slide1
Download
Skip this Video
Download Presentation
DAIDS IPCP-HTM

Loading in 2 Seconds...

play fullscreen
1 / 32

DAIDS IPCP-HTM - PowerPoint PPT Presentation


  • 127 Views
  • Uploaded on

DAIDS IPCP-HTM. NIH/NIAID: 1 st IPCP on Rectal Microbicides Developments (2004-2011) Two Phase 1 Clinical Trials: RMP-01 : Topical UC781 (single & 7-day topical) RMP-02 / MTN-006 : Tenofovir (single oral, single & 7-day topical). Peter Anton, UCLA: PI

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' DAIDS IPCP-HTM' - may-buckner


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

DAIDS IPCP-HTM

NIH/NIAID: 1st IPCP on Rectal Microbicides Developments

(2004-2011)

Two Phase 1 Clinical Trials:

RMP-01: Topical UC781 (single & 7-day topical)

RMP-02 / MTN-006: Tenofovir (single oral, single & 7-day topical)

Peter Anton, UCLA: PI

Ian McGowan, MWRI/University of Pittsburgh: co-PI

NIH/NIAID: 2nd IPCP on Rectal Microbicides Developments

(2009-2014)

Ian McGowan, MWRI/University of Pittsburgh: PI

slide2

NIH IP/CP

Outline

  • Intent
  • Assays for use in RM trials
  • 1st Phase 1 RM Clinical Trial utilizing assays:

RMP-01 (UC781)

  • 2nd Phase 1 RM Clinical trial:

RMP-02/MTN-006 (Tenofovir)

context

slide3

NIH IP/CP

Assay Optimization: selected for Phase 1

  • Assay factors addressed prior to trial (some still to address) :
    • Apply to both vaginal and rectal samples
    • Anticipate effect of standard clinical trial / home use such as enemas/douches/gels (osm; pH; dilution effect)
    • Sequence of sample collection: inherent confounder
    • Multi-site trials: determine where samples (Flow, explants etc) collected versus where/when processed (fresh, frozen, O/N, batched: 1 lab?)
    • Semen/seminal fluid alter results/drug delivery? Same with sexual activity / trauma
        • Relevance for interpreting “biopsy infection” experiments
    • Compartment dilution effect on delivered drug concentrations?
        • Quantify [microbicide] likely exposed to tissue. Challenge much greater in rectal than cervicovaginal explants
    • NORMATIVE VALUES: to assess implications/actions of “out-of-range” values (and then: clinical relevance)
slide4

McGowan et al, HPTN 056 JAIDS 2007

HPTN 056:Characterization of Baseline Mucosal Indices of Injury and Inflammation in Men for Use in Rectal Microbicide Trials

Pre-Phase 1 rectal safety study:

  • normative ranges; inherent variability

Primary Objective

  • Determine variability of mucosal immunological, virological and histopathological parameters in biopsies from 10cm & 30cm in the recto-sigmoid colon in 4 defined study groups (n=16):
      • HIV-/RAI-
      • HIV-/RAI+
      • HIV+/RAI+: high PVL
      • HIV+/RAI+: high PVL

Secondary Objective

  • Determine within group stability of defined measures over time (3 flexible sigs over 6 weeks) & biological variability between groups

Assays

  • Histopathology (qual/quant); flow cytometry, tissue cytokine mRNA, rectal secreted Ig, tissue VL)

Total: 48 procedures; 1,440 biopsies

hptn 056 data analysis

McGowan et al, HPTN 056 JAIDS 2007

HPTN-056: Data Analysis
  • Data analyzed by group means
  • Subject variability around means explored
  • Definitions:
    • Sig: within subject standard deviation
    • Tau: between subject standard deviation
    • Intra-class correlation (ICC) [ICC = Tau^2/ (Tau^2 + Sig^2)]
  • ICC thresholds
    • >0.75 shows strong stability
    • >0.5 shows moderate stability
stability of flow cytometry data

