# Presentation: 130620

## Microbiologic Surrogate Endpoints in Clinical Trials-IDSAFDA/IDSA/ISAP WorkshopApril 15, 2004

- Sheldon L. Kaplan, MD
- Baylor College of Medicine
- Texas Children’s Hospital
- Houston, TX

## Sridhara et al http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm

## Sridhara et al http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm

## Infections For Which Microbiologic Surrogate EndpointsAre Useful for Clinical Trials

- Group A streptococcus pharyngitis
- Uncomplicated lower urinary tract infection
- Shigella gastroenteritis

## Infections For Which Microbiologic Surrogate EndpointsAre Useful for Clinical Trials

- Group A Streptococcus Pharyngitis
-     -symptoms will resolve regardless of therapy; time to resolution can be compared
-     -suppurative and non-suppurative complications occur too infrequently to use as endpoints

## Infections For Which Microbiologic Surrogate EndpointsAre Not Useful or Unproven for Clinical Trials

- Skin and skin structure infections
- Pneumonia
- Acute hematogenous osteomyelitis or septic arthritis
- Intra-abdominal infections
- Viral meningitis or encephalitis

## Infections For Which Microbiologic Surrogate EndpointsAre Not Useful or Unproven for Clinical Trials

- Sites of infection are difficult to resample in order to document microbiologic eradication
- Lack of eradication of the organism may not equal clinical failure-VAP and tracheal aspirates
- Eradication of organism may not equal substantial clinical benefit-URI and pleconaril

## Infections For Which Microbiologic Surrogate EndpointsMay be Useful for Clinical Trials

- Bacterial meningitis
- Acute otitis media and sinusitis
- VP shunt infections
- Coagulase-negative staphylococcus line-associated bacteremia
- Pertussis

## Antimicrobial Drug Development for Acute Bacterial Meningitis Joint FDA/IDSA/PhRMA Workshop 

- Imo Ibia, MD, MPH
- Medical Officer
- FDA/CDER/DSPIDP
- November 20, 2002

**Office of New Drugs IV**
**Center for Drug Evaluation and Research**** **

-    www.fda.gov

## Outcomes

- Are there data to show bacteriologic outcome is a good surrogate for clinical outcome?
- Would bacterial endpoint alone miss the potential differential effect of drugs on inflammatory response?
- How should clinical success/failure be defined and what should constitute the primary efficacy population?
- ITT or evaluable?
- How best can preclinical and early phase clinical trial data be used in meningitis trials to help address some of these issues?

-        Imo Ibia 2002 FDA/IDSA/PhRMA Workshop 2002

## Evaluations

- Timing of repeat lumbar puncture
- Is there data to establish the best time?
- What factors could impact that time and how should they be factored in?
- organism, baseline quantity, drug, host factors
- How many organisms in repeat LP constitute delayed sterilization and what is its utility in trials?
- Few and patient improving, optional (IDSA 1992)
- Quantification of baseline CSF pathogens
- How feasible and consistent across multinational sites?

- Imo Ibia 2002 FDA/IDSA/PhRMA Workshop 2002

## Outcome of Bacterial meningitis

- IDSA Guidelines 1992:  Endpoints of
-       -cure
-       -survival with mild neurologic sequelae
-       -survival with severe neurologic sequelae (somewhat
-       dependent on the observer and some sequelae
-       improve with time)
-       -death
- Mortality is low in US
- Audiology testing is an objective and quantifiable measure
- As with other sequelae, hearing loss may improve over time

## Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

- Prospective, randomized multicenter study
- Ceftriaxone (n=53) or cefuroxime (n=53)
- Repeat CSF culture at 18-36 hours
- No significant differences in clinical characteristics between the groups at enrollment
-           Schaad et al N Engl J Med 1990;332:141-7

## Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

| Variable | Ceftriaxone | Cefuroxime | P value |
| --- | --- | --- | --- |
| + CSF culture at f/up (all Hib) | 1/52 | 6/52 | 0.112 |
| Hearing loss | 2 (4%) | 9 (17%) | 0.052 |

- Schaad et al N Engl J Med 1990;332:141-7

## Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

- Hearing loss for *H. influenzae* type b
-    Ceftriaxone-2/27 (7%); Cefuroxime-6/35 (17%)
- 2 of 6 children who had hearing loss after cefuroxime therapy for Hib had delayed sterilization of the CSF i.e. 4 did not have delayed sterilization of CSF

- Schaad et al N Engl J Med 1990;332:141-7

## Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

- Hearing loss for *S. pneumoniae*
* *Ceftriaxone-0/7; Cefuroxime-2/6
- None with hearing loss due to *S. pneumoniae* had delayed CSF sterilization

- Schaad et al N Engl J Med 1990;332:141-7

## Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

| Hearing | Repeat CSF sterile | Repeat CSF positive | Total |
| --- | --- | --- | --- |
|  Normal | 90 | 5 | 95 |
| Impaired | 9 | 2 | 11 |
| Total | 99 | 7 | 106 |

-              Sensitivity-90/99=91%     Specificity-2/7=29%

## Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

- Four prospective studies conducted in Dallas-last 3 were dexamethasone trials.  None of the studies were direct comparisons
- Ceftriaxone-174; Cefuroxime-159
- No significant differences between the groups  at initiation of therapy

-     Lebel et al J Pediatr 1989;114:1049-54

## Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

| Variable | Ceftriaxone | Cefuroxime | P value |
| --- | --- | --- | --- |
| + CSF culture at f/up | “Uniformly sterile” | 14/157
(8.9%) | < 0.001 |
| Hearing loss | 16/148
(11%) | 25/139
 (18%) | NS |

- Lebel et al J Pediatr 1989;114:1049-54

## Meropenem vs Cefotaxime for Bacterial Meningitis in Children

| End of Treatment
Evaluable | Meropenem
N=79 | Cefotaxime
N=75 |
| --- | --- | --- |
| Cure  | 36 (46%) | 42 (58%) |
| Mild sequelae | 21 | 20 |
| Severe sequelae | 20 | 10 |
| 2nd CSF sterile | 75 (95%) | 72 (96%) |
| 2nd CSF delayed sterilization | 2
Hib | 1
Hib |
|        Odio et al Pediatr Infect Dis J 1999;18:581-90 |  |  |

## Trovafloxacin vs Ceftriaxone for Bacterial Meningitis in Children

| End of Treatment
Evaluable | Trovafloxacin
N=108 | Ceftriaxone
N=95 |
| --- | --- | --- |
| Cure  | 53 (49%) | 57 (60%) |
| Mild sequelae | 28 | 21 |
| Severe sequelae | 20 | 13 |
| Failure | 5 | 1 |
| 2nd CSF delayed sterilization | 5
 | 3
 |
|    Sáez-Llorens et al Pediatr Infect Dis J 2002;21:14-22 |  |  |

## Conclusions

- Not clear how well repeat CSF culture at 24-36 hours after initiation of treatment  predicts hearing impairment or
-    overall outcome (vast majority of patients with severe sequelae have sterile 2nd CSF)
- ●   Not clear if findings for Hib meningitis are applicable to pneumococcal or meningococcal meningitis