Lumbar Puncture and Syphilis Outcome

Sponsor
University of Washington (Other)
Overall Status
Completed
CT.gov ID
NCT02031146
Collaborator
National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
231
1
2
88
2.6

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Procedure: Lumbar puncture
N/A

Study Design

Study Type:
Interventional
Actual Enrollment :
231 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
Lumbar Puncture and Syphilis Outcome
Study Start Date :
Aug 1, 2013
Actual Primary Completion Date :
Dec 1, 2020
Actual Study Completion Date :
Dec 1, 2020

Arms and Interventions

Arm Intervention/Treatment
Other: LP

Participants undergo lumbar puncture for CSF evaluation

Procedure: Lumbar puncture

No Intervention: No LP

Participants do not undergo lumbar puncture and CSF is not examined.

Outcome Measures

Primary Outcome Measures

  1. 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.

  2. 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts 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

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Washington Harborview Medical Center Seattle Washington United States 98104

Sponsors and Collaborators

  • University of Washington
  • National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

  • Principal Investigator: Christina M Marra, MD, University of Washington

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Christina Marra, Professor, Neurology, University of Washington
ClinicalTrials.gov Identifier:
NCT02031146
Other Study ID Numbers:
  • STUDY00001718
  • R01NS082120
First Posted:
Jan 9, 2014
Last Update Posted:
May 25, 2021
Last Verified:
May 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail 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.
Arm/Group Title Randomized, Lumbar Puncture (LP) Reenrolled, Randomized, LP Randomized, no LP Not Randomized, LP Not Randomized, no LP Reenrolled, Not Randomized, no LP Reenrolled, Not Randomized, LP
Arm/Group Description Randomized to lumbar puncture (LP) arm Randomised after a second enrollment, underwent LP Randomized and did not undergo LP. Includes one person for whom LP was unsuccessful. Not randomized and underwent LP. Not randomized and did not undergo LP. Not randomized during another episode of syphilis. Did not undergo LP. Not randomized with a new episode of syphilis, underwent LP
Period Title: Overall Study
STARTED 11 3 18 148 42 4 5
Considered in Analysis 11 3 18 48 16 0 0
COMPLETED 11 3 18 48 16 0 0
NOT COMPLETED 0 0 0 100 26 4 5

Baseline Characteristics

Arm/Group Title Lumbar Puncture Group No Lumbar Puncture Group Total
Arm/Group Description Underwent lumbar puncture Did not undergo lumbar puncture Total of all reporting groups
Overall Participants 62 34 96
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]
36
34
35
Sex: Female, Male (Count of Participants)
Female
1
1.6%
0
0%
1
1%
Male
61
98.4%
34
100%
95
99%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
1
1.6%
1
2.9%
2
2.1%
Native Hawaiian or Other Pacific Islander
1
1.6%
2
5.9%
3
3.1%
Black or African American
6
9.7%
4
11.8%
10
10.4%
White
45
72.6%
26
76.5%
71
74%
More than one race
9
14.5%
1
2.9%
10
10.4%
Unknown or Not Reported
0
0%
0
0%
0
0%
Serum Rapid Plasma Reagin test (RPR) titer (titer) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [titer]
128
128
128
Impaired on CogState Battery (participants) [Number]
Number [participants]
42
67.7%
20
58.8%
62
64.6%

Outcome Measures

1. Primary Outcome
Title Appropriate Decline in Serum Rapid Plasma Reagin Test (RPR) Titer
Description 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

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Lumbar Puncture (LP), Treatment Based on Cerebrospinal Fluid (CSF ) Results No Lumbar Puncture Group
Arm/Group Description Underwent lumbar puncture and treatment based on the results of cerebrospinal fluid findings. Specifically, those with abnormal CSF were treated for neurosyphilis and those without CSF abnormalities were treated for uncomplicated syphilis. The number of participants with late syphilis was too small to allow for separate analysis of early and late stages. Did not undergo lumbar puncture. All were treated for uncomplicated syphilis. The number of participants with late syphilis was too small to allow for separate analysis of early and late stages.
Measure Participants 42 31
Count of Participants [Participants]
38
61.3%
30
88.2%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lumbar Puncture (LP), Treatment Based on Cerebrospinal Fluid (CSF ) Results, No Lumbar Puncture Group
Comments
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.29
Comments
Method Two sample test of proportion in Stata
Comments
2. Primary Outcome
Title Time to Improvement in Performance on CogState Battery.
Description 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

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Lumbar Puncture (LP), Treatment Based on Cerebrospinal Fluid (CSF ) Results No Lumbar Puncture Group
Arm/Group Description Underwent lumbar puncture and treatment based on the results of cerebrospinal fluid findings. Specifically, those with abnormal CSF were treated for neurosyphilis and those without CSF abnormalities were treated for uncomplicated syphilis. Did not undergo lumbar puncture. All were treated for uncomplicated syphilis.
Measure Participants 34 20
Median (95% Confidence Interval) [months]
11.3
12.2
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lumbar Puncture (LP), Treatment Based on Cerebrospinal Fluid (CSF ) Results, No Lumbar Puncture Group
Comments
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.69
Comments
Method Log Rank
Comments
3. Post-Hoc Outcome
Title Time to Decline in Performance on the CogState Battery
Description 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

Outcome Measure Data

Analysis Population Description
Time to decline in performance on the CogState battery by log rank test.
Arm/Group Title Underwent Lumbar Puncture (LP), Abnormal Cerebrospinal Fluid (CSF), Treated for Neurosyphilis (NS) No LP or Normal CSF and Not Treated for Neurosyphilis
Arm/Group Description Cerebrospinal fluid (CSF) white cells above 5/ul, supporting the diagnosis of neurosyphilis, and treated for neurosyphilis with antibiotics. Combination of participants who didn't undergo LP and those who did but had CSF white cells less than or equal to 5/ul and nonreactive cerebrospinal fluid Venereal Disease Research Laboratory (CSF-VDRL) test, and weren't treated for neurosyphilis. In other words, those who didn't undergo LP and those who did have an LP but didn't meet diagnostic criteria for neurosyphilis.
Measure Participants 20 55
Median (95% Confidence Interval) [months]
NA
12.3
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lumbar Puncture (LP), Treatment Based on Cerebrospinal Fluid (CSF ) Results, No Lumbar Puncture Group
Comments
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.04
Comments
Method Log Rank
Comments

Adverse Events

Time Frame One year
Adverse Event Reporting Description No difference
Arm/Group Title Underwent Lumbar Puncture Did Not Undergo Lumbar Puncture
Arm/Group Description Participants who underwent lumbar puncture. Participants who did not undergo lumbar puncture.
All Cause Mortality
Underwent Lumbar Puncture Did Not Undergo Lumbar Puncture
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/62 (0%) 0/34 (0%)
Serious Adverse Events
Underwent Lumbar Puncture Did Not Undergo Lumbar Puncture
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/62 (0%) 0/34 (0%)
Other (Not Including Serious) Adverse Events
Underwent Lumbar Puncture Did Not Undergo Lumbar Puncture
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/62 (0%) 0/34 (0%)

Limitations/Caveats

Inclusion of a non-randomized group introduces risk of bias; however, the groups were comparable with regard to neurosyphilis risk factors.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Christina Marra, MD
Organization University of Washington
Phone 206-744-3251
Email cmarra@uw.edu
Responsible Party:
Christina Marra, Professor, Neurology, University of Washington
ClinicalTrials.gov Identifier:
NCT02031146
Other Study ID Numbers:
  • STUDY00001718
  • R01NS082120
First Posted:
Jan 9, 2014
Last Update Posted:
May 25, 2021
Last Verified:
May 1, 2021