fsgs-combined-presentation

Slide 1: 

01/01/2006 1 FOCAL SEGMENTAL GLOMERULOSCLEROSIS THERAPEUTIC INTERVENTIONAL TRIAL Multi-center, prospective, randomized trial with two active arms 500 Children and young adults 175 Participating Sites

External Advisory Committee : 

01/01/2006 2 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

STEERING COMMITTEE : 

01/01/2006 3 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

INCLUSION CRITERIA : 

01/01/2006 4 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 >2.0 1st am void at time of randomization Biopsy confirmed as primary FSGS (including all subtypes) by CCC pathologist

INCLUSION CRITERIA : 

01/01/2006 5 INCLUSION CRITERIA 6. Steroid resistance prior to time of randomization marked by failure to achieve sustained urine protein/creatinine ratio <2.0 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

EXCLUSION CRITERIA : 

01/01/2006 6 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

EXCLUSION CRITERIA : 

01/01/2006 7 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

EXCLUSION CRITERIA : 

01/01/2006 8 EXCLUSION CRITERIA Obesity defined as a. BMI > 97th %‑ile for age 2‑20 years b. BMI > 35 for age >21 c. based on estimated dry weight at onset of disease prior to steroid therapy Allergy to study medications Inability to consent/assent

SURVEY OF PARTICIPATING CENTERS : 

01/01/2006 9 SURVEY OF PARTICIPATING CENTERS 58% unwilling to consider >6 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

ARM A : 

01/01/2006 10 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

ARM B : 

01/01/2006 11 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

ARM B : 

01/01/2006 12 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

Logistics : 

01/01/2006 13 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

OUTCOMES : 

01/01/2006 14 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

Basis of Primary Outcome : 

01/01/2006 15 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

Definition of Remission : 

01/01/2006 16 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.

Primary Outcome (first 52 Weeks) : 

01/01/2006 17 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 > 0.2 in Weeks 26 – 52

Main Secondary Outcome (Weeks 52-78) : 

01/01/2006 18 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

Study Power : 

01/01/2006 19 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.

Data Flow : 

01/01/2006 20 Data Flow Data entered in data base Paper form provided to core Query to CCC and PS CCC and PS resolve inquiry 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 study’s data entry web site: http://clinapps.bio.ri.ccf.org PS = Participating Site CCC = Core Coordinating Center DCC = Data Coordinating Center

Central Biochemistry Laboratory (CBL) (Spectra East) : 

01/01/2006 21 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

Biopsy Confirmation : 

01/01/2006 22 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

Drug Distribution Center(McKesson BioServices) : 

01/01/2006 23 Drug Distribution Center(McKesson BioServices) - MMF - CSA - Dexamethasone - Prednisone Centrally provided drugs (free): - 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

REIMBURSEMENTProposed : 

01/01/2006 24 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

REIMBURSEMENTProposed : 

01/01/2006 25 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

REIMBURSEMENTProposed : 

01/01/2006 26 REIMBURSEMENTProposed Per subject reimbursement based on Biopsy slide prep and mailing Clinic visits with H&P Lab draws and specimen handling Pharmacy dispensing, relapse therapy CRF completion Subject parking, meals, etc Study coordination Reasonable indirects for non-patient care

FSGS Clinical Trial (FSGS-CT)Ancillary Studies : 

01/01/2006 27 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.

Slide 28: 

01/01/2006 28 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. Definition of Ancillary Studies

Instructions for Requests : 

01/01/2006 29 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)

FOCAL SEGEMENTAL GLOMERULOSCLEROSIS NOVEL THERAPY (FONT) WORKING GROUP : 

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

Slide 31: 

01/01/2006 31 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

Slide 32: 

01/01/2006 32 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

FONT : 

01/01/2006 33 FONT Target Population Clinical trial screen failures Clinical trial treatment failures Timeline Protocol complete and grant submission 3/18/04 Recruitment 2005

Concept Development Grant: Pathogenesis of FSGS : 

01/01/2006 34 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.

Pathophysiology CDG: Structure : 

01/01/2006 35 Pathophysiology CDG: Structure PI: Bill Schnaper Grouped into “pods” to develop projects for a program project grant application

Pathophysiology CDG: Process : 

01/01/2006 36 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.

ACTION TIME LINE : 

01/01/2006 37 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

Back-up Slides Follow : 

01/01/2006 38 Back-up Slides Follow

OTHER CONSIDERATIONS : 

01/01/2006 39 OTHER CONSIDERATIONS Relapse Definition: Up/c > 2.0, at least 2X the nadir and serum alb < 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

Study Power (Detailed) : 

01/01/2006 40 Study Power (Detailed) 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 Remission at 52 Wks No remission at 52 Wks

Necessary Covered Costs : 

01/01/2006 41 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.

Instructions for Requests : 

01/01/2006 42 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 - @ of participants - type of storage & proposed lab - need for study data (baseline, etc)

Instructions for Requests : 

01/01/2006 43 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

Analysis of Results : 

01/01/2006 44 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.