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The Rockefeller University Center for Clinical and Translational Science
Minutes of the Advisory Committee on Clinical and Translational Science (ACCTS)
October 3, 2012
Voting Members Present: Robert Darnell - Chair, Ed Barbour, Jon Blumenfeld, Gila Budescu, Barry Coller,
Lynn Dustin, Emil Gotschlich, Peter Holt, Lisa Hudgins, Florian Klein, Rhonda Kost, James Krueger,
Michelle Lowes, Barbara O’Sullivan, Neil Renwick, Andrea Ronning, Sarah Schlesinger, Terry Solomon,
Mayte Suarez-Farinas, Maija Williams
Invited: Donna Brassil, Joel, Correa da Rosa, Lynda Olender, Rita Devino
_______________________________________________________________________________
The meeting was called to order at 2:31 pm
_______________________________________________________________________________
1. Approve minutes from the July 17, 2012 ACCTS meeting
2. Initial Review(s) - 5 Submissions
Kemal Akat
KAK-0793 - RNA metabolism and post-transcriptional
regulation of gene expression in liver disease
[Primary Reviewer: Michelle Lowes]
Scientific Initial Review
What are the background and goals of study?
Not much is known about liver disease and stellate cells. Scott Freidman is a world expert on hepatic
stellate cells. This is a collaboration to be able to conduct studies on liver tissue collected at MSSM
here at RU.
If this is a clinical trial, please specify:
Intervention: N/A
Primary endpoint:
The research hypothesis is that there will be different mRNA and miRNA transcriptomes in different
liver cell types and different disease states due to different liver insults.
Human liver is resected as part of medically-indicated, routine surgery at Mt Sinai School of Medicine
(MSSM).
Investigators will collect the tissue that would be discarded, without any patient-related data.
Primary human liver cells will be isolated in the Division of Liver Disease at MSSM.
Cell-lines (LX-1 and LX-2) have been established in the Freidman Lab.
Specimens will be collected from (1) fibrotic livers, (2) non-fibrotic livers, and (3) established human
liver cell lines to study
1) mRNA-sequencing
2) miRNA-sequencing
3) miRNA-binding sites by PAR-CLIP
1
Secondary endpoint:
Additional parameters include: differences in small RNA profiles in blood samples, miRNA/mRNA situ
hybridization/ tissue proteomics
What are the major risks? Nil risks
Statistical Analysis (optional: comments in addition to Biostatistician review)
Analysis will be done using a “customized bioinformatics pipeline”
The objective of this protocol is to study the role of microRNAS and other RNA species in the biology of
hepatic stellate cells. The writting and structure of the protocol is very poor. The hypothesis, aims and
outcomes are all mispecified. The first hypotheis is "The liver is composed of different cell type" which
the investigator agrees is obvious, hence it should never be the primary hypothesis of any study.
There is no specification of the number of subjects who will be enrolled in the study. There is no a
comprenhesive data anlaysis plan even though RNA-seq and other transcriptomics tecniques will be
used. For example we dont know how the counts for RNA seq will be calculated and which
normalizations will be done. This lab does have experience in working and analyzing omics and
sequencing data.
What is the potential significance of the study?
There is a lot to be learned from this study
Ratings:
Scientific Merit:
Priority:
Resource Intensity:
High
Moderate
Low
Recommendation
Reviewer's Recommendation of Submission
Approve with recommendations
Reviewer's Comments
This is an example of obtaining de-identified samples from another institution for study here at RU.
However it would benefit from some clarification.
1. As written, the flow of specimens and data is not clear. My assumption is that the Freidman lab
collects the liver specimens at MSSM, along with clinical data, under an MSSM IRB-approved protocol.
Liver tissue (and cell lines, and blood) will be sent to RU in a de-identified manner. Once the RNA
analysis is performed, the data will be sent back to the Friedman lab. Please clarify if this is correct.
2. The IRB approval from MSSM was not available for review. A letter of approval of Mt Sinai Grants
and Contracts Office was included, but it is not clear what this pertains to as the study has a different
tiltle. A manual on MSSM IRB was attached. The MSSM IRB-approval for the study to collect liver
tissue and blood at MSSM should be included in the application.
3. Analysis will be performed using a “customized bioinformatics pipeline”. However, the sample size
was not mentioned.
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4. No CV is supplied for the PI.
Indication of Review Completion
Yes
No
Date the Review was completed: 10/01/2012
MOTION: Approved w/ Recommendations
Mary Elizabeth Hatten
Purkinje Cell function in Induced Pluripotent Stem Cell
Models of Angelman's Syndrome and Isodicentric 15
Syndrome
[Primary Reviewer: Michelle Lowes]
Scientific Initial Review
What are the background and goals of study?
The Hattan lab at RU will obtain de-identified induced pluripotent stem cell (IPS) from UCONN.
UCONN received these tissues from McGill under ESCRO and has approval to share them.
Some samples will be sent to Uni Miami (after IRB-approval there).
The iPS cell lines samples are:
(1) a patient with Angelman Syndrmoe
(2) Isodicentric 15 Syndrome
(3) unaffected control tissue
These iPS cells will be differentiated into Purkinjie cells and anayzed by gene expression, protein
expression, cellular morphology, and tranplantation into a mouse model of cerebellar dysfunction.
This project has received some Pilot Project funding.
If this is a clinical trial, please specify:
Intervention: N/A
Primary endpoint:
The ubiquitin lgase UBE3A gene dosage will be studied by various assays.
Secondary endpoint:
What are the major risks?
N/A
Statistical Analysis (optional: comments in addition to Biostatistician review)
Not described
What is the potential significance of the study?
Highly significant
3
Ratings:
Scientific Merit:
Priority:
Resource Intensity:
High
High
Low
Recommendation
Reviewer's Recommendation of Submission
Approve with recommendations
Reviewer's Comments
The PI is listed in section 3.0as Mary Elizabeth Hatten, but on section 5 it lists David Bucholz- please
correct.
Indication of Review Completion
Yes
No
Date the Review was completed: 10/01/2012
Motion: Approve w/ Recommendations
Mary Elizabeth Hatten
Derivation of Induced Pluripotent Stem Cells From Plucked
Hair Keratinocytes
[Primary Reviewer: Emil C Gotschlich]
∆ Exempt by Reviewer
Scientific Initial Review
What are the background and goals of study?
Dr. Buchholz a postdoctoral fellow is working with Mery-Beth Hatten on Angelman’s disease. This
protocol is designed to determine whether a particular method of inducing pluripotent cells from
keratinocytes attached to plucked hair will work. The method is comercially available from Stemgent as
the mRNA Reprogramming Factors Set: hOKSML. It contains mRNA encoding Oct4, Klf4, Sox2, c-Myc,
Lin-28, and nuclear GFP (nGFP). These in vitro transcribed mRNAs incorporate both pseudouridine
and 5-methylcytidine-modified nucleotides to minimize the cellular interferon response to single
stranded RNA. This has been used to reprogram human fibroblasts.
If this is a clinical trial, please specify:
Intervention:
Plucking hair from the co-investigator
Primary endpoint:
1. Derivation of keratinocyte cultures: 1-2 hairs will be plucked from the top of the head of the coinvestigator and cultured following standard keratinocyte cell culture methods.
2. Reprogramming of keratinocytes into induced pluripotent stem cells: Keratinocytes will be transfected
with RNA from the Stemgent,Inc. reprogramming kit for a period of 10-20 days until morphologically
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distinct stem cell colonies are formed.
3. Analysis of keratinocyte-iPSC lines: Derived iPSC lines will be tested by gene/protein expression for
Oct4, Nanog, SSEA3, SSEA4, TRA-1-60, TRA-1-81. iPSCs will be tested for their ability to differentiate
into all three embryonic germ layers following standard in vitro protocols.
4. This procedure will be repeated twice to provide reproducibility.
Secondary endpoint:
None
What are the major risks?
None
Statistical Analysis (optional: comments in addition to Biostatistician review)
This feasibility study with only 1 patient. No statistics considerations are needed.
What is the potential significance of the study?
IPs have been derived from plucked hair keratinocytes by viral transfection. This method that does not
involve genomic insertions is preferable. This is a feasibility study to see whether thi mRNA dependent
method will work with hair samples. If it does it would obviate the need to obtain skin biopsies.
Ratings:
Scientific Merit:
Priority:
Resource Intensity:
Moderate
Moderate
Low
Recommendation
Reviewer's Recommendation of Submission
Approve, exempt from Review
Reviewer's Comments
From an IRB point of view this study does not meet the definition of "Research" under 45CFR46.102(d)
and hence not subject to further IRB review.
Indication of Review Completion
Yes
No
Date the Review was completed: 10/01/2012
Motion: Approved
James Krueger
Phase II randomized double blind placebo controlled,
multiple-dose regimen study to assess the rate of
histological clearance and effect on molecular pathways as
as well as on biomarkers of 12 months secukinumab 300
mg s.c. treated patients with chronic plaque-type psoriasis
[Primary Reviewer: Lisa Hudgins]
5
Scientific Initial Review
What are the background and goals of study?
This is an initial, industry-initiated, double-blind, randomized, placebo-controlled study to test the
hypothesis that a recombinant anti-human interleukin 17A antibody, secukinumab, will reverse
histological changes of psoriasis compared with placebo. Three scientific questions will be addressed
by the Krueger Lab: 1) What is the molecular basis of the histological improvement 2) What are the
effects on T cell function? 3) Are there useful biomarkers that predict response?
Rockefeller will enroll 36 patients over 2 years as one of 12 centers which will enroll 300 patients, 18-75
years of age, with uncontrolled moderately severe chronic plaque psoriasis for at least 6
months. Patients who are immunosuppressed, have active TB, HIV or hepatitis, or other systemic
infections, congestive heart failure, hypersensitivity reactions to biologic agents, liver disease, kidney
failure, low blood counts or malignancy will be excluded. Procedures include s.c. injections of study
drug/placebo, blood sampling, skin photos and skin biopsies at baseline, 3 and 12
months. Compensation is $893 or $35/visit if study is not completed.
If this is a clinical trial, please specify:
Intervention:
After wash-out of psoriasis treatment and screening visit, eligible enrollees will be randomized 2:1 to
receive study drug (300 mg s.c. divided into 2 doses) or placebo for 12 weeks. Study drug will be given
weekly for 4 weeks then monthly. Study drug will be given to placebo group and placebo to drug group
weekly for 4 weeks; a 36 week open label period follows with everyone receiving the drug. External
monitoring is listed as “unknown”. A DSMB will not be used.
Primary endpoint:
Proportion of patients with skin reversal at 12 weeks compared to control
Secondary endpoint:
Proportion of patients with response defined several ways at 4 and 52 weeks,
safety, immunogenicity, pharmacokinetics, quality of life. Several exploratory objectives are listed in
the industry protocol summary, including detailed histological and molecular studies of T cell function
and pharmacogenetics (separate optional consent)
What are the major risks?
Moderate risk
-Study drug: infection, allergic reaction. Excellent safety profile in studies of this drug thus far in over
2500 subjects, over 600 with psoriasis. Low rate of local reactions.
-Skin biopsy: fainting, infection, scar
-Venipuncture: fainting, infection
Statistical Analysis (optional: comments in addition to Biostatistician review)
What is the potential significance of the study?
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Provides the information necessary for FDA approval of a new treatment for psoriasis. The exploratory
studies in the Krueger Lab will increase our understanding of the role of IL17 in the pathology of the
disease.
Ratings:
Scientific Merit:
Priority:
Resource Intensity:
High
High
High
Recommendation
Reviewer's Recommendation of Submission
Approve with recommendations
Reviewer's Comments
Mention should be made in the protocol of the pharmacogenetic objective that is described in an
optional, separate consent form.
Indication of Review Completion
Yes
No
Date the Review was completed: 10/03/2012
Motion: Approve w/ Recommendations
Sohail Tavazoie
multi-miRNA Targeting of ApoE Drives Melanoma
Metastasis and Angiogenesis316170
[Primary Reviewer: Neil Renwick]
Scientific Initial Review
What are the background and goals of study?
miRNA regulation of melanoma metastasis
Authors have previously discovered that three small RNAs suppress metastatatic spread and
angiogenesis of melanoma tumors, targeting ApoE and DNAJA4 genes; inhibition of these mRNAs
suppresses metastasis of human melanoma cells in mice.
