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CJD (Creutzfeldt-Jakob Disease) Quinacrine Study

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ClinicalTrials.gov Identifier: NCT00183092
Recruitment Status : Completed
First Posted : September 16, 2005
Results First Posted : May 29, 2014
Last Update Posted : June 9, 2014
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
University of California, San Francisco

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Creutzfeldt-Jakob Disease
Interventions Drug: Quinacrine
Drug: Placebo
Enrollment 69
Recruitment Details 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).
Pre-assignment Details 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.
Arm/Group Title Quinacrine Placebo Study Drug (Quinacrine) During Open-Label Period Study Drug (Placebo) During Open-Label Period
Hide Arm/Group Description 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. 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. Participants received Quinacrine during Double-Blind period and opted to continue study drug during Open-Label period Participants received Placebo during Double-Blind period and opted to continue study drug during Open-Label period
Period Title: Double-blind (Baseline - Month 2)
Started 23 28 0 0
Alive at Month 2 13 19 0 0
Came in for Month 2 Visit 10 16 0 0
Completed 11 16 0 0
Not Completed 12 12 0 0
Period Title: Open-label Period (Month 2 Until Death)
Started 10 [1] 14 [2] 1 [3] 1 [4]
Completed 0 0 0 0
Not Completed 10 14 1 1
[1]
Participants initially assigned to Quinacrine opted to begin open-label Quinacrine at Month 2
[2]
Participants initially assigned to Placebo opted to begin open-label Quinacrine at Month 2
[3]
Participants assigned to Quinacrine opted to continue assigned drug during open-label period
[4]
Participants assigned to Placebo opted to continue assigned drug during open-label period
Arm/Group Title Placebo Quinacrine Total
Hide Arm/Group Description Placebo : 100mg by mouth three times a day Quinacrine : 100mg by mouth three times a day Total of all reporting groups
Overall Number of Baseline Participants 28 23 51
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 28 participants 23 participants 51 participants
64.4
(38 to 82)
60.5
(40 to 75)
62.5
(38 to 82)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 28 participants 23 participants 51 participants
Female
9
  32.1%
11
  47.8%
20
  39.2%
Male
19
  67.9%
12
  52.2%
31
  60.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 28 participants 23 participants 51 participants
28 23 51
1.Primary Outcome
Title Primary Survival
Hide Description Participants alive after 2 months on study treatment
Time Frame Randomization to Month-2
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Quinacrine
Hide Arm/Group Description:
Placebo : 100mg by mouth three times a day
Quinacrine : 100mg by mouth three times a day
Overall Number of Participants Analyzed 28 23
Measure Type: Number
Unit of Measure: participants
19 13
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Quinacrine
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.43
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.43
Confidence Interval (2-Sided) 95%
0.58 to 3.53
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change in Mini–Mental State Examination (MMSE) After 2 Months
Hide Description 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.
Time Frame Baseline to Month-2
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Quinacrine
Hide Arm/Group Description:
Placebo : 100mg by mouth three times a day
Quinacrine : 100mg by mouth three times a day
Overall Number of Participants Analyzed 15 9
Mean (Full Range)
Unit of Measure: units on a scale
-6.9
(-18 to 4)
-3.9
(-10 to 1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Quinacrine
Comments The difference between change scores, adjusted for Month-0 performance. Positive adjusted differences indicate greater adjusted change (worsening) in the placebo group; negative indicate greater adjusted changed (worsening) in the quinacrine group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .54
Comments Threshold for statistical significance = 0.05. One subject in the placebo group was administered only 25 items on the MMSE due to visual impairment, and this subject's score was scaled based on percentage correct.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 1.5
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Barthel Score Change After 2 Months
Hide Description 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.
Time Frame baseline, 2 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Quinacrine
Hide Arm/Group Description:
Placebo : 100mg by mouth three times a day
Quinacrine : 100mg by mouth three times a day
Overall Number of Participants Analyzed 19 11
Mean (Full Range)
Unit of Measure: units on a scale
-23.2
(-85 to 70)
-13.2
(-65 to 5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Quinacrine
Comments The difference between scores, adjusted for Month-0 performance.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .36
Comments significance threshold p=0.05
Method Quade's rank analysis of covariance
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 7.9
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change in Clinical Dementia Rating Scale Sum of Boxes (CDRS-SB) After 2 Months
Hide Description 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.
