Pentoxifylline in Lupus Nephritis
Paraules clau
Resum
Descripció
Glomerulonephritis occurs in up to one-half of patients with systemic lupus erythematosus (SLE) and is a major cause of morbidity and mortality. Guidelines published by the American College of Rheumatology in 2012 (1) suggested a multi-targeted treatment approach that has been shown to lead to clinical remission in up to one-half of patients (2,3).
However, at least one-third of patients continue to have active disease; many of these individuals may eventually develop renal failure. Therefore, there is an unmet need for more effective therapeutic approaches for lupus nephritis (LN). Although the pathogenesis of LN is almost certainly multifactorial, the presence and persistence of immune complexes are thought to play a major role in disease pathogenesis by attracting inflammatory cells of the innate immune system, such as neutrophils and monocytes, resulting in cell activation and secretion of inflammatory cytokines, including interferon alpha, TGF-beta, IL-1, IL-6, and TNF-alpha (6-7). Pentoxifylline (PTX) is a nonselective phosphodiesterase inhibitor with minimal toxicity. It has been in clinical use since 1972 for treatment of patients with intermittent claudication secondary to peripheral vascular disease. This generic drug has also recently been increasingly used off-label for several other conditions, including patients with diabetic nephropathy, in whom the unexpected finding of significant reduction of proteinuria has been repeatedly demonstrated (34-38). The mechanism of this phenomenon is unclear, although experimental studies in animals and humans have observed suppression of inflammatory cytokine production following PTX administration (24-28). In LN, 2 small, uncontrolled observational studies of PTX reported reduction in proteinuria following 2-6 months of treatment with PTX (8,9). The level and chronicity of proteinuria have long been associated with disease prognosis in patients with LN (10). Thus, a novel treatment that could significantly and persistently reduce or even eliminate proteinuria could result in substantial improvement in the long-term outcome of patients with this most serious manifestation of SLE.
Dates
| Darrera verificació: | 03/31/2020 |
| Primer enviat: | 02/21/2019 |
| Inscripció estimada enviada: | 02/26/2019 |
| Publicat per primera vegada: | 02/28/2019 |
| Última actualització enviada: | 04/01/2020 |
| Publicació de l'última actualització: | 04/05/2020 |
| Data d'inici de l'estudi real: | 08/31/2020 |
| Data estimada de finalització primària: | 11/30/2021 |
| Data estimada de finalització de l’estudi: | 11/30/2022 |
Condició o malaltia
Intervenció / tractament
Drug: Pentoxifylline
Drug: Placebo
Fase
Grups de braços
| Braç | Intervenció / tractament |
|---|---|
| Experimental: Pentoxifylline Pentoxifylline and standard of care therapy | Drug: Pentoxifylline Pentoxifylline (PTX) is a methylxanthine derivative that is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). This enzyme, which has at least 5 subtypes, is responsible for inactivation of the important second messengers, Cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) |
| Placebo Comparator: Placebo Placebo and standard of care therapy | Drug: Placebo Placebo |
Criteris d'elegibilitat
| Edats elegibles per estudiar | 18 Years Per a 18 Years |
| Sexes elegibles per estudiar | All |
| Accepta voluntaris saludables | Sí |
| Criteris | Inclusion criteria: 1. Patients 18 and older, who meet the 1997 update of the1982 criteria for classification of systemic lupus erythematosus and have established lupus nephritis as documented by any of the following: 1. Kidney biopsy documenting class II, III, IV, or V (RPS/ISN 2004) lupus nephritis within 3 years or 2. Abnormal urine protein excretion on 2 occasions, at least 2 weeks apart, characterized by more than 500 mg urine protein, quantitated either by 24-hour urine collection or by urine protein/creatinine ratio (UPCR) more than 0.5 mg/mg, measured on a first void morning specimen, in the absence of other glomerulopathies; or 3. Abnormal urine sediment, containing more than 5 RBC, more than 5 WBC, or cellular casts on 2 occasions, at least 2 weeks apart, in the absence of infection, concurrent menstruation, anatomic genitourinary abnormalities, or pathologic disorders other than lupus nephritis. 2. Absence of changes in immunosuppressive agents or dose of immunosuppressive agents administered during the 2 months before enrollment. Patients with newly-diagnosed lupus nephritis will not be invited to participate until after they have completed 6 months of initial induction therapy. 3. Unless contraindicated, patients will be required to be taking an ACE inhibitor or ARB, with stable dose for at least 1 month prior to enrollment. Patients with intolerance of ACE/ARB therapies will be eligible to participate, but will be analyzed separately, as indicated in the trial synopsis. 4. Urine protein more than 500 mg/24 hours and/or UPCR more than 0.5 mg/mg at time of baseline. 5. Willingness to remain on stable immunosuppressive drugs for the 6-month duration of the study unless safety issues arise. 6. The SELENA-SLEDAI will be measured at screening but no minimal SLEDAI score will be required for inclusion. 7. Although kidney biopsy is not required for enrollment in this clinical trial, the standard of care at all participating institutions is to recommend renal biopsy for all patients with lupus nephritis, and generally at least 75% of such patients at each participating institution will be expected to have had this procedure. Subjects who qualify for this study according to clinical criteria noted in 1b and 1c above must be confirmed to have lupus nephritis, and no other renal disorder, by the site PI, prior to enrollment. Exclusion criteria: 1. History of retinal, cerebral, or peptic ulcer hemorrhage within 3 months prior to enrollment 2. Current use of warfarin, long-acting heparin, or an oral anti-coagulant (other than low dose aspirin) 3. Pregnancy or currently breast-feeding 4. History of theophylline, pentoxifylline, or caffeine allergy 5. Currently taking theophylline-containing medications 6. Malignancy within 2 years, other than basal cell carcinoma 7. Congestive heart failure, class III or IV 8. Abnormal AST/ALT, more than 2 times ULN 9. Obstructive uropathy 10. Acute kidney injury defined as greater than 50% decrease in GFR within 30 days prior to screening. 11. Myocardial infarction, percutaneous coronary intervention, coronary bypass graft surgery, or unstable angina within 6 months prior to screening 12. BP greater than 150/95 on 2 measurements in the sitting position after 5 minutes of rest, using a manual BP cuff 13. Known diagnosis of diabetes mellitus or hemoglobin A1c greater than 8.0 14. Current (within 3 months) GFR less than 30 mL/min 15. Surgery within 3 months prior to enrollment 16. Concurrent diagnosis of antiphospholipid syndrome (APS), or presence of APS antibodies on 2 occasions, more than 12 weeks apart. |
Resultat
Mesures de resultats primaris
1. Level of proteinuria [9 months]
Mesures de resultats secundaris
1. Histopathologic subclass [6 months]
2. Serum albumin [6 months]
3. Glomerular Filtration Rate [6 months]
4. Serologic markers [6 months]
5. SELENA-Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Instrument Score [6 months]
6. Longitudinal changes in patient global activity score [6 months]
7. Longitudinal changes in physician global activity score [6 months]
8. Prednisone dose [6 months]
9. Serum and urinary cytokine levels [6 months]
