Thursday, October 15, 2009

ANA: No Benefit for Quinacrine in CJD

ANA: No Benefit for Quinacrine in CJD

By Richard Robinson, Contributing Writer, MedPage Today Published: October 15, 2009 Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit for reading medical news

Action Points --------------------------------------------------------------------------------

¦Explain to interested patients that sporadic CJD is a progressive brain disease due to accumulation and spread of misfolded protein.

¦Explain that the drug quinacrine did not extend survival in patients with CJD despite its ability to eliminate prions in vitro.

¦Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

BALTIMORE -- The first U.S. treatment trial for sporadic Creutzfeldt-Jakob disease (CJD) has shown that quinacrine does not extend survival compared with placebo, a researcher reported here.

Nonetheless, the trial represents progress in understanding the natural history of CJD and provides researchers with a prototype for future trials, according to lead investigator Michael Geschwind, MD, PhD, Assistant Professor of Neurology at the University of California San Francisco, and a researcher at the Memory and Aging Center there.

Geschwind described the study at the annual meeting of the American Neurological Association.

CJD is a prion disease, caused by accumulation of misfolded prion proteins in neurons: the misfolded proteins then cause others to misfold, spreading the pathology.

A small percentage of CJD cases are due to mutation in the prion gene, but most cases are sporadic. There are approximately 300 new cases of sporadic CJD in the U.S. every year. It is rapidly progressive, with few patients surviving more than a year after onset.

Quinacrine is an antimalarial drug that can eliminate prions in cell cultures. Open-label treatment in a handful of patients seemed to suggest a benefit for survival, so Geschwind developed a protocol for a blinded trial.

"We struggled with whether it was ethical to do a placebo-controlled trial in a uniformly fatal disease, but really that's the only way we are going to get the correct answer," Geschwind said. Using historical controls was not an option, because there was too much variability among samples.

Fifty-four patients with confirmed sporadic CJD were randomized to either quinacrine or placebo for two months, after which they could elect to switch to open-label quinacrine. The main outcome measure was survival from randomization, with follow-up at months two, six, and 12.

"Unfortunately, there was no survival difference between the two groups, either at two months or over the course of the disease," he said.

But the trial nonetheless produced important results. "It was not a complete loss. We know we can do a trial in a rapidly progressive, fatal disease. We now have very quantifiable data on natural history, so when the next drug becomes available, we'll be able to do a trial very quickly. And I am confident we will find more compounds."

For effective therapy, Geschwind said, "We are probably going to need more than one drug -- one to help clearance, one to prevent conversion of normal to abnormal protein, and perhaps even one to diminish the level of normal protein itself, so there is less substrate for the abnormal protein. We and other labs are screening compounds for these effects."

Geschwind reported no financial conflicts. The study was funded by the National Institutes of Health.

Primary source: American Neurological Association Source reference: Geschwind MD, et al "The first U.S. treatment trial for sporadic CJD" ANA 2009; Abstract T-71.

View of NCT00183092 on 2009_03_10 ClinicalTrials Identifier: NCT00183092 Updated: 2009_03_10 Descriptive Information Brief title CJD (Creutzfeldt-Jakob Disease) Quinacrine Study

Official title Novel Therapeutics For Prion Diseases: A Randomized, Double-Blinded, Placebo-Controlled Study of the Efficacy of Quinacrine in the Treatment of Sporadic Creutzfeldt-Jakob Disease

Brief summary The purpose of this clinical trial is to determine the effectiveness of the medication quinacrine on survival in sporadic Creutzfeldt-Jakob disease (sCJD).

Detailed description Creutzfeldt-Jakob disease (CJD)is a rapidly progressive, invariably fatal and untreatable neurodegenerative disease with a mean duration of about eight months. Beyond the debilitating cognitive and motor deficits that accompany CJD, the difficulty in treating behavioral and mood disturbances and the rapidity of its course compound its tragedy. Recent results from experiments show that, at physiological concentrations, the anti-malarial drug quinacrine permanently clears abnormal prion proteins from cell culture. The demonstrated efficacy of quinacrine in cell culture, its relative safety and well known side-effects in the clinical setting, and the universal fatality of CJD justify quinacrine as an immediate candidate for the treatment of CJD.

