Assessing Protection from Intracranial Hemorrhage in Clinical Studies for Investigational Agents in Patients with Hemophilia

Abstract Background: Intracranial hemorrhage (ICH) is a serious complication for patients with Hemophilia. In the Universal Data Collection (UDC) program (Witmer C et al., 2011), the rate of ICH in patients with hemophilia (PWH) was 3.9 per 1000 patient-years, with the majority of events (74.4%) taking place in patients with severe hemophilia. The incidence of mortality for hemophilia patients experiencing ICH approaches 20%. Prophylaxis with replacement factor remains the standard of care for PWH and is efficacious in reducing the incidence of ICH by 48% in HIV-negative, severe hemophilia patients and by 50% in severe hemophilia patients with inhibitors. Multiple investigational non-factor products are currently undergoing clinical evaluation for the treatment of Hemophilia. Given their different mechanisms of action, it is unknown if they will provide the same level of protection from ICH as the current standard of care. Aims: We aimed to estimate the sample size needed to power a clinical study adequately to detect a reduction in the risk of ICH in PWH using a hypothetical investigational agent compared to the rates of ICH observed in the UDC Hemophilia cohort. Methods: We conducted a simulated power analysis to quantify the number of patients needed to detect a reduction in risk of ICH in PWH exposed to a hypothetical investigational agent compared to the risk of ICH observed in the UDC cohort. Based on published data, we assumed an overall ICH risk of 1.9% over a 10-year follow-up (average follow-up 5 years). We assumed a risk of ICH of 1.7% over an average of 5 years in patients prescribed prophylaxis with replacement factor and a risk of mortality due to ICH within patients with hemophilia of 0.4%. We used a two-sided Z test with pooled variance and targeted the significance level of the test at 0.05 and the power at 0.8. Results: A sample size of 11,595 patients per group followed for 1 year is required to achieve 80% power to detect a 2-fold reduction in ICH risk for patients receiving investigational treatment compared to the overall observed risk in PWH receiving treatment at federally funded HTCs. Sample sizes of 13,650 would be required per group, to demonstrate a 2-fold reduction in ICH risk for patients receiving investigational treatment vs. patients prescribed prophylaxis with replacement factor. Additionally, sample sizes of 11,737 per group, would be required to achieve 80% power to detect a 2-fold reduction in the risk of ICH mortality in a population of patients treated with an investigational agent vs. patients with hemophilia under the current standard of care. Conclusions: The relatively high mortality associated with incidence of ICH, highlights a need to determine how efficacious investigational agents are in protecting from these events. However, the relatively infrequent incidence of ICH represents an obstacle for current clinical studies to adequately evaluate protection against these types of events. These analyses demonstrate that clinical trials of investigational non-factor products would require extremely large samples sizes in order to demonstrate a level of protection that is comparable or superior to that observed with the current standard of care. Additional clinical and scientific strategies will be required in order to thoroughly assess the efficacy of non-factor agents in protecting from ICH. Disclosures Gallo: Shire: Employment. Chiuve:Shire: Employment. Rowan:Baxalta: Consultancy. Valentino:Shire: Employment.

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A community-based comprehensive intervention to reduce syphilis infection among low-fee female sex workers in China: a matched-pair, community-based randomized study

Infectious Diseases of Poverty ◽

10.1186/s40249-019-0611-z ◽

2019 ◽

Vol 8 (1) ◽

Cited By ~ 4

Author(s):

Wei Dong ◽

Chu Zhou ◽

Ke-Ming Rou ◽

Zun-You Wu ◽

Jun Chen ◽

...

Keyword(s):

Sex Workers ◽

Standard Of Care ◽

Matched Pair ◽

Intervention Package ◽

Current Standard ◽

Community Based ◽

Syphilis Infection ◽

Intervention Measures ◽

Comprehensive Intervention

Abstract Background Low-fee female sex workers (FSWs) are at high risk of acquiring and spreading human immunodeficiency virus (HIV)/sexually transmitted diseases (STDs) in China. There is an urgent need to develop comprehensive intervention measures targeted towards low-fee FSWs to reduce HIV/STD infections. Thus, this study aimed to reduce HIV/STD infections among low-fee FSW through a matched-pair, community-based randomized intervention trial carried out in 12 cities in three provinces in China. Methods Four cities from Guangxi Zhuang Autonomous Region, four from Yunnan Province, and four from Hunan Province were paired and participants received either the intervention package (including condom promotion, HIV and syphilis testing, reimbursement for syphilis treatment costs, and free anti-retroviral therapy or the current standard of care. Venue-based, convenience sampling was used to recruit FSWs. A face-to-face interview and HIV and syphilis blood testing was conducted at baseline and follow-up intervals of 24 months. Generalized linear mixed models (GLMM) were used to evaluate the effect of the intervention package on reducing HIV/STD infection in the FSWs. Results A total of 1024 eligible FSWs were enrolled in the baseline survey and 843 in the follow-up. GLMM results showed that syphilis infection was reduced by 49% in the intervention group compared to the current standard of care group (P = 0.0378, OR = 0.51, 95% CI: 0.27–0.96). FSWs aged 35 years or older were 2.38 times more likely to get syphilis infection compared to those younger than 35 years old (P < 0.0001, OR = 2.38, 95% CI: 1.55–3.65). The risk of syphilis infection among more educated FSWs was 0.43 times less than those with lower levels of education (P < 0.05, OR = 0.43, 95% CI: 0.63–0.93). Conclusions This study demonstrates that comprehensive interventions can lead to significant declines in syphilis infection amongst low-tier FSWs. Integrating both behavioral and biomedical intervention measures should be considered when developing programs for low-fee FSWs. Trial registration CHiCTR-TRC-12002655.

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A Phase II Add-on Study of Vorinostat (VOR) in Higher Risk Myelodysplastic Syndrome with Failure of Hypomethylating Agents (HMA): The GFM Azavor Study

Blood ◽

10.1182/blood.v126.23.2900.2900 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2900-2900

Author(s):

Thomas Prebet ◽

Jacques Delaunay ◽

Eric Wattel ◽

Thorsten Braun ◽

Pascale Cony-Makhoul ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Response Rate ◽

Standard Of Care ◽

Median Number ◽

Current Standard ◽

Stage Design ◽

Early Evaluation ◽

Positive Results

Abstract Background: Azacitidine (AZA) is the current standard of care for patients treated for higher risk MDS, but 40-50% patients do not respond and most responders eventually relapse. Median survival after AZA failure is only 5 months and no standard of care is defined for this population. Preclinical studies and positive results of phase I-II trials support a synergistic effect of the histone deacetylase (HDAC) vorinostat (VOR) and AZA in terms of response, although no survival advantage of the combination has as yet been demonstrated. We hypothesized that adding VOR to AZA in patients with primary or secondary AZA resistance could rescue response and prolong survival. Methods: inclusion criteria inGFM AZAVOR study (NCT 01748240) were: 1/IPSS int 2 or high risk MDS at the time of initiation of AZA 2/treatment with at least 6 cycles of AZA and either failure to achieve any response or loss of response (per IWG2006 criteria) 3/a maximum of 3 months between AZA failure and inclusion with no other treatment in between. Patients received VOR 300mg bid from day 3 to day 9 of each cycle. AZA was given at standard 75mg/m2/d day 1 to 7 or at the maximum previously tolerated dose in case of dose reduction. Patients were evaluated after 6 cycles and responding patients treated until progression. The trial used a two-stage design, and accrual was to be stopped if less than 3 responses were seen in the first 14 evaluable patients. Results 21 patients were included between march 2013 and September 2014. Nineteen patients were treated (1 patient died and 1 progressed before treatment). Median age was 72 years. All pts had higher risk MDS and had received a median of 6 cycles of AZA before entering the trial. The median number of AZA+ VOR cycles administered was 3 (range: 1-12). No unexpected SAEs were seen, and the most common AEs were infection, thrombocytopenia, GI toxicities, and fatigue. After 6 cycles of treatment, only 2 patients (11%) achieved response (1 erythroid hematological improvement, 1 partial remission), , which, per protocol, triggered the stop of accrual. At last follow-up, 18 patients were off study and one patient was still on treatment. Nine patients stopped treatment because of progression (42%), 4 stopped treatment for lack of response (21%), 2 stopped treatment because of intolerance (11%), 1 patient stopped at his request (5%), and 1 patient died of complications of cytopenias while on treatment (5%). Median overall survival was 13 months. Conclusion This is the first report of an add-on study in high risk MDS, a strategy that may be useful for the early evaluation of drugs for which synergy with AZA is expected. Our results show that the proposed regimen of AZA +VOR can be used safely. However, the observed response rate was not above the "background" response rate expected from AZA alone continuation in a comparable patient population, indicating that the addition of VOR cannot reverse resistance to AZA. Disclosures Prebet: CELGENE: Research Funding. Off Label Use: lenalidomide. Wattel:Janssen: Consultancy, Honoraria, Research Funding; PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.

