Pioglitazone in Early Parkinson’s Disease: A Phase 2, Multicentre, Double-Blind, Randomised Trial


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
n 72 67 71
Age (years) 61.3 +/- 10.6 58.8 +/- 9.2 59.0 +/- 9.9
Males 74% 70% 68%
Non-Latino whites 81% 94% 89%
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
Oedema 6% 19%
Cardiovascular events 6% 9%
Diarrhoea 10% 4%
Nausea 8% 10%
Raised blood creatine phosphokinase 17% 10%
Dizziness 7% 9%
Fatigue 11% 3%
Serious Adverse Events:
Pioglitazone 15mg Pioglitazone 45mg
Ankle fracture 1.39% Spondylolisthesis 1.49%
Ovarian cyst rupture

Atrial flutter

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%
Myocardial infarction 1.49%
Intestinal obstruction 1.49%
Dyspnea , and Hypoxia 1.49%
Respiratory failure 1.49%
Confusion 2.98%
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.

References

  1. 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.
  2. Anderson, David. “Parkinson’s Disease: Diagnosis and Management in Primary and Secondary Care.” Parkinson’s Disease”, June 2006. Web. 21 July 2015.
  3. Pioglitazone in Early Parkinson’s Disease: A Phase 2, Multicentre, Double-Blind, Randomised Trial. Lancet Neurol. 2015;14(8):795-803.
Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s