New deep brain stimulation guideline by Dr. Rughani

Dr. Anand Rughani of Maine Medical Partners Neurosurgery is the first author of a new guideline for deep brain stimulation (DBS) in the treatment of Parkinson disease (PD). The paper was accepted for publication by the journal Neurosurgery in February, 2018 (1).    Neurosurgery is the official journal of the Congress of Neurological Surgeons, and publishes research on clinical and experimental neurosurgery.

The guideline by Rughani, et al. is for physicians helps establish whether the DBS target should be the subthalamic nucleus (STN), or globus pallidus internus (GPi), and is a useful tool which forms recommendations on the basis of seven key questions in order to tailor the choice for each patient.  The questions regard efficacy, reduction of medications, treatment of dyskinesias, improvement in quality of life, impact on cognitive function, impact on mood, and risk of adverse events.  The article can be read online (2).

Congratulations to Dr. Rughani, and thank you for this contribution to medicine.

REFERENCES

  1. Advani, et al. Congress of neurological surgeons systematic review and evidence-based guideline on subthalamic nucleus and globus pallidus internus deep brain stimulation for the treatment of patients with Parkinson’s disease: executive summary.  Neurosurgery.   2018 Mar 12. doi: 10.1093/neuros/nyy037. [Epub ahead of print]
  2. https://academic.oup.com/neurosurgery/advance-article/doi/10.1093/neuros/nyy037/4925265

Pipeline drugs, part 1: levodopa

A frequent question in the clinic is “What’s new in Parkinson’s?”  It is a deceptively simple question, because the truth is that there are thousands of researchers around the world working on Parkinson disease (PD), and there is no way to answer the question in anything close to the time of a follow-up appointment in the office. The volume of information is enormous.  A quick search for the term “Parkinson disease” in PubMed indicates that in 2017 there were 2,450 articles published in peer-reviewed medical journals. A search going back to 1947 yields 65,022 articles, with the majority in the last decade – a huge and growing database. Navigating that data requires a specialized skill set such as an advanced degree and training in medicine.  People with PD who don’t have that degree of training can arm themselves with knowledge by reading articles from MPDN, the Michael J. Fox Foundation, the National Parkinson Foundation, or other reputable sources. Mainers can attend meetings such as the April Parkinson Conference.

The purpose of this article, and the series on pipeline drugs that will follow, is to focus on some of the medications and therapies in development or under trial for the treatment of PD.  Search for the information occurred in two main ways. First was review of peer-reviewed medical journal articles describing completed studies. As described in the spring, 2018 MPDN article “the drug development process as outlined by the FDA,” studies proceed through phases prior to FDA approval.  Briefly, phase I trials provide information about how drugs work in the body and may be used to find appropriate drug doses and drug tolerance. Phase II trials are designed to give more safety data, refine research questions, develop research methods, and design new phase III protocols.  Phase III trials evaluate how effective a treatment is, and monitor for side effects or adverse reactions. After completion of a successful phase III trial a drug may receive FDA approval for a specific disease indication, such as PD, dyskinesias in PD, etc.  

If the drug is new, doctors may then begin to write prescriptions after FDA approval, though prescribing physicians are not limited to FDA approved indication.  

The second method in the search for information was via ClinicalTrials.gov, a freely accessible database provided by the U.S. National Library of Medicine that, as this article was being written, listed over 268,000 privately and publicly funded studies in the United States and 203 other countries.  Every study on the website is assigned a unique number, the ClinicalTrials.gov Identifier, a.k.a. the NCT number, which may be used to search for a particular trial.  With the ongoing trials described below NCT numbers are included for the reader because the contents are updated periodically and may give information regarding a more detailed description of the study itself, requirements of the study, participant inclusion versus exclusion criteria, study locations, contact information, and status of the study (recruiting, completed, etc.).  It is a very valuable resource for those who want to participate in, or keep up with certain areas of research, and it covers a wide array of worldwide PD investigation. On March 18, 2018 a search for the term “Parkinson disease” for example, produced 1,982 results. Fortunately, searches can be narrowed to contain only certain terms such as the NCT number, study drug, location, age of patient, etc.

As this article begins a series, I will divide into topics, which will include new developments with levodopa (this article), dopamine agonists, drugs already approved for another indication that have value in PD, some interventions that may seem unusual, such as blood transfusions for PD, and other topics.  

The accordion pill, a “novel gastroretentive delivery system,” is being developed by Intec Pharma.  The drug levodopa is only absorbed in the first part of the small bowel and competes with proteins for absorption, and thus diet may interfere (see the MPDN article “PD and Diet,” winter, 2016/17).  Likewise, many people with PD have problems with gastric motility (for eg., the stomach does not empty properly, to be covered later in the this series), constipation, or infection with Helicobacter pylori, all of which may change the rate of absorption of levodopa and negatively affect the window of opportunity for drug absorption. In other words, the drug may not wind up in the right place at the right time for absorption.  With immediate release levodopa, the half-life of time that a drug is at its therapeutic concentration in the blood, is only about 90 minutes; whereas the controlled release forms may have a half-life of several hours, though it is variable, and sometimes not well tolerated.  This is why some patients reach for liquid levodopa, Rytary, or the DUOPA pump (see article in this issue). A new attempt to address the problem is called the accordion pill because it expands in the GI tract to keep it in a region where dopamine will be absorbed while it slowly releases medication.  This approach to treating PD completed a phase II trial of 60 PD patients with doses of 250-500 mg levodopa, given once or twice daily over a 7-21 day period. Per the company’s website (unpublished data) there was a reduction in OFF time and dyskinesias. The baseline characteristics of the patients, including disease severity, were not apparent on the website.  The drug will need to complete a phase III trial before FDA approval is sought.

ClinicalTrials.gov lists two current phase III trials testing the accordion pill, though one must have completed the first 27 week trial to enter the second, a 12 month trial:

NCT02605434 is a  randomized, double-blind study in adult subjects with fluctuating PD (1).  Patients will be given a six week period to establish proper dosing of either carbidopa/levodopa (Sinemet) or the accordion pill (AP-CD/LD) before starting the double-blind maintenance period lasting 13 weeks.  In a double-blind study neither the patient nor the evaluator know which treatment is being given in order to eliminate bias.  Investigators plan to enroll 328 patients across 96 study sites (including Dartmouth and Boston University), and estimated primary completion is June, 2018.  Primarily, they want to measures a change in the percentage of daily OFF time (time medications have worn off and motor symptoms are not controlled) during waking hours.  Secondarily, they will measure a change from baseline through study completion in ON time (time medications are working and motor symptoms are improved or controlled) without troublesome dyskinesia during waking hours, a change in the number of total daily levodopa doses, and change in total Unified Parkinson Disease Rating Scale (UPDRS).  UPDRS is a standardized tool used by doctors to measure the effects of PD.   

NCT02615873  is an open extension trial taking place at 80 study sites that will follow patients who have completed NCT02605434 and evaluate the clinical effect and safety of the accordion pill over 12 months (2).

Subcutaneous (SC) levodopa, ND0612, is a patch/pump system being developed by Neuroderm, and is a delivery system of up to 360 mg levodopa over a 24 hour continuous infusion of a patch/pump (a patch with a small needle placed under the skin, thus subcutaneous).  It is designed for moderate to severe PD as an alternative to the Duopa pump or deep brain stimulation. Two phase II studies have shown the drug is safe and tolerable. Reportedly, the phase III studies will begin soon.  At this point, Boston will probably be the closest option.

NCT02726386 is an active trial, no longer recruiting, involving 100 advanced PD patients spread over 57 international study sites over a 12 month period (3). The primary outcome of this open-label safety study is to assess the long term safety and tolerability of continuous infusion of ND0612 by recording adverse events, vital signs, and local tolerability of the device and the drug.  Estimated study completion date is May, 2018.

NCT02782481, is a phase III, randomized, double-blind, parallel group study of the efficacy, tolerability, and safety of continuous ND0612 in addition to oral levodopa compared to placebo infusion over a 16 week study period (4).  The study is multicenter, and intended to include 150 people with PD who experience “motor complications despite optimized anti-PD therapy.” The study is past the estimated completion date, but is listed as still recruiting, though the single recruiting site listed on ClinicalTrials.gov is in Israel.  

NCT03462043  was announced in March, 2018 – not yet recruiting at announcement, and is an open-label, randomized, crossover study to assess the relative bioavailability (the proportion of the drug that will enter the circulation, and is thus able to have an effect) of ND0612 (the patch) versus jejunal pump levodopa (an external pump similar to DUOPA) in patients with advanced PD (5).  As yet, the only location listed is in Roma, Italy.

NCT02577523 is a multicenter, parallel-group, rater-blinded, randomized phase II clinical study in subjects with advanced PD investigating the efficacy, safety and tolerability of continuous SC infusion of 2 dosing regimens of ND0612H, a solution of  carbidopa/levodopa delivered continuous ND0612 infusion, compared to standard oral carbidopa/levodopa (6). Participants will be given the drug for a total of about 2.5 months. Investigators are recruited 38 participants at five international locations, and the study is ongoing, not recruiting.  

Inhaled levodopa, CVT-301, (INBRIJA) is a self-administered, inhaled form of levodopa by Acorda Pharmaceuticals.  The concept is to avoid the problems with GI tract absorption of levodopa by administering a powder with an inhaler which is absorbed by the lungs, enters the bloodstream, and is carried to the brain.  Phase I and II trials were in part funded by the Michael J. Fox Foundation for Parkinson’s Research.

A phase II study evaluated CVT-301, which PD patients self-administered to relieve OFF episodes (times when medications are not working and symptoms are not controlled) (7).  Study participants had to have two or more hours per day of OFF time despite oral levodopa four or more times per day. Patients were randomized: 43 to inhaled CVT-301, and 43 to inhaled placebo for 4 weeks.  Both groups used inhalers up to 3 times per day for OFF episodes. After two weeks the study-drug dose was increased from 35 to 50 mg. At the end of the fourth week investigators measured the change in UPDRS III score (a measure of the motor signs of PD) from OFF state to the post-dosing scores at 10, 20, 30, and 60 minutes.  The treatment effect was evident at 10 minutes and average OFF time changed by close to an hour daily. This might mean that as one was wearing off at the end of dose they used the inhaler to feel ON until the next dose.  Typically, this was the case for an average of two 25 minute periods daily. The most frequently reported adverse events among those receiving the drug were dizziness, cough, and nausea, each seen in 3 patients). Investigators concluded that CVT-301 was generally safe and well-tolerated.

The same group next entered a second phase II study which evaluated lung function in patients given a single dose of CVT-301 versus placebo, and in patients who received multiple doses/day over 4 weeks (8).  Assessment of pulmonary function (before and three hours after a dose) by spirometry (a portable way to measure lung function) was within normal ranges. The most common side effect was mild-to-moderate cough (21% in the single dose group, 7% in the four week treatment group).     

February, 2017 Acorda  announced positive phase III clinical trial results for CVT-301 with the SPAN-PD trial (9).   SPAN-PD was a phase III, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of CVT-301 compared with placebo in people with PD who experienced motor fluctuations (OFF periods). All took a stable regimen of oral carbidopa/levodopa, and were maintained on other existing PD medications.  The study included 339 study participants who were randomized to CVT-301 84 mg, CVT-301 60 mg, or placebo. Participants self-administered treatment up to five times daily for 12 weeks.

At week 12 the change in UPDRS III score compared with placebo was measured at 30 minutes after using the inhaler.  SPAN-PD reportedly showed the 84 mg dose resulted in a 9.83 point improvement in the UPDRS III compared with a 5.91 drop for the placebo group.  In the 84 mg dose group nausea was reported in 5.3% (2.7% with placebo), cough in 15% (1.8% with placebo), upper respiratory tract infection in 6% (2.7% with placebo).   When cough was reported, it was “typically mild and reported once per participant during the course of treatment.” Three of 227 participants receiving CVT-301 discontinued the study due to cough.

Data from the SPAN-PD trial were presented at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) in June 2017.

February 20, 2018 Acorda Therapeutics, Inc. announced that the FDA had accepted for filing its New Drug Application (NDA) for INBRIJA, “an investigational inhaled levodopa treatment for symptoms of OFF periods in people with Parkinson’s disease taking a carbidopa/levodopa regimen” (10).  Under the Prescription Drug User Fee Act (PDUFA), the FDA has set a target date of October 5, 2018.  

REFERENCES

  1. https://clinicaltrials.gov/ct2/show/NCT02605434?term=accordion+pill&cond=Parkinson+Disease&rank=1
  2. https://clinicaltrials.gov/ct2/show/NCT02615873?term=accordion+pill&cond=Parkinson+Disease&rank=2
  3. NCT02726386 https://clinicaltrials.gov/ct2/show/NCT02726386?term=subcutaneous&cond=Parkinson+Disease&rank=1
  4. https://clinicaltrials.gov/ct2/show/NCT02782481?term=subcutaneous+levodopa%2C+neuroderm&cond=Parkinson+Disease&rank=2
  5. https://clinicaltrials.gov/ct2/show/NCT03462043?term=subcutaneous+levodopa%2C+neuroderm&cond=Parkinson+Disease&rank=3
  6. https://clinicaltrials.gov/ct2/show/NCT02577523?term=subcutaneous+levodopa%2C+neuroderm&cond=Parkinson+Disease&rank=5
  7. LeWitt, et al.  A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson’s disease. Mov Disord. 2016;31(9):1356-65.
  8. LeWitt, et al. Pulmonary Safety and Tolerability of Inhaled Levodopa (CVT-301) Administered to Patients with Parkinson’s Disease.J Aerosol Med Pulm Drug Deliv. 2017 Nov 21. doi: 10.1089/jamp.2016.1354. [Epub ahead of print] full artice: https://www.liebertpub.com/doi/10.1089/jamp.2016.1354
  9. http://ir.acorda.com/investors/investor-news/investor-news-details/2017/Acorda-Announces-Positive-Phase-3-Clinical-Trial-Results-for-CVT-301/default.aspx
  10. http://ir.acorda.com/investors/investor-news/investor-news-details/2018/Acorda-Announces-FDA-Acceptance-of-New-Drug-Application-for-INBRIJA-levodopa-inhalation-powder/default.aspx

 

Coastal Rehab of Cape Elizabeth to offer Rock Steady Boxing

by Nathalie Descheneaux, OTR/L, MS

Coastal Rehab is a therapist owned practice that offers occupational, physical and speech therapy.  Our main office is located in Cape Elizabeth and we have satellite clinics in Kennebunk (Huntington Common), Scarborough (Scarborough Terrace), Falmouth (Ocean View) and Brunswick (Sunnybrook). We also travel to clients’ homes from Wells to Brunswick.

We are doubling our Cape Elizabeth clinic space to offer Rock Steady Boxing classes.

From left to right: Anna Chornyak, PT, RSB coach, Lynd Blatchford (corner man), Jeanne Blatchford (boxer), Tia Parady, CPT, RSB coach.

Rock Steady is a non-contact, boxing-based fitness curriculum.  Boxers condition for optimal agility, speed, muscular endurance, accuracy, hand-eye coordination, footwork and overall strength to defend against and overcome opponents.  At Rock Steady Boxing, Parkinson’s disease is the opponent. Exercises vary in purpose and form but share one common trait: they are rigorous and intended to extend the perceived capabilities of the participant. You can visit our website  http://capeelizabeth.rsbaffiliate.com for up-to-date class information or

Construction is underway

call Coastal Rehab’s office at 767-9773.”

19 of our therapists are LSVT BIG and LOUD certified clinicians.  Treating PD is a passion for us at Coastal. We love to expand our knowledge and share our experience. We facilitate 4 PD support groups, in Kennebunk, Westbrook, Falmouth and Brunswick.

Nathalie Descheneaux, OTR/L, MS, is the Executive Director of Coastal Rehab, LLC.  2 Davis Point Lane • Suite 1A, Cape Elizabeth • ME 04107, tel 207.767.9773, fax 207.541.9212. 

http://coastalrehab.me

 

 

 

The drug development process as outlined by the FDA

An often-quoted statement is that new drug development may take over ten years from the lab to Food and Drug Administration (FDA) approval, and that cost of that research and development may be over a billion dollars.  These numbers understandably upset people, especially those suffering from a disease for which treatments are inadequate, or the condition is fatal.  During the early days of the AIDS epidemic for example, activists called for the FDA to speed approval of drugs they believed would be life-saving.  And, the FDA has developed four ways to speed up approval for drugs to treat serious disease (1):

priority review: FDA attempts to take action on an application within six months

breakthrough therapy: a process to expedite the development of new drugs which may be a significant improvement over available treatment

accelerated approval: a drug for a serious condition, filling an unmet need, and based on a surrogate endpoint, such as improvement in a lab, imaging finding, or physical sign, that is used to predict benefit

fast track: a process to facilitate development and expedite review of drugs for a serious condition, and fill an unmet need

There is also a special consideration for orphan drugs (those drugs intended to treat conditions which affect fewer than 200,000 U.S. citizens) (2) (see the interview with Dr. Moore in this issue on DUOPA).  Orphan drug designation allows for incentives to the developer, such as tax credits.  Even with these steps, the FDA’s role is that of safety, and the process may still take several years.  Consider this 2018 statement from FDA commissioner Scott Gottlieb, M.D. on the mission of the agency (3):

“The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.”

This brief article is meant to summarize how drugs reach FDA approval (4), and hopefully give a better understanding of why it takes so long to safely bring a drug to the doctor’s office.  I hope this writing will serve as a point of entry for other upcoming articles about the drug development pipeline in PD.   The article is not meant to disentangle the problem of drug cost, which several authors have tackled (5-7) and is under consideration for a future topic in MPDN.

The FDA lists five steps in the new drug development process.  Nested within these steps we find clinical trials.  At first, the process may cumbersome to understand, but it can be summarized as follows:

Step 1: Discovery and development, research for a new drug beginning in the laboratory

Most commonly, researchers discover new drugs through a variety of mechanisms: new understanding of a disease process (how something happens in a disease); testing several different compounds to see if they help against a disease (test tube work); observing an unexpected benefit in an existing treatment (for example, a medication for the flu also prevents dyskinesia); or new technologies/ways to target medical products to specific sites within the body or manipulate genetic material.  Thousands of compounds may be potential candidates, but most fail, and only a small number may warrant more study.

If a compound is to be tested, information must be learned about it, such as:

  • how it is absorbed, distributed, metabolized, and excreted
  • what are the potential benefits and mechanisms of action
  • what is the best dosage
  • what is the best way to deliver the drug (mouth, skin, injection)
  • what are the possible side effects or toxicity
  • how does it affect different groups of people (gender, race, age)
  • how does it interact with other drugs or treatments
  • how effective is it compared with similar drugs

Step 2: Preclinical research, drugs undergo laboratory and animal testing to answer basic questions about safety

The two types of preclinical research are:  in vitro (outside of living organisms in test tubes or petri dishes, for example), and in vivo (in living organisms such as lab animals or people).  These are usually small studies which are meant to find out about proper dosing: how much is enough, and how much is too much.  This also helps researchers to decide if the compound should be tested in people.

Step 3:  Clinical research, drugs tested on people to make sure they are safe and effective

The FDA makes the following statement (4):

“While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body. ‘Clinical research’ refers to studies, or trials, that are done in people…”

The steps through human clinical trials may allow a drug to become FDA approved.  Some compounds go through trials but never receive approval.

Clinical trials are often referred to as “translational research,” which brings a drug from the laboratory bench to the human being for testing.  Trials at this stage are designed to answer very specific questions related to a drug or device, and follow a protocol that is written prior to starting the study.  They must determine the selection criteria (who is included), how many people will be recruited, if there will be a control (placebo) group, how long the study will last, how to give drug, what dose will be given, what questions will be asked in the trial (what data collected), and how that data will be analyzed.  Clinical trials proceed from small phase I to large phase III studies.

Phase I trials provide information about how drugs work in the body.  These trials typically involve from 20-100 healthy people, or people with the disease being considered for treatment.  The study may go on for several months.  People are closely monitored to learn how a drug interacts with the human body, how to adjust dosing (usually based on animal data), how much of a drug the body can tolerate, and side effects at the doses given.  Per the FDA, about 70% of drugs move to phase II.

Phase II may involve up to several hundred people with the disease or condition, and the study might last years (though the FDA reports it is usually no more than 2 years).  These studies aren’t large enough to show whether a drug will be beneficial, and are instead designed to give additional safety data, refine research questions, develop research methods, and design new phase III protocols.  Per the FDA, about 33% of drugs move to phase III.

Phase III trials may include thousands of people who have the disease or condition, and the study may last for years.  The purpose of a phase III study is to learn how effective a treatment is and to monitor for side effects or adverse reactions (which may be more evident with a longer study and a larger population).  These studies may recruit very specific populations of people, and are sometimes known as pivotal studies.  Completing a successful phase III trial moves a drug along to what the FDA refers to as step 4 in the overall process.

Step 4: FDA Review, teams “thoroughly examine all of the submitted data related to the drug or device and make a decision to approve or not to approve it”

If FDA approved, it is available for prescription from a doctor.  Per the FDA about 25-30% of drugs move to phase IV.

Phase IV studies may include several thousand volunteers with the disease or condition, and are meant to learn even more about safety and effectiveness. These studies are collected after the drug or device has been approved by FDA, and give post-market safety monitoring, also known as step 5 in overall process.

Step 5: “FDA monitors all drug and device safety once products are available for use by the public”

At this point many thousands of patients may be using a drug, and for much longer periods of time than trials were able to cover.  This means hidden or rare problems may become more obvious, some of them very serious.   A consequence is that many drugs found to be unsafe have been removed from the market over the years.  A key issue is that we humans can have very different reactions to medications.  What is life-saving for one person may be deadly for another.  That is not to say a certain drug which is dangerous for some will always be removed.  Instead, it might be the case that it can used by the right person, in the right way.   That distinction takes a lot of clarity about the medicines, and about the differences between us.  As my second grade teacher used to say, “people are like snowflakes, no two are the same.”  It is so true, and it applies to medicine in a deep way.  That is why safety is so hard to establish.  This applies to “natural” products as well. We are told constantly by advertisers that if something is natural, it is better, or safer. That is not always the case.  Natural remedies may be very potent, or they may be very harmful.  Just as much scrutiny and care should be taken to make sure any substance given to treat or prevent illness is safe for people.   However, in the United States vitamins and supplements are not required to go through the steps above.  Sometimes giving these compounds to people results in a bad outcome, and those reports are not rare in the medical literature.  For more information on that topic, see the MPDN article “Dietary supplements,” Fall 2016.   For more information on drugs in development, stay tuned.

REFERENCES

  1. https://www.fda.gov/ForPatients/Approvals/Fast/default.htm
  2. https://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/howtoapplyfororphanproductdesignation/ucm364750.htm
  3. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm594009.htm 
  4. https://www.cdc.gov/ForPatients/Approvals/Drugs/default.htm
  5. Marcia Angell, M.D. The Truth About the Drug Companies: How They Deceive Us and What to Do About It.  New York: Random House, 2004, 291 pages(A lengthy and well-cited appraisal of the pharmaceutical industry and laws affecting it in 2004 by an internist and 20 year editor of the New England Journal of Medicine.)
  6. Robert Love, editor in chief AARP Bulletin. Why Our Drugs Cost So Much: Nothing stops drug companies from charging the highest price the market will bear, AARP Bulletin May 2017  https://www.aarp.org/health/drugs-supplements/info-2017/rx-prescription-drug-pricing.html 
  7. Gina Shaw. The Price Isn’t Right: Breakthrough drugs for rare neurologic diseases are staggeringly expensive. We explain why and how to effect change. Neurology Now, February/March 2018 – Volume 14 – Issue 1 – p 40–45 or https://journals.lww.com/neurologynow/Fulltext/2018/14010/The_Price_Isn_t_Right__Breakthrough_drugs_for_rare.15.aspx

Thoughts on the dopamine pump, an interview with Conner Moore, M.D. (retired)

DUOPA, the dopamine pump, was FDA approved in January 2015 as an orphan drug (drugs or products intended for treatment of rare conditions affecting fewer than 200,000 people in the United States).  Though there are probably closer to a million people with Parkinson disease (PD) in the U.S., only a minority would be considered for DUOPA use.  DUOPA approval was based on a Phase III, 12-week, double-blind, double-placebo, active control, parallel group, multi-center trial with 71 patients (1).  In the trial, DUOPA was compared to oral, immediate-release (IR) carbidopa/levodopa tablets in advanced PD patients.  At 12 weeks DUOPA patients had reduced daily OFF time (when medications are not working and symptoms are not controlled) an average of about two hours.  At the same time, this group had also improved average ON time (when the medication is working and symptoms are controlled) without troublesome dyskinesia (uncontrolled movement that does not interfere with normal daily activities) by two hours (footnote).  Use has been limited in the United States for a variety of reasons.  We are happy in this interview to hear about the DUOPA pump from someone who is well-versed in medicine and in PD.

Conner Moore, M. D. is a retired pediatrician who practiced for 40 years in the Saco/Biddeford area until 2008, and worked part-time in 2010. That same year he began to notice the signs of PD.  Like his mother, who also had the condition, tremors were never a big part of the disease.  Over time, his PD progressed and fortunately he responded to carbidopa/levodopa (Sinemet).  As far as I know among Maine movement disorder neurologists, he is the first patient in our state to have the DUOPA pump.  Dr. Moore took some time to speak with me by phone and describe his experience with DUOPA at the end of February 2018.  This was a casual conversation and he was speaking strictly from his own experience, not offering medical advice on a professional basis, and not representing AbbVie Pharmaceuticals.  I appreciate his thoughts and insight.

MPDN: What was your PD like in the years prior to getting the pump?

CM: It started out gradually and on one side like most people.  But I was always very active, and I knew that there were studies supporting the role of exercise in Parkinson’s.  I took a fairly high dose of carbidopa/levodopa to participate in sports and other activities.  It was a trade-off and I knew that might also mean dyskinesias might come earlier.  It seemed worth it to me.  And, I’ve been involved in the New England Parkinson’s Ride (see article in the summer, 2016 issue) and 4 years ago I was able to complete 30 miles.  In 2016 I was only able to do 10 miles and took more rest stops, mostly due to fatigue.  Last September, 2017 I wasn’t able to participate because of balance and other factors.  Also, I wasn’t using the pump yet.

MPDN:  I understand that for the two years leading up to the pump dyskinesias had become an increasing problem, sometimes severe enough to be exhausting, and medication failure was an issue.  This led to you taking more frequent doses of carbidopa/levodopa.  But, this meant trying to work with diet was also a problem because certain foods might interfere with levodopa absorption.  How did you manage that before the pump?