The goal of the current study is to analyze expression levels of these miRNAs in primary melanoma
lesions resected at MSKCC and see if they correlate with the likelihood of metastatic spread. These
samples were previously obtained, sectioned, and anonymized by MSKCC pathology. Results will not
be shared with MSKCC.
The total cohort consists of 71 patients; roughly half relapsed and half not. Specifically looking at levels
of 199a-3p, 199a-5p, and miR-1908. Total RNA will be extracted from paraffin-embedded cross
sections and then analyzed using Taqman miRNA assays. ApoE and DNAJA4 will also be analyzed by
qRT-PCR. The prognostic power to predict metastatic outcomes will be determined.
If this is a clinical trial, please specify:
7
Intervention: This is not a clinical trial.
Primary endpoint:
Secondary endpoint:
What are the major risks?
There are no major risks.
Statistical Analysis (optional: comments in addition to Biostatistician review)
More detail on cohort data would help biostats assessment.
It is said that miRNA expression will be measured with TaqMan in “blinded manner”. The important
“blinding” here is not with respect to the patient ID but with respect to the metastatic status of the
patient. Since the number of patient/samples to be processed is large, I will advise to randomize the
order of samples for TaqMan as to not divide the samples in batches that say, are related with the
metastatic status. This may sound evident but it is very common for researches to reorder samples
based on a variable and then process them in batches defined by the samples by the order they appear
in the spreedsheet. Since the main pourpose here is to classify sampels an oversigh on this with a
subsequent batch-effect may lead to invalid results.
What is the potential significance of the study?
Study may identify a miRNA biomarker that predicts melanoma relapse.
Ratings:
Scientific Merit:
Priority:
Resource Intensity:
Moderate
Moderate
Low
Recommendation
Reviewer's Recommendation of Submission
Approve with recommendations
Reviewer's Comments
Would be helpful to have more information on the cohort data to assess biostatistics approach. Also
helpful to know the RNA extraction method.
Indication of Review Completion
Yes
No
Date the Review was completed: 10/05/2012
Motion: Approved
8
Alexander Tomasz
Pathways From the Antibiotic Resistance Gene to the
Antibiotic Resistant Phenotype in Epidemic Clones of
MRSA - Opportunities for Novel Therapeutic Intervention
[Primary Reviewer: Lisa Hudgins]
∆ Exempt by Reviewer
Scientific Initial Review
What are the background and goals of study?
The inhibition of conserved metabolic pathways may resensitize methicillin resistant strains of Staph
aureus to methicillin. The growth, biochemical and genetic characteristics of 1) prototypic lab strain
(COL) 2) deidentified clinical isolates varying in degree of methicillin resistance and 3) de-identified
isolates from the bloodstream of 5 WCMC patients will be studied.
If this is a clinical trial, please specify:
Intervention:
Primary endpoint:
Secondary endpoint:
What are the major risks?
No risks.
Statistical Analysis (optional: comments in addition to Biostatistician review)
Methicillin-resistance in clinical s. aureus isolates is associated with and dependent on the activity of
specific metabolic pathways, knowledge of which may identify new targets that could re-sensitize
resistant strains to methicillin.
The hypothesis is that methicillin-resistance in clinical Staphylococcus aureus isolates is associate with
and dependent on activity of specific metaboloic pathways.
Metabolic differences identified will be analyzed using Ingenuity Pathway Analysis plataform.
They will obtain a random sample of 5 and there is no explanation for this number. In the grant
application they will come Microbiology Laboratory of the New York Presbyterian Hospital.
Maybe there is a small conflict with the application form that says that the samples may come from :
1) Tomasz Laboratory Samples or
2) clinical blood stream associate isolates from the clinical microbiology of New York Presbyterian
Hospital
The document for the grant application make it clear that the experiment is insufficient to establish a
causal relationship between metabolic pathways and the expression of methicilinn resistance.
The setup for the pathway analysis seems to be well stablished and the writing in the grant application
points the limitations of the study.
Based on the completeness of the study, apart from the sample size question that maybe could be
better sustained, I recommend approval.
Revised by Dr. Correa da Rosa
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What is the potential significance of the study?
Better understanding of the mechanism of methicillin resistance of Staph Aureus. This could lead to
ways to better treat this serious infection.
Ratings:
Scientific Merit:
Priority:
Resource Intensity:
High
High
Low
Recommendation
Reviewer's Recommendation of Submission
Approve, exempt from Review
Reviewer's Comments
Indication of Review Completion
Yes
No
Date the Review was completed: 10/02/2012
Motion: Approved
Knut Wittkowski
Reanalysis of publicly available Asthma GWAS data
[Primary Reviewer: Lynn B. Dustin]
Scientific Initial Review
What are the background and goals of study?
The goal of the study is to devise new and test new strategies for analyzing genome-wide association
data. The investigators propose to use a non-parametricstatistical method, termed µGWAS, based on
u-statistics for multivariate data, to analyze publicly available GWAS datasets collected in asthma
studies. They propose that analyzing pairs of neighboring SNPs may be more informative than
analyzing single SNP associations with asthma.
If this is a clinical trial, please specify:
Intervention: None
Primary endpoint: The primary endpoint will be allele counts associated with asthma.
Secondary endpoint: none
What are the major risks?
No patients are involved in this study of publicly available datasets.
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Statistical Analysis (optional: comments in addition to Biostatistician review)
This protocol is a re-analysis of existing data deposited in dbGAP. I have no concerns regarding this
study, which will be conducted by Dr. Wittkowski.
What is the potential significance of the study?
The study may permit the testing of novel statistical approaches to mining GWAS data.
Ratings:
Scientific Merit:
Priority:
Resource Intensity:
Moderate
Moderate
Low
Recommendation
Reviewer's Recommendation of Submission
Approve with recommendations
Reviewer's Comments
The Specific Aims statement is unclear due to typographical errors, and should be corrected.
There are two Aims called Aim 2.
The first Aim 2 reads "To screen for intragenic regions discriminating asthma patients with from asthma
patients without a history of atopic dermatitis."
Indication of Review Completion
Yes
No
Date the Review was completed: 10/02/2012
3. Continuing Review(s) - 1 Submission
Dana Orange
DOR-0722 - Evaluation of Immune Activation in
Rheumatoid Arthritis
[Primary Reviewer: Jennifer Belasco]
Reviewer's Comments
I don't see any issues with the study, Evaluation of Immune Activation in RA. My only question was
about whether she should be excluding people on biologics, but she addresses this in her progress
report. I think it weakens the study, but I know it is difficult to find patients with arthritis who are not on
these drugs.
4. Amendment(s) - 5 Submissions
Emma Guttman
JKR-0737 - Randomized Pilot Study of Ustekinumab for
Subjects with Chronic Atopic Dermatitis Who Have Suboptimal Response to Prior Therapy
[Primary Reviewer: Sarah J Schlesinger]
∆ Exempt by Reviewer
11
Scientific Continuing Review
Provide a brief description of the protocol:
Atopic dermatitis (AD) is a chronic disease associated with intense itching, which affects most aspects
of everyday life in the majority of patients. Acute inflammation and extensor/facial involvement is
common in infants, whereas chronic inflammation increases in prevalence with age, as do localization
to flexures. AD has a complex background characterized by immune activation, increased epidermal
thickness in chronic diseased skin, and defective barrier function. In normal, healthy skin, the outer
layer of the epidermis, the stratum corneum is made up flattened dead cells called corneocytes held
together by a mixture of lipids and proteins. The stratum corneum and, in particular, the lipid layer are
vital in providing a natural barrier function that locks water inside the skin and keeps allergens and
irritants out. In people with AD, the barrier function is defective, which leads to dry skin. As the skin
dries out, it cracks allowing allergens and irritants to penetrate.
Mild AD can be controlled with emollients and topical medications. However, moderate to severe AD is
extremely difficult to control and requires systemic treatment that is often unsatisfactory due to
impracticality and lack of effectiveness. Only three therapeutic options exist for moderate to severe AD,
including: 1) oral steroids 2) cyclosporine A (CsA), that is not widely used in the US as it is not FDA
approved for AD and 3) ultraviolet phototherapy. Oral steroids and CsA treatments have major side
effects and UV radiation therapy is highly inconvenient for patients. Several biologic medications, such
as TNF-alpha inhibitors, are effective, convenient, and relatively safe therapies for psoriasis, but have
thus far not shown efficacy in AD. Ustekinumab is a unique biologic medication that may specifically
target AD.
Our study will determine whether there is a reversal of the skin thickness and the immune pathways
involved in the disease during treatment with Ustekinimab and what specific immune cells are
involved. We are also interested to understand how the clinical reversal of the disease will correlate
with tissue reversal of the disease.
What was the enrollment over past year compared with the expected enrollment?
Volunteers have not yet been enrolled at RUH. The investigators project 35 subjects to be enrolled over
5 years.
Were there any notable adverse events?
no
What were the notable scientific findings?
no
Describe publications and presentations in the last year:
no
Describe changes in:
Protocol:
1-patients will now be seen at Rockefeller University, not at another clinical site. This is reflected in
application (and study plan). Also, for this reason a consent is now submitted.
2-An IND number was obtained from the FDA (30 day waiting period expires 9/28/12).
3-The design of the changed to cross-over design
4-No dropouts will be replaced
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5-Statistics section is changed
6-The PI is changed
7-the number of patients has been increased
Resources, Utilization:
none
Recommendation
Reviewer's Recommendation of Submission
Approve, exempt from Review
Reviewer's Comments
Indication of Review Completion
Yes
No
Date the Review was completed: 10/02/2012
Motion: Approved
Mary Elizabeth Hatten
Purkinje Cell function in Induced Pluripotent Stem Cell
Models of Angelman's Syndrome and Isodicentric 15
Syndrome
[Primary Reviewer: Michelle Anne Lowes]
Scientific Initial Review
What are the background and goals of study?
This is an amendment to a study that was presented for intial review at this meeting.
In the parent study, pluripotent stem cells (IPS) will be obtained from UCONN (who obtained them from
ESCRO), and some samples will be shared with Uni MIami. These IPS cell lines are from a patient with
Angleman Syndrom, isodicentric 15 syndrome, and from unaffected control tissue. These IPS cells will
be differentiated into Purkinjie cells and analyze by gene expression, protein expression, cellular
morphology, and translpantation into a mouse model of cerebellar dysfunction.
In this amentment, patients and family members (age 2-100 years) will be recruited with these
diseases, and 4-5 hairs plucked, as well as 12 mls of blood drawn.
If this is a clinical trial, please specify:
Intervention: N/A
Primary endpoint:
Primary hypothesis is that UBE3A gene dosage is responsible for clinical phenotype of these
syndromes.
Purkinjie cell function will be studied by a variety of assays.
Secondary endpoint:
1. Create a model to study role of UBE3A in Purkinjie cell function
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2. Hypothesis: Ubiquitin ligase UBE3A dosage affects Purkinjie cell morhology, synapse formation, and
expression of substrates.
3. To find novel ubiquitin ligase substrates for UBE3A
4. Ubiquitin ligase UBE3A dosage affects Purkinjie cell global gene expression.
What are the major risks?
Minimal: Hair pull and blood draw
Statistical Analysis (optional: comments in addition to Biostatistician review)
Not included- still says 3 samples as for parent protocol, yet study says 12 subjects, and ICF says 20
subjects over 3 years.
This is an observational study inlcuing 1 sample per group derived from patients with AS, IC15 and
Healthy control. Since n=1 no statistics are planned or needed. However, the aims state that "we will
test the hypothesis that UBE3A gene dosage alters Purkinje cell global gene expression ", which
can not be - strictily speaking - done with a sample size of 1. I suggest the aims are rewriten to "
explore the diferences...". Since gene expression arrays witll be used, and determination of Diferentially
Expressed genes can not be achived (n=1) we recomend the investigators to use Gene Set
Enrichement Analysis tecniques to get overall significance in changes in important/relevant Pathways.
What is the potential significance of the study?
Highly significant
Ratings:
Scientific Merit:
Priority:
Resource Intensity:
High
High
Low
Recommendation
Reviewer's Recommendation of Submission
Defer
Reviewer's Comments
Investigators should consider the sample size of this study, and include more details of the informed
consent process.
Although Dr Jenn Belasco (MD) has been added, her roles have not been identified, and no one is
listed to be able to perform the consent process, which may involve children and incapacitated
individuals.
It may actually be simpler for this to be a separate study.
Navigation through the Clinical Support Office for this protocol is recommended.
Indication of Review Completion
Yes
No
Date the Review was completed: 10/04/2012
14
James Krueger
JKR-0766 - A randomized placebo-controlled study to
determine the safety, tolerability, pharmacodynamics and
clinical efficacy of ILV-094 (an IL-22 antibody)
administered intravenously to subjects with atopic
dermatitis (AD)
[Primary Reviewer: Emil C Gotschlich]
Scientific Initial Review
What are the background and goals of study?
This proposal was reviewed in February 2012, and was approved pending finding a source of funding
and obtaining FDA approval. The Investigators submitted a grant request to the NIH in March, and this
was reviewed favorably but with a mandate to change the methods for statistical analysis of the data.
The 30 day period of review of the IND by the FDA ended on 9/28/2012 and that means it is approved.
However, the IND will have to be re-submitted with the changes requested by the NIH review.
The currently submitted documents already contain most of the changes in the analysis plan to meet
the NIH review. However, one additional change has been proposed on the basis of the power
calculations and that is an increase in the study population to 60. Approximately 60 subjects with atopic
dermatitis (AD) will participate in this study at two investigational sites (The Department of Dermatology
at the Mount Sinai School of Medicine, and the Rockefeller University Hospital). Subjects will be
randomly assigned in a 2:1 ratio to one of the two treatments schedules (ILV-094 vs placebo). The
sample size was calculated to achieve 80% power to test the hypothesis that the proportion of patients
that respond to treatment is higher in the treatment group than in the placebo group.
There is an antibody to IL-22 called ILV-094 and this study is to test the safety, tolerability, clinical
efficacy and mechanism of action of this antibody in patients with AD. The antibody is prepared by
Pfizer under IND 100,762. The IND for the proposed study will be held by the PI rather than the drug
company because the drug company is not interested in further developing it for this application at this
time. This antibody has been tested at similar doses in patients with psoriasis and while it was well
tolerated it had rather poor efficacy in that condition. It may be more efficacious in AD if the T22
hypothesis for causation is the main factor operative in the disease.
If this is a clinical trial, please specify:
Intervention:
This will be a phase 2 double blinded placebo controlled trial. Patients will be randomized 2:1 to receive
IV every 2 weeks for total of 6 doses with the 10 week follow-up placebo or study drug. Study activities
consist of safety labs, skin biopsies, clinical assessment, clinical photography, physical exams and
adverse event assessment. 40 patients to receive antibody and 20 to receive placebo. The first IV dose
will be 600 mg of either agent followed every 2 weeks by 300 mg doses. Follow-up will be every 2
weeks for the additional 10 weeks after last dose for total study duration of 20 weeks. Blood draws for
biochemical and lipid profile will occur at screening, baseline, and weeks 4, 8 and 12. Serum samples
(Cytokines) and IgE blood samples will occur at weeks 0, 4, 8, 12 and 16. Comprehensive metabolic
panel and complete blood count (CBC) with differential blood samples will occur at screening and
weeks 0, 4, 8, 12 and 16. PAX gene RNA blood samples will take place at weeks 0, 4 and 12. PAX
gene DNA blood sample for genetic analysis of filaggrin and other mutations will occur at baseline
Week 0. Lesional and non-lesional biopsies will occur at weeks 0, 4, and 12. SCORAD and IGA
assessments will take place at every visit), as well as the recording of any adverse events (AE).
Primary endpoint:
The primary efficacy variable is the proportion of subjects who achieve an percentage change of 50%
or greater at Week 12 from baseline in objective AD clinical severity index (SCORAD).
15
Secondary endpoint:
1. Change of the pathological epidermal disease phenotype of lesional skin at week 12 of ILV-094
treatment (as compared with baseline). This will be assessed by a reduction of epidermal
thickness and K16 expression.
2. Change of IL-22 regulated keratinocyte products (S100A7, A8) at week 12 of ILV-094 treatment
(as compared with baseline). This will be assessed by a reduction of the mRNA gene
expression levels of S100A7 and S100A8 after 12 weeks of treatment by RT-PCR.
What are the major risks?
Risks with study drug include increases headache, dizziness, GI discomfort, itching, infection, infusion
reactions (see attachment for more details), and/or allergic reaction. The agent has been well tolerated
in normal volunteers and population of about 70 patients with psoriasis.
Statistical Analysis (optional: comments in addition to Biostatistician review)
The protocol has been changed due to request from NIH reviewers - who will potentially fund teh study.
The last observation carried forward approach to missing values was deemed not appropriate. A more
robust design and analysis is now presented. As a consequence, the sample size has been
reassessed.
What is the potential significance of the study?
If the results were to show strong effectiveness in clearing AD lesions this study would go a long way to
favoring the Th22 hypothesis being the underlying cause of the disease.
Ratings:
Scientific Merit:
Priority:
Resource Intensity:
High
High
Moderate
Recommendation
Reviewer's Recommendation of Submission
Approve
Reviewer's Comments
Indication of Review Completion
Yes
No
Date the Review was completed: 10/02/2012
Marcelo Magnasco
MAG-0694 - The Auditory Time-Frequency Uncertainty
Principle
[Primary Reviewer: Neil Renwick]
Scientific Continuing Review
Provide a brief description of the protocol:
16
The Auditory Time-Frequency Uncertainty Principle (Amendment)
This study involves testing untrained and musically trained individuals to discriminate changes in tone
characteristics (timing and frequency).
What was the enrollment over past year compared with the expected enrollment?
Were there any notable adverse events?
No
What were the notable scientific findings?
Study in progress
Describe publications and presentations in the last year:
Study in progress
Describe changes in:
Protocol:
Changes:
Pavel Isakov has been added as a co-investigator and will be involved in obtaining infomred consent,
recruitment, data analysis, data management, and conducting psychoacoustic tests. Veronica Whalen
has stopped on this study. He will be trained in obtaining informed consent.
Additional data will be generated regarding a two-down-one-up paradigm.
The total number of participants to be enrolled in this study has been increased from 20 to 50-60.
Resources, Utilization:
The total number of participants to be enrolled in this study has been increased from 20 to 50-60.
Recommendation
Reviewer's Recommendation of Submission
Approve
Reviewer's Comments
Indication of Review Completion
Yes
No
Date the Review was completed: 10/05/2012
Martin Markowitz
MMA-0728 - A Phase 3, randomized, double-blind study of
the safety and efficacy of GSK1349572 plus
abacavir/lamivudine fixed-dose combination therapy
administered once daily compared to Atripla over 96 weeks
in HIV-1 infected antiretroviral therapy naive adult subjects
(GSK ING114467)
17
[Primary Reviewer: Lynn B. Dustin]
Scientific Initial Review
What are the background and goals of study?
This is an ongoing phase 3 clinical trial of the investigational drug, GSK1349572, a second generation
integrase inhibitor, in ART-naive patients with HIV infection. Patients will receive the investigational
drug plus Epzicom (abacavir and lamivudine); a control group will receive Atripla (tenofovir,
emtricitibine, and efavirenz), a currently recommended multidrug therapy.
The current submission is an ammendment to add additional visits to permit long-term follow up of
enrolled patients. Visits will be added at weeks 108, 120, 132, 144, 156, 168, 180, and 192. Patients
receiving the investigational drug may continue to take the investigational drug combination during this
time; those in the standard of care group will have to make other arrangements for treatment.
If this is a clinical trial, please specify:
Intervention:
Enrolled subjects will be treated with either GSK1349572 plus Epzicom or with a standard of care drug,
Atripla.
Primary endpoint:
Antiviral activity of GSK1349572 plus Epzicom (ABC/3TC FDC) once daily
therapy compared to Atripla over 48 weeks in HIV-1 infected ART-naïve subjects
Secondary endpoint:
Multiple secondary endpoints including
-demonstartion and evaluation of antiviral activity,
-comparison of tolerability, symptoms "bother count," quality of life, safety, antiviral activity, and
immunologic effects of the investigational treatment vs. Atripla,
-development of viral resistance,
-development of HIV-associated conditions,
-compare response to the investigational therapy by gender, race, and HIV-1 subtype
What are the major risks?
Patients may develop drug-related toxicities including liver injury, renal injury, and hypersisnsitivity
reactions. To reduce the risk of severe hypersensitivity reactions, persons carrying the high-risk HLAB5701 allele will not be enrolled. Mild-moderate nausea and headaches are frequent complaints in those
treated with the drugs in question. Psychiatric complications have also been observed in some patients
treated with these drugs.
Since the study entails frequent blood samples, there is a risk of injury or infection resulting from
venipuncture.
Statistical Analysis (optional: comments in addition to Biostatistician review)
A Phase 3 double blinded randomized study on a FDA Approved Drug, with an Investigational New
Drug and Placebo.
The statistical methodology is clearly stablished in the protocol. The sample size, power and data
analysis are all documented in the protocol with solid basis.
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What is the potential significance of the study?
The study tests an important class of antiretroviral drugs. The next-generation integrase inhibitors are
expected to have a higher barrier to virological resistance.
Ratings:
Scientific Merit:
Priority:
Resource Intensity:
Recommendation
High
High
Moderate
Reviewer's Recommendation of Submission
Approve
Reviewer's Comments
Indication of Review Completion
Yes
No
Date the Review was completed: 10/02/2012
5. Exempt Review(s) - 72 Submissions
Kemal Akat
KAK-0750 - RNA Biology in the Cardiovascular System in
Health and Disease
Amendment Form
Niroshana Anandasabapathy
NAN-0756 - A Phase 1 Safety, Pharmacokinetic, and
Immunologic Study to Evaluate CDX-301 (rhuFlt3L) in
Healthy Volunteers
Continuing Review Submission Form
Niroshana Anandasabapathy
NAN-0756 - A Phase 1 Safety, Pharmacokinetic, and
Immunologic Study to Evaluate CDX-301 (rhuFlt3L) in
Healthy Volunteers
Amendment Form
Niroshana Anandasabapathy
NAN-0756 - A Phase 1 Safety, Pharmacokinetic, and
Immunologic Study to Evaluate CDX-301 (rhuFlt3L) in
Healthy Volunteers
Amendment Form
JBL-0496 - Autosomal Dominant Polycystic Kidney
Disease Repository
Amendment Form
Jon Blumenfeld
Sean Brady
SBR-0752 - Metagenomic Analysis of Natural Product
Pathways in the Intestinal Microbiome
Continuing Review Submission Form
Jean-Laurent Casanova
JCA-0701 - Genetic Predisposition to severe respiratory
viral diseases
Amendment Form
GTR-0733 - Genetic Predisposition to Appendicitis: A Pilot
Jean-Laurent Casanova
19
Study
Amendment Form
Jean-Laurent Casanova
JCA-0699 - Genetic Predisposition to Mycobacterial
Diseases
Amendment Form
Jean-Laurent Casanova
JCA-0640 - Human Genetics of Infectious Diseases
Amendment Form
Jean-Laurent Casanova
JCA-0640 - Human Genetics of Infectious Diseases
Amendment Form
Jean-Laurent Casanova
JCA-0709 - Healthy Volunteers for the Human Genetics of
Infectious Diseases (HGID)
Amendment Form
Marina Caskey
MAC-0682 - A Randomized, Placebo-Controlled, Phase 1
Study to Evaluate the Safety and Immunogenicity of Poly
ICLC (Hiltonol) in Healthy Volunteers
Study Closure Form
Marina Caskey
BYI-0736 - A Randomized, Blinded, Placebo-Controlled
Phase 1 Study to Evaluate the Safety and Immunogenicity
of GLA in Healthy Volunteers
Amendment Form
Marina Caskey
MCA-0784 - A Randomized, Single-Blinded Phase 1 Study
to Evaluate the Safety and Immunogenicity of a Single
Administration of 5µg GLA in Healthy Volunteers
Amendment Form
Edgar Charles
Pilot Study to Assess Gut Mucosal B Cells in Individuals
Co-Infected with HCV and HIV
Miscellaneous Submission Form
Barry Coller
BCO-0738 - Establishment of the International Society on
Thrombosis and Haemostasis Bleeding Assessment Tool
Repository
Amendment Form
Barry Coller
BCO-0738 - Establishment of the International Society on
Thrombosis and Haemostasis Bleeding Assessment Tool
Repository
Amendment Form
Barry Coller
BCO-0726 - Studies of: 1. normal and abnormal blood
cells, 2. genetic disorders of blood cells and coagulation
factors, and 3. transforming growth factor-ß1 in health and
disease: NORMALS
Amendment Form
Ronald Crystal
RCR-0391 - The Natural History of Gene Expression in
20
Lung Cells of Non-Smokers, Smokers, and Ex-Smokers in
Health and Disease
Continuing Review Submission Form
Ana Emiliano
EKE-0724 - Effect of Metabolic State on Anxiety in Human
Subjects
Continuing Review Submission Form
Ana Emiliano
EKE-0724 - Effect of Metabolic State on Anxiety in Human
Subjects
Miscellaneous Submission Form
Elaine Fuchs
EFU-0529 - Gene Expression, Differentiation, and Hair
Disorders in Human Skin (Protocols EFU-0472 and 0473
were combined into this one protocol)
Amendment Form
Daniel Gareau
DGA-0775 - Melanoma Advanced Imaging Dermascope
(mAID)
Amendment Form
Emma Guttman
Analysis of Immune Reactions Occurring Upon
Administration of
Patch Tests and Contact Dermatitis Affected Skin
Continuing Review Submission Form
Peter Holt
PHO-0785 - Diet Induced Weight Loss Reduces
Inflammation and Crown-like Structures and Corrects
Immune Dysfunction in Subcutaneous Adipose Tissue In
Class 2-3 Obese Women: A Pilot Study
Amendment Form
Peter Holt
PHO-0785 - Diet Induced Weight Loss Reduces
Inflammation and Crown-like Structures and Corrects
Immune Dysfunction in Subcutaneous Adipose Tissue In
Class 2-3 Obese Women: A Pilot Study
Amendment Form
Peter Holt
PHO-0735 - Pilot: Obesity Associated Circulating Derived
Factors and Cancer.
Amendment Form
Peter Holt
SWP-0620 - Obesity associated Colorectal inflammation;
the effects of weight loss
Study Closure Form
Ali Jabbari
AJA-0740 - Analysis of Skin Biopsies from Discoid Lupus
Patients
Study Closure Form
Ana Krieger
AKR-0102 - Mechanisms of Endothelial Cell Dysfunction in
Sleep Apnea
Amendment Form
21
James Krueger
JKR-0744 - A Phase 3, multi-site, randomized, doubleblind, placebo-controlled, parallel-group study of the
efficacy and safety of 2 oral doses of CP-690,550 in
subjects with moderate to severe chronic plaque
psoriasis Protocol Number: A3921079
Amendment Form
James Krueger
JKR-0686 - Screening for entry into skin disease studies
Continuing Review Submission Form
James Krueger
JKR-0641 - A Study to Document The Natural History of
Atopic Dermatitis Before, During, and After Treatment with
Conventional Therapies
Amendment Form
James Krueger
JKR-0788 - An Open Label study employing the topical
immunomodulator diphenylcyclopropenone in a stabilized
gel to treat cutaneous metastases in melanoma
Amendment Form
James Krueger
JKR-0723 - Randomized, Double-Blinded, PlaceboControlled Parallel-Design dose-Range Finding Study of
Subcutaneous SCH 900222 in Subjects with Moderate-toSevere Chronic Plaque Psoriasis
Amendment Form
James Krueger
JKR-0491 - Skin biopsy for analysis of cell growth, cell
differentiation and inflammation in the skin
Amendment Form
James Krueger
JKR-0744 - A Phase 3, multi-site, randomized, doubleblind, placebo-controlled, parallel-group study of the
efficacy and safety of 2 oral doses of CP-690,550 in
subjects with moderate to severe chronic plaque
psoriasis Protocol Number: A3921079
Amendment Form
James Krueger
JKR-0641 - A Study to Document The Natural History of
Atopic Dermatitis Before, During, and After Treatment with
Conventional Therapies
Amendment Form
James Krueger
JKR-0663 - A study to evaluate reversal of the pathological
epidermal phenotype in severe AD with suppression of
immune activation during cyclosporine A therapy
Amendment Form
James Krueger
JKR-0744 - A Phase 3, multi-site, randomized, doubleblind, placebo-controlled, parallel-group study of the
efficacy and safety of 2 oral doses of CP-690,550 in
subjects with moderate to severe chronic plaque psoriasis
Protocol Number: A3921079
22
Amendment Form
James Krueger
JKR-0742 - Analysis of Immune Reactions Occurring in
Normal Volunteers Upon Administration of the Topical
Immunomodulator Diphenylcyclopropenone
Amendment Form
Martin Markowitz
MMA-0774 - Correlates and Consequences of Increased
Immune Activation in Injection Drug Users
Amendment Form
Martin Markowitz
MMA-0776 - Correlates and Consequences of Increased
Immune Activation in HIV-1 infected Injection Drug Users
Amendment Form
Martin Markowitz
MMA-0781 - A Phase IIb, dose ranging study of oral
GSK1265744 in combination with nucleoside reverse
transcriptase inhibitors for induction of HIV-1 virologic
suppression followed by an evaluation of maintenance of
virologic suppression when oral GSK1265744 is combined
with oral rilpivirine in HIV-1 infected, antiretroviral therapy
naive adult subjects
Amendment Form
Martin Markowitz
MMA-0761 - A Phase 3b Randomized, Open Label Study
to Evaluate Switching from Regimens Consisting of a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) plus
Emtricitabine (FTC) and Tenofovir DF (TDF) to the
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil
Fumarate Single-Tablet Regimen (EVG/COBI/FTC/TDF) in
Virologically Suppressed, HIV 1 Infected Patients (GS-US236-0121)
Amendment Form
Martin Markowitz
MMA-0754 - A Phase 2b Randomized, Double-Blind,
Double-Dummy Trial of 100 or 200 mg Once-Daily Doses
of Cenicriviroc (CVC, TBR-652) or Once-Daily EFV, Each
With Open-Label FTC/TDF, in HIV-1-Infected,
Antiretroviral Treatment-Naïve, Adult Patients With Only
CCR5Tropic Virus (TBR-652-2-202)
Amendment Form
Martin Markowitz
MMA-0774 - Correlates and Consequences of Increased
Immune Activation in Injection Drug Users
Amendment Form
Martin Markowitz
MMA-0776 - Correlates and Consequences of Increased
Immune Activation in HIV-1 infected Injection Drug Users
Amendment Form
Martin Markowitz
MMA-0448 - Viral and Host Factors in the Transmission
and Pathogenesis of HIV (This protocol was formerly RKO23
0201; PI has changed from Kost to Markowitz, therefore,
number was changed.)
Continuing Review Submission Form
Martin Markowitz
MMA-0592 - The Transmission and Fitness of Drug
Resistant HIV-1 (NIH Grant #2R01-AI-47033-06)
Study Closure Form
Martin Markowitz
MMA-0755 - The STOP Project-Screening Targeted
Populations to Interrupt On-going Chains of HIV
Transmission with Enhanced Partner Notification
Continuing Review Submission Form
Martin Markowitz
MMA-0781 - A Phase IIb, dose ranging study of oral
GSK1265744 in combination with nucleoside reverse
transcriptase inhibitors for induction of HIV-1 virologic
suppression followed by an evaluation of maintenance of
virologic suppression when oral
GSK1265744 is combined with oral rilpivirine in HIV-1
infected, antiretroviral therapy naive adult subjects
Amendment Form
Martin Markowitz
MMA-0761 - A Phase 3b Randomized, Open Label Study
to Evaluate Switching from Regimens Consisting of a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) plus
Emtricitabine (FTC) and Tenofovir DF (TDF) to the
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil
Fumarate Single-Tablet Regimen (EVG/COBI/FTC/TDF) in
Virologically Suppressed, HIV 1 Infected Patients (GS-US236-0121)
Amendment Form
Martin Markowitz
MMA-0597 - A Phase 2, Open-Label, Multicenter Study of
the Safety of Ritonavir-Boosted GS-9137 (GS-9137/r)
Administered in Combination with Other Antiretroviral
Agents for the Treatment of HIV-1 Infected Subjects
Study Closure Form
Martin Markowitz
MMA-0781 - A Phase IIb, dose ranging study of oral
GSK1265744 in combination with nucleoside reverse
transcriptase inhibitors for induction of HIV-1 virologic
suppression followed by an evaluation of maintenance of
virologic suppression when oral
GSK1265744 is combined with oral rilpivirine in HIV-1
infected, antiretroviral therapy naive adult subjects
Amendment Form
Martin Markowitz
MMA-0639 - Acute HIV-1 Infection Prospective Cohort
Study (CHAVI-001)
Study Closure Form
Ana Pereira
APE-0767 - Sleep Disordered Breathing and GlutamateInduced Excitotoxicity in the Human Hippocampus as a
24
Risk for Alzheimer’s Disease
Amendment Form
Donald Pfaff
DPF-0743 - Correlations Amongst Sympathetic Arousals,
Cortical Arousals, and Quality of Sleep
Amendment Form
Manish Ponda
MPO-0787 - The Effect of Oral Vitamin D vs. Narrow-Band
UV-B Exposure on the Lipid Profile
Amendment Form
Manish Ponda
MAP-0683 - The Effect of Vitamin D3 Repletion on Small
LDL Particle Number in Subjects at Elevated
Cardiovascular Risk
Study Closure Form
Charles Rice
CRI-0657 - Isolation and Culture of Tissue Culture
Infectious HCV from Blood
Continuing Review Submission Form
Nicholas Schiff
NSC-0764 - Neurophysiologic Studies of Neurological
Disorders of Consciousness
Miscellaneous Submission Form
Nicholas Schiff
NSC-0764 - Neurophysiologic Studies of Neurological
Disorders of Consciousness
Amendment Form
Peter Schlegel
PSC-0633 - A three-part trial assessing the effects of 7
alpha-methyl-19-nortestosterone (MENT) on blood
pressure in normal men: an open-label pilot study, a
nested pharmacokinetic study, followed by a randomized,
double-blind, placebo-controlled study
Continuing Review Submission Form
Sarah Schlesinger
SSC-0710 - A randomized, placebo-controlled, doseescalating, double-blinded phase 1 study to evaluate
safety and immunogenicity of anti-DEC-205 monoclonal
antibody (mab) targeted HIV gag p24 vaccine (DCVax001) with poly ICLC (Hiltonol) as adjuvant in HIVuninfected healthy volunteers
Amendment Form
Yevgeniy Sirotin
YSI-0760 - The Effect of Adaptation on Olfactory
Perception
Continuing Review Submission Form
Yevgeniy Sirotin
YSI-0760 - The Effect of Adaptation on Olfactory
Perception
Amendment Form
Agata Smogorzewska
AAU-0112 - Entrance into the International Fanconi
Anemia Registry (IFAR)
25
Amendment Form
Sohail Tavazoie
STA-0681 - Identification of microRNAs that predict
metastatic relapse and sensitivity to chemotherapy in
human colorectal cancer
Continuing Review Submission Form
Vosshall, Leslie
LVO-0684 - Genetic Basis of Odor Discrimination
Continuing Review Submission Form
John Zabriskie
JZA-0540 - Natural History of Rheumatic Fever at
Rockefeller University Hospital
Continuing Review Submission Form
6. Reports of Director and Co-Director
Dr. Coller reports that Dr. Christopher P. Austin has been named director of NIH’s newest center, the
National Center for Advancing Translational Sciences. NIH director Dr. Francis Collins made the
announcement at the inaugural meetings of the NCATS Advisory Council and Cures Acceleration
Network (CAN) review board. Austin succeeded NCATS acting director Dr. Thomas Insel on Sept. 23.
Dr. Coller noted that Dr. Rosenblum was present at the Rockefeller University Clinical and Translational
Research Day and was very supportive of the program.
Ms. Budescu suggested for the future that there be a brainstorming session to discuss where
translational research is headed.
Dr. Coller noted that the Center continues to recruit Mid-Career lever researchers.
Dr. Krueger noted that the SINGULEX is up and running and will be available shortly for campus use.
7. Reports of Subcommittees
a. Pilot Project and Collaborative Studies subcommittee (James Krueger)
Request to support Pilot funding was approved.
b. Research Education Training and Career Development Subcommittee (Sarah Schlesinger)
Dr. Schlesinger noted that the Certificate Program is underway and the second round is
currently being planned. She also noted that the groups trip to Ellis Island was extremely
informative regarding the way in which people were screened.
8. Review of Center Metrics and Resource Utilization
9. Assessment of Underutilization, Inappropriate Use, and Low Productivity
10. Review of Budget
11. Strategic Planning Issues
The meeting was adjourned at 4:58pm
26
Respectfully submitted,
_________________________________
Maija Williams, MPH
ACCTS Administrator
_________________________________
Barry S. Coller , MD
Acting Chair
27