Syphilis
Conditions
Brief summary
Treponema pallidum, the bacterium that causes syphilis, invades the central nervous system in about 40% of patients with syphilis. This happens early after infection. Patients with neuroinvasion are at risk of developing serious neurological complications, including vision or hearing loss, stroke and dementia. Because neuroinvasion can happen without symptoms, the only way to identify it is by performing a lumbar puncture (LP) to examine cerebrospinal fluid (CSF).The overall hypothesis to be tested in this study is that a strategy of immediate LP, followed by therapy based on CSF evaluation, results in better serological and functional outcomes in patients with syphilis who are at high risk for neuroinvasion.
Interventions
PROCEDURELumbar puncture
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females age 18 years or older 2. Current syphilis 3. Primary language is English or English is a second language but patient self-describes as fluent in English 4. Able to provide informed consent 5. If treated with benzathine penicillin G (BPG), it must have occurred less than 14 days before the entry visit (before the first visit if there is more than one entry visit)
Exclusion criteria
1. Provider plans neurosyphilis (NS) treatment regardless of whether the patient has an lumbar puncture (LP) 2. Receipt of antibiotic treatment that would be effective for NS (for example, IV or intramuscular (IM) beta-lactam antibiotics \[other than BPG\]) within one month before study entry; single dose of IM ceftriaxone in the last month is not exclusionary 3. Allergy to penicillin or lidocaine 4. Contraindication to LP, including untreatable coagulation disorder, use of anticoagulants that cannot be temporarily discontinued, thrombocytopenia, focal neurological examination 5. Other known cause of central nervous system (CNS) infection in the last year, including that due to bacterial, fungal, protozoal or viral agents, such as tuberculosis, Cryptococcus, toxoplasmosis or herpes zoster that could confound interpretation of CSF results 6. Unlikely to be able to comply with study requirements or complete the study, for example, planning to leave the area \< 6 months after enrollment 7. Subjects will not be allowed to re-enroll in this study with a new episode of syphilis Individuals who are unwilling to be randomized can choose LP or no LP. Eligibility criteria for these individuals are: 1. 18 years of age or older 2. Current syphilis infection 3. Primary language is English or fluent in English 4. No contraindications to LP 5. Have not received antibiotics within one month that would treat neurosyphilis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Appropriate Decline in Serum Rapid Plasma Reagin Test (RPR) Titer | 6-12 months +/- 4 weeks | Decline in serum RPR titer by four-fold or to nonreactive at 6 months (+/- 4 weeks) in early syphilis or at 12 months (+/- 4 weeks) in late syphilis. This is the definition of treatment success according to the US Centers for Disease Control and Prevention guidelines. |
| Time to Improvement in Performance on CogState Battery. | 6-12 months +/- 4 weeks | Assessment of cognitive impairment was based on age adjusted normative data from CogState and was categorized as none (all test scores \> -1 standard deviation \[SD\] of normative data), mild impairment (two test scores \< -1 SD, or one test score \< -2 SD), moderate impairment (two test scores \< -2 SD) or severe impairment (three test scores \< -2 SD). Participants were categorized as improved if they had any impairment at study entry and improved by at least one category. |
Countries
United States
Participant flow
Pre-assignment details
The protocol section asks how many participants were enrolled. 219 unique participants were enrolled, but 12 had two enrollments. Thus there are 231 enrollment visits.
Participants by arm
| Arm | Count |
|---|---|
| Lumbar Puncture Group Underwent lumbar puncture | 62 |
| No Lumbar Puncture Group Did not undergo lumbar puncture | 34 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Did not meet criteria for inclusion in data analysis | 0 | 0 | 0 | 100 | 26 | 4 | 5 |
Baseline characteristics
| Characteristic | Lumbar Puncture Group | No Lumbar Puncture Group | Total |
|---|---|---|---|
| Age, Continuous | 36 years | 34 years | 35 years |
| Impaired on CogState Battery | 42 participants | 20 participants | 62 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 9 Participants | 1 Participants | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 45 Participants | 26 Participants | 71 Participants |
| Serum Rapid Plasma Reagin test (RPR) titer | 128 titer | 128 titer | 128 titer |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 61 Participants | 34 Participants | 95 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 62 | 0 / 34 |
| other Total, other adverse events | 0 / 62 | 0 / 34 |
| serious Total, serious adverse events | 0 / 62 | 0 / 34 |
Outcome results
Primary
Appropriate Decline in Serum Rapid Plasma Reagin Test (RPR) Titer
Decline in serum RPR titer by four-fold or to nonreactive at 6 months (+/- 4 weeks) in early syphilis or at 12 months (+/- 4 weeks) in late syphilis. This is the definition of treatment success according to the US Centers for Disease Control and Prevention guidelines.
Time frame: 6-12 months +/- 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lumbar Puncture (LP), Treatment Based on Cerebrospinal Fluid (CSF ) Results | Appropriate Decline in Serum Rapid Plasma Reagin Test (RPR) Titer | 38 Participants |
| No Lumbar Puncture Group | Appropriate Decline in Serum Rapid Plasma Reagin Test (RPR) Titer | 30 Participants |
p-value: 0.29Two sample test of proportion in Stata
Primary
Time to Improvement in Performance on CogState Battery.
Assessment of cognitive impairment was based on age adjusted normative data from CogState and was categorized as none (all test scores \> -1 standard deviation \[SD\] of normative data), mild impairment (two test scores \< -1 SD, or one test score \< -2 SD), moderate impairment (two test scores \< -2 SD) or severe impairment (three test scores \< -2 SD). Participants were categorized as improved if they had any impairment at study entry and improved by at least one category.
Time frame: 6-12 months +/- 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lumbar Puncture (LP), Treatment Based on Cerebrospinal Fluid (CSF ) Results | Time to Improvement in Performance on CogState Battery. | 11.3 months |
| No Lumbar Puncture Group | Time to Improvement in Performance on CogState Battery. | 12.2 months |
p-value: 0.69Log Rank
Post Hoc
Time to Decline in Performance on the CogState Battery
Participants were categorized as declined if they were not severely impaired at entry and declined by at least one category. The impairment categories are: none (all test scores \> -1 standard deviation \[SD\] of normative data), mild impairment (two test scores \< -1 SD, or one test score \< -2 SD), moderate impairment (two test scores \< -2 SD) or severe impairment (three test scores \< -2 SD).
Time frame: 6-12 months +/- 4 weeks
Population: Time to decline in performance on the CogState battery by log rank test.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lumbar Puncture (LP), Treatment Based on Cerebrospinal Fluid (CSF ) Results | Time to Decline in Performance on the CogState Battery | NA months |
| No Lumbar Puncture Group | Time to Decline in Performance on the CogState Battery | 12.3 months |
p-value: 0.04Log Rank