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Efficacy safety and immunogenicity of rurioctocog alfa pegol for prophylactic treatment in previously treated patients with severe hemophilia A: a systematic review and meta-analysis of clinical trials

F1000Research ◽

10.12688/f1000research.73884.1 ◽

2021 ◽

Vol 10 ◽

pp. 1049

Author(s):

Bendix Samarta Witarto ◽

Visuddho Visuddho ◽

Andro Pramana Witarto ◽

Henry Sutanto ◽

Bayu Satria Wiratama ◽

...

Keyword(s):

Hemophilia A ◽

Meta Analysis ◽

Standard Of Care ◽

Cochrane Library ◽

Severe Hemophilia ◽

Current Standard ◽

Serious Adverse Events ◽

Bleeding Prophylaxis ◽

Previously Treated Patients ◽

Previously Treated

Background: Patients with severe hemophilia often present with painful joint and soft tissue bleeding which may restrict them from their daily activities. The current standard of care still relies on a regular prophylactic factor VIII (FVIII), which has a high daily treatment burden. Recently, rurioctocog alfa pegol, a third-generation recombinant FVIII with a modification in its polyethylene glycol (PEG) component, has been developed. Several trials have studied this synthetic drug as bleeding prophylaxis in severe hemophilia A. This study aims to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol for previously treated patients with severe hemophilia A. Methods: This study was conducted in conformity with the PRISMA guidelines. Data were retrieved from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost). Study qualities were assessed using the Methodological Index for Non-Randomized Studies (MINORS) and Modified Jadad scales. Results: Four studies involving 517 previously treated severe hemophilia A patients were included in this study. The pooled mean of total annualized bleeding rate (ABR) and hemostatic efficacy was 2.59 (95% CI = 2.04–3.14) and 92% (95% CI = 85%–97%), respectively. Only 30 (2.3%) non-serious and one (1.4%) serious adverse events were considered related to rurioctocog alfa pegol treatment. At the end of the studies, no development of FVIII inhibitory antibodies was observed. None of the developed binding antibodies to FVIII, PEG-FVIII, or PEG was correlated to the treatment efficacy and safety. Conclusions: Despite the limited availability of direct comparison studies, our analyses indicate that rurioctocog alfa pegol could serve as a safe and effective alternative for bleeding prophylaxis in previously treated hemophilia A patients. Moreover, it appears to have low immunogenicity, which further increases the safety profile of the drug in such clinical conditions.

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Consolidation therapy using cyberknife radiosurgery in NSCLC patients with low-volume residual disease upon completion of systemic therapy

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.18213 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 18213-18213

Author(s):

M. P. McLaughlin ◽

R. Bordoni ◽

T. Whitaker ◽

P. Zolty ◽

M. Andrews ◽

...

