Keywords
Creutzfeldt-Jakob Syndrome - Prion Diseases - Therapeutics
Palavras-chave
Síndrome de Creutzfeldt-Jakob - Doenças Priônicas - Terapêutica
INTRODUCTION
Prion diseases make up a large group of neurodegenerative conditions known as spongiform
encephalopathies, affecting both animals and humans.[1]
[2] These conditions are fatal, with no current effective form of treatment.[1] However, increased understanding of their pathogenesis has recently led to the promise
of effective therapeutic interventions, particularly for the Creutzfeldt-Jakob disease
(CJD).
The CJD has a long incubation period, but once its clinical manifestations appear,
a very rapid progression to a fatal outcome can be expected.[3]
[4] It can have a myriad of causes, namely sporadic, genetic, iatrogenic, or idiopathic.[5] The current accepted hypothesis for CJD's etiological agent is mainly an abnormal
conformation of a host-encoded glycoprotein called prion protein.[6]
[7]
The global incidence of CJD is estimated to be approximately 1 to 2 cases per million
per year.[8] Sporadic CJD has a rapidly progressive clinical course, invariably progressing to
death within 6 to 14 months, with an average of 8 months,[8] occurring worldwide without significant differences between ethnic groups or genders.
The mean age of onset of sporadic CJD is 62 years, and among individuals aged 60 to
74 years the incidence is 5 cases per million population.[9] Although it is very uncommon, it can affect individuals under the age of 55.
Clinically, CJD is characterized by rapidly progressive dementia associated with myoclonic,
pyramidal, extrapyramidal, and cerebellar symptoms, with abnormalities in the electroencephalogram.
In some cases, patients may have symptoms of peripheral neuropathy preceding the central
involvement. In addition to these elements, elevated cerebrospinal fluid 14-3-3 protein
and magnetic resonance imaging (MRI) scans with findings of cortical ribbons help
in determining a suspected case of CJD.[3]
[4]
[10] Because it is a diagnosis of exclusion, patients with suspected CJD undergo extensive
complementary evaluations to rule out other possible causes that make a differential
diagnosis.
Several potential therapeutic interventions are under development over the last years,[10]
[11]
[12] but no treatment has been proven effective for CJD. In this perspective, some chemotherapeutic,
immunological, or pharmacological neuroprotection stimulation approaches have been
studied in patients with CJD to extend the supportive therapeutic possibilities already
employed.[13]
[14]
[15] Thus, it is important to know in detail the advances in the pharmacological management
of CJD in the international medical literature to improve patient care and enlightenment.
METHODS
The present study consists of a systematic review of the literature, using controlled
and uncontrolled clinical trials and case series, on the efficacy of pharmacological
treatments offered to prolong survival time and reduce cognitive deterioration in
patients with CJD. The studies included in this paper focus on the effects of drugs
studied and prescribed in the management of CJD, and include pharmacological intervention
groups whose effect are compared with placebo, other drugs, or simply compared with
previous literature findings.
The inclusion criteria were patients with probable or possible cases of CJD regardless
of gender, age, comorbidities, or concomitant or prior use of any type of pharmacological
management. The probable case of CJD is characterized by the neuropsychiatric disorder
plus positive real-time quaking-induced conversion (RT-QuIC) in the cerebrospinal
fluid or other tissues, or rapidly progressive dementia syndrome with at least two
of the listed findings: myoclonus, visual changes, cerebellar syndrome, pyramidal
or extrapyramidal symptoms, akinetic mutism with typical findings on electroencephalogram
(EEG), or a positive 14-3-3 CSF assay in patients with a disease duration of less
than 2 years, or typical findings on MRI and without routine investigations indicating
an alternative diagnosis.[16] The probable case of CJD requires progressive dementia syndrome, in addition to
duration of illness of less than 2 years, absence of a positive result for any of
the 4 tests listed above that would classify a case as “probable”, and without routine
investigations indicating an alternative diagnosis, and, finally, at least two out
of the following four clinical features: myoclonus, visual changes, cerebellar syndrome,
pyramidal or extrapyramidal symptoms, or akinetic mutism.[16]
The efficacy of pharmacological treatments in CJD was evaluated by assessing the number
of patients per group that demonstrated increased survival time in months or reduction
in cognitive deterioration, using specific scales. The studies that were selected
for this review were identified through an electronic search conducted in July 2021
in the MedLINE (PubMed), SciELO, and Lilacs databases. The search was conducted in
the English language, including articles from the year 2000 onwards, using the following
descriptors: prion diseases, Creutzfeldt-Jakob disease, pharmacologic therapy, therapeutics, quinacrine, doxycycline, flupirtine, pentosan polysulfate, associated with the Boolean operators AND and OR. In addition to the directly searched works, the bibliographic references of relevant
studies, metanalyses, and review articles found on the subject were also analyzed,
with the aim of expanding the number of eligible works that were eventually not located
in the previous steps.
