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| ID | Type | Description | Link |
|---|---|---|---|
| P01AG021601 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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The purpose of this clinical trial is to determine the effectiveness of the medication quinacrine on survival in sporadic Creutzfeldt-Jakob disease (sCJD).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| quinacrine | Experimental |
| |
| placebo | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Quinacrine | Drug | 100mg by mouth three times a day |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Primary Survival | Participants alive after 2 months on study treatment | Randomization to Month-2 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Mini-Mental State Examination (MMSE) After 2 Months | The mini-mental state examination (MMSE) is a brief 30-point questionnaire that is used to screen for cognitive impairment. In about 10 minutes it samples functions including arithmetic, memory and orientation. A score greater than or equal to 25 points (out of 30) indicates a normal cognition. Lower scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-24 points) cognitive impairment. Low to very low scores correlate closely with the presence of dementia, although other mental disorders can also lead to abnormal findings on MMSE testing. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Geschwind, MD, PhD | UCSF Memory & Aging Center, University of California, San Francisco | Principal Investigator |
| Bruce L. Miller, MD | UCSF Memory & Aging Center, University of California, San Francisco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, San Francisco | San Francisco | California | 94143 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 9811807 | Background | Prusiner SB. Prions. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83. doi: 10.1073/pnas.95.23.13363. | |
| 11504948 | Background | 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. doi: 10.1073/pnas.161274798. |
| Label | URL |
|---|---|
| UCSF Memory \& Aging Center | View source |
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425 patients referred; 69 subjects consented/enrolled; 54 subjects eligible/randomized; 3 randomized subjects identified as carriers of PrP (prion protein) gene mutations as determined by analysis of sequence variability of the bovine prion protein gene (PRNP) and excluded from analyses.
Enrollment began in April 2005 and ended in January 2009. Subjects came from across the USA, as well as Canada, with a plurality from California, and enrolled at one U.S. clinical site (University of California, San Francisco).
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| ID | Title | Description |
|---|---|---|
| FG000 | Quinacrine | Double Blind Period: 100mg Quinacrine by mouth three times a day. Open Label Period: Choice of study drug or open-label Quinacrine 100mg by mouth three times a day. |
| FG001 | Placebo | Double Blind Period: 100mg Placebo by mouth three times a day. Open Label Period: Choice of study drug or Quinacrine 100mg by mouth three times a day. |
| FG002 | Study Drug (Quinacrine) During Open-Label Period | Participants received Quinacrine during Double-Blind period and opted to continue study drug during Open-Label period |
| FG003 | Study Drug (Placebo) During Open-Label Period | Participants received Placebo during Double-Blind period and opted to continue study drug during Open-Label period |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Double-blind (Baseline - Month 2) |
| |||||||||||||||||||
| Open-label Period (Month 2 Until Death) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Placebo : 100mg by mouth three times a day |
| BG001 | Quinacrine | Quinacrine : 100mg by mouth three times a day |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Primary Survival | Participants alive after 2 months on study treatment | Posted | Number | participants | Randomization to Month-2 |
|
|
1 year
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo Random Assignment | Placebo : 100mg by mouth three times a day, Baseline-Month 2 = random assignment (n=28), Month 2+ = optional continuation of assigned drug (n=1). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal abscess | Gastrointestinal disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Michael Geschwind, MD, PhD | UCaliforniaSF | 415-476-2901 | mgeschwind@memory.ucsf.edu |
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| ID | Term |
|---|---|
| D007562 | Creutzfeldt-Jakob Syndrome |
| D003704 | Dementia |
| D017096 | Prion Diseases |
| D009422 | Nervous System Diseases |
| D034062 | Insomnia, Fatal Familial |
| ID | Term |
|---|---|
| D002494 | Central Nervous System Infections |
| D007239 | Infections |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D011796 | Quinacrine |
| ID | Term |
|---|---|
| D000609 | Aminoacridines |
| D000166 | Acridines |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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| Placebo | Drug | 100mg by mouth three times a day |
|
| Baseline to Month-2 |
| Barthel Score Change After 2 Months | An ordinal scale used to measure performance in activities of daily living. Scores range from 0 (worst, fully dependent) to 100 (best, independent); higher score associated with a greater likelihood of being able to live at home with a degree of independence following discharge from hospital. 10 individual items are scored and summed to derive the overall Barthel index score. Each item may be scored 0, 5, 10 or 15; not all items use the full range of 4 possible values. The amount of time and physical assistance required to perform each item are considered in scoring each item. For subjects unable to return for month-2 visit, Barthel Index was performed via telephone. | baseline, 2 months |
| Change in Clinical Dementia Rating Scale Sum of Boxes (CDRS-SB) After 2 Months | Clinical Dementia Rating Scale Sum of Boxes (CDRS-SB). The CDR is obtained through semistructured interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The global CDR score is computed via an algorithm. The CDR-SB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18. A higher value and/or positive change is worse. For subjects unable to return for month-2 visit, CDRS-SB was performed via telephone. | Baseline, 2 months |
| Change in Rankin Score After 2 Months | The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms.