Time Frame Baseline, 2 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
For subjects still alive at month 2 and assessed at the 2-month visit or via telephone
Arm/Group Title Placebo Quinacrine
Hide Arm/Group Description:
Placebo : 100mg by mouth three times a day
Quinacrine : 100mg by mouth three times a day
Overall Number of Participants Analyzed 19 12
Mean (Full Range)
Unit of Measure: units on a scale
3.2
(-1 to 8)
0.3
(-1 to 2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Quinacrine
Comments The difference between change scores, adjusted for Month-0 performance. Positive adjusted differences indicate greater adjusted change (worsening) in the placebo group; negative indicate greater adjusted changed (worsening) in the quinacrine group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .01
Comments Significance threshold p<0.05
Method Quade's rank analysis of covariance
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 2.8
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change in Rankin Score After 2 Months
Hide Description

The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms.

  1. - No significant disability. Able to carry out all usual activities, despite some symptoms.
  2. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
  3. - Moderate disability. Requires some help, but able to walk unassisted.
  4. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
  5. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
  6. - Dead. For subjects unable to return for the 2-month visit, Rankin score was assessed via telephone.
Time Frame Baseline, 2 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
For subjects still alive at month 2 and assessed at the 2-month visit or via telephone
Arm/Group Title Placebo Quinacrine
Hide Arm/Group Description:
Placebo : 100mg by mouth three times a day
Quinacrine : 100mg by mouth three times a day
Overall Number of Participants Analyzed 19 12
Mean (Full Range)
Unit of Measure: units on a scale
0.8
(0 to 2)
0.3
(-1 to 2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Quinacrine
Comments The difference between change scores, adjusted for Month-0 performance. Positive adjusted differences indicate greater adjusted change (worsening) in the placebo group; negative indicate greater adjusted changed (worsening) in the quinacrine group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.03
Comments Threshold for significance p<0.05
Method Quade's rank analysis of covariance
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.5
Estimation Comments [Not Specified]
6.Secondary Outcome
Title ADAS-Cog Change After 2 Months Among Survivors
Hide Description 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.
Time Frame Baseline, 2 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Subjects still alive and able to tolerate cognitive testing at Month 2 visit.
Arm/Group Title Placebo Quinacrine
Hide Arm/Group Description:
Placebo : 100mg by mouth three times a day
Quinacrine : 100mg by mouth three times a day
Overall Number of Participants Analyzed 9 4
Mean (Full Range)
Unit of Measure: units on a scale
13.0
(0 to 23)
12.6
(-2 to 37)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Quinacrine
Comments The difference between change scores, adjusted for Month-0 performance. Positive adjusted differences indicate greater adjusted change (worsening) in the placebo group; negative indicate greater adjusted changed (worsening) in the quinacrine group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.92
Comments Significance threshold p<0.05
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.7
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Change in Phonemic Fluency (Words Beginning With Letter "D")
Hide Description 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.
Time Frame Baseline, 2 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Subject still alive and able to tolerate cognitive testing at month 2 visit
Arm/Group Title Placebo Quinacrine
Hide Arm/Group Description:
Placebo : 100mg by mouth three times a day
Quinacrine : 100mg by mouth three times a day
Overall Number of Participants Analyzed 9 5
Mean (Full Range)
Unit of Measure: number of words generated
-2.4
(-8 to 1)
-2.2
(-5 to 0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Quinacrine
Comments The difference between change scores, adjusted for Month-0 performance. Positive adjusted differences indicate greater adjusted change (worsening) in the placebo group; negative indicate greater adjusted changed (worsening) in the quinacrine group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.71
Comments Significance threshold p<0.05
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.4
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change in Semantic Verbal Fluency (Naming Animals)
Hide Description 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.
Time Frame Baseline, 2 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Subjects still alive and able to tolerate cognitive testing at month 2 visit.
Arm/Group Title Placebo Quinacrine
Hide Arm/Group Description:
Placebo : 100mg by mouth three times a day
Quinacrine : 100mg by mouth three times a day
Overall Number of Participants Analyzed 9 5
Mean (Full Range)
Unit of Measure: number of words generated
-3.2
(-9 to 2)
-2.2
(-9 to 5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Quinacrine
Comments The difference between change scores, adjusted for Month-0 performance. Positive adjusted differences indicate greater adjusted change (worsening) in the placebo group; negative indicate greater adjusted change (worsening) in the quinacrine group.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.70
Comments Significance threshold p<0.05
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.8
Estimation Comments [Not Specified]
Time Frame 1 year
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Random Assignment Quinacrine Random Assignment Quinacrine Open-label
Hide Arm/Group Description Placebo : 100mg by mouth three times a day, Baseline-Month 2 = random assignment (n=28), Month 2+ = optional continuation of assigned drug (n=1). Quinacrine: 100mg by mouth three times a day. Baseline-Month 2 = random assignment (n=23), Month 2+ = optional continuation of assigned drug (n=1). Quinacrine: Month 2 until death = optional open-label Quinacrine 100mg by mouth three times a day
All-Cause Mortality
Placebo Random Assignment Quinacrine Random Assignment Quinacrine Open-label
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Random Assignment Quinacrine Random Assignment Quinacrine Open-label
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   14/28 (50.00%)   13/23 (56.52%)   14/24 (58.33%) 
Gastrointestinal disorders       
Diarrhea *  0/28 (0.00%)  1/23 (4.35%)  0/24 (0.00%) 
General disorders       
Death *  11/28 (39.29%)  10/23 (43.48%)  8/24 (33.33%) 
Unclassified shaking *  0/28 (0.00%)  1/23 (4.35%)  0/24 (0.00%) 
Injury, poisoning and procedural complications       
Fall *  0/28 (0.00%)  0/23 (0.00%)  2/24 (8.33%) 
Post-LP infection *  2/28 (7.14%)  0/23 (0.00%)  0/24 (0.00%) 
Post-LP headache *  2/28 (7.14%)  0/23 (0.00%)  0/24 (0.00%) 
Post-LP Dizziness *  2/28 (7.14%)  0/23 (0.00%)  0/24 (0.00%) 
Nervous system disorders       
Hemorrhage  [1]  1/28 (3.57%)  0/23 (0.00%)  1/24 (4.17%) 
Seizure *  0/28 (0.00%)  1/23 (4.35%)  0/24 (0.00%) 
Psychiatric disorders       
Agitation * [2]  0/28 (0.00%)  0/23 (0.00%)  1/24 (4.17%) 
Hallucinations *  0/28 (0.00%)  0/23 (0.00%)  1/24 (4.17%) 
Renal and urinary disorders       
Elevated renal function labs   0/28 (0.00%)  0/23 (0.00%)  1/24 (4.17%) 
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
[1]
Hemorrhagic brain bleed found on autopsy
[2]
Present prior to randomization
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Placebo Random Assignment Quinacrine Random Assignment Quinacrine Open-label
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   9/28 (32.14%)   9/23 (39.13%)   16/24 (66.67%) 
Blood and lymphatic system disorders       
Potential thrombi * [1]  1/28 (3.57%)  0/23 (0.00%)  1/24 (4.17%) 
Pulmonary embolism *  0/28 (0.00%)  1/23 (4.35%)  1/24 (4.17%) 
Leukopenia   1/28 (3.57%)  0/23 (0.00%)  0/24 (0.00%) 
Gastrointestinal disorders       
Abdominal abscess *  0/28 (0.00%)  1/23 (4.35%)  0/24 (0.00%) 
Diarrhea *  1/28 (3.57%)  1/23 (4.35%)  5/24 (20.83%) 
Nausea *  1/28 (3.57%)  1/23 (4.35%)  5/24 (20.83%) 
Vomiting *  1/28 (3.57%)  1/23 (4.35%)  5/24 (20.83%) 
General disorders       
Dizziness *  0/28 (0.00%)  0/23 (0.00%)  1/24 (4.17%) 
Fever *  1/28 (3.57%)  0/23 (0.00%)  0/24 (0.00%) 
Hepatobiliary disorders       
Elevated Liver Function Tests   0/28 (0.00%)  3/23 (13.04%)  12/24 (50.00%) 
Infections and infestations       
Urinary Tract Infection *  3/28 (10.71%)  1/23 (4.35%)  1/24 (4.17%) 
Injury, poisoning and procedural complications       
Post-LP complications *  1/28 (3.57%)  0/23 (0.00%)  1/24 (4.17%) 
Hip Fracture *  0/28 (0.00%)  0/23 (0.00%)  1/24 (4.17%) 
Musculoskeletal and connective tissue disorders       
Elevated creatine kinase *  0/28 (0.00%)  0/23 (0.00%)  1/24 (4.17%) 
Nervous system disorders       
Seizure *  0/28 (0.00%)  0/23 (0.00%)  2/24 (8.33%) 
Psychiatric disorders       
Agitation *  1/28 (3.57%)  2/23 (8.70%)  2/24 (8.33%) 
Hallucination *  2/28 (7.14%)  0/23 (0.00%)  0/24 (0.00%) 
Skin and subcutaneous tissue disorders       
Rash *  1/28 (3.57%)  0/23 (0.00%)  3/24 (12.50%) 
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
[1]
Present prior to randomization
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Michael Geschwind, MD, PhD
Organization: UCaliforniaSF
Phone: 415-476-2901
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00183092     History of Changes
Other Study ID Numbers: IA0083
P01AG021601 ( U.S. NIH Grant/Contract )
First Submitted: September 14, 2005
First Posted: September 16, 2005
Results First Submitted: January 21, 2014
Results First Posted: May 29, 2014
Last Update Posted: June 9, 2014