irmwg tc 12-7-06 - aids foundation of chicago€¦ · irmwg tc rectal safety update 7th december...
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IRMWG TCRectal Safety Update7th December 2006
Ian McGowan MD PhD FRCP
Center for Prevention Research
David Geffen School of Medicine at UCLA
Los Angeles, California
Recent Microbicide Meetings
�HPTN Microbicide Safety Meeting,
March 2006
�DAIDS Toxicity Table Meeting,
Washington DC, November 2006
Background
� Increasing awareness of RAI in general
population
� Several microbicide candidates in late stage
development
� Post licensure vaginal microbicides will be
used rectally
� Extensive non-human primate rectal safety
data
� More limited non-human primate efficacy data
– Cyanovirin-N and PMPA
Human Rectal Phase 1 Studies
UK MRC MDP
STI CTG
� UCLA/UPMC
DAIDS
� UCLA U-19 (V)
� UCLA U-19 (R)
University of Washington
Site
Under designPro-2000
Approved for protocol development
VivaGel™
Q4 2006
Q1 2008
UC-781
CompletedNonoxynol-9
StatusStudy
HPTN Microbicide Safety Meeting, March 2006
HPTN Microbicide Safety Meeting, March 2006
� Lecture sessions
�Break-Out Sessions
– Preclinical safety
– Phase 1/2 vaginal microbicide safety
– Phase 2B/3 vaginal microbicide safety
– Community issues
– Viral resistance
– Rectal safety
The Delegates
� HIV Networks– HPTN
– MTN
– SCHARP
� Federal agencies– DAIDS
– DMID
– FDA
– CDC
� Regulatory– EMEA
– WHO
� Sponsors– CONRAD
– IPM
– FHI
– UK MRC MDP
� Pharmaceutical Industry
– GSK
– Indevus
� Community
� Academic centers & investigators
Key Findings from the Rectal Group
� No current FDA guidelines for rectal microbicide (RM) development
� RMs will probably need two approaches
– Vaginal products used rectally
– Rectal specific products
� Sequence of studies
– Phase 1 / sexually abstinent / HIV negative
– Phase 1 / sexually active / HIV negative
– Phase 1 / sexually active / HIV positive
Safety Measurements
� Required
– Signs & symptoms of rectal irritation
– Endoscopy
– Safety labs
– Pharmacokinetics
� Strongly encouraged
– Acceptability
– Rectal lavage
– Histology
– Assessment of immunological toxicity
– Tissue viral load and viral shedding in HIV+ participants
RM Phase 1 Trial Design
Randomization: 0.1% UC-781, 0.25% UC-781, or placebo
Visit 1 Visit 2 Visit 3 Outpatient Visit 4 Visit 5
ScreeningPhone
interviewSingle-dose
Clinical Eval
7 daily
dosesClinical EvalBaseline
<4 wk ≥≥≥≥ 1 wk ≥≥≥≥ 1 wk~ 8 days
Week 0 Week 2 Week 5 Week 6 Week 8
Flex Flex Flex
RM Phase 1 Endpoints
�Primary endpoints:– Frequency of ≥ Grade 2 adverse events
– Acceptability assessments
�Secondary endpoints:– Epithelial sloughing
– Histopathology
– Mucosal mononuclear cell phenotype (flow)
– Mucosal cytokine mRNA (tissue)
– Mucosal immunoglobulins
– Fecal calprotectin
– Explant susceptibility to HIV infection
Product Labeling Issues
� No products licensed yet
� Will first vaginal product have labeling
about rectal use?
� FDA said they could not imagine labeling a
vaginally product as rectally safe on the
basis of one Phase 1 study
DAIDS Toxicity Table Meeting
What is a Toxicity Table?
+
An Example
GradeSymptom
Life threatening
> 6 over BL
4-6 over BL
< 4 over BL
Diarrhea
(Stool frequency)
G4G3G2G1
Scope of Meeting
� Vaginal Toxicity– Colposcopy
– Pregnancy
– Masses
– Pain
– Dysplasia / Malignancy
– Bleeding issues etc.
� Penile Toxicity
� Rectal toxicity– Anal
– Rectal
– Other
The Rectal Team
� Ian McGowan
� Amy Adler
� Peter Anton
� Larry Allan
� Charlene Brown
� Ross Cranston
� Cherlynn Mathias
� David Phillips
� Sharof Tugizov
� Yvonne Cosgrove Sweeney
� Ita Yuen
Prevalence of Anorectal Symptoms
� Benign anal conditions highly prevalent in the general population
� 1.5 million anorectal preparations dispensed by prescription each year in US
� 80% of US population with anal symptoms
self-medicate
Janicke 1996, Nagle 1996, Nelson 1995
Anorectal Anatomy
Ryan et al. N Engl J Med. 2000 16;342(11):792-800.
Anorectal Diagnosis and Presentation
Pain, swelling, dischargeAbscess
Itch, painDermatophyte
Itch, painPsoriasis
Itch, pain, dischargeEczema
Itch, pain, massHemorrhoids
Itch, pain, discharge, swellingFistula
Pain, bleedingFissure
Symptom/sDiagnosis
Anorectal STD Diagnosis and Presentation
Mass, painSyphilis
Itch, massHPV
Pain, itchLGV
Pain, itch, systemic/autonomicHerpes simplex
Discharge, pain, tenesmusChlamydia
Discharge, pain, tenesmusGonorrhea
Symptom/sSTD
High-Resolution Anoscopy and Image Capture
� Rectum
� Anorectal
transition zone
� Anal canal
� Perianal area
� Lesion/s
HRA Clinical Signs/Diagnoses
Skin tagSwelling
AbscessFissure
ErythemaLeukoplakia
Condylomata lataCondyloma accuminata
BlisteringDischarge
BruisingExcoriation
Piercing/tattooUlceration
Fistula openingHemorrhoids
MolluscumBleeding
Diagnosis
Colorectal Key Issues
� AIM of toxicity tables:accurately report change from baseline and/or any findings?
� ‘Terms’ vary greatly between individuals
� Less ‘inter-reporter’ variability with sign
� Detection and reporting of symptoms vary with subject
� High prevalence of underlying IBS
� Many patients will have abnormal mucosal and
perianal signs with no symptoms
� Many patients will have not-normal (but not diseased) mucosal findings with no symptoms.
Irritable Bowel Syndrome (IBS)
� Common!
� Functional, not anatomic
� Few objective criteria but reliable history-based/symptom-based indices (Rome Criteria)
� Often present with abdominal pain, altered bowel habits, diarrhea, constipation, systemic symptoms,
urgency, fullness, bloating etc
� Often hyper-responsive to intra-rectal introductions (scope, balloon, DRE)
Goals of Rectal Toxicity Table
� Comprehensive:
– Anal
– Colorectal
– Other
– STIs
� Relevant for Phases 1-3 of RM
development
� Easy to use at site level
Anal
Colorectal
Other
Sexually Transmitted Infections
Topics Not Addressed
�Histological toxicity scales
�Emerging endpoints of uncertain
validity:
– Cytokines
– Immunological toxicity
– Fecal calprotectin
– ESR, CRP
Questions?