Transcript Document

The Evolving Design of Rectal
Microbicide Safety Studies:
a Perspective from Two Trials
Peter Anton
Center for HIV Prevention, UCLA AIDS Institute
UCLA/McGee-U Pitt/CONRAD/NIH
an NIH IP/CP for Topical Microbicides
Always more questions than answers
• New?
• definition of ‘safety’? what to compare to? What’s “normal”
• first populations to study?
• where to look: anus, rectum, rectosigmoid, colon, SI??
• what assays?
• how to interpret changes that have clinical relevance?
NIH IP/CP
Distinct ‘rectal-compartment’ issues
• fragile epithelia – single cell
• increased absorptive potential/resistance profiles
• minimal benefit of endoscopic appearance in
healthy subjects
• tube with constant cleansing flow
• untested, still developing safety indices
• suspected but not proven gender differences
• sequence of rectal fluid, tissue sampling critical to
avoid confounders
• ‘preparatory enema’ injurious itself?
• rectal-specific applicator-avoid trauma/AE
NIH IP/CP
Not clear what is “not safe” in RM
• assumption: N9-induced epithelial sloughing dangerous
• assumption: biopsy sites increase risk, alter absorption
• assumption: preparatory enemas safe
• assumption: not many heterosexuals have RAI, it’s an MSM issue
• fact: gut is continuously sloughing
• fact: lining is both exquisitely fragile and extremely resilient, reparative
• fact: physiologically inflamed (cells, cytokines, trafficking…)
• fact: rectal tissue is a rapid portal to systemic areas
• fact: in health, much injury and repair is ongoing…
So, how do we determine “not safe” without knowing what to
measure and what are normative “ranges”?
NIH IP/CP
Rectosigmoid mucosa
following mild endoscope trauma
..raises the question of how long infection remains ‘a mucosal disease’.
..raises the question of how quickly are injury and repair reflected as inflammation.
Pivotal: HPTN 056
• first effort to try to define these normative ranges…“immnuotoxicity”
• for primarily financial and some scientific reasons, limited to men
• HPTN 056 (McGowan PI) attempted to quantify these ranges in 4
groups (N = 4/group); each subject seen every 2 weeks for 6
weeks to evaluate reproducibility and stability of readouts.
Groups:
HIV- men, no hx of RAI
HIV- men, + hx RAI
HIV+ men, undetectable PVL
HIV+ men, PVL >5000 copies/ml
Indices…at 2 sites (10cm and 30 cm):
 Histology (quantitative & qualitative)
 secreted IgG and IgA
 cytokine mRNA from tissue
 MMC phenotypes
 not endoscopic appearance
McGowan et al JAIDS 2007
NIH IP/CP
What did we learn from HPTN 056?
• at least at this stage, not a huge difference in readouts
between 10cm and 30cm (to be tested)
• quantitative histology far too variable in health
• HIV+ have some (predictable) baseline differences from
HIV• HIV- with RAI no different from HIV- without RAI (? frequency)
• rectal Ig readouts have large intra-subject, intra-group
variability
• cytokines and cell phenotypes quite stable
• caveats to 056: not very sexually-active population, older, men
NIH IP/CP
1st trial: UC-781 RM
• first effort: as first RM trial, many potholes to avoid
• first effort: first interventional test of HPTN 056 indices
• preferential assays for ‘safety’? Others (calprotection, fluid
cytokines)?
• how interpret findings without “positive control”?
• IND study; great collaboration with Biosyn, now CONRAD
• Pre-PSRC very helpful in preparation for PSRC
• Critical first steps by NIAID to adapt toxicity tables for AE
reporting to enable efforts to distinguish anticipated
procedure-related findings
NIH IP/CP
A Phase I Randomized, Blinded, Placebo-Controlled
Safety and Acceptability Study
of the UC-781 Vaginal Microbicide Gel Formulation
Applied Rectally
in HIV-1 Seronegative Adults
 Sponsored by CONRAD (previously Biosyn) with NIAID’s U19 IP/CP
 Single site: UCLA
 NNRTI evaluated in 36 seronegatives (men and women)
 2 concentrations/placebo with single and 7d exposures
 UC-781 gel:
 Universal Placebo: (not excipient; same as vaginal trials)
 Acceptability
 pilot PK
Indices/Assays used in UC-781 RM safety trial
• “routine” clinical sn/sx and laboratories
• rectal swabs for STI, microflora
• rectal sponges for secreted IgG, IgA and cytokines *
• stool calprotectin *
• rectal lavage for epithelial sloughing *
• tissue at 10cm and 30cm for:
Histology (qualitative)(quantitative dropped)
Cytokine mRNA
MMC for phenotype by FACS
Explant infection studies *
• plasma pK (to 24 hours)
* Not in HPTN 056
NIH IP/CP
RM UC-781: Phase 1 Trial Design
Randomization: 0.1% UC-781, 0.25% UC-781, or placebo
flex
<4 wk
flex
 1 wk
Week 0
Visit 1
Visit 2
Screening Baseline
flex
 1 wk
Week 2
Visit 3
~ 8 days
Week 5 Week 6
Outpatient
Visit 4
Week 8
Visit 5
Phone
Single-dose 7 daily
Clinical Eval
interview
Clinical Eval doses
UCLA IRB # 02-05-001;
approved for 30 bx per visit
Multiple publications,
Near 100% adherence
No AE
‘post-biopsy’ appearance
Applicator (vaginal form) issues
• Participants will apply small
amount of lubricant to
applicator for insertion.
• Not to use OTC lubricants as
they may cause toxicity and
interact with the study
product.
• Not optimal for rectal
application, but tolerated.
Sequence of sampling important
• type and timing of enema important
• collect rectal fluid (sponges/swabs) prior
• sampling of epithelia should follow RM introduction (post
enema) and prior to scope trauma
• rapid coordination for explant experiments (9 bx gives 2
viral doses)
• while safe to bx within a few days, if assessing for
inflammation, may want longer interval…
NIH IP/CP
Findings thus far in UC-781..still blinded
• nearly completed; end study date mid 3/08
• intensive recruiting/scheduling (~80 phone
calls/emails per subject): HIGH adherence
• no significant AE or procedure problems
• lessons from blinded results that have guided next trial:
 no apparent difference between 10cm and 30cm;
therefore, only 10cm in next trial. Can anal bx
with stool and sponges suffice?
 Ig variabilty even greater in this trial that in HPTN
056..therefore, dropped as future
immunotox/safety assay in next trial
NIH IP/CP
Boxplots of IgA
UC-781 (All) U19 (Low) U19 (Med) U19 (High) HPTN056
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
(n=8,v=24)
150000
50000
0
IgA (ng/ml)
250000
350000
Boxplots comparing range of IgA at UC-781 baseline (V2) with HPTN 056
Group
NIH IP/CP
Boxplots comparing range of IgG at UC-781 baseline (V2) with HPTN 056
U19 (All)
U19 (Low) U19 (Med) U19 (High) HPTN056
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
(n=8,v=24)
40000
20000
0
IgG (ng/ml)
60000
80000
Boxplots of IgG
Group
NIH IP/CP
A two-site, Phase 1, double-blind, placebo-controlled
safety and pharmacokinetic trial of
topical, vaginally-formulated 1% tenofovir gel applied
rectally with an
exploratory pharmacokinetics study comparing
topical with oral tenofovir levels in
rectal tissue, rectal fluid, and blood.
 Sponsored by CONRAD, Gilead with NIAID’s U19 IP/CP
 Sites: UCLA & McGee/U Pitt
 Tenofovir (oral/topical) evaluated in 18 seronegatives (men and
women)
 Oral: all get 300 mg tablet (single exposure only)
 Topical: Randomized 2:1 (1% drug: Universal placebo)(single; 7-day)
 pilot PK: plasma
 exploratory pK: 5 comparments
NIH IP/CP
Indices/Assays used in UC-781 Tenofovir RM safety trial
• “routine” clinical sn/sx and laboratories
• rectal swabs for STI, microflora
• rectal sponges for secreted IgG, IgA and cytokines *
• stool calprotectin *
• rectal lavage for epithelial sloughing *
• tissue at 10cm and 30cm for:
Histology (qualitative)(quantitative dropped)
Cytokine mRNA
MMC for phenotype by FACS
Explant infection studies *
• plasma pK (to 24 hours)
* Not in HPTN 056
NIH IP/CP
Oral/Topical Tenofovir RM trial
Baseline
Week:
Visit:
0
1
Single
Topical
Oral
2
3
1
2
3
Screen
Flex
Flex
4 A/B
4
5
5 A/B
Flex 50%
Flex 50%
6
7
6
7 A/B
Flex
7-day
Topical
8
9
10
9
10
Flex 50%
Flex
8 A/B
Flex 50%
Randomization: 2:1 (drug:placebo)
Group A or Group B (50:50)
ALL get 6 flex sigs
11
Phone
call
Lessons and questions
• RM trials are fast evolving. Asset for VM trials.
• can we rationally continue to reduce (or add) assays?
• how to determine if CHANGE in assays means anything
clinically, even in those studied for stability in
HPTN 056?
• using the best we have at present, are we now erring
on the side of being too sensitive? May be tough
to actually INCREASE risk…Sx best guide?
• back to original question: given reparative capacity of
gut, WHAT is “not safe” and how to capture that?
• biopsies are safe
• explants may be biomarkers of efficacy
• other assays may be bio-indicators of injury
• although N9 may not be the optimal + control, still worth it
NIH IP/CP
•NIH NIAID U19 IP/CP #AI060614: “Microbicide Development Program”
Biosyn, Inc
Anne Marie Corner
Linda Knapp
Linda Kristekas
CONRAD
Henry Gabelnick
Christine Mauck
Tim McCormick
Marianne Callahan
UCLA
Ian McGowan (U Pitt)
Chomchay Siboliban
Amy Adler
Terry Saunders
Elena Khanukhova
Charlie Price
Julie Elliott
John Boscardin
Ying Zhao
Daniel Cho
Karen Andrews
Elizabeth Johnson
Alexis Dominguez
Julia Klein
NIH
Jim Turpin
Jeanna Piper
Cherylnn Mathias
Grace Chow
Consultants
Alex Carballo-Dieguez
Ana Vetuneac
VOLUNTEERS!
an NIH IP/CP for Topical Microbicides