All patients will receive nCPAP at 5-6 cm H2O pressure with an oxygen concentration of 21% or more to maintain preductal saturation between 90% and 95%. Patients assigned to the active group will be treated with 0.15 mg/kg body weight (diluted in 3 mL 0.9% NaCl) nebulised salbutamol (Ventolin®, GlaxoSmithKline, Dublin, Ireland) for 30 min.

Patients assigned to the active group will be treated with 0.15 mg/kg body weight (diluted in 3 mL 0.9% NaCl) nebulized salbutamol (Ventolin®, GlaxoSmithKline, Dublin, Ireland) for 30 min.

Salbutamol

Patients in the placebo group will also receive nCPAP at 5-6 cm H2O pressure with an oxygen concentration of 21% or more to maintain preductal saturation between 90% and 95%. In addition, patients will receive 3 mL nebulised 0.9% NaCl administered for 30 min. as a placebo

3 mL nebulized 0.9% NaCl administered for 30 min.

0,9% Chloride Sodium

Patients receive radium Ra 223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.

Biopsy Procedure

Biospecimen Collection

Computed Tomography

Laboratory Biomarker Analysis

Magnetic Resonance Imaging

Olaparib

Quality-of-Life Assessment

Radium Ra 223 Dichloride

Patients receive radium Ra 223 dichloride as in Arm I. Patients with radiographic progression may crossover to Arm I. If patients have already completed all 6 infusions of radium, they will receive monotherapy with olaparib. If they have not yet completed all 6 radium-223 infusion, they will continue radium-223 infusion until completion and receive concurrent treatment with olaparib. Patients also undergo CT or MRI as well as blood sample collection and a tissue biopsy during screening and on study.

Patients receive radium-223 dichloride IV over 1 minute on day 1. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

Bone Scan

Questionnaire Administration

Patients receive radium-223 dichloride as in Arm A and peposertib PO or BID on days 3-26. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

Peposertib

Patients receive radium-223 dichloride IV as in Arm A and peposertib PO QD or BID as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 15 of cycles 2-6. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, and CT or MRI throughout the study.

Avelumab

Site Public Contact

Savita V. Dandapani

Anishka D'Souza

Nataliya Mar

Russ A. Kuker

Zin W. Myint

Hiram A. Gay

Edmund Folefac

Adanma Anji Ayanambakkam Attanathi

Umang Swami

Adult men with bone mCRPC having \< 6 bone metastases

Drug will be administered as aqueous solution intravenously at a dose of 55 kBq/kg body weight every 4 weeks for 6 cycles (cycle length = 4 weeks).

Radium-223 dichloride (Xofigo, BAY88-8223)

Adult men with bone mCRPC having ≥ 6 bone metastases

Trained village health workers (VHWs) in IA, provided behaviour change communication, treatment and referral. VHWs started treatment of HTN, diarrhoea, malaria, pneumonia, asthma and COPD by Amlodipine/Enalapril, ORS, tab-lets Norfloxacin, Chloroquine, Azithromycin, and Salbutamol Rotacaps/ tablet Der-riphylline respectively as per guidelines in villages. The VHW referred suspected TB patients to the hospital for early diagnosis and treatment un-der national TB program, and followed confirmed TB patients for completion of treatment. We started BCC about hypertension, tuberculosis, pneumonia, diarrhoea, malaria, asthma and COPD, in phase wise manner. The VHWs advised appropriate referrals to the some needy patients where they received standard hospital care. Contamination of the interventions were prevented as the IA and CA are different villages.

Unlike traditional vertical programs that focus on a single disease, this study utilizes Village Health Workers (VHWs) to manage a broad diseases spectrum in villages, ranging from chronic NCDs like Hypertension (Amlodipine) and COPD/Asthma (Salbutamol Rotacaps/Derriphylline) to acute infectious diseases like diarrhoea, malaria, pneumonia, requiring Norfloxacin, Chloroquine, and Azithromycin.

Key Differentiators

* Holistic Mortality Targeting: While most Cluster Randomized Controlled Trials (CRCTs) focus on maternal or child health, this study specifically targets the Adult Specific Mortality Rate (ASMR).
* Operational Sustainability: We combined Behavior Change Communication (BCC) with an integrated treatment and referral algorithm, a factor rarely captured in other intervention studies.
* Temporal Stability: The 18-year duration ensures the findings are not skewed by transient epidemics/ seasonal outbreaks, establishing a benchmark for scalable, long-term health system strengthening.

Trained village health workers (VHWs) , provided treatment of HTN, diarrhoea, malaria, pneumonia, asthma and COPD by Amlodipine, ORS, Norfloxacin, Chloroquine, Azithromycin, salbutamol rotacaps

The VHWs in control area provided appropriate referral.

Appropriate referral

This arm received appropriate referral and the standard care of treatment from hospital only. The VHWs did not provide treatment in villages.

Nicotinamide Riboside Chloride (Niagen) 75mg or 250mg capsules provided by ChromaDex, Inc. Dosing is recommended at 12.5mg/kg/day.

The dosing plan is as follows (in mg po qD):

20-25 kg 250mg; 25-30 kg 325mg; 30-35 kg 400mg; 35-40 kg 475mg; 40-45 kg 500mg; 45-50 kg 575mg; 50-55 kg 650mg; 55-60 kg 725mg; 60-65 kg 750mg; 65-70 kg 825mg; \>70 kg 900mg (max dosing).

The intervention consists of 6 months to 1 year of daily oral therapy with Nicotinamide Riboside Chloride (Niagen) in addition to standard therapy.

Nicotinamide Riboside Chloride

Standard of Care

Placebo 75mg or 250mg capsules provided by ChromaDex, Inc. Dosing is recommended at 12.5mg/kg/day.

The dosing plan is as follows (in mg po qD):

20-25 kg 250mg; 25-30 kg 325mg; 30-35 kg 400mg; 35-40 kg 475mg; 40-45 kg 500mg; 45-50 kg 575mg; 50-55 kg 650mg; 55-60 kg 725mg; 60-65 kg 750mg; 65-70 kg 825mg; \>70 kg 900mg (max dosing).

The intervention consists of 6 months to 1 year of daily oral therapy with placebo (Maltodextran capsules of similar size, shape and color as Niagen) in addition to standard therapy.

Placebo

Min Shi

Kevin P Mollen, MD

Patients receive enzalutamide PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive radium Ra 223 dichloride IV on day 1. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Enzalutamide

Patients receive enzalutamide as in Arm I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive radium Ra 223 dichloride IV over 1 minute on day 1 of cycles 1-6 and cabozantinib S-malate PO QD on days 1-28 of every cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and urine sample collection, bone scan, CT, or MRI, and may undergo FDG-PET or NaF-PET throughout the study.

Undergo blood and urine sample collection

Cabozantinib S-malate

Positron Emission Tomography

Patients receive cabozantinib S-malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and urine sample collection, bone scan, CT, or MRI, and may undergo FDG-PET or NaF-PET throughout the study.

Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and radium Ra 223 dichloride IV over 1 minute on day 1 of each cycle. Treatment with radium Ra 223 dichloride repeats every 28 days for 6 cycles and treatment with paclitaxel repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan, bone scan and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.

Electronic Health Record Review

Paclitaxel

Single Photon Emission Computed Tomography

Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan, bone scan, and/or MRI, as well as collection of blood samples throughout trial. Patients may optionally undergo SPECT on trial.

살부타몰, 0.9% 염화물 나트륨

생검 절차, 생체 시료 채취, 컴퓨터 단층 촬영, 실험실 생체 표지자 분석, 자기 공명 영상, 올라파립, 삶의 질 평가, 라듐 Ra 223 이염화물

아벨루맙, 생체 시료 채취, 골 스캔, 컴퓨터 단층 촬영, 자기 공명 영상, 페포서팁, 설문 조사, 라듐 Ra 223 이염화물

라듐-223 이염화물(Xofigo, BAY88-8223)

니코틴아미드 리보사이드 염화물, 위약, 표준 치료

엔잘루타미드, 실험실 생체지표 분석, 라듐 Ra 223 이염화물

생체 시료 채취, 골 스캔, 카보잔티닙 S-말레이트, 컴퓨터 단층 촬영, 자기 공명 영상, 양전자 방출 단층 촬영, 설문 조사, 라듐 Ra 223 이염화물

생체 시료 채취, 골 스캔, 컴퓨터 단층 촬영, 전자 건강 기록 검토, 자기 공명 영상, 파클리탁셀, 라듐 Ra 223 이염화물, 단일 광자 방출 컴퓨터 단층 촬영