Seth Schulman

Subcutaneous Methylnaltrexone for Treatment of Opioid-Induced Constipation in Patients With Chronic, Nonmalignant Pain: A Randomized Controlled Study

UNLABELLED Methylnaltrexone is effective for opioid-induced constipation (OIC) in advanced illness patients. This 4-week, double-blind, randomized, placebo-controlled study investigated the effect of subcutaneous methylnaltrexone on OIC in patients receiving opioids for chronic, nonmalignant pain. Patients (N = 460) received subcutaneous methylnaltrexone 12 mg once daily (QD) or every other day (alternating with placebo) compared with placebo. Assessments included bowel movement count, time of bowel movement, straining, sense of complete evacuation, Bristol Stool Form Scales, and quality of life. Within 4 hours of first dose, 34.2% of patients in both methylnaltrexone groups had rescue-free bowel movements (RFBMs) versus 9.9% on placebo (P < .001). The estimated number needed to treat was about 4. On average, 28.9% of methylnaltrexone QD and 30.2% of methylnaltrexone alternate-day dosing resulted in RFBMs within 4 hours versus 9.4% QD and 9.3% alternate-day placebo injections (both P < .001). Both methylnaltrexone groups had significantly shorter time to first RFBM (P < .001) and greater increase in number of weekly RFBMs (P < .05) versus placebo. Adverse events included abdominal pain, diarrhea, nausea, and hyperhidrosis. Bristol Stool Form Scale scores (P = .002) and sensation of complete evacuation (P < .04) were significantly superior with methylnaltrexone QD; both methylnaltrexone groups reported no or mild straining during RFBMs in the first 2 weeks (P < .02). At 4 weeks, a significantly greater improvement in patient-reported, constipation-specific quality of life was seen in the alternate-day dosing (P < .05) and QD (P < .001) groups. PERSPECTIVE We present data demonstrating that subcutaneous methylnaltrexone 12 mg given once daily (QD) or every other day provides significant relief of OIC and was generally well tolerated in patients with chronic, nonmalignant pain. These results expand on prior effectiveness observed for the treatment of OIC in advanced illness patients to a broader population.

Comparison of sirolimus plus tacrolimus versus sirolimus plus cyclosporine in high-risk renal allograft recipients: results from an open-label, randomized trial.

Background. The efficacy and safety of sirolimus (SRL) plus tacrolimus (TAC) versus SRL plus cyclosporine (CsA) were compared in high-risk renal allograft recipients. Methods. Evaluable patients (448) were randomly assigned (1:1) before transplant to receive SRL+TAC or SRL+CsA with corticosteroids. Eligible patients were black and/or repeat transplant recipients, and/or those with high titer of panel-reactive antibodies. Results. Demographics were similar between groups. Both treatments demonstrated equivalent efficacy of the composite endpoint at 12 months with efficacy failure rates of 21.9% vs. 23.2% (SRL+TAC vs. SRL+CsA, respectively, 95% CI −10.0 to 7.1, P=0.737). Biopsy-confirmed acute rejection rate (13.8% vs. 17.4%) and graft survival rate (89.7% vs. 90.2%) were similar (SRL+TAC vs. SRL+CsA, respectively). In evaluable patients (received at least 1 dose of study drug), renal function (calculated Nankivell glomerular filtration rate) was not superior in SRL+TAC versus SRL+CsA (54.5 vs. 52.6 mL/min, P=0.466); however, in on-therapy patients, glomerular filtration rate was significantly higher in SRL+TAC at most time points. At 12 months, there were no significant differences in rates of death, discontinuation because of adverse events, hypercholesterolemia, hyperlipemia, or proteinuria. Diarrhea and herpes simplex infections occurred significantly more often in SRL+TAC patients. Hypertension, cardiomegaly, increased creatinine, overdose (primarily calcineurin inhibitor toxicity), acne, urinary tract disorders, lymphocele, and ovarian cysts occurred significantly more often in SRL+CsA patients. Conclusions. This study demonstrated that SRL-based therapy was efficacious in high-risk renal allograft recipients in the first year after transplant, providing equivalent efficacy with CsA or TAC, similar graft survival, low biopsy-confirmed acute rejection rates, excellent renal function, and an acceptable safety profile.

Safety and Efficacy of Methylnaltrexone in Shortening the Duration of Postoperative Ileus Following Segmental Colectomy: Results of Two Randomized, Placebo-Controlled Phase 3 Trials

PURPOSE: Postoperative ileus contributes to surgical morbidity and is associated with prolonged hospitalization and increased health care costs. The efficacy and safety of the peripherally acting &mgr;-opioid receptor antagonist methylnaltrexone in shortening the duration of postoperative ileus following segmental colectomy was evaluated. METHODS: Two identically designed, multicenter, double-blind, parallel-group, placebo-controlled studies randomly assigned patients undergoing segmental colectomy (study 1, N = 515; study 2, N = 533) to receive 12 or 24 mg of methylnaltrexone intravenously or placebo every 6 hours starting within 90 minutes of surgery completion, continuing for up to 10 days or up to 24 hours after gastrointestinal recovery. The primary efficacy end point was the time from the end of surgery to the first bowel movement. Safety was evaluated via standard assessments (ie, adverse events and related withdrawals, physical examinations, laboratory tests, vital signs, electrocardiograms) and assessment of surgical complications. RESULTS: The primary and secondary efficacy outcomes (time to discharge eligibility, time to hospital discharge, and clinically meaningful events of nausea and vomiting following segmental colectomy) did not differ significantly between patients treated with either a dose of methylnaltrexone or with placebo. Rates of adverse events and serious adverse events were comparable across all treatment groups in both studies. The most commonly observed adverse events were nausea, pyrexia, and vomiting. CONCLUSIONS: Although the efficacy of methylnaltrexone in reducing the duration of postoperative ileus was not demonstrated in these studies, intravenous methylnaltrexone at doses of 12 mg and 24 mg was safe, in general, and well tolerated in postcolectomy patients. The utility of intravenous methylnaltrexone in treating postoperative ileus remains unproven.

Effect of subcutaneous methylnaltrexone on patient-reported constipation symptoms.

BACKGROUND Methylnaltrexone, a selective peripheral acting mu-opioid receptor antagonist, alleviates the constipating effects of opioids without affecting centrally mediated analgesia. OBJECTIVES To assess the effect of subcutaneous (SC) methylnaltrexone injection on patient-reported constipation symptoms and pain scores. METHODS A total of 469 subjects on opioids for chronic non-malignant pain with opioid-induced constipation were randomized to methylnaltrexone SC with once daily (QD) or every other day (QOD) dosing or placebo for 4 weeks. Constipation symptoms and pain were assessed using the patient assessment of constipation-symptoms (PAC-SYM) questionnaire and a 11-point scale, respectively, at baseline, Day 14 and Day 28. Change from baseline in PAC-SYM and pain scores were compared between methylnaltrexone and placebo arms at Day 28 using analysis of covariance, with treatment group as factor and baseline score as covariate. RESULTS A majority of patients were women (60%), average age was 49 years old, and back pain (60%) was the primary pain condition. At Day 28, the methylnaltrexone SC QD group showed a significant improvement over placebo for rectal symptoms (-0.56 vs. -0.30; P < 0.05), stool symptoms (-0.76 vs. -0.43; P < 0.001) and global scores (-0.62 vs. -0.37; P < 0.001). Improvement in stool symptoms (-0.69 vs.-0.43; P < 0.05) and the global scores (-0.52 vs. -0.37; P < 0.05) were significantly greater than placebo in the methylnaltrexone QOD group. Differences in change from baseline in abdominal symptoms and pain scores between the methylnaltrexone SC QD or QOD dosing arms and placebo were not significant. CONCLUSION The results of our study indicate significant improvement in constipation symptoms with methylnaltrexone QD or QOD dosing compared to placebo without a significant effect on pain scores.

A Randomized, Open-label Study of Sirolimus Versus Cyclosporine in Primary De Novo Renal Allograft Recipients

Background Despite a decreased incidence of acute rejection and early renal allograft loss due to calcineurin inhibitors (CNIs) in transplant recipients, nephrotoxicity associated with long-term CNI use remains an important issue. This study evaluated whether a CNI-free regimen, including sirolimus, mycophenolate mofetil, corticosteroids, and anti–interleukin-2 receptor antibody induction, results in improved long-term renal function. Methods This open-label, randomized, parallel group, comparative study in primary de novo renal transplant recipients was planned for 48 months but terminated early because of high acute rejection rates in the sirolimus arm. Results Enrollment was stopped after ≈12 months, with 475 transplanted patients randomized (2:1) to sirolimus (n=314) or cyclosporine A (CsA) treatment (n=161). Mean length of follow-up after transplantation was 190 days; this article focuses on available data through 6 months. Mean±SD on-therapy Nankivell-calculated glomerular filtration rate was not significantly different between the sirolimus (69.1±18.7 mL/min) and CsA (66.0±15.2 mL/min) treatment groups. Occurrence and length of delayed graft function was not significantly different between groups. Patients in the sirolimus group experienced numerically lower survival rates (96.9% vs. 99.4%; P=0.14), with nine deaths reported with sirolimus and one with CsA; higher rates of biopsy-confirmed acute rejection (21.4% vs. 6.1%; P<0.001); and higher rates of discontinuations due to adverse events (17.4% vs. 6.8%; P=0.001). Conclusion A sirolimus-based, CNI-free immunosuppressive regimen, when used with mycophenolate mofetil, corticosteroids, and anti–interleukin-2 receptor antibody induction, was associated with high rates of biopsy-confirmed acute rejection compared with CsA-based immunosuppression and is not recommended.

Efficacy of Subcutaneous Methylnaltrexone in the Treatment of Opioid‐Induced Constipation: A Responder Post Hoc Analysis

OBJECTIVE Methylnaltrexone, a selective peripherally acting mu-opioid receptor antagonist, effectively treats opioid-induced constipation (OIC) in patients with advanced illness and shows efficacy in patients with chronic nonmalignant pain. The objective was to identify patients who achieved maximal treatment effect based on response to initial four methylnaltrexone doses. DESIGN A post hoc analysis of a randomized, double-blind, placebo-controlled study evaluating patients with OIC and chronic nonmalignant pain who received 12 mg subcutaneous methylnaltrexone daily for 4 weeks was performed to determine if response to the first four methylnaltrexone doses predicted overall response during the study. Patients receiving ≥8 doses were included. OUTCOME MEASURES Patients having ≥3 rescue-free bowel movements (RFBMs)/week; change from baseline in RFBMs/week; percentage of doses with RFBMs within 4 hours after dosing. RESULTS Of 137 patients, 58 patients (42.3%) had RFBMs after ≥2 of four doses. Among those with response to ≥2 of four doses, 81% had ≥3 RFBMs/week vs. 43% for those with response to <2 of four (P < 0.0001). Those with RFBMs after ≥2 of first four doses averaged 4.8 RFBMs/week vs. 2.0 RFBMs/week for those with <2 of four (P < 0.0001). Percentage of subsequent injections resulting in RFBMs within 4 hours was 45.9 ± 27.6 for those with response to ≥2 of four doses vs. 17.1 ± 19.1 for those with response to <2 of four (P < 0.0001). Abdominal pain was the most frequently reported adverse event. CONCLUSION Early response to ≥2 of first four doses of methylnaltrexone identified patients who demonstrated a particularly robust effect of treatment over the duration of use.

Effect of Ramipril on Urinary Protein Excretion in Maintenance Renal Transplant Patients Converted to Sirolimus

This prospective, randomized, double‐blind, placebo‐controlled study evaluated the effects of ramipril on urinary protein excretion in renal transplant patients treated with sirolimus following conversion from a calcineurin inhibitor. Patients received ramipril or placebo for up to 6 weeks before conversion and 52 weeks thereafter. Doses were increased if patients developed proteinuria (urinary protein/creatinine ratio ≥0.5); losartan was given as rescue therapy for persistent proteinuria. The primary end point was time to losartan initiation. Of 295 patients randomized, 264 met the criteria for sirolimus conversion (ramipril, 138; placebo, 126). At 52 weeks, the cumulative rate of losartan initiation was significantly lower with ramipril (6.2%) versus placebo (23.2%) (p < 0.001). No significant differences were observed between ramipril and placebo for change in glomerular filtration rate from baseline (p = 0.148) or in the number of patients with biopsy‐confirmed acute rejection (13 vs. 5, respectively; p = 0.073). One patient in the placebo group died due to cerebrovascular accident. Treatment‐emergent adverse events were consistent with the known safety profile of sirolimus and were not potentiated by ramipril co‐administration. Ramipril was effective in reducing the incidence of proteinuria for up to 1 year following conversion to sirolimus in maintenance renal transplant patients.

Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients

Background Calcineurin inhibitor–associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients. Methods This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus. The primary end point was percentage of patients with 5 mL/min per 1.73 m2 or greater improvement in estimated glomerular filtration rate from randomization to month 24. Results The on-therapy population included 195 patients (sirolimus, 86; tacrolimus, 109). No between-group difference was noted in percentage of patients with 5 mL/min per 1.73 m2 or greater estimated glomerular filtration rate improvement (sirolimus, 34%; tacrolimus, 42%; P = 0.239) at month 24. Sirolimus patients had higher rates of biopsy-confirmed acute rejection (8% vs 2%; P = 0.02), treatment discontinuation attributed to adverse events (21% vs 3%; P < 0.001), and lower rates of squamous cell carcinoma of the skin (0% vs 5%; P = 0.012). Conclusions Our findings suggest that renal function improvement at 24 months is similar for patients with early conversion to sirolimus after kidney transplantation versus those remaining on tacrolimus.

Steady-state pharmacokinetics of sirolimus in stable adult Chinese renal transplant patients.

This open‐label, nonrandomized study was conducted to evaluate the steady‐state pharmacokinetics of sirolimus in 24 stable Chinese renal transplant patients receiving daily oral maintenance doses of sirolimus (1–4 mg). Repeated trough and serial whole blood sirolimus concentrations over a 24‐hour dosing interval were collected and assayed using high‐performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS). Non‐compartmental analysis (NCA) was employed to calculate sirolimus pharmacokinetic parameters. Cytochrome P450 (CYP) 3A5 genotyping was performed. Cyclosporine (CsA) levels were determined for patients who took concomitant CsA. Mean (±SD) sirolimus maximum concentration (Cmax), area under the concentration–time curve within a dosing interval of τ (AUCτ), oral clearance (CL/F), and trough concentration (Ctrough) at steady state were: 14.1 ± 13.4 ng/mL, 199 ± 210 ng · h/mL, 10.1 ± 4.4 L/h, and 5.9 ± 6.3 ng/mL, respectively. Median tmax (range) was 2.49 hours (1–12 hours). A strong correlation was observed between Ctrough and AUCτ. Pharmacokinetics of sirolimus in patients with and without concomitant CsA were comparable. Allele frequency of CYP3A5*3 was 70.9% and a trend of higher oral clearance was observed in CYP3A5 expressers compared with non‐expressers although the number of subjects in each genotype was small.

THU0126 Evaluation of the Effect of Tofacitinib on Measured Glomerular Filtration Rate in Patients with Active Rheumatoid Arthritis

Background In the clinical development programme of the novel oral Janus kinase inhibitor tofacitinib for the treatment of rheumatoid arthritis (RA), small mean increases in serum creatinine (SCr) (<4 μmol/L least mean squares difference from placebo [PBO] for tofacitinib 5 and 10 mg twice daily [BID] at Month 3) were observed and which plateaued early. In studies to date, with up to 5 years follow-up on and over 12,000 patient (pt)-years of exposure to tofacitinib,1,2 mean increases in SCr remain small (mean change from baseline <8.84 μmol/L). While <5% of pts discontinued per protocol for SCr increases greater than 50% above baseline, these increases were generally not associated with clinical events of renal failure. Objectives To assess changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to PBO in pts with active RA. Methods In this double-blind, PBO-controlled, Phase 1 study (NCT01484561) RA pts were randomised 2:1 to one of two fixed sequences (Seq): Seq 1 received oral tofacitinib 10 mg BID in Period 1 (P1) then PBO BID in Period 2 (P2); Seq 2 received oral PBO BID in both P1 and P2. P1and P2 were 6-7 and 4-5 weeks in duration, respectively. Each pt underwent mGFR evaluations by iohexol serum clearance at 4 time points (run-in, pre-dose 1 in P1, end of P1, and end of P2); estimated GFR (eGFR) was calculated using the Cockcroft-Gault equation. The primary endpoint was the geometric mean change in mGFR from baseline to end of P1. Secondary endpoints included the geometric mean change in mGFR from baseline to end of P2 and from end of P1 to end of P2; change in eGFR and SCr; RA clinical efficacy and safety. Results 148 pts were randomised to Seq 1 (N=97) and Seq 2 (N=51). Baseline characteristics were similar between groups. In Seq 1, tofacitinib treatment in P1 was associated with a reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in geometric mean mGFR vs Seq 2. The reduction in geometric mean mGFR associated with tofacitinib in P1 reversed on PBO in P2, and there was no difference vs Seq 2 in the adjusted geometric mean fold change of mGFR at the end of the study (Seq 1:Seq 2: 1.04; 90% CI: 0.97, 1.11). However, from P1 to P2 there was a 5% reduction (90% CI: 1%, 10%) in mGFR in Seq 2 (PBO). eGFR and SCr showed similar changes to mGFR in Seq 1 but remained constant in Seq 2 (Table). Clinical efficacy and safety were consistent with prior studies. Conclusions This study suggests that small mean increases in SCr and mean decreases in eGFR in pts with RA treated with tofacitinib occur in parallel with small mean decreases in mGFR, and that changes in these parameters with short term tofacitinib treatment appear reversible after discontinuation. Safety monitoring will continue in ongoing and future clinical trials and routine pharmacovigilance. References Isaacs JD et al. Ann Rheum Dis 2012; 71 (Suppl 3): 672. Wollenhaupt J et al. Arthritis Rheum 2013; 65(Suppl 10): S993. Acknowledgements This study was sponsored by Pfizer Inc. Medical writing support was provided by AM Reid, PhD, of CMC and funded by Pfizer Inc. Disclosure of Interest : J. Kremer Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, A. Kivitz Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, J. Simon-Campos: None declared, E. Nasanov: None declared, H. Tony: None declared, B. Vlahos Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Hammond Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bukowski Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Li Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Schulman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Raber Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Zuckerman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Isaacs Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.2492