Using the aforementioned methodology, four independent reviewers evaluated the titles,
keywords, and abstracts identified as of interest in the initial steps. The potentially
relevant studies were analyzed in full. Following this, the same reviewers independently
selected the articles that met the inclusion criteria, and all reviewers completed
a data extraction form for each paper. Any discrepancies were resolved by a fifth
independent reviewer.
This is a systematic review built upon secondary data made available through selected
articles, with no form of personal interest whatsoever, this research did not present
any risk of violating normative ethical rights and, therefore, did not need to be
submitted to the Ethics Committee on Research with Human Beings.
RESULTS
In the initial stages of article collection, a total of 85 papers were identified.
After analyzing the titles, keywords, and abstracts, 20 studies were considered potentially
relevant in the methodological terms described. Of these, only 9 articles met the
inclusion criteria. Divergences were resolved by the fifth reviewer ([Figure 1]). Of the total number of studies included in this systematic review ([Table 1]), 4 evaluated the effects of quinacrine,[17]
[18]
[19]
[20] 2 of pentosan polysulfate (PPS),[21]
[22] and 2 of doxycycline[23]
[24] on increasing survival times (months) of CJD patients, while 1 paper analyzed the
effects of flupirtine on cognitive deterioration in this population.[25] Among the articles elected for this review, 4 studies conducted double-blind randomized
clinical trials[18]
[23]
[24]
[25] ([Table 2]).
Table 1
Selected studies at the end of the analyses
|
Authors
|
Study design
|
Sampling
|
Intervention
|
Control
|
Primary outcome
|
|
Bone et al. (2008)[21]
|
Case series
|
n = 7
|
PPS
|
−
|
Increased survival
|
|
Collinge et al. (2009)[17]
|
NRCT
|
n = 107
|
Quinacrine
|
−
|
Increased survival
|
|
Geschwind et al. (2013)[18]
|
RCT
|
n = 51 (I= 23, C= 28)
|
Quinacrine
|
Placebo
|
Increased survival
|
|
Haïk et al. (2004)[19]
|
Case series
|
n = 32
|
Quinacrine
|
−
|
Increased survival
|
|
Haïk et al. (2014)[23]
|
RCT
|
n = 121 (I= 62, C= 59)
|
Doxycycline
|
Placebo
|
Increased survival
|
|
Nakajima et al. (2004)[20]
|
NCI
|
n = 4
|
Quinacrine
|
−
|
Increased survival
|
|
Otto et al. (2004)[25]
|
RCT
|
n = 28 (I= 13, C= 15)
|
Flupirtine
|
Placebo
|
Cognitive decline reduction
|
|
Tsuboi et al. (2009)[22]
|
NCI
|
n = 11
|
PPS
|
−
|
Increased survival
|
|
Varges et al. (2017)[24]
|
RCT*
|
n = 13 (I= 7, C= 6)
|
Doxycycline
|
Placebo
|
Increased survival
|
|
Varges et al. (2017)[24]
|
NRCT*
|
n = 88 (I= 55, C= 33)
|
Doxycycline
|
−
|
Increased survival
|
Abbreviations: C, control group; I, intervention group; NCI, non-controlled intervention; NRCT,
non-randomized clinical trial; PPS, pentosan polysulfate; RCT, randomized clinical
trial.
