BAY88-8223/15396

Bayer AG

Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

No

No

No

Interim

31 Oct 2019

No

No

The primary objective of this study was to compare, in subjects with asymptomatic or mildly symptomatic chemotherapy-naïve bone-predominant metastatic CRPC, the clinical benefit of radium-223 dichloride versus placebo in combination with abiraterone and prednisone/prednisolone.

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

30 Mar 2014

Yes

Yes

Australia: 55

Belgium: 7

Canada: 51

Germany: 25

Spain: 72

Finland: 14

France: 29

United Kingdom: 64

Italy: 52

Netherlands: 5

Norway: 8

Sweden: 13

United States: 90

Israel: 59

Japan: 114

Singapore: 40

Brazil: 51

Poland: 28

Russian Federation: 29

806

317

0

0

0

0

0

0

167

601

38

Overall Study (overall period)

Randomised - controlled

Yes

Abiraterone acetate

Tablet

Oral use

Subjects received abiraterone acetate tablets 1000 milligrams (mg) every day until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Radium-223 dichloride

BAY88-8223

Solution for injection

Intravenous use

Subjects received 6 IV administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of NIST update) at intervals of 4 weeks.

Prednisone/prednisolone

Tablet

Oral use

Subjects received 5 mg prednisone/prednisolone twice daily until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Abiraterone acetate

Tablet

Oral use

Subjects received abiraterone acetate tablets 1000 milligrams (mg) every day until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Prednisone/prednisolone

Tablet

Oral use

Subjects received 5 mg prednisone/prednisolone twice daily until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met).

Placebo

Solution for injection

Intravenous use

Subjects received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks.

Radium-223 dichloride + Abi/Pred

Placebo + Abi/Pred

Radium-223 dichloride + Abi/Pred

Placebo + Abi/Pred

Intent-to-treat analysis set (ITT)

Included all randomized subjects.

Safety analysis set (SAF)

Included all randomized subjects who received at least one dose of any study drug.

SSE-FS was defined as time (months) from randomization to the earliest of onset date of skeletal symptoms treated with external beam radiotherapy (EBRT), onset date of pathological bone fracture, onset date of spinal cord compression, procedure date of tumor-related orthopedic surgery, or death from any cause. Subjects who died without prior SSE and ≥ 13 weeks after the last SSE assessment are censored at the last SSE assessment date. Subjects alive at the survival cut-off date are censored at the last date known to be alive. Subjects with multiple events are only counted for the category in which the first event occurred. If multiple SSE (component events) occur on the same date for 1 subject, the subject is only counted into 1 category in the order of: spinal cord compression > bone fracture > orthopedic surgery > EBRT.

Primary

From randomization until first onset of on-study symptomatic skeletal event (SSE) or death, up to 47 months

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

806

Pre-specified

1.122

2-sided

OS was defined as the time (months) from the date of randomization to the date of death due to any cause. Subjects alive at the survival cut-off date were censored at the last date known to be alive. In the below table, "99999" indicates that upper limit cannot be estimated due to censored data.

Secondary

From randomization until death from any cause, up to 67 months

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

806

Pre-specified

1.151

2-sided

rPFS was defined as the time (months) from the date of randomization to the date of confirmed radiological progression or death (if death occurred before progression) based on independent assessment.

Secondary

From randomization until the date of confirmed radiological progression or death, up to 47 months

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

806

Pre-specified

1.152

2-sided

Time to pain progression was defined as the interval from randomization to the first date a subject experienced pain progression, assessed by BPI-SF (see Baseline Characteristics) and defined as: an increase of 2 or more points in the average worst pain score (WPS) from baseline observed at 2 consecutive evaluations >= 4 weeks apart or initiation of short- or long-acting opioid use for pain for subjects with WPS 0 at baseline; an increase of 2 or more points in the average WPS from baseline observed at 2 consecutive evaluations ≥ 4 weeks apart and an average WPS of ≥ 4 OR initiation of short- or long-acting opioid use for pain for subjects with WPS 1 to 3 at baseline. Subjects without pain progression at the end of study are censored at the last date known to have not progressed: the last evaluation date for pain scores or last visit when recorded opiate use, whichever is last. Subjects with no on-study assessment or no baseline assessment are censored at the date of randomization.

