# Presentation: 049591

## Lyme DiseaseGuidance to Industry on Antimicrobial Drug Development

- Janice Soreth, M.D.

- July 1998

## Indications

- 	Lyme Disease
- Early Localized Lyme Disease
- 	(Erythema Migrans)
- Early Disseminated Lyme Disease
- With Meningitis
- Late Lyme Disease

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## Early Lyme Disease: Defintion

- 	local infection: ixodid tick inoculates *Borrelia burgdorferi* into the skin
- 	initial sign: annular, erythematous lesion (erythema migrans, EM)
- 	EM: red macule/papule expands to form large round lesion
- 	often accompanied by non-specific flu-like illness

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## Early Lyme Disease

- Diagnosis rests on clinical grounds

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## Early Lyme Disease Diagnosis

- 	serology is often negative early in infection
- 	patients treated for early Lyme disease can relapse and still be seronegative

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## Early Lyme Disease: Untreated

- 	EM fades, usually within 4 weeks
- 	Infection spreads:
- secondary EM lesions, neurologic abnormalities, lymphocytic meningitis, carditis, and/or acute arthritis
- late Lyme disease with chronic meningitis or meningoencephalitis, encephalopathy, peripheral neuropathy, migratory polyarthritis, and/or acrodermatitis

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## Staging of Lyme Disease

- Early Infection/ Stage 1:
- Localized Erythema Migrans
- Early Infection/ Stage 2:
- Disseminated Infection
- Late Infection/ Stage 3
- Persistent Infection

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## Study Considerations:Early Localized Lyme Disease (EM)

- 	Two trials recommended
-  ideally double blind, randomized, multicenter prospective study designs
- 	Placebo-controlled trials inappropriate
- 	Choice of comparator discussed with FDA

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## Early Localized Lyme Disease (EM)Inclusion Criteria

- EM: physician documented and photographed
- male and female patients of any age
- exposure to endemic area
- punch biopsy (2mm) of EM encouraged

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## Early Localized Lyme Disease (EM)Exclusion Criteria

- active arthritis
- signs/symptoms of CNS infection, meningitis, meningismus, or 7th nerve palsy
- heart block
- history of nervous system, cardiac, rheumatic, collagen vascular or immunodeficiency disease

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## Early Localized Lyme Disease (EM)Exclusion Criteria

- use of systemic antimicrobial active against* B. burgdorferi* within 10 days of enrollment
- concurrent systemic steroid therapy
- antimicrobial treatment for Lyme disease within 12 months of enrollment
- concurrent tick-borne diseases
-  (babesiosis or ehrlichiosis)

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## Assessments

- 	Pre-therapy
- 	On therapy: half-way through drug course
- 	End of therapy: 1 week
- 	Post-therapy: short- and long-term					(1, 3, and 12 months)

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## Intent to Treat Analysis

- All patients randomized who meet case definition
- Important to collect outcome information on all patients

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## Per Protocol

- 		Short-term efficacy:
- physician-diagnosed erythema migrans
- _>_ 80% medication course completed with documentation
- clinical evaluation during treatment, within 1 week post therapy, and 1 month post therapy
- no intervening courses of antimicrobials with activity against *B. burgdorferi*

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## Per Protocol

**	**Long-term efficacy:
- evaluable for short-term efficacy
- clinical assessments at 3 and 12 months after completion of therapy, with telephone contacts in between (6 and 9 months)
- no intervening courses of antimicrobials with activity against *B. burgdorferi*

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## Efficacy Evaluation: Short-term

_**Early Response**_**:**
-  Resolution of EM and any objective signs, together with >75% reduction in symptoms, by 1-week post-treatment, maintained through the 1-month post-treatment period.

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## Efficacy Evaluation: Short-term

_**Early Partial Response**_**:**
- Resolution of EM but incomplete resolution of any signs and 50% to 75% reduction in symptoms by 1-week post-treatment, with further improvement or complete resolution by the 1-month post-treatment visit.

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## Efficacy Evaluation: Short-term

_**Failure**_:
- Persistence of objective signs, or symptom reduction of < 50%, by the 1-month post-treatment visit.

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## Efficacy Evaluation: Long-term

**	****Cure**: Early response short-term with >75 % reduction in symptoms maintained through the 12-month post-therapy visit.
**	****Failure**: Early response short-term with subsequent development of objective signs or symptoms requiring re-treatment.

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## Consultant’s Corner

- Choice of comparators in registration trials for early Lyme disease
- Serologic testing in subjects vaccinated against Lyme disease

- July 1998