Notes: *The study by Varges et al.[24] was composed of 2 groups, one as RCT and the other as NRCT.
Table 2
Double-blind randomized clinical trials
|
Study
|
Geschwind et al. (2013)[18]
|
Haïk et al. (2014)[23]
|
Otto et al. (2004)[25]
|
Varges et al. (2017)[24]
|
|
Design
|
Crossover
|
Crossover
|
Crossover
|
Crossover
|
|
Intervention (I)
|
Quinacrine
|
Doxycycline
|
Flupirtine
|
Doxycycline
|
|
Dosage
|
300 mg/day
|
100 mg/day
|
300 mg/day
|
100 mg/day
|
|
Median follow-up time (months)
|
2
|
5.5
|
1.3
|
7
|
|
Control (C)
|
Placebo
|
Placebo
|
Placebo
|
Placebo
|
|
Sampling (I:C)
|
51 (23:28)
|
121 (62:59)
|
28 (13:15)
|
13 (7:6)
|
|
Median age (±DP)
|
63 (±9.4)
|
63 (±10.1)
|
59 (±9.9)
|
65 (±10.0)
|
|
Gender (M–F)
|
31–20
|
51–70
|
13–15
|
7–5
|
|
Previous intervention
|
No
|
No
|
No
|
No
|
|
Primary outcome
|
Increased survival
|
Increased survival
|
Cognitive decline reduction*
|
Increased survival
|
|
Results
|
I = C
|
I = C
|
I > C
|
I = C
|
|
Measure of association
|
HR: 95% CI = 1.43 (0.58–3.53);
p = 0.43
|
HR: 95% CI= 1.10 (0.8–1.7);
p = 0.50
|
One-tailed t-test;
p = 0.02
|
HR: 95% CI = 0.84 (0.24–2.97);
p ≤ 0.50**
|
Abbreviations: CI, confidence interval.
Notes: *Assessed by ADAS-Cog: cognitive subscale of the Alzheimer disease assessment scale
(ADAS); ** the study did not specify the p-value associated with this HR on the double-blind randomized clinical trial group.
Figure 1 Abbreviations: NRCT, nonrandomized clinical trial; RCT, randomized clinical trial.
Methodological flowchart of the systematic review steps, PRISMA 2020 statement.[42] *The study by Varges et al.[24] was composed of 2 groups, one as RCT and the other as NRCT.
In a case series written by Haïk et al.,[19] the quinacrine efficacy was evaluated in 32 patients, 30 of whom were carriers of
sporadic CJD (sCJD) and 2 of variant Creutzfeldt-Jakob disease (vCJD). Patients were
reevaluated every 30 days until death. The experimental group did not demonstrate
a significant increase in survival compared with untreated patients. It should be
noted that this same study demonstrated a slight increase in survival time among treated
patients, but that was attributed to the excess presence of methionine/valine and
valine/valine genotypes when compared with methionine/methionine.
In a study of 11 patients by Tsuboi et al.[22] the increased survival with PPS infusion was investigated. During the research,
7 of the patients died with infectious complications and the remaining 4 continued
receiving the treatment. According to the results of the study, all patients had increased
survival times when compared with similar cases, at a mean time of 24.2 months. All
treated cases reported deterioration of cognitive functions to varying degrees, in
addition to subdural fluid collection. No other side effects were observed in the
patients of the group, although side effects such as thrombocytopenia and coagulation
disturbances are common in the administration of this drug.
This study has shown that the infusion of the drug does not directly affect the reversal
or preservation of the patients' pathology, although it does result in an improvement
in life expectancy. It has not been established whether higher doses of the drug would
result in a better outcome. Postmortem analysis of the patients showed that administration
of the drug reduced the prion deposition in the brain.[22]
In a double-blind, randomized clinical trial with 28 patients conducted by Otto et
al.,[25] the use of flupirtine maleate (n = 13) and placebo (n = 15) were compared regarding cognitive function improvement in patients with CJD.
For inclusion and continuation in the study, patients were required to achieve at
least 50% on 2 of the 12 subscales of the dementia tests used. A battery of standardized
questionnaires was employed to monitor disease progression. The main outcome variable
was the cognitive portion of the Alzheimer disease assessment scale (ADAS-Cog). The
difference between baseline and the best score under treatment was defined as the
primary efficacy variable for hypothesis testing.
Patients treated with flupirtine were found to have significantly less deterioration
in dementia tests for memory and orientation items, when compared with patients treated
with placebo, while there was no improvement in communicative functions of this population.
This outcome was restricted to the patients' cognitive issues, and was not observed
positively in patients' survival time. This shows that flupirtine has beneficial effects
in partially reducing the deterioration of cognitive functions in patients with CJD,
but does not alter the survival time of these patients.[25]
In a study using a daily dose of 100 mg doxycycline, Varges et al.[24] randomized 13 patients with sCJD into group 1, which was double-blinded; 7 patients
were placed in the intervention group and 6 in the placebo control group. There was
no significant difference between the groups in the increase in survival time, which
was the primary endpoint; the hazard ratio (HR), measured with 95% confidence interval
(CI), was 0.84 (0.24–2.97). There was also no significant difference in the quality
of life of this population, as measured by the mini mental status examination and
the Barthel index.
In this same study, another 88 patients were followed in a non-randomized fashion,
of which 55 were enrolled in the doxycycline protocol, and 33 were not, making up
group 2 of this study. Patients with sCJD started the study with a longer time to
diagnosis and received the treatment for a longer time, when compared with group 1.
In the stratified analysis, there was increased survival time in the intervention
group (HR: 95% CI = 0.61, 0.37–0.99), and the association with the genetic profile
was also a significant factor in the primary outcome analysis, with the methionine/valine
genotype having the greatest increase in survival, followed by the valine/valine genotype.
The authors merged the 2 groups in a meta-analysis, with heterogeneity estimated at
0 and observed superiority of doxycycline use (HR: 95% CI = 0.63, 0.40–0.99; p = 0.049) when compared with the control group.[24]
In another study using doxycycline, Haïk et al.[23] conducted a double-blind, randomized clinical trial, in which all selected patients
were over 18-years-old, with probable or definitive diagnosis of CJD through Italian
and French reference centers, with age and gender in similar proportions. The outcome
analyzed was the increase in survival times after the intervention, compared with
the placebo group. For this, 121 patients were included. The intervention group had
a total of 62 patients, who received a dosage of 100 mg of doxycycline per day, while
the control group, containing 59 patients, received placebo.
In this study, it was observed that using a dosage of 100 mg/day of doxycycline compared
with placebo brought no increase in survival times (HR: 95% CI = 1.1, 0.8–1.7). There
were no significant side effects related to the therapy implementation. The authors
stated that even with the failure of the study, the benefits of using this drug in
higher dosages, such as 200 mg/day, are not ruled out, and can be researched further.
Additionally, it was suggested that further research involving the use of doxycycline
should select patients with early stages of the disease, or even presymptomatic patients,
where benefit may be more possible, as demonstrated in animal models.[23]
In a study evaluating the quinacrine efficacy in the treatment of prion diseases,
Nakajima et al.[20] included 4 patients, 3 with probable sCJD and 1 with iatrogenic sCJD. As a result,
quinacrine was well tolerated by all 4, who had improved arousal levels after quinacrine
treatment. Other changes in global brain function included decreased reflex frequencies
or action myoclonus, startle response, and mitigation of the hyperkinetic state. No
other medications were administered during the quinacrine administration period.
In this study, the four patients received 300 mg/day of quinacrine via nasogastric
tube for 3 months. Transaminase values were elevated in 3 of the 4 patients, but never
reached 5 times the upper normal limits. Patients 1 and 2 had quinacrine temporarily
suspended because of aspiration pneumonia, urinary tract infection, and diarrhea,
but completed the 3-month course of treatment.[20]
In an observational study evaluating the efficacy of continuous PPS infusion in the
treatment of prion diseases, Bone et al.[21] evaluated 7 patients, 3 with vCJD. In this study, there was no standardization of
the dose administered and the results indicated that the drug was well tolerated over
a wide therapeutic range (11–110 µg/kg/day). According to the study results, the time
for disease onset of all patients in this study exceeded the average reported in the
literature.
Another study, conducted by Collinge et al.,[17] had a total of 107 patients with prion diseases who were recruited through the UK
national referral system and had the option of choosing between quinacrine (300 mg/day),
no quinacrine, or randomization to immediate quinacrine or deferred quinacrine in
an open trial of patient preference. The primary endpoints were death and serious
adverse events related to the experimental drug.
In this study, among the 107 patients included, 45 were sporadic, two iatrogenic,
18 variant, and 42 hereditary. From those, 23 patients were allocated to a pilot study,
and 84 to the main study. Only two patients chose randomization; 40 took quinacrine
during follow-up; and 37 of these chose it at enrollment. Treatment choice was associated
with disease severity, with the least and most severely affected being more likely
to choose not to receive quinacrine. Of the 78 (73%) patients who died, 1 was randomly
assigned to deferred treatment, 26 (68%) chose immediate quinacrine, and 51 (75%)
did not choose quinacrine. There was no difference in mortality between the groups
after adjustment.[17]
A double-blind, placebo-controlled, stratified randomization, clinical trial was conducted
by Geschwind et al.[18] to evaluate the effect of 300 mg quinacrine on survival in patients with sCJD. Patients
were randomized 1:1 between quinacrine or placebo, with hospitalizations for patient
evaluation planned at months 2, 6, and 12 of treatment. Patients who returned for
the 2-month evaluation were offered an open trial of quinacrine. Of the 425 patients
referred, only 51 participated in the trial and survival analysis, with 28 in the
placebo group and 23 in the intervention group.
The survival for the randomized portion of this trial over the first 2 months showed
no significant difference between both groups (HR: 95% CI = 1.43, 0.58–3.53). Patients
who took quinacrine treatment, however, showed a smaller decline in 2 of 3 functionality
assessment scales (the modified Rankin and the clinical dementia rating) when compared
with the placebo group in the first 2 months. Starting at 2 months, subjects who returned
for evaluation were able to choose whether or not to start quinacrine, eliminating
randomization. Because of this, the secondary survival analysis was performed using
a Cox proportional hazards model with a time-dependent treatment group variable. The
survival of patients who chose quinacrine did not differ significantly from those
who did not (HR: 95% CI = 0.86, 0.44–1.70; p = 0.67).[18]
DISCUSSION
The planning and execution of clinical trials in patients with CJD is hampered by
several difficulties inherent to the context of this condition. Moreover, as expected
for systematic reviews and metanalyses, the quality of the aggregated results is directly
proportional to, among other things, the individual robustness and homogeneity of
the selected primary studies. Thus, the adoption of quality assessment criteria and
in-depth critical analysis of the available evidence allows for a greater possibility
of extrapolation of the results to this population of interest, since it reduces the
influence of systematic and random errors on the final product of the analysis.
Due to the low incidence of CJD, there is a difficulty in patients' clinical management,
both due to the assisting professionals' lack of knowledge and the difficulty of having
well-defined flowcharts.[3]
[15] It is also important to highlight that the diagnostic criteria are not fully elucidated
or consolidated, which contributes to the delay in diagnosis, classification for studies,
as well as the underreporting of cases. As it is known, CJD progresses to death in
a few months,[4] making the quality of life of these patients of paramount importance in this short
period. Good communication with the family, along with a multidisciplinary care is
fundamental for the patient to have the best assistance possible, since most patients
with CJD will be indicated for palliation, to reduce their suffering and improve their
quality of life.
Studies have shown that the malaria treatment drug quinacrine and the antipsychotic
chlorpromazine are effective in clearing prions in non-human models.[26]
[27]
[28] However, chlorpromazine probably has a higher risk of toxicity at its estimated
therapeutic dose when compared with quinacrine.[28] Although the antiprionic mechanism of quinacrine in ScN2a cells is unknown, some
investigators suggest that quinacrine works through binding to the cellular prion
protein (PrPC).[14]
[29]
[30] Favorable results were obtained in inhibiting the accumulation of protease-resistant
prion protein (PrPres) in N2a58/22L and ScN2a cells, but this drug did not show any
defibrillogenic effects, nor did it alter prion resistance to Protease K.[31] This suggests that quinacrine is not effective in breaking down preformed PrPres
aggregates, and, consequently, its effects on the course of the disease are limited,
since these neuronal-damaging aggregates are very slowly degraded in the brain. Quinacrine
has also been observed to reduce microglia-mediated cell death in ScN2a cells, possibly
due to an inhibition of PrPres formation and consequent reversal of cell membrane
changes that are recognized by mycroglia.[28]
[31] However, in mouse studies it has been shown that quinacrine has a balancing role,
so that the drug interferes with PrPres synthesis and catabolism at different levels
depending on the cell type, proving it is not an efficient treatment.[31]
Flupirtine is a triaminopyridine derivative that acts as a non-opioid analgesic. It
is a well-tolerated drug that acts on the CNS, and has demonstrated a high cytoprotective
effect in vitro and in vivo on neurons induced to apoptosis.[14]
[32]
[33] The antiapoptotic effect has a potential for good results in patients with dementia,
although more studies are needed. Its pharmacodynamic effects are mainly attributed
to its function of selectively opening neuronal potassium channels and its NMDA antagonist
property.[34] It has also been hypothesized that patients treated with flupirtine have a neuroprotective
effect, due to positive regulation of the bcl 2 proto-oncogene, in addition to normalization
of glutathione levels.[35] In vitro and in vivo tests suggest that flupirtine antagonizes neurotoxicity caused
by the abnormal prion protein (PrPSc).[14]
[29]
[35] The study conducted by Otto et al.[25] demonstrated partial beneficial effects in reducing cognitive deterioration in patients
with CJD.
Doxycycline is an antibiotic from the tetracycline group, whose effect is directly
aimed at inhibiting protein synthesis, which prevents the nutrition of bacteria. Unlike
quinacrine, evidence suggests that this drug has a defibrillogenic role and reverses
proteinase K resistance in CJD patients.[36]
[37] Tetracyclines have an amphiphilic structure, which allows strong interaction with
the lipophilic domains of PrPSc.[35]
[36] Additionally, tetracyclines interact with oligomeric structures and inhibit the
protein folding failure that is associated with PrPSc formation.[14]
[29]
[36]
[37]
[38] It was clear from the studies reviewed that the drug is able to cross the blood-brain
barrier and remain there for days, possibly due to its ability to remain bound to
prion aggregates.
Finally, PPS is a drug with anticoagulant and fibrinolytic effects.[14]
[29] Studies conducted have hypothesized that infusion of the drug could inhibit PrPSc
formation.[14]
[29]
[39] Its mechanism of action has not yet been identified, but it is suggested that PPS
competitively interferes with the binding of PrPC and PrPSc with endogenous glycosaminoglycans,
which are essential for the formation or stabilization of PrPSc.[39]
[40] However, PPS does not penetrate the blood-brain barrier when administered orally
or parenterally. To address this, Doh-ura et al.[41] administered it intraventricularly via an infusion pump device in an animal model.
This work evaluated a wide therapeutic range and demonstrated that PPS infusion decreased
not only PrPSc deposition, but also neurodegenerative and infectious changes. These
changes were observed within the cerebral hemisphere that received the intraventricular
infusion, but not in the contralateral hemisphere.[41] In contrast, human studies have been plagued by small sample sizes and many of the
expected complications for this drug.[21]
[22]
The difficulty of grouping a significant number of patients is evident in all published
studies. The study with the largest population was performed by Haïk et al., in 2014,
with 121 patients, which added strength to their findings.[23] With less robustness, the same can be said of Geschwind et al. (n = 51).[18] Another well-structured factor of the selected articles was the division of patients
into groups according to presentation, with majority use of sporadic CJD cases. Studies
such as Geschwind et al. used only sCJD patients,[18] whereas Haïk et al. used both sCJD and genetic CJD patients.[23] Additionally, articles such as Tsuboi et al. presented cases of sCJD, genetic CJD,
and iatrogenic CJD.[22] Thus, a wide distribution among the subtypes of CJD studied was observed, which
has made it possible to compare therapeutic action within a wide spectrum of the disease,
and helped to give strength to the resulting outcomes.
As a rapidly progressive dementia with high mortality, added to the presence of a
vacuum in viable treatment alternatives, a range of studies have been mounted in the
hopes of achieving minimal progression in the treatment of CJD. However, the fact
that many of the applied drugs have never reported significant reduction in prion
accumulation in vitro or shown positive development in animal models raises doubts
in the initial validity of clinical trials, as is the case, for instance, with preclinical
data from studies of doxycycline.[23]
It is important to highlight that the analyzed studies have as common characteristics
association measures anchored in p-values very close to the significance limit, a fact present in 3 of the randomized
clinical trials,[18]
[23]
[24] except for the study by Otto et al.,[25] which observed a p-value far from the significance margin. Although the analyzed randomized clinical
trials had exposed their treatment protocol's follow-up flowcharts, some deficiencies
were observed. The simplicity of the variables exposed in this flowchart, the intermediate
number of patients submitted to randomization, and unclear treatment periods,[25] borderline confidence intervals, with a mixture of observational design and unfavorable
clinical trial, and the small sample size[22] are some of the weaknesses of these studies.
Regarding the non-controlled studies, they are basically divided into non-randomized
clinical trials and case series. Case series have major limitations for analyzing
outcomes, mainly because there is no control group, and therefore they are restricted
to analyses within the limits of the sample studied, without much power of extrapolation.
The article conducted by Bone et al.,[21] besides the limitations inherent to the design itself, also used a very small number
of patients (n = 7), of which only 4 were followed throughout the study, thus compromising the reach
of the results obtained. The study by Haïk et al.,[19] although with a larger sample (n = 32), is also limited to affirm some advantage in the use of quinacrine in patients
with CJD, since it analyzes outcomes from observation, with p-values at levels below those required. The study conducted by Varges et al.,[24] despite having a slightly larger sample (n = 88) and a form of patient allocation that aimed to include only patients in the
early stage of the disease, did not randomly distribute its patients, with a large
numerical predominance in the intervention group over the control group.
These non-randomized clinical trials also presented important limitations in the sense
of extrapolation of results, since the randomization of patients avoids several biases
that can be introduced when allocating patients. The study by Collinge et al.[17] had the largest sample size of all these studies. In it, patients had the option
to choose whether or not to be treated with quinacrine from the start, or even during
the course of the study. This type of design meant that the vast majority of patients
did not opt for randomization. Moreover, the severity profile of the patients within
the study was diverse, preventing a proper conclusion of the inefficiency of the drug
by the advanced stage of the pathology in some, or by the lack of response to the
drug itself.
Given the above, this review has demonstrated that the vast majority of the papers
analyzed here lack strong methodologies and, consequently, possibilities for extrapolation
relevant to clinical practice on the management of CJD patients. To date, there are
no robust studies that provide support for pharmacological approaches with doxycycline,
PPS, or quinacrine in increasing survival of CJD patients. However, one clinical trial
has suggested success of flupirtine in partially reducing cognitive deterioration
in this population, when compared with the control group. Therefore, this review supports
the need for further studies to evaluate the efficacy of different pharmacological
options used in patients with CJD, to establish more solid treatment alternatives
for these patients in the future.
