Ignite Creation Date:
2024-05-05 @ 11:58 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00193648
Status:
COMPLETED
Last Update Posted:
2007-10-22
First Post:
2005-09-10
Brief Title:
Pilot Studies of Novel Therapies to Treat Resistant Focal Segmental Glomerulosclerosis FSGS
Sponsor:
Northwell Health
Organization:
Northwell Health
Study Overview
Official Title:
Novel Therapies for Resistant FSGS
Status:
COMPLETED
Status Verified Date:
2007-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The current management of primary FSGS is predicated on the assumption that the disease is caused by an immune-mediated disturbance in glomerular barrier function Therefore most treatment protocols have involved immunosuppressive drugs given singly or in combination However the efficacy of this type of therapy has been disappointing and the long-term prognosis for renal survival in patients with resistant FSGS is poor An alternative approach that targets the fibrosis pathway may represent a novel approach to the treatment of resistant FSGS In this R21 the investigators will test the hypothesis that two novel agents - a tumor necrosis factor-alpha TNF-α antagonist and a peroxisome proliferator activator receptor-gamma PPARγ agonist - can be administered safely to patients with resistant FSGS In the R21 feasibilitypilot phase pharmacokinetic studies will be conducted to assess the impact of proteinuria on the kinetics of the novel drugs in children and adults
Specific Aim 1 To assess the safety and tolerability of two novel drugs - a TNF-α antagonist and a PPARγ agonist - in patients with resistant FSGS
Specific Aim 2 To conduct a pharmacokinetic PK assessment of the selected agents to enable selection of medication regimens for investigation in a randomized Phase II study
Specific Aim 1 To assess the safety and tolerability of two novel drugs - a TNF-α antagonist and a PPARγ agonist - in patients with resistant FSGS
Specific Aim 2 To conduct a pharmacokinetic PK assessment of the selected agents to enable selection of medication regimens for investigation in a randomized Phase II study
Detailed Description:
Description of study visits
Screening Visit Eligibility Studies
1 History and physical examination
2 Urine protein and creatinine excretion Proteinuria Upc will be expressed as the proteincreatinine ratio mgmg in a single early morning specimen
3 Serum creatinine and calculated GFR The GFR will be calculated using the Schwartz formula for patients below 18 years of age and Cockroft-Gault for those 18 years or older
4 Serum Na K HCO3- Cl- glucose BUN albumin cholesterol AST ALT alkaline phosphatase CBC ANA CH50 pregnancy test
5 HIV Hepatitis B and C serology if not done in the previous 12 months
6 TB skin test if not done in the previous 12 months
7 Existing renal biopsy tissue will be assessed for all subjects who have not had the diagnosis of FSGS confirmed by an FSGS-CT core pathologist only in screen failures
Baseline Visit Week 0 Visit
1 Serum glucose albumin and creatinine concentrations
2 TNF-alpha level
3 Baseline anti-adalimumab antibody AAA level in patients assigned to Humira treatment
4 A urine plasma serum and DNA sample will be collected for storage in the NIDDK FONT Biorepositories at Fisher Bioservice and the Rutgers Cell DNA Repository for patients who consent to this procedure A request will be made to store any residual renal tissue collected for clinical indications during the FONT trial in the NIDDK Biorepository
5 PK assessment see below
Follow-up Assessment Week 2 4 8 and 12 Visits
1 Interval history physical examination assessment of adverse events
2 Urine protein excretion
3 Serum creatinine and calculated GFR serum Na K HCO3 Cl- glucose BUN ALT AST at all visits
4 Serum albumin cholesterol ANA CH50 at 8-week visit CBC at all visits except 2-week visit
5 Trough serum adalimumab level in patients assigned to receive Humira at all visits except 2-week visit
6 Serum AAA level at 12-week visit in patients assigned to Humira treatment
7 Pregnancy test at 12-week visit
Final Assessment Week 16 Visit
1 Interval history physical examination assessment of adverse events
2 Urine protein excretion
3 Serum creatinine and calculated GFR
4 Serum Na K HCO3 Cl- glucose BUN albumin cholesterol AST ALT alkaline phosphatase CBC ANA CH50 and serum TNF-alpha levels
5 Serum AAA level in patients assigned to Humira treatment
6 Serum plasma and urine samples to the NIDDK Biosample Repository at Fisher Bioservice
7 Assessment of patient satisfaction with treatment using TSQM
8 Steady state PK assessment see below
The following Table summarizes the laboratory assessment during the R21 study
Study Medications
Study medication will be shipped in a single batch sufficient to complete the 4-month treatment period A supply will be shipped to the participating site for each individual patient that is enrolled Please complete the Site Registration Form and provide a complete and accurate shipping address for receipt of study medication during the week Monday though Friday 9 AM - 5 PM This information will be forwarded to the pharmaceutical companies to enable timely shipment of drug to each site
Formulation and administration of experimental novel therapies
Adalimumab Humira TNF-α antibody BB-IND 11714