CM: I was taking Sinemet every two hours and was very sensitive to protein with the oral drug.  I could eat maybe four grams of protein at a time and I’d have to try to get more in later in the day.  All the while, weight loss was a problem.

MPDN:  Did carbidopa/levodopa work as long as you took it every two hours?

CM: As is often the case after several years, unpredictable OFF times began to occur more frequently, and sometimes I couldn’t leave the house.  Even when I was ON, a troublesome issue was that OFF times would come on suddenly, like somebody slammed a window down.

MPDN:  Did you consider other options such as deep brain stimulation (DBS) before the pump?

CM:  I saw Dr. Kleinman and discussed options.  They don’t like to put the wires of DBS in your brain when you’re older, and I asked about other choices.  It didn’t take two minutes to decide about the DUOPA pump.

MPDN: When did you go through this process?

CM:  I started using the pump in late September 2017 and participated in the PROVIDE study, which monitored bodily movement for two months prior, and three months after starting the pump.

MPDN: How are the results?

CM: Dyskinesia is now less overall.  There is less OFF time.  I was getting a lot of blank shots with Sinemet, but the pump works every time.  My mood is better, and I can do more around the house.  There have been adjustments, but it’s been very good so far.  The people at AbbVie have been fantastic and there is a number you can call 24/7.  The nurse coordinator is very helpful.  After the pump I started to put a little weight back on.  It is complicated because some people have actually gone off the pump due to weight loss.  Since it was already an issue for me I have watched calories to make sure I’m getting enough.  I’m up about 10 pounds.  I am exercising and using a Theracycle about 30 minutes daily, also using a stationary bike at the gym.

MPDN:  Are there other dietary considerations?

CM:  Apropos to your article (B6, friend or foe?, fall 2016), there have been reports of neuropathy with dopamine pumps and I have checked my B vitamins.  It is a really fascinating disease.  The more I learn about this illness, the less I find that I know about it, and there are new questions.  But that is often the case in science and medicine.

MPDN: Too true.  The pump requires a PEG J tube, a tube that is placed through the upper abdomen (below the ribs) and enters the small intestine downstream from the stomach.   Is it difficult to manage?

CM: Care of the pump, tubing, and the PEG tube is not as complicated as I thought it might be. There is also the opening in your skin for the tube, known as a stoma. The only complication I’ve run into has to do with soup.  If I eat a little too much there might be a little leakage, not a big problem.

MPDN:  How do you get the medication for the pump?

CM:  It comes in 16 hour cassettes air shipped frozen from the Midwest and

“The pouch on the vest, etc. that holds the pump has a clear plastic window that you push buttons through for bolus function or to change rate or shut down pump to remove when showering.  It has a number of alarms – for kinked tubing, or high pressure when I fail to loosen a clamp.”

FedEx has been right on time, even in a snow storm this winter.  It runs on AA batteries but they send those too, they send everything you need.  The 16 hour daily cassettes contain the carbo/levodopa in gel form and clip onto the pump.  The total unit size is 7.5 x 3.5 inches and weighs a pound. There are vests, hip packs and shoulder slings available to hold the pump.  I quickly adapted to my new addition and am generally not aware of its presence.

MPDN: Is it difficult to operate?

CM: There are considerations about operating the pump, a learning curve and some getting used to.  It takes some dedication to this project.  Most people use the pump during the day and turn it off at night.

MPDN: What is a typical day with the pump?

CM:  I wake around 5am and feel I am not yet in an OFF state.  I’m able to get up and do a few things around the house for about an hour.  Then I start to feel the typical tightening of the face and decrease in left arm swing that let me know I’m wearing off.  When I attach and turn on the pump after about 20 minutes there may be a brief period of dyskinesia.   After that it levels out.  During the day the pump provides a base rate of medication such as 40 mg levodopa every hour.  It has given me a sense of freedom.  I can go into a theatre now, have dinner, and don’t have to worry about wearing off.  If that happens it is much more gradual, a slow process that I can feel coming on, unlike before.  If that feeling comes on I can give myself a 50 mg bolus by pushing a little button on the pump and it kicks in within minutes.  It has improved my quality of life tremendously.

MPDN: Do you still sometimes have wearing OFF?

CM:  There might be wearing OFF with a high protein meal, but I can eat about twice as much protein in one sitting than I could before.  The other thing is exercise.  Sometimes I need to give myself a bolus if I’m working out too hard.  Usually I don’t think about it.

MPDN: Are there any personal limitations with the pump?