| Baseline, 2 months |
| ADAS-Cog Change After 2 Months Among Survivors | ADAS-cog measures cognitive performance by combining ratings of 11 components (word recall, word recognition, constructional praxis, orientation, naming objects and fingers, commands, ideational praxis, remembering instruction, spoken language, word finding, comprehension) representing six areas of cognition: memory; language; orientation to time, place and person; construction of simple designs and planning; and performing simple behaviors in pursuit of a basic, predefined goal. Seven components are scored as the 'number incorrect'. For example, in the commands component, the number of five commands performed incorrectly (range: 0-5). Four components are scored from 0 (no limitations) to 5 (max limitations) as the examiner's perception of remembering instructions, spoken language ability, word finding and comprehension. Component scores are summed into a total ADAS-cog score ranging from 0-75, with low scores indicating better cognitive performance. | Baseline, 2 months |
| Change in Phonemic Fluency (Words Beginning With Letter "D") | Verbal fluency tests are a kind of psychological test in which participants have to say as many words as possible from a category in 60 seconds. This category (words beginning with letter "D") is phonemic. Higher scores indicate better cognition. | Baseline, 2 months |
| Change in Semantic Verbal Fluency (Naming Animals) | Verbal fluency tests are a kind of psychological test in which participants have to say as many words as possible from a category in 60 seconds. This category (naming animals) is semantic. Higher scores indicate better cognition. | Baseline, 2 months |
| 12666126 | Background | 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. doi: 10.1002/ana.10530. No abstract available. |
| 10787002 | Background | Wallace DJ. Is there a role for quinacrine (Atabrine) in the new millennium? Lupus. 2000;9(2):81-2. doi: 10.1191/096120300678828163. No abstract available. |
| 5952734 | Background | Engel GL. Quinacrine effects on the central nervous system. JAMA. 1966 Aug 8;197(6):515. No abstract available. |
| 24122181 | Derived | Geschwind MD, Kuo AL, Wong KS, Haman A, Devereux G, Raudabaugh BJ, Johnson DY, Torres-Chae CC, Finley R, Garcia P, Thai JN, Cheng HQ, Neuhaus JM, Forner SA, Duncan JL, Possin KL, Dearmond SJ, Prusiner SB, Miller BL. Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease. Neurology. 2013 Dec 3;81(23):2015-23. doi: 10.1212/WNL.0b013e3182a9f3b4. Epub 2013 Oct 11. |
| UCSF Institute for Neurodegenerative Diseases | View source |
| COMPLETED |
|
| NOT COMPLETED |
|
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| Secondary | Change in Mini-Mental State Examination (MMSE) After 2 Months | The mini-mental state examination (MMSE) is a brief 30-point questionnaire that is used to screen for cognitive impairment. In about 10 minutes it samples functions including arithmetic, memory and orientation. A score greater than or equal to 25 points (out of 30) indicates a normal cognition. Lower scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-24 points) cognitive impairment. Low to very low scores correlate closely with the presence of dementia, although other mental disorders can also lead to abnormal findings on MMSE testing. | Subjects still alive, who attended the month-2 visit and were willing and able to tolerate cognitive testing. 1 subject in each arm did attend the 2-month visit but did not cooperate fully with the MMSE, which was therefore not scored. | Posted | Mean | Full Range | units on a scale | Baseline to Month-2 |
|
|
|
|
| Secondary | Barthel Score Change After 2 Months | An ordinal scale used to measure performance in activities of daily living. Scores range from 0 (worst, fully dependent) to 100 (best, independent); higher score associated with a greater likelihood of being able to live at home with a degree of independence following discharge from hospital. 10 individual items are scored and summed to derive the overall Barthel index score. Each item may be scored 0, 5, 10 or 15; not all items use the full range of 4 possible values. The amount of time and physical assistance required to perform each item are considered in scoring each item. For subjects unable to return for month-2 visit, Barthel Index was performed via telephone. | One surviving subject in the quinacrine arm did not attend the 2-month visit and was lost-to-followup; for a second surviving subject in the quinacrine arm, the Barthel Index was inadvertently not performed at the 2-month visit. | Posted | Mean | Full Range | units on a scale | baseline, 2 months |
|
|
|
|
| Secondary | Change in Clinical Dementia Rating Scale Sum of Boxes (CDRS-SB) After 2 Months | Clinical Dementia Rating Scale Sum of Boxes (CDRS-SB). The CDR is obtained through semistructured interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The global CDR score is computed via an algorithm. The CDR-SB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18. A higher value and/or positive change is worse. For subjects unable to return for month-2 visit, CDRS-SB was performed via telephone. | For subjects still alive at month 2 and assessed at the 2-month visit or via telephone | Posted | Mean | Full Range | units on a scale | Baseline, 2 months |
|
|
|
|
| Secondary | Change in Rankin Score After 2 Months | The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms.
| For subjects still alive at month 2 and assessed at the 2-month visit or via telephone | Posted | Mean | Full Range | units on a scale | Baseline, 2 months |
|
|
|
|
| Secondary | ADAS-Cog Change After 2 Months Among Survivors | ADAS-cog measures cognitive performance by combining ratings of 11 components (word recall, word recognition, constructional praxis, orientation, naming objects and fingers, commands, ideational praxis, remembering instruction, spoken language, word finding, comprehension) representing six areas of cognition: memory; language; orientation to time, place and person; construction of simple designs and planning; and performing simple behaviors in pursuit of a basic, predefined goal. Seven components are scored as the 'number incorrect'. For example, in the commands component, the number of five commands performed incorrectly (range: 0-5). Four components are scored from 0 (no limitations) to 5 (max limitations) as the examiner's perception of remembering instructions, spoken language ability, word finding and comprehension. Component scores are summed into a total ADAS-cog score ranging from 0-75, with low scores indicating better cognitive performance. | Subjects still alive and able to tolerate cognitive testing at Month 2 visit. | Posted | Mean | Full Range | units on a scale | Baseline, 2 months |
|
|
|
|
| Secondary | Change in Phonemic Fluency (Words Beginning With Letter "D") | Verbal fluency tests are a kind of psychological test in which participants have to say as many words as possible from a category in 60 seconds. This category (words beginning with letter "D") is phonemic. Higher scores indicate better cognition. | Subject still alive and able to tolerate cognitive testing at month 2 visit | Posted | Mean | Full Range | number of words generated | Baseline, 2 months |
|
|
|
|
| Secondary | Change in Semantic Verbal Fluency (Naming Animals) | Verbal fluency tests are a kind of psychological test in which participants have to say as many words as possible from a category in 60 seconds. This category (naming animals) is semantic. Higher scores indicate better cognition. | Subjects still alive and able to tolerate cognitive testing at month 2 visit. | Posted | Mean | Full Range | number of words generated | Baseline, 2 months |
|
|
|
|
| 14 |
| 28 |
| 9 |
| 28 |
| EG001 | Quinacrine Random Assignment | Quinacrine: 100mg by mouth three times a day. Baseline-Month 2 = random assignment (n=23), Month 2+ = optional continuation of assigned drug (n=1). | 13 | 23 | 9 | 23 |
| EG002 | Quinacrine Open-label | Quinacrine: Month 2 until death = optional open-label Quinacrine 100mg by mouth three times a day | 14 | 24 | 16 | 24 |
| Hemorrhage | Nervous system disorders | Systematic Assessment | Hemorrhagic brain bleed found on autopsy |
|
| Death | General disorders | Non-systematic Assessment |
|
| Seizure | Nervous system disorders | Non-systematic Assessment |
|
| Unclassified shaking | General disorders | Non-systematic Assessment |
|
| Agitation | Psychiatric disorders | Non-systematic Assessment | Present prior to randomization |
|
| Elevated renal function labs | Renal and urinary disorders | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Post-LP infection | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Hallucinations | Psychiatric disorders | Non-systematic Assessment |
|
| Post-LP headache | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Post-LP Dizziness | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Agitation | Psychiatric disorders | Non-systematic Assessment |
|
| Elevated Liver Function Tests | Hepatobiliary disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Urinary Tract Infection | Infections and infestations | Non-systematic Assessment |
|
| Potential thrombi | Blood and lymphatic system disorders | Non-systematic Assessment | Present prior to randomization |
|
| Post-LP complications | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Hallucination | Psychiatric disorders | Non-systematic Assessment |
|
| Pulmonary embolism | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Hip Fracture | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Elevated creatine kinase | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Dizziness | General disorders | Non-systematic Assessment |
|
| Seizure | Nervous system disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Non-systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Fever | General disorders | Non-systematic Assessment |
|
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| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D019636 | Neurodegenerative Diseases |
| D007319 | Sleep Initiation and Maintenance Disorders |
| D020919 | Sleep Disorders, Intrinsic |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D006571 | Heterocyclic Compounds |