McGowan et al, HPTN 056 JAIDS 2007

Stability of Flow Cytometry Data

ICC: Intra-class correlation >.75 shows strong stability

stability of cytokine data

McGowan et al, HPTN 056 JAIDS 2007

Stability of Cytokine Data

ICC: Intra-class correlation >.75 shows strong stability

where to sample explants

NIH IP/CP

Where to sample…”explants”
  • Colorectal (10cm)
  • Colonic (30cm)
  • Colorectal (higher than 10cm)
  • Upper intestinal tract (systemic delivery to targets)

When to sample…explants

  • Real-life factors: bowel movements, prep, pre/post sexual prep, menses
  • Drug trial factors: how long post exposure, frequency, # samples

Safe to sample…?

slide9

X

X

NIH IP/CP

Colorectal: Biopsy location

slide10

NIH IP/CP

Colorectal Biopsy safety and location

slide11

~10cm

~30cm

Microbicide

Failure

Success

HIV

no effect?

+ effect?

RM Clinical Relevance:

Selection Site for Explants

Concentration

Anus

Rectum

Colon

Ano-Rectal Distance

Diagram courtesy: C Hendrix)

slide12

Rectal Explant Model used in RM Clinical Trials:

“ex vivo biopsy infection” experiments

Explant media soaked collagen rafts

HIV-1 infected and washed explants

a) Explants transferred by transfer pipet to a dry petri-dish, cut-side down

b)1 cm2 raft placed atop the explant and inverted.

Media 100% exchanged q 3 daysfor ~2 weeks (D1/D4/D7/D11/D14) Supernatant frozen for batched p-24 ELISA (= qPCR of HIVRNA)

Mounted explants transferred to well of 24-well plate containing 500ul of explant medium

Fletcher et al AIDS 2006

slide13

A PHASE 1 SAFETY AND ACCEPTABILITY STUDY OF THE UC-781 MICROBICIDE GEL APPLIED RECTALLY

IN HIV SERONEGATIVE ADULTS:

RMP-01

P Anton, T Saunders, A Adler, C Siboliban, E Khanukhova, C Price,

J Elliott, K Tanner, Ana Ventuneac, Alex Carballo-Dieguez, J Boscardin, Y Zhao,

W Cumberland, AM Corner, C Mauck, I McGowan

UCLA, NIH, CONRAD

submitted

slide14

Rectal Biopsy Infections ex vivo: RMP-01

  • Samples acquired endoscopically (large-cup forceps): 14 biopsies at each site (10cm and 30cm)
  • NO DRUG ADDED TO EXPLANTS (except at V2): all drug applied in vivo
  • To laboratory and set up within 2 hours
  • HIV (pre-determined strain, titers) applied to explants, incubated 2 hrs
  • Biopsies washed (>3-5 times), then mounted on gelfoam, placed in well of 24-well plate; incubated for 12-14 days.
  • Controls: media (uninfected control); UC781 at baseline visit only to demonstrate in vitro efficacy
  • Supernatants for p24 taken every 3 days (100%); each time point is mean of 2 biopsies pooled; cumulative p24 graphed

NIH IP/CP

slide15

HEC Placebo

UC781 0.10%

UC781 0.25%

10cm

30cm

NIH IP/CP

Confidence from RMP-01 UC781 RM trial (n=36; 3 arms)

(V2 = baseline) (V3 = single topical application UC781)

Bx infection data

(V2 vs V3)104

virus titer

in vivo exposed

ex vivo infected

slide16

HEC Placebo

UC781 0.10%

UC781 0.25%

10cm

30cm

NIH IP/CP

RMP-01 UC781 RM trial: now 102 virus titer

Baseline variability looks same….

but only 60% infected with this titer

(V2 = baseline) (V3 = single topical application UC781)

slide17

Lessons learned thus far for these types of trials:Do infectibility results from 30cm and 10cm differ: NONeed infectibility of ‘all’ baseline sample explants: YES

NIH IP/CP

Baseline infectibility

No difference seen when using 36 subjects’ baseline data:

“OK” to use 1 site in next trial

Use higher titer virus for explant infection studies

slide18

DAIDS IPCP-HTM

RMP-02/MTN-006: A Phase 1, Placebo-Controlled Trial of Rectally Applied 1%Vaginal Tenofovir Gel with Comparison to Oral Tenofovir Disoproxil Fumarate

P Anton1, R Cranston3, A Carballo-Dieguez4, A Kashuba5,

E Khanukhova1, J Elliott1, L Janocko6,8, N Richardson-Harman7,

W Cumberland9, C Mauck10, C Hendrix2,8, I McGowan6,8

UCLA: Dept. of Medicine1 & School of Public Health9, Johns Hopkins University2, University of Pittsburgh: Dept. of Medicine3 & Magee-Womens Research Institute6, Columbia University4, UNC CFAR & School of Pharmacy5, Alpha StatConsult LLC7, MTN8, CONRAD10

Presented: CROI 2011, Boston, MA

slide19

Study Rationale

  • Rectal intercourse is commonly practiced by men and women
  • HIV transmission during receptive anal intercourse (RAI) is significantly greater per sexual act
  • CAPRISA 004 demonstrated 39% reduction in HIV infection using 1% tenofovir gel formulated for vaginal use
  • Given the prevalence of RAI and the success of this agent, this Phase 1 trial aimed to evaluate safety of the hyper- osmolar, vaginally formulated 1% tenofovir gel when used rectally; in addition, aims were to investigate acceptability, mucosal injury and multi-compartment PK
slide20

Safety, PK / PD, acceptability

Single

rectal

tenofovir

(N = 18)

2:1

7 Day

Rectal

tenofovir

(N = 18)

2:1

Open label

Oral tenofovir

(N = 18)

Baseline

Evaluation

RMP-02/MTN-006 Study Design

  • 3 stage trial at 2 sites (UCLA/MWRI): open label TDF (oral) followed by 2:1 randomization of tenofovir: HEC placebo (for single rectal topical dose; 7-day rectal topical dosing)
  • Each dosing stage with 2 weeks of sampling (then: 2 weeks wash-out/healing)
  • Product: Tenofovir Disoproxil Fumarate (TDF) 300mg tablet, Tenofovir 1% gel (vaginal formulation/applicator) or HEC placebo gel
  • 8.5 months; 3.5 months/participant
  • all 18 enrolled → completed. 100% retention (78% male; 22% female)

Each participant completed 12 visits with 8 flexible sigmoidoscopies in 3.5 months → ~2300 bx

>10,000 study samples

slide21

DAIDS IPCP-HTM

Subject’s Samples Workflow: ‘chain of custody’

Clinical Unit

Blood

Urine

Vaginal

Sponge

Rectal Swabs

Rectal

Sponges

Stool Sample

Rectal Lavages

Biopsies

UCLA/MG

Cytokines

UCLA/MG

Magee

NAAT GC/CT

UCLA/MG

UCLA/MG

UCLA/MG

(Sloughing Assay)

UCLA/MG

Clin Lab

(Safety labs, HIV, RPR

HSV 1 & 2)

UCLA/MG

Beta HcG &

U/A

Magee NAAT

GC, CT

MTN

PK Lab

UCLA/MG

Plasma PBMC

MTN Micro

(rectal microflora)

Genova

(calprotectin)

UCAL/MG

(Explant Culture,

Immunophenotyping

PK processing

UCLA

Research Pathology

(Qualitative)

MTN

PK Lab

MTN

PK Lab

Magee-WRI

(gram stain,pH)

MTN

PK Lab

slide22

Study Endpoints

  • Primary Objective:Safety of 1% vaginally-formulated tenofovir gel, applied rectally
    • Endpoint:≥ Grade 2 AE
  • Secondary Objectives:Acceptability, Mucosal Immunotoxicity, PK
    • Endpoints - Acceptability: - % of those at last visit liking product
    • - likely to use the candidate in the future if helps
    • Endpoints - Mucosal Injury: - fecal calprotectin
    • - rectal microflora
    • - secreted rectal cytokines
    • - rectal epithelial sloughing
    • - rectal histology
    • - rectal mucosal CD4+ T cell phenotype/activation
    • Endpoints - PK:Tenofovir/diphosphate concentrations (9-10 compartments):
      • Blood: plasma, PBMC, PBMC subsets (CD4+/CD4-)
      • Fluids: rectal fluid, vaginal fluid (sponges)
      • Tissue: Whole biopsy homogenates, isolated mucosal mononuclear cells (MMC) & CD4+/CD- subsets
  • Exploratory Objective:ex vivo infectibility of in vivo exposed rectal tissue biopsies
    • Endpoint: cumulative HIV-1 p24 levels in colorectal explant supernatants at 14d
slide23

p=0.002

p=0.002

p=0.001

p=0.10

Safety

Clinical Grade 3 Events

acceptability
Acceptability

75% likely to use TFV in the future

if they felt it might be helpful,

despite relatively more dislike and discomfort.

slide25

DAIDS IPCP-HTM

Mucosal Injury Indices

slide26

PK: TFV Exposure in Plasma

  • With RECTAL dosing: plasma TFV Cmax & AUC: 2% of ORAL
  • ‘7-day’ RECTAL dosing: no TFV accumulation in plasma
slide27

7/18

10/12

12/12

PK: TFV-DP in Rectal Tissue

(30 minutes post dose)

Single ORAL: (i) TFV DP Tmax ≥ 24h post-dose. (ii) At 10 days, TFV DP detectable in 55% subjects

Single RECTAL dose: (i) Tissue TFV DP Cmax was 112x > single ORAL and AUCall was 1.5x > single ORAL. (ii) At 10 days, TFV DP detectable in 80%

‘7-day’ RECTAL dosing: Tissue TFV DP accumulated: Cmax was 5x > singleRECTAL dose

slide28

ANCOVA p=0.005

Biopsy Infection ex vivo of 7-day RECTAL dosing in vivo:

Significant suppression seen

(HIV-1BaL TCID50=104at ~10 cm)

effect size: 0.80

Single ORAL dosing: no significant changes (p=0.65)

Single RECTAL dosing: no significant changes (p=0.12)

slide29

Dose-Response Relationship:

rectal tissue TFV DP with rectal biopsy infectibility

  • Virus inhibition correlated with increasing tissue TFV-DP, even with small study n
  • Feasible to assess both dose and response following in vivo exposure to drug
slide30

CONCLUSIONS

  • The vaginal formulation of 1% TFV gel was sub-optimal for clinical safety and acceptability when rectally applied.
  • Despite extensive mucosal indices of injury, none were seen with product use.
  • Consistent with other studies, the systemic absorption of rectally-delivered TFV was ~2% of oral dose.
  • Rectal dosing was associated with 100x more active TFV-DP in the target mucosa than oral dose.
  • Rectal tissue biopsy infection ex vivo was significantly reduced compared to control; may be a potential biomarker of efficacy.
  • PK/PD:Dose/response correlations were evaluable and significant in this intensive small trial.
slide31

DAIDS IPCP-HTM

Acknowledgments

  • U19 Integrated Preclinical-Clinical Program for HIV Topical Microbicides (IPCP-HTM) grant funded by DAIDS, NIAID, NIH grant (AI060614)
  • Participants
  • Study Teams at each site:

UCLA

MWRI, University of Pittsburgh

  • NIH/DAIDS
  • MTN Network Support
  • MTN Microbiology Laboratory
  • MTN Clinical Pharmacology Analytical Lab at JHU
  • CONRAD
  • Gilead
  • Alpha StatConsult LLC
  • Support from MTN: funded by NIAID (5U01AI068633), NICHD, NIMH, all of NIH.
slide32

DAIDS IPCP-HTM

QUESTIONS ?

ad