A Phase II Randomized, Placebo-Controlled, Double-Blind, Parallel Arms with Switchover, Pilot Study to Evaluate the Efficacy and Safety of Intravenous Abatacept in Treatment Resistant Nephrotic Syndrome (Focal Segmental Glomerulosclerosis/ Minimal Change)
Study ID: STU 062016-068
The is a Phase 2 placebo controlled, double -blind parallel arms switchover study. Subjects will be randomized to intravenous (iV) abatacept in Period 1: adults will use the weight-tiered dose: [Less Than] 60 kg: 500 mg, 60 to 100 kg: 750 mg, [Greater Than] 100 kg: 1000 mg; pediatric patients 6 to 17 years who weigh [Less Than] 75 kg will receive:10 mg/kg and those who weigh greater than of equal 75 kg will follow adult dosing. Dosing is on Day 1, 15, 29 and then every 28 days for 113 days. Subject in the placebo arm will receive normal Saline or D5W following the same dosing schedule). in Period 2, subjects will switchover treatment groups and follow the age and weight-based dose and intervals as subjects in Period 1 for 113 days. in the open-label extension, subjects who enter will all receive age and weight-based iV abatacept every 28 days for 169 days and a 6 month follow up after the last study drug dose. The following endpoints will be assessed: renal response to study drug at Day113 based on labs results assessing urine protein levels, associated ae and Saes, number of subjects with positive antibody response over time from baseline, number of responder relaspses, and changes in cholesterols.
Prior to study participation, written informed consent from subjects, or in the case of minors (< 18 years), written permission (informed consent) from parents, guardians, or legally acceptable representatives must be obtained according to local laws and regulations. b) Assent from minor subjects should be obtained per local requirements. Target Population a) Subjects diagnosed with TRNS (FSGS/MCD). i) Pathological findings of either FSGS (excluding collapsing FSGS) or MCD on the most recent renal biopsy (renal biopsies will not be part of this study). This will be confirmed by review of the pathology report (not slides) by a central pathologist. The criteria for pathology review are in Appendix 1. ii) UPCR >= 3 at screening. iii) Treatment resistant defined as: (1) Persistence of UPCR >= 3 in spite of therapy with any one of the following agents: corticosteroids (CS), calcineurin inhibitors (cyclosporine and tacrolimus), sirolimus, mycophenolate mofetil (MMF), mycophenolic acid (MPA), or cyclophosphamide. (2) Duration of therapy: The duration of CS therapy required to determine treatment resistance will be 6 weeks in subjects < 18 year of age and 12 weeks for subjects >= 18 years. For all other agents, the minimum duration of therapy will be 16 weeks, regardless of age. (3) Intolerance to any 2 of these agents, regardless of duration of treatment or age. b) Subjects must be receiving either an angiotensin-converting-enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), at stable doses for at least 2 weeks, prior to randomization unless intolerance is documented. Combined use of renin-angiotensin system (RAS) inhibitors will not be allowed. If aldosterone inhibitors (spirolactone or eplerenone) or aliskiren (direct renin inhibitor) are used, they must also be at stable doses. c) A minimal level of renal function at screening based on estimated glomerular filtration rate (eGFR) will be required. i) >= 60 for subjects < 18 years (new Schwartz equation).48 ii) >= 45 for subjects >= 18 years (CKD-EPI equation).47 d) APOL1 genotyping: Subjects will be genotyped for the APOL1 renal risk variants SNPs [Risk allele G1 (rs73885319 and rs60910145) and risk allele G2 (rs71785313)]. Subjects with 2 copies of the high-risk APOL1 variants are in the APOL1 high-risk group which will be used for stratification at randomization. Genotyping during screening will not be necessary if results of previous testing are available. Subjects will be allowed to opt-out of genotyping for APOL1. Subjects who refuse genotyping will still be eligible to be randomized. e) Concomitant Medication: i) Subjects may enroll with or without the following background agents used to treat TRNS (FSGS/MCD): (1) CS (low dose, prednisone or equivalent at doses <= 10 mg/day) (2) calcineurin inhibitors (cyclosporine and tacrolimus) (3) MMF (4) MPA ii) Agents must be used at standard doses, must not have been started within 8 weeks of enrollment iii) Agents must be stable for at least 4 weeks prior to randomization. iv) No adjustment in doses of concomitant medications will be allowed during the double-blind period other than for dose reductions or holds to address drug-related toxicity. f) Subjects who had previously been treated with rituximab are allowed in the study if use had occurred more than 6 months prior to randomization and there are laboratory results indicating the presence of circulating B cells (CD19+). g) Hypertension must be controlled and stable. Hypertension control is defined as a blood pressure (BP) <= 140/90 for subjects >= 18 years of age and < 95th percentile for subjects < 18 year of age by gender, age and height percentile.49 h) Changes in diuretic use should be avoided prior to the Day 113 assessment unless necessary to manage an adverse event. i) Treatment to manage dyslipidemia is allowed. HMG CoA reductase (hydroxymethylglutaryl CoA reductase) inhibitors or statins use must be stable 2 weeks prior to randomization and throughout the treatment periods. j) Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been randomized / has not been treated). If re-enrolled, the subject must be re-consented. 3. Age and Reproductive Status a) Males and Females, ages >= 6 years. b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. c) Women must not be breastfeeding d) Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (abatacept/placebo) plus 5 half-lives (70 days) plus 30 days (duration of ovulatory cycle) for a total of 100 days post-treatment completion. e) Females who are not of childbearing potential must have documented proof that they are not of childbearing potential (eg, not experienced menarche, surgically sterile). f) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (abatacept/placebo) plus 5 half-lives of the study drug (70 days) plus 90 days (duration of sperm turnover) for a total of 160 days post-treatment completion. In addition, male subjects must be willing to refrain from sperm donation during this time. g) Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements and still must undergo pregnancy testing as described in this section.
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- Elizabeth J Brown
BRISTOL-MYERS SQUIBB COMPANY