The purpose of this clinical trial is to determine the efficacy of the medication quinacrine on survival in sporadic CJD (sCJD). This will be accomplished by bringing approximately 60 patients with probable or definite sCJD over approximately three years to UCSF for evaluation and initiation of a randomized, double-blinded, placebo-controlled (delayed treatment start) treatment study of quinacrine. Each patient will have a 50:50 chance of being placed on quinacrine or placebo upon study enrollment; however, all patients will be offered quinacrine after two months. Prior to study enrollment, patients will have a comprehensive clinical assessment to confirm the diagnosis of sCJD. Participants will come to UCSF for initial evaluation, potential study enrollment and, if possible, return to UCSF for follow-up at two and twelve months. Patients will receive telephone follow-up (every 2 weeks for the first two months and monthly thereafter) and local blood and testing to monitor for possible medication toxicity.

Phase Phase 2 Study type Interventional Study design Treatment Study design Randomized Study design Double Blind Study design Placebo Control Study design Parallel Assignment Study design Efficacy Study Primary outcome Survival from the time of randomization Secondary outcome Scores on functional scales, neurological exam and functional testing Condition Creutzfeldt-Jakob Disease Intervention Drug: Quinacrine

Reference Citation: Prusiner SB. Prions. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83. Review. MEDLINE: 9811807 Reference Citation: Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9836-41. MEDLINE: 11504948 Reference Citation: Scoazec JY, Krolak-Salmon P, Casez O, Besson G, Thobois S, Kopp N, Perret-Liaudet A, Streichenberger N. Quinacrine-induced cytolytic hepatitis in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 2003 Apr;53(4):546-7. No abstract available. MEDLINE: 12666126 Reference Citation: Wallace DJ. Is there a role for quinacrine (Atabrine) in the new millennium? Lupus. 2000;9(2):81-2. No abstract available. MEDLINE: 10787002 Reference Citation: Engel GL. Quinacrine effects on the central nervous system. JAMA. 1966 Aug 8;197(6):515. No abstract available. MEDLINE: 5952734



See also UCSF Memory & Aging Center

See also UCSF Institute for Neurodegenerative Diseases

Recruitment Information Status Active, not recruiting Start date 2005-04 Criteria Inclusion Criteria: - Diagnosis of probable or definite sCJD: Definite--biopsy confirmed sCJD; Probable--a progressive dementia with either a typical EEG or a typical MRI consistent with sCJD, and at least two of the following clinical features: myoclonus, pyramidal or extrapyramidal signs, visual symptoms, cerebellar signs, akinetic mutism, other focal higher cortical neurologic signs (e.g. neglect, apraxia, aphasia) - 18 years of age or older - Able to swallow - Able to follow simple one-step commands - Have had a brain MRI within 6 months and an EEG within 3 months ruling out other etiologies such as masses, strokes, or non-convulsive status epilepticus - Consent to autopsy in the event of their death during or after the study

Exclusion Criteria: - History of other significant or life-threatening disease, including: cancer; end-stage liver or renal disease; severe heart disease - History of other disease requiring regular supportive care - Liver disease - Active alcoholism - Bone marrow suppression - Severe hypotension - Severe psoriasis - Poorly controlled diabetes - Women who are pregnant or breast-feeding - Men, or women of childbearing age, not practicing reliable contraception - Serious allergies to quinacrine or other acridines - Current or recent use of quinacrine (within 6 months) - < 18 years of age - Any other contraindication to taking quinacrine - Genetic form of prion disease is identified prior to study enrollment - Current use of anti-arrhythmics (at discretion of investigator) - G6PD (Glucose 6-Phosphate Dehydrogenase) deficiency (at discretion of investigator)

Gender Both Minimum age 18 Years Healthy volunteers No Administrative Data Organization name National Institute on Aging (NIA) Organization study ID IA0083 Secondary ID AG21601-03 Lead sponsor National Institute on Aging (NIA) Health Authority United States: Food and Drug Administration

Saturday, June 13, 2009

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009

Tuesday, August 11, 2009

Characteristics of Established and Proposed Sporadic Creutzfeldt-Jakob Disease Variants

Brian S. Appleby, MD; Kristin K. Appleby, MD; Barbara J. Crain, MD, PhD; Chiadi U. Onyike, MD, MHS; Mitchell T. Wallin, MD, MPH; Peter V. Rabins, MD, MPH

Background: The classic Creutzfeldt-Jakob disease (CJD), Heidenhain, and Oppenheimer-Brownell variants are sporadic CJD (sCJD) phenotypes frequently described in the literature, but many cases present with neuropsychiatric symptoms, suggesting that there may be additional sCJD phenotypes.