CM: I don’t think there is anything I would put in that category.  I have only tried one overnight away from home, but have talked with PD pump patients who have traveled with the pump.  It requires planning because of refrigeration requirements.

MPDN: How about shutting it down for the day?

CM:  At first I was concerned I might have to write down a lot of complicated procedure. There are about 15 steps to turning it off and putting everything away at night, but it all becomes so routine that it’s like brushing your teeth.  When you shut it off you flush the tubing with tap water and the nice thing about that is that you are flushing medicine into yourself and get about 30 minutes more levodopa from the tube.  Then, it is time to sleep.  Not everyone shuts it down at bedtime.  Some people run it all night.  I don’t think I need that at this time.

MPDN: There is a peer mentor program for people considering the pump.  What was your experience?

CM: I used the peer mentor program before getting the pump and met people who had been in the study, and had the pump for about six years. They told me the maintenance was low with the equipment and it had generally lasted that long.  I wound up signing on myself for that program.  People interested in the pump can call and get one of us on the phone to talk about our experience.  It’s a good resource because you are talking to a person with experience.

MPDN: Any last thoughts Dr. Moore?

CM: Just that it has been positive for me, and I hope it helps others to know about this.

Dr. Moore also sent me a comment by email after we talked:

We did not talk about the cost.  My Medicare and supplemental insurance pays everything.  But I think the President is going to look at entitlement programs to balance the budget.  The DUOPA is part of the pump package so it falls under Part B durable equipment and does not go through Part D and the drug insurance process.  The government gets a discount, but not much.


Comments by Michael Kleinman, D.O.

The most common indication for the pump is for patients with severe motor fluctuations.  If someone is taking medication every 3 hours or less and is still with a significant amount of off time then I would consider them for the DUOPA pump.  Traditionally these patients would be first considered for deep brain stimulation surgery but for those patients who may not be good candidates for deep brain stimulation surgery or who are not willing to go through the surgery, then this is a good option.  The percent increase in ON time is actually similar to that achieved with surgery.

The company which supplies the medication has a support system in place to help patients get used to administering the medication themselves at home.  This has run very smoothly in the experience that we have had here.  The medication is started for the first time in the office.  At that visit the patient will come in without having taken their medication from the prior night.  That visit will be 3-6 hours long.  The initial bolus dose and continual infusion dose of the DUOPA infusion will be set based on how much oral medication the patient was taking prior to starting DUOPA.  We will then monitor how long it takes for the medication to start working, whether there is evidence of too much medication such as dyskinesia, and whether there is any wearing off.  The patient and their caregiver are also educated during that visit on how to operate the pump.

Follow up visits will be more frequent than usual in the beginning to fine tune the dose of medication.  If the initial programmed dosing is working well then visits can quickly go back to being every few months.  Patients can be given a range of settings to work with at home as well.  They can call with a report on how they are doing and be instructed on what change to make to their infusion settings without the need to come in for a visit to have the pump settings changed.


Footnote: In the above mentioned phase III trial of DUOPA, the most common adverse events were listed if occurring in more than 7% of patients, and occurring more frequently with DUOPA than carbidopa/levodopa IR and included complication of device insertion, nausea, constipation, incision site erythema (redness), dyskinesia, depression, post procedural discharge, peripheral edema, hypertension, upper respiratory tract infection, oropharyngeal pain, atelectasis, confusional state, anxiety, dizziness and hiatal hernia.

REFERENCES

  1. Olanow, et al; for LCIG Horizon Study Group. Lancet Neurol. 2014;13(2):141-149.

Spring 2018

Ready or not, it is spring, and time for more articles on MPDN.

This time we include an interview with Maine retired physician Dr. Conner Moore regarding his experience with the DUOPA pump.   He very thoughtfully went over his observations on various issues related to choices of treatment with advancing PD, and a few of the ins and outs of using the pump as a patient himself.   In that article, Dr. Michael Kleinman of MMP Neurology also gave comment on DUOPA.

As so many of you have raised questions about the topic, we will discuss the drug approval process in the U.S.  It is a little complicated, and hopefully that brief article will shed some light and segue into the area of drugs in the development pipeline for Parkinson disease (PD).  Regardless of the decision of a certain giant pharmaceutical company to withdraw from PD research, there is a huge amount of work going on worldwide to bring new drugs and therapies to treat PD.   The articles included here will be part of an ongoing series on the topic.   We will also take an updated look at focused ultrasound (FUS) for PD.

Finally, MPDN is seeing more email subscribers all over the state, and we have now reached 12,000 site visits since we started in April, 2016.   We are glad this resource is useful.