EPI-303

RIVM

Antonie van Leeuwenhoeklaan 9, Bilthoven, Netherlands, 3720 MA

Secretariat Epid. and Surveillance, National Institute of Health and the Environment (Dutch acronym: RIVM), +31 88 6892910, kees.van.den.wijngaard@rivm.nl

Secretariat Epid. and Surveillance, National Institute of Health and the Environment (Dutch acronym: RIVM), +31 88 6892910, kees.van.den.wijngaard@rivm.nl

No

No

No

Final

12 Jun 2020

Yes

09 Dec 2016

Yes

09 Dec 2016

No

To determine the efficacy of antibiotic prophylaxis after a tick bite in the Dutch setting in relation to Borrelia infection of the tick, tick engorgement and attachment time.

In the non-treatment group there is no additional health risk, as not taking prophylaxis after a tick bite is standard procedure in the current CBO guideline. In the prophylaxis group, the participants are likely to have a smaller risk of developing Lyme disease after the tick bite and a small possible risk of AEs by the prophylaxis. People who voluntarily report a recent tick bite on the web portal Tekenradar.nl will be included in the study if they meet the inclusion criteria and provide informed consent. People are randomly assigned to the prophylaxis group and this group will receive a letter by internet to inform their GP. The GP decides, in consultation with the participant, whether it is safe to prescribe prophylaxis regarding the medical history of the participant. Prophylaxis is prescribed as one dose 200mg doxycycline, following the draft CBO-guideline. If the participant has a contraindication for doxycycline, the GP may decide to prescribe a different antibiotic as prophylaxis although this is not part of the study. Doxyxycline is a bacteriostatic antibiotic belonging to the class of tetracyclines. For this study a single dose of 200 mg in tablet form of the generic product is prescribed. Any registered doxycycline from any marketing authorisation holder (MAH) is allowed. A single dose of 200 mg doxycycline is dispensed by the subjects’ local pharmacy via the GP’s prescription according to common health care practice. Any subjects in the study are advised to seek medical advice as soon as they develop possible symptoms of Lyme disease; the RIVM will facilitate additional advice and diagnostics upon request. The burden for the participants of sending in ticks and filling-in questionnaires will be minimal, as all questionnaires will be online and ticks can be sent in by mail.

01 Apr 2013

No

No

Netherlands: 2844

2844

2844

0

0

0

0

182

138

2079

443

2

prophylaxis after a tick bite (overall period)

Randomised - controlled

The study was not blinded.

Yes

doxycycline

Capsule, Suspension for oral suspension, Tablet

Oral use

A single dose of 200 mg doxycycline (or with a body weight below 50 kg a lower dose of 4 mg/kg body weight) to be taken within 72 h after tick removal, upon subscription of the participant's own GP.

No investigational medicinal product assigned in this arm

prophylaxis after a tick bite

no-treatment group

modified intention-to-treat prophylaxis group

For the modified-ITT analysis participants were excluded if they: a) reported chronic complaints attributed to Lyme borreliosis at t = 0; b) did not timely finish their questionnaire at t = 0; c) missed both of the questionnaires at t = 1 week and t = 1 month; d) missed both of the questionnaires at t = 3 and 6 months; e) reported new tick bites within 3 months after inclusion unless Lyme borreliosis developed before these new tick bites; f) at t = 0 reported medication use – other than the prescribed study prophylaxis – which might have had an effect on the development of Lyme borreliosis, such as immunosuppressants, other antibiotic prescriptions than the study prophylaxis, or erroneously prescribed study prophylaxis (i.e. other antibiotics than doxycycline, wrong dosage or taking the prophylaxis more than 72 h after removing the tick); g) at t = 0 reported medication use that possibly had an effect on the efficacy of the prophylaxis such as antacids and anti-epileptics.

Per-protocol prophylaxis group

For the per-protocol analysis, compared to the mITT population we additionally excluded all participants that reported crossover between study groups. Some of the participants in the prophylaxis group reported crossover to the no-treatment group due to erythema migrans developed within 72 h after tick removal, which called for an immediate full antibiotic treatment instead of the study prophylaxis. To balance the per-protocol study groups, we therefore excluded all participants diagnosed with Lyme borreliosis within 72 h after tick removal.

modified intention-to-treat no-treatment group

For the modified-ITT analysis participants were excluded if they: a) reported chronic complaints attributed to Lyme borreliosis at t = 0; b) did not timely finish their questionnaire at t = 0; c) missed both of the questionnaires at t = 1 week and t = 1 month; d) missed both of the questionnaires at t = 3 and 6 months; e) reported new tick bites within 3 months after inclusion unless Lyme borreliosis developed before these new tick bites; f) at t = 0 reported medication use – other than the prescribed study prophylaxis – which might have had an effect on the development of Lyme borreliosis, such as immunosuppressants, other antibiotic prescriptions than the study prophylaxis, or erroneously prescribed study prophylaxis (i.e. other antibiotics than doxycycline, wrong dosage or taking the prophylaxis more than 72 h after removing the tick); g) at t = 0 reported medication use that possibly had an effect on the efficacy of the prophylaxis such as antacids and anti-epileptics.