Objective: To characterize clinical, diagnostic, and molecular features of 5 sCJD variants.

Design: Retrospective analysis.

Setting: The Johns Hopkins and Veterans Administration health care systems.

Participants: Eighty-eight patients with definite or probable sCJD.

Main Outcome Measures: Differences in age at onset, illness progression, diagnostic test results, and molecular subtype.

Results: The age at onset differed among sCJD variants (P=.03); the affective variant had the youngest mean age at onset (59.7 years). Survival time (P.001) and the time to clinical presentation (P=.003) differed among groups. Patients with the classic CJD phenotype had the shortest median survival time from symptom onset (66 days) and those who met criteria for the affective sCJD variant had the longest (421 days) and presented to clinicians significantly later (median time from onset to presentation, 92 days; P=.004). Cerebrospinal fluid analyses were positive for 14-3-3 protein in all of the affective variants, regardless of illness duration. Periodic sharp-wave complexes were not detected on any of the electroencephalography tracings in the Oppenheimer-Brownell group; basal ganglia hyperintensity was not detected on brain magnetic resonance imaging in this group either. All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.

Conclusions: The classic CJD phenotype and the Heidenhain, Oppenheimer-Brownell, cognitive, and affective sCJD variants differ by age at disease onset, survival time, and diagnostic test results. Characteristics of these 5 phenotypes are provided to facilitate further clinicopathologic investigation that may lead to more reliable and timely diagnoses of sCJD.

Arch Neurol. 2009;66(2):208-215



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Thursday, September 24, 2009

Suit: Meatpacker used `downer' cows for 4 years TO FEED OUT CHILDREN ALL ACROSS THE NATION, the most high risk for mad cow disease

Monday, May 11, 2009

Rare BSE mutation raises concerns over risks to public health


Wednesday, March 11, 2009

PRION1 trial reports quinacrine does not increase survival in patients with prion disease

PRION1 trial reports quinacrine does not increase survival in patients with prion disease

10 March 2009

The drug quinacrine does not increase survival in patients with prion diseases including variant Creutzfeldt-Jakob Disease (vCJD). The finding comes from evidence collected during the PRION-1 trial, the first clinical trial of a potential treatment for human prion diseases in the UK. The results are published in Lancet Neurology.

Human prion diseases, such as Creutzfeldt-Jakob disease (CJD), can arise spontaneously, be inherited through a genetic mutation, or develop through infectious transmission. The most common form is sporadic CJD, which affects about one to two people in a million worldwide every year. The neurodegenerative disorders caused by prion disease are fatal and progress rapidly. Currently, there are no therapeutic interventions that prevent or reverse progression in human prion diseases.

The Chief Medical Officer for England asked the Medical Research Council to prepare a protocol for a clinical trial in human prion disease to investigate quinacrine’s therapeutic potential, activity and safety. There are no other drugs currently available which are considered suitable for human evaluation. PRION-1 was led by Professor John Collinge, Director of the MRC Prion Unit, and was funded by the MRC and Department of Health.

Quinacrine (Mepacrine), a drug used to treat malaria and some arthritic illnesses, has been shown to be effective in treating prion-infected cells in the laboratory, by blocking the conversion of normal prion proteins into the abnormal disease-causing form. Oral quinacrine is also known to be safe and well-tolerated in humans and can cross the difficult blood-brain barrier. Interest in this potential treatment grew, and some patients requested immediate access to quinacrine.

A formal consultation process with patients, families, carers and representatives of patients was undertaken to develop an acceptable study design to assess the efficacy and safety of oral quinacrine in all forms of prion disease in the UK.

Patients in the PRION-1 trial were offered the choice of quinacrine, no quinacrine, or to be randomly assigned to receive quinacrine either immediately or after a delay. In total 107 patients with prion disease were recruited to the trial from across the UK using a national referral system. Of these people, 45 had sporadic prion disease, two had iatrogenic (acquired from a hospital procedure), 18 had variant CJD and 42 had inherited prion disease. Patients were eligible if they had any form of prion disease and were more than 12 years old. Neurological assessments and clinical investigations were carried out at the start of the study, again after one, two, four and six months, and then at regular intervals of three months.

Only two of 84 patients, or their carers where the individuals did not have the capacity to make the decision themselves, agreed to randomisation. This means that PRION-1 was primarily an observational study of patients who did or did not choose quinacrine. The authors identified disease severity as a strong determinant of this choice, with those least and most severely affected least likely to choose the drug.

In total, 78 patients died—one randomly assigned to deferred treatment, 26 of 38 who took the drug immediately, and 51 of 69 who initially chose no quinacrine. Mortality was lower in patients who chose to take quinacrine than in those who did not, but after adjusting for confounding factors such as disease severity and type of disease there was no difference in survival significant enough to suggest quinacrine is a successful treatment option.

Importantly, the authors believe that although the study demonstrated that national recruitment and retention to trials of treatment of prion disease is both feasible and acceptable to patients and carers, it highlighted the difficulty of conducting randomised controlled trials. Patients who have a fatal disease that progresses rapidly often want whatever potential treatment is available. This means they are reluctant to be randomised to a deferred treatment option. Similarly when a patient has advanced disease, families are not prepared to accept an intervention that is expected to merely slow or halt disease progression.

The authors conclude that earlier diagnosis must be: ‘‘A high priority if patients are to be included in treatment trials, as those with mild to moderate disease are probably most likely to accept randomisation, and likely to benefit most from any effective treatment.”

Original research paper: Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial is published in Lancet Neurology 2009; 8: 334–44.

Press contact: 020 7637 6011 mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000555/!

Experimental treatments for human TSE (prion)


Wednesday, February 11, 2009

Father’s relief at £3m vCJD victims study

Father’s relief at £3m vCJD victims study

3:50pm Wednesday 11th February 2009

Holly Mills with her mum, Linda, and dog, Jack, at Dalby Forest

By Mike Laycock »

HOLLY MILLS has survived for more than five years since doctors diagnosed her as suffering from the devastating illness variant CJD – and warned that she had only weeks to live.

Her father, Peter, convinced the 23-year-old is only alive today because of a revolutionary treatment she has been given since 2003, has been pressing for years for research into the drug, pentosan polysulphate (PPS).

Now Mr Mills, of Thornton-le-Dale, near Pickering, has told of his relief after being informed that the Department of Health has finally ordered a £3 million study into all types of vCJD (Creutzfeldt-Jakob disease) and its treatment.

He said he had been asked to sit on an oversight group for the cohort study, which was set to be launched next month and would be led by Professor John Collinge, of the National Prion Unit at the National Hospital for Neurology and Neurosurgery in London.

Mr Mills said the study was the breakthrough he and his wife, Linda, had been hoping for ever since October 2003, when Holly became one of the first people in the world to have PPS pumped directly into their brain.

Holly, who had previously been fit and healthy, fell ill when she was 17. Her parents do not know why she caught vCJD, although they suspect it may have been through eating contaminated beef products more than two decades ago.

The Mills went public on Holly’s condition in 2005 – lifting a High Court ban on her identification – so they could demand research into the drug and its effects on the illness.

Mr Mills said today her condition had remained stable over the years since the treatment started, with her weight remaining constant, and he and Linda believed she had continued to show slight, but significant improvements.

She could make oral noises to communicate with them and used an exercise bike daily, albeit strapped safely into position. Mr Mills said: “It’s not dramatic, but we are hoping that one day, within five years, diagnostics and treatment will be devised that can reverse her illness.”

Neuological expert Ian Bone conducted a study of several patients receiving PPS treatment on behalf of the Medical Research Council (MRC) in 2005.

An MRC report said afterwards PPS was a molecule derived from beech wood which had many properties such as blood thinning, and it was licensed to treat bladder inflammation.

Prof Bone said some of the patients treated with PPS appeared to have survived for long periods, but it could not be concluded the treatment had a beneficial effect, because it was impossible to make direct comparisons with similar, but untreated patients.

Rare disease research

THE Department of Health has confirmed it will fund a three-year, £3 million National Prion Monitoring Cohort study through its Policy Research Programme.

A spokesman said human prion disease remained very rare, but it was possible that the numbers of people affected by variant CJD – the prion disease linked to BSE – might increase.

He said an extensive research programme was seeking to promote early diagnosis and develop treatments for such diseases.

“We have conducted the first clinical trial for prion disease in the UK. We are now launching the National Prion Monitoring Cohort study,” he said.

This observational cohort study would collect data on all patients diagnosed with, or at high risk of developing prion disease, regardless of whether or not they were receiving treatment, and would monitor changes in the progression of the disease during their natural history or in response to therapeutic and other interventions.

Experimental treatments for human TSE (prion)