Trial Outcomes & Findings for Permeability Factor in Focal Segmental Glomerulosclerosis (NCT NCT00007475)

Last Updated: 2016-02-10

Results Overview

Outcomes for FSGS occurring in native kidneys: A. Complete remission: proteinuria \<0.3 g/d ; B. Partial remission: proteinuria between 0.3 and 2 g/d ; C. Incomplete response: proteinuria between 2 and 3.5 g/d ; D. Relapse: return to proteinuria ≥3.5 g/d ; Note that counts within each category A-D may be summarized relative to remaining categories, as a proportion (relative to complement of the whole group count) with calculations implicitly based on zero/one valued binary variables, whose means are proportions, so to report 95% confidence intervals calculated using an exact binomial distribution.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

15 participants

Primary outcome timeframe

every 3 months up to a year followed with native kidneys

Results posted on

2016-02-10

Participant Flow

Enrollment of subjects occurred at fraction of the anticipated rate despite over a decade of study conduct; the discrepancy between actual (15) and projected (100) enrollment is due to (a) lack of revising the registry entry with revisions of the protocol (n=50, excluding historical controls) and (b) lower referral rates by external nephrologists.

Participant milestones

Participant milestones
Measure	FPF NOT Assayed, Plasma Exchange + Cyclophosphamide Completed Participants not assayed for FSGS Permeability Factor (FPF) levels pre-treatment (Tx), yet still complete both series of protocol-specified treatment; FPF levels NOT available as its assay has not yet been developed to an extent that it could be applied to all enrollees of this current trial	FPF Assayed Pre-Tx as Low, PE + Cyclophosphamide Completed Protocol Groups A/B/C (FPF \< 0.6); group size is limited due to limited availability of provisionally validated FPF assay and discrepancy with protocol groups due to low-FPF participants receiving PE and Cyclophosphamide (contrast to protocol Figure 1)	FPF Assayed Pre-Tx as High, PE + Cyclophosphamide Completed Protocol Group D (FPF 0.6 or greater pre-initial Transplant); group size is limited due to limited availability of provisionally validated FPF assay and discrepancy with protocol groups due to low-FPF participants receiving PE and Cyclophosphamide (contrast to protocol Figure 1)
Overall Study STARTED	12	1	2
Overall Study FSGS Permeability Factor (FPF) Assayed	0	1	2
Overall Study Initial Transplant	12	1	2
Overall Study Post-initial Transplant Proteinuria	12	1	2
Overall Study Initial Plasma Exchange	12	1	2
Overall Study Initiate Cyclophosphamide	12	1	2
Overall Study COMPLETED	8	1	2
Overall Study NOT COMPLETED	4	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	FPF NOT Assayed, Plasma Exchange + Cyclophosphamide Completed Participants not assayed for FSGS Permeability Factor (FPF) levels pre-treatment (Tx), yet still complete both series of protocol-specified treatment; FPF levels NOT available as its assay has not yet been developed to an extent that it could be applied to all enrollees of this current trial	FPF Assayed Pre-Tx as Low, PE + Cyclophosphamide Completed Protocol Groups A/B/C (FPF \< 0.6); group size is limited due to limited availability of provisionally validated FPF assay and discrepancy with protocol groups due to low-FPF participants receiving PE and Cyclophosphamide (contrast to protocol Figure 1)	FPF Assayed Pre-Tx as High, PE + Cyclophosphamide Completed Protocol Group D (FPF 0.6 or greater pre-initial Transplant); group size is limited due to limited availability of provisionally validated FPF assay and discrepancy with protocol groups due to low-FPF participants receiving PE and Cyclophosphamide (contrast to protocol Figure 1)	Historical Controls Noted as Group F in study protocol: historical control patients, including patients at NIH or other institutions who have previously undergone renal transplant, for whom stored sera are available, and for whom consent to measure FPF has been can be obtained. In some cases, these measurements have been performed by Dr. Savin under pre-existing protocols and these data are already available.
Overall Study Withdrawal by Subject	1	0	0	0
Overall Study Adverse Event	3	0	0	0