Keyword(s):

Systemic Therapy ◽

Residual Disease ◽

Local Therapy ◽

Standard Of Care ◽

Initial Therapy ◽

Consolidation Therapy ◽

Current Standard ◽

End Point ◽

Ecog Ps

18213 Background: Pts with unresectable IIIB and IV NSCLC with PS 0–1 are usually treated with chemotherapy (CH) ± targeted therapy (TT) with overall survival (OS) improvement. Upon completion, standard of care is observation. Pts eventually progress within 9 to 12 months. If still in good PS, they are treated with salvage CH or TT; otherwise, they receive palliative care. We evaluated 12 patients with PR to initial therapy, found to have small volume residual disease (SVRD) defined as one or two sites to receive “consolidation” local therapy with Cyberknife Radisurgery (CRS). Methods: Since September 2006, 12 pts with NSCLC, stage IIIB unresectable (3) or IV (9), median age 64 (range 61–78), adenocarcinoma (7), squamous cell carcinoma(5), 9 males, all ECOG PS 0–1, were treated with induction CH (carboplatin/paclitaxel ± bevacizumab, cisplatin/gencitabine) with PR. CT/PET imaging showed SVRD. Eight patients had only one site; four had 2. These patients received CRS consolidative therapy to the following areas: lung-9, mediastinal node - 3, adrenal-2, liver-2. CRS dose depended on the disease site. Peripheral lung lesions - 54 Gy in 3 fractions (fx); medistinal lesions - 50 Gy in 4 fx; adrenal - 24 Gy in 3 fx and liver - 16 Gy. in 1 fx. The primary end point was efficacy (response rate, time to progression in or out of the radiosurgical fields, and OS) compared with historical matched controls. The secondary end point was safety and tolerability of CRS. Results: After a median follow up period of 65 days, all evaluable pts are still alive and without clinical or radiological (CT/PET) evidence of disease progression in or outside the sites of CRS. The treatment was well tolerated with no Grade 3–5 complications. PS remained 0–1 in all patients. Conclusions: Patients with advanced NSCLC benefit from systemic therapy with symptoms control and improved QoL and OS. Upon completion of therapy, observation is the current standard or care. Patients with good PS and SVRD tolerated CRS consolidation therapy remarkably well and may benefit with added symptoms control, improved TTP and even OS. At the June meeting efficacy and toxicity data of a projected population of 30+ patients, with a medial follow up of 8 months, will be presented. No significant financial relationships to disclose.

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Efficacy, safety, and immunogenicity of rurioctocog alfa pegol for prophylactic treatment in previously treated patients with severe hemophilia A: a systematic review and meta-analysis of clinical trials

F1000Research ◽

10.12688/f1000research.73884.2 ◽

2021 ◽

Vol 10 ◽

pp. 1049

Author(s):

Bendix Samarta Witarto ◽

Visuddho Visuddho ◽

Andro Pramana Witarto ◽

Henry Sutanto ◽

Bayu Satria Wiratama ◽

...

Keyword(s):

Hemophilia A ◽

Meta Analysis ◽

Standard Of Care ◽

Cochrane Library ◽

Severe Hemophilia ◽

Current Standard ◽

Serious Adverse Events ◽

Bleeding Prophylaxis ◽

Previously Treated Patients ◽

Previously Treated

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Penetrance of hypertrophic cardiomyopathy and outcome in sarcomeric mutation carriers

European Heart Journal ◽

10.1093/ehjci/ehaa946.2074 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Lorenzini ◽

G Norrish ◽

E Field ◽

J.P Ochoa ◽

M Cicerchia ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Gene Mutations ◽

Standard Of Care ◽

Current Standard ◽

Mutation Carriers ◽

Disease Penetrance ◽

Long Term Follow Up ◽

Few Data

Abstract Background Predictive genetic screening of the first degree relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM. Purpose To establish the role of sex and genotype in HCM penetrance as well as the rate of major adverse clinical events in SP mutation carriers and following the diagnosis of HCM. Methods Retrospective analysis of consecutive adult and paediatric SP mutation carriers identified during family screening and who did not fulfill diagnostic criteria for HCM at first evaluation. Results 321 individuals from 170 families [median age first evaluation 15.2 years (IQR 7.3–32.6); 153 (47.7%) males] were evaluated. Causal SP genes were: MYBPC3 (n=133 (41.4%)), MYH7 (n=77 (24.0%)), TNNI3 (n=51 (15.9%)), TNNT2 (n=40 (12.5%)), TPM1 (n=9 (2.8%)), MYL2 (n=6 (1.9%)), and ACTC1 (n=1 (0.3%)); 4 (1.3%) carried multiple mutations. After a median follow up of 7.4 years (IQR 2.5–12.7), 89 (27.7%) patients developed HCM. Disease penetrance at the age of 50 years was 47% (95% CI 38%-56%). One hundred and fifty three (47.7%) individuals underwent cardiac magnetic resonance (CMR) imaging; among those diagnosed with HCM, 22/89 (24.7%) fulfilled criteria on CMR but not echocardiography. In a multivariable model adjusted for genotype, follow up duration and evaluation with CMR, independent predictors of HCM development were male sex (HR 3.11; CI 1.82–5.32) and abnormal ECG (HR 7.87; CI 4.43–13.97). Patients with MYH7 and multiple mutations were more likely to develop HCM than those with MYBPC3 mutations (HR 2.03; CI 1.04–3.96 and HR 10.13; CI 1.40–72.92, respectively). Disease penetrance was lowest in carriers of TNNI3 mutations (HR 0.13; CI 0.03–0.48). There were no major adverse events in individuals without HCM. Following the diagnosis of HCM, the combined rate of all-cause death, appropriate defibrillator shock or resuscitated cardiac arrest was 1.1%/year [median follow up 4.0 years (IQR 2.1–8.9)]. Conclusions Approximately 50% of SP mutation carriers develop HCM by the age of 50 and become prone to disease complications during long-term follow-up. Sex, MYH7 mutations and the presence of an abnormal ECG are associated with a higher risk of disease development. CMR should be employed systematically in long-term screening. HCM penetrance by sex Funding Acknowledgement Type of funding source: None

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Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.688 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 688-688 ◽

Cited By ~ 11

Author(s):

Scott Kopetz ◽

Axel Grothey ◽

Rona Yaeger ◽

Pieter-Jan AR Cuyle ◽

Sanne Huijberts ◽

...

Keyword(s):

Objective Response ◽

Braf Inhibitor ◽

Progression Free Survival ◽

Standard Of Care ◽

Mek Inhibitor ◽

Weekly Dose ◽

Current Standard ◽

Grade 3 ◽

Tract Infections

688 Background: BRAFV600E mutation occurs in 10%-15% of patients (pts) with mCRC and confers a poor prognosis. After first-line therapy, standard second-line therapies provide limited benefit, with objective response rates (ORRs) < 10%, and overall survival (OS) of 46 months (mo). BEACON CRC (NCT02928224) is a 3-arm phase 3 trial of triplet therapy with the BRAF inhibitor ENCO + MEK inhibitor BINI + antiEGFR antibody CETUX vs ENCO + CETUX vs a control arm (irinotecan/FOLFIRI + CETUX) in pts with BRAFV600E mCRC in the second or third-line setting. A safety lead-in (SLI) of the triplet therapy was conducted in 30 pts prior to initiation of the randomized part of the trial. Previously reported confirmed ORR in 29 pts with BRAFV600E mCRC was 48% and median progression-free survival (PFS) was 8.0 mo (Van Cutsem E, et al. Ann Oncol. 2018;29:O-027). Here we present updated safety and efficacy results including mature OS. Methods: All pts in the SLI received ENCO 300 mg once daily + BINI 45 mg twice daily + CETUX standard weekly dose. Assessments included efficacy (ORR, duration of response, time to response, PFS, and OS), safety, and tolerability. Results: Among 30 pts treated, 1 had a BRAF non-V600E mutation and is not included in the efficacy analyses. At data cutoff, the median follow-up time for survival was 18.2 mo and median exposure was 7.8 mo (range 0.521.4 mo). The confirmed ORR and median PFS remain unchanged from the previous report (ORR, 48% [95%CI, 29.467.5]; PFS, 8.0 mo [95% CI, 5.69.3 mo]). Mature median OS is 15.3 mo (95% CI, 9.6 monot reached). The triplet continues to be well-tolerated with no unexpected toxicities. The most common grade 3/4 toxicities were fatigue (13%), anemia, increases in creatine phosphokinase and/or aspartate aminotransferase, and urinary tract infections (each 10%). The rate of grade 3/4 skin toxicities continues to be lower than generally observed with CETUX in mCRC. Conclusions: With longer follow-up, triplet therapy with ENCO + BINI + CETUX continues to be well tolerated. Median PFS and now mature median OS are substantially improved over historical data for current standard-of-care options. Clinical trial information: NCT02928224.

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Non-brachytherapy approach for locally advanced cervical cancer treatment.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18023 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18023-e18023

Author(s):

Nidal Salim ◽

Vladimir Nosov ◽

Daria Zvereva ◽

Olga Novikova ◽

Anna Tedeeva ◽

...

Keyword(s):

Cervical Cancer ◽

Dose Escalation ◽

Locally Advanced ◽

Standard Of Care ◽

Advanced Cervical Cancer ◽

Current Standard ◽

Locally Advanced Cervical Cancer ◽

Oncological Outcomes ◽

Pet Ct

e18023 Background: Concomitant chemoradiation therapy (CRT) that includes both external beam radiotherapy (EBRT) and brachytherapy (BT) is the current standard of care in treatment of locally advanced cervical cancer (LACC). Adaptive EBRT using volumetric modulated arc technology without BT allows dose escalation and decreases toxicities. Non-brachytherapy treatment is an evolving alternative approach provides geographical radiation accuracy but the oncological outcomes still to be evaluated. Methods: Patients with LACC (stages 1B3–IVA) who underwent non-brachytherapy CRT using adaptive EBRT with simultaneous integrated boost at our institution were evaluated prospectively from May 2015 to December 2019. All patients were initially assessed by a gynecologic oncologist, pelvic MRI and 18FDG-PET/CT scan were conducted. Follow-up pelvic examinations with cytology every 3 months and PET/CT at 3 and 12 months after completion of treatment were performed. Oncological outcomes and toxicities were assessed. Results: Twenty-one patients were analyzed: median age was 54 years (30–76 years); 19 patients had squamous cell histology and 2 had adenocarcinoma. Median follow-up was 32 months (8–56). The average dose administered to the gross tumor volume was 90.2 Gy (79.5–96.6), 79.8 Gy to all PET/MRI positive lymph nodes (63.0–89.7). No patents received BT; all but 3 received chemotherapy. Three-year local control was 100% (PFS = 90.4% and OS = 100%). There were 2 recurrences: a solitary skull lesion 18 months following CRT in a patient with mesonephric adenocarcinoma and a metastasis to a transposed ovary 15 months after CRT. No grade 3–4 toxicities were seen. Only 1 patient (4.7%) had late rectal grade II toxicity. Conclusions: Non-brachytherapy adaptive CRT for LACC is feasible. It allows for a significant dose escalation, thus providing better local control and likely increases PFS and OS at no cost of serious toxicity. Randomized studies comparing this approach to the current standard of care are needed.

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The Safety of Hemophilia Product Use: a Simulation Analysis

Blood ◽

10.1182/blood.v128.22.5914.5914 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5914-5914

Author(s):

Stephanie Chiuve ◽

Daniel Gallo ◽

Christopher Rowan ◽

Leonard A. Valentino

Keyword(s):

Treatment Group ◽

Safety Concern ◽

Standard Of Care ◽

Current Therapy ◽

Published Data ◽

Sample Sizes ◽

Investigational Agent ◽

Fold Reduction ◽

Current Therapies ◽

Bleeding Episodes

Abstract Background:In hemophilia patients with inhibitors, the primary safety concern associated with the administration of bypassing agents, such arecombinant factor VIIa (rFVIIa)andFactor Eight Inhibitor Bypass Activity (FEIBA)to manage bleeding episodes is the risk ofthromboembolic events (TEs). Replacement FVIII may also increase TEs in patients with hemophilia without inhibitors, although the incidence of TE is extremely rare. The low incidence of hemophilia and low rate of TE associated with current therapies in these patients provide a significant challenge to study the comparative safety of novel non-factor therapies with the current standard of care. Aims: We aimed to estimate the sample size needed to adequately power a clinical trial that would detect a reduction in TEs in hemophilia patients exposed to a hypothetical investigational agent compared to current therapies for the management of bleeding episodes (FVIII replacement, FEIBA and rFVIIa). Methods: We conducted a simulated power analysis to quantify the number of infusions that would be needed in each treatment arm (investigational therapy vs. current therapy) to detect a reduction in the rate of TE in hemophilia patients across a range of effects. Based on published data, the rate of TE was 2 per 106 infusions of replacement FVIII. We assumed conservative rates of TE of 2 per 105 infusions of replacement FVIII to account for the potential imprecise rates estimated from the low number of events observed in prior studies. In the MedWatch database, the rate of TE was 8.24 per 105 infusions of FEIBA and 24.6 per 105 infusions of NOVOSEVEN. To account for the known underreporting of adverse events in this database, we assumed conservative estimates of and, 1.34 per 103 infusions of FEIBA and 3.12 per 103 infusions of NOVOSEVEN. We applied a two-sided Z test with pooled variance and targeted the significance level of the test at 0.05 and the power at 0.8. Results: The number of infusions needed to detect a significant reduction TE rate in patients exposed to the investigational agent compared to all 3 standard of care therapies across a range of potential effects are provided in the Table. Sample sizes of 735,821 infusions per treatment group (replacement FVIII vs. investigational agent) are needed to achieve 80% power to detect a 5 fold reduction in the rate of TE among hemophilia patients exposed to the investigational agent compared to replacement FVIII. Over 1 million infusions per treatment group would be needed to detect a 2 fold reduction in rate of TE comparing an investigational agent to replacement FVIII. Sample sizes of 35,108 infusions in each treatment group would be required to detect a 2-fold decrease in TE rates in patients exposed to the investigational agent compared to FEIBA. To detect a 2 fold reduction in rate of TE in patients receiving the investigational agent compared to rFVIIa, the study would require 15,058 infusions in each treatment group. Conclusions: Current therapies to manage bleeding episodes in patients with hemophilia have demonstrated a high degree of safety.Clinical trials of alternative non-factor therapies with mechanisms of action that differ from the standard of care will require extremely large samples sizes and/or large reduction in TE risk to demonstrate significantly greater safety with respect to TE. Disclosures Chiuve: Shire: Employment. Gallo:Shire: Employment. Rowan:Baxalta: Consultancy. Valentino:Shire: Employment.

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Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure

Journal of Clinical Oncology ◽

10.1200/jco.2011.35.8135 ◽

2011 ◽

Vol 29 (24) ◽

pp. 3322-3327 ◽

Cited By ~ 276

Author(s):

Thomas Prébet ◽

Steven D. Gore ◽

Benjamin Esterni ◽

Claude Gardin ◽

Raphael Itzykson ◽

...

Keyword(s):

High Risk ◽

Myelodysplastic Syndrome ◽

Treatment Failure ◽

Clinical Care ◽

Standard Of Care ◽

Analysis Data ◽

Refractory Anemia ◽

International Prognostic Scoring System ◽

Current Standard ◽

Investigational Agents

Purpose Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described. Patients and Methods Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program). Results The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care. Conclusion Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.

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