Research Roundup

by Margaret Wahl

FDA confirms rat study results are reason for arimoclomol trial hold

According to a Feb. 11 press release from CytRx, developer of arimoclomol, the company has received written correspondence from the U.S. Food and Drug Administration (FDA) clarifying the agency’s decision to place a hold on the phase 2b trial of arimoclomol in ALS. (See “Arimoclomol trial,” ALS Newsmagazine, March.)

The FDA has confirmed CytRx’s understanding that the agency’s decision pertained to a previously completed toxicity study in rats and was not related to data from any human arimoclomol studies.

Steven Kriegsman, CytRx’s president and CEO, is quoted as saying the company will “take the necessary steps to resolve this matter as expeditiously as possible” and that it plans to “work with the FDA to address their questions and allow us to move forward with our phase 2b trial.”

What’s going on with TDP-43?

Two new research papers, both published in February, show that mutations (flaws) in the gene for the TDP-43 protein can result in familial and sporadic (nonfamilial) ALS.

Nigel Cairns at Washington University School of Medicine in St. Louis, and colleagues, announced online Feb. 20 in Annals of Neurology that a mutation in the gene for TDP-43 is the cause of ALS in a family of European descent.

And a week later, Christopher Shaw at King’s College London, and colleagues, published findings online in Science Express showing that a TDP-43 mutation caused ALS in a family of British descent and in a few people with nonfamilial ALS. (Out of 2,500 unaffected people who also were screened, only one had a TDP-43 mutation.)

These findings come shortly after the announcement last spring that abnormal cellular clusters containing TDP-43 are present in sporadic ALS and in the type of familial ALS that’s not related to the SOD1 gene, but are not present in SOD1-related ALS; and a subsequent finding that a deficiency of the protein progranulin leads to fragmentation and mislocation of the TDP-43 protein in cells.

These results could mean TDP-43 is a factor in the ALS disease process and that its apparent involvement only in non-SOD1 ALS signifies a difference between SOD1-related ALS and the other more common forms of the disease.

Scientists now should be able to breed mice with TDP-43 mutations and further explore TDP-43’s actions.

“It will be very interesting if academics can develop a TDP-43 animal model that mimics ALS in a robust fashion,” wrote John McCarty, treatment investigator at the MDA-supported ALS Therapy Development Institute in Cambridge, Mass., on the Institute’s online forum (www.als.net/forum) March 4. McCarty cautioned that the presence of TDP-43-containing clusters in ALS-affected cells doesn’t necessarily mean the protein plays a disease-causing role.

However, he noted, mice with TDP-43 mutations “would be a very welcome new tool for us and other researchers.”

Nerve-muscle signals are a two-way street

Chemical signals from nerve cells are known to influence muscle cells. Lin Mei’s team has found that signals from muscle cells also influence nerve cells.

Researchers in the laboratory of MDA-supported Lin Mei at the Medical College of Georgia in Augusta have found that muscle fibers do more than passively receive signals from nerve fibers that tell them to contract or relax.

Instead, say Mei and colleagues, who published their findings online in Nature Neuroscience Feb. 17, “backwards” (retrograde) signals coming from muscle fibers to nerve fibers profoundly influence nerve-fiber location and function. The finding could have implications for ALS, in which nerve cells that interact with muscle fibers degenerate.

When the investigators bred mice lacking a protein called beta-catenin in their muscles, they saw that branches of the phrenic nerves, which go to the respiratory diaphragm, were mislocated in the diaphragm muscle and that signal transmission was reduced.

However, when beta-catenin was depleted only in nerve cells in the mice, they didn’t have this type of neurological problem.

“These observations demonstrate that muscle beta-catenin is a key ingredient for neuromuscular junction formation,” Mei said, referring to places where nerve and muscle fibers meet. The findings also showed that beta-catenin may control other proteins necessary to nerve-cell health, she added.

“Muscles are known to produce elusive nutritional factors for nerve-cell survival and development,” Mei said. “And these findings could provide leads to their identification.”

VEGF-B may save nerve cells without collateral damage

A protein called vascular endothelial factor B (VEGF-B) appears to protect nerve cells without causing unwanted proliferation of blood vessels, as its chemical relative VEGF can do, says a new report in the Journal of Clinical Investigation.

Xuri Li at the National Institutes of Health in Bethesda, Md., and colleagues, who published their results online Feb. 7, describe how treatment with VEGF-B injections rescued nerve cells in mice with injuries to the retina and optic nerve, without undesirable effects. They conclude that VEGF-B might provide a new option for treating different types of neurodegenerative disease.

MDA is funding Peter Carmeliet at the Flanders Interuniversity Institute for Biotechnology in Ghent, Belgium, to study VEGF and VEGF-B in rodents with ALS.

Review of evidence supports link between toxic exposures and illness in Gulf War vets

A review of multiple studies of veterans of the 1990-1991 Persian Gulf War who developed ALS and other illnesses strongly supports a link between illness and exposure to chemicals known as acetylcholinesterase inhibitors (AChEis). (This topic was explored in “ALS and Vets: Searching for Connections” in the March issue.)

In this new review, published March 18 in Proceedings of the National Academy of Sciences, Beatrice Golomb at the University of California-San Diego describes 21 studies of Gulf War veterans that link this type of chemical exposure to later development of a variety of health problems.

The AChEis studied included pyridostigmine bromide, a medication given to some 250,000 Gulf War service personnel to counteract expected attacks with toxic nerve agents; carbamate and organophosphate pesticides, which were aggressively used in that conflict to control insects and to which 41,000 service members may have been overexposed; and sarin, a nervous-system toxin to which the Department of Defense estimates about 100,000 personnel were possibly exposed after demolition of a munitions depot.

The review also found that low activity levels of two enzymes involved in detoxification of AChEis (PON and BChE enzymes) also correlated with the presence of illness. Genetic variations are one cause of activity level variation in these enzymes.

The author notes that emerging evidence links ALS incidence to PON gene variants and perhaps their interaction with AChEi pesticides. She says this evidence supports a connection between organophosphate pesticide exposures during the Gulf War and the observed elevated rate of ALS development in Gulf War veterans.

People With ALS Face Tough Decisions About Experimental Medications

by Margaret Wahl

Deciding whether to take an experimental medication outside or inside a clinical trial can be tough for people with ALS.

With the excitement about lithium as a potential treatment for ALS (see ALS Newsmagazine, March) and the proliferation of clinical trials, people with the disease are facing some tough decisions.

Although everyone hopes for benefit from an experimental medication, trials are conducted to gather broad data, not necessarily to help any individual. Risks of participating in a trial range from being assigned to a placebo (inactive substance) group, to being exposed to a compound that may worsen the disease, as was the case in the recent trial of minocycline.

On the other hand, bypassing a clinical trial to take an approved medication such as lithium, which lacks a track record in ALS, has its own risks, including exposure to a possibly harmful substance and exclusion from most clinical trials. It does, however, eliminate the guess work about placebo assignments and allows for individualized adjustments in dosage and timing of treatment.

Medical sociologists and other trial watchers worry that research subjects may not fully understand the differences between treatment and a clinical trial. Sociologist Gail Henderson at the University of North Carolina says most people are in a “gray zone” on this subject. They know they’re in a research study, but they may think of the research as more like an extension of treatment than it really is. This “therapeutic misconception” can be heightened if the investigator is also the patient’s doctor.

Would have asked more questions

Deb Wehrlin, 48, of South Burlington, Vt., begged her husband, Jeff, to drop out of the minocycline trial in 2005, when it was clear his ALS was worsening rapidly. He died in August of that year, at age 51. (Minocycline was later shown to have a harmful effect in ALS. See “ALS Specialists Discuss Clinical Trial Results,” ALS Newsmagazine, January.)

Wehrlin says she wasn’t aware of the risks going into the trial, although Jeff might have been. “We were told it’s an antibiotic that’s been used for acne, and there didn’t seem to be any issues,” Wehrlin says, “but I also know my husband, and he could be very strong-willed, and it’s possible he didn’t share all the information with me.” Jeff, she says, was committed to finishing the trial because of his desire to help others, even when he realized he wasn’t going to survive.

If she had it to do over again, she says, “I think I would do more research on any product that offered hope, and be more careful, ask more questions. We all want a miracle, and who knows what that might be, but I think caution is needed.”

Might as well try it

Tim Kokojan of Euless, Texas, whose ALS was diagnosed in March 2005, isn’t concerned about the risks of taking lithium. He says he’s reassured by its long record in treating bipolar disorder.

Kokojan asked his doctor to prescribe lithium shortly after reading about the Italian trial on the Living with ALS listserv (http://health.groups.yahoo.com/group/living-with-als/).

“When this came up about lithium, I thought I might as well try it,” Kokojan says. “I’ve noticed progression in the last year. My right arm and both legs are pretty weak now. In the last few months, I’ve noticed a big turn for the worse. I live alone. I’m in the middle of a divorce. I feel like I have nothing to lose.”

Kokojan, who says he’s now “willing to try anything,” says he wouldn’t want to enroll in a clinical trial of lithium if it meant the possibility of a placebo group assignment. “I don’t want to stop taking it [lithium] now that I’m getting the ball rolling,” he says.

Being a little cautious

Laura McWhorter, 37, of Bridgewater, N.J., says she’s not ready to jump on the lithium bandwagon just yet, even though her ALS, diagnosed in 2005, is progressing. “It started out just as a foot drop in the right leg,” she says, “but at this point, I really can’t walk at all. My arms and hands are starting to get weak, and that’s been making a big difference in what I can do for myself.”

McWhorter worked in the pharmaceutical industry, where she designed, monitored and interpreted clinical trials. Now she’s having to decide whether to enroll in a clinical trial herself.

As a professional, she’s skeptical of the lithium study. “It’s important to have replication to make sure something isn’t by chance,” she says. “I’m not really convinced that [the lithium findings] are not by chance. I also think, if it did work, there must have been some patients out there with ALS with bipolar disorder, and you’d think it would have been noticed.” Her search of the medical literature turned up nothing.

However, she says, “As a patient, I hold onto hope. I’m not completely doubting it. I’m watching the ALS space (alslithium.atspace.com). As people get out to 90 or 120 days [on lithium], I’ll see how it looks. I check that every week to see how they’re doing, because the flip side is, it’s not a picnic to take lithium. You need a lot of blood tests, you have to watch your diet, and your fluid intake is important. For those reasons I’m being a little cautious.”

Risks, rights, responsibilities

If you decide to enroll in a clinical trial, you’re taking on risks and responsibilities. In the United States, the Food and Drug Administration spells out the legal rights of trial participants by saying they should know what risks they’re facing, as well as what procedures they’ll undergo and for how long.

There are no legal responsibilities for trial participants, but it’s problematic if participants leave a trial for a trivial reason; fail to comply with study procedures or appointments for less than compelling reasons; are dishonest (for instance, about medication use); or take the study compound to a lab to determine whether it’s a placebo.

McWhorter has been in two previous trials. In one of them, she was assigned to what she later learned was creatine plus minocycline.

“There’s risk in doing everything,” she says. For her, the lithium jury is still out. “I would tell [people with ALS] that if they were doing relatively well to wait to join a study, but if they felt like they were getting toward the end of their rope, to try it. That’s probably what I’m going to do.”

“Being a Co-adventurer” in the May-June issue of Quest will also address issues surrounding clinical trials.

WWW Dot W-O-W!
iPals get connected via the World Wide Web

by Amy Labbe

To some, the Internet is a good time; to others it’s a time-waster. Some say it promotes isolation, while others point out that it lets them reach out and touch someone on the other side of the world. 

Some praise its virtues; others decry its faults.

Say what you will, but to people with ALS, having the World Wide Web at their fingertips (or their toes, eyes or even eyebrows) opens the door to a world that otherwise may have been lost to them.

Web of connection

Rose Kisker

Rose Kisker of Rochester, N.Y., learned she had ALS in the summer of 2007 just before her 44th birthday. Following the diagnosis, Kisker says she spent a lot of time in bed pondering what her life could have been like and mourning her own death, which led to increasing depression.

“So I changed my attitude, and with that came a newfound hope,” Kisker says. “I had to change my way of thinking — after all, ‘terminal’ is just a word.”

Kisker began to research every aspect of ALS she could and says, “The most powerful tool I’ve found has been the Internet.”

For four to eight hours a day, Kisker surfs the Web for the resources, information and support she can find, and for the wonderful friendships she cultivates through chat sites and forums.

She recalls her mom’s death from ALS in December 1996.

“My parents didn’t have access to the Internet during that time, and I only wish my mom could have experienced that type of support,” she notes, adding that with the increasing difficulty of getting out of the house due to the physical challenges of the disease, “I would be lost without the Internet — it has become part of my life.”

Kisker says there’s “enormous benefit” in “staying connected,” and urges everyone to take advantage of the Internet. In the process, she says, “you may just find you’re enjoying the moment.”

Web of communication

Steve Smith

Steve Smith, whose bulbar-onset ALS was diagnosed in June 2001, has lost the ability to talk but not to communicate.

Although like many, he uses the Internet to keep in touch with family and friends, the 56-year-old from Winterville, N.C., points out the value of the Internet in facilitating communication with health professionals involved in the management of his ALS.

Smith spends 10 hours a day online, during which he talks with physicians, nursing staff and other members of his medical team. He describes the Net as a “vital portal” for maximizing doctor-patient interaction.

The ability to talk with physicians and others online, Smith explains, allows him to have a hand in development and management of his medical care, often saving him a trip to the doctor, enabling him to request prescription renewals and providing the conduit through which he can discuss possible new treatments or options with those who can advise him.

The ability of the Internet to reopen the lines of communication ALS closes reduces stress levels, Smith says.

“It gives you a voice again.”

Web of control

For Marie Dunman of Roxboro, N.C., the Internet is a tool for maintaining control over as many aspects of her life as possible.

Marie Dunman with neighbor girls Arissa and Anica Stewart

Dunman, 56, has weakness in her arms and legs. She uses a walker and braces for walking short distances on uncarpeted floors and an electric wheelchair otherwise. She requires assistance with dressing, showering and cooking.

But for two to four hours a day, through the Internet, Dunman researches her disease, prices on hotels, and anything else she’s in need of or that sparks her curiosity. She communicates with family, friends and physicians, pays her bills, and monitors and manages her bank accounts daily.

She shops for clothes, books and medical or assistive equipment, listens to audio excerpts from the Bible, and seeks and enjoys games and other online entertainment.

Dunman says life with ALS and without the Internet would be “boring to the point of depression,” and that it would make her feel “helpless” and “more disabled.”

“It keeps me informed and in touch,” she says, adding she hopes she never has “to do without it.”

Web of contributions

Beth Rookey, 47, of Enfield, Conn., says the Internet is “the gateway” to her world. She gets on the computer at 6:30 a.m., takes a break for lunch, and then finishes up at 5 p.m., Monday through Friday.

Beth Rookey with husband Ralph and son Robert

In addition to communication, Rookey uses the Internet to read her local paper and keep up with local, national and world news. She takes e-classes, sends e-cards to family and friends, checks her son’s school Web site and talks to his teachers, and keeps up with the shows she misses on TV by watching the episodes online.

Rookey also built and manages a Web site for her husband Ralph, a professional photographer. Ralph photographs two football games a week from September through November for their son’s high school football team in addition to a repertoire of wedding, family, sports and nature, and other types of photos. Beth spends her days working on the photographs and posting them to the site for clients to view.

Rookey says the Internet has helped keep her mind active and always learning, and that she’d “be bored to tears without it.”

Most importantly, “It has helped me contribute to life,” she says, “rather than watch it go by.”

Web of wonders

Through its offerings of e-mail, chat groups, forums and instant messaging; through its search engines and online resources; through newsgroups, and interest- or hobby-related professional and amateur Web sites; through online business, banking and retail outlets; and through the endless possibilities it offers for learning from others and making one’s own contribution in return, the Internet offers something for everyone — and most assuredly, with the independence it imparts, a little something extra for anyone dealing with ALS.

How has the Internet helped in your journey with ALS?  What sites would you recommend to others?  Send responses to publications@mdausa.org, and mark “ALS Internet Survey” in the subject line.

Three Years Later
A “Homebound Amendment” remains in limbo

by Bill Norman

After two years of testing the waters and one year of studying test results, the federal government’s Home Health Independence Demonstration has little to show for the time and money invested in it.

The demonstration project was an experiment to test what would happen if the government loosened restrictions imposed on severely disabled people receiving Medicare’s “homebound” home health care benefits.

Former Senator Bob Dole and David Jayne, who has ALS, pushed Congress to loosen Medicare homebound restrictions.

Approved by Congress in 2003, the demonstration project represented a hard-won victory for disability advocate David Jayne, 46, of Rex, Ga., who has ALS. Armed with a communication device, the Internet and dogged persistence, Jayne had mounted a three-year national campaign to change what he considered unreasonable restrictions on Medicare home health care beneficiaries.

Unfortunately, based on the evaluation of the project, it appears it was poorly structured by the Centers for Medicare and Medicaid (CMS) and has yielded no meaningful results other than details of how it didn’t work out.

The perils of disobeying

In order to receive Medicare in-home care (skilled nursing assistance with bathing, feeding and other basic functions), recipients must be certified “homebound” by a doctor, and only may leave their homes infrequently and for short periods, such as to go to the doctor or attend religious services. In the past, this restriction has resulted in people losing their benefits for leaving home to do such things as attend a funeral — or in Jayne’s case to attend a pro football game.

Jayne attended that game more than seven years ago, relying on the help of friends because ALS had left him unable to speak or breathe on his own, and with movement in only two fingers.

When Medicare learned of Jayne’s outing, it rescinded his home health care benefits.  He chose to fight and, with the help of his congressman, got his benefits back. But he chafed at what he considered Medicare’s unfair policy.

Congress acts … sort of

Jayne recruited supporters, including former senator Bob Dole, and formed the National Coalition to Amend the Medicare Homebound Restriction Act for Americans with Disabilities. He testified before Congress several times.

Eventually, legislators concurred that Medicare should investigate the situation and funded a demonstration project to run from 2004 to 2006 in Colorado, Massachusetts and Missouri. Medicare home health care beneficiaries in those states would be allowed to leave home whenever they wanted, for as long as they wanted, keeping a log of their excursions. 

When the project concluded, Mathematica Policy Research of Princeton, N.J., was hired to evaluate the results. The essence of its evaluation is conveyed in the title of its 2007 report: “Barriers to a Successful Experiment Were Multifaceted, and Difficult Policy Issues Remain.”

Multiple barriers to enrollment

Although Congress authorized CMS to enroll up to 15,000 participants in the project, only 58 participated.
Mathematica listed several factors that contributed to the low enrollment:

• Money fears.  Some home health care agencies with Medicare home health care contracts thought enrolling “demonstration patients” would cost them more in care than Medicare would reimburse.
• Benefit doubts.  Some agencies felt their patients would get no more benefit from the loosened regulations than they already enjoyed.
• Money, again. Some agency patients were eligible for both Medicaid and Medicare home health benefits, but participation in the demonstration required they be enrolled in Medicare. Some agencies balked at enrolling them, saying they got more reimbursements for their Medicaid patients.

Medicare home health care beneficiaries didn’t rush to sign up, either.  Mathematica found:

• Some people didn’t want to get involved if it meant they had to switch care arrangements — even if it would save them money.
• “Dual-eligible” individuals found their Medicaid home health care benefits superior to Medicare’s.
  

CMS’ own eligibility requirements had a chilling effect on enrollment, Mathematica found.  To current home health care requirements, CMS added six definitions of what constitutes “homebound.”  Among them: “The beneficiary requires skilled nursing services for the rest of the beneficiary’s life and the skilled nursing is more than medication management.”

What to do?

Mathematica concluded:

• CMS needs to communicate more effectively with home health care agencies to explain/translate how to handle patients who are dually eligible for Medicaid and Medicare.
• CMS needs to develop a more equitable compensation system for home health care agencies.
• CMS needs to clarify the meanings of project enrollment, qualifying terms such as permanent skilled care need, permanent disabling condition and homebound.

Participants liked it

Mathematica interviewed eight of the 58 participants about their participation.

Of those, three were in such fragile health that they derived no added benefit from being able to leave home.

Three others, all with paraplegia, said they weren’t able to leave home due to the difficulty involved in doing so.

The interviewee who spent most time away from his home (about 96 hours monthly) had muscle atrophy. His wife was his full-time caregiver/driver, and she enjoyed getting out to eat, shop and take long drives.

