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Would Parents Consent to a Comparative Effectiveness Trial of Oral Doxycycline Versus Intravenous Ceftriaxone for the Treatment of Children with Lyme Meningitis?

Garro, Aris MD, MPH*; Koster, Michael MD*; LaRue, Molly BA; Hipolito, Evelyn BA; Congdon, Elizabeth BA; Burnett, Kathleen; Cullen, Nicole BS; Nigrovic, Lise E. MD, MPH§

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The Pediatric Infectious Disease Journal: May 2018 - Volume 37 - Issue 5 - p e140-e142
doi: 10.1097/INF.0000000000001793
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Abstract

In North America, Lyme disease is a tick-borne infection with a peak incidence in children 5–14 years old.1 Lyme meningitis affects approximately 1% of children with Lyme disease.2 Current treatment guidelines recommend intravenous (IV) ceftriaxone as first-line therapy for Lyme meningitis. However, almost one third of children will have complications associated with either the peripherally inserted central catheter (PICC) often used for prolonged IV therapy or reactions to ceftriaxone.3

Available evidence suggests that oral doxycycline may be equally effective to IV ceftriaxone for the treatment of Lyme meningitis,4–8 but a rigorous comparative effectiveness trial of oral doxycycline versus IV ceftriaxone for the treatment of children with Lyme meningitis is needed. Designing such a trial requires careful consideration of methodologic challenges, including parents’ willingness to consent to their child’s participation. Our primary goal in this study was to present a hypothetical treatment trial of oral doxycycline versus IV ceftriaxone to parents and to determine the proportion that would consent to their child’s participation in a trial. Our secondary goal was to determine whether a noninferiority trial design would be acceptable to parents.

MATERIALS AND METHODS

Study Design/Setting

We surveyed parents presenting to a single tertiary care emergency department located in a Lyme disease endemic region between November 2016 and January 2017. The Institutional Review Board deemed the study protocol exempt from review.

Participants

On days with available research staff, we approached consecutive parents of children who were not undergoing evaluation for potential Lyme disease. We selected parents of children who were not undergoing evaluation for potential Lyme disease during the current encounter to avoid potential conflicts with clinical treatment decisions. We limited our sample to parents of children 8 to 17 years of age as doxycycline is approved for use in children 8 years of age and older. We excluded parents if English was not their primary language.

Survey Instrument

The participants first completed a presurvey to collect demographic data, as well as to assess their knowledge of Lyme disease and its treatment. Parents were then shown a 9-minute video created for this study (Supplemental Digital Content 1, http://links.lww.com/INF/C854). The video transcript was at an 11th-grade reading level using the Flesch–Kincaid readability scale.9 The video is narrated by a pediatrician (M.K.) with board certification in Pediatric Infectious Disease and addresses the following concepts:

  1. Lyme disease—cause and manifestations
  2. Lyme meningitis—pathophysiology and symptoms
  3. Current recommendations for IV treatment of Lyme meningitis
  4. Clinical equipoise of oral doxycycline versus IV ceftriaxone
  5. Purpose of a comparative effectiveness trial
  6. Informed consent process for proposed trial
  7. Meaning of randomization
  8. Details of 2 trial treatment arms (including potential adverse events)
  9. PICC insertion and use

Outcome Measures

After watching the study video, the participants completed a postsurvey (Supplemental Digital Content 2, http://links.lww.com/INF/C855). The primary outcome was the proportion of parents who would consent to study participation. Secondary outcomes included parent beliefs about treatment efficacy and safety and parent preferences for a treatment arm. Another secondary outcome was the number of additional days of symptoms that would be acceptable to parents if their child was treated with oral doxycycline, after parents were given the hypothetical statement that IV ceftriaxone is more effective.

Data Analysis

Data analysis was performed using Stata version 12 (StataCorp LLC, College Station, TX). We used standard descriptive statistics to summarize demographic data and survey responses. We investigated the relationship between which treatment they believed “worked best” and “was safer” and the “preferred” treatment regimen using Pearson’s correlation coefficient.

RESULTS

We approached 222 parents, 17 of whom were excluded (15 did not have sufficient English fluency and 2 had a child being tested for Lyme disease). Overall, 102 parents agreed to participation (response rate 50%). Respondents were 67% white, 19% Latino, 13% black and 1% other. The majority (68%) had graduated from a 2- or 4-year college, while 25% graduated from high school and 7% had not graduated from high school. When asked about baseline Lyme disease knowledge, 66% of respondents reported “some” or “a lot” of knowledge about the disease and 45% reported “some” or “a lot” of knowledge about the treatment.

After viewing the video, 84 parents (82%; 95% confidence interval: 74%–89%) reported they would consent for their child to participate in the proposed Lyme meningitis treatment trial. There were no differences in the likelihood of consent based on child’s age, parent’s ethnicity, parent’s education or parent’s previous knowledge about Lyme disease or treatment. There were also no differences in the likelihood of consent and parents’ perception of which treatment regimen “worked best”, “was safer” or was preferred.

After reviewing the educational video, fewer parents felt that oral doxycycline “worked best” when compared with IV ceftriaxone (14% vs. 31%; 55% responded they were equal). More parents felt that oral doxycycline “was safer” than IV ceftriaxone (41% vs. 17%; 42% equal). Overall, parents preferred oral doxycycline to IV ceftriaxone (47% vs. 29%; 24% equal). Perceived efficacy and treatment preference were weakly correlated (r = 0.29, P = 0.012), and perceived safety and treatment preference were moderately correlated (r = 0.47, P < 0.0001).

Parents were then asked about the trade-off between oral and IV medicine in terms of the number of additional days of symptoms that would be acceptable. Forty percent of parents would always prefer IV medication and 20% would always prefer oral medication. Of the 41 remaining parents, 44% responded that one additional day of symptoms was acceptable, 37% chose 2 days, 12% chose 3 days and 7% chose 1 week (Figure 1).

FIGURE 1.
FIGURE 1.:
Participant responses about the number of additional days of symptoms that would be acceptable if oral doxycycline could be used instead of IV ceftriaxone. Before answering this question, participants were told to assume that IV antibiotics were known to be better than antibiotics by mouth for Lyme meningitis. They were then asked, “How many days more of symptoms like headache, stiff neck and fatigue would you think is OK if you could use antibiotics by mouth instead of through the IV?”. In this context, 40% of parents responded they would always prefer IV medication, and 20% said they would always prefer oral medication. Of the remaining respondents, 44% responded that one additional day of symptoms was acceptable, 37% chose 2 days, 12% chose 3 days and 7% would accept up to 1 week.

DISCUSSION

More than 80% of parents would consent to a child participating in a comparative effectiveness trial of oral doxycycline versus IV ceftriaxone for Lyme meningitis. Our results suggest that a comparative effectiveness trial would be both feasible and generalizable.

Although most parents reported treatment preferences for either oral doxycycline or IV ceftriaxone after watching the brief educational video, the presence of a treatment preference did not correlate with parents’ willingness to participate in the study. More parents believed IV ceftriaxone is more effective and that oral doxycycline is safer. Treatment arm preferences were more strongly correlated with beliefs about treatment safety. The parental response to our survey supports the use of a noninferiority trial design.

Our survey also explored the appropriate size of the noninferiority margin. We asked parents to consider a scenario in which IV ceftriaxone was known to “work better” than oral doxycycline for the treatment of Lyme meningitis symptoms. When considering the number of additional days of symptoms that would be acceptable, most parents choose 1 or 2 days. Therefore, the most acceptable inferiority margin for daily symptom measures would be no greater than 2 days in a treatment trial.

While there are several Lyme meningitis treatment options available to clinicians, the most commonly used is IV ceftriaxone administered via a PICC. Parenteral antibiotics can be administered via alternative means (eg, peripheral IV), but this is less common, especially when therapy is delivered at home. Other β-lactam antibiotics are also effective treatment for Lyme meningitis but require more frequent dosing than ceftriaxone.10 Therefore, we chose to compare the most common parental to oral treatment regimens. The results of this study are not applicable to other antibiotic options for Lyme meningitis.

Our study had several additional limitations. First, we only approached parents when research staff was available and only half of those approached agreed to participate. Although these factors could affect generalizability, we did not identify systematic differences between respondents and nonrespondents. Second, the hypothetical nature of this study may overestimate the proportion of parents who would consent in an actual trial. Finally, we did not ask whether children would be willing to provide assent for trial participation, which could affect enrollment rates, considering that the clinical trial would include older children and adolescents. We believe that children would be likely to assent to a trial with a 50% chance of using oral rather than IV medication, when the alternative is 100% chance of IV medication at most institutions.

CONCLUSION

Most parents of children evaluated in the emergency department would consent to a hypothetical treatment trial of oral doxycycline versus IV ceftriaxone if their child had Lyme meningitis. Our study supports a future clinical trial comparing these 2 antibiotic regimens with a noninferiority study design, with a maximum inferiority margin of 2 additional days for resolution of symptoms.

REFERENCES

1. Centers for Disease Control and Prevention. Confirmed Lyme disease cases by age and sex—United States, 2001–2010. 2015. Available at: http://www.cdc.gov/lyme/stats/graphs.html. Accessed June 10, 2016.
2. Christen HJ, Hanefeld F, Eiffert H, et al. Epidemiology and clinical manifestations of Lyme borreliosis in childhood. A prospective multicentre study with special regard to neuroborreliosis. Acta Paediatr Suppl. 1993;386:175.
3. Thompson AD, Cohn KA, Shah SS, et al. Treatment complications in children with lyme meningitis. Pediatr Infect Dis J. 2012;31:10321035.
4. Dersch R, Freitag MH, Schmidt S, et al. Efficacy and safety of pharmacological treatments for acute Lyme neuroborreliosis—a systematic review. Eur J Neurol. 2015;22:12491259.
5. Halperin JJ, Shapiro ED, Logigian E, et al. Practice Parameter : Treatment of nervous system Lyme disease (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2007;69:91102.
6. Karlsson M, Hammers S, Nilsson-Ehle I, et al. Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis. Antimicrob Agents Chemother. 1996;40:11041107.
7. Borg R, Dotevall L, Hagberg L, et al. Intravenous ceftriaxone compared with oral doxycycline for the treatment of Lyme neuroborreliosis. Scand J Infect Dis. 2005;37:449454.
8. Ljøstad U, Skogvoll E, Eikeland R, et al. Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial. Lancet Neurol. 2008;7:690695.
9. Kincaid JP, Fishburne RP, Rogers RL. Derivation of new readability formulas (automated readability index, fog count, and flesch reading ease formula) for Navy enlisted personnel. In: Research Branch Report. 1975. Millington, TN.Naval Air Station Memphis.
10. Karlsson M, Hammers-Berggren S, Lindquist L, et al. Comparison of intravenous penicillin G and oral doxycycline for treatment of Lyme neuroborreliosis. Neurology. 1994;44:12031207.
Keywords:

Lyme disease; Lyme neuroborreliosis; meningitis; comparative effectiveness research; informed consent

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