This medication will be provided by Abbott Laboratories and will be available as a liquid It will be administered as a subcutaneous injection every other week The therapeutic dose of adalimumab will be 24 mgm2 to a maximum of 40 mgdose every other week for the entire treatment period
Patients should be instructed to rotate the site of injection In order to reduce the pain associated with the biweekly adalimumab injections patients can apply EMLA crème or steroid inhaler spray prior to administration of the medication After the injection is completed the patient can take Tylenol as needed or apply ice to the site for symptomatic pain relief
Patients receiving Humira will be required to write down dates and times of drug administration and bring the administration log to each study visit In addition when a patient is assigned to the Humira arm a per protocol dose schedule listing the week and the optimal date of drug administration will be sent with the medication to the site This sheet can be used to facilitate scheduling of visits and it can be shared with the patient
Rosiglitazone Avandia PPARgamma agonist IND69782
This medication will be provided by Glaxo Smith Kline and will be available as pills It will be administered orally in two divided daily doses The therapeutic dose of rosiglitazone will be 3 mgm2day administered in two divided doses to a maximum of 4 mg twice a day The twice daily dosing schedule is based on studies indicating greater antiproteinuric effect of rosiglitazone in type 2 diabetes when administered in this manner
Pharmacokinetic PK Studies
Sampling Scheme
The blood and urine collection scheme for the PK analysis will be conducted over 48 hours in a GCRC when the patient is scheduled to receive the first dose single dose PK assessments of adalimumab or rosiglitazone and after the 8th dose of adalimumab steady state of 105 days or during the 4th month of rosiglitazone therapy for multiple dose PK assessments
A blood sample 25-4 mlsample 1-25 ml plasmaserum will be drawn at each time point For adalimumab a total of 6 serum samples 4 ml each 24 ml of blood in total will be obtained For rosiglitazone a total of 11 plasma samples 25 ml each 25 ml of blood in total will be obtained during the 48-hour PK study The total amount of blood drawn should be 3 mlkg over this period
Urine will be collected at the following intervals 0-2 2-12 12-24 24-36 and 36-48 hours The total volume of urine for each time interval should be recorded in mL and an aliquot should be analyzed for proteincreatinine ratio in the local laboratory The measurements of urinary protein excretion over the 48 hour period will be used to correlate PK parameters of the study medication with concurrent level of proteinuria
An aliquot of the urine sample collected during each time interval should be saved in the specimen kit for determination of urinary excretion of rosiglitazone However because adalimumab cannot be measured in the urine urinary excretion of the monoclonal antibody will not be performed and an aliquot of urine will NOT be saved in the specimen kit for measurement of Humira
If patients must go home after the first day of testing then they will return to the GCRC on day 2 for repeat blood draws and to return urine collections
The exact sampling times hours for the 48-hour PK studies for each novel therapy which coincide with the midpoint of the urine collections see below are outlined in the following Table
DRUG 0 05 1 2 4 6 8 12 18 30 42 Adalimumab X X X X X X Rosiglitazone X X X X X X X X X X X
Serum glucose concentration will be measured at each time point
Trough serum adalimumab levels should be drawn at 1 week after the first dose of the drug as part of the PK study but not as part of a formal patient visit In addition to the PK studies trough serum adalimumab levels will also be drawn prior to the dose at the 2- 4- 8- and 12-week visits
Screening Visit Eligibility Studies
1 History and physical examination
2 Urine protein and creatinine excretion Proteinuria Upc will be expressed as the proteincreatinine ratio mgmg in a single early morning specimen
3 Serum creatinine and calculated GFR The GFR will be calculated using the Schwartz formula for patients below 18 years of age and Cockroft-Gault for those 18 years or older
4 Serum Na K HCO3- Cl- glucose BUN albumin cholesterol AST ALT alkaline phosphatase CBC ANA CH50 pregnancy test
5 HIV Hepatitis B and C serology if not done in the previous 12 months
6 TB skin test if not done in the previous 12 months
7 Existing renal biopsy tissue will be assessed for all subjects who have not had the diagnosis of FSGS confirmed by an FSGS-CT core pathologist only in screen failures
Baseline Visit Week 0 Visit
1 Serum glucose albumin and creatinine concentrations
2 TNF-alpha level
3 Baseline anti-adalimumab antibody AAA level in patients assigned to Humira treatment
4 A urine plasma serum and DNA sample will be collected for storage in the NIDDK FONT Biorepositories at Fisher Bioservice and the Rutgers Cell DNA Repository for patients who consent to this procedure A request will be made to store any residual renal tissue collected for clinical indications during the FONT trial in the NIDDK Biorepository
5 PK assessment see below
Follow-up Assessment Week 2 4 8 and 12 Visits
1 Interval history physical examination assessment of adverse events
2 Urine protein excretion
3 Serum creatinine and calculated GFR serum Na K HCO3 Cl- glucose BUN ALT AST at all visits
4 Serum albumin cholesterol ANA CH50 at 8-week visit CBC at all visits except 2-week visit
5 Trough serum adalimumab level in patients assigned to receive Humira at all visits except 2-week visit
6 Serum AAA level at 12-week visit in patients assigned to Humira treatment
7 Pregnancy test at 12-week visit
Final Assessment Week 16 Visit
1 Interval history physical examination assessment of adverse events
2 Urine protein excretion
3 Serum creatinine and calculated GFR
4 Serum Na K HCO3 Cl- glucose BUN albumin cholesterol AST ALT alkaline phosphatase CBC ANA CH50 and serum TNF-alpha levels
5 Serum AAA level in patients assigned to Humira treatment
6 Serum plasma and urine samples to the NIDDK Biosample Repository at Fisher Bioservice
7 Assessment of patient satisfaction with treatment using TSQM
8 Steady state PK assessment see below
The following Table summarizes the laboratory assessment during the R21 study
Study Medications
Study medication will be shipped in a single batch sufficient to complete the 4-month treatment period A supply will be shipped to the participating site for each individual patient that is enrolled Please complete the Site Registration Form and provide a complete and accurate shipping address for receipt of study medication during the week Monday though Friday 9 AM - 5 PM This information will be forwarded to the pharmaceutical companies to enable timely shipment of drug to each site
Formulation and administration of experimental novel therapies
Adalimumab Humira TNF-α antibody BB-IND 11714
This medication will be provided by Abbott Laboratories and will be available as a liquid It will be administered as a subcutaneous injection every other week The therapeutic dose of adalimumab will be 24 mgm2 to a maximum of 40 mgdose every other week for the entire treatment period
Patients should be instructed to rotate the site of injection In order to reduce the pain associated with the biweekly adalimumab injections patients can apply EMLA crème or steroid inhaler spray prior to administration of the medication After the injection is completed the patient can take Tylenol as needed or apply ice to the site for symptomatic pain relief
Patients receiving Humira will be required to write down dates and times of drug administration and bring the administration log to each study visit In addition when a patient is assigned to the Humira arm a per protocol dose schedule listing the week and the optimal date of drug administration will be sent with the medication to the site This sheet can be used to facilitate scheduling of visits and it can be shared with the patient
Rosiglitazone Avandia PPARgamma agonist IND69782
This medication will be provided by Glaxo Smith Kline and will be available as pills It will be administered orally in two divided daily doses The therapeutic dose of rosiglitazone will be 3 mgm2day administered in two divided doses to a maximum of 4 mg twice a day The twice daily dosing schedule is based on studies indicating greater antiproteinuric effect of rosiglitazone in type 2 diabetes when administered in this manner
Pharmacokinetic PK Studies
Sampling Scheme
The blood and urine collection scheme for the PK analysis will be conducted over 48 hours in a GCRC when the patient is scheduled to receive the first dose single dose PK assessments of adalimumab or rosiglitazone and after the 8th dose of adalimumab steady state of 105 days or during the 4th month of rosiglitazone therapy for multiple dose PK assessments
A blood sample 25-4 mlsample 1-25 ml plasmaserum will be drawn at each time point For adalimumab a total of 6 serum samples 4 ml each 24 ml of blood in total will be obtained For rosiglitazone a total of 11 plasma samples 25 ml each 25 ml of blood in total will be obtained during the 48-hour PK study The total amount of blood drawn should be 3 mlkg over this period
Urine will be collected at the following intervals 0-2 2-12 12-24 24-36 and 36-48 hours The total volume of urine for each time interval should be recorded in mL and an aliquot should be analyzed for proteincreatinine ratio in the local laboratory The measurements of urinary protein excretion over the 48 hour period will be used to correlate PK parameters of the study medication with concurrent level of proteinuria
An aliquot of the urine sample collected during each time interval should be saved in the specimen kit for determination of urinary excretion of rosiglitazone However because adalimumab cannot be measured in the urine urinary excretion of the monoclonal antibody will not be performed and an aliquot of urine will NOT be saved in the specimen kit for measurement of Humira
If patients must go home after the first day of testing then they will return to the GCRC on day 2 for repeat blood draws and to return urine collections
The exact sampling times hours for the 48-hour PK studies for each novel therapy which coincide with the midpoint of the urine collections see below are outlined in the following Table
DRUG 0 05 1 2 4 6 8 12 18 30 42 Adalimumab X X X X X X Rosiglitazone X X X X X X X X X X X
Serum glucose concentration will be measured at each time point
Trough serum adalimumab levels should be drawn at 1 week after the first dose of the drug as part of the PK study but not as part of a formal patient visit In addition to the PK studies trough serum adalimumab levels will also be drawn prior to the dose at the 2- 4- 8- and 12-week visits
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None