The eighth interviewee could walk with a cane and drive herself. Her time out of the house averaged 46 hours a month.

All eight participants — even though they couldn’t always take advantage of the loosened restrictions — still supported the concept of the demonstration.

However, the low enrollment numbers left Mathematica unable to draw conclusions about who might benefit, and in what ways, if the homebound restriction was dropped. Nor could it predict how frequently and for how long people might elect to leave their homes.

A chorus of nays

Without exception, the home health care leaders interviewed by Mathematica gave the demonstration project a uniform thumbs down.

• “Initially, we were excited that Missouri was one of the demonstration states, and we were anxious to see the project get under way. Then we found that CMS had put so many handholds on it, the project was unwieldy from the start.” — Mary Schantz, executive director of the Missouri Alliance for Home Care.

  Home heath care leaders gave the project a uniform thumbs down.

• “CMS provided no funds to compensate home health care agencies for the extra visits they would have had to make to the homebound participants, as required by the demonstration. I tried and tried to get people [agencies] to participate, but they almost all just said, ‘no thanks, not without compensation for the extra work we’d have to do.’” — Ellen Caruso, executive, Home Care Association of Colorado
• “It seems to me that the crafters of the demonstration were overly worried about having people come out of the woodwork to enroll in the program. I believe that’s why they designed the additional criteria … to discourage excess participation. But those added criteria proved far too narrow and restrictive to permit much enrollment at all. I also think there was a perception on the part of the crafters that many people out there were deliberately keeping themselves at home simply to ensure that they would continue receiving
  Medicare home health benefits. That proved to be totally incorrect. I think we need to start over.”
  — Patricia McDonald Kelleher, executive director of Home Care Alliance of Massachusetts.

Once more, with feeling

U.S. Representative Edward Markey, D-Mass., was one of the initial sponsors of homebound legislation. Despite the disappointing results, he says he remains convinced that loosening restrictions is the way to go.

“Individuals with late-stage Alzheimer’s disease, ALS and similar permanent diseases are not trying to ‘game’ the home health system,” he says, adding he will “continue to push for more freedom and independence for these types of patients … and look forward to continuing to work on this vital issue.”

To view Mathematica’s full 140-page evaluation of the project, visit the CMS Web site and select Medicare/Demonstration Projects and Evaluation Reports/2004.

When the Travel Bug Bites
Ride the silver rails

by Bill Norman

Richard and Susan Govoni of Cape Cod, Mass., are big train travel buffs, in part because they say air travel “has become a tremendous nuisance and hassle.”

Susan, who received an ALS diagnosis April 2007, and Richard find trains less congested, quieter and more convenient, even though “the journeys are longer and trains are notoriously late.”

The Govonis have traveled by train from Boston to Buffalo and Montreal, and from Montreal to Toronto, then on to Edmonton, Canada. The return trip home to Boston from Edmonton lasted 15 days. Some things they learned while riding the rails:

Ship Luggage. To reduce the amount of luggage they have to carry, the Govonis send clothing and medical supplies ahead to their travel destination via carriers like UPS. At the end of a trip, they ship clothes back home while they take the train.

Use power lifts. Some train station platforms are at the same level as passenger cars, so a wheelchair easily can make the transition between the two, but access to most train cars still requires a step up or two. A power lift then is needed to elevate a wheelchair user to car floor level. The Govonis found it’s important to call ahead to arrange for the lift, so the train doesn’t have to spend extra time in the station.

Love those red caps. “They’re an invaluable asset,” the couple says of red caps, otherwise known as porters. “At train stations they’ve been able to help us with preboarding so we were seated on the train with all our luggage and the [manual] wheelchair stowed well before any other passengers boarded.”

Conductors are pals. Train conductors are another important resource, the couple found. Their conductor agreeably called ahead to destination stations to alert red caps they’d be needed to help with off-loading a wheelchair user and luggage. Another time, their conductor willingly moved them forward to another compartment that was closer to the dining car.

Use the skinny chair. Susan traveled to meals in a slender wheeled contrivance called a “Washington” (or aisle or boarding) chair. It has no armrests; straps hold the occupant in place. People they encountered in hallways when headed to the dining car still had to step aside to make room, but the chair navigated passageways that would have been too tight for a standard wheelchair.