Last week’s cancellation of a clinical trial in Albany, N.Y., researching treatment of CCSVI is a big setback for those trying to glean scientific insight into whether venous angioplasty mitigates multiple sclerosis (MS) symptoms in people with MS who have obstructed venous flow. It’s very bad news for the Saskatchewan government, which allocated $2.2 million to fund the trial and recruited volunteers to travel to the U.S. And it is a major blow for those who’d taken part in the trial or were lined up to go. But, like all failures, it’s also instructive. And the lesson here? That the best thing for CCSVI research, moving ahead, would be for the so-called “liberation” treatment to be liberated from MS itself—more specifically, from its exclusive relationship with the degenerative condition, a point CCSVI activists have been making for years.
For those not up on the medical drama, here’s a recap: In 2006, Italian venous specialist Paulo Zamboni posited a new condition he’d identified as “cerebro-spinal venous insufficiency,” or CCSVI, was closely related to MS. Typically, vascular experts don’t have anything to do with MS; neurologists are the traditional MS gatekeepers. The only reason Zamboni was investigating it was because his wife was afflicted. (That said, MS had been linked to the vascular system in medical research before famed French neurologist Jean-Martin Charcot classified it in 1868, but a correlation had never been proven.) Employing ultrasound technology, Zamboni saw a condition in the extra-cerebral veins with similar markers to venous insufficiency in legs, a condition routinely treated. Left untreated, venous insufficiency in the legs can lead to serious debilitation and medical complications. Zamboni found CCSVI treated by angioplasty reduced, and even eliminated, symptoms experienced by people with MS.
When CCSVI made big headlines in Canada in 2009, it was as a “cure” (without the corroborating science) for MS, not as a separate vascular condition linked to neurodegeneration. That swept it into the MS infrastructure, a research-pharmaceutical complex populated by neurologists and MS societies that is currently based on the unproven theory that MS is an autoimmune condition. The autoimmune theory, taught in medical schools, has buttressed decades of research and given rise to a drug industry estimated to grow to $20 billion by 2017. So it isn’t surprising that most MS neurologists were skeptical, even dismissive, of CCSVI from the get-go. (Imagine BlackBerry execs being asked to critique the first iPhone, and you’ll get the idea.) Provinces refused to cover scanning or treatment of CCSVI, making the valid point that they couldn’t cover every unproven treatment simply on the basis of patient advocacy. (Provinces do, however, cover treatment for venous insufficiency in legs, and for angioplasty of extra-cerebral veins for other conditions.) When MS patients began travelling offshore for treatment in the hundreds, and then thousands, then militating at home, the government, neurologists and MS societies acquiesced and agreed to double-blinded randomized clinical trials, the cornerstone of drug approval. Clinical trials for drugs are themselves a huge industry, particularly in the lucrative MS drug arena, with neurologists being paid upward of $5,000 for every patient recruited.
The clinical-trial process has been under scrutiny of late, criticized for lack of transparency, suppression of negative data, even whether they work at all. The issue of making medical treatments conform to a drug model has also raised ethical concerns. Many treatments, including angioplasty, are introduced without them. Just last year, the Ontario government gave special dispensation for some patients to receive renal denervation treatment, an experimental procedure to reduce blood pressure for patients who don’t respond to drugs. It was backed by only one study of 106 patients funded by a medical-device company poised to profit from its introduction. The Canadian Medical Association, quick out of the gate to say CCSVI must be “based on science not hope,” called the unproven renal denervation treatment a medical “breakthrough,” despite concerns voiced within the medical community. But renal denervation treatment differs from CCSVI treatment for MS in significant ways: It didn’t challenge any medical orthodoxies or interfere with pharmaceutical therapies.
Tethering CCSVI to MS created an either-or equation. Either CCSVI caused MS or it didn’t. Either CCSVI was found in people with MS exclusively or it wasn’t. Either CCSVI could cure MS or it couldn’t. Any potential benefit in new insight into the understudied role of the venous system in neurodegeneration was eclipsed. Caught in the middle were people diagnosed with MS, a widely heterogeneous condition, with no cure. MS drugs, which run as high as $60,000 per patient per year, and whose side effects include death, have failed many. Now, studies indicate the drug approval has been based on benchmarks that have not been validated and that, contrary to claims, they are ineffective at halting progression.
The provinces’ varied responses to CCSVI reflected an increasingly decentralized medical system—Ontario ignored it, while New Brunswick set up a fund to subsidize MS patients travelling offshore for treatment. Newfoundland and Labrador funded a small observational study based on patients who’d travelled to various clinics that reported in 2012 “no measurable” change in MS symptoms. The feds flip-flopped before finally announcing in 2011 that they would fund phases I and II of a Canadian clinical trial, with 100 people to look at safety and efficacy. That trial began recruiting patients this year, with results expected by 2016 at the earliest.
Saskatchewan was the first province to pledge actual clinical trials, putting up $5 million and issuing a call for proposals in October 2010. When Premier Brad Wall announced his government was sending 86 patients to the U.S. to participate in a phase III clinical trial in January 2012, it was a rogue move destined to resonate in the province that’s home to Canada’s highest incidence of MS. But there was also irony: The home of Canada’s much-vaunted universal health care program had to ship residents out of country for medical research.
Now, two and a half years later, that research is kaput. The trial’s principal investigator, interventional radiologist Gary Siskin, needed 197 participants for the study to have statistical credibility. But only 23—six from Canada, 17 from the U.S.—had participated. Others were lined up to come. The problem wasn’t Saskatchewan, Siskin tells Maclean’s. “They were confident that they could get their 86. It was me who was not confident we could get the rest.” Failure to do so posed ethical concerns about making people travel and receiving funding, without confidence they’d be able to produce a statistically valid study, he says.
Numbers provided by the Saskatchewan government indicate interest was high: 682 volunteered. Of that pool, 533 met criteria for age and residency. Then 130 were randomly drawn for the first round of assessment; 95 were identified by the Albany team as eligible candidates. Of this number, 32 had been assessed by a Saskatchewan neurologist; 13 were awaiting assessment. Sixteen had received the go-ahead to travel to Albany. The first patient was sent in August 2012; in total, seven were sent. One didn’t meet final criteria; of the six, half were treated, half were given a sham procedure. Another nine were ready to go.
As Siskin tells it, the challenge was recruiting the remaining 111 patients in the U.S. A big impediment, he believes, is the fact that only half of participants would receive treatment; the other half, the “placebo arm,” would be given a sham procedure. “If we said, ‘Everyone who signs up is going to be treated,’ then I’m sure we would have had people banging down the door.” There was also a climate of diminished interest, in light of negative CCSVI studies, including a much-publicized study out of Buffalo University based on 19 participants that concluded CCSVI treatment was ineffective. That study was too small to be definitive, Siskin says. “I believe they made conclusions that were outside of what was statistically appropriate.”
Saskatchewan Health Minister Dustin Duncan is disappointed, he tells Maclean’s: “We wanted to be part of answering whether CCSVI was, or was not, part of the solution of symptomatic relief for MS patients. But without the science behind it, we cannot say this is the standard of care.” There were bumps. It took a year to send the first volunteer to Albany, in part, due to a change in neurologists during the screening process. “Part of it was the availability of neurologists that can dedicate the time to this.” There was also a divergence of what Siskin was looking for in his protocol for the assessment and what the neurologists in Saskatchewan believed that protocol should be, he says. Those close to the trial say there were other snafus: The FDA imposed stringent parameters on the level of disability participants had to have; there was concern some patients sent from Saskatchewan were very disabled, even though it’s understood that venoplasty is most effective for those who still have some mobility. There were also reports neurologists in the U.S. were discouraging patients from participating and that funding was a challenge.
The government was warned in July that the trial could be shut down, says Duncan. They tried to keep it afloat by reaching out to other provincial health ministries to ask them if they would help recruit more participants, with no luck: “We knew that was a long shot; other provinces have made their own decisions about involvement in this type of research.”
Saskatchewan MLA Mark Docherty, diagnosed with MS in 1998, is also disappointed by the cancellation. He travelled offshore twice for CCSVI treatment: The first time, he experienced immediate improvements, including sensation in his fingertips for the first time in a decade. His mobility, balance, energy and sensitivity to heat also improved. It lasted three months before his veins closed again. The second treatment, in 2011, did not have as pronounced benefits, but he experienced better heat sensitivity and energy. Docherty ran for the Saskatchewan Party in 2011, in part, because of its proactive attitude toward CCSVI research, he says: “I have seen and felt first-hand the benefits, as well as the hope and merit of advancing and investigating the hypothesis and, ultimately, the science further.”
