Common use of PROCEDURES AND ASSESSMENTS Clause in Contracts

PROCEDURES AND ASSESSMENTS. Efficacy The primary efficacy endpoint will be the number of BA058-treated patients showing new vertebral fractures at End-of-Treatment when compared to Placebo. New incident vertebral fractures will be evaluated according to the method of Genant (1). Efficacy assessments will therefore include documentation of the incidence of clinical and radiographic fractures of the lumbar and thoracic spine. Patients will undergo baseline and End-of-Treatment antero-posterior and lateral radiographs of the lumbar and thoracic spine. All radiographs will be viewed and assessed by a blinded, independent assessor (radiologist) on the basis of existing baseline and study-acquired vertebral deformity, and fracture will be assessed according to a set of pre-determined criteria. A second blinded radiologist will review the assessment of the first reviewer for all patient radiographs in which an incident fracture has been identified. In the case of any disagreement, a third consensus assessment will be made to adjudicate the incident fracture. A standardized graded scale of severity of the vertebral deformity will be evaluated according to the method of Genant (1). Secondary efficacy parameters will also include reduction in the incidence of non-vertebral fractures (wrist, hip, rib, etc.) and reduction in moderate and severe vertebral fractures. Clinical fracture occurring de novo at these anatomical sites during the study will also be assessed and analyzed. Other secondary efficacy endpoints will include changes in BMD of spine, hip, and femoral neck, and wrist from baseline to end-of-treatment as assessed by DXA. Patients will undergo BMD assessments at Screening (spine and hip; all patients), at Day 1 (wrist; in a subset of patients), and at Months 6, 12 and 18 (End-of-Treatment) of study participation. Any patient who shows a continuing significant deterioration (>7%) of BMD at spine or hip will have the assessment repeated and, if confirmed, will be discontinued from the study. Patients sustaining an incident vertebral or non-vertebral fragility fracture will be informed of the finding and offered the opportunity to remain in or discontinue from the study. Additional secondary endpoints will include change in standing height and changes in serum bone markers across treatment, such as PINP, osteocalcin, and bone-specific alkaline phosphatase. Serum C-telopeptides (CTX), a marker of bone resorption and collagen breakdown, will be measured and reported. Bone markers will be assessed Pretreatment and at Months 6, 12 and 18 (End-of-Treatment). Urine samples will be collected for the measurement of calcium and creatinine to determine the Calcium:Creatinine ratio. The Calcium:Creatinine ratio will be measured at each visit during the Treatment Period. The frequency of hypercalcemia across treatment groups will also be assessed. Patients who discontinue study participation prematurely will undergo End-of-Treatment and End-of-Study assessments once their discontinuation is confirmed. Safety evaluations to be performed will include physical examinations, ▇▇▇▇▇ ▇▇▇▇▇, 12-lead ECGs, clinical laboratory tests, and monitoring and recording of adverse events. Specific safety assessments will include post-dose (4 hours) determination of serum calcium, determination of Creatinine Clearance, post-dose ECG assessments at selected visits, and assessments of postural hypotension (60 minutes post-dose) at selected clinic visits. The incidence and severity of adverse events by dose and cumulative dose and pathological changes in hematology, chemistry and urinalysis data will be recorded and summarized. Changes in physical examination (including height), ▇▇▇▇▇ ▇▇▇▇▇, ECG and clinical laboratory tests will be descriptively summarized. Shift frequencies will be summarized for clinical laboratory tests. Injection sites will be graded to assess local tolerance to study medication. ECG and safety laboratory assessments will be performed at all scheduled visits and at any unscheduled visit as deemed necessary by the Investigator. QT interval assessments will be performed for all study subjects across the Treatment Period. Bone biopsy of the iliac crest will be performed in a subset of patients receiving BA058 80 µg and Placebo (up to 100 per group to obtain 75 evaluable biopsies per treatment group) between Visits 8 and 9 for assessment of quantitative bone histomorphometry using a duel-labeling procedure. All bone biopsies will be read blinded to treatment at a central specialized facility. A further subset of patients, 100 per treatment group in all 3 groups, will undergo a renal CT scan at the end of the study, which will also be read (blinded as to treatment) centrally, to assess the renal parenchyma and collecting system. Study safety will be monitored by an independent Data Safety Monitoring Board. Complete details of the study assessments are provided in Section 7.0, in the Schedule of Visits and Procedures (Appendix 14.1) and in the Suggested Schedule of Events and Procedures by Study Visit (Appendix 14.2). Statistical Considerations: Sample Size A sample size of 622 patients per treatment arm provides 90% power at a two-sided alpha of 0.05 to detect a superiority difference of 4% between placebo patients and BA058 80 µg for injection-treated patients on vertebral fracture incidence. To ensure an evaluable population of 622 patients, an overall sample size of 800 patients per treatment arm will be recruited. For statistically powered secondary endpoints the sample size will have greater than 90% power at an alpha of 0.05 to detect a 1.15%, 2.45%, and 2.00% difference for spine, hip, and femoral neck BMD, respectively, between BA058 and teriparatide. The study sample size will also provide more than 90% power to detect differences between BA058 and teriparatide in the number of patients reporting one or more events of hypercalcemia. Baseline Comparisons Baseline characteristics, medical history, physical examination, ▇▇▇▇▇ ▇▇▇▇▇ and ECG, will be summarized using standard descriptive statistics by treatment group. Specific demographic and baseline parameters will be tested for overall agreement across treatment groups using one-way ANOVA or Chi-square tests as appropriate for the type of data. Efficacy Analyses The primary efficacy endpoint will be the number of BA058-treated patients showing new vertebral fractures at End-of-Treatment when compared to Placebo. Key secondary endpoints that will be statistically analyzed include change in BMD (spine, hip, and femoral neck) and differences in the number of patients reporting one or more events of hypercalcemia from baseline to End-of-Treatment for BA058 80 µg when compared to teriparatide. Additional secondary efficacy endpoints will include the change in vertical height in BA058 80 µg patients when compared to Placebo and the incidence of BA058 80 µg patients with new non-vertebral fractures from baseline to End-of-Treatment when compared to Placebo. Severity of vertebral fractures, fracture incidence over time by treatment group, and new vertebral fractures in teriparatide patients compared to Placebo will also be assessed. Other efficacy endpoints will include change in wrist BMD in BA058-treated patients, and changes in serum PINP, bone-specific alkaline phosphatase, osteocalcin, and CTX across treatment. Population PK/PD Analysis Samples for measurement of serum levels of BA058 will be taken to evaluate population PK effects on demographics, efficacy, and safety. Safety Analysis All patients who receive at least one dose of study medication will be included in the safety analysis that will be performed on the following parameters: Incidence and severity of AEs; dose and cumulative dose at which the AE occurred. Pathological changes in hematology, chemistry and urinalysis data based on normal ranges supplied by the clinical laboratory. Frequency of hypercalcemia will also be compared across treatment groups. Bone histomorphometry as assessed by bone biopsy at End-of-Treatment in a randomized subset of BA058 and Placebo patients. Renal safety as assessed at End-of-Treatment by renal CT scan in a randomized subset of patients in all treatment groups. All AEs collected prior to first injection will be separately summarized in a fashion similar to the TEAEs. Treatments Administered: