Applying Data Warehousing to a Phase III Clinical Trial From the Fondazione Italiana Linfomi Ensures Superior Data Quality and Improved Assessment of Clinical Outcomes

PURPOSE Data collection in clinical trials is becoming complex, with a huge number of variables that need to be recorded, verified, and analyzed to effectively measure clinical outcomes. In this study, we used data warehouse (DW) concepts to achieve this goal. A DW was developed to accommodate data from a large clinical trial, including all the characteristics collected. We present the results related to baseline variables with the following objectives: developing a data quality (DQ) control strategy and improving outcome analysis according to the clinical trial primary end points. METHODS Data were retrieved from the electronic case reporting forms (eCRFs) of the phase III, multicenter MCL0208 trial (ClinicalTrials.gov identifier: NCT02354313 ) of the Fondazione Italiana Linfomi for younger patients with untreated mantle cell lymphoma (MCL). The DW was created with a relational database management system. Recommended DQ dimensions were observed to monitor the activity of each site to handle DQ management during patient follow-up. The DQ management was applied to clinically relevant parameters that predicted progression-free survival to assess its impact. RESULTS The DW encompassed 16 tables, which included 226 variables for 300 patients and 199,500 items of data. The tool allowed cross-comparison analysis and detected some incongruities in eCRFs, prompting queries to clinical centers. This had an impact on clinical end points, as the DQ control strategy was able to improve the prognostic stratification according to single parameters, such as tumor infiltration by flow cytometry, and even using established prognosticators, such as the MCL International Prognostic Index. CONCLUSION The DW is a powerful tool to organize results from large phase III clinical trials and to effectively improve DQ through the application of effective engineered tools.

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Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group (GCLLSG)

Haematologica ◽

10.3324/haematol.2019.231027 ◽

2019 ◽

Vol 105 (11) ◽

pp. 2598-2607 ◽

Cited By ~ 8

Author(s):

Sonia Jaramillo ◽

Andreas Agathangelidis ◽

Christof Schneider ◽

Jasmin Bahlo ◽

Sandra Robrecht ◽

...

Keyword(s):

Clinical Trials ◽

Chronic Lymphocytic Leukemia ◽

Early Stage ◽

International Prognostic Index ◽

Prognostic Index ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Prognostic Impact ◽

Advanced Stage ◽

Multicenter Clinical Trials

Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinicobiological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: i) early-stage patients (watch-and-wait arm of the CLL1 trial) (n=592); ii) patients in need of treatment, enrolled in 3 phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1861). Subset #1 was associated with del(11q), higher CLL international prognostic index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (HR: 4.2, CI: 2-8.6, p<0.001), and shorter time-to-next-treatment (TTNT) in the advanced-stage cohort (HR: 2, CI: 1.2-3.3, p=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other M-CLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset # 2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients.

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Matching comparisons of therapeutic efficacy suggest better clinical outcomes for patients treated with peginterferon beta-1a than with glatiramer acetate

Therapeutic Advances in Neurological Disorders ◽

10.1177/1756286420975916 ◽

2021 ◽

Vol 14 ◽

pp. 175628642097591

Author(s):

Thomas F. Scott ◽

Ray Su ◽

Kuangnan Xiong ◽

Arman Altincatal ◽

Carmen Castrillo-Viguera ◽

...

Keyword(s):

Clinical Trials ◽

Propensity Score ◽

Clinical Outcomes ◽

Glatiramer Acetate ◽

Therapeutic Efficacy ◽

Individual Patient Data ◽

Patient Data ◽

Phase Iii ◽

Lower Probability ◽

Phase Iii Clinical Trials

Background: Peginterferon beta-1a and glatiramer acetate (GA) are approved first-line therapies for the treatment of relapsing forms of multiple sclerosis, but their therapeutic efficacy has not been compared directly. Methods: Clinical outcomes at 2 years, including no evidence of disease activity (NEDA), for patients receiving peginterferon beta-1a 125 mcg every 2 weeks (Q2W) or GA 20 mg/ml once daily (QD) were compared by propensity score matching analysis using individual patient data from ADVANCE and CONFIRM phase III clinical trials. In addition, clinical outcomes at 1–3 years for patients receiving peginterferon beta-1a Q2W or GA 40 mg/ml three times a week (TIW) were evaluated using a matching-adjusted comparison analysis of individual patient data from ADVANCE and the ADVANCE extension study, ATTAIN, and aggregate patient data from the phase III GALA and the GALA extension studies. Results: Propensity-score-matched peginterferon beta-1a patients ( n = 336) had a significantly lower annualized relapse rate [ARR (0.204 versus 0.282); rate ratio = 0.724; p = 0.045], a significantly lower probability of 12-week confirmed disability worsening (10.0% versus 14.6%; hazard ratio = 0.625; p = 0.048), and a significantly higher rate of NEDA (20.3% versus 11.5%; p = 0.047) compared with GA 20 mg/ml QD patients after 2 years of treatment. Matching-adjusted peginterferon beta-1a patients (effective n = 276) demonstrated a similar ARR at 1 year (0.278 versus 0.318; p = 0.375) and significantly lower ARR at 2 years (0.0901 versus 0.203; p = 0.032) and 3 years (0.109 versus 0.209; p = 0.047) compared with GA 40 mg/ml TIW patients ( n = 834). Conclusion: Results from separate matching comparisons of phase III clinical trials and extension studies suggest that peginterferon beta-1a 125 mcg Q2W may provide better clinical outcomes than GA (20 mg/ml QD or 40 mg/ml TIW).

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The case for introducing pre-registered confirmatory pharmacological pre-clinical studies

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18760109 ◽

2018 ◽

Vol 38 (5) ◽

pp. 749-754 ◽

Cited By ~ 1

Author(s):

Olivia Kiwanuka ◽

Bo-Michael Bellander ◽

Anders Hånell

Keyword(s):

Clinical Trial ◽

Traumatic Brain Injury ◽

Clinical Trials ◽

Brain Injury ◽

Network Analysis ◽

Clinical Studies ◽

Phase Iii ◽

Phase Iii Clinical Trial ◽

Phase Iii Clinical Trials ◽

Experimental Drugs

When evaluating the design of pre-clinical studies in the field of traumatic brain injury, we found substantial differences compared to phase III clinical trials, which in part may explain the difficulties in translating promising experimental drugs into approved treatments. By using network analysis, we also found cases where a large proportion of the studies evaluating a pre-clinical treatment was performed by inter-related researchers, which is potentially problematic. Subjecting all pre-clinical trials to the rigor of a phase III clinical trial is, however, likely not practically achievable. Instead, we repeat the call for a distinction to be made between exploratory and confirmatory pre-clinical studies.

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A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

Annals of The Royal College of Surgeons of England ◽

10.1308/003588407x179125 ◽

2007 ◽

Vol 89 (3) ◽

pp. 207-211 ◽

Cited By ~ 18

Author(s):

JF Thorpe ◽

S Jain ◽

TH Marczylo ◽

AJ Gescher ◽

WP Steward ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Clinical Trials ◽

Cancer Prevention ◽

Age Of Onset ◽

Cancer Chemoprevention ◽

Phase Iii ◽

Phase Iii Clinical Trials ◽

Prostate Cancer Prevention ◽

Phase Iii Trials

INTRODUCTION Prostate cancer is an excellent target for chemoprevention strategies; given its late age of onset, any delay in carcinogenesis would lead to a reduction in its incidence. This article reviews all the completed and on-going phase III trials in prostate cancer chemoprevention. PATIENTS AND METHODS All phase III trials of prostate cancer chemoprevention were identified within a Medline search using the keywords ‘clinical trial, prostate cancer, chemoprevention’. RESULTS In 2003, the Prostate Cancer Prevention Trial (PCPT) became the first phase III clinical trial of prostate cancer prevention. This landmark study was terminated early due to the 24.8% reduction of prostate cancer prevalence over a 7-year period in those men taking the 5α-reductase inhibitor, finasteride. This article reviews the PCPT and the interpretation of the excess high-grade prostate cancer (HGPC) cases in the finasteride group. The lack of relationship between cumulative dose and the HGPC cases, and the possible sampling error of biopsies due to gland volume reduction in the finasteride group refutes the suggestion that this is a genuine increase in HGPC cases. The other on-going phase III clinical trials of prostate cancer chemoprevention – the REDUCE study using dutasteride, and the SELECT study using vitamin E and selenium – are also reviewed. CONCLUSIONS At present, finasteride remains the only intervention shown in long-term prospective phase III clinical trials to reduce the incidence of prostate cancer. Until we have the results of trials using alternative agents including the on-going REDUCE and SELECT trials, the advice given to men interested in prostate cancer prevention must include discussion of the results of the PCPT. The increased rate of HGPC in the finasteride group continues to generate debate; however, finasteride may still be suitable for prostate cancer prevention, particularly in men with lower urinary tract symptoms.

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Clinical Trial Design and Statistics

10.2310/psych.2189 ◽

2018 ◽

Author(s):

Julie Ann Sosa

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Data Analysis ◽

Trial Design ◽

New Technologies ◽

Drug Application ◽

Clinical Trial Design ◽

Double Blind Study ◽

Type I ◽

End Points

A clinical trial is a planned experiment designed to prospectively measure the efficacy or effectiveness of an intervention by comparing outcomes in a group of subjects treated with the test intervention with those observed in one or more comparable group(s) of subjects receiving another intervention. Historically, the gold standard for a clinical trial has been a prospective, randomized, double-blind study, but it is sometimes impractical or unethical to conduct such in clinical medicine and surgery. Conventional outcomes have traditionally been clinical end points; with the rise of new technologies, however, they are increasingly being supplemented and/or replaced by surrogate end points, such as serum biomarkers. Because patients are involved, safety considerations and ethical principles must be incorporated into all phases of clinical trial design, conduct, data analysis, and presentation. This review covers the history of clinical trials, clinical trial phases, ethical issues, implementing the study, basic biostatistics for data analysis, and other resources. Figures show drug development and clinical trial process, and type I and II error. Tables list Food and Drug Administration new drug application types, and types of missing data in clinical trials. This review contains 2 highly rendered figures, 2 tables, and 38 references

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International Prognostic Index for aggressive non-Hodgkin's lymphoma is valid for all malignancy grades

Blood ◽

10.1182/blood.v86.4.1460.bloodjournal8641460 ◽

1995 ◽

Vol 86 (4) ◽

pp. 1460-1463 ◽

Cited By ~ 99

Author(s):

J Hermans ◽

AD Krol ◽

K van Groningen ◽

PM Kluin ◽

JC Kluin-Nelemans ◽

...

Keyword(s):

Clinical Trial ◽

Hodgkin’S Lymphoma ◽

Performance Status ◽

International Prognostic Index ◽

Prognostic Index ◽

Population Based ◽

Hodgkin's Lymphoma ◽

Intermediate Grade ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

An International Prognostic Index (IPI) for patients with aggressive non-Hodgkin's lymphoma (NHL) has recently been published. The IPI is based on pretreatment clinical characteristics and developed on clinical trial patients, classified as intermediate grade according to the Working Formulation (WF). We applied this IPI in a population-based registry of NHL patients. This registry does not have the restrictions that usually hold for patients in clinical trials, eg, with respect to age and performance status. Moreover, it covers all the three WF classes (low, intermediate, and high). The IPI turned out to be of prognostic value for response rate and survival in our unselected cohort of 744 patients, as well. In each of the three WF classes separately, the four IPI classes showed going from low to high substantially decreasing response rates and survival percentages. For our cohort of WF intermediate grade patients 5-year survival levels were lower in all four IPI classes (59%, 34%, 14%, and 10%, respectively), probably reflecting the selection of clinical trial patients in the original study (73%, 51%, 43%, and 26%).

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End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain

Blood Advances ◽

10.1182/bloodadvances.2019000882 ◽

2019 ◽

Vol 3 (23) ◽

pp. 3982-4001 ◽

Cited By ~ 5

Author(s):

Ann T. Farrell ◽

Julie Panepinto ◽

C. Patrick Carroll ◽

Deepika S. Darbari ◽

Ankit A. Desai ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Patient Reported Outcomes ◽

Cell Disease ◽

End Points ◽

Additional Clinical Trial ◽

Patient Reported ◽

The Brain

Abstract To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.

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Timing of high-dose methotrexate CNS prophylaxis in DLBCL: an analysis of toxicity and impact on R-CHOP delivery

Blood Advances ◽

10.1182/bloodadvances.2020002421 ◽

2020 ◽

Vol 4 (15) ◽

pp. 3586-3593

Author(s):

Matthew R. Wilson ◽

Toby A. Eyre ◽

Nicolas Martinez-Calle ◽

Matthew Ahearne ◽

Katrina E. Parsons ◽

...

Keyword(s):

International Prognostic Index ◽

Multivariable Analysis ◽

Prognostic Index ◽

B Cell Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

End Points ◽

Cns Prophylaxis ◽

Dose Methotrexate ◽

Cns Relapse

Abstract High-dose methotrexate (HD-MTX) is increasingly used as prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse. However, there is limited evidence to guide whether to intercalate HD-MTX (i-HD-MTX) between R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 21-day intervals) or to give it at the end of treatment (EOT) with R-CHOP-21. We conducted a retrospective, multicenter analysis of 334 patients with DLBCL who received CNS prophylaxis with i-HD-MTX (n = 204) or EOT HD-MTX (n = 130). Primary end points were R-CHOP delay rates and HD-MTX toxicity. Secondary end points were CNS relapse rate, progression-free survival, and overall survival. The EOT group had more patients with a high CNS international prognostic index (58% vs 39%; P < .001) and more concurrent intrathecal prophylaxis (56% vs 34%; P < .001). Of the 409 cycles of i-HD-MTX given, 82 (20%) were associated with a delay of next R-CHOP (median, 7 days). Delays were significantly increased when i-HD-MTX was given after day 9 post–R-CHOP (26% vs 16%; P = .01). On multivariable analysis, i-HD-MTX was independently associated with increased R-CHOP delays. Increased mucositis, febrile neutropenia, and longer median inpatient stay were recorded with i-HD-MTX delivery. Three-year cumulative CNS relapse incidence was 5.9%, with no differences between groups. There was no difference in survival between groups. We report increased toxicity and R-CHOP delay with i-HD-MTX compared with EOT delivery but no difference in CNS relapse or survival. Decisions on HD-MTX timing should be individualized and, where i-HD-MTX is favored, we recommend scheduling before day 10 of R-CHOP cycles.

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Diagnosis-to-Treatment Interval Is an Important Clinical Factor in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Has Implication for Bias in Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2017.76.5198 ◽

2018 ◽

Vol 36 (16) ◽

pp. 1603-1610 ◽

Cited By ~ 39

Author(s):

Matthew J. Maurer ◽

Hervé Ghesquières ◽

Brian K. Link ◽

Jean-Philippe Jais ◽

Thomas M. Habermann ◽

...

Keyword(s):

Clinical Trials ◽

Odds Ratio ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Newly Diagnosed ◽

Clinical Factors ◽

Large B Cell Lymphoma ◽

Large B Cell

Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosis-to-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1,444). All patients received anthracycline-based immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P < .001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95% CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95% CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.

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Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.13.5376 ◽

2008 ◽

Vol 26 (28) ◽

pp. 4579-4586 ◽

Cited By ~ 422

Author(s):

Robert Marcus ◽

Kevin Imrie ◽

Philippe Solal-Celigny ◽

John V. Catalano ◽

Anna Dmoszynska ◽

...

Keyword(s):

Follicular Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

Response Duration ◽

Complete Response ◽

Phase Iii ◽

Term Outcome ◽

Bulky Disease ◽

Long Term Outcome ◽

Trial Treatment

PurposeTo compare the long-term outcome of patients with previously untreated follicular lymphoma (FL) needing therapy, after treatment with cyclophosphamide, vincristine and prednisone (CVP) versus CVP plus rituximab (R-CVP) and to evaluate the predictive value of known prognostic factors after treatment with R-CVP.Patients and MethodsPatients with previously untreated CD20-positive stage III/IV FL were randomly assigned to eight cycles of R-CVP (n = 159) or CVP alone (n = 162). The median follow-up period was 53 months.ResultsThe primary end point—time to treatment failure (TTF), which included patients without a response after four cycles as an event—was significantly prolonged in patients receiving R-CVP versus CVP (P < .0001). Improvements in all other end points, including overall and complete response rates (P < .0001), time to progression (TTP; P < .0001), response duration (P < .0001), time to next antilymphoma treatment (P < .0001), and overall survival (OS; P = .029; 4-year OS: 83% v 77%;) were achieved with R-CVP versus CVP alone. Univariate analyses demonstrated an improvement in TTP with R-CVP versus CVP irrespective of the Follicular Lymphoma International Prognostic Index (FLIPI) subgroup, the International Prognostic Index (IPI) subgroup, baseline histology, and the presence or absence of B symptoms or bulky disease. By multivariate analysis, FLIPI retains a strong predictive power for TTP in the presence of the trial treatment effect.ConclusionAnalysis of all outcome measures, including OS, confirm the benefit of adding R to CVP in the front-line treatment of FL.

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