No Evidence of Benefit of Lithium on Survival in Patients with ALS

Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial

From the UKMND-LiCALS Study Group

Summary article posted online in The Lancet Neurology, February 27, 2013 •


Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS.


The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31.


Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank ?2 on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40—1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event.


We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments.


The Motor Neurone Disease Association of Great Britain and Northern Ireland.

ALS Community Tells FDA ‘We Have No Time To Waste’; Urges Changes in Trial Design and Review Process

Rare FDA hearing on ALS provides a chance for organizations, scientists, clinicians, patients and families to tell their urgent stories

TUCSON, Arizona, February 25, 2013 — It was a full house as members of the amyotrophic lateral sclerosis (ALS) community presented, commented and listened in during the first-ever public hearing for ALS held by the FDA’s Neurology Division in Washington today.

The unprecedented hearing included presentations from the nation’s ALS nonprofit organizations, research scientists, clinicians, industry representatives, people with ALS, family members and caregivers.

One of the first to speak at the hearing was Muscular Dystrophy Association President and CEO Steven M. Derks, who thanked the FDA for including the ALS patient perspective in its decision-making process.

“Today’s hearing is proof that you understand the views of those living with ALS are instrumental and must be taken into account throughout the drug development and approval process,” Derks said. “We are asking you to also include these voices in your discussions regarding expanded access to trials, accelerated approval decisions and clinical trial design and enrollment.”

Along with other ALS patient organizations, MDA played a significant role in making the FDA hearing a reality. The Association is the largest nongovernmental funder of ALS research, and has served the ALS community since the 1950s when Lou Gehrig’s widow, Eleanor Gehrig, was MDA’s honorary national chair.

Because of the relentless effects of ALS, a diverse group of ALS voices — patients, families, organizations and the community — came together to speak about their experiences with ALS and to urge the FDA to work with them to overcome some of the obstacles faced in ALS research, clinical trials and standards of care.

Among the strongest and most poignant voices in the room — some of them computer-generated — came from people with ALS, whose common themes included weighing the benefits versus risks in participating in early-phase clinical trials.

“When a trial is going well, those with ALS should be able to keep taking the drugs,” said Robert Anderson, an individual living with ALS. “What is the risk — you think it might kill him sooner? It does not matter, if you may be dying in a year from ALS anyway. You need to step beyond that in your heads.”

Physical therapist Sara M. Feldman, who works at the MDA/ALS Center of Hope in Philadelphia, underscored Anderson’s comments.

“The people we work with that come into these clinical trials are truly heroes,” she said. “They’re doing this not because they think they’re going to benefit from it, but because they are hoping that someone will benefit in the future.”

International ALS expert Stan Appel, a physician-scientist who directs the MDA/ALS Clinic at Methodist Neurological Institute in Houston and is a member of the MDA Board of Directors, asked the FDA for help in more quickly assessing the probable success of an experimental therapy.

“ALS can progress extremely rapidly and time is of the essence in assisting respiratory function,” stated Appel. “Our patients suffer when such devices are not available because of the time it may take to get something approved. Accelerated review of such devices, and rapid implementation would be of tremendous value to the ALS patients and would help prolong meaningful quality and length of life.”

Appel wants the FDA to work with to the ALS community to design trials that answer questions in a timely and cost-effective manner.

“ALS is a heterogeneous disease with varying sites of onset, rates of progression and survival, and this heterogeneity complicates our clinical efforts at therapy,” he said. “In order to move faster toward effective therapeutics, it may be necessary to develop short, less-expensive trials to determine if a drug can hit a therapeutic target in order to test therapeutic hypotheses, prior to the initiation of efficacy trials. This will give a quicker answer to whether a potential therapeutic has any chance of success in treating ALS.”

Throughout the day, the panel heard similar comments urging the FDA to think differently about its clinical trial and drug approval process.

“Regulatory barriers inhibit treatment, based on a traditional model that I believe should be updated,” said Jonathan Glass, a physician conducting a phase 2 clinical trial at Emory University in Atlanta involving the injection of neural stem cells into the spines of people with ALS. “A major impediment to developing new treatments is adherence to standardized paths that are counterproductive and do not address the complexities of this disease.”

The ALS community made it clear it wants to work with the FDA to address and fast-track solutions to its unique needs.

“Today’s hearing was a historic opportunity to bring the ALS community together around a therapeutic development partnership with the FDA,” said MDA Senior Vice President of Advocacy Annie Kennedy. “MDA is eager to leverage our national clinical infrastructure and MDA-funded ALS experts around the world to help move the ball down the field as quickly and safely as possible.”

About ALS

ALS (also known as Lou Gehrig’s disease) attacks the nerve cells that control muscles, ultimately resulting in paralysis of all voluntary muscles, including those used for breathing. Average life expectancy for people with the disease is three to five years after diagnosis.

About MDA

MDA is the nonprofit health agency dedicated to finding treatments and a cure for ALS and related muscle diseases by funding worldwide research. The Association also provides comprehensive health care and support services, advocacy and education.

Over the years, MDA has led the fight against ALS, investing more than $307 million in its ALS research, services and information programs. MDA currently funds more than 250 research projects worldwide. It also operates 200 clinics across the county, 42 of which are designated as ALS-specific research and care centers.

The Association’s unparalleled research, health care services, advocacy and education programs provide help and hope to more than 1 million Americans affected by ALS and the more than 40 other progressive neuromuscular diseases in MDA’s program. MDA also facilitates hundreds of support groups for families affected by neuromuscular diseases.

For more information, contact:

Roxan Olivas
MDA Vice President — Public Relations
(520) 529-5317

For the latest research news and information about ALS and the other diseases in MDA’s program, visit and follow MDA on Facebook ( and Twitter (@MDAnews).

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The material presented here is for informational purposes only and should not be construed as medical advice, or relied upon as a substitute for medical advice from a health care provider.