scholarly journals Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at < 4 years of age with phenylketonuria: results of the 3-year extension of the SPARK open-label, multicentre, randomised phase IIIb trial

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Ania C. Muntau ◽  
Alberto Burlina ◽  
François Eyskens ◽  
Peter Freisinger ◽  
Vincenzo Leuzzi ◽  
...  
Keyword(s):  
Phenylalanine Hydroxylase ◽  
Growth Parameters ◽  
Continuous Group ◽  
Restricted Diet ◽  
Neurodevelopmental Outcomes ◽  
Long Term Treatment ◽  
Extension Group ◽  
Previously Treated ◽  
Extension Period

Abstract Background During the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH4), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0–4 years with BH4-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with sapropterin. Results All 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only (‘sapropterin extension’ group; n = 26), were initiated on sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with sapropterin plus Phe-restricted diet, remained on this regimen in the extension period (‘sapropterin continuous’ group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the ‘sapropterin continuous’ group (95% CI 28.9, 48.6; p < 0.0001). In the ‘sapropterin extension’ group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI − 2.8, 13.8; p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters. Conclusions Long-term treatment with sapropterin plus a Phe-restricted diet in patients who initiated sapropterin at < 4 years of age with BH4-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for sapropterin in paediatric patients (< 4 years of age) with BH4-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of sapropterin treatment. Trial registration ClinicalTrials.gov, NCT01376908. Registered 17 June 2011, https://clinicaltrials.gov/ct2/show/NCT01376908.

Atezolizumab (atezo) in patients with metastatic urothelial carcinoma (mUC): A 2-year clinical update from a phase Ia study.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 290-290 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Thomas Powles ◽  
Joaquim Bellmunt ◽  
Fadi S. Braiteh ◽  
Yohann Loriot ◽  
...  
Keyword(s):  
Objective Response ◽  
The United States ◽  
Term Treatment ◽  
Long Term Results ◽  
Platinum Based Chemotherapy ◽  
Long Term Treatment ◽  
Previously Treated ◽  
Ecog Ps

290 Background: Atezo (anti–PD-L1) has demonstrated safety and efficacy in a broad range of cancers and is approved in the United States for mUC previously treated with platinum-based chemotherapy. Here we report long-term results in mUC from Phase Ia study NCT01375842 (PCD4989g). Methods: Previously treated mUC patients received atezo 15 mg/kg or 1200 mg IV q3w. Enrollment in this Phase Ia expansion cohort initially required PD-L1–selected status and later opened to patients regardless of PD-L1 expression on tumor-infiltrating immune cells. The primary endpoint was safety/tolerability. Secondary endpoints included investigator-assessed RECIST v1.1 ORR (confirmed), DOR and OS. Results: 95 patients were safety evaluable (Table). Median age was 66 years, 76% were male and 80% had primary bladder tumors. 61% had ECOG PS 1. 52% received ≥ 3 prior systemic therapies for mUC (70% platinum). Median treatment duration was 3 months (range: 0-32 months); 24% were treated for ≥ 1 year. Treatment-related AEs occurred in 66% (all Grade) and 8% (Grade 3-4) of patients. No treatment-related deaths were reported. In 94 objective response–evaluable patients (follow-up ≥ 12 weeks), the ORR was 27% (95% CI: 18, 37%), and the CR rate was 10%; the SD rate was 19%. mDOR was 22.1 months (95% CI: 12.1, NE months) in all patients; 56% of responses (7/9 CRs and 7/16 PRs) were ongoing at the December 15, 2015 data cutoff. With a 24-month median follow-up duration (range: 1+ to 32 months), the 1-year OS rate was 47% (95% CI: 36, 58%), and the 2-year rate was 29% (19, 40%); mOS is in the Table. Updated clinical data with further follow-up and analyses by PD-L1 status will be presented. Conclusions: Long-term treatment with atezo was well tolerated, without new safety signals in heavily pre-treated mUC patients. The durability of responses, including CRs, along with extended OS, confirm atezo as a new standard for previously treated mUC patients. Clinical trial information: NCT01375842. [Table: see text]

Spanish BH4-responsive phenylalanine hydroxylase-deficient patients: Evolution of seven patients on long-term treatment with tetrahydrobiopterin

2005 ◽  
Vol 86 ◽  
pp. 61-66 ◽  
Author(s):  
Amaya Bélanger-Quintana ◽  
María José García ◽  
Margarita Castro ◽  
Lourdes R. Desviat ◽  
Belén Pérez ◽  
...  
Keyword(s):  
Phenylalanine Hydroxylase ◽  
Term Treatment ◽  
Long Term Treatment

A432 Long-Term Treatment with Lenalidomide in Previously Treated Subjects with Multiple Myeloma

2009 ◽  
Vol 9 ◽  
pp. S68-S69
Author(s):  
AA Amor ◽  
B Aguado ◽  
C Camara ◽  
A Velasco ◽  
F Garcia-Escribano
Keyword(s):  
Multiple Myeloma ◽  
Term Treatment ◽  
Long Term Treatment ◽  
Previously Treated

Long-term treatment risks in multiple sclerosis: risk knowledge and risk perception in a large cohort of mitoxantrone-treated patients

2012 ◽  
Vol 19 (7) ◽  
pp. 920-925 ◽  
Author(s):  
A Hofmann ◽  
JP Stellmann ◽  
J Kasper ◽  
F Ufer ◽  
WG Elias ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Patient Information ◽  
Risk Estimation ◽  
Term Treatment ◽  
Risk Awareness ◽  
Treatment Benefits ◽  
Long Term Treatment ◽  
Previously Treated ◽  
Risk Knowledge

Background: Balancing treatment benefits and risks is part of a shared decision-making process before initiating any treatment in multiple sclerosis (MS). Patients understand, appreciate and profit from evidence-based patient information (EBPI). While these processes are well known, long-term risk awareness and risk processing of patients has not been studied. Mitoxantrone treatment in MS is associated with long-term major potential harms – leukaemia (LK) and cardiotoxicity (CT). The risk knowledge and perception among patients currently or previously treated with mitoxantrone is unknown. Objectives: The objective of this article is to conduct a retrospective cohort study in greater Hamburg, Germany, to estimate risk awareness and perception in MS patients treated with mitoxantrone. Methods: MS patients with at least one dose of mitoxantrone between 1991 and 2010 from six major MS centres in greater Hamburg received a questionnaire assessing risk awareness and perception as well as a written EBPI about mitoxantrone-associated LK and CT. Results: Fifty-one per cent in the cohort of n = 575 patients returned the questionnaire. Forty per cent correctly estimated the risk of LK (CT 16%); 56% underestimated the risk (CT 82%). Reading the information increased the accuracy of LK risk estimation, and patients did not report an increase of worries. The EBPI was appreciated and recommended by 85%. Conclusion: Risk awareness of mitoxantrone-treated patients is insufficient, but can be increased by EBPI without increasing worries. Continued patient information during and after treatment should be implemented in management algorithms.

Long-Term Treatment with Slow-Release Frusemide Compared with Thiazide Treatment in Arterial Hypertension

1989 ◽  
Vol 17 (6) ◽  
pp. 552-559 ◽  
Author(s):  
H. Jørgensen ◽  
N. Anderssen ◽  
T. Silsand ◽  
L.-E. Peterson
Keyword(s):  
Arterial Hypertension ◽  
Antihypertensive Effect ◽  
Slow Release ◽  
Serum Glucose ◽  
Term Treatment ◽  
Moderate Essential Hypertension ◽  
Fasting Serum ◽  
Long Term Treatment ◽  
Previously Treated

The effect of 30 mg/day slow-release frusemide given orally for 12 months was studied in 64 patients previously treated with thiazides for mild to moderate essential hypertension. Frusemide had a significant antihypertensive effect ( P<0.001), and compared to thiazides significantly reduced fasting serum glucose ( P<0.015), haemoglobin A1c ( P<0.025), albumin ( P<0.025) and serum calcium ( P<0.025), and significantly increased serum sodium and chloride concentrations ( P<0.0001). There was also a non-significant trend for frusemide to reduce serum total cholesterol, triglycerides and urate, and to increase serum potassium. Frusemide was well tolerated in all but three patients. It is concluded that slow-release frusemide has a comparable antihypertensive effect to that of thiazide diuretics, but has fewer metabolic side-effects, and should be used in preference to thiazides for the treatment of arterial hypertension when a diuretic is indicated.

Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7510-7510 ◽  
Author(s):  
John C. Byrd ◽  
Peter Hillmen ◽  
Susan Mary O'Brien ◽  
Jacqueline Claudia Barrientos ◽  
Nishitha M. Reddy ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Term Treatment ◽  
Lymphocytic Leukemia ◽  
Major Hemorrhage ◽  
Prior Therapy ◽  
Long Term Treatment ◽  
Long Term Follow Up ◽  
Previously Treated

7510 Background: Ibr, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is FDA-approved for all pts with CLL/SLL. We report updated safety and efficacy results with up to 4 y follow-up from the ph III RESONATE trial of ibr vs ofatumumab (ofa). Methods: Pts had ≥1 prior therapy. Pts received 420 mg ibr PO until PD or ofa up to 24 wks. At interim analysis (median 9 mo follow-up), the DMC declared superiority of ibr vs ofa for PFS and OS, and ibr access was recommended for all ofa pts. Long-term follow-up efficacy endpoints are per investigator assessment. Ofa pts were censored at crossover for OS. Results: 391 pts were randomized to receive ibr (n = 195) or ofa (n = 196). Median age was 67 y (40% ≥70 y); 57% had Rai stage III/IV. With median follow-up of 44 mo (53 mo max) for ibr arm, PFS was significantly longer for ibr vs ofa (median NR vs 8 mo, [HR 0.133; P< 0.0001]; 3-y PFS 59% vs 3%) with significant benefit across subgroups. PFS with ibr for del11q subgroup trended to have the most favorable outcome; however, PFS was not statistically different for pts with del17p or del11q or without these FISH abnormalities. At analysis, with the majority of pts (68%) randomized to ofa crossing over to ibr, OS was longer for ibr vs ofa (median OS NR for either arm). The OS rate for ibr at 3 y was 74%. ORR for ibr was 91% with CR/CRi rates (now 9%) increasing over time. Baseline cytopenias improved with extended ibr therapy for hemoglobin (85%), platelet (95%), and absolute neutrophil counts (95%). AE profile of ibr was consistent with previous reports. Major hemorrhage, Gr ≥3 atrial fibrillation, and Gr ≥3 hypertension occurred in 6%, 6%, and 8% of pts, respectively, over a follow-up of up to 4 y. Incidence of most Gr ≥3 AEs decreased from y 1 vs y 2-3: neutropenia- 18% vs 8%; pneumonia- 11% vs 4%; atrial fibrillation- 4% vs 2%, respectively. Discontinuations were most frequently PD (27%) and AE (12%). At analysis, 90 ibr pts (46%) continue ibr on study. Conclusions: Long-term treatment with ibr in this international ph III RESONATE study is tolerable and continues to show sustained PFS and OS regardless of high-risk cytogenetics. Ph III results in relapsed del17p and del11q pts compare favorably to prior ph II reports. Clinical trial information: NCT01578707.

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