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if the inclusion criteria 12-15

Day 1 of each cycle (up to 14 days prior to Ra-223 or Placebo administration)
- Vital signs: weight, resting heart rate, blood pressure, respiratory rate, and temperature. - ECOG performance status - Adverse event (AE) assessment - Abbreviated Physical Exam (C4D1 only)
- Concomitant medication review
- Review of other anti-cancer therapies - Assessment of bone fractures (AESIs) and SSEs - Review of other anti-cancer therapies - CBC including hemoglobin, hematocrit, WBC with 3-part differential and platelets
- CMP including glucose, BUN, creatinine, estimated creatinine clearance (CockcroftGault), sodium, potassium, chloride, calcium, CO2, AST, ALT, total bilirubin, total protein, and albumin.  
- ALP and LDH - PSA
- Research biomarkers, with optional patient consent, at the next visit following confirmed radiographic progression or prior to initiation of a prohibited treatment only, whichever occurs earlier
- Administration of Ra-223 or placebo (only after the site investigator deems it is safe for patient to be dosed after review of the above)
- Enzalutamide or Darolutamide Estimated Compliance
- Darolutamide Dispensation (if applicable) - Darolutamide Accountability (if applicable)
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10.6 12-week imaging visits

Patients will be evaluated for response to treatment every 12 weeks (+/- 7 days). Visits should be scheduled from the first dose of radium-223 or placebo (Cycle 1, Day 1) regardless of treatment delays. The following assessments will be performed:
- CT scan of the chest, abdomen and pelvis (preferred modality), given with IV
contrast unless contraindicated. An MRI may be used in place of a CT scan. The same modality must be used throughout the study.  
- Bone scan - RECIST
- PCWG3 assessment (bone scan) - Assessment of bone fractures (AESIs) and SSEs
- Adverse event assessment All radiographic scans (CT, MRI and bone scans) will be collected and held in the site's eISF.
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10.7 telephone end of study

The following evaluations are required 30 days +/- 7 days after the last dose of RT1 (enzalutamide or darolutamide) and/or RT2 (radium-223/placebo). Separate visits may be required, in the event RT1 and RT2 are not discontinued simultaneously. If repeat labs are needed, unscheduled labs may be done.  
- Adverse event (AE) assessment - all AEs must be followed for 30 calendar days after the last dose of study medication(s)
- Concomitant medication review
- Assessment of bone fractures (AESIs) and SSEs
- Review of other anti-cancer therapies
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10.8 q12 week progression follow-up

After completion or discontinuation of randomized Ra-223 or placebo treatment (RT2), patients without radiological progression that have not started a prohibited treatment will have visits every 12 weeks (±7 days) to monitor for radiological progression post completion or discontinuation of Ra-223. During this phase, all assessments should occur according to the original radiology schedule (every 12 weeks following C1D1). The following assessments will be performed until either radiologic progression or start of a prohibited treatment:
- Vital signs: weight, resting heart rate, blood pressure, respiratory rate, and temperature.  
- Adverse event (AE) assessment - only adverse events identified by the site investigator to be related to radium-223 (i.e. new primary malignancies, chronic myelosuppression, etc.), darolutamide, or enzalutamide AEs, SSE-related AEs, and adverse events of special interest
- Review of other anti-cancer therapies
- Concomitant medication review
- CBC including hemoglobin, hematocrit, WBC with 3-part differential and platelets
- CMP including glucose, BUN, creatinine, estimated creatinine clearance (CockcroftGault), sodium, potassium, chloride, calcium, CO2, AST, ALT, total bilirubin, total protein, and albumin
- PSA
- ALP and LDH
- Research biomarkers, with optional patient consent, at the next visit following confirmed radiographic progression or prior to initiation of a prohibited treatment, whichever occurs earlier
- CT scan of the chest, abdomen and pelvis (preferred modality), given with IV contrast unless contraindicated. An MRI may be used in place of a CT scan. The same modality must be used throughout the study.  
- Bone scan - RECIST and PCWG3 assessment - Assessment of bone fractures (AESIs) and SSEs
- Survival status
- Enzalutamide or Darolutamide Estimated Compliance - Darolutamide Dispensation (if applicable) - Darolutamide Accountability (if applicable) - The following are required every 48 weeks after C1D1:
o ECOG performance status o ePRO Assessments (FACT-P, FACT-COG) o TUG (timed up and go) o 12-lead ECG
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10.9 overall survival

Patients that have radiological progression or start a prohibited treatment will be followed every 6 months (+/- 1 month) after the last Q12-Week Imaging Visit showing progression is performed (during RT2 treatment or during follow-up). Patients will have visits until the required number of events for the primary endpoint has been reached or death, whichever comes first. Patients may be contacted during outpatient visits or by telephone and/or chart review. Subjects continuing on darolutamide may be re-supplied with study medications between visits. The following assessments will be performed:
- Assessment of bone fractures (AESIs) and SSEs
- Review of other anti-cancer therapies
- AE assessment - Only adverse events identified by the site investigator to be related to radium-223, enzalutamide, or darolutamide (i.e. new primary malignancies other than basal cell carcinoma, chronic myelosuppression, etc.), SSE-related AEs, and adverse events of special interest
- Enzalutamide or Darolutamide Estimated Compliance  
Final Protocol: 04 MAY 2020 VERSION 1.2 Page 55 of 102  
- Darolutamide Dispensation (if applicable) - Darolutamide Accountability (if applicable)
- Survival status
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10.10 end of study administrative

Investigational Product Dosage Form and Strength **Manufacturer**  
Radium-223 1,100 kBq/mL Algeta's Institute for Energy  
Technology  
The alpha-pharmaceutical radium-223 is a ready-to-use, sterile, non-pyrogenic, clear and  
colorless aqueous solution of radium-223 dichloride (223RaCl2) for IV administration. It should  
not be diluted or mixed with any solutions. Each vial is for a single use only.  
When patients permanently discontinue the study due to any reason (screen failure, lost to follow-up, withdrawn consent, etc.), End of Study Administrative Assessments will capture the reason for permanent discontinuation and will record:
- Reason for Discontinuation
- Study Disposition - For subjects that are still in contact with the site and have not withdrawn consent: AE
assessment via outpatient visit or by telephone and/or chart review.  
o Adverse events identified by the site investigator to be related to radium-223 (i.e.  
new primary malignancies other than basal cell carcinoma, chronic myelosuppression, etc.) or darolutamide, SSE-related AEs, and adverse events of special interest.  
- Public Records Search: any Deaths that occur after Early Termination (if known).  
Attempts to locate patients should be documented via phone contacts and certified letter. At least three (3) documented phone calls and (1) certified letter should be attempted in an effort to reinstate contact. If no response from contact attempts, the patient can be considered lost to follow-up. Patients that are lost to follow-up should still be followed for survival status using available methods for public records search. The method for search used to confirm death, date of death and cause of death (if known) will be entered into the EDC- End of Study Record and the public record should be filed to the patient's eISF PHI folder. Radium-223 is an alpha particle emitter with a physical half-life of 11.4 days. The product is isotonic and has a pH of 6.0-8.0. The radioactive concentration at the reference date is 1,100 kBq/mL. The product has a pre-calibration of 14 days. When administered on a day other than the reference day, the volume should be corrected according to the physical decay table accompanying each shipment.
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labelling packaging and supply

Radium-223, is manufactured for Bayer Consumer Care AG by the contract manufacturer Algeta Institute for Energy Technology, Isotope Laboratories, Kjeller, Norway. The product is produced according to Good Manufacturing Practice (GMP). The product will be delivered in a glass vial or pre-filled syringe, ready-to-use with a certified activity. Radium-223 is shipped in a lead container and Type A radioactive package according to international transportation guidelines for radioactive materials. For study sites in the US, it is possible to have patient-ready doses (PRD) prepared by the country depot. Dose will be delivered to the sites in pre-filled syringes. Both radium-223 and placebo syringes will be covered with a label masking the syringe content. The investigational drug is supplied in single-use vials containing 6 mL of solution at a concentration of 1,100 kBq/mL (30 microcurie/mL) with a total radioactivity of 6,600 kBq/vial (178 microcurie/vial) at the reference date. Radium-223 has a shelf life of 28 days from production day, when stored at ambient temperature. The shelf life has been demonstrated for temperatures from cold storage (2-8°C) up to 40°C. In addition, it has been shown that the product quality is not jeopardized upon freezing. The shelf life should not be confused with the half-life of Radium-223 which is 11.4 days. All study drugs will be labeled according to the requirements of local law and legislation. For all study drugs, a system of numbering in accordance with all requirements of GMP will be used, ensuring that each dose of study drug can be traced back to the respective bulk ware of the ingredients.  
General warning Radium-223 should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal of radium-223 are subject to the regulations and/or appropriate licenses of the competent official organization. Radium-223 should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.
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radiation protection

The administration of radium-223 is associated with potential risks for other persons (e.g., medical staff, caregivers, and members of the patient's family) from radiation or contamination from spills of body fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. Since the study is blinded, radiation protection must be in place for patients, blinded staff, and members of the patient's family, even when placebo is administered. The immediate packaging will contain a statement to conform with U.S. Food and Drug Administration (FDA) Investigational New Drug (IND) requirements as follows: "Caution: New Drug - Limited by Federal (or United States) law to investigational use."  
Final Protocol: 04 MAY 2020 VERSION 1.2 Page 57 of 102 All study drugs must be kept in a secure place under appropriate storage conditions. Storage conditions for radium-223 are included on the investigational product label.
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preparation and administration of radium-223

Personnel should use appropriate protective clothing and equipment during syringe filling (if applicable) and application to prevent contamination with the radioactive solution (medical gloves / protective glasses). For sites receiving radium-223 in a vial, the individual responsible for study drug preparation will draw the correct volume of study drug from the vial into a syringe. The size of the syringe should be chosen according to the applied volume to reach the required dosing accuracy. Radium-223 should not be diluted or mixed with any solutions. Do not store above 40°C (104°F). If the vials or pre-filled syringes have been stored in a refrigerator, they should be left at room temperature for 1 hour prior to use, since cold material should not be injected in a patient. Store radium-223 in the original container or equivalent radiation shielding. This preparation is approved for use by persons under license by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State.
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11.1.4.2 dose administration

Before administration of study drug, the patient must be well hydrated; the patient should be instructed to drink ad libitum. Aseptic technique should be used in the administration of radium223. The syringe should be handed over to the individual who will perform the injection. The study medication will be administered as a bolus IV injection over approximately 1 minute. After administration, the equipment used in connection with the preparation and administration of drug (including placebo) is to be treated as radioactive waste and should be disposed in accordance with local procedure for the handling of radioactive material. The dosage regimen of radium-223 injection is 55 kBq (1.49 microcurie) per kg body weight, given at 4-week intervals. Safety and efficacy beyond 6 injections with radium-223 have not been studied.  
The volume to be administered to a given patient should be calculated using the:
- Patient's body weight (kg) - Dosage level 55 kBq/kg body weight or 1.49 microcurie/kg body weight - Radioactivity concentration of the product (1,100 kBq/mL; 30 microcurie/mL) at the reference date.  
- Decay correction factor to correct for physical decay of 223Ra.
The total volume to be administered to a patient is calculated by the formula below: Volume to be administered (mL) = (Body weight in kg x 55 kBq/kg body weight)/ (Decay factor x 1,100 kBq/mL) The Decay Correction Factor is determined from the Table below:  
| Decay Correction Factor Table Days from Reference  Decay Factor                           | Days from Reference   | Decay Factor   |       |
|-------------------------------------------------------------------------------------------|-----------------------|----------------|-------|
| Date                                                                                      | Date                  |                |       |
| -14                                                                                       | 2.296                 | 0              | 0.982 |
| -13                                                                                       | 2.161                 | 1              | 0.925 |
| -12                                                                                       | 2.034                 | 2              | 0.870 |
| -11                                                                                       | 1.914                 | 3              | 0.819 |
| -10                                                                                       | 1.802                 | 4              | 0.771 |
| -9                                                                                        | 1.696                 | 5              | 0.725 |
| -8                                                                                        | 1.596                 | 6              | 0.683 |
| -7                                                                                        | 1.502                 | 7              | 0.643 |
| -6                                                                                        | 1.414                 | 8              | 0.605 |
| -5                                                                                        | 1.330                 | 9              | 0.569 |
| -4                                                                                        | 1.252                 | 10             | 0.536 |
| -3                                                                                        | 1.178                 | 11             | 0.504 |
| -2                                                                                        | 1.109                 | 12             | 0.475 |
| -1                                                                                        | 1.044                 | 13             | 0.447 |
| 14                                                                                        | 0.420                 |                |       |
| The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To |                       |                |       |  
-14 2.296 0 0.982 -13 2.161 1 0.925  
-12 2.034 2 0.870  
-11 1.914 3 0.819 -10 1.802 4 0.771 -9 1.696 5 0.725  
-8 1.596 6 0.683 -7 1.502 7 0.643 -6 1.414 8 0.605 -5 1.330 9 0.569 -4 1.252 10 0.536 -3 1.178 11 0.504 -2 1.109 12 0.475 -1 1.044 13 0.447  
14 0.420  
The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To determine the decay correction factor, count the number of days before or after the reference date. The Decay Correction Factor Table includes a correction to account for the 7-hour time difference between 12 noon Central European Time (CET) at the site of manufacture (Norway) as 12 noon US CST, which is 7 hours later than CET. Immediately before and after administration, the net patient dose of administered radium-223 should be determined by measurement in an appropriate radioisotope dose calibrator that has been CT and corrected for decay using the date and time of calibration. The dose calibrator must be calibrated with nationally recognized standards, carried out at the time of commissioning, after any maintenance procedure that could affect the dosimetry and at intervals not to exceed one year. The dose calibration procedure should be conducted by an unblinded person in a location where blinded persons are prohibited entry. Dose calibration data must be recorded in a manner that cannot be viewed by the site investigator or any other study personnel. Clinical monitors must confirm the security of the unblinded procedures and data.  
Additional details will be included in the Ra-223/Placebo section of the Study Medication Guide.
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precautions and risks associated with

Please refer to the Xofigo Full Prescribing Information for information regarding precautions and risks.
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11.2 enzalutamide

Enzalutamide is to be administered in accordance with the terms of its marketing authorization and in accordance with institutional standard of practice. Subjects randomized to enzalutamide at R1 will be expected to take 160 mg PO QD after R1 during the lead-in RT1 period and the RT2 period. After RT2 period is concluded, it may be continued until no longer providing benefit or per site's standard of care. Dose reductions are allowed to manage adverse events or toxicities. Subjects will be asked about their compliance taking the prescribed enzalutamide at routine visits and will be asked to bring their prescription bottles to clinic visits for verification that prescriptions are being filled.
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labelling packaging and supply

Patients randomized to open-label enzalutamide at R1 will be given a prescription to obtain commercial enzalutamide.
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11.3 darolutamide

Darolutamide is to be administered in accordance with the terms of its marketing authorization with the exception of indication. Darolutamide is not currently indicated for patients with mCRPC. In this study, subjects randomized to darolutamide at R1 will receive 600 mg PO BID through the study and will be expected to take darolutamide after R1 during the lead-in RT1 period and the RT2 period. After RT2 period is concluded, it may be continued until no longer providing benefit. Dose reductions are allowed to manage any adverse events or toxicities. Subjects will be asked about their compliance taking darolutamide at routine visits and will be asked to bring partial and empty dispensed bottles to clinic visits to measure compliance.
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labelling packaging and supply

Patients randomized to open-label darolutamide at R1 will be provided with darolutamide sourced through the study. Additional details will be included in the darolutamide section of the Study Medication Guide.
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11.4 accountability for all study

The Site Investigator (or designee) is responsible for accountability of all used and unused study drugs (Ra-223 or Placebo, and darolutamide only) supplies at the site.
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double-blinded drug accountability

All study drug inventories for Ra-223 or Placebo must be made available for inspection by the (unblinded) Sponsor or its representatives and regulatory agency inspectors upon request. Drug accountability data will be collected on electronic forms viewable only by unblinded study staff. Any paper records (e.g., shipment forms) will be certified as electronic copies and uploaded to a separate unblinded area of the eISF. Accountability data for Ra-223 or Placebo will only be assessible by designated/trained unblinded monitor(s) and unblinded study staff. Documentation of IP chain of custody will also be included in the Site's electronic Investigator Site File archive. As the Sponsor, MANA RBM's unblinded staff will access electronic records to perform checks of drug storage, dispensing procedures, and accountability records for Ra-223 or Placebo.
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open-label drug accountability

All study drug inventories for darolutamide must be made available for inspection by the Sponsor or its representatives and regulatory agency inspectors upon request. Drug accountability data will be collected on electronic forms. Any paper records (e.g., shipment forms) will be certified as electronic copies and uploaded to the eISF. Documentation of IP chain of custody will also be included in the Site's electronic Investigator Site File archive. As the Sponsor, MANA RBM central reviewers will access electronic records to perform checks of drug storage, dispensing procedures, and accountability records. Darolutamide accountability activity oversight will be performed by the central reviewers and monitor remotely using electronic records completed by the study site.
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12. response evaluations and measurements

Skeletal response will be evaluated using PCWG3 measured by 99Tc bone scan imaging. Soft tissue response will be evaluated in this study using RECIST 1.1 (see Appendix D). Soft tissue lesions are either measurable or non-measurable according to the criteria. The term "evaluable" in reference to measurability will not be used, as it does not provide additional meaning or accuracy. Radiological progression will be interpreted by local assessment only.
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13. statistical considerations 13.1 statistical

This is a randomized, multi-center, double-blind, Phase III study of radium-223 plus enzalutamide or darolutamide compared to enzalutamide or darolutamide treatment plus placebo.
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13.2 stratification factors

The following stratification variables will be used in the RT2 randomization process:
- PSA response (≥90% vs < 90% decline at any time from initiation of RT1)
- ECOG Score 1 or 0 at Pre RT2 visit
- Prior docetaxel use (yes vs no)
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13.3 sample size considerations

1:1 randomized Phase III study with primary endpoint of SSE-FS Assumptions: based on information provided by Bayer.  
- The ERA-223 study (published data) suggests that the median SSE-FS rate for the placebo control are is 24 months, as per the Bayer adjustment of -4 months.  
- HR = 0.70 - Median SSE-FS for enzalutamide of 34.3 months (under the exponential assumption).  
- Two-sided alpha = 0.05
- Power = 0.80 - Cumulative drop-out rate by the end of the study = 10%  
| Power           | Recruitment Period  (months)   | Follow-up                      | Expected Number   | Total Number   |
|-----------------|--------------------------------|--------------------------------|-------------------|----------------|
| Period (months) | of Events                      | of Patients  Randomized at  R2 |                   |                |
| 80%             | 18                             | 32                             | 246               | 414            |  
No interim analysis for efficacy or futility is being planned. Fifty nine percent of patients randomized would be expected to contribute with an event. Under the expectation that 83% **[ per Bayer]** of RT1 patients would have a ≥ 30% decrease in PSA within 12 weeks, then a total of 499 patients would be involved in the first randomization (RT1), to yield the 414 patients needed for the second randomization (RT2).
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13.4 analysis population

The following analysis populations will be used:
- Full Analysis Set is defined as all patients randomized. Patients will be included in the treatment group to which they were randomized, following the intent-to-treat principle.  
- Safety Analysis Set is defined as all randomized patients who have received at least one dose of at least one of the study treatments (enzalutamide, darolutamide, radium-223 or placebo). Patients will be included in the treatment group in which they have been actually treated.
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13.5 data analysis

Descriptive statistics, including mean, median, standard deviations and ranges for all continuous measures will be tabulated and reported. Percentages and frequencies for all categorical measures will also be presented. Time-to-events endpoints will be reported using Kaplan-Meier estimates, with 95% CI for median time-to-event.
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demographics and baseline characteristics

Demographic and disease characteristics prior to lead in treatment as well as prior to randomization will be summarized in order to assess the comparability of the treatment groups  
Final Protocol: 04 MAY 2020 VERSION 1.2 Page 62 of 102 descriptively. Data to be tabulated will include demographic features such as age, ethnicity, race, and highest level of education as well as disease-specific characteristics. The number and percentages of patients screened, treated in the lead-in portion, randomized, who received randomized study drug treatment, and who were withdrawn from treatment/study for any reasons will be presented overall and also by treatment group.
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efficacy analysis all efficacy analyses

The SSE-FS, rPFS, time to total ALP progression, time to first skeletal progression, time to LDH progression, time to chemotherapy, and overall survival will be compared between the two arms using a stratified log-rank test with the same stratification factors as for randomization. The HR (radium-223 dichloride / placebo) will be computed together with the 2-sided 95% CI using a Cox regression model stratified by the same factors. Kaplan-Meier estimates and plots for both treatment groups will be produced to accompany these analyses. The median, 2- and 3-year event free rates with associated 95% CI will be generated. Additional details, including detailed censoring rules for these endpoints will be described in a separate statistical analysis plan (SAP). For ALP and LDH response rate, the estimates and associated 95% CI (Clopper et al. 1934), in each treatment group will be calculated. The absolute and relative difference in rate estimates between the two treatment groups will also be presented.
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safety analysis

Safety will be assessed through the analysis of the reported incidence of treatment-emergent AEs. Treatment-emergent AEs are those with an onset on or after the initiation of therapy after randomization 1 and will be graded according to NCI CTCAE 5.0. A copy of CTCAE scoring system may be downloaded from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R eference_8.5x11.pdf. The AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized using system organ class and preferred term by treatment group for all patients in the Safety Analysis Set. In addition, summaries of SAEs, AEs leading to treatment discontinuation, AEs by maximum NCI CTCAE grade, and AEs related to study treatment will also be presented by treatment group. Other safety endpoints, including laboratory results and vital signs findings, will be summarized for all patients in the Safety Analysis Set. Concomitant medications will be coded using the World Health Organization Drug Dictionary and they will be listed and summarized by treatment group for the Safety Analysis Set.
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13.6 analysis time points planned

Interim analyses to compare the safety and cognitive function of enzalutamide and darolutamide after RT1 randomization through 12 weeks of enzalutamide or darolutamide (prior to RT2) is planned. The details and timing of the planned interim analyses will be fully described in the Statistical Analysis Plan.  
After 25% of patients complete Randomization 2 and are followed for 9 months, a safety analysis focusing on fractures and death between the blinded arms, with and without radium-223 will be carried out by the IDMC.
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final analysis

The final analysis of the study will occur after the last visit of the last patient.
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13.7 primary completion date

The primary completion date is defined as the date on which the last participant in the study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ends according to the protocol or is terminated early does not affect this date.
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13.8 independent data monitoring committee

An independent data monitoring committee (IDMC) will be formed for this study. The specific roles and responsibilities of the IDMC and its members will be documented and described in a separate document. Special analyses of rates of falls, seizures, cardiovascular events (MI's, sudden death, angina, hypertension, heart failure), fatigue, and neurocognitive decline will be evaluated as part of the IDMC safety evaluation.
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13.9 steering committee

The Steering Committee will be chaired by Dr. Neal Shore, Study Lead-Principal Investigator. The specific roles and responsibilities of the Steering Committee and its members will be documented and described in a separate document.
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14. safety reporting and analyses

Safety assessments will consist of monitoring and recording AEs, AESIs and SAEs, measurement of protocol-specified hematology and clinical chemistry variables, measurement of protocol-specified vital signs, and other protocol-specified tests that are deemed critical to the safety evaluation of the study drug. The Site Investigator is responsible for recognizing and reporting AEs using the electronic data collection system. It is the Sponsor's responsibility to report SUSARs to the applicable local, national, or international regulatory bodies. In addition, Site Investigators must report SAEs and follow-up information to their responsible IRB according to the policies of that IRB. The Site Investigator is also responsible for ensuring that every staff member involved in the study is familiar with the content of this section.
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14.1 definitions adverse events

Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An adverse event (also known as adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality. An adverse event can arise with any use of the drug (e.g., off-label use, use in combination with another drug) and with any route of administration, formulation, or dose including overdose.
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adverse events of special interest

Adverse events of special interest (AESIs) are events of scientific and clinical interest specific to the safety profile of the study treatment regimen and may require close safety monitoring, reporting of events within 24 hours of the first knowledge of the event by the treating physician or research personnel, and will be considered in all safety analyses. An AESI may be either a serious or non-serious event. Adverse events of special interest for the combination of radium-223 plus enzalutamide or darolutamide in mCRPC patients include bone fractures. Appropriate efforts should be made to rule out disease progression or other etiologic cause of the AESI. If the Site Investigator has any questions regarding an AE being an AESI, they should immediately contact the Medical Monitor. These will be collected for the duration of the study, even after the patient has discontinued therapy. Adverse events of special interest observed in this study include:
- All bone fractures, either pathologic or non-pathologic.
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serious adverse event

An AE or a suspected adverse reaction (SAR) is considered "serious" if it results in any of the following outcomes:
- Death - A life-threatening AE - Inpatient hospitalization of at least 24 hours or prolongation of existing hospitalization
- A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse. It is important to distinguish between "serious" and "severe" AEs, as the terms are not synonymous. "Severity" is a measure of intensity; however, an AE of severe intensity need not necessarily be considered serious. Seriousness serves as the guide for defining regulatory reporting obligations. "Serious" is a regulatory definition and is based on patient/event outcome or action usually associated with events that pose a threat to a patient's life or vital functions. For example, nausea which persists for several hours may be considered severe nausea but may not be considered an SAE. On the other hand, a stroke which results in only a limited degree of disability may be considered only a mild stroke but would be considered an SAE. Severity and seriousness should be independently assessed when recording AEs on the eCRF and SAEs on the SAE Report Form. All SAEs will be reported to the FDA upon completion of the study in the final study report.
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suspected unexpected serious adverse reactions

MANA RBM will be responsible for determining whether the SAE meets the criteria for a SUSAR and will report any relevant potential SUSARs to Bayer Consumer Care AG (Ra-223 or darolutamide) or the FDA (enzalutamide).
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14.2 recording and reporting of

All AEs and SAEs of any patient during the course of the research study will be recorded in the EDC, and the Site Investigator will give his or her opinion as to the relationship of the AE to the study drug treatment (i.e., whether the event is related or unrelated to study drug administration and the drug that is suspected, if related). All AEs should be documented. A description of the event, including its date of onset and resolution, whether it constitutes an SAE or not, any action taken (e.g., changes to study treatment), and outcome, should be provided, along with the Site Investigator's assessment of causality (i.e., the relationship to the study treatment[s]). For an AE to be a suspected treatment-related event there should be at least a reasonable possibility of a causal relationship between the protocol treatment and the AE. Adverse events will be graded according to the NCI CTCAE v5.0, and changes will be documented. Serious Adverse Events will be reported by the research sites using the EDC system within 24 hours of the site being notified of the SAE. MANA RBM will evaluate each SAE to determine whether it meets the criteria for a SUSAR. All SAEs will be reported in the Clinical Study Report at the end of the study. SUSARs will be immediately reported to the FDA (and Bayer Consumer Care AG for those related to Ra-223 or darolutamide). Death related to disease progression is not considered a SAE and will be reported as part of the overall survival assessment. Other untoward events occurring in the framework of a clinical study are to be recorded as AEs (i.e., AEs that occur prior to assignment of study treatment that are related to a protocolmandated intervention, including invasive procedures such as biopsies, medication washout, or no treatment run-in). Any clinically significant signs and symptoms, abnormal test findings, changes in physical examination; hypersensitivity; and other measurements that occur will be reported as an AE and collected on the relevant eCRF screen. Test findings will be reported as an AE if: the test result requires an adjustment in the study drug(s) or discontinuation of treatment, and/ or test findings require additional testing or surgical intervention, a test result or finding is associated with accompanying symptoms, or a test result that is clinically significant by the Site Investigator is considered to be an AE.
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reporting period for adverse events

All AEs will be reported regardless of seriousness or relationship to radium-223 or placebo treatment or enzalutamide/darolutamide, spanning from the period from signing the informed consent until 30 calendar days after discontinuation of these treatments (whichever is discontinued last). All AEs resulting in discontinuation from the study should be followed until resolution or stabilization. All new AEs occurring during this period must be reported and followed until resolution unless, in the opinion of the Site Investigator, the AE or laboratory abnormality is/ are not likely to improve because of an underlying disease. In this case, the Site Investigators must record his or her reasoning for this decision in the patient's medical record and as a comment on the eCRF screen. After 30 days following completion of protocol-specific treatment or discontinuation (end of study drug visit), AEs, SAEs, or deaths assessed by the Site Investigator as treatment-related are to be reported. In addition, AESIs and SSE-related AEs (e.g. bone pain requiring EBRT) are to be reported. SSEs and AESIs are reported throughout the study. These are the only adverse events to be reported after the final end of study drug visit.
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assessment of adverse events

All AEs and SAEs whether volunteered by the patient, discovered by study personnel during questioning; or detected through physical examination, laboratory test, or other means, will be reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and end dates), severity, regulatory seriousness criteria if applicable, suspected relationship to the study drug (see following guidance), and actions taken. To ensure consistency of AE and SAE causality assessments, Site Investigators should apply the following general guideline: YES: There is a plausible temporal relationship between the onset of the AE and administration of the study medication, and the AE cannot be readily explained by the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to the study drug; and/or the AE abates or resolves upon discontinuation of the study drug or dose reduction and, if applicable, reappears upon rechallenge.  
NO: Evidence exists that the AE has an etiology other than the study drug (e.g., pre-existing medical condition, underlying disease, intercurrent illness, or concomitant medication), and/or the AE has no plausible temporal relationship to study drug administration (e.g., cancer diagnosed 2 days after first dose of study drug).
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14.3 recording and reporting of

All AESIs and SSEs regardless of seriousness or relationship to the study medications, spanning from the start of randomized study treatments until the subject completes the study are to be reported using the EDC system within 24 hours of the first knowledge of the event by the treating physician or research personnel. Additional data will be collected for all AESI.
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14.4 recording of adverse events

All AEs should be recorded individually in the patient's own words (verbatim) unless, in the opinion of the Site Investigator or designated physician, the AEs constitute components of a recognized condition, disease, or syndrome. In the latter case, the condition, disease, or syndrome should be named rather than each individual sign or symptom. If a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, each individual event should be recorded as an AE or SAE as appropriate on the relevant form(s) in the EDC. If a diagnosis is subsequently established, it should be reported as follow-up information is available. If a diagnosis is determined subsequent to the reporting of the constellation of symptoms, the signs/symptoms should be updated to reflect the diagnosis. Progression of malignancy (including fatal outcomes), if documented by use of appropriate method, should not be reported as an SAE.
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persistent or recurrent adverse events

A persistent AE is one that extends continuously, without resolution, between patient evaluation time points. Such events should only be recorded once on the SAE Report Form and/or the AE eCRF screen. If a persistent AE becomes more severe or lessens in severity, it should be recorded on a separate AE or SAE with the relevant change in severity captured in the EDC. A recurrent AE is one that occurs and resolves between patient evaluation time points and subsequently recurs. Each instance of the AE should be recorded with appropriate start and stop dates in the EDC.
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abnormal laboratory values

If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or vital sign should be considered additional information that must be collected on the relevant eCRF screen. If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis needs to be recorded on the SAE Report Form or AE eCRF screen. All ≥CTCAE Grade 2 will be flagged for review of clinical significance by site investigator. Abnormal laboratory values will be reported as an AE if laboratory result or finding is associated with accompanying symptoms, laboratory result is ≥CTCAE Grade 3, or is considered to be clinically significant by the Site Investigator. Abnormal laboratory values will also be reported as an AE if laboratory result requires:  
- adjustment in the study drug(s)
- discontinuation of treatment - additional testing, or
- surgical intervention
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deaths

Deaths that occur during the protocol-specified AE reporting period that are attributed by the Site Investigator solely to progression of disease will be recorded on the "End of Study" eCRF screen. All other on-study deaths, regardless of attribution, that occur within the protocolspecified AE reporting period will be recorded on an SAE Report Form within the EDC within 24 hours of being notified of the death. When recording a SAE with an outcome of death, the event or condition that caused or contributed to the fatal outcome should be recorded as the single medical concept on the AE/SAE Report Form in the EDC. If the cause of death is unknown and cannot be ascertained at the time of reporting, record "Death NOS" on the eCRF Adverse Event screen.
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hospitalization prolonged hospitalization or surgery

Any AE that results in hospitalization of >24 hours or prolongation of pre-existing hospitalization should be documented and reported as an SAE unless specifically instructed otherwise in this protocol. There are some hospitalizations that do not require reporting as an SAE. Treatment within or admission to the following facilities is not considered to meet the criteria of "inpatient hospitalization" (although if any other SAE criteria are met, the event must still be treated as an SAE and immediately reported):
- Emergency department or emergency room
- Outpatient or same-day surgery units - Observation or short-stay unit - Rehabilitation facility - Hospice or skilled nursing facility - Nursing homes, custodial care or respite care facility Hospitalization during the study for a pre-planned surgical or medical procedure (one which was planned prior to entry in the study), does not require reporting as an SAE.
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pre-existing medical conditions

A pre-existing medical condition is one that is present at the start of the study. Such conditions should be recorded on the Medical History eCRF page. A pre-existing medical condition should be recorded as an AE or SAE only if the frequency, severity, or character of the condition worsens during the study. When recording such events on the AE/ SAE EDC Case Report Form, it is important to convey the concept that the pre-existing condition has changed by including applicable descriptors.
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new cancers

The development of a new primary cancer, other than non-melanoma skin cancer, should be regarded as an SAE and will generally meet at least one of the seriousness criteria. These will be collected for the duration of the study, even after treatment discontinuation. New primary cancers are those that are not the primary reason for the administration of the study treatment and have developed after the inclusion of the patient into the study. They do not include metastases of the original cancer.
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radium-223 overdose

Symptomatic and non-symptomatic overdose must be reported in the eCRF. Any accidental or intentional overdose with the study treatment that is symptomatic, even if not fulfilling a seriousness criterion, is to be reported to the Medical Monitor no greater than 24 hours from first knowledge of the event using the corresponding screens in the eCRF and following the same process described for SAE reporting if the overdose is symptomatic. For information on how to manage an overdose of radium-223, see the Ra-223 Full Prescribing Information.
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14.5 sponsor serious adverse event

MANA RBM will forward all SUSARs within 7 days of identifying an SAE meeting the SUSAR criteria to Bayer Pharmacovigilance Department for darolutamide or Ra-223. Bayer Consumer Care AG will be notified by automatic email notification of any reported SAEs entered into the EDC. SUSARs related to enzalutamide will be reported directly to the FDA. Bayer AG will be responsible for reporting relevant SUSARs to the competent authority, other applicable regulatory authorities, and participating Site Investigators, in accordance with International Conference on Harmonisation (ICH) guidelines, FDA regulations, and/or local regulatory requirements. All SAEs will be reported by MANA RBM to the IRB and a final summary of all SAEs will be provided in the Clinical Study Report.
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sponsor assessment of suspected unexpected

Known as Suspected Unexpected Serious Adverse Reactions (SUSARs), these events suspected (by the Site Investigator or Sponsor) to be related to the study drug, are unexpected (not listed in the IB or USPI), and are serious (as defined by the protocol) and require expedient submission to relevant health authorities within 7 days (fatal or life-threatening event) or 15 days (all serious events), or as defined by law. The Sponsor is responsible for final determination of whether a SAE is as "unexpected." MANA RBM will forward all SUSARs for Ra-233 or darolutamide to Bayer Consumer Care AG. All Ra-223 SUSARs will be unblinded to treatment. MANA RBM will forward all SUSARs within 7 days of identifying an SAE meeting the SUSAR criteria. Bayer AG will be responsible for reporting relevant SUSARs to the competent authority, other applicable regulatory authorities, and participating Site Investigators, in accordance with International Conference on Harmonisation (ICH) guidelines, FDA regulations, and/or local regulatory requirements.
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sponsor reporting for clinical studies

Any written IND Safety Reports will be submitted to the FDA by the MANA RBM. Copies will be provided by email to Bayer Consumer Care AG.
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15. ethical financial and regulatory

This research study will be conducted according to the standards of Good Clinical Practice outlined in the ICH E6(R2) Tripartite Guideline and CFR Title 21 part 312, applicable government regulations, institutional research policies and procedures and any other local applicable regulatory requirement(s).
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15.1 institutional review board approval

The clinical study protocol, ICF, patient documents (e.g., ePRO), patient recruitment procedures (e.g., advertisements), information about payments and compensation available to the patients, and documentation evidencing the Site Investigator's qualifications should be submitted to the IRB for ethical review and approval if required by local regulations, prior to the study start. The Site Investigator/Sponsor and/or designee will follow all necessary regulations to ensure appropriate, initial, and on-going IRB study review. The Site Investigator/Sponsor (as appropriate) must submit and, where necessary, obtain approval from the IRB for all subsequent protocol amendments and changes to the informed consent document. Site Investigators will be advised by the Sponsor or designee whether an amendment is considered substantial or nonsubstantial and whether it requires submission for approval or notification only to an IRB.  
Safety updates for radium-223 and darolutamide will be prepared by the Bayer Consumer Care AG and distributed by MANA RBM to the Site Investigators and relevant IRB.
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15.2 regulatory approval

As required by local regulations, the Sponsor will ensure all legal aspects are covered, and approval of the appropriate regulatory bodies obtained, prior to study initiation. If required, the Sponsor will also ensure that the implementation of substantial amendments to the protocol and other relevant study documents happen only after approval by the relevant regulatory authorities.
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15.3 informed consent

Informed consent is a process by which a patient voluntarily confirms his or her willingness to participate in a particular study after having been informed of all aspects of the study that are relevant to the patient's decision to participate. Informed consent is documented by means of a written, signed, and dated ICF. An electronic informed consent (eConsent) will be used except in extenuating circumstances (e.g., if the internet is not functioning at the time the patient must sign the consent). The ICF, including translations, will be submitted for approval to the IRB that is responsible for review and approval of the study. Each consent form must include all of the relevant elements currently required by the FDA, as well as local county authority or state regulations and national requirements. Before screening into the study, each prospective candidate will be given a full explanation of the research study. Once the essential information has been provided to the prospective candidate, and the Site Investigator (or designee) is sure that the individual candidate understands the implications of participating in this research study, the candidate will be asked to give consent to participate in the study by signing an ICF. A copy of the ICF, to include the patient's signature, will be provided by the Site Investigator (or designee) to the patient. Patients will be given the option to participate in the collection of biomarker samples for research. Patients can participate in the main study and opt out of the collection of biomarker samples for research. Patients can withdraw approval for participating in the research samples at any time. Patients can withdraw consent to main study or biorepository sampling, at any time.  
All data and documents collected between when the informed consent was signed by the patient and when the patient withdraws consent will remain in the study databases. If an amendment to the protocol substantially alters the study design or the potential risks to patients, each ongoing patient's consent to continue participation in the study should be obtained.
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15.4 patient confidentiality

Confidentiality of patient's personal data stored in the eISF or eSource limited-access sections containing protected health information (PHI) will be protected in accordance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA). HIPAA regulations require that, in order to participate in the study, as part of the informed consent process, the patient must sign an authorization form for the study that he or she has been informed of the following:
- What PHI will be collected from patients in this study - Who will have access to that information and why? - Who will use or disclose that information? - That health information may be further disclosed by the recipients of the information, and that if the information is disclosed the information may no longer be protected by federal or state privacy laws
- The information collected about the research study will be kept separate from the patient's medical records, but the patient will be able to obtain the research records after the conclusion of the study
- Whether the authorization contains an expiration date
- The rights of a research patient to revoke his or her authorization In the event that a patient revokes authorization to collect or use his or her PHI, the Site Investigator, by regulation, retains the ability to use all information collected prior to the revocation of patient authorization. For patients that have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e., that the patient is alive) during the Overall Survival phase of the study. In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that the Site Investigator and institution permit authorized representatives of the Sponsor, the regulatory authorities and the IRB direct access to review the patient's original medical records at the site for verification of study-related procedures and data. Measures to protect confidentiality include identification of subjects by using a unique subject ID that will identify patients in the eCRF or other documents submitted to the Sponsor. This information, together with the patient's year of birth, will be used in the database for patient identification. Patient names or addresses will not be entered in the eCRF portions that are accessible to non-site study personnel. No material bearing a patient's name or other PHI will be transmitted to Bayer Consumer Care AG. Patients will be informed of their rights within the ICF.
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15.5 site investigator and staff

Professional data of the Site Investigators and sub-Investigators may be included in the MANA RBM database and shall be treated in compliance with all applicable laws and regulations. When archiving or processing personal data pertaining to the Site Investigator or sub Investigator, MANA RBM shall take all appropriate measures to safeguard and prevent access to this data by any unauthorized party.
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15.6 financial information

The finances for this clinical study will be subject to a separate written agreement between MANA Consulting LLC d/b/a MANA RBM, and/or CUSP and applicable parties. Any Site Investigator financial disclosures as applicable to 21CFR Part 54 shall be appropriately provided.
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16. research retention and documentation

Amendments to the protocol shall be planned, documented, and signature-authorized prior to implementation. If an amendment to the protocol is required, the amendment will be originated and documented by the Sponsor. All amendments require review and approval of all pharmaceutical companies and the Study Lead-Principal Investigator supporting the study. The written amendment must be reviewed and approved by the Sponsor and submitted to the IRB at the Site Investigator's facility for the board's approval. Amendments specifically involving change to study design, risk to patient, increase to dosing or exposure, patient number increase, or addition or removal of new tests or procedures, shall be reviewed and approved by the IRB of record for the Site Investigator's facility. The amendment will be submitted formally to the FDA or other regulatory authorities by the Sponsor as applicable, and IRB approval obtained, specifically when an increase to dosing or patient exposure and/or patient number has been proposed. Items requiring a protocol amendment approval from IRB and/or FDA or other regulatory authorities include, but are not limited to, the following:
- Change to study design
- Increased risk to subjects - Increase to dose or patient exposure to drug
- Patient number increase
- Addition of tests and/or procedures It should be further noted that if an amendment to the protocol substantially alters the study design or the potential risks to the patients as determined by the IRB, a revision to the ICF and their consent to continue participation in the study should be obtained.
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16.2 documentation required to initiate

Before the study may begin certain documentation required by FDA regulations and ICH GCP must be provided by the Site Investigator. The required documentation will be provided in electronic format or as certified electronic documents and stored in the Site's electronic Investigator Site File (eISF) Documents required to begin a study in the US include, but are not limited to, at a minimum, the following:
- A signed protocol signature page and contract - A copy of the official IRB approval of the study and the IRB members list - Current curricula vitae for the Site Investigator and any Sub-Investigator(s) who will be involved in the study
- Appropriate nuclear medicine licensing - Indication of appropriate accreditation for any laboratories to be used in the study and a copy of the normal ranges for tests to be performed by that laboratory
- Original Form FDA 1572 (Statement of Investigator), appropriately completed and signed
- A copy of the IRB-approved consent form (and patient information sheet, if applicable)
containing permission for audit by representatives of MANA RBM, the IRB, and the FDA and other regulatory agencies (as applicable)
- Financial disclosure forms for all Site Investigators listed on Form FDA 1572
- Site qualification reports, where applicable - Verification of Site Investigator acceptability from local and/or national debarment list(s)
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16.3 study documentation and storage

All documents for the trial will be stored in an electronic Investigator Site File or electronic Trial Master File. Documentation of staff associated with the trial, training, delegation of duties, and access to all electronic systems will be collected electronically using the Site Tracker Analyzing Risk (STAR database). All data collected de novo for the trial will be entered directly into the electronic source system (eSource) using the principles of ALCOA (attributable, legible, contemporaneous, original, and accurate). The entry of subject data contemporaneous with subject visits aligns with the FDA Guidance on electronic Source and ICHE6(2). Source documents such as medical history, lab reports, and other documents needed to confirm inclusion criteria, safety, or efficacy that reside in another location may be uploaded as certified electronic copies and stored in the PHI protected section of the eISF, available only to the Site and individuals identified in the Informed Consent. The eISF should will contain as a minimum all relevant documents and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57.  
Drug accountability records will be collected electronically and will contain information regarding receipt, dosing, lot number, and disposition. They will be archived in the site's eISF. The Sponsor shall maintain adequate investigational product records and financial interest records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing application has been approved by the FDA; or, in the event that the marketing application has not been approved by the FDA, for no less than 2 years after the last shipment / delivery of the drug for investigational use is discontinued and the FDA has been notified of the discontinuation. The IRB shall maintain adequate documentation/records of IRB activities as per 21CFR Part 56.115 for at least 3 years after completion of the research. The Site Investigator shall maintain adequate records of drug disposition, case histories, and any other study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing application has been approved by the FDA; or, in the event that the marketing application has not been approved by the FDA, for no less than 2 years after the last shipment/delivery of the drug for investigational use is discontinued and the FDA has been notified of the discontinuation. To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its representative, the Site Investigator additionally agrees to keep records, including the identity of all participating patients (sufficient information to link records e.g., eCRFs, medical records). Informed consents will be collected electronically and will be archived in the eISF. The documents listed above must be retained by the Site Investigator for as long as needed to comply with national and international regulations (generally 2 years after discontinuing clinical development or after the last marketing approval). If the Site Investigator relocates, retires, or for any reason withdraws from the study, both the Sponsor and its representative should be prospectively notified. The study records must be transferred to an acceptable designee, such as another Site Investigator, another institution, or to the Sponsor. All study files will be maintained by the Sponsor throughout the study and will be transferred to Bayer Consumer Care AG at the conclusion of the study. Note any patient-related data containing PHI will only be stored in the eISF and will not be provided to Bayer Consumer Care AG.
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16.4 data collection

The study eCRF is the primary data collection instrument for the study. The eCRF, and all data collection tools are validated. Systems and processes align with 21 CFR Part 11. Case report forms will be completed using the English language. For data collected *de novo* for the study will be entered as direct data capture. Patient reported outcomes, cognitive testing, and informed consents will be provided in English and Spanish. In order to maintain confidentiality, only subject ID and year of birth will identify the patient in the eCRF. All documents containing PHI will be stored as certified copies in a special restricted access section of the Site's electronic Investigator Site File or the site's protected portion of the eSource (EDC) system. Only individuals with the roles described in the informed consent and the Site staff will have access to the data and files containing PHI. The Site Investigator may file a personal patient identification list (Subject IDs with corresponding patient identifiers) in the PHI section of the eISF to enable records to be identified and verified as authentic. Patient data/information will be kept confidential, and will be managed according to applicable local, state, and federal regulations. At the end of the study or at the end of a patient's participation, the Site Investigator will electronically sign and date the patient eCRF casebook indicating that the data in the eCRF has been reviewed and approved by the Site Investigator.
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16.5 study monitoring auditing and

The study will be monitored using a remote Risk Based Monitoring Approach (MANA Method) as described in Appendix E. The Site Investigator will permit study-related monitoring, quality audits, and inspections by the Sponsor or its representative(s), government regulatory authorities, and the IRB of all studyrelated documents (e.g., source documents, regulatory documents, data collection instruments, case report forms). The Site Investigator will ensure the capability for inspections of applicable study-related facilities. The Site Investigator will ensure that the study monitor, or any other compliance or Quality Assurance reviewer is given access to all study-related documents and study-related facilities. Participation as a Site Investigator in this study implies the acceptance of potential inspection by government regulatory authorities, the Sponsor or its representative(s).
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16.6 quality assurance and quality

Each study site shall be required to have Table of Contents of Standard Operating Procedures to define and ensure quality assurance/control processes for study conduct, safety reporting, handling radiopharmaceutical, data generation and collection, recording of data/documentation and reporting according to the protocol, GCP and any applicable local, national or international regulations.
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16.7 disclosure and publication policy

All information provided regarding the study, as well as all information collected/documented during the course of the study, will be regarded as confidential. The Sponsor reserves the right to release literature publications based on the results of the study. Results from the study will be published/presented as per the Sponsor's publication strategy.
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17. references alibhai et al.

