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| ID | Type | Description | Link |
|---|---|---|---|
| 01-DK-0053 | Other Identifier | National Institutes of Health |
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Focal segmental glomerulosclerosis (FSGS) is a renal syndrome characterized by proteinuria (usually nephrotic range), limited response to conventional therapy, and a poor renal prognosis, with progression to end stage renal failure in at least 50% of patients. As a syndrome, FSGS likely has many specific etiologies, only a few of which are well-defined. Recently, it has been suggested that some idiopathic FSGS patients have elevated circulating levels of a protein that induces glomerular permeability in vitro and in vivo. While there has been no consistent term for this factor, it will be termed here FSGS permeability factor (FPF).
The purposes of the present study are five fold:
Patient participation is divided into an evaluation phase, in which FPF levels, RNA expression profiles, and patient eligibility for participation in treatment protocols are determined, and a treatment phase in which specific immunomodulatory therapy is introduced in an open label fashion. We propose to define carefully the relationship between elevated FPF and remission of proteinuria in patients with FSGS in native kidneys, following treatment with standard therapies (daily prednisone, cyclophosphamide) and experimental therapies (pulse dexamethasone, pirfenidone). In patients with recurrent FSGS in renal allografts, we will determine the kinetics of FPF following plasma exchange and following plasma exchange plus cyclophosphamide. In patients with elevated FPF levels who are awaiting renal transplantation, we will determine the kinetics of FPF following plasma exchange and following plasma exchange plus cyclophosphamide, and examine the rate of recurrent FSGS in these patients.
Focal segmental glomerulosclerosis (FSGS) is a renal syndrome characterized by proteinuria (usually nephrotic range), limited response to conventional therapy, and a poor renal prognosis, with progression to end stage renal failure in at least 50% of patients. As a syndrome, FSGS likely has many specific etiologies, only a few of which are well-defined. Recently, it has been suggested that some idiopathic FSGS patients have elevated circulating levels of a protein that induces glomerular permeability in vitro and in vivo. While there has been no consistent term for this factor, it will be termed here FSGS permeability factor (FPF).
The purposes of the present study are five fold:
To identify a population of FSGS patients with elevated FPF levels
To examine RNA expression profiles of peripheral blood mononuclear cells (PBMC)
in FSGS patients with elevated FPF levels
To define the kinetics of FPF disappearance and reappearance in FSGS patients
receiving immunomodulatory therapy and in the case of patients with recurrent FSGS
following renal transplant, those receiving plasma exchange
To identify immunosuppressive agents which are successful in inducing sustained
reduction in FPF levels
To determine in patients with FSGS who are awaiting renal transplant, whether
sustained reduction in FPF levels is associated with reduced risk of recurrent FSGS.
Patient participation is divided into an evaluation phase, in which FPF levels, RNA expression profiles, and patient eligibility for participation in treatment protocols are determined, and a treatment phase in which specific immunomodulatory therapy is introduced in an open label fashion. We propose to define carefully the relationship between elevated FPF and remission of proteinuria in patients with FSGS in native kidneys, following treatment with standard therapies (daily prednisone, cyclophosphamide) and experimental therapies (pulse dexamethasone, pirfenidone). In patients with recurrent FSGS in renal allografts, we will determine the kinetics of FPF following plasma exchange and following plasma exchange plus cyclophosphamide. In patients with elevated FPF levels who are awaiting renal transplantation, we will determine the kinetics of FPF following plasma exchange and following plasma exchange plus cyclophosphamide, and examine the rate of recurrent FSGS in these
patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Plasma Exchange + Cyclophosphamide | Experimental | Procedure/Surgery: Plasma exchange A course of plasma exchange of 5 treatments over 10 days, then administration of cyclophosphamide. Drug: Cyclophosphamide For GFR > 50 ml/min/1.73 m2 received oral cyclophosphamide at a dose of 2 mg/kg/ day for 3 months. For GFR < 50 ml/min/1.73 m2 but > 10 ml/min/1.73 m2 will receive oral cyclophosphamide at a 25% reduced dose or 1.5 mg/kg/d for 3 months. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Plasma exchange | Procedure | A course of plasma exchange of 5 treatments over 10 days, then administration of cyclophosphamide. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Reduction in Proteinuria in Recurrent FSGS Following Renal Transplant With Plasma Exchange and Cyclophosphamide. | 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. | every 3 months up to a year followed with native kidneys |
| Measure | Description | Time Frame |
|---|---|---|
| Comparison of RNA Expression Profiles in PBMC From Patients With FPF, Without FPF and Control Subjects | 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:
|
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INCLUSION CRITERIA:
Patients with idiopathic focal segmental glomerulosclerosis on renal biopsy, including the following categories:
A) Untreated FSGS
B) Steroid-dependent FSGS
C) Steroid resistant FSGS
D) Recurrent FSGS, with functioning allograft
E) FSGS in ESRD, receiving hemodialysis
Adults greater than or equal to18 will be eligible for all studies.
Children greater than 20 kilograms, will be eligible for all branches of the study except for treatment of steroid resistant FSGS with pirfenidone, as pirfenidone has not previously been administered to pediatric patients in any setting. Children less than 20 kilograms will be excluded from the study for the following reason: plasma exchange in patients less than 20 kilograms requires a red blood cell transfusion, which significantly increases the risk of the procedure by exposing the patient to the risk of transfusion associated infections, and the safety of an aggressive course of plasma exchange has not been established in this population.
EXCLUSION CRITERIA:
A) Allergy or hypersensitivity to cyclophosphamide
B) Leukocyte less than 3000 cells/microliter or ANC less than 1500 cells/microliter or evidence of bone marrow compromise
C) Prior irradiation to the heart or therapy with doxorubicin or other cardiotoxic medication (may increase the risk for cardiotoxicity)
D) Peritoneal dialysis, as there is no published evidence that cyclophosphamide metabolites can be safely removed.
E) Certain drugs will be used with caution or avoided. Barbiturates and phenytoin induce the hepatic enzymes that metabolize cyclophosphamide and therefore if these medications are required, cyclophosphamide doses may need to be increased to achieve a comparable immunosuppressive effect. Drugs that inhibit cyclophosphamide metabolism include allopurinol, imipramine, and phenothiazines, chloramphenicol and chlorpromazine; these drugs will be avoided. NSAID increase the risk of hyponatremia; these drugs will be avoided.
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| Name | Affiliation | Role |
|---|---|---|
| Jeffrey B Kopp, M.D. | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 9644647 | Background | Korbet SM. Primary focal segmental glomerulosclerosis. J Am Soc Nephrol. 1998 Jul;9(7):1333-40. doi: 10.1681/ASN.V971333. No abstract available. | |
| 7881983 | Background | Cameron JS. Recurrent renal disease after renal transplantation. Curr Opin Nephrol Hypertens. 1994 Nov;3(6):602-7. doi: 10.1097/00041552-199411000-00007. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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) |
| FG002 | 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) |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | FPF NOT Assayed Provisionally, PE + Cyclophosphamide Completed | 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) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Reduction in Proteinuria in Recurrent FSGS Following Renal Transplant With Plasma Exchange and Cyclophosphamide. | 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. | all participants, regardless of amount of follow-up | Posted | Mean | 95% Confidence Interval | proportion of participants with outcome | every 3 months up to a year followed with native kidneys |
|
Entire course of study follow-up, from study enrollment to closure
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Plasma Exchange + Cyclophosphamide, Complete Treatment | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rejection of Kidney Graft | Immune system disorders | Systematic Assessment | Determined after 1 week of cyclophosphamide treatment |
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Note: definitive FSGS Permeability Factor (FPF) assays still in development. Data/samples transferred to the NIH-CC Glomerulosclerosis Consolidation protocol: focus on cardiotrophin like cytokine 1 & antibodies to a panel of podocyte proteins as FPF.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jeffrey B. Kopp, MD | National Institute of Diabetes & Digestive & Kidney Diseases | +1 (301) 594-3403 | jbkopp@nih.gov |
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| ID | Term |
|---|---|
| D005923 | Glomerulosclerosis, Focal Segmental |
| D011507 | Proteinuria |
| ID | Term |
|---|---|
| D005921 | Glomerulonephritis |
| D009393 | Nephritis |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
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| ID | Term |
|---|---|
| D010951 | Plasma Exchange |
| D010956 | Plasmapheresis |
| D003520 | Cyclophosphamide |
| ID | Term |
|---|---|
| D001803 | Blood Transfusion |
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
| D001781 | Blood Component Removal |
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| Cyclophosphamide | Drug | For GFR > 50 ml/min/1.73 m2 received oral cyclophosphamide at a dose of 2 mg/kg/ day for 3 months. For GFR < 50 ml/min/1.73 m2 but > 10 ml/min/1.73 m2 will receive oral cyclophosphamide at a 25% reduced dose or 1.5 mg/kg/d for 3 months. |
|
|
