Method Article

Bawei Aiguning Granules For Lung Cancer Bone Metastases: A Randomized, Double-blind, Placebo-Controlled Trial Protocol With A Representative Case

DOI:

10.3791/69906

⸱

June 12th, 2026

 ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  , 
1Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 2Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, 3Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine

In This Article

Summary

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This protocol describes a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate Bawei Aiguning Granules as an adjunctive intervention for skeletal-related events in patients with lung cancer bone metastases. It also presents currently available descriptive observations from a representative participant.

Abstract

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Bone metastases (BM) frequently lead to skeletal-related events (SREs) and significant pain in lung cancer patients, requiring more effective supportive management strategies. We designed a prospective, multicenter, randomized, double-blind, placebo-controlled trial to evaluate Bawei Aiguning Granules (BWAGN) in combination with standard bone-targeted therapy. A total of 156 patients will be randomized across six centers. The primary endpoint is the 1-year incidence of SREs. Secondary endpoints include time to first SRE, pain assessment, quality of life, survival, Traditional Chinese Medicine symptom score, and bone turnover markers. Safety will be assessed according to Common Terminology Criteria for Adverse Events v5.0. Alongside the trial protocol, this manuscript presents currently available descriptive observations from a representative participant. During follow-up, no SREs were documented, and serial Electron Computed Tomography (ECT) examinations showed no obvious new imaging abnormalities suggestive of bone progression or SRE-related change. Functional status, symptom burden, and tumor markers showed favorable changes over time, while routine safety assessments remained generally stable, with no adverse events or serious adverse events recorded. These observations are descriptive only and should be interpreted with caution. Definitive conclusions regarding efficacy and safety will require completion of the protocol-defined follow-up and formal analysis of the full study cohort.

Introduction

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Lung cancer is the most common malignant tumor worldwide and remains the leading cause of cancer-related deaths, with approximately 2.5 million new cases and 1.8 million deaths annually1,2. Its high mortality rate is primarily attributed to distant metastasis3, with bone being one of the most common sites of metastasis. Approximately 30–40% of patients develop BM during their disease course4,5,6. Once BM occurs, the median survival of patients is approximately 9 months4,7,8. The occurrence of SREs, including severe bone pain, pathologic fractures, spinal cord compression, and hypercalcemia, further reduces survival to about 7 months while severely compromising patients' quality of life (QoL) and treatment adherence9,10,11.

Current therapeutic strategies for BM from lung cancer mainly include bisphosphonates, denosumab, radiotherapy, surgery, and supportive care12. Although current bone-targeted therapies reduce skeletal complications, they have limitations in incomplete symptom control with potential adverse effects, and a high economic burden13,14,15,16. Consequently, there remains an urgent need for novel, effective, and well-tolerated adjunctive treatments to improve patient outcomes.

Traditional Chinese Medicine (TCM) has long been used as an adjunct therapy in cancer treatment, with its role in symptom control and immune modulation increasingly supported by evidence17,18,19,20. Bawei Aiguning Granules (BWAGN) consists of eight botanical drugs: Astragali Radix (Huang-qi), Notoginseng Radix et Rhizoma (San-qi), Drynariae Rhizoma (Gu-sui-bu), Ligustri Lucidi Fructus (Nv-zhen-zi), Moutan Cortex (Mu-dan-pi), Clematidis Radix et Rhizoma (Wei-ling-xian), Spatholobi Caulis (Ji-xue-teng), and Phellodendri Chinensis Cortex (Huang-bai). According to TCM therapeutic principles, this combination of herbs exerts synergistic effects by tonifying the kidney, strengthening the spleen, promoting meridian circulation, and alleviating pain. Accordingly, the formula is proposed to restore bone metabolic balance and modulate the tumor microenvironment, and relieve cancer-associated pain.

Compared to existing therapeutic alternatives that primarily target osteoclast activity12, the active compounds in the herbal formula of BWAGN are anticipated to exert multi-targeted benefits by restoring bone metabolic equilibrium whilst simultaneously modulating the tumor microenvironment21,22. Furthermore, unlike other TCM interventions such as acupuncture or rehabilitation, which require frequent in-person visits and lack standardization, the use of standardized BWAGN facilitates multicenter implementation and ensures rigorous dosing control23,24,25.

However, high-quality randomized controlled trials (RCTs) evaluating the efficacy and safety of TCM interventions for lung cancer patients with BM remain scarce26,27. To address this gap, we designed a prospective, multicenter, randomized, double-blind, placebo-controlled trial to systematically evaluate whether BWAGN can reduce the incidence of SREs within one year, delay the time to first SRE, alleviate bone-related pain, and improve patients’ quality of life, while maintaining a favorable safety profile. This study also seeks to provide robust clinical evidence for the integration of BWAGN as an adjunctive therapy in the management of lung cancer BM, thereby promoting the standardized application of TCM in this field and enhancing clinicians' and the public's awareness of its value.

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Protocol

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This study complies with the Declaration of Helsinki (2024 version) and the Good Clinical Practice (GCP) guidelines. Ethical approval has been obtained from the Ethics Committee of Longhua Hospital, Shanghai University of TCM (Approval number: 2023LCSY099), and the trial has been registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR2400080798). Written informed consent was obtained from all participants, and their rights and privacy were fully protected.

A prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial has been designed. Participating centers include Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Longhua Hospital, Shanghai Chest Hospital, Shanghai Pulmonary Hospital, Putuo District Central Hospital, and Shanghai Seventh People’s Hospital. