Is a Clinical Trial Right for Me?


woman looking at doctor

Making the decision to sign up for a clinical trial can be complicated.

When 45-year-old James learned that, despite surgery and chemotherapy, his colon cancer had recurred, he found himself faced with a difficult choice: try the standard of care again (the same chemo he had just gotten, which had not been wiped out the cancer), or sign up for a clinical trial and get an investigational chemotherapy regimen.

James felt overwhelmed having to make such a decision. “When I was first diagnosed, the doctors told me what to do and I did it, but now I have to decide what to do! It feels unfair that I have to make this decision, how am I supposed to know what to do?”

Though clinical follow very strict guidelines to make sure the trial is safe and ethical, clinical trials are, by definition, investigational, meaning that the outcome is not certain. For patients like James this uncertainty can be very difficult to deal with: “I already don’t know why my cancer is back or how long I will live (cancer prognosis anxiety), so why would I do a clinical trial when I don’t even know if it will work?”

Patients decide to participate in a clinical trial, and work on tolerating the uncertainty, for a variety of reasons. Some sign up because there is no other evidence based therapy that is proven to work for their cancer situation (tumor type and stage-how far it has spread). Some patients are motivated by a desire to be part of the search for the cure, the ultimate goal of cancer research, getting rid of cancer all together. And others participate because they want to gain access to medication that may not be available otherwise, new drugs that are yet to be approved by the Food and Drug Administration or yet to be sold on the open market or paid for by insurance companies.

For James, this third reason was enough for him to want to participate in the clinical trial instead of repeating the chemotherapy regimen he had already been through. “I would rather try something that may work then hope that the old way works the second time. I just don’t have faith that the old chemo will work for me now.”

James did have to work hard to control his worry related to the clinical trial outcome. In some ways, the actual participation in the clinical trial itself was therapeutic. Being part of a clinical trial meant that he came into the cancer center on a more regular basis, and saw a specifically trained group of clinical trial researchers each time. “I like meeting with my trial team, they follow my labs really closely, they all know my story and they really pay close attention to all my symptoms.” James did have extra paperwork to complete for the trial, but he was able to do that in the mornings so that his afternoons were free to spend time with his kids. Having the investigational medication cost covered by the clinical trial was also reassuring to James. “By participating in this trial I know that I am helping medical researchers understand and fight cancer, and it does feel good to know the trial is paying for the medication!”

For as upbeat as James was most of the time, he still struggled with worry about his cancer progressing (cancer prognosis anxiety) and how much time he had left. James accepted the reality of his cancer being advanced, and that he could only stay in the clinical trial until the cancer progressed (then he would likely return to old chemotherapy medications or consider palliative hospice care), but he still wanted to be able to live as fully as possible while he could. “I am young, and if I worry about cancer all the time then I won’t be able to really live my life. I have to find a way to hang out with my kids and get my work done without cancer worry all the time.” James developed a plan for managing his cancer prognosis anxiety, and it really helped him live in the moment, appreciate and even enjoy each day a bit, even while he was in the clinical trial for colon cancer.

Here are some of the things that helped James:

1. Stay informed. You can find information about medical research all over the country at clinicaltrials.gov.

2. Know your team and pick a point person. The point person is who you call with questions or symptoms while you are being treated with the investigational medication.

3. Remind yourself that by participating in the clinical trial you are contributing to the cure for cancer and thus helping countless other people.

4. Remind yourself that you have access to medications in a clinical trial that you would not otherwise receive.

5. Pay attention to self-care. Good sleep habits, time for relaxation and gentle exercise, healthy foods all help manage side effects of cancer and treatment.

6. Put cancer away every day. Make time for life (friends, family, pets, work) and try to put cancer away (“I will think about this, deal with this, later” – even if for 1 hour at a time).

WHO Demands Better Clinical Trial Transparency


The WHO prompts regulatory agencies to impose specific clinical trial reporting processes..

The World Health Organization (WHO), in a new position statement, has joined the chorus calling for more comprehensive reporting of clinical trial results worldwide.

Its statement called for all trial leaders to report to the WHO’s registry within 12 months of completion, and also to publish results in a peer-reviewed journal within 24 months and retroactively report results from older, as-yet-unpublished trials.

“WHO calls for ethics committees, regulatory authorities, professional bodies, sponsors, investigators, and funding agencies to act in their jurisdictions to ensure results from all interventional clinical trials are reported and publicly disclosed,” Vasee S. Moorthy, BMBCh, PhD, Technical Officer of the WHO in Switzerland, and colleagues wrote.

The statement appeared online in PLOS Medicine.

“From this point forward, whenever the methods and results of a trial are withheld, doctors, patients, researchers, campaigners, and healthcare providers will be able to point at an unambiguous statement from WHO,” Ben Goldacre, MBBS, MA, of the University of Oxford, and co-founder of AllTrials, in the U.K., wrote in an accompanying commentary.

In 2005, the WHO released a statement calling for registration of all interventional clinical trials. By 2007 in the U.S., the FDA imposed a mandate requiring certain clinical trials to register on ClinicalTrials.gov. But trial quality as well as complete, honest, and timely results reporting have lagged, according to recent reports.

Goldacre pointed to the lack of enforcement on the FDA’s part, as they have failed to levy the $10,000-per-day penalties afforded in the mandate.

In the WHO’s 2015 update, the organization has included more specifics on what should be standard procedure, including a call to report older, unpublished trials as well as defining acceptable reporting time frames and the need to link clinical trial registries with published results.

The authors cited four studies that found egregious under-reporting of clinical trial results, overlong delays in reporting, and what they viewed as an unacceptable percentage of trials that did not publish or post their primary outcomes.

This lack of responsible trial reporting violates many of the ethical principles outlined by the World Medical Association’s Declaration of Helsinki, the statement argued.

“Furthermore, it is unethical to conduct human research without publication and dissemination of the results of that research. In particular, withholding results may subject future volunteers to unnecessary risk,” it added.

The WHO recognized the strides made in boosting trial transparency — including efforts by the U.S. National Institutes of Health and the Department of Health and Human Services — but noted that “gaps remain.”

 Specifically, the WHO proposed the following changes to clinical trial reporting:
  • Main findings should be submitted to a peer-reviewed journal within 12 months of the end of the trial, and then published within 24 months.
  • Main findings should also be posted on the primary clinical trial registry within 12 months of trial completion.
  • Older, currently unreported clinical trial results should be made available.
  • All drug trials should be registered before any individual receives the medication.

Goldacre called this statement a “landmark,” representing important progress in managing a global structure that has the potential to have a “negative impact on patient care.”

However, Goldacre suggested the insistence of publishing in peer-reviewed literature could be a “red herring, as an indicator of transparency,” as “academic papers have been shown to be incomplete and inconsistent,” as well as subject to delays and nonstandardized reporting requirements.

Both the WHO and Goldacre agreed that sites like ClinicalTrials.gov provide a good structure for reporting. Uploading results into this standardized system makes them immediately available and leaves little room for tweaking prespecified outcomes.

To boost compliance with the emerging standards, Goldacre proposed that routine audits, which he called “medicine’s most basic research tool,” be conducted on registered trials.

Plaque-fighting Drug Passes Early Clinical Test in Humans


On March 20, from a conference in France, the Cambridge, Mass.-based biotech company,Biogen Idec reported success in the PRIME trial, an early clinical trial of its Alzheimer’s drug, aducanumab. Results proved “better than expected,” the company said, from its phase 1 trial enrolling 166 subjects with prodromal-to-mild Alzheimer’s. Individuals treated with aducanumab had a significant reduction in amyloid and symptoms of cognitive impairment were slowed compared with untreated controls.

“Prodromal” Alzheimer’s is also referred to asmild cognitive impairment (MCI). On the continuum leading up to Alzheimer’s, it lies between preclinical Alzheimer’s, when it’s possible to detect biochemical changes associated with disease but no changes in cognition, and mild Alzheimer’s, where cognitive decline from Alzheimer’s begins to have an impact on mood and functioning. Not all people with MCI progress to Alzheimer’s.

These trial results, while promising, are among the earliest attempts to test aducanumab in humans,and have to be viewed with caution. Phase 1 trials are deliberately small and narrow in scope, designed to assess safety and establish safe dosing levels for promising agents as they head out of the starting gate. From a safety standpoint, aducanumab appears to be safe, although side effects were reported at higher dosing levels. These concerns will be analyzed further in data from this trial, and from phase 3 trials up ahead, which the company has announced it will pursue.

Phase 3 trials are considered the gold standard proof of clinical effectiveness, and are meant to test a drug’s effectiveness over time in the patient population it’s designed to treat. If successful, they typically lead to a drug’s approval by the U.S. Food and Drug Administration, at which point companies are free to market their product for specific conditions under a brand name.

New Hope—Could This Be the Dawn of Disease Modifying Therapies?

Aducanumab’s early success may signals a turn in the tide for anti-amyloid therapy. A New York Times story suggested as much, but also cataloged earlier, failed trials of similar agents. They included a joint effort by the pharmaceutical giants Johnson & Johnson and Pfizer to develop a plaque-fighting drug, which was abandoned at the clinical trial stage due to poor results. Disappointing early results also forced the Swiss pharmaceutical, Roche, to close a phase 3 trial of its anti-amyloid agent gantenerumab; however, development efforts are said to be ongoing.

Graph showing how brain functin, vascular regulation, and neuropathology change during the latent, prodromal, and disease phase of Alzheimer's.

It’s believed that anti-amyloid therapies will be most effective when they attack the disease early. Preclinical (“latent”) and prodromal stages can last as long or longer than the “disease stage” shown above, meaning after Alzheimer’s is diagnosed, when clinical symptoms are evident. In the build-up to that point, it may be possible to “modify” the disease and avert damage.

Solanezumab, another anti-amyloid agent being developed by Lilly, also produced negative results in its first phase 3 clinical trials, which tested treatment for later stages of Alzheimer’s disease. However, results suggested the drug might be beneficial in subgroups who had very early Alzheimer’s. Now solanezumab is being retested at earlier disease stages in the large A4 trial, which is recruiting patients at dozens of sites in the United States and internationally (see our reports from September 2014 and June 2014). Reisa Sperling, MD, of Harvard, who received a 2010-14 BrightFocus grant for her amyloid imaging research, is helping to lead A4. (To learn more, watch this video.)

Despite fitful progress, anti-amyloid agents currently represent the nearest, best hope of taking Alzheimer’s treatment to a new level, where it’s possible to do more than achieve mild improvement in symptoms. These complexly designed biologically-active drugs have earned the title of potential “disease-modifying” agents because they’re believed capable of slowing down the disease and delaying onset of symptoms, including memory loss and cognitive decline.

All the evidence so far, including valuable knowledge gained from anti-amyloid trials that have failed, points to the likelihood that in order to stop Alzheimer’s, it has to be attacked very early in its 10- to 20-year course. That’s why disease-modifying agents are being targeted to the prodromal level and to very early, mild stages of Alzheimer’s disease.

Also, many experts now believe that Alzheimer’s disease doesn’t follow just one disease pattern, but make take several forms based on a patient’s genetic risk and other factors. That means anti-amyloid therapy may have to be customized to individual patients, and that more than one drug and/or approach may have to be used in combination. It will be important to have more than one plaque-fighting agent, as well as drugs attacking other aspects of the disease, at our disposal as clinical weapons.

