Global Clinical Trial Program Research Articles

A Novel Case Study of the Use of Real-World Evidence to Support the Registration of an Osteoporosis Product in China

On June 23, 2020, Prolia® (denosumab) was approved by the National Medical Products Administration (NMPA) in the People’s Republic of China as the first monoclonal antibody for the treatment of postmenopausal women with osteoporosis at high risk of fractures. Its brand name in Chinese is 普罗力, a transliteration from the English name “Prolia”, which has an implied meaning of “to give strength to everyone”— a suitable name for a potent anti-resorptive therapy. The approval was supported by a novel marketing authorization application (MAA) that included data from Prolia’s global clinical trial program establishing favorable efficacy and safety, augmented by results from a real-world evidence (RWE) study confirming the effectiveness and safety of Prolia in clinical practice within Taiwan and Hong Kong. Key constructs for this registration-quality RWE study included the fit-for-purpose assessment of data quality, methodology and quantitative assessment of potential biases, good practices of study conduct, and reproducibility of results. Using data from clinical practice in Taiwan and Hong Kong to evaluate the benefits versus risks of Prolia treatment in ethnic Chinese women with postmenopausal osteoporosis, the RWE study results for effectiveness were comparable to efficacy demonstrated in the global clinical trial program and results for safety were consistent with the incidence observed in global post-marketing safety studies. While RWE is often used to monitor postmarket safety of drug products, support health insurance coverage decisions, and inform clinicians on real-world use of medicines, it has not been widely used to support regulatory approval for new medicines in lieu of clinical bridging studies in countries where such studies are required. Well-conducted registrational RWE studies can play a pivotal role in complementing the totality of evidence presented in an MAA. The benefits of such an approach include avoiding the collection of additional placebo-controlled trial data in populations where adequate ethnic characterization of efficacy, effectiveness, and safety may already exist from postmarketing sources, and accelerate access for patients to innovative medicines in important regions. Here, we describe a regulatory case study of a novel MAA incorporating RWE that provided important evidence to confirm the benefit:risk of a new drug and facilitated a label expansion to a new patient population.

Risk of Malignancies in Patients with Rheumatoid Arthritis Treated with Rituximab: Analyses of Global Postmarketing Safety Data and Long-Term Clinical Trial Data.

IntroductionPatients with rheumatoid arthritis (RA) are at an increased risk of developing malignancies, but it is unclear whether this increased risk is the result of disease pathobiology or immunosuppressant treatments for RA. This analysis evaluated the potential risk of malignancy in patients with RA treated with rituximab (MabThera®/Rituxan®) a CD20+ B-cell depleting agent manufactured by F. Hoffmann-La Roche Ltd.MethodsMalignancy rates were obtained from the rituximab global company safety database for adverse event reporting and from the rituximab global clinical trial program for RA consisting of eight randomized clinical trials, two long-term open-label extensions, and one open-label prospective study. Global company safety database searches were performed using the standard Medical Dictionary for Regulatory Activities (MedDRA) queries “Malignant tumors wide” and “Skin malignant tumors wide” up to April 30, 2017. Age- and sex-specific comparator values from the general population were obtained from the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database.ResultsFor the 409,706 patients with RA in the rituximab global company safety database since first market approval in 2006, 1739 cumulative malignant events were reported, with an overall malignancy reporting rate of approximately 4.2 events per 1000 patients. No evidence of increased risk of malignancy, of any organ-specific type, was found following rituximab treatment. The rate of malignancies from rituximab-treated patients in RA clinical trials was 7.4 per 1000 patient-years. This is within the expected range, with no evidence for increased risk over time or with additional rituximab courses.ConclusionsAnalyses of the global postmarketing safety database and long-term clinical trial data showed no evidence of an increased risk of malignancy of any type following rituximab treatment in patients with RA.FundingF. Hoffmann-La Roche Ltd.