Siskin, who began treating CCSVI at his clinic in late 2010 and has performed it several hundred times, says the end of his trial hasn’t dampened his commitment to CCSVI research. “It has nothing to do with my belief that CCSVI is a true disease entity, or my belief that treating people for CCSVI makes a difference for patients—clinically or in their overall quality of life,” he says. His experience treating patients has been largely positive, he says. “But I can’t prove that in a way that would be scientifically appropriate.”
The problem, he says, is that many MS neurologists feel that, if CCSVI can’t be consistently diagnosed, then it doesn’t exist: “I respect that they’ve been asking questions that the interventional radiologist community has not answered to their satisfaction. But the neurology community has turned to a lot of those diagnostic studies and said, ‘See, it’s not consistently diagnosed with ultrasound, therefore, it must not exist; therefore, why would you treat it?’ ” There’s a certain level of proof that the neurology community expects before they’re going to get behind a treatment for their patients, Siskin says. “And I think the one thing we can all agree on is that the burden of proof has not yet been met, when it comes to CCSVI.”
Science and patients’ experiences are at odds, Siskin says: “A literature review of all of the CCSVI studies over the past year or two reveal the vast majority of the ones that focus on treatment are positive. But when you look at the studies that have focused on the diagnosis of CCSVI—the ability of ultrasound to diagnose, the ability of MRI to diagnose—they’ve all been negative. But, once we actually go in there and look at veins, if we see an area of narrowing and treat it, many patients say they feel better. I think that’s the best way to summarize the state of knowledge right now.”
Siskin believes the research process was hijacked when CCSVI was introduced as a “miracle cure” for MS. “This was broadcast around the world as an explanation and/or cure for MS. If you could turn back the clock and say, ‘We think we found some condition characterized by narrowing of the veins, and this condition is associated with a certain group of symptoms, and if you treat this condition, those symptoms get better for a certain period of time,’ I don’t think we’ve been having this conversation. But because it came out as a cure for MS, you riled up a community of physicians and patients in a way that wasn’t substantiated at that time.” Siskin would like to see CCSVI studied and described as an isolated vascular condition, then investigated to see if it’s associated with other diseases, such as MS, Parkinson’s or Alzheimer’s.
Salvatore Sclafani, a Brooklyn-based interventional radiologist, agrees. “We need to put MS on the back burner and focus on the symptoms,” says Sclafani, who has performed some 500 CCSVI treatments. “It’s about whether venous outflow obstructions can result in neurological symptoms. It is about whether opening venous outflow improves some clinical manifestations often seen in MS.” CCSVI has been “politicized, discredited, misunderstood, denigrated, slandered and rejected out of hand,” he says. He would like to see a movement away from whether CCSVI causes MS and toward a focus on the most effective treatment techniques and an understanding of which patients are most likely to benefit. “Failure to do so would do an injustice to those who have venous obstructions of the cerebro-spinal venous outflow,” he says.
Now, Saskatchewan is sitting on slightly less than $5 million earmarked for CCSVI research; only $150,000 has been spent. Meetings are being planned with the research community, patients and other “MS stakeholders,” to figure out the next move.
“Research may involve the “liberation” therapy, but we’re realistic that may not be possible in a research context, so we may be looking outside of liberation,” the health minister says. There is no research currently in the works at the level of the Albany trial, which was more evolved than the Canadian clinical trial, he says: “We felt Dr. Siskin was taking the research to another level.”
Following the money here will be instructive. Saskatchewan earmarked the funds to study the unorthodox “MS treatment” because it’s home to the country’s highest incidence of MS. CCSVI represented an iconoclastic alternative to the MS status quo that appeared to help a portion of the MS population. Now, the government has a choice: give the money to the MS infrastructure that has rejected CCSVI from the get-go, or fund research that identifies CCSVI as a vascular condition frequently linked to those also diagnosed with MS. What the province does next will determine whether it wants to continue its historical role as a medical trailblazer.