Baseline Characteristics

Permeability Factor in Focal Segmental Glomerulosclerosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	FPF NOT Assayed Provisionally, PE + Cyclophosphamide Completed n=12 Participants Participants not provisionally assayed for FPF, yet still complete both series of protocol treatment: Plasma Exchange (PE) and Cyclophosphamide; note that these form a majority of enrollees due to limited availability of validated FPF assay (such an assay has not yet been developed to an extent that it could be applied to all enrollees of this current trial; see Outcome Measures for more details)	FPF Assayed Pre-Tx as Low, PE + Cyclophosphamide Completed n=1 Participants Protocol Groups A/B/C (FPF \< 0.6); group size is limited due to limited availability of validated FPF assay and discrepancy with protocol groups due to low-FPF participants receiving PE and Cyclophosphamide (contrast to protocol Figure 1)	FPF Assayed Pre-Tx as High, PE + Cyclophosphamide Completed n=2 Participants Protocol Group D (FPF 0.6 or greater pre-initial Transplant); group size is limited due to limited availability of validated FPF assay	Total n=15 Participants Total of all reporting groups
Age, Continuous	39.5 years at consent n=5 Participants	63 years at consent n=7 Participants	19 years at consent n=5 Participants	37 years at consent n=4 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	9 Participants n=4 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	6 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	9 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United States	12 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants	15 participants n=4 Participants
Treated for Prior Recurrence Yes	2 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	3 participants n=4 Participants
Treated for Prior Recurrence No	10 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants	12 participants n=4 Participants
Time from onset/diagnosis of Focal Segmental Glomerulosclerosis to study enrollment/consent	10 years n=5 Participants	6 years n=7 Participants	1.5 years n=5 Participants	8 years n=4 Participants

PRIMARY outcome

Timeframe: every 3 months up to a year followed with native kidneys

Population: all participants, regardless of amount of follow-up

Outcome measures

Outcome measures
Measure	FPF NOT Assayed, Plasma Exchange + Cyclophosphamide Completed n=12 Participants Participants complete both series of protocol treatment, Plasma Exchange and Cyclophosphamide.	FPF Assayed Pre-Tx as Low, PE + Cyclophosphamide Completed n=1 Participants Protocol Groups A/B/C (FPF \< 0.6); group size is limited due to limited availability of validated FPF assay and discrepancy with protocol groups due to low-FPF participants receiving PE and Cyclophosphamide (contrast to protocol Figure 1)	FPF Assayed Pre-Tx as High, PE + Cyclophosphamide Completed n=2 Participants Protocol Group D (FPF 0.6 or greater pre-initial Transplant)
Reduction in Proteinuria in Recurrent FSGS Following Renal Transplant With Plasma Exchange and Cyclophosphamide. A. Complete remission: proteinuria <0.3 g/d	0 proportion of participants with outcome Interval 0.0 to 0.00049	0 proportion of participants with outcome Interval 0.0 to 0.975	0.5 proportion of participants with outcome Interval 0.01258 to 0.9874
Reduction in Proteinuria in Recurrent FSGS Following Renal Transplant With Plasma Exchange and Cyclophosphamide. B. Partial remission: proteinuria in [0.3,2] g/d	0.25 proportion of participants with outcome Interval 0.05486 to 0.5719	0 proportion of participants with outcome Interval 0.0 to 0.975	0 proportion of participants with outcome Interval 0.0 to 0.8419
Reduction in Proteinuria in Recurrent FSGS Following Renal Transplant With Plasma Exchange and Cyclophosphamide. C. Incomplete response: proteinuria in (2,3.5) g/d	0 proportion of participants with outcome Interval 0.0 to 0.0	0 proportion of participants with outcome Interval 0.0 to 0.0	0 proportion of participants with outcome Interval 0.0 to 0.0
Reduction in Proteinuria in Recurrent FSGS Following Renal Transplant With Plasma Exchange and Cyclophosphamide. D. Relapse: return to proteinuria ≥3.5 g/d	0.1667 proportion of participants with outcome Interval 0.02086 to 0.4841	1 proportion of participants with outcome Interval 0.025 to 1.0	0 proportion of participants with outcome Interval 0.0 to 0.8419

SECONDARY outcome

Timeframe: End of study

Population: Participants with FPF, without FPF and control subjects who have also had RNA expression profiling done in PBMCs.

No RNA expression profiles have been obtained as FSGS Permeability Factor (FPF) levels NOT available -- its assay has not yet been developed to an extent that it could be applied to all enrollees of this current trial. Note that provisional values (targeting current candidate molecule: cardiotrophin-like cytokine 1) were assayed for 3 of the first 4 enrollees using assay by Dr. Virginia Savin, whose lab is actively investigating a molecular identification of FPF using an isolation approach based on sequential precipitation results in a 100-fold purification, but the fraction remains a complex mixture on SDS-PAGE (Sharma 1999). Other investigators of FPF include: 1. Terry Phillips at NIH developed an assay that looked promising but after his retirement it has not been possible for other researchers to get this working. 2. Avi Rosenberg, NCI has developed a promising ELISA-style assay, as well as some work in a mass spectrometry assay, and this is being further refined.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: End of study

Provisional assay of a molecular identification of FPF (current candidate: cardiotrophin-like cytokine 1) using an isolation approach based on sequential precipitation results in a 100-fold purification. Note: Focal segmental glomerulosclerosis Permeability Factor (FPF) assay had not yet been developed to an extent that it could be applied to all enrollees in the current trial; provisional values were assayed for 3 of the first 4 enrollees using a version implemented by Dr. Virginia Savin, whose lab is actively investigating the above isolation approach, but the fraction remains a complex mixture on SDS-PAGE (Sharma 1999). Other investigators of FPF, mentioned here for interested readers of this trial report, include: 1. Terry Phillips at NIH developed an assay that looked promising prior to his retirement. 2. Avi Rosenberg, NCI has developed promising ELISA-style assay, and mass spectrometry assay, being refined.

Outcome measures

Outcome measures
Measure	FPF NOT Assayed, Plasma Exchange + Cyclophosphamide Completed Participants complete both series of protocol treatment, Plasma Exchange and Cyclophosphamide.	FPF Assayed Pre-Tx as Low, PE + Cyclophosphamide Completed n=1 Participants Protocol Groups A/B/C (FPF \< 0.6); group size is limited due to limited availability of validated FPF assay and discrepancy with protocol groups due to low-FPF participants receiving PE and Cyclophosphamide (contrast to protocol Figure 1)	FPF Assayed Pre-Tx as High, PE + Cyclophosphamide Completed n=2 Participants Protocol Group D (FPF 0.6 or greater pre-initial Transplant)
Define the Kinetics of FPF in FSGS Patients Receiving Immunomodulatory Therapy or Plasma Exchange.	—	0.41 1- albumin glomerular permeability ratio Interval 0.41 to 0.41	0.865 1- albumin glomerular permeability ratio Interval 0.82 to 0.91

SECONDARY outcome

Timeframe: End of study

Population: Participants with FPF levels assayed following immunosuppressive therapies (currently none). Note: its assay had not yet been developed to an extent that it could be applied beyond the provisional values assayed for 3 of the first 4 enrollees using a version implemented by Dr.Virginia Savin, VA Medical Center/Kidney Institute, Kansas City, Missouri

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: End of study

Population: Participants whose post-transplantation follow-up yields 1 or more assayed FPF levels

Outcome measures

Outcome data not reported

Adverse Events

Plasma Exchange + Cyclophosphamide, Complete Treatment

Serious events: 3 serious events

Other events: 0 other events

Deaths: 0 deaths

FPF Assayed Pre-Tx as Low, PE + Cyclophosphamide Completed

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

FPF Assayed Pre-Tx as High, PE + Cyclophosphamide Completed

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Plasma Exchange + Cyclophosphamide, Complete Treatment n=12 participants at risk Participants for whom the Focal Segmental Glomerulosclerosis (FSGS) Permeability Factor, or FPF was not able to be assayed, yet enrolled and completed both protocol-specified interventions: the plasma exchange procedure and treatment by cyclophosphamide.	FPF Assayed Pre-Tx as Low, PE + Cyclophosphamide Completed n=1 participants at risk Original protocol Groups A/B/C (FPF \< 0.6); group size is limited due to limited availability of validated FPF assay and discrepancy with protocol groups due to low-FPF participants receiving PE and Cyclophosphamide (contrast to protocol Figure 1)	FPF Assayed Pre-Tx as High, PE + Cyclophosphamide Completed n=2 participants at risk Original protocol Group D (FPF 0.6 or greater pre-initial Transplant)
Immune system disorders Rejection of Kidney Graft	8.3% 1/12 • Number of events 1 • Entire course of study follow-up, from study enrollment to closure	0.00% 0/1 • Entire course of study follow-up, from study enrollment to closure	0.00% 0/2 • Entire course of study follow-up, from study enrollment to closure
Infections and infestations Hemorrhagic cystitis	8.3% 1/12 • Number of events 1 • Entire course of study follow-up, from study enrollment to closure	0.00% 0/1 • Entire course of study follow-up, from study enrollment to closure	0.00% 0/2 • Entire course of study follow-up, from study enrollment to closure
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of the Prostate Gland	8.3% 1/12 • Number of events 1 • Entire course of study follow-up, from study enrollment to closure	0.00% 0/1 • Entire course of study follow-up, from study enrollment to closure	0.00% 0/2 • Entire course of study follow-up, from study enrollment to closure
Blood and lymphatic system disorders Neutropenia	8.3% 1/12 • Number of events 1 • Entire course of study follow-up, from study enrollment to closure	0.00% 0/1 • Entire course of study follow-up, from study enrollment to closure	0.00% 0/2 • Entire course of study follow-up, from study enrollment to closure

Other adverse events

Adverse event data not reported

Additional Information

Jeffrey B. Kopp, MD

National Institute of Diabetes & Digestive & Kidney Diseases

Phone: +1 (301) 594-3403

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place