The toxicity of anti-VEGF agents when coupled with standard chemotherapeutics


Abstract

Bevacizumab (Avastin®, Genentech, CA) was granted accelerated approval by the FDA for metastatic breast cancer in 2008. This occurred after the initial clinical trial, E2100, demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) with the addition of bevacizumab to a standard chemotherapy. Unfortunately, the approval was rescinded in 2011 when two subsequent trials, AVADO and RIBBON-1, failed to show survival benefit. We compare and analyze the landmark trials E2100, AVADO and RIBBON-1, and suggest that the present-day clinical trial model may not be suited for the investigation of targeted therapies such as bevacizumab. The existing clinical trial model does not allow for modification of chemotherapeutic doses in a manner that maximizes the effect of biologic response modifiers and does not account for its “chemosensitizing” effect. The E2100, AVADO, and RIBBON-1 trials differed in the type and dose of chemotherapy, the dose and frequency of bevacizumab, and in the trial design, making it difficult to effectively compare and evaluate the results. The efficacy of combining bevacizumab with a maximum tolerated dose (MTD) of chemotherapy is also discussed in view of the observation that increased tumor response did not translate to an increase in survival. We suggest that even though angiogenesis inhibitors are non-toxic as monotherapies, they increase the toxicity of standard chemotherapy, and consequently a re-design of the now classic clinical trial model should be considered. Modifying the existing clinical trial model will lead to a more accurate evaluation of the safety and efficacy of bevacizumab and other biological agents in treating metastatic cancer.

World-first clinical trials for better prosthetics based on antlers


Researchers in the UK are conducting the first clinical trials in the world where they are drilling prosthetics right into the bone, instead of moulded and strapped into place.

ITAP

Image: Royal National Orthopaedic Hospital

Right now, if a patient needs a prosthetic limb fitted, one will be made with a cup-shaped end that will be moulded to the base of their arm or leg and strapped on. It’s not elegant, or secure, or comfortable. But now a team of biomedical engineers at the Royal National Orthopaedic Hospital in London has just completed the first clinical trials of a new technique that has prosthetics drilled straight into the bone.

Named ITAP (Intraosseous Transcutaneous Amputation Prostheses), this technique grafts a little anchor directly onto the bone. The major problem with this technique though, is that this foreign body, which protrudes of the skin, has a high risk of getting infected. So the team looked at deer antlers, of all things, to find a solution.

Chris Higgins at Wired explains:

“Usually, any sustained breach of the skin barrier will allow foreign bodies through to invade. Antlers are specialised bone structures that transition from the skull into external features through the skin, but do not cause any adverse effects. The key to their organic survival is tiny, porous holes in the antler bone, allowing skin to grow into it and tightly infuse with the transdermal object, creating a barrier.”

With this in mind, the team at the hospital created a porous metal anchor that can be used to attach an array of specialised prosthetic limbs directly to the bone. The initial pain of having metal drilled into the bone will be offset by the increased comfort of the better-attached limb. According to Higgins, the 20 patients who took part in the clinical trial reported a better quality of life, some even describing it as “life-changing”.

Sitting out hunger pangs on a five-day fast


Kale chips

Scientists in California are conducting a clinical trial to test a diet that may help people lose weight while also boosting resistance to some diseases. One of their guinea pigs was the BBC’s Peter Bowes, who reports here on his experience of fasting for five days per month.

It’s been tried on mice and now it’s being tried on humans – a diet that involves multiple five-day cycles on an extremely low-calorie diet. Each of those five days is tough, but the upside is that for much of the time – about 25 days per month – people eat normally, although not excessively.

The low-calorie period includes small amounts of food to minimise the negative effects of a total fast. Designed by scientists to provide a minimum level of essential vitamins and minerals, the diet consists of:

  • vegetable-based soups
  • energy bars
  • energy drinks
  • dried kale snacks
  • chamomile tea
“Start Quote

I was so hungry I would practically lick the soup bowl and shake the last kale crumb from its bag”

These meals are extremely low in calories – about 1,000 on day one and 500 for each of the next four days.

With the exception of water and black coffee, nothing else is consumed.

The limited selection of food (with no choice of flavours) means that everything has to be eaten. It’s monotonous… but at least it makes meal planning easy for five days.

“The reason why diets don’t work is because they are very complicated and people have an interpretation problem,” says Dr Valter Longo, director of the University of Southern California (USC) Longevity Institute.

Spinach soup
Spinach soup: Dinner, three nights out of five

“The reason I think these diets work is because you have no interpretation. You either do it or you don’t do it. And if you do it you’re going to get the effect.”

Dr Longo established a company to manufacture the food, based on research in his department at USC. He has shown in mice that restricting calories leads to them living longer with less risk of developing cancer.

The food used during the trial is the result of years of experimenting. The idea is to develop a diet that leads to positive cellular changes of the same kind seen in mice that have been made to fast.

“It turned out to be a low-protein, low-sugar-and-carbohydrate diet, but a high-nourishment diet,” explains Longo.

“We wanted it to be all natural. We didn’t want to have chemicals in there and did not want to have anything that is associated with problems – diseases. Every component has to be checked and tested. It’s no different to a drug.”

Peter Bowes

Peter Bowes

The popularity of intermittent fasting has grown over the past year or so. The 5:2 diet, which involves dramatically reducing your calorific intake on certain days of the week, is one example. But more clinical data is needed to confirm the benefits of such regimes. Doctors are generally reluctant to recommend them.

Longo stresses that the experimental food could not be made in your kitchen.

But it is a big leap from laboratory mice to human beings. Restricting the diets of rodents is easy, but people have minds of their own – and face the culinary temptations of the modern world.

I knew the diet cycles would be difficult.

I love to eat. I enjoy a big, healthy breakfast, exercise a lot and – left to my own devices – snack all day before digging in to a hearty evening meal. At 51, I am in good shape. I weigh 80kg (12 stone 8lbs / 176lbs) but like most middle-aged men, I struggle with belly fat. I have never tried any kind of fasting regime before.

The diet meals were better than I expected – at least initially. I was so hungry I would practically lick the soup bowl and shake the last kale crumb from its bag, to tide me over to the next feeding time.

Note: it is no longer lunch or dinner. It is a feeding opportunity. It is certainly not a social occasion.

The diet

Day 1 (1,000-1,100 cals) Day 2 (500 cals) Day 3 (500 cals) Day 4 (500 cals) Day 5 (500 cals)
Morning snack Chamomile tea + bar Chamomile tea + bar Chamomile tea + bar Chamomile tea + bar Chamomile tea + bar
Lunch Carrot soup + dried kale Carrot soup + drink Beetroot soup + drink Carrot soup + drink Carrot soup + drink
Afternoon snack Tea + energy bar Tea Tea Tea Tea
Dinner Beetroot soup + dried kale Spinach soup + dried kale Spinach soup + dried kale Beetroot soup + dried kale Spinach soup + dried kale

Headaches, a typical side effect of fasting, started on Day 2 but they waned within 24 hours, leaving me in a state of heightened alertness. During the day – and especially in the morning – I was more alert and productive. Hunger pangs came and went – it was just a matter of sitting them out. But they did go.

Fasting feedback

Alex de la Cruz and Angelica Compos

Alex de la Cruz: I downright hated it. I actually detested it. The first day I had a splitting headache – it felt like someone had punched me in the head. And the weight loss was really dramatic – 4.5kg (10lbs) in the first five days. I was tempted to give up, but I didn’t. After that everything started getting better.

Angelica Campos: There were some positives in being able to be more clear-minded, especially in the morning. I tended to feel worse as the day progressed… I don’t want to do it again, but if someone were to tell me that yes, science proves that it has long-term benefits, I think I would. I need to see proof that it really is effective.

By the evening – especially on Day 5, I was exhausted. Tiredness set in early. But I made it through the five days – for three cycles – without deviating from the regime. I lost an average of 3kg (6.6lbs) during each cycle, but regained the weight afterwards.

All participants keep a diary, noting their body weight, daily temperature reading, meals and mood. The feedback – positive and negative – is vital to the integrity of the study, which is partly designed to establish whether the diet could work in the real world.

For me, and for all but about 5% of the volunteers who have completed all three cycles, the diet was do-able – although opinions vary about the taste of the food.

“It is not an experience for the faint of heart. It was extremely difficult because the little bit of food that you’re offered gets very tiresome as time wears on,” says Angelica Campos, aged 28.

“I had to isolate myself because my family were constantly offering me food. They thought I was crazy.”

She would not want to go through the experience again, but says she would if it were proven to have long-term benefits.

Her boyfriend, Alex de la Cruz, aged 29, says the fasting made him very tired, but when he woke up he was “as alert as could be”.

“My overriding memory of the experience is that the food was horrible, but the results were totally positive,” he says.

Energy bar

Lead investigator Dr Min Wei says that for some people the diet is a greater wrench than for others, depending on their lifestyle. The absence of carbohydrates and desserts, can hit some people hard, for example, and also the restriction to black coffee alone. “We are fairly strict,” he says. “We recommend people stick to the regimen. If people enjoy special coffee – lattes for example – they won’t be able to enjoy them.”

Data from the volunteers is still being collected and analysed. The early signs are that the diet is safe and could be adopted by most healthy people, providing they are suitably motivated to endure the periods of hunger.

But the full effect can only be measured over the long term. Initial changes in the body may not tell the full story.

“Having dietary factors influence your body sometimes takes years and years,” explains Dr Lawrence Piro, a cancer specialist at the Angeles Clinic and Research Institute.

This particular trial now moves into the laboratory. Based on blood tests, has anything changed inside my body to suggest extreme dieting improves my chances of avoiding the diseases of old age?

Vagus Nerve Stimulation for Children With Epilepsy.


The Vagus Nerve Stimulator

The first vagus nerve stimulator (VNS) was implanted in 1988.[1]Since then, more than 70,000 have been implanted for epilepsy worldwide.[2]

The VNS consists of a generator, typically implanted in the chest, and an electrode surgically fastened to the left vagus nerve. In addition, an external handheld magnet may be used if the patient senses an aura or to stop a seizure already in progress.

US Food and Drug Administration Approval

In 1997, VNS received US Food and Drug Administration (FDA) approval for the adjunctive treatment of refractory seizures in patients older than 12 years.[3] In 2005, the VNS was approved for the treatment of chronic or recurrent depression in patients older than 18 years.

VNS may also have a beneficial effect on mood in patients with epilepsy in addition to its antiepileptic effect.[1] The mechanism of action of VNS is uncertain, but may be related to metabolic activation of brain stem, limbic, or thalamic structures.[4]

To date, the VNS is the only FDA-approved medical device for the treatment of epilepsy. However, other approaches, such as deep-brain stimulation of the anterior nucleus of the thalamus, responsive neurostimulation, trigeminal nerve stimulation, and transcranial magnetic stimulation, are in development.

Phase 3 Trials for Epilepsy

A randomized, multicenter, clinical trial (Study E03) of 114 patients with partial seizures demonstrated a mean seizure reduction of 31% and a 50% seizure reduction in 39% of patients.[5] A second randomized trial (Study E05) of 254 patients with intractable partial seizures demonstrated an average reduction in seizure frequency of 28% in the high-stimulation group vs a 15% reduction in the low-stimulation (pseudo-placebo) group (P = .04).[4] These results are modest, but similar to those obtained with new antiepileptic drugs in phase 3 trials. Unlike antiepileptic drugs, VNS efficacy appears to improve over time.[3]

Adverse Effects of VNS

Compared with antiepileptic drugs, VNS has a completely different side effect profile. Adverse effects are related to the surgical implantation of the generator, which may result in discomfort and deep or superficial infection. The lead attached to the vagus nerve is subject to breakage. In addition, the electrical stimulation in the neck may be uncomfortable and result in cough, hoarseness, or a feeling of shortness of breath.[4] On the other hand, VNS does not cause sedation or adverse cognitive effects, which are often limiting factors with antiepileptic drug treatment.[6]

Magnet Activation of VNS

Neurostimulation by the VNS occurs at prespecified, continuous intervals (eg, 30 seconds on, 5 minutes off). In addition, the patient may trigger additional stimulation on demand by holding a magnet over the implanted device. Magnet-activated stimulation may abort, diminish, or terminate a seizure.

A retrospective analysis of seizure data collected from the E03 trial demonstrated an increased likelihood of improved seizure control (aborted and decreased) after magnet activation (P = .0479). In the E04 trial, 31% of patients were able to diminish seizures and 22% of patients terminated seizures, but 47% reported no effect with the magnet.[1] The magnet may offer psychological benefits to patients by providing some sense of control over seizures when they occur.[1]

Personal Experience

Years ago, I enrolled 5 of my patients with intractable epilepsy in the open-label E04 VNS safety trial. None of the patients became seizure-free, although as a group they experienced a modest benefit in seizure reduction. One college student did not like the stimulator and insisted that it be removed, even though he had not allowed adequate time for us to assess its therapeutic effects. The other 4 patients continued to use the VNS.

Source: Medscape.com

Treatment for Dormant Malaria Shows Promise.


The first new drug in half a century to target malaria parasites in one of their best hideouts is showing encouraging results. The researchers developing the drug, called tafenoquine, said today that data from a recently completed phase II trial were promising enough that they will soon start a phase III trial—the last step before asking drug regulators for approval.

Tafenoquine kills the malaria parasite when it is lurking in liver cells, in a form called the hypnozoite, or “sleeping parasite.” Hypnozoites don’t cause any symptoms and are impossible to detect with blood tests. But when triggered by signals that aren’t fully understood, they can reactivate to cause a new bout of malaria—which can then be picked up by mosquitoes and passed on to new victims. Five species of Plasmodium can cause malaria in humans. Two of them—Plasmodium vivax, which is widespread, and the relatively rare P. ovale—can form hypnozoites. This ability to hide is one of the things that makes P. vivax so difficult to eliminate from a region.

Now, the only treatment that can cure vivax malaria—hiding parasites and all—is a 14-day course of a drug called primaquine, which was developed in the 1940s. It works fairly well, but it is difficult for people who don’t feel ill to complete the whole 2 weeks. “The compliance with the current regimen is really a problem,” says JP Kleim, director of clinical development for the pharmaceutical company GlaxoSmithKline (GSK). “The acute malaria is gone after a few days [of treatment],” so patients’ motivation to continue taking drugs is low. That’s why GSK decided to develop tafenoquine, together with the Medicines for Malaria Venture, a Geneva-based nonprofit. The partners launched a trial in 2011 to test whether a single dose of tafenoquine could work as well as the 2-week course of primaquine.

Vivax malaria, shown here in the blood stream, can hide out—undetectable—in liver cells.

The data, presented today at the American Society of Tropical Medicine and Hygiene Annual Meeting in Washington, D.C., suggest that a single dose works very well. The trial involved 329 patients in Brazil, India, Thailand, and Peru. In patients who received either a 300 mg or 600 mg dose of the drug, 90% had no relapses after 4 months. The partners will now go forward with a phase III trial, testing the safety and efficacy of the 300 mg dose in 600 patients, says Marcus Lacerda of the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado in Manaus, Brazil, who helped coordinate the study and presented the results at the meeting today.

A single-dose drug would be a huge advantage in the fight against vivax malaria, says Ric Price of the Menzies School of Health Research in Darwin, Australia, and the University of Oxford in the United Kingdom. “One of the biggest challenges we face is how can we adequately and reliably treat the hypnozoite stage.”

Gabapentin Treatment for Alcohol Dependence.


A Randomized Clinical Trial

Importance  Approved medications for alcohol dependence are prescribed for less than 9% of US alcoholics.

Objective  To determine if gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid–modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner.

