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)
• Enrollment: 231
• Location: 1
• Arms: 2
• Duration (Months): 88
• Patients Per Site Per Month: 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
Syphilis	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)

• Study Protocol and Statistical Analysis Plan - Dec 16, 2020

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: Syphilis

Study Results

Participant Flow

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.