FOCAL SEGMENTAL GLOMERULOSCLEROSIS

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FOCAL SEGMENTAL GLOMERULOSCLEROSIS

• THERAPEUTIC INTERVENTIONAL TRIAL
• Multi-center, prospective, randomized trial with
  two active arms
• 500 Children and young adults
• 175 Participating Sites

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External Advisory Committee

• Aaron Freidman, Univ of WI Chair
• James Balow MD, NIH
• Marie Diener-West PhD, Johns Hopkins
• Agnes Fogo MD, Vanderbilt
• Normon Fost MD, MPH, Univ of WI
• Andrew Levey MD, NEMC
• John Lewy MD,Tulane
• John Sedor MD, Cleveland Metro Health

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STEERING COMMITTEE

• Chairman
• Norman Siegel
• Core Coordinating Centers
• Richard Fine
• Debbie Gipson
• Ron Hogg
• Rick Kaskel
• Sandra Watkins
• Data Coordinating Center
• Tom Greene
• NIH Project Officer
• Marva Moxey-Mims

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INCLUSION CRITERIA

• Age 2-35 years at onset of proteinuria
• Age 35 years at time of randomization
• Estimated GFR 50 ml/min/1.73m2 at time of
  randomization
• Urine protein/creatinine ratio gt2.0 1st am void
  at time of randomization
• Biopsy confirmed as primary FSGS (including all
  subtypes) by CCC pathologist

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INCLUSION CRITERIA

• 6. Steroid resistance prior to time of
  randomization marked by failure to achieve
  sustained urine protein/creatinine ratio lt2.0
  during
• a. minimum 8 weeks prednisone therapy
• i. ? 4 weeks alternate day
• ii. minimum daily dose on treatment days,
  the lower of 2 mg/kg or 60 mg
• iii. maximum 3 doses of IV pulse MP
• b. may include ACEI, ARB, Vitamin E, or
  lipid-lowering therapy

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EXCLUSION CRITERIA

• Secondary FSGS
• Prior therapy with, cyclosporine, tacrolimus,
  mycophenalate mofetil, sirolimus, or azathioprine
• Therapy during last 30 days cytoxan,
  chlorambucil, levamisole, methotrexate or
  nitrogen mustard
• Lactation, pregnancy or refusal of birth control
  in women of child-bearing age
• Participation in another therapeutic trial
  concurrently or 30 days prior to randomization

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EXCLUSION CRITERIA

• Active/serious infection (including but not
  limited to Hepatitis B or C, HIV)
• Malignancy
• Uncontrolled hypertension
• Diabetes mellitus Type I or II
• Organ transplantation

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EXCLUSION CRITERIA

• Obesity defined as
• a. BMI gt 97th -ile for age 2-20 years
• b. BMI gt 35 for age gt21
• c. based on estimated dry weight at onset of
  disease prior to steroid therapy
• Allergy to study medications
• Inability to consent/assent

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SURVEY OF PARTICIPATING CENTERS

• 58 unwilling to consider gt6 mo qod prednisone
• 38 unwilling to consider IV pulse MP
• 34 unwilling to consider MMF pulse cytoxan
• 20 unwilling to consider MMF, Tacro, CSA MMF,
  MMF pulse MP, or sirolimus

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ARM A

• Cyclosporine for 12 months
• 5-6 mg/kg/day BID
• Adjust to trough level 100-250 mg/dl
• Adjust for toxicity related to
• ?GFR
• ? K
• Other significant side effects
• Lisinopril or Losartan for 18 months
• dose of each based on wgt and tolerance
• Prednisone tablets or prednisolone liquid
• 0.3 mg/kg/dose, max 15 mg QOD x 6 mos

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ARM B

• MMF for 12 months
• 25-36 mg/kg/day, max 2 g/day
• Adjust for toxicity related to
• GI
• Leukopenia
• Anemia
• Lisinopril or Losartan for 18 months
• dose of each based on wgt and tolerance
• Prednisone tablets or prednisolone liquid
• 0.3 mg/kg/dose, max 15 mg QOD x 6 mos

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ARM B

• Dexamethasone
• 0.9 mg/kg/dose, max 40 mg
• 2 consecutive days
• Q wk for 8 wks
• Then Q2 wks over 18 wks
• Then Q4 wks over 24 wks
• Total 46 doses

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Logistics

• 18 Month trial
• 15 visits with specimens obtained
• Baseline follow-up labs
• Then Q 6 mo until close
• Central laboratory All tests provided
• Central pharmacy All drugs provided
• On-line or paper reports

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OUTCOMES

• Primary outcome
• Attainment of partial or complete remission
• Main Secondary Outcome
• Relapse after withdrawal of immunosuppressive
  agents
• Secondary Outcomes
• Treatment failures
• Change in est GFR
• Side effects
• Quality of life

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Basis of Primary Outcome

• Large decline of proteinuria required to
  demonstrate clear benefit
• Non-responders at 6 months designated failures so
  patients may switch to alternative therapy
  without affecting primary outcome
• Outcome based on remission of proteinuria through
  12 months for partial or complete responders at 6
  months

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Definition of Remission

• Partial Remission 50 decline in the first
  morning urine Up/c from the mean of two baseline
  measurements to a level between 0.2 and 2.0
• Complete Remission Decline in Up/c to a level no
  greater than 0.2.

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Primary Outcome (first 52 Weeks)
Without partial or complete remission at Week 26
With partial or complete remission at Week 26
1 but Up/c gt 0.2 in Weeks 26 52
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Main Secondary Outcome (Weeks 52-78)

• To determine if interventions lead to remissions
  which are sustained following withdrawal of
  therapy
• Assigned to worst level (E) for patients with no
  remission at Weeks 26 or 52
• For patients with a primary outcome of 3 or
  better

1 but Up/c between 0.2 and 2 throughout Weeks
52-78 2 with partial/complete remission
maintained throughout Weeks 52-78
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Study Power

• Assumes 5 Type I error, and that the primary
  outcome is ascertained in 95 of the 500
  randomized patients
• Depending on the remission rate in the CSA
  group, the study has 80 power to detect an
  absolute increase of 10.5 to 11.5 in the
  remission rate (levels 4, 5, or 6) for MMF
  pulse steroid vs. CSA.

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Data Flow

• PSs may enter data online or provide paper forms
  to their CCC for key entry
• DCC sends inquiries to PS and its CCC
• CCC and PS resolve data
• discrepancies
• Study materials, including current forms to be on
  the studys data entry web site
  http//clinapps.bio.ri.ccf.org

Data entered in data base
Paper form provided to core
Query to CCC and PS
PS Participating Site CCC Core Coordinating
Center DCC Data Coordinating Center
CCC and PS resolve inquiry
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Central Biochemistry Laboratory (CBL) (Spectra
East)

• CBL measurements Urine protein/creatinine,
• 18 serum measurements, Fasting Lipids, CSA
  level, Hematology, Screening for HIV, HEP B, and
  HEP C
• CBL to send kits with Fed Ex labels, shipping
  boxes, tubes, collection cups, ice packs, etc.
• CBL faxes routine results to PSs, transmits
  results to central data base overnight.
• Immediate panic reports of life-threatening
  values

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Biopsy Confirmation

• 5 Core Biopsy Reading Centers associated with 5
  Core Coordinating Centers
• PSs to send Biopsy Core
• At least one H and E slide
• at least one special stain slide
• electron microscopy prints
• immunofluorescence report

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Drug Distribution Center(McKesson BioServices)

• Centrally provided drugs (free)

• - MMF
• - CSA

• - Dexamethasone
• - Prednisone

- Lisinopril - Losartan

• During baseline, PS specifies pill or liquid
  form, and whether ACEi or ARB is required
• Drug Distribution Center to ships 6-month
  supplies at randomization, 6 mos, and 12 mos
• PSs can request emergency shipments in rare
  event of shortfall

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REIMBURSEMENTProposed

• Based on survey of PSs
• 1600 per center start-up
• Effort for IRB application and contract
• Pharmacy start-up
• Lab start-up
• Administrative fees
• Dispersed upon receipt of IRB approval and signed
  contract with Clinical Coordinating Center
• 1000 per patient bonus for enrollment in the
  first year study is open for enrollment
• Travel reimbursement to training sessions

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REIMBURSEMENTProposed

• 4200 per subject randomized
• 1500 upon randomization
• 500 upon receipt of Wk 26 CRFs
• 500 upon receipt of Wk 52 CRFs
• 1500 upon receipt of Wk 78 CRFs
• 200 at close of study
• 250 transfer fee

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REIMBURSEMENTProposed

• Per subject reimbursement based on
• Biopsy slide prep and mailing
• Clinic visits with HP
• Lab draws and specimen handling
• Pharmacy dispensing, relapse therapy
• CRF completion
• Subject parking, meals, etc
• Study coordination
• Reasonable indirects for non-patient care

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FSGS Clinical Trial (FSGS-CT)Ancillary Studies

• To enhance the value of the FSGS-CT, the Steering
  Committee welcomes proposals from individual
  investigators to carry out ancillary studies
  which will be reviewed by the Ancillary Studies
  Committee (ASC) the Steering Committee.
• An ancillary study will be used for the
  collection of additional data not collected or
  analyzed as part of the routine FSGS-CT data set.

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Definition of Ancillary Studies

• Must have direct relevance to the FSGS-CT goals
  not interfere with or impede the completion of
  its objectives the resources of the DCC the
  participating sites/cores.
• Applicants must partner with at least one current
  investigator in the FSGS-CT.
• Studies REQUIRE external funding R01s, private
  foundations, institutions, or industry.
• Sufficient funds MUST be available.

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Instructions for Requests

• Written request submitted in 2-4 pages excluding
  references and NIH biosketches.
• List PI co-investigators
• FSGS-CT liaison investigator
• Hypothesis to be tested
• Background significance (1 page)
• Design-Methods (2 pages)

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FOCAL SEGEMENTAL GLOMERULOSCLEROSIS NOVEL THERAPY
(FONT) WORKING GROUP

• PI Debbie Gipson
• Lead Investigator Howard Trachtman
• Concept Development Award UO1 DK63455-02S1
• Funding period 10/1/04-4/1/04
• Goals Identify potential novel therapeutic
  agents
• for the treatment of FSGS

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FONT WORKING GROUP

• Coordinators Erica Christen, Tonya Jenkins
• IM Jeff Kopp, Dan Cattran, John Middleton
• Basic/clinical science Agnes Fogo, Allison Eddy.
  Mary Anne Dooley
• Industry Sandy Bryant, Steve Ledbetter, Henry
  Hsu
• Pharmacology Melanie Joy
• Biostatistics Tom Greene, Jennifer Gassman
• Moral support Norm Siegel, Marva Moxey Mims

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POTENTIAL NOVEL THERAPIES

• Anti-TNF? soluble receptor or MAb
• Anti-TGF? MAb or oral antagonist
• Pirfenidone
• Other possibilities
• Ideas/suggestions welcome by DG and HT

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FONT

• Target Population
• Clinical trial screen failures
• Clinical trial treatment failures
• Timeline
• Protocol complete and grant submission 3/18/04
• Recruitment 2005

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Concept Development Grant Pathogenesis of FSGS

• Primary Goal To develop a comprehensive approach
  to examining patient materials to investigate the
  pathogenesis of FSGS.
• Specific aims
• To maximize the opportunity afforded by the
  clinical trial to investigators interested in
  examining the origin, pathophysiology and natural
  history of FSGS.
• To facilitate communication and collaboration
  among these investigators.
• To encourage the recruitment of additional
  investigators into the science of FSGS.

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Pathophysiology CDG Structure

• PI Bill Schnaper
• Grouped into pods to develop projects for a
  program project grant application

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Pathophysiology CDG Process

• Each pod will be expanded by the inclusion of
  several nationally-recognized experts in their
  respective fields.
• Ongoing discussions will lead to the
  crystallization of several overlapping projects.
• Intent is to be as inclusive as possible,
  balanced against need for scientific focus and
  rigor in proposal so that it will be competitive
  for funding.
• Anticipated design of proposal will include
  opportunities for additional pilot/feasibility
  studies to bring new investigators and new ideas
  into the process.
• Also, will request support for specific sample
  handling to complement resources of the clinical
  trial.

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ACTION TIME LINE

• 10/02-9/03 Protocol development and EAC
• approval
• NOW IRB approval
• Contract with Clinical Coordinating Center
• 3/04-2/06 Subject enrollment
• 3/06-4/07 Study completion
• 5/07-9/07 Analysis and manuscript

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Back-up Slides Follow
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OTHER CONSIDERATIONS

• Relapse
• Definition Up/c gt 2.0, at least 2X the nadir
  and serum alb lt 3 g/dl
• Therapy Prednisone 2 mg/kg/day (max 60 mg) x 2
  wk then qod x 1 wk. 2 full courses allowed
• Whether to treat is optional but if treated this
  protocol must be employed

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Study Power (Detailed)
Remission at 52 Wks
No remission at 52 Wks

• The study has 80 power to detect the
  following increases
• in remission rate for MMF pulse steroid
  vs. CSA
• Scenario A From 32.5 to 43.3
• Scenario B From 45.0 to 56.5
• Scenario C From 60.0 to 70.5

Assumes 5 Type I error, primary outcome
ascertained in 95 of patients
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Necessary Covered Costs

• Costs incurred by FSGS-CT Core Coordinating
  Centers, Participating Sites Central Lab
  (shipment of samples, etc), the DCC for sample
  selection, preparing tracking analysis files,
  statistics, integration of new ancillary data
  back in the combined FSGS-CT database.

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Instructions for Requests

• Description of specimen or data request (2)
• - specific type of samples, volume,
• - time of collection (base vs post)
• - use of thawed specimens
• - _at_ of participants
• - type of storage proposed lab
• - need for study data (baseline, etc)

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Instructions for Requests

• Time table with key dates
• Local IRB approval (HIPPA)
• Agreement to return unused specimens
• Budgetary issues source of funding draft
  budget
• Proposals reviewed monthly

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Analysis of Results

• Unless specifically arranged, all analyses will
  take place at the DCC or the PI will submit the
  analyses to the DCC for quality assurance.
• Proposals for manuscripts will be submitted for
  review to the Publications Committee.
• Results will be reported to enrolled patients.