Design, Participants and Setting  A 12-week, double-blind, placebo-controlled, randomized dose-ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single-site, outpatient clinical research facility adjoining a general medical hospital.

Interventions  Oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual-guided counseling.

Main Outcomes and Measures  Rates of complete abstinence and no heavy drinking (coprimary) and changes in mood, sleep, and craving (secondary) over the 12-week study.

Results  Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P < .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups.

Conclusions and Relevance  Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence.

Soure: JAMA

Anticonvulsant Promising for Alcohol Dependence.


The anticonvulsant gabapentin, a widely prescribed anticonvulsant used to treat epilepsy and neuropathic pain, is showing promise in the treatment of alcohol dependence, new research suggests.

Results from a 12-week, randomized, placebo-controlled trial show that participants taking 1800 mg of gabapentin were twice as likely to refrain from heavy drinking and 4 times as likely to stop drinking altogether compared with participants taking placebo.

“Gabapentin’s effect on drinking outcomes is at least as large or greater than those of existing FDA-approved treatments,” lead researcher Barbara Mason, PhD, Scripps Research Institute, La Jolla, California, said in a statement.

The study was published online November 4 in JAMA Internal Medicine.

Filling a Treatment Gap

According to investigators, gabapentin has the potential to fill a large gap in the treatment of alcohol dependence. They note that of the estimated 8.5 million alcohol-dependent Americans, statistics show that only 720,000 prescriptions were filled for US Food and Drug Administration (FDA)–approved medications for alcohol dependence in 2007, most of them prescribed by psychiatrists.

Previous studies of gabapentin for alcohol-dependent persons have suggested that the drug may be safe and effective, but conclusive results have been hampered by small sample size and methodologic or dosing issues.

To provide a more definitive evaluation of the drug for alcohol dependence, the researchers conducted a 12-week, double-blind, placebo-controlled, randomized, dose-ranging trial of 150 adults with current alcohol dependence who were attending a single outpatient center.

Participants were randomly assigned to receive 900 mg/day, 1800 mg/day, or placebo. All patients received concomitant counseling.

The study’s primary outcomes included sustained abstinence and no heavy drinking, and decreases in alcohol-related insomnia, dysphoria, and craving in a dose-dependent manner.

Results showed that gabapentin significantly improved the rates of abstinence and no heavy drinking with rates of 4.1% (95% confidence interval [CI], 1.1% – 13.7%) in the placebo group, 11.1% (85% CI, 5.2% – 22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9% – 30.1%) in the 1800-mg group.

Further, the investigators report that the no-heavy-drinking rate was 22.5% (95% CI, 13.6% – 37.2%) in the placebo group, 29.6% (95% CI, 19.1% – 42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4% – 58.8%) in the 1800-mg group.

In addition, the results showed that the drug significantly reduced cravings, depression, and sleeplessness. The researchers report that gabapentin had a favorable safety profile with no reports of serious adverse events.

According to Dr. Mason, gabapentin offers several potential advantages over the 3 other FDA-approved medications for alcohol dependence. It is “the only medication shown to improve sleep and mood in people who are quitting or reducing their drinking, and it’s already widely used in primary care ― that’s an appealing combination,” she said.

Broader Access to Treatment

In an accompanying editorial,Edward V. Nunes, MD, writes that the finding that gabapentin prevents relapse in alcohol-dependent patients is “an important development.”

“This well-designed and well-powered trial replicates the positive findings of several previous smaller trials,” Dr. Nunes writes.

He notes that a large proportion of alcohol-dependent patients presenting to family physicians fall into the mild to moderate range of alcohol dependence, which further suggests “the strong potential for gabapentin in the treatment of alcohol dependence in primary care.”

Acting director of the National Institute on Alcohol Abuse and Alcoholism, Kenneth R. Warren, PhD, said, “Gabapentin adds to the list of existing medications that have shown promise in treating alcohol dependence. We will continue to pursue research to expand the menu of treatment options available for alcoholism in the hopes of reaching more people.”