| End of study |
| Define the Kinetics of FPF in FSGS Patients Receiving Immunomodulatory Therapy or Plasma Exchange. | 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:
| End of study |
| Correlate the Effect of Immunosuppressive Agents Which Reduce Proteinuria in Recurrent FSGS With the Effect on FPF Levels | 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:
| End of study |
| Determine Whether Renal Transplantation in Patients Whose Elevated FPF Levels Have Been Reduced for a Sustained Period is Associated With a Reduced Prevalence of Recurrent FSGS. | 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:
| End of study |
| 8914044 | Background | Valeri A, Barisoni L, Appel GB, Seigle R, D'Agati V. Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study. Kidney Int. 1996 Nov;50(5):1734-46. doi: 10.1038/ki.1996.493. |
| Adverse Event |
|
| BG001 | 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 validated FPF assay and discrepancy with protocol groups due to low-FPF participants receiving PE and Cyclophosphamide (contrast to protocol Figure 1) |
| BG002 | 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 validated FPF assay |
| BG003 | Total | Total of all reporting groups |
| years at consent |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Treated for Prior Recurrence | Number | participants |
|
| Time from onset/diagnosis of Focal Segmental Glomerulosclerosis to study enrollment/consent | Note: calculated in terms of whole years, subject to coarsening due to integer subtraction (whole-year age at consent - whole-year age at onset) | Median | Inter-Quartile Range | years |
|
Participants complete both series of protocol treatment, Plasma Exchange and Cyclophosphamide. |
| OG001 | 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 validated FPF assay and discrepancy with protocol groups due to low-FPF participants receiving PE and Cyclophosphamide (contrast to protocol Figure 1) |
| OG002 | FPF Assayed Pre-Tx as High, PE + Cyclophosphamide Completed | Protocol Group D (FPF 0.6 or greater pre-initial Transplant) |
|
|
|
| Secondary | Comparison of RNA Expression Profiles in PBMC From Patients With FPF, Without FPF and Control Subjects | 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:
| Participants with FPF, without FPF and control subjects who have also had RNA expression profiling done in PBMCs. | Posted | End of study |
|
|
| Secondary | Define the Kinetics of FPF in FSGS Patients Receiving Immunomodulatory Therapy or Plasma Exchange. | 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:
| Posted | Mean | Full Range | 1- albumin glomerular permeability ratio | End of study |
|
|
|
| Secondary | Correlate the Effect of Immunosuppressive Agents Which Reduce Proteinuria in Recurrent FSGS With the Effect on FPF Levels | 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:
| 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 | Posted | End of study |
|
|
| Secondary | Determine Whether Renal Transplantation in Patients Whose Elevated FPF Levels Have Been Reduced for a Sustained Period is Associated With a Reduced Prevalence of Recurrent FSGS. | 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:
| Participants whose post-transplantation follow-up yields 1 or more assayed FPF levels | Posted | End of study |
|
|
| 3 |
| 12 |
| 0 |
| 12 |
| EG001 | FPF Assayed Pre-Tx as Low, PE + Cyclophosphamide Completed | 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) | 0 | 1 | 0 | 1 |
| EG002 | FPF Assayed Pre-Tx as High, PE + Cyclophosphamide Completed | Original protocol Group D (FPF 0.6 or greater pre-initial Transplant) | 0 | 2 | 0 | 2 |
|
| Hemorrhagic cystitis | Infections and infestations | Systematic Assessment | BK viral infection confirmed by high urine BK count per mil 14 weeks after cyclophosphamide initiation; managed by NIH urology team |
|
| Adenocarcinoma of the Prostate Gland | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment | diagnosed at a point six weeks into treatment by cyclophosphamide |
|
| Neutropenia | Blood and lymphatic system disorders | Systematic Assessment | As defined in Protocol for Patient group 4 (Recurrent FSGS with functioning allograft), having a nadir ANC <500 cells/µl during cyclophosphamide treatment is a serious AE |
|
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| D052776 |
| Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D014555 | Urination Disorders |
| D020924 | Urological Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D016060 |
| Sorption Detoxification |
| D005112 | Extracorporeal Circulation |
| D013514 | Surgical Procedures, Operative |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |