Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease

Abstract

Objective: To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD).

Methods: This NIH/National Institute on Aging-funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (ClinicalTrials.gov, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2.

Results: Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months.

Conclusion: This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials.

Classification of evidence: This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months.

Figure 1. Quinacrine CJD treatment trial flowchart

^a Ineligible includes referred subjects who did not meet inclusion criteria (e.g., had an alternative diagnosis, were too advanced to participate [could not follow simple commands and swallow], did not live in the United States or Canada, had no caregiver, or did not fulfill other inclusion criteria). Many potential or probable sCJD referrals did not want to participate in research, did not respond to follow-up, died before evaluation, were unable to travel, or did not wish to prolong life. ^b Includes one subject who was given a clinical diagnosis of possible Sprue and did not wish to have a brain biopsy to confirm CJD. The subject was therefore not randomized. Autopsy later revealed a diagnosis of sCJD. ^c Three subjects, who were originally randomized to the quinacrine arm, were clinically diagnosed with probable sCJD, but genetic results revealed one fCJD (D178N) case, one case with 9-OPRI mutation, and one fCJD (V180I) case. ^d Although formal study follow-up was discontinued on May 1, 2009, some families remained in contact with the research team after that date. These numbers reflect the number of subjects that were still alive at last contact as of October 15, 2010. ^e Two subjects, one in each arm, were still alive as of the last follow-up, but were both receiving life-extending measures. CJD = Creutzfeldt-Jakob disease; fCJD = familial CJD; 9-OPRI = 9 octapeptide repeat insertion; sCJD = sporadic CJD; UCSF = University of California, San Francisco.

Figure 2. Kaplan-Meier survival analysis from baseline to month 2 and to death

(A) Kaplan-Meier survival analysis from month 0 (baseline) to month 2 for 51 randomized subjects with sCJD (placebo, n = 28; quinacrine, n = 23). These differences were not statistically significant (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43 quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). (B) Kaplan-Meier survival analysis from baseline to death or date of life-extending measures (censored) or to date of last contact (censored) for 51 randomized subjects with sCJD. Four groups were based on the treatment arm at randomization and the treatment arm chosen at month 2, to obtain the placebo-placebo group (n = 5); the placebo-quinacrine group (n = 14); the quinacrine-placebo group (n = 3); and the quinacrine-quinacrine group (n = 10). Because groups in this figure are not based solely on randomization, but include subject choice at month 2, we did not conduct a formal statistical test of differences in survival. Note that these curves might appear to suggest a greater benefit of quinacrine than the data indicate, as the subjects who went on open-label quinacrine were survivors (and most in good enough condition to return for their month-2 visit) from the placebo and quinacrine groups. sCJD = sporadic Creutzfeldt-Jakob disease.