2966 A Sub-Analysis of Puerto Rican Hepatitis C Infected Patients Enrolled in the Phase 2 and 3 Glecaprevir-Pibrentasvir Clinical Program

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis and advanced liver disease, and viral clearance is associated with reduced risk of developing cirrhosis, hepatic decompensation, and death. Glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) are direct-acting antivirals (DAAs) co-formulated as a once-daily, fixed-dose combination regimen (G/P) to treat genotype (GT) 1‒6 HCV infection. G/P has been licensed in the United States and Europe, supported by a phase 2/3 global clinical trial program demonstrating high efficacy with a favorable safety profile. The objective of this study was to describe the clinical characteristics and virologic response to G/P in Puerto Rican (PR) patients included in the G/P clinical program. METHODS: Data were pooled from 14 phase 2, 3, and 3b clinical trials conducted in 32 countries and representing 3,233 treatment-naive and treatment-experienced patients with chronic HCV GT1–6 infection who received G/P once-daily for 8, 12, or 16 weeks. The primary endpoints were percentage of patients with sustained virologic response 12 weeks after treatment (SVR12) and percentage with treatment-emergent adverse events (AEs). RESULTS: From the 3,233 patients included in the G/P clinical program, this sub-analysis included 79 (2%) patients from sites in Puerto Rico. Overall, 52 (66%) were male, 64 (81%) were white race and the median age was 56 years (range: 29–78). Most patients were infected with HCV GT1 (n = 69; 87%), of whom 71% (49/69) had GT1a infection, and overall, 63 (80%) were treatment-naïve. Additionally, 39 (53%) patients had baseline fibrosis stage F0–F1, while 25 (34%) had stage F4. The overall SVR12 rate was 97.5% (77/79), with two patients not achieving SVR12 due to non-virologic reasons (both missing SVR12 data). AEs occurred in 38 (48%) patients, with none leading to discontinuation. Serious AEs occurred in 4 (5%) patients but none were deemed by investigators to be related to DAAs. There were 4 (5%) grade ≥3 laboratory abnormalities, and none were deemed clinically meaningful. CONCLUSION: G/P achieved high SVR12 rates and was well-tolerated in Puerto Rican patients enrolled in the G/P clinical trial program. The efficacy and safety profile of G/P in Puerto Rican patients was comparable to the overall patient population in the G/P registrational trial program, and SVR12 rates were comparable to real-world studies of G/P.

Greater Combined Reductions in Hba1C ≥1.0% and Weight ≥5.0% with Semaglutide Versus Comparators in type 2 Diabetes

Objective: Semaglutide is a glucagon-like peptide 1 (GLP-1) analog for the once-weekly treatment of type 2 diabetes (T2D). In the global SUSTAIN clinical trial program, semaglutide demonstrated superior glycated hemoglobin (HbA1c) and body weight reductions versus comparators. This post hoc analysis compared the proportion of patients achieving combined reductions in glycemia and body weight versus comparators. Methods: A total of 5,119 subjects with T2D in the phase 3 SUSTAIN 1 through 5 and 7 trials, from 33 countries, were included in this post hoc analysis. Subjects received subcutaneous semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg, insulin glargine, dulaglutide 0.75 or 1.5 mg). The main endpoint was a composite of ≥1.0% HbA1c reduction and ≥5.0% weight loss at end of treatment. Results: Significantly greater proportions of subjects achieved the composite endpoint with semaglutide 0.5 (25 to 38%) and 1.0 mg (38 to 59%) versus comparators (2 to 23%). More subjects treated with semaglutide versus comparators achieved ≥1.0% HbA1c reductions (58 to 77% and 75 to 83% for semaglutide 0.5 and 1.0 mg versus 12 to 68%) and ≥5.0% weight loss (37 to 46%, 45 to 66% versus 4 to 30%). Proportions of subjects achieving targets were significantly higher with semaglutide 1.0 versus 0.5 mg in four of five trials. Semaglutide was well tolerated, with a safety profile similar to other GLP-1 receptor agonists. Conclusion: Significantly more subjects achieved both ≥1.0% HbA1c reduction and ≥5.0% weight loss with once-weekly subcutaneous semaglutide treatment versus comparators in the SUSTAIN trials. A dose-dependent effect was observed with semaglutide. Abbreviations: AE = adverse event; CV = cardiovascular; ER = extended release; GLP-1 = glucagon-like peptide 1; GLP-1 RA = glucagon-like peptide 1 receptor agonist; HbA1c = glycated hemoglobin; OAD = oral antidiabetic drug; sc = subcutaneous; T2D = type 2 diabetes.