Alibhai SM, Breunis H, Timilshina N, et al. Impact of androgen-deprivation therapy on cognitive function in men with nonmetastatic prostate cancer. J Clin Oncol. 2010;28: 5030-5037.
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armstrong et al. 2018

Armstrong AJ, Lin P, Higano CS et al. Prognostic Association of Prostate-specific Antigen Decline with Clinical Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide in a Randomized Clinical Trial. Eur Urol Oncol 2018; https://doi.org/10.1016/j.euo.2018.11.005.
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beer et al. 2014

Beer TM, Armstrong AJ, Rathkopf D et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. 2017; 71: 151–154.
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clopper et al. 1934

Clopper C and Pearson ES. The use of confidence or fiducial limits illustrated in the case of binomial. Biometrika 1934; 26: 404-413.
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ferlay et al. 2015

Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136: E359-86.
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flaig et al. 2016

Flaig TW, Potluri RC, Ng Y, et al. Treatment evolution for metastatic castration‐resistant prostate cancer with recent introduction of novel agents: retrospective analysis of real‐world data. Cancer Med. 2016 Feb; 5(2): 182–191.
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hussain et al. 2018

Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36: 3.
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jim et al. 2010

Jim HS, Small BJ, Patterson S, Salup R, Jacobsen PB. Cognitive impairment in men treated with luteinizing hormone-releasing hormone agonists for prostate cancer: a controlled comparison. Support Care Cancer. 2010;18: 21-27.
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joly et al. 2006

Joly F, Alibhai SM, Galica J, et al. Impact of androgen deprivation therapy on physical and cognitive function, as well as quality of life of patients with nonmetastatic prostate cancer. J Urol. 2006;176: 2443-2447.
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mcginty et al. 2014

McGinty HL, Phillips KM, Jim HS, et al. Cognitive functioning in men receiving androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis. Support Care Cancer. 2014;22: 2271-2280.
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nead et al. 2016

Nead KT, Gaskin G, Chester C, et al. Androgen Deprivation Therapy and Future Alzheimer's Disease Risk. J Clin Oncol. 2016;34: 566-571.
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parker et al. 2013

Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. New Engl J Med. 2013; 269: 213-223.
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ryan et al. 2011

Ryan CJ1, Shah S, Efstathiou E, et al. Phase II study of abiraterone acetate in chemotherapyI metastatic castration-resistant prostate cancer displaying bone flare discordant with serologic response. Clin Cancer Res. 2011; 17: 4854-4861.
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scher et al. 2012

Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-97
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scher et al. 2016

Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016; 34: 1402-1418.
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shore et al. 2016

Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomized, doubleblind, phase 2 study. Lancet Oncol. 2016; 17: 153-163.
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smith et al. 2019

Matthew Smith, Chris Parker, Fred Saad, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20: 408–19
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tannock et al. 2014

Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004: 351:1502-1512.
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tran et al. 2009

Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009; 324: 787-790.
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wefel et al. 2011

Wefel JS, Vardy J, Ahles T, et al. International Cognition and Cancer Task Force Recommendations to Harmonise Studies of Cognitive Function in Patients with Cancer. Lancet Oncology. 2011; 12:703-708. Nubeqa (darolutamide) **[package insert].** Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 7/2019. Xofigo (radium Ra 223 dichloride) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 8/2018. Xtandi **(enzalutamide) [package insert].** Northbrook, IL: Astellas Pharma US, Inc; 7/2018.
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18. appendices appendix a ecog

| ECOG Performance Status Scale                                                                                                                                                             | Karnofsky Performance Scale                                                                                    |                                                                        |                                                             |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|-------------------------------------------------------------|
| Grade                                                                                                                                                                                     | Descriptions                                                                                                   | Percent                                                                | Description Normal, no complaints, no evidence of  disease. |
| 100                                                                                                                                                                                       |                                                                                                                |                                                                        |                                                             |
| Normal activity. Fully active, able to carry                                                                                                                                              |                                                                                                                |                                                                        |                                                             |
| 0                                                                                                                                                                                         | on all pre-disease performance without  restriction.                                                           | Able to carry on normal activity; minor  signs or symptoms of disease. |                                                             |
| 90                                                                                                                                                                                        | Normal activity with effort; some signs or  symptoms of disease.                                               |                                                                        |                                                             |
| 80                                                                                                                                                                                        |                                                                                                                |                                                                        |                                                             |
| Symptoms, but ambulatory. Restricted in  physically strenuous activity, but  ambulatory and able to carry out work of a  light or sedentary nature (e.g., light  housework, office work). |                                                                                                                |                                                                        |                                                             |
| 1                                                                                                                                                                                         | Cares for self, unable to carry on normal                                                                      |                                                                        |                                                             |
| 70                                                                                                                                                                                        | activity or to do active work. Requires occasional assistance, but is able  to care for most of his/her needs. |                                                                        |                                                             |
| 60                                                                                                                                                                                        |                                                                                                                |                                                                        |                                                             |
| In bed <50% of the time. Ambulatory and  capable of all self-care, but unable to carry  out any work activities. Up and about  more than 50% of waking hours.                             |                                                                                                                |                                                                        |                                                             |
| 2                                                                                                                                                                                         | Requires considerable assistance and  frequent medical care.                                                   |                                                                        |                                                             |
| 50                                                                                                                                                                                        | Disabled, requires special care and  assistance                                                                |                                                                        |                                                             |
| 40                                                                                                                                                                                        |                                                                                                                |                                                                        |                                                             |
| In bed >50% of the time. Capable of only                                                                                                                                                  |                                                                                                                |                                                                        |                                                             |
| 3                                                                                                                                                                                         | limited self-care, confined to bed or chair  more than 50% of waking hours.                                    | Severely disabled, hospitalization                                     |                                                             |
| 30                                                                                                                                                                                        | indicated. Death no imminent. Very sick, hospitalization indicated.  Death not imminent.                       |                                                                        |                                                             |
| 20                                                                                                                                                                                        |                                                                                                                |                                                                        |                                                             |
| 100% bedridden. Completely disabled.                                                                                                                                                      |                                                                                                                |                                                                        |                                                             |
| 4                                                                                                                                                                                         | Cannot carry on any self-care. Totally  confined to bed or chair.                                              | Moribund, fatal processes progressing                                  |                                                             |
| 10                                                                                                                                                                                        | rapidly.                                                                                                       |                                                                        |                                                             |
| 5                                                                                                                                                                                         | Dead                                                                                                           | 0                                                                      | Dead                                                        |
untitled h1
fact-p (version 4)

Below is a list of statements that other people with your illness have said are important. Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
| PHYSICAL WELL-BEING      | Not                                                                                                                                                                           | A little   | Somewhat      | Quite   | Very   |    |
|--------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|------|---------|--------|----|
| at all                   | bit                                                                                                                                                                           | a bit      | much |         |        |    |
| GP1                      | I have a lack of energy                                                                                                                                                       | 0          | 1    | 2       | 3      | 4  |
| GP2                      | I have nausea                                                                                                                                                                 | 0          | 1    | 2       | 3      | 4  |
| GP3                      | Because of my physical condition, I have trouble  meeting the needs of my family                                                                                              | 0          | 1    | 2       | 3      | 4  |
| GP4                      | I have pain                                                                                                                                                                   | 0          | 1    | 2       | 3      | 4  |
| GP5                      | I am bothered by side effects of treatment                                                                                                                                    | 0          | 1    | 2       | 3      | 4  |
| GP6                      | I feel ill                                                                                                                                                                    | 0          | 1    | 2       | 3      | 4  |
| GP7                      | I am forced to spend time in bed                                                                                                                                              | 0          | 1    | 2       | 3      | 4  |
| SOCIAL/FAMILY WELL-BEING | Not                                                                                                                                                                           | A little   | Somewhat      | Quite   | Very   |    |
| at all                   | bit                                                                                                                                                                           | a bit      | much |         |        |    |
| GS1                      | I feel close to my friends                                                                                                                                                    | 0          | 1    | 2       | 3      | 4  |
| GS2                      | I get emotional support from my family                                                                                                                                        | 0          | 1    | 2       | 3      | 4  |
| GS3                      | I get support from my friends                                                                                                                                                 | 0          | 1    | 2       | 3      | 4  |
| GS4                      | My family has accepted my illness                                                                                                                                             | 0          | 1    | 2       | 3      | 4  |
| GS5                      | I am satisfied with family communication about my  illness                                                                                                                    | 0          | 1    | 2       | 3      | 4  |
| GS6                      | I feel close to my partner (or the person who is my main  support)                                                                                                            | 0          | 1    | 2       | 3      | 4  |
| Q1                       | Regardless of your current level of sexual activity, please  answer the following question. If you prefer not to answer it,  please mark this box and go to the next section. |            |      |         |        |    |  
GS7 I am satisfied with my sex life ............................................ 0 1 2 3 4  
  
  
English (Universal) 19 November 2007 Copyright 1987, 1997 Page 1 of 3  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
FUNCTIONAL WELL-BEING Not  
at all  
A little  
bit  
Somewhat Quite  
a bit  
Very  
much  
GF1 I am able to work (include work at home) .......................... 0 1 2 3 4  
GF2 My work (include work at home) is fulfilling..................... 0 1 2 3 4 GF3 I am able to enjoy life.......................................................... 0 1 2 3 4  
GF4 I have accepted my illness................................................... 0 1 2 3 4  
GF5 I am sleeping well ............................................................... 0 1 2 3 4 GF6 I am enjoying the things I usually do for fun ...................... 0 1 2 3 4  
GF7 I am content with the quality of my life right now.............. 0 1 2 3 4  
English (Universal) 19 November 2007 Copyright 1987, 1997 Page 2 of 3  
| EMOTIONAL WELL-BEING   | Not                                                 | A little   | Somewhat   | Quite   |    |    |
|------------------------|-----------------------------------------------------|------------|---|---------|----|----|
| at all                 | bit                                                 |            |   |         |    |    |
| GE1                    | I feel sad                                          | 0          | 1 | 2       | 3  | 4  |
| GE2                    | I am satisfied with how I am coping with my illness | 0          | 1 | 2       | 3  | 4  |
| GE3                    | I am losing hope in the fight against my illness    | 0          | 1 | 2       | 3  | 4  |
| GE4                    | I feel nervous                                      | 0          | 1 | 2       | 3  | 4  |
| GE5                    | I worry about dying                                 | 0          | 1 | 2       | 3  | 4  |
| GE6                    | I worry that my condition will get worse            | 0          | 1 | 2       | 3  | 4  |  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
| ADDITIONAL CONCERNS   | Not at                                                  | A little   | Somewhat      | Quite   | Very   |    |
|-----------------------|---------------------------------------------------------|------------|------|---------|--------|----|
| all                   | bit                                                     | a bit      | much |         |        |    |
| C2                    | I am losing weight                                      | 0          | 1    | 2       | 3      | 4  |
| C6                    | I have a good appetite                                  | 0          | 1    | 2       | 3      | 4  |
| P1                    | I have aches and pains that bother me                   | 0          | 1    | 2       | 3      | 4  |
| P2                    | I have certain parts of my body where I experience pain | 0          | 1    | 2       | 3      | 4  |
| P3                    | My pain keeps me from doing things I want to do         | 0          | 1    | 2       | 3      | 4  |
| P4                    | I am satisfied with my present comfort level            | 0          | 1    | 2       | 3      | 4  |
| P5                    | I am able to feel like a man                            | 0          | 1    | 2       | 3      | 4  |
| P6                    | I have trouble moving my bowels                         | 0          | 1    | 2       | 3      | 4  |
| P7                    | I have difficulty urinating                             | 0          | 1    | 2       | 3      | 4  |
| BL2                   | I urinate more frequently than usual                    | 0          | 1    | 2       | 3      | 4  |
| P8                    | My problems with urinating limit my activities          | 0          | 1    | 2       | 3      | 4  |
| BL5                   | I am able to have and maintain an erection              | 0          | 1    | 2       | 3      | 4  |
untitled h1
fact-cognitive function (version 3)

Below is a list of statements that other people with your condition have said are important. Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
| Never                           | About  once a  week                                                                            | Two to  three  times a  week   | Nearly  every  day   | Several  times  a day   |    |
|---------------------------------|------------------------------------------------------------------------------------------------|--------------------------------|----------------------|-------------------------|----|
| PERCEIVED COGNITIVE IMPAIRMENTS |                                                                                                |                                |                      |                         |    |
| CogA1                           | I have had trouble forming thoughts 0 0                                                        | 1                              | 2                    | 3                       | 4  |
| CogA3                           | My thinking has been slow 0 0                                                                  | 1                              | 2                    | 3                       | 4  |
| CogC7                           | I have had trouble concentrating 0 0                                                           | 1                              | 2                    | 3                       | 4  |
| CogM9                           | I have had trouble finding my way to a familiar  place 0 0                                     | 1                              | 2                    | 3                       | 4  |
| CogM10                          | I have had trouble remembering where I put things,  like my keys or my wallet 0 0              | 1                              | 2                    | 3                       | 4  |
| CogM12                          | I have had trouble remembering new information,  like phone numbers or simple instructions 0 0 | 1                              | 2                    | 3                       | 4  |
| CogV13                          | I have had trouble recalling the name of an object  while talking to someone 0                 | 1                              | 2                    | 3                       | 4  |
| CogV15                          | I have had trouble finding the right word(s) to  express myself 0 0                            | 1                              | 2                    | 3                       | 4  |
| CogV16                          | I have used the wrong word when I referred to an  object 0 0                                   | 1                              | 2                    | 3                       | 4  |
| CogV17b                         | I have had trouble saying what I mean in  conversations with others 0 0                        | 1                              | 2                    | 3                       | 4  |
| CogF19                          | I have walked into a room and forgotten what I  meant to get or do there 0 0                   | 1                              | 2                    | 3                       | 4  |
| CogF23                          | I have had to work really hard to pay attention or I  would make a mistake 0 0                 | 1                              | 2                    | 3                       | 4  |
| CogF24                          | I have forgotten names of people soon after being  introduced 0 0                              | 1                              | 2                    | 3                       | 4  |  
FACT-Cog V3 Copyright 2006, 2016 Page 1 of 3 Last Revised 10 February 2008
untitled h1
fact-cog (version 3)

Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
| Several  times a  day   |                                                                                                |                              |                    |    |    |
|-------------------------|------------------------------------------------------------------------------------------------|------------------------------|--------------------|----|----|
| CogF25                  | My reactions in everyday situations have been  slow 0 0                                        | 1                            | 2                  | 3  | 4  |
| Never                   | About  once a  week                                                                            | Two to  three  times a  week | Nearly  every  day |    |    |
| CogC31                  | I have had to work harder than usual to keep track  of what I was doing 0 0                    | 1                            | 2                  | 3  | 4  |
| CogC32                  | My thinking has been slower than usual 0 0                                                     | 1                            | 2                  | 3  | 4  |
| CogC33a                 | I have had to work harder than usual to express  myself clearly 0 0                            | 1                            | 2                  | 3  | 4  |
| CogC33c                 | I have had to use written lists more often than  usual so I would not forget things 0 0        | 1                            | 2                  | 3  | 4  |
| CogMT1                  | I have trouble keeping track of what I am doing if I  am interrupted 0 0                       | 1                            | 2                  | 3  | 4  |
| CogMT2                  | I have trouble shifting back and forth between  different activities that require thinking 0 0 | 1                            | 2                  | 3  | 4  |  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
| Never                | About  once a  week                                                             | Two to  three  times a  week   | Nearly  every  day   | Several  times a  day   |    |    |
|----------------------|---------------------------------------------------------------------------------|--------------------------------|----------------------|-------------------------|----|----|
| COMMENTS FROM OTHERS |                                                                                 |                                |                      |                         |    |    |
| CogO1                | Other people have told me I seemed to have trouble  remembering information 0 0 | 1                              | 2                    | 3                       | 4  |    |
| CogO2                | Other people have told me I seemed to have trouble  speaking clearly 0 0        | 1                              | 2                    | 3                       | 4  |    |
| CogO3                | Other people have told me I seemed to have trouble  thinking clearly 0 0        | 1                              | 2                    | 3                       | 4  |    |
| CogO4                | Other people have told me I seemed confused                                     | 0                              | 1                    | 2                       | 3  | 4  |  
FACT-Cog v3 Copyright 2006, 2016 Page 2 of 3 Last Revised 10 February 2008  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
Not  
at all  
A little  
bit  
Somewhat**Quite**  
a bit  
Very  
much  
| Not                                                                               | A little                                                                                   |    |    |    |    |
|-----------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|----|----|----|----|
| at all                                                                            | bit                                                                                        |    |    |    |    |
| PERCEIVED COGNITIVE ABILITIES                                                     |                                                                                            |    |    |    |    |
| PC1                                                                               | I have been able to concentrate 0                                                          | 1  | 2  | 3  | 4  |
| PV1                                                                               | I have been able to bring to mind words that I wanted to  use while talking to someone 0   | 1  | 2  | 3  | 4  |
| PM1                                                                               | I have been able to remember things, like where I left  my keys or wallet 0                | 1  | 2  | 3  | 4  |
| PM2                                                                               | I have been able to remember to do things, like take  medicine or buy something I needed 0 | 1  | 2  | 3  | 4  |
| PF1                                                                               | I am able to pay attention and keep track of what I am  doing without extra effort 0       | 1  | 2  | 3  | 4  |
| 1                                                                                 | My mind is as sharp as it has always been 0                                                | 1  | 2  | 3  | 4  |
| 2                                                                                 | My memory is as good as it has always been 0                                               | 1  | 2  | 3  | 4  |
| I am able to shift back and forth between two activities  that require thinking 0 | 1                                                                                          | 2  | 3  | 4  |    |
| I am able to keep track of what I am doing, even if I am  interrupted 0           | 1                                                                                          | 2  | 3  | 4  |    |  
Please circle or mark one number per line **to indicate your response as it applies to** the past 7 days.  
FACT-Cog v3 Copyright 2006, 2016 Page 3 of 3 Last Revised 10 February 2008  
| Not                       | A little                                                                 |     |    |    |    |
|---------------------------|--------------------------------------------------------------------------|-----|----|----|----|
| IMPACT ON QUALITY OF LIFE | at all                                                                   | bit |    |    |    |
| CogQ35                    | I have been upset about these problems 0 0                               | 1   | 2  | 3  | 4  |
| CogQ37                    | These problems have interfered with my ability to  work 0 0              | 1   | 2  | 3  | 4  |
| CogQ38                    | These problems have interfered with my ability to  do things I enjoy 0 0 | 1   | 2  | 3  | 4  |
| CogQ41                    | These problems have interfered with the quality of  my life 0 0          | 1   | 2  | 3  | 4  |  
  
ASSESSMENT
imed up & go
fact-cog (version 3)

Purpose: To assess mobility Equipment: A stopwatch Directions: Patients wear their regular footwear and can use a walking aid, if needed. Begin by having the patient sit back in a standard arm chair and identify a line 3 meters, or 10 feet away, on the floor.  
  
② On the word "Go," begin timing.  
③ Stop timing after patient sits back down.  
❏ Record time.  
Time in Seconds:
An older adult who takes ≥12 seconds to complete the TUG is at risk for falling.  
CDC's STEADI tools and resources can help you screen, assess, and intervene to reduce your patient's fall risk. For more information, visit ywou.cdc.gov/steadi
imed up & go
appendix b guidelines for fertile

Fertile male patients, defined as all males physiologically capable of conceiving offspring with female partners of child-bearing potential, must use condoms plus spermicidal agent during the study treatment period and for 3 months after the last dose of Ra-223/Placebo, and should not father a child during this period. Male patients must also refrain from donating sperm during their participation in the study and for 3 months after the last dose of study drug. The following are acceptable forms of barrier contraception:
- Latex condom, diaphragm or cervical/vault cap when used with spermicidal foam/gel/film/cream/suppository  
| Appendix C: Schedule of Assessments Open-Label Period  Screening R1 Lead-in RT1   | Lead-in RT1                                               | Lead-in RT1         | Lead-in RT1        | Pre-R2a          | R2       |    |
|-----------------------------------------------------------------------------------|-----------------------------------------------------------|---------------------|--------------------|------------------|----------|----|
| Assessments                                                                       | (Day 1)                                                   | (Day 28)            | (Day 56)           | (Day 84)         |          |    |
| -42 to -2 days                                                                    | After R1 and                                              |                     |                    |                  |          |    |
| prior to R1                                                                       | before 1st dose  of RT1                                   | 28 days +/- 7 days  | 56 days +/- 7 days | 84 days + 7 days | At 12-16 |    |
| from Day 1                                                                        | from Day 1                                                | from Day 1          | weeks              |                  |          |    |
| after starting  RT1                                                               | Final I/E review completed at least 48  hours prior to R2 |                     |                    |                  |          |    |
| Tests and Observations Informed Consent                                           | X                                                         |                     |                    |                  |          |    |
| I/E Review (to be completed  at least 48 hours prior to  each randomization).     | X                                                         | Review Inc. #12-15. |                    |                  |          |    |
| Demographics                                                                      | X                                                         |                     |                    |                  |          |    |
| Medical History                                                                   | X                                                         |                     |                    |                  |          |    |
| Prostate Cancer History                                                           | X                                                         |                     |                    |                  |          |    |
| Physical Exam (PE)                                                                | X                                                         |                     |                    |                  |          |    |
| Abbreviated PE                                                                    | X                                                         |                     |                    |                  |          |    |
| Vital Signsb                                                                      | X                                                         | X                   |                    |                  |          |    |
| Adverse Event Evaluation                                                          | X                                                         | X                   | X                  | X                | X        | X  |
| Relevant Prior Medication                                                         | X                                                         |                     |                    |                  |          |    |
| Revieww Concomitant Medication                                                    | X                                                         | X                   |                    |                  |          |    |
| Review Randomization(s)                                                           | Xs                                                        | Xs                  |                    |                  |          |    |
| Bone Fracture Risk                                                                | X                                                         |                     |                    |                  |          |    |
| Assessmentc CANTAB Practice                                                       | Xu                                                        |                     |                    |                  |          |    |
| CANTAB Assessmentsx                                                               | Xt                                                        | X                   |                    |                  |          |    |
| TUG (timed up and go)                                                             | Xt                                                        | X                   |                    |                  |          |    |
| ECOG PS                                                                           | X                                                         | Xt                  | X                  |                  |          |    |
| FACT-P                                                                            | Xt                                                        | X                   |                    |                  |          |    |
| FACT-COG                                                                          | Xt                                                        | X                   |                    |                  |          |    |
| 12-lead ECG                                                                       | X                                                         | X                   |                    |                  |          |    |
| Use of other anti-cancer                                                          | X                                                         |                     |                    |                  |          |    |
| therapies                                                                         | Confidential                                              |                     |                    |                  |          |    |
| STUDY DRUG: RADIUM-223                                                            |                                                           | PC18-1005           |                    |                  |          |    |
| Final Protocol: 04 MAY 2020                                                       |                                                           | VERSION 1.2         |                    |                  |          |    |  
| Open-Label Period                                                                          | Screening                                                 | R1                 | Lead-in RT1        | Lead-in RT1      | Lead-in RT1   | Lead-in RT1   | Pre-R2a        | R2   |
|--------------------------------------------------------------------------------------------|-----------------------------------------------------------|--------------------|--------------------|------------------|---------------|---------------|----------------|------|
| Assessments                                                                                | (Day 1)                                                   | (Day 28)           | (Day 56)           | (Day 84)         |               |               |                |      |
| -42 to -2 days                                                                             | After R1 and                                              |                    |                    |                  |               |               |                |      |
| prior to R1                                                                                | before 1st dose  of RT1                                   | 28 days +/- 7 days | 56 days +/- 7 days | 84 days + 7 days | At 84-112     |               |                |      |
| from Day 1                                                                                 | from Day 1                                                | from Day 1         | days               |                  |               |               |                |      |
| after starting  RT1                                                                        | Final I/E review completed at least 48  hours prior to R2 |                    |                    |                  |               |               |                |      |
| Lab Observations CBC, 3-part differential, and                                             | X                                                         | X                  | Review Inc. 15     |                  |               |               |                |      |
| plateletsd,aa CMPe,aa                                                                      | X                                                         | X                  | Review Inc. 15     |                  |               |               |                |      |
| PSAaa                                                                                      | X                                                         | Xo                 | Xo                 | Xo               | Xo            | X             | Review Inc. 12 |      |
| LDHaa                                                                                      | X                                                         | X                  |                    |                  |               |               |                |      |
| ALPaa                                                                                      | X                                                         | X                  |                    |                  |               |               |                |      |
| Research Biomarkersq,aa                                                                    | X                                                         | X                  |                    |                  |               |               |                |      |
| , (Optional consent) Treatments Bone Health Agent                                          | X                                                         | X                  | Review Inc. 14     |                  |               |               |                |      |
| administrationt All subjects : Write Enza  prescription/and begin  insurance qualification | X                                                         |                    |                    |                  |               |               |                |      |
| Enza Compliance (or) Daro Dispensing/  Accountability                                      | X                                                         | X                  | X                  | X                | X             | X             | Review Inc. 14 | X    |
| Staging                                                                                    | X                                                         | Xp                 | Review Inc. 13     |                  |               |               |                |      |
| CT or MRI Scan of the  chest/ abdomen/pelvisf MRI or CT scan of the braing                 | X                                                         |                    |                    |                  |               |               |                |      |
| Bone Scanf                                                                                 | X                                                         | Xp                 |                    |                  |               |               |                |      |
| RECIST Assessment                                                                          | Xac                                                       | Review Inc. 13     |                    |                  |               |               |                |      |
| PCWG3 Assessment                                                                           | Xac                                                       | Xac                |                    |                  |               |               |                |      |
| Bone fracturesh                                                                            | X                                                         | X                  | X                  | X                | X             |               |                |      |
| Symptomatic Skeletal                                                                       | X                                                         | X                  | X                  | X                | X             |               |                |      |
| Events                                                                                     |                                                           |                    |                    |                  |               |               |                |      |  
Final Protocol: 04 MAY 2020 VERSION 1.2 Page 92 of 102  
| Double-Blind Period                          | RT2                                                             | RT2                 | Telephone End of   | Q12-Week Progression   | Overall   | End of Study   |
|----------------------------------------------|-----------------------------------------------------------------|---------------------|--------------------|------------------------|-----------|----------------|
| Cycles 1-6                                   | Imaging                                                         | Study Drugi         | Follow-upj         | Survivalk              |           |                |
| Assessments                                  | Q28 days                                                        | Q12 weeks           |                    |                        |           |                |
| ±7 days, from previous dosen                 | ±1 week,  from C1D1 through Cycle 6, or  until Q12 week Prog FU | Q12 weeks           | Q24 weeks          | At time of             |           |                |
| ±1 week                                      | ±4 weeks                                                        | Permanent Study  DC |                    |                        |           |                |
| Tests and Observations Abbrev. Physical Exam | Xab                                                             |                     |                    |                        |           |                |
| Vital Signsb                                 | X                                                               | X                   |                    |                        |           |                |
| Adverse Event Evaluation                     | X                                                               | X                   | X                  | Xl                     | Xl        | Xl             |
| Concomitant Medication                       | X                                                               | X                   | X                  |                        |           |                |
| Review SSE Assessment                        | X                                                               | X                   | X                  | X                      |           |                |
| Survival Status                              | X                                                               | X                   | X                  |                        |           |                |
| TUG (timed up and go)                        | Xz                                                              |                     |                    |                        |           |                |
| ECOG PS                                      | X                                                               | Xz                  |                    |                        |           |                |
| 12-lead ECG                                  | Xz                                                              |                     |                    |                        |           |                |
| RECIST and PCWG3                             | X                                                               | X                   |                    |                        |           |                |
| assessment Bone fractures and                | X                                                               | X                   | X                  | X                      |           |                |
| AESI assessmenth Use of other anti-cancer    | X                                                               | X                   | X                  | X                      |           |                |
| therapies                                    |                                                                 |                     |                    |                        |           |                |  
Final Protocol: 04 MAY 2020 VERSION 1.2  
Page 93 of 102  
| Double-Blind Period  Assessments                                                    | RT2                 | RT2                 | End of    | Q12-Week Progression   | Overall   | End of Study   |
|-------------------------------------------------------------------------------------|---------------------|---------------------|-----------|------------------------|-----------|----------------|
| Study Drugi                                                                         | Follow-upj          | Survivalk           |           |                        |           |                |
| Cycles 1-6                                                                          | Imaging             |                     |           |                        |           |                |
| Q28 days                                                                            | Q12 weeks           |                     |           |                        |           |                |
| ±7 days, from previous dosen                                                        | ±1 week,  from C1D1 | Q12 weeks           | Q24 weeks | At time of             |           |                |
| ±1 week                                                                             | ±4 weeks            | Permanent Study  DC |           |                        |           |                |
| Laboratory Observations CBC, 3-part differential, and                               | Xy                  | X                   |           |                        |           |                |
| plateletsd CMPe                                                                     | Xy                  | X                   |           |                        |           |                |
| PSA                                                                                 | Xy                  | X                   |           |                        |           |                |
| LDH                                                                                 | Xy                  | X                   |           |                        |           |                |
| ALP                                                                                 | Xy                  | X                   |           |                        |           |                |
| Research Biomarkersq                                                                | X                   | X                   |           |                        |           |                |
| (Optional consent) Treatments Enza Compliance (or) Daro Dispensing/  Accountability | Xm                  | Xm                  | Xm        |                        |           |                |
| RT2 : Ra-223 or Placebo                                                             | Xn                  |                     |           |                        |           |                |
| Staging CT or MRI Scan of the                                                       | X                   | X                   |           |                        |           |                |
| chest/ abdomen/pelvisf Bone Scanf                                                   | X                   | X                   |           |                        |           |                |
| Final Assessments Reason for Discontinuation                                        | X                   |                     |           |                        |           |                |
| Study Disposition                                                                   | X                   |                     |           |                        |           |                |
| Public Records Search                                                               | X                   |                     |           |                        |           |                |  
Final Protocol: 04 MAY 2020 VERSION 1.2 Page 94 of 102
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appendix c schedule of assessments

a Only done if ≥ 30% PSA decline during the initial 12 weeks of RT1 exposure.  
b Vital signs will include height (first visit only), weight, resting heart rate, blood pressure, respiratory rate, and oral temperature)
c The bone fracture risk assessment includes a history of prior fractures, comorbidities, history of androgen deprivation therapy, history of prior bisphosphonate/denosumab use, prior bone density assessment (most recent bone density assessment prior to screening), and any relevant prior and ongoing medications.  
d CBC includes hemoglobin, hematocrit, white blood cell (WBC) with 3-part differential and platelets. It must be done within 14 days prior to each Ra-223 cycle to determine safety of proceeding with each cycle.  
e CMP will include measurements of glucose, blood urea nitrogen (BUN), creatinine, estimated creatinine clearance (CockcroftGault), sodium, potassium, chloride, calcium, carbon dioxide (CO2), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, total protein, and albumin. CMP may be done up to 14 days prior to RT2 cycles.  
f A Screening CT or MRI scan (of the chest, abdomen, and pelvis) and bone scan will be performed within 42 days prior to LeadIn RT1 therapy. After Cycle 1, Day 1 (C1D1), assessments will occur every 12 weeks (+/- 7 days) after C1D1 irrespective of treatment delays, and will continue until the patient experiences radiological progression or initiates a prohibited treatment. All radiographic scans (CT, MRI and bone scans) will be collected and held by MANA RBM.  
g MRI or CT scan of the brain ≤4 weeks required at screening only if clinically indicated h Patients will be followed for all bone fractures throughout the course of the study.  
i Patients should visit the site 30 days (±7 days) after the last dose of radium-223/placebo and 30 days (±7 days) after the last dose of enzalutamide/darolutamide. Patients must be followed for all AEs/AESI's for 30 calendar days after the last dose of radium-223/placebo and enzalutamide/darolutamide irrespective of the visit date.  
j Patients who discontinue Ra-223 randomized treatment prior to progression or starting prohibited treatment will have progression follow-up visits every 12 weeks (±7 days) according to their original radiology schedule to determine disease progression. Patients enter Overall Survival Follow-up after documented radiological progression or initiation of a prohibited treatment.  
k Patients will be followed every 6 months (±1 month) after the last Q12-Week Imaging Visit is performed (during randomized treatment or during follow-up) for survival status (e.g., date and cause of death) until the required number of events have been reached in the study or death, whichever occurs first. Provider or telephone visits are allowed.  
l Only adverse events identified by the site investigator as SSE-related AEs, and Adverse Events of Special Interest (Section 14.1.2, 14.2.2) are to be reported after the end of Study drug treatment assessment.  
m RT1 will be taken during the 12 weeks prior to RT2 randomization and continue to be taken throughout the 6 cycles of RT2 treatment and thereafter. Post Ra-223 or placebo, patients may continue to receive RT1 until no longer clinically beneficial or until contraindicated.  
n C1D1 must occur ≤14 days after RT2 randomization. Ideally, radium-223 or placebo should be administered every 28 days (+/-
7 days) from the preceding dose after the C1D1. Subsequent cycles must be within >3 weeks and <8 weeks from last cycle.  
Delays are allowed to manage treatment-limiting toxicities or other limitations. Safety assessments needed before each cycle should be done within 14 days of the next cycle.  
o PSA will be monitored every 28 days (+/- 7 days) from RT1 initiation during the 84-day (12 week) lead-in phase of the study.  
p Scans will be done at Pre-R2 ONLY for patients who demonstrate ≥ 30% PSA decline during the initial 12 weeks of RT1 exposure. Window for obtaining repeat scans is within 28 days prior to RT2 randomization.  
q If consented to optional research blood biomarkers, optional samples may be collected at screening (Pre-RT1), Pre-R2, and at the time of radiological progression or prior to initiating a prohibited treatment, whichever occurs earlier.  
r Laboratory assessments do not need to be repeated on Cycle 1 Day 1 if performed within the prior 14 days. Labs may be collected up to 14 calendar days prior to Ra-223 cycles. s R1 randomization is only done after all inclusion/exclusion criteria are satisfied. R2 randomization is only done if all (4) R2 randomization conditions are met.  
t To be completed before taking first dose of enzalutamide or darolutamide. u Cantab and ePRO practice to be done at screening to familiarize the patient with the iPad technologies used, and with testing instructions.  
w Prior anticancer/relevant medication and procedure history review- including history of androgen deprivation therapy, orchiectomy, history of prior bisphosphonate/ denosumab use, vitamin D, calcium, anticancer medications, and exclusionary medications x A battery of CANTAB Cognitive Function Tests.  
y Repeat Labs are not needed for Cycle 1, Day 1, if they were drawn at Pre-R2 visit within 14 days of C1D1.  
z Should be performed Q48 weeks after C1D1. aa Should be done </= 14 days prior to Lead-in RT1 visit ab Only required at C4D1.  
ac Screening PCWG3 and Pre-R2 RECIST/PWG3 may be done any time prior to first Q12Week imaging visit. Only required to be done if ALL inclusion and exclusion criteria are met and subject is randomized to Ra-223 or Placebo.  
Final Protocol: 04 MAY 2020 VERSION 1.2 Page 95 of 102
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appendix d response evaluation criteria

| will not be used, as it does not provide additional meaning or accuracy. Baseline Eligibility Measurable Disease: Tumor lesions: Must be accurately measured in at least one dimension  (longest diameter in the plane of measurement is to be recorded) with a  minimum size of: - 10 mm by CT (CT scan slice thickness no greater than 5 mm). - 10 mm caliper measurement by clinical exam (lesions that cannot be  accurately measured with calipers should be recorded as nonmeasurable). - 20 mm by chest x-ray. Skin lesions: Documentation by color photography, including a ruler to  estimate the size of the lesion, is recommended. Malignant lymph nodes: To be considered pathologically enlarged and  measurable, a lymph node must be ≥15 mm in short axis when assessed by  CT scan. At baseline and in follow-up, only the short axis will be measured  and followed.  Non-Measurable Disease: All other lesions, including small lesions (longest diameter <10 mm or  pathological lymph nodes with ≥10- to <15-mm short axis) as well as truly  non-measurable lesions. Lesions considered truly non-measurable include:  leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory  breast disease, lymphangitic involvement of skin or lung, abdominal masses,  and abdominal organomegaly identified by physical exam that is not  measurable by reproducible imaging techniques. Target Lesions: The most reproducible measurable lesions, up to a maximum of 2 lesions per  organ and 5 lesions in total, representative of all involved organs should be  identified as target lesions and recorded and measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the  longest diameter), should be representative of all involved organs, and in  addition should be those that lend themselves to reproducible repeated  measurements. Pathological nodes which are defined as measurable and that  may be identified as target lesions must meet the criterion or a short axis of  ≥15 mm by CT scan. A sum of the diameters (longest for non-nodal lesions, short axis for nodal  lesions) for all target lesions will be calculated and reported as the baseline  sum diameters. If lymph nodes are to be included in the sum, then as noted  above, only the short axis is added into the sum. The baseline sum diameters  will be used as reference to further characterize any objective tumor  response.Confidential STUDY DRUG: RADIUM-223 PC18-1005 Final Protocol: 04 MAY 2020 VERSION 1.2 Page 96 of 102   |
|---|  
| Non-Target Lesions:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | All other lesions should be identified as non-target lesions at baseline.  Measurements of these lesions are not required, but the presence or absence  of each should be noted throughout follow-up.   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Guidelines for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation, using a ruler or calipers. All baseline evaluations  should be performed as closely as possible to the beginning of treatment, as per protocol screening requirements. The same method of assessment and the same technique should be used to characterize each identified and reported  lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination  when both methods have been used to assess the anti-tumor effect of a treatment. Clinical Lesions: Clinical lesions will only be considered measurable when they are superficial  (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter. In  the case of skin lesions, documentation by color photography, including a  ruler to estimate the size of the lesion, is recommended. Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are  clearly defined and surrounded by aerated lung. However, a CT scan is  preferable. Conventional CT and MRI: CT, MRI: CT is the best currently available and reproducible method to  measure lesions selected for response assessment. This guideline has defined  measurability of lesions on CT scan based on the assumption that CT slice  thickness is 5mm or less. When CT scans have slice thickness greater than  5 mm, the minimum size for a measurable lesion should be twice the slice  thickness. MRI is also acceptable in certain situations (e.g. for body scans).  Ultrasound: When the primary study endpoint is objective response, ultrasound should  not be used to measure tumor lesions. It is, however, a possible alternative to  clinical measurements of superficial palpable lymph nodes, subcutaneous  lesions, and thyroid nodules. Ultrasound may also be useful to confirm the  complete disappearance of superficial lesions usually assessed by clinical  examination. Endoscopy and Laparoscopy: Use of endoscopy and laparoscopy for objective tumor evaluation has not yet  been fully and widely validated. Therefore, use of these techniques for  objective tumor response should be restricted to validation purposes in  specialized centers. Such techniques can be useful in confirming complete  pathological response when biopsies are obtained. Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are  initially above the upper limit of normal, they must normalize for a patient to  be considered in complete clinical response when all lesions have  disappeared. Cytology and Histology: Cytology and histology can be used to differentiate between partial response  (PR) and complete response (CR) in rare cases (e.g., after treatment to  differentiate between residual benign lesions and residual malignant lesions  in tumor types such as germ cell tumors). |                                                                                                                                                                                                         |  
| Evaluation of Target Lesions Complete Response (CR):   | Disappearance of all target lesions.                                                                                                                                                                                                                                                   |
|--------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Partial Response (PR):                                 | At least a 30% decrease in the sum of diameters of target lesions, taking as  reference the baseline sum diameters.                                                                                                                                                                    |
| Stable Disease (SD):                                   | Neither sufficient shrinkage to qualify for PR nor sufficient increase to  qualify for PD, taking as reference the smallest (nadir) sum of diameters  since the treatment started.                                                                                                     |
| Progressive Disease (PD):                              | At least a 20% increase in the sum of the diameters of target lesions, taking  as reference the smallest (nadir) sum since the treatment started, or the  appearance of one or more new lesions. Requires not only 20% increase,  but absolute increase of a minimum of 5 mm over sum. |
| Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor  markers. All lymph nodes must be non-pathological in size (<<10 mm  short axis). Stable Disease (SD): Persistence of one or more non-target lesions and/or persistence of tumor  marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of  existing non-target lesions. When the patient also has measurable disease,  to achieve "unequivocal progression" on the basis of the non-target  disease, there must be an overall level of substantial worsening in nontarget disease such that, even in presence of SD or PR in the target disease,  the overall tumor burden has increased sufficiently to merit discontinuation  of therapy.                                                        |                                                                                                                                                                                                                                                                                        |
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evaluation of best overall response

As detailed above, the best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
Confirmation of response (by repeat scans after 4 weeks or as specified in the protocol) is required for studies in which response rate is the primary endpoint, but is not required in randomized studies or studies with primary survival endpoints (i.e., where response is not a primary endpoint).  
| Target Lesions              | Non-Target Lesions   | New Lesions   | Overall Response   |
|-----------------------------|----------------------|---------------|--------------------|
| CR                          | CR                   | NO            | CR                 |
| CR                          | SD                   | NO            | PR                 |
| CR                          | NE                   | NO            | PR                 |
| PR                          | SD OR NE             | NO            | PR                 |
| SD                          | SD OR NE             | NO            | SD                 |
| PD                          | ANY                  | YES OR NO     | PD                 |
| Confidential                |                      |               |                    |
| STUDY DRUG: RADIUM-223      |                      | PC18-1005     |                    |
| Final Protocol: 04 MAY 2020 |                      | VERSION 1.2   |                    |
| Page 98 of 102              |                      |               |                    |  
| Target Lesions   | Non-Target Lesions   | New Lesions   | Overall Response   |
|------------------|----------------------|---------------|--------------------|
| ANY              | PD                   | YES OR NO     | PD                 |
| ANY              | ANY                  | YES           | PD                 |  
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the evaluation of a CR depends upon this determination, it is recommended that the residual lesion be investigated by fine needle aspirate or biopsy to confirm the CR status. When nodal disease is included in the sum of target lesions, and the nodes decrease to "normal" size (<10 mm), they may still have a measurement reported on scans. This measurement should be recorded even though the nodes are normal in order not to overstate progression, should it be based on increase in size of the nodes. As noted earlier, this means that patients with CR may not have a total sum of "zero" on the eCRF.
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pcwg3 bone scan disease progression

Appearance of 2 or more new lesions on bone scan, and, for the first reassessment only, a confirmatory scan performed 6 or more weeks later that shows a minimum of 2 or more additional new lesions (2+2 rule). The date of progression is the date of the first scan that shows the change. Or Soft tissue disease progression by modified RECIST v1.1 to report changes in lymph nodes that were ≥ 2 cm in diameter at baseline with additional requirement that progression at first assessment be confirmed by a second scan 6 or more weeks later. Note that for some treatments, a lesion may increase in size before it decreases.  
  
For eligibility based on prostate-specific antigen (PSA) changes (Inc \#7a) use the diagram above for guidance on how to determine if the criterion "series of rising PSA" has been met. "Series" will refer to more than 1 rising value.  
For the purposes of this protocol, the reference value (\#1) will be the nadir PSA (1st PSA), with subsequent values obtained a minimum of 1 week apart. In the diagram above, \#2 (2nd PSA)
represents an example of the first increase in PSA after nadir. If the 3rd PSA (example \#3A) is greater than \#2, and total rise from nadir is >1 ng/mL, then eligibility has been met.  
If the 3rd PSA (example \#3B) is not higher than \#2, but value \#4 is, the patient is eligible if \#4 is 1 ng/mL or higher than nadir PSA (\#1).
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appendix e remote risk based

All data and essential documents are collected electronically directly or converted to certified electronic copies. Data and documents are reviewed remotely using the following methodology:
1. Risk Assessment- the study team will conduct a Risk Assessment to identify the errors that matter (i.e., errors that affect primary endpoints, human subject protection, subject safety, GCP, and investigational product management). Each risk is categorized by Impact, Likelihood of Occurring, and Ability to Detect. A risk score is derived for each risk. For risks with a score of 75 or above, an oversight approach, usually an analytic report, is developed to monitor those risks.  
2. Assuring data sources for all errors that matter: the study team will review all data needed to perform Errors that Matter Analytics and will assure that the data are collected in one of the electronic systems. Usually the data will be captured in the EDC, Site Tracker Analyzing Risk Database (STAR Database), or REACHER, but other data sources may be used to collect the critical data needed for the analysis of Errors that Matter 3. Developing Errors that Matter Analytics—following identification of all high risks (score of 75 or above) and major deviations that affect analysis or subject safety, study specific analytic reports are designed, programmed, and validated. The analytic reports are listed in the Study Report Specifications Document. The number of the report is mapped to the Risk Assessment to provide traceability between the Risk and Oversight.  
4. Automating complex analytics--Complex analytics are automated through REACHERTM, the MANA RBM clinical quality management system. This set up includes designing workflow and decision support notifications that result from the analytics. Additional oversight reports are also developed in JReview including the Subject Profile Analyzing Risk (SPARTM), which provides a comprehensive subject specific view of critical data for efficacy and safety data across all timepoints, normalized to first date of treatment.  
5. Developing Data and Document Review Guidelines (DDRG)—The data and document review guidelines map the review of all critical data and documents by reviewer and report number. The DDRGs define the review by all oversight members, regardless of role (e.g., data reviewer, site monitor, central monitor, medical monitor). The frequency of review is included in the DDRG. Confirmation of critical data for recruitment or efficacy may be confirmed by a comparison of certified copies of document when compared to data entered in the data collectors, but traditional SDV or page by page eCRF review is not performed.  
6. Training of study team members is performed following completion of analytic reports and the DDRGs. It includes training on the data collection system specific for the trial and all reports that will be used for oversight by each role.  
7. Review of data for errors that matter is conducted independent of the EDC using REACHER analytic reports or JReview, which combine data across databases. Review of documents is conducted in the eTMF/eISF. Documentation of review is completed in the Site Tracker Analyzing Risk Database (STAR) or REACHER.  
8. Trend analysis--Monthly the central monitor and lead data manager review all trends in errors that matter, issues, major deviations, screening, reason for screen failure, reason for early termination, site performance, reviewer performance, query topics, and document review. Trends are reviewed with the Site Monitor who provides feedback monthly to the Site Investigators and Study Coordinators.