Secondary

From randomization until the date of pain progression based on pain score, up to 47 months

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

806

Pre-specified

1.145

2-sided

Time to cytotoxic chemotherapy is time (months) from randomization to the earliest date of the first cytotoxic chemotherapy. Subjects who have not started cytotoxic chemotherapy during the study were censored at the last assessment date. In the below table, "99999" indicates that upper limit cannot be estimated due to censored data.

Secondary

From randomization until the date of first cytotoxic chemotherapy, up to 47 months

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

806

Pre-specified

1.033

2-sided

Time to opiate use for cancer pain was defined as the interval from the date of randomization to the date of opiate use.

Secondary

From randomization until the date of opiate use, up to 47 months

Radium-223 dichloride + Abi/Pred v Placebo + Abi/Pred

790

Pre-specified

1.126

2-sided

An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. A serious adverse event (SAE) was any untoward medical occurrence that at any dose was resulting in death, was lifethreatening, requires hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity. AEs or SAEs occurring after start of study treatment until the end of the treatment period were defined as treatment-emergent AEs (TEAEs) or serious TEAEs. Drug-related TEAEs or serious TEAEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.

Secondary

From start of study treatment until the end of the treatment period, up to 65 months

An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. A serious adverse event (SAE) was any untoward medical occurrence that at any dose was resulting in death, was lifethreatening, requires hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity. AEs or SAEs occurring after start of study treatment until the end of the treatment period were defined as treatment-emergent AEs (TEAEs) or serious TEAEs. Radium-223/placebo-related TEAEs or serious TEAEs were those with "reasonable causal relationship" to radium-223 or placebo decided by the investigators.

Secondary

From start of study treatment until the end of the treatment period, up to 65 months

Treatment-emergent additional primary malignancies were adverse events identified as additional primary malignancies that occurred after start of study treatment until the end of the treatment period.

Secondary

From start of study treatment until 4 weeks after last study treatment, up to 65 months

Treatment-emergent fractures were adverse events identified as fractures that occurred after start of study treatment until the end of the treatment period. All bone fractures and bone-associated events (e.g., osteoporosis) were reported as either AEs, or SAEs if the criteria of SAE were met, regardless of the investigator’s causality assessment.

Secondary

From start of study treatment until 4 weeks after last study treatment, up to 65 months

An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. Any bleeding event occurring during the study was not documented as an AE because this event was planned to be captured in the assessment of efficacy. AEs that started after the treatment period were defined as post-treatment AEs. Drug-related AEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.

Secondary

After the treatment period, up to 46 months

An adverse event (AE) was any untoward medical occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a participant in the study. Any bleeding event occurring during the study was not documented as an AE because this event was planned to be captured in the assessment of efficacy. AEs that started after the treatment period were defined as post-treatment AEs. Drug-related AEs were those with "reasonable causal relationship" to the study treatment decided by the investigators.

Secondary

After the treatment period, up to 46 months

Post-treatment blood and lymphatic system disorders were adverse events identified as blood and lymphatic system disorders that occurred after the end of the treatment period until participant died, was lost to follow-up, withdrew informed consent, actively objected to collection of further data, or was transitioned to the extended safety follow-up study.

Secondary

After the treatment period, up to 46 months

Post-treatment fractures were adverse events identified as fractures that occured after the end of the treatment period until participant died, was lost to follow-up, withdrew informed consent, actively objected to collection of further data, or was transitioned to the extended safety follow-up study. All bone fractures and bone-associated events (e.g., osteoporosis), were reported as either AEs, or SAEs if the criteria of SAE were met, regardless of the investigator’s causality assessment.

Secondary

After the treatment period, up to 46 months

From start of study treatment to cut-off date 31-OCT-2019, which is about 67 months.

Adverse events (AEs) included any event arising or worsening from the start of the study treatment. All occurrences of additional malignancies, chemotherapy-related events, bone fractures and bone associated events were reported as AE regardless of the investigator’s causality assessment.

22.1

Placebo + Abi/Pred

Radium-223 dichloride + Abi/Pred