Shayne Kreutzer, Mercer University College of Pharmacy
According to Practice Parameter: Diagnosis and Prognosis of New Onset Parkinson Disease, Parkinson’s disease (PD) is a neurodegenerative disorder caused by a loss of dopaminergic neurons in the substantia nigra, as well as other dopaminergic and nondopaminergic areas of the brain. Although PD is common, it is difficult to diagnose clinically, particularly in early stages. It suggested that approximately 5 to 10% of patients with PD are misdiagnosed.1
According to Parkinson’s Disease: Diagnosis and Management in Primary and Secondary Care, there is no consistent, reliable test that can distinguish PD from other conditions that have a similar presentation. It is suggested that the diagnosis of PD is primarily clinical, it is based on a thorough history and physical exam.2 Neither of the above guidelines mention the use of Actos® for the treatment of PD.
|Title: Pioglitazone in Early Parkinson’s Disease: A Phase 2, Multicentre, Double-Blind, Randomised Trial3|
|Design||Multicentre, three-group, double-blind, placebo-controlled parallel group study; N = 604|
|Objective||Assess the effect of pioglitazone on the progression of PD|
|Study Groups||Pioglitazone 15 mg/day vs pioglitazone 45 mg/day vs placebo|
|Methods||Patients were randomly assigned (1:1:1) to one of the study drugs. At the initial screening, participants had a baseline medical history interview, physical and neurological examination, electrocardiogram, Unified Parkinson Disease Scale (UPDRS), and assessments of mood, cognition, and disability. After the baseline visit, participants were reassessed at 2 weeks (within 3 days) by telephone and at 4, 16, 28, and 44 weeks (within 5 days) in person. The participants were given three capsules by mouth once daily, of the study drug. Dose reduction for intolerability was allowed at any point during the study and participants were maintained on the highest tolerated dose up to their assigned dose.|
|Duration||May 10, 2011 to July 31, 2013|
|Primary Outcome Measure||Change in total UPDRS score between baseline and 44 weeks|
|Baseline Characteristics||Pioglitazone 15 mg||Pioglitazone 45 mg||Placebo|
|Age (years)||61.3 +/- 10.6||58.8 +/- 9.2||59.0 +/- 9.9|
|Duration of PD diagnosis (years)||2.3 +/- 1.9||2.0 +/- 1.2||2.3 +/- 2.3|
|UPDRS total||23.8 +/- 9.9||21.2 +/- 8.8||21.7 +/- 8.7|
|UPDRS mental||0.8 +/- 0.9||0.8 +/- 0.9||0.9 +/- 1.1|
|UPDRS motor||17.1 +/- 7.7||15.0 +/- 7.1||15.3 +/- 6.5|
|UPDRS ADL*||5.9 +/- 3.2||5.5 +/- 2.9||5.5 +/- 3.0|
|*ADL – activities of daily living|
|Results||Pioglitazone 15 mg||Pioglitazone 45 mg||Placebo|
|Mean total change in UPDRS at 44 weeks||4.42+ (95% CI*; 2.55 – 6.28)||5.13+ (95% CI*; 3.17 – 7.08)||6.25+ (95% CI*; 4.35 – 8.15)|
|+ The higher change in score is worse when looking at UPDRS
*CI – confidence interval
|Adverse Events||Common Adverse Events:|
|Pioglitazone 15 mg||Pioglitazone 45 mg|
|Raised blood creatine phosphokinase||17%||10%|
|Serious Adverse Events:|
|Pioglitazone 15mg||Pioglitazone 45mg|
|Ovarian cyst rupture
|1.39%||Osteoarthritis requiring surgery||1.49%|
|Intestinal obstruction||1.39%||Transient ischemic attack||1.49%|
|Intervertebral disc protrusion or degeneration||2.78||Dehydration||1.49%|
|Dyspnea , and Hypoxia||1.49%|
|Percentage that Discontinued due to Adverse Events: 0%|
|Study Author Conclusions||Pioglitazone is unlikely to be efficacious as a disease-modifying intervention in early Parkinson’s disease and therefore is not recommended for further testing for that indication.|
This study showed that the use of pioglitazone is ineffective for the prevention of progression in PD. Pioglitazone was chosen for this trial based on results from a preclinical study showing reproduced neuroprotective effects in tissue cultures and animal models. In the case of this study, reproducible tissue cultures and animal models did not predict any efficacy in human individuals. A limitation of this study was length of therapy for PD patients, as well as the possibility of pioglitazone not reaching the substantia nigra and achieving the correct amount of drug exposure. By allowing greater drug exposure, pioglitazone, through an unknown mechanism, inhibits the activation of microglia and astrocytes. This allows for less activation of pro-inflammatory cytokines and nitric oxide release, essentially a neuroprotective effect of pioglitazone.
- Montgomery EB. Practice Parameter: Diagnosis and Prognosis of New Onset Parkinson Disease (An Evidence-Based Review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;67(12):2266.
- Anderson, David. “Parkinson’s Disease: Diagnosis and Management in Primary and Secondary Care.” Parkinson’s Disease”, June 2006. Web. 21 July 2015.
- Pioglitazone in Early Parkinson’s Disease: A Phase 2, Multicentre, Double-Blind, Randomised Trial. Lancet Neurol. 2015;14(8):795-803.