major decrease in dopaminergic treatment. This withdrawal syndrome correlated with a diffuse mesolimbic dopaminergic denervation. To confirm our hypothesis of parkinsonian apathy being related to mesolimbic dopaminergic denervation, we performed a randomized controlled study using piribedil, a relatively selective D2/D3 dopamine agonist to treat parkinsonian apathy, using the model of postoperative apathy. A 12-week prospective, placebo-controlled, randomized, double-blinded trial was conducted in 37 patients with Parkinson's disease presenting with apathy (Starkstein Apathy Scale score 4 14) following subthalamic nucleus stimulation. Patients received either piribedil up to 300 mg per day (n = 19) or placebo (n = 18) for 12 weeks. The primary end point was the improvement of apathy under treatment, as assessed by the reduction of the Starkstein Apathy Scale score in both treatment groups. Secondary end points included alleviation in depression (Beck Depression Inventory), anxiety (Beck Anxiety Inventory), improvement of quality of life (PDQ39) and anhedonia (Snaith-Hamilton Pleasure Scale). Exploratory endpoints consisted in changes of the Robert Inventory score and Hamilton depression scales. An intention to treat analysis of covariance analysis was performed to compare treatment effects (P 5 0.05). The number of premature study dropouts was seven in the placebo and five in the piribedil groups, mostly related to intolerance to hypodopaminergic symptoms. At follow-up evaluation, the apathy score was reduced by 34.6% on piribedil versus 3.2% on placebo (P = 0.015). With piribedil, modifications in the Beck depression and anxiety scores were À19.8% and À 22.8%, respectively versus + 1.4% and À 8.3% with placebo, without reaching significance level. Piribedil led to a trend towards improvement in quality of life ( À 16.2% versus + 6.7% on placebo; P = 0.08) and anhedonia (À 49% versus À 5.6% on the placebo; P = 0.08). Apathy, assessed by the Robert Inventory score, improved by 46.6% on piribedil and worsened by 2.3% on placebo (P = 0.005). Depression, measured by the Hamilton score, improved in the piribedil group (P = 0.05). No significant side effects were observed. The present study provides a class II evidence of the efficacy of the dopamine agonist piribedil in the treatment of apathy in Parkinson's disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil

Thobois

Lhommée

Klinger

et al. 2013

Brain

225

177

View full text Add to dashboard Cite

show abstract

“…In a 7-month randomized double-blind placebo-controlled trial conducted in 405 patients with early PD, psychiatric disorders were reported with the same prevalence on piribedil (23 % of the patients) and placebo (18 %) [32]. Nevertheless, in the same study, hallucinations were among the most common reasons for discontinuation in the active group (4 patients, 1 %) as compared with placebo (none).…”

Section: Tolerability As Assessed In Clinical Trialsmentioning

confidence: 87%

“…Piribedil was reported to be effective in reducing the UPDRS III score at the first evaluation timepoint of 15 min, and in reversing the OFF state in 7 of 10 patients. In another study, the efficacy of an oro-dispersible sublingual formulation of piribedil for aborting OFF episodes was studied in 30 fluctuating PD patients by means of a randomized, double-blind, placebocontrolled crossover trial [32]. The primary endpoint was the maximal change versus baseline in UPDRS III assessed after drug administration following an overnight withdrawal of antiparkinsonian medications.…”

