DISEASE CLASSIFICATION(S):
Amyotrophic Lateral Sclerosis(ALS)
NAME OF CLINICAL TRIAL/STUDY:
Arimoclomol-Phase 2b Study of Safety and Efficacy in ALS
TRIAL UPDATES:
December 2009
According to a Dec. 2, 2009, press release, CytRx announced that the U.S. Food and Drug Administration (FDA) has permitted the company to restart its trial of arimoclomol using a revised protocol. The revised study (not yet officially open to recruitment as of Dec. 2, 2009), will test increasing doses of arimoclomol in 20 to 30 ALS patients over a three-month treatment period. Fifteen patents will receive a combination of arimoclomol at various dose levels with the ALS drug riluzole at a fixed dose of 50 miligrams twice daily. Between five and 15 additional ALS patients will receive a placebo and riluzole at the same fixed dose.
The first group will receive 100 milligrams of arimoclomol three times a day. Every four weeks, another group of ALS patients will begin three-month testing, with six people receiving arimoclomol three times a day at a 75-milligram per dose increase over the prior dosage level. The maximum dose will be 400 milligrams three times a day.
An independent monitoring board will review safety results prior to each dosage increase.
August 2009
In an Aug. 6, 2009, press release, CytRx said it expects to receive written correspondence from the U.S. Food and Drug Administration (FDA) regarding this arimoclomol trial. The company said that, based on a brief phone conversation with the FDA, it is optimistic about being able to resume this phase 2b trial.
January 2008
In a Jan. 22, 2008, press release, CytRx announced that the U.S. Food and Drug Administration (FDA) has placed this trial on hold until the agency receives and evaluates additional data from previously completed toxicity studies conducted in animals.
You can listen to a Webcast of a conference call concerning this FDA hold.
On the conference call, Steven Kriegsman, CytRx’s president and CEO, said the company is committed to responding as quickly as possible to the FDA’s requests and is committed to developing arimoclomol for ALS.
PURPOSE AND RATIONALE:
Arimoclomol is a small molecule that increases levels of proteins called molecular “chaperones” in cells under stress.
Molecular chaperone proteins are critical in the cellular response to stress and in preventing incorrect and potentially toxic folding of cellular proteins.
Recent data suggest that the SOD1 gene mutation responsible for ALS in some patients with familial disease reduces the availability of a variety of molecular chaperones.
Protein misfolding and aggregation (clumping) may play a role in the pathogenesis of both the familial and sporadic (nonfamilial) forms of ALS.
Therapeutic agents such as arimoclomol that improve cellular chaperone response to protein misfolding may be helpful in ALS.
When given to mice with a genetic form of ALS before symptoms began or when they began, arimoclomol extended survival by five weeks. It has also been shown to have neuroprotective and neuroregenerative effects in rats with nerve damage.
In a trial of approximately 80 people with ALS conducted in 2005 and 2006, arimoclomol was found to be safe and well tolerated at three dosage levels tested (25, 50 or 100 milligrams three times a day for 12 weeks). See Arimoclomol -- Safety and Dose-Ranging Study in ALS.
CytRx subsequently conducted studies in healthy volunteers showing that doses of arimoclomol up to 600 milligrams three times daily were safe and well tolerated for seven days, and that 400 milligrams three times daily for 28 days was also safe and well tolerated. See the company’s Dec. 20, 2007, press release.
STUDY DETAILS:
This is a phase 2b, placebo-controlled, randomized, double-blind study. This means the study drug will be compared to a placebo (inert look-alike substance); that participants will be randomly assigned to receive either the study drug or the placebo, in addition to riluzole (Rilutek), a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALS; and that neither participants nor investigators will know who is receiving which substance until after results are analyzed.
The revised protocol for this study, initiated Dec. 2, 2009, is as follows:
Arimoclomol will be administered in combination with riluzole (Rilutek).
The trial will now involve ascending doses of arimoclomol. Progressive doses will be tested on between 20 and 30 ALS patients over a three-month treatment period for each group.
Fifteen people will receive arimoclomol at various dose levels plus riluzole at a fixed dose of 50 milligrams twice daily, and between five and 15 people will receive a placebo and riluzole at the same riluzole dose.
The first group will recerive 100 milligrams of arimoclomol three times a day. Every four weeks, a new group of ALS patients will begin three months of testing, with six people receiving arimoclomol three times a day at an increase of 75 milligrams per dose over the prior group. The maximum dosage will be 400 milligrams of arimoclomol three times a day.
An independent monitoring board will review safety results prior to each dosage level increase.
The trial's end points include a preliminary evaluation of efficacy using the revised ALS Functional Rating scale and vital capacity, a respiratory measurement. The trial is designed to detect only extreme responses in these two categories.
The investigators estimate that data will be available approximately 18 months from the time the trial actually restarts.
The principal investigators are Merit Cudkowicz, M.D., at Massachusetts General Hospital in Boston; and Jeremy Shefner, M.D., Ph.D., at the State Universityof New York Upstate Medical University in Syracuse.
OPENING DATES:
about January 2008
CLOSING DATES:
uncertain
TARGET NUMBER OF PARTICIPANTS:
uncertain
RECRUITMENT STATUS:
Closed
ELIGIBILITY REQUIREMENTS:
Inclusion Criteria
Participants must
- be 18 or older
- have familial or sporadic ALS (laboratory-supported probable; probable; or definite), diagnosed according to the World Federation of Neurology El Escorial criteria
- have had the diagnosis for less than or equal to 36 months prior to the screening visit
- have a vital capacity (respiratory measurement) equal to or greater than 70 percent predicted value for gender, height and age at screening visit
- have geographic accessibility to a study site
- be able to take oral medication at screening visit
- be fluent in English, Spanish or Canadian French
Exclusion Criteria
Participants must not
- have a history of known sensitivity or intolerability to arimoclomol or any related compound
- have had prior exposure to arimoclomol
- have been exposed to any investigational agent within 30 days of the screening visit
- have abused any substances within the past year
- have unstable cardiac, pulmonary, kidney, liver, endocrine or blood condition
- have an active malignancy
- have an infectious disease
- have AIDS or AIDS-related complex
- have an unstable psychiatric illness defined as psychosis (hallucinations or delusions) or untreated major depression within 90 days of screening visit
- have any abnormalities in screening blood tests
- be breast-feeding
