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Radium-223 Dichloride and Abiraterone Acetate Compared to Placebo and Abiraterone Acetate for Men With Cancer of the Prostate When Medical or Surgical Castration Does Not Work and When the Cancer Has Spread to the Bone, Has Not Been Treated With Chemotherapy and is Causing no or Only Mild Symptoms (ERA 223)

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ClinicalTrials.gov Identifier: NCT02043678
Recruitment Status : Active, not recruiting
First Posted : January 23, 2014
Results First Posted : March 5, 2019
Last Update Posted : May 7, 2020
Sponsor:
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Bayer

Brief Summary:
To determine if the addition of radium-223 dichloride to standard treatment is able to prolong life and to delay events specific for prostate cancer which has spread to the bone, such as painful fractures or bone pain which needs to be treated with an X-ray machine.

Condition or disease Intervention/treatment Phase
Prostatic Neoplasms Drug: Radium-223 dichloride (Xofigo, BAY88-8223) Drug: Matching placebo (normal saline) Drug: Abiraterone Drug: Prednisone/Prednisolone Phase 3

Detailed Description:
This study is a phase III multinational, multicenter,randomized, double blind, placebo controlled, study with a randomization allocation ratio of 1:1 (radium-223 dichloride plus abiraterone acetate plus prednisone/prednisolone: placebo plus abiraterone acetate plus prednisone/prednisolone). Until the final overall survival (OS) analysis, the study period consisted of screening / randomization, treatment, active follow-up with clinic visits, active follow-up without clinic visits, and longterm follow-up phases. Up until this point, subjects received study treatment (radium-223 dichloride or placebo in addition to abiraterone acetate plus prednisone / prednisolone for the first 6 cycles followed by abiraterone acetate plus prednisone / prednisolone thereafter) until an on-study SSE occurred (or other withdrawal criteria were met). After the final OS analysis (after implementation of Amendment 7), in order to reduce the burden to study subjects, evaluation of efficacy and exploratory endpoints will be discontinued, except for symptomatic skeletal event (SSE) and OS. Subjects who are discontinued from study treatment will initiate the long-term follow-up period; therefore, active follow-up periods will no longer be applicable. Subjects who are in active follow-up at the time of Amendment 7 is implemented should have the end of active follow-up completed (protocol driven decision) and should be directly transitioned into the extended safety follow-up study. Long term follow-up will continue until the subject dies, is lost to follow-up, withdraws informed consent, actively objects to collection of further data, or is transitioned to the extended safety follow-up study. Subjects will be followed for safety for up to 7 years, which eventually will be completed in the extended safety follow-up study.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 806 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase III Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride in Combination With Abiraterone Acetate and Prednisone/Prednisolone in the Treatment of Asymptomatic or Mildly Symptomatic Chemotherapy-naïve Subjects With Bone Predominant Metastatic Castration-resistant Prostate Cancer(CRPC)
Actual Study Start Date : March 30, 2014
Actual Primary Completion Date : February 15, 2018
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Radium-223 dichloride + Abi/Pred
Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met)
Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of NIST update) body weight, intravenous injection (IV-slow bolus), every 4 weeks for 6 cycles

Drug: Abiraterone
1000 mg once daily, oral, with best supportive care

Drug: Prednisone/Prednisolone
5 mg twice daily, oral, with best supportive care

Placebo Comparator: Placebo + Abi/Pred
Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met)
Drug: Matching placebo (normal saline)
Intravenous injection ( IV-slow bolus), every 4 weeks for 6 cycles

Drug: Abiraterone
1000 mg once daily, oral, with best supportive care

Drug: Prednisone/Prednisolone
5 mg twice daily, oral, with best supportive care




Primary Outcome Measures :
  1. Symptomatic Skeletal Event Free Survival (SSE-FS) [ Time Frame: From randomization until first onset of on-study symptomatic skeletal event (SSE) or death, up to 47 months ]
    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.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: From randomization until death from any cause, up to 47 months ]
    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.

  2. Radiological Progression Free Survival (rPFS) [ Time Frame: From randomization until the date of confirmed radiological progression or death, up to 47 months ]
    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.

  3. Time to Pain Progression [ Time Frame: From randomization until the date of pain progression based on pain score, up to 47 months ]
    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.

  4. Time to Cytotoxic Chemotherapy [ Time Frame: From randomization until the date of first cytotoxic chemotherapy, up to 47 months ]
    Time to cytotoxic chemotherapy is time (months) from randomization to the earliest date of the first cytotoxic chemotherapy. Participants who have not started cytotoxic chemotherapy during the study were censored at the last assessment date.

  5. Time to Opiate Use for Cancer Pain [ Time Frame: From randomization until the date of opiate use, up to 47 months ]
    Time to opiate use for cancer pain was defined as the interval from the date of randomization to the date of opiate use.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed adenocarcinoma of the prostate
  • Male subjects of age ≥ 18 years
  • Prostate cancer progression documented by prostate specific antigen (PSA) according to the Prostate Cancer Working Group 2 (PCWG2) criteria or radiological progression according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1
  • Two or more bone metastases on bone scan within 4 weeks prior to randomization with no lung, liver, other visceral and/or brain metastasis
  • Asymptomatic or mildly symptomatic prostate cancer
  • Subjects who received combined androgen blockade with an anti-androgen must have shown PSA progression after discontinuing the anti-androgen prior to enrollment
  • Maintenance of medical castration or surgical castration with testosterone less than 50 ng/dL (1.7nmol/L)
  • Eastern Cooperative Oncology Group performance status (ECOG PS) score 0 or 1

Exclusion Criteria:

  • Prior cytotoxic chemotherapy for the treatment of CRPC, including taxanes, mitoxantrone and estramustine
  • Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg prednisone/prednisolone twice daily
  • Pathological finding consistent with small cell carcinoma of the prostate
  • History of visceral metastasis, or presence of visceral metastasis detected by screening imaging examinations
  • History of or known brain metastasis
  • Malignant lymphadenopathy exceeding 3 cm in short-axis diameter
  • Blood transfusion or erythropoietin stimulating agents prior 4 weeks of screening and during the whole screening period before randomization
  • Imminent spinal cord compression based on clinical findings and/or magnetic resonance imaging (MRI). Subjects with history of spinal cord compression should have completely recovered
  • Use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime during the 4- week period prior to randomization.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02043678


Locations
Show Show 164 study locations
Sponsors and Collaborators
Bayer
Janssen Research & Development, LLC
Investigators
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Study Director: Bayer Study Director Bayer
  Study Documents (Full-Text)

Documents provided by Bayer:
Study Protocol  [PDF] April 3, 2018
Statistical Analysis Plan  [PDF] July 10, 2017


Additional Information:
Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02043678    
Other Study ID Numbers: 15396
2013-003438-33 ( EudraCT Number )
First Posted: January 23, 2014    Key Record Dates
Results First Posted: March 5, 2019
Last Update Posted: May 7, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Phase III
Radium-223 dichloride
Abiraterone acetate
Combination therapy
Chemotherapy-naive
Bone metastasis
Castration-resistant prostate cancer (CRPC)
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Prednisone
Prednisolone
Radium Ra 223 dichloride
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents