irmwg tc 12-7-06 - aids foundation of chicago€¦ · irmwg tc rectal safety update 7th december...

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?