Per-protocol no-treatment group

For the per-protocol analysis, compared to the mITT population we additionally excluded all participants that reported crossover between study groups. Some of the participants in the prophylaxis group reported crossover to the no-treatment group due to erythema migrans developed within 72 h after tick removal, which called for an immediate full antibiotic treatment instead of the study prophylaxis. To balance the per-protocol study groups, we therefore excluded all participants diagnosed with Lyme borreliosis within 72 h after tick removal.

prophylaxis after a tick bite

no-treatment group

modified intention-to-treat prophylaxis group

For the modified-ITT analysis participants were excluded if they: a) reported chronic complaints attributed to Lyme borreliosis at t = 0; b) did not timely finish their questionnaire at t = 0; c) missed both of the questionnaires at t = 1 week and t = 1 month; d) missed both of the questionnaires at t = 3 and 6 months; e) reported new tick bites within 3 months after inclusion unless Lyme borreliosis developed before these new tick bites; f) at t = 0 reported medication use – other than the prescribed study prophylaxis – which might have had an effect on the development of Lyme borreliosis, such as immunosuppressants, other antibiotic prescriptions than the study prophylaxis, or erroneously prescribed study prophylaxis (i.e. other antibiotics than doxycycline, wrong dosage or taking the prophylaxis more than 72 h after removing the tick); g) at t = 0 reported medication use that possibly had an effect on the efficacy of the prophylaxis such as antacids and anti-epileptics.

Per-protocol prophylaxis group

For the per-protocol analysis, compared to the mITT population we additionally excluded all participants that reported crossover between study groups. Some of the participants in the prophylaxis group reported crossover to the no-treatment group due to erythema migrans developed within 72 h after tick removal, which called for an immediate full antibiotic treatment instead of the study prophylaxis. To balance the per-protocol study groups, we therefore excluded all participants diagnosed with Lyme borreliosis within 72 h after tick removal.

modified intention-to-treat no-treatment group

For the modified-ITT analysis participants were excluded if they: a) reported chronic complaints attributed to Lyme borreliosis at t = 0; b) did not timely finish their questionnaire at t = 0; c) missed both of the questionnaires at t = 1 week and t = 1 month; d) missed both of the questionnaires at t = 3 and 6 months; e) reported new tick bites within 3 months after inclusion unless Lyme borreliosis developed before these new tick bites; f) at t = 0 reported medication use – other than the prescribed study prophylaxis – which might have had an effect on the development of Lyme borreliosis, such as immunosuppressants, other antibiotic prescriptions than the study prophylaxis, or erroneously prescribed study prophylaxis (i.e. other antibiotics than doxycycline, wrong dosage or taking the prophylaxis more than 72 h after removing the tick); g) at t = 0 reported medication use that possibly had an effect on the efficacy of the prophylaxis such as antacids and anti-epileptics.

Per-protocol no-treatment group

For the per-protocol analysis, compared to the mITT population we additionally excluded all participants that reported crossover between study groups. Some of the participants in the prophylaxis group reported crossover to the no-treatment group due to erythema migrans developed within 72 h after tick removal, which called for an immediate full antibiotic treatment instead of the study prophylaxis. To balance the per-protocol study groups, we therefore excluded all participants diagnosed with Lyme borreliosis within 72 h after tick removal.

Our primary outcome measure was development of Lyme borreliosis within 6 months after inclusion, in line with the clinical case definitions for Lyme borreliosis described by Stanek et al. 2011.

Primary

Within 6 months after inclusion

For both the modified-intention-to-treat and per-protocol analysis, we used the Newcombe-Wilson method to estimate the absolute risk in both groups, relative risk, relative risk reduction and number-needed-to-treat to prevent one case of Lyme borreliosis.

modified intention-to-treat prophylaxis group v modified intention-to-treat no-treatment group

1689

Pre-specified

3.1

2-sided

For both the modified-intention-to-treat and per-protocol analysis, we used the Newcombe-Wilson method to estimate the absolute risk in both groups, relative risk, relative risk reduction and number-needed-to-treat to prevent one case of Lyme borreliosis.

Per-protocol prophylaxis group v Per-protocol no-treatment group

1424

Pre-specified

4.3

2-sided

The IMP being a registered product and given as a single dose, we limited the period of AE collection to one month after exposure, because no related AEs are reasonably expected after that time period.

There were no SAEs and SUSARs.

26.0

Prophylaxis group