9 research outputs found
Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial
Introduction This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the
efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients.
Methods Twenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo
patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the
extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min
stair-climb test (3MSCT).
Results Mean relative change in S-oligo in the VA arm was −77.6% [95% confidence interval (CI) −81.6 to −72.8] at week 52
and −62.9% (95% CI −85.8 to −40.0) at LO; mean relative change in the placebo arm was −24.1% (95% CI −40.3 to −3.6) at
week 52 and −55.7% (95% CI −76.4 to −34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52
was −1.1% (95% CI −9.0 to 7.6) and − % (95% CI −13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative
change was 3.9% (95% CI −5.5 to 13.2) in the VA arm and 9.0% (95% CI −10.3 to 28.3) in placebo patients after switch to active
treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some
factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age.
Conclusions These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when
treatment is started in the paediatric age
Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis
Introduction Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such
data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM).
Methods Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were
integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II
or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a
comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and
the 3-minute stair climb test (3MSCT).
Results Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the
overall population at 12 months (mean change: –72.7%, P < 0.001) and remained statistically significant at last observation
(−62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained
statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric
subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation.
Conclusions Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were
maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and
well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of
treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints
Procedure-specific Risks of Thrombosis and Bleeding in Urological Cancer Surgery : Systematic Review and Meta-analysis
Context: Pharmacological thromboprophylaxis involves balancing a lower risk of venous thromboembolism (VTE) against a higher risk of bleeding, a trade-off that critically depends on the risks of VTE and bleeding in the absence of prophylaxis (baseline risk). Objective: To provide estimates of the baseline risk of symptomatic VTE and bleeding requiring reoperation in urological cancer surgery. Evidence acquisition: We identified contemporary observational studies reporting symptomatic VTE or bleeding after urological procedures. We used studies with the lowest risk of bias and accounted for use of thromboprophylaxis and length of follow-up to derive best estimates of the baseline risks within 4wk of surgery. We used the GRADE approach to assess the quality of the evidence. Evidence synthesis: We included 71 studies reporting on 14 urological cancer procedures. The quality of the evidence was generally moderate for prostatectomy and cystectomy, and low or very low for other procedures. The duration of thromboprophylaxis was highly variable. The risk of VTE in cystectomies was high (2.6-11.6% across risk groups) whereas the risk of bleeding was low (0.3%). The risk of VTE in prostatectomies varied by procedure, from 0.2-0.9% in robotic prostatectomy without pelvic lymph node dissection (PLND) to 3.9-15.7% in open prostatectomy with extended PLND. The risk of bleeding was 0.1-1.0%. The risk of VTE following renal procedures was 0.7-2.9% for low-risk patients and 2.6-11.6% for high-risk patients; the risk of bleeding was 0.1-2.0%. Conclusions: Extended thromboprophylaxis is warranted in some procedures (eg, open and robotic cystectomy) but not others (eg, robotic prostatectomy without PLND in low-risk patients). For "close call'' procedures, decisions will depend on values and preferences with regard to VTE and bleeding. Patient summary: Clinicians often give blood thinners to patients to prevent blood clots after surgery for urological cancer. Unfortunately, blood thinners also increase bleeding. This study provides information on the risk of clots and bleeding that is crucial in deciding for or against giving blood thinners. (C) 2017 European Association of Urology. Published by Elsevier B.V.Peer reviewe