Parkinson’s Disease

A Look At The JournalRotigotine Transdermal Patch in

Early Parkinsons Disease: A Randomised, Double Blind,

Controlled Study versus Placebo and RopiniroleFong Siew Li

Provisionally Registered Pharmacist. May 17 2012

What is Parkinson’s Disease?• Parkinson’s Disease (PD) is a

progressive, degenerative disease.• It is caused by a lack of dopamine in

the brain (the substantia nigra)1

Dopamine

• Neurotransmitter Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain.2

• In PD patients, dopamine transmitting neurons in the substatia nigra die, causing a lack of dopamine.

• Dopamine is important in the coordination of movements.

Early symptoms in PD include3 • trembling of hands, arms, legs, jaw

and face• Stiffness of the arms, legs and trunk• Slowness of movement• Poor balance and coordination• Loss of facial expression, drooling

And it is degenerative

• As the disease progresses, the symptoms will become worse and worse, until the patient may not be able to perform simple tasks, such as chewing, swallowing, or speaking.3

• In some PD patients, as the disease progresses, memory loss may take place.4

How can we treat PD?5

• As PD is a degenerative, progressive disease, the earlier it is treated, the better the treatment can help slow down the rate of disease progression.

• In PD patients, there is a lack of dopamine in the brain. Treatment options should be targeted to combat this problem.

Dopamine Replacement

• Levodopa (L-dopa) • L-dopa is a dopamine precursor, meaning,

L-dopa will enter the body, go through the blood brain barrier (BBB) and be converted into dopamine in the brain.

• Carbidopa helps slow the conversion of L-dopa into dopamine outside the CNS, ensuring a higher concentration of L-dopa, and subsequently dopamine, will be available for CNS functions. Thus the combination of levodopa and carbidopa.4

• Dopamine agonists can mimic the effects of dopamine in the brain

• Dopamine agonists include:RopinirolePramipexoleRotigotine

Dopamine Mimetics

Slow down the break down

• Selective enzyme inhibitors, like Monoamine oxidase inhibitors (MAO Inhibitors) like Selegiline Hydrochloride and Cathechol-O-methyltransferase inhibitors (COMT Inhibitors) like Entacapone can help slow down the breakdown of the precious little amounts of dopamine left in the brain

Anti-muscarinic agents

• Antimuscarinic drugs reduce the effects of relative central cholinergic excess that occurs as a result of dopamine deficiency.

• Useful in drug induced parkinsonism, but not generally used in idiopathic Parkinson’s disease as they are less effective than dopaminergic drugs and are associated with cognitive impairment.

• Examples are Orphenadrine HCl, Trihexyphenidyl HCl (Benzhexol)

Parkinsons in Malaysia?

• The Malaysian Parkinson’s Disease Association runs a website

http://www.mpda.org.my/

Journal

• Rotigotine Transdermal Patch in Early Parkinson’s Disease

*Rotigotine and Ropinirole are both dopamine receptor agonists and have a direct action on dopamine receptors

Study

• To investigate the efficacy and safety of the rotigotine transdermal patch in the treatment of early Parkinson’s Disease

• Primary endpoint=proportion of patients with a minimum of 20% decrease in the combined Unified Parkinson’s Disease Rating Scale (UPDRS) Part II and Part III scores.

Patient Inclusion Criteria

• 30 years and older• Has a diagnosis of PD based on UK

Brain Bank Criteria and with mild to moderate disease (Hoehn and Yahr clinical stage of 3 or less)

• Score at least 10 on motor examination section of Unified Parkinsons’s Disease Rating Scale

• Patient permitted to take other CNS drugs if maintained at stable dosages for 28 days before baseline and throughout trial.

Exclusion criteria

• Mini-Mental State Examination score <25

• Clinically significant psychiatric or cognitive condition

• Inability to apply and remove patches appropriately

• History of skin sensitivity to adhesives or other transdermal medications

• Administration of a dopamine agonist or levodopa withing 28 days of baseline visit or have ever taken levodopa for longer than 6 months

• Clinically relevant hepatic, renal or cardiac dysfunction

• An average QTc interval of > 450ms for men and > 470ms for women

• Symptomatic orthostatic hypotension• Recent exposure to monoamine

oxidase type A inhibitors and neuroleptics.

Trial• Randomised = Patients are

randomised using a computerised randomisation schedule, each patient will be issued a random number.

• Double blind= not mentioned in journal who is blinded and who is not

• Double dummy=placebo tablets and patches are prepared, so all patients will take capsules and patches

Study

• 3 groups• Rotigotine patch only: Ropinirole only:

placebo, to the ratio of 2:2:1• 4 week titration period to reach

maximum dose of rotigotine (8mg/24 hours)

• 13 week titration period to reach maximum sose of ropinirole (24mg/day)

Efficacy Assessment

• Primary efficacy variable was the proportion of patients who responded to treatment.

• Responder = patient with a 20% or greater decrease in UPDRS Part II (activities of basic living; ADL) + Parts III (motor score) from baseline visit to the end of the double blind maintenance trial

• Secondary efficacy variable include absolute change in UPDRS II and III scores from baseline visit to the end of the double blind maintenance period, changes in the UPDRS Part II and III subscale scores and demonstration of noninferiority to ropinirole.

• The titration period was different for Rotigotine and Ropinirole.

• Analysis was carried out using the first 24 weeks after the end of titration of each drug (Weeks 5-29 for Rotigotine and weeks 14-38 for Ropinirole)

• 92% of patients on Rotigotine reached maximum dose of 8mg/24hours

• For ropinirole, the median dose was 14.1mg/day, only 26% of patients in Ropinirole group reached max dose 24mg/day.

Primary Efficacy Endpoint

• For Rotigotine versus placebo, 52% of responders achieved primary end point for Rotigotine group, as opposed to placebo group. (30%; P<0.0001)

• For Ropinirole group, 68% achieved primary end point compared with placebo.

(P<0.0001)

Secondary Efficacy Endpoint

• Mean decrease in UPDRS score at end of treatment for rotigotine was -7.2 (SD+ 9.9)

• Mean decrease in UPDRS score at end of treatment for placebo was -2.2(SD+ 10.2)

• Mean decrease in UPDRS score at end of treatment for ropinirole was -11(SD+ 10.5)

Disclaimer

• The study was not powered to show the superiority of any active treatment over the other.

• Cannot tell from the study if rotigotine or ropinirole is superior to each other.

• Study is just to test the efficacy and safety of the drug.

Safety

• Adverse reactions occurred more frequently in the rotigotine group compared to placebo group.

• With exception of application site reactions, there is a similar incidence and profile of adverse effects in the rotigotine and ropinirole group.

• Serious adverse events was reported in 8% of the placebo group, 10% of the rotigotine group, and 13% of the ropinirole group.

• These occur across multuple bpdy systems with no obvious trends.

• The SAE are not stated in the journal.

• Mentioned that out of the rotigotine group, 8% of the group included application site reactions as the SAE

Discountinuation because of SAE

• 5% of placebo group• 17% of rotigotine group• 13% of ropinirole group• Not mentioned specifically what are the

SAEs, but just mentioned

“The majority of the remaining adverse events that led to discontinuation were typical of those that occur in patients who have PD or who are treated with dopamine agonsits or transdermal systems.”

Discussion

• This trial does not tell us if rotigotine is superior to ropinirole

• The trial shows that rotigotine is safe and well tolerated up to 37 weeks

• The trial shows that rotigotine is clinically efficacious over placebo

• It is acknowledged that Ropinirole has a better symptomatic effect compared to Rotigotine.

• The argument used was that patients on Rotigotine was underdosed compared to Ropinirole, which was used in higher doses. (8mg/day versus 14.1mg/day median dose)

• It is mentioned that in subsequent studies, rotigotine transdermal patch was safe and well tolerated in doses up to 16mg/day in advanced PD.7

• Another limitation was the titration time of the two drugs

• The journal argues that because titration was reached earlier for rotigotine group, and as the beneficial results of the medicine declines as time passes, the limitation could give an impression of declining beneficial effects.

• Rotigotine was a transdermal patch as opposed to Ropinirole capsule

• The application site adverse events is reported to be mild to moderate.

• Transdermal application was once daily application, which could increase patient compliance.

• Erratic gastric emptying or changes in gastric motility will not effect drug delivery.

• Easier to administer to patients who are stubborn and refuse to swallow capsules.

Thank you for your kind attention!

Have a good day!

References

1. CNS Degenerative Diseases. The University of Utah Eccles Health Sciences Library. Internet connection. Available at URL: http://library.med.utah.edu/WebPath/TUTORIAL/CNS/CNSDG.html

2. Dopamine, A sample neurotransmitter, Addiction Science Research and Education Center, College of Pharmacy, The University of Texas. Internet connection. Available at URL: http://www.utexas.edu/research/asrec/dopamine.html

3. Parkinson’s Disease. Medline Plus. US National Library of Medicine, National Institues of Health. Internet connection. Available at URL:http://www.nlm.nih.gov/medlineplus/parkinsonsdisease.html

4. Parkinson’s Disease. The University of Maryland Medical Center. Internet Connection. Available at URL: http://www.umm.edu/altmed/articles/parkinsons-disease-000123.htm

5. Drugs used in Parkinsonism and related disorders. British National Formulary 60th Edition. Page 296

6. Giladi N, Boroojerdi B, Korczyn AD, et al. Rotigotine Transdermal Patch in Early Parkinsons’s Disease: A randomised, double blind, controlled study versus placebo and ropinirole. Mov Disord 2007;22(16);pg2398-2404

7. Poewe W, Giladi N. Boothman B, et al. Rotigotine transdermal system in patients with advanced stage Parkinson’s Disease as adjunctive therapy to levodopa:results of a placebo and pramipexole controlled trial. Mov Disord 2006; 21:S48