Section: Motor Fluctuationsmentioning

confidence: 99%

See 1 more Smart Citation

Piribedil for the Treatment of Motor and Non-motor Symptoms of Parkinson Disease

Pérez-Lloret

Rascol

2016

CNS Drugs

Self Cite

View full text Add to dashboard Cite

Dopamine agonists are well-established symptomatic medications for treating early and advanced Parkinson disease (PD). Piribedil was one of the first agonists to be marketed (1969) and is widely used as an extended-release oral formulation in European, Latin-American, and Asian countries. Piribedil acts as a non-ergot partial dopamine D2/D3-selective agonist, blocks alpha2-adrenoreceptors and has minimal effects on serotoninergic, cholinergic, and histaminergic receptors. Animal models support the efficacy of piribedil to improve parkinsonian motor symptoms with a lower propensity than levodopa to induce dyskinesia. In PD patients, randomized double-blind studies show that piribedil (150-300 mg/day, three times daily) is superior to placebo in improving motor disability in early PD patients. Based on such evidence, piribedil was considered in the last Movement Disorder Society Evidence-Based Medicine review as "efficacious" and "clinically useful" for the symptomatic treatment of PD, either as monotherapy or in conjunction with levodopa, in non-fluctuating early PD patients. This effect appears comparable to what is known from other D2 agonists. However, randomized controlled trials are not available to assess the effect of piribedil in managing levodopa-induced motor complications. Pilot clinical studies suggest that piribedil may improve non-motor symptoms, such as apathy, but confirmatory trials are needed. The tolerability and safety profile of piribedil fits with that of the class of dopaminergic agonists. As for other non-ergot agonists, pneumo-pulmonary, retroperitoneal, and valvular fibrotic side effects are not a concern with piribedil. The original combination of piribedil D2 dopaminergic and alpha-2 adrenergic properties deserve further investigations to better understand its antiparkinsonian profile.

show abstract

“…The study was completed (11 instead of 14 per-protocol analysis set [PPAS] completers) soon after this reassessment of the primary end point variability indicated that the number of completed subjects was already sufficient to achieve minimum 80% power to detect the primary efficacy signal based on the initially assumed effect size. For testing MDS-UPDRS-III, assuming the effect size is 7 and SD of the paired difference is 12.6 [14, 29-31], a sample size of 22 subjects was initially projected to reach 81.1% power at a one-sided 0.05 significance level. …”

Section: Methodsmentioning

confidence: 99%

Evaluation of D<sub>1</sub>/D<sub>5</sub> Partial Agonist PF-06412562 in Parkinson’s Disease following Oral Administration

et al. 2018

View full text Add to dashboard Cite

Background: PF-06412562 is a moderately potent, highly selective oral D₁/D₅ dopamine receptor partial agonist. Objective: To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson’s disease. Methods: Following overnight levodopa (L-dopa, Sinemet®) washout, subjects received a single dose of levodopa in open-label period 1. Periods 2 and 3 had a double-blinded, sponsor-open, randomized, 2-way cross-over, placebo-controlled design, during which subjects were randomized to PF-06412562 30 mg (+ 20 mg 4 h later) or placebo. Maximum percent improvement from baseline in finger-tapping speed (measure of bradykinesia) measured using Kinesia^TM technology (as the primary end point) and change from baseline in the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III) motor section scores (the preferred exploratory end point) were evaluated. Results: Nineteen subjects received levodopa; 13 met the period 2/3 entry criteria and received PF-06412562, 30 + 20 mg, or placebo. The prespecified primary efficacy criterion for significant improvement in finger-tapping was not met due to inconsistencies in the task leading to large between-period fluctuations of within-patient baseline values. Change from baseline in MDS-UPDRS-III score with PF-06412562 resulted in a placebo-adjusted point estimate of –10.59 with a one-sided 90% upper CI of PF-06412562 versus placebo model-based contrast of (–inf, –7.44) at 1.5–2.5 h after the dose (p < 0.0001). All adverse events were mild-to-moderate. Conclusions: We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D₁/D₅ partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D₁ agonists.

show abstract

Orodispersible sublingual piribedil to abort OFF episodes: A single dose placebo‐controlled, randomized, double‐blind, cross‐over study

Cited by 22 publications

References 24 publications

Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil

Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil

Piribedil for the Treatment of Motor and Non-motor Symptoms of Parkinson Disease

Evaluation of D<sub>1</sub>/D<sub>5</sub> Partial Agonist PF-06412562 in Parkinson’s Disease following Oral Administration

Contact Info

Product

Resources

About