1111-P: The Qualitative and Quantitative Effect of IDegLira Compared with the Nonfixed Administration of Degludec and Liraglutide

Background: The efficacy and safety of IDegLira and the benefits of its complementary mode of action have been examined in the large global DUAL clinical trial program. Aim: The aim of this study is to examine the effect of the IDegLira on the glycemic control and the cardiometabolic risk factors compared to the non-fixed adiministration of degludec and liraglutide. Material and Methods: 473 patients with type 2 diabetes mellitus (T2DM) were included in the study. 158 patients on oral antidiabetic drugs (OADs) switched to OADs and IDegLira (Group A), 163 under OADs and liraglutide treatment added degludec to their regimen (Group B) and in 152 patients using degludec and OADs, liraglutide was added (Group C). Follow-up period was 52 ±2 weeks and changes in HbA1c, cardiometabolic risk factors and treatment adherence (with the 8-item Morisky Medication Adherence Scale (MMAS-8)) were recorded. Results: There was no difference at baseline between the three groups as to age (61.88 ± 9.98 years, p =0.212), diabetes duration (12.08 ± 5.83, p = 0.332), HbA1c (mean HbA1c: 8.59± 1.13, p = 0.118) καιΒΜΙ (BMI 32.08 ± 3.22, p = 0.144). Mean HbA1c levels after the follow-up period was 6.79 ± 0.77, 7.14 ± 1.19, 7.18 ± 1.07 (p = 0.033) for Group A, B and C, respectively. Most of patients in Group A reached the treatment target for HbA1c (p = 0.041). Weight change was -3.2 ± 1.2 kg for Group A, -1.2 ± 1.1 kg for Group B and -4.3 ± 1.7 kg for Group C (p < 0.001). There was no difference in the hypoglycemic episodes between the groups (p = 0.251). The highest levels of adherence were noticed in Group A compared to Group B and C (7.58 ± 1.08, 6.38 ± 1.28 and 6.44 ± 1.16, p = 0.031, respectively) while total insulin dose was lower for Group A compared to the other groups (p=0.041). Conclusion: Uncontrolled patients on oral antidiabetic drugs when switched to an IDegLira regimen achieved a significant improvement in their glycemic control and a more significant adherence compared the non-fixed combination of degludec and liraglutide. Disclosure A. Koutsovasilis: None. A. Sotiropoulos: None. A. Antoniou: None. M. Pappa: None. S. Bousboulas: None. T. Peppas: None.

Qualitative and Quantitative Effect of IDegLira Compared with the Nonfixed Administration of Degludec and Liraglutide

Introduction: The efficacy and safety of IDegLira and the benefits of its complementary mode of action have been examined in the large global DUAL clinical trial program. Aim: The aim of this study is to examine the qualitative and quantitative effect of IDegLira compared to the non-fixed adiministration of degludec and liraglutide. Methods: Uncontrolled type 2 diabetes (T2D) patients (n=473) were included in the study. 158 patients on oral antidiabetic drugs (OADs) switched to OADs and IDegLira (Group A), 163 on OADs and liraglutide switched to degludec and the existing therapeutic regime (Group B) and 152 patients on degludec and OADs switched to liraglutide and the existing treatment (Group C). All patients also received metformin while none of them received sulfonylurea. Follow-up was 12 months and changes in HbA1c, cardiometabolic risk factors, and treatment adherence (with the 8-item Morisky Medication Adherence Scale) were recorded. Results: There was no difference at baseline between the three Groups as to age (p=0.224), diabetes duration (p=0.322), HbA1c (8.56±1.12, p=0.116) and BMI (32.14±3.56, p=0.142). The mean HbA1c after 12 months was 6.79±0.77, 7.14±1.19, 7.18±1.07 (p=0.033) for Groups A, B and C respectively. More patients achieved the therapeutic target for HbA1c in Group A (p=0.048). The weight change was -3.2±1.2 Kg for Group A, 1.2±1.1 Kg for Group B and -4.3±1.7 Kg for Group C (p<0.001). There was no difference in the hypoglycemic episodes between the three Groups (p=0.251). Greater adherence was achieved in Group A compared to Group B and C (7.58±1.08, 6.38±1.28 and 6.44±1.16, p=0.031). Total insulin dose was lower for Group A (p=0.040). Conclusions: Uncontrolled patients on oral antidiabetic drugs when switched to a therapeutic regimen with IDegLira achieved a significant improvement in their glycemic control with a significant adherence to their therapeutic regimen while the adherence in a non-fixed combination was not significant enough. Disclosure A. Koutsovasilis: None. A. Sotiropoulos: None. D. Papadaki: None. E. Bletsa: None. G. Kokotos: None. I. Kounelakis: None. S. Bousboulas: None. T. Peppas: None.

5-Year Safety and Efficacy of Resolute Zotarolimus-Eluting Stent: The RESOLUTE Global Clinical Trial Program

ObjectivesThe authors evaluated the 5-year cumulative incidence of cardiovascular events following Resolute zotarolimus-eluting stent (R-ZES) implantation. BackgroundIndividual trials are often underpowered to show differences for low-frequency adverse events. The R-ZES was studied in 10 prospective clinical trials, designed with identical adverse event definitions, ascertainment, and adjudication. MethodsThe RESOLUTE Global Clinical Trial Program includes 7,618 patients treated with R-ZES: RESOLUTE first-in-human study (N = 139), RESOLUTE All Comers (N = 1,140), RESOLUTE International (N = 2,349), RESOLUTE US (N = 1,402), RESOLUTE US 38 mm (N = 114), RESOLUTE Japan (N = 100), RESOLUTE Japan Small Vessel Study (N = 65), RESOLUTE Asia (N = 311), RESOLUTE China Randomized Controlled Trial (N = 198), and RESOLUTE China Registry (N = 1,800). The 5-year cumulative incidence of events was calculated. ResultsThe 5-year cumulative incidence of cardiac events was 13.4% for target lesion failure and included 5.0% cardiac death, 4.4% target vessel myocardial infarction, and 6.3% clinically driven target lesion revascularization. Dual-antiplatelet therapy at 1, 3, and 5 years was 91%, 37%, and 32%, respectively. The 5-year cumulative incidence of definite or probable stent thrombosis was 1.2%, which comprised 0.7% at 1 year and an annualized rate of 0.1% thereafter. Five-year use of dual-antiplatelet therapy varied geographically from 63% in Japan to 11% in Europe. ConclusionsIn the largest group of R-ZES patients examined to date, the majority of stent-related events, including target vessel myocardial infarction and stent thrombosis, occurred within the first year of implantation with much lower risks of these events out to 5 years.

Long-term outcomes after Resolute zotarolimus-eluting stent implantation in patients with ST-segment elevation acute myocardial infarction: insights from the RESOLUTE All Comers Trial and the RESOLUTE Global Clinical Trial Program.

We examined long-term outcomes after implantation of the Resolute zotarolimus-eluting stent (R-ZES) in ST-segment elevation acute myocardial infarction (STEMI) patients. We compared long-term outcomes of STEMI patients undergoing primary angioplasty <12 hours from symptom onset who were randomised to the R-ZES (n=122) or the everolimus-eluting stent (EES, n=158) in the RESOLUTE All Comers Trial after propensity score adjustment. The five-year cumulative incidence of target lesion failure (TLF) was 7.6% versus 10.4% among patients treated with R-ZES versus EES, respectively, (adjusted p=0.304), and comprised clinically driven target lesion revascularisation (TLR, 2.5% versus 2.0%, adjusted p=0.766) and cardiac death/target vessel MI (5.1% versus 9.1%, adjusted p=0.123). The five-year cumulative incidence of stent thrombosis was 0.8% for R-ZES patients versus 1.3% for EES patients (adjusted p=0.868). In the RESOLUTE Global Clinical Trial Program, excluding RESOLUTE All Comers, the three-year cumulative incidence of TLF with R-ZES was 9.8% and comprised 7.0% clinically driven TLR and 4.5% cardiac death/target vessel MI. Patients with STEMI who received R-ZES had excellent long-term clinical outcomes which were similar to those of patients who received EES.

The SPYRAL HTN Global Clinical Trial Program: Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications

Renal sympathetic activation plays a key role in the pathogenesis of hypertension, as demonstrated by high renal norepinephrine spillover into plasma of patients with essential hypertension. Renal denervation has demonstrated a significant reduction in blood pressure in unblinded studies of hypertensive patients. The SYMPLICITY HTN-3 trial, the first prospective, masked, randomized study of renal denervation versus sham control, failed its primary efficacy end point and raised important questions around potentially confounding factors, such as drug changes and adherence, study population, and procedural methods. The SPYRAL HTN Global Clinical Trial Program is designed to address limitations associated with predicate studies and provide insight into the impact of pharmacotherapy on renal denervation efficacy. The 2 initial trials of the program focus on the effect of renal denervation using the Symplicity Spyral multielectrode renal denervation catheter in hypertensive patients in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. The SPYRAL HTN ON-MED study requires patients to be treated with a consistent triple therapy antihypertensive regimen, whereas the SPYRAL HTN OFF-MED study includes a 3- to 4-week drug washout period followed by a 3-month efficacy and safety end point in the absence of antihypertensive medications. The studies will randomize patients with combined systolic-diastolic hypertension to renal denervation or sham procedure. Both studies allow renal denervation treatments in renal artery branches and accessories. These studies will inform the design of the second pivotal phase of the program, which will more definitively analyze the antihypertensive effect of renal denervation.

EYE ON CHINA

Sareum enters co-development agreement in China for Aurora+FLT3 program. Helsinn Group opens representative office in China. Biotech China to be held in Nanjing Clinic's Center for individualized medicine. Shanghai Ajinomoto Amino Acid Co., Ltd. expands amino acid production capacity. Agilent Technologies Thought Leader Award supports Dr. Junying Yuan, Chinese Academy of Sciences. to-BBB and Sihuan enter into collaboration agreement. JHL Biotech selects GE's FlexFactory™ bio manufacturing platform for Taiwan facility. Senhwa Biosciences raises $17M in Series B. New bat virus in China can infect people. Chi-Med and Sinopharm form China drug distribution and marketing joint venture. MicuRx expands global clinical trial program for oral antibiotic MRX-I. TaiGen Biotechnology receives Qualified Infectious Disease Product and Fast Track designations from the U.S. FDA.

Incidence and predictors of unplanned non-target lesion revascularization after drug-eluting stent implantation: insights from a pooled analysis of the global RESOLUTE clinical trial program

Incidence and predictors of unplanned non-target lesion revascularization after drug-eluting stent implantation: insights from a pooled analysis of the global RESOLUTE clinical trial program

FRI0127 Using epidemiological registry data to provide background rate context for adverse events in a rheumatoid arthritis drug development program - a coordinated approach

BackgroundObservational studies may provide context for adverse events observed in clinical trial programs, particularly for infrequent events or potential long-term risks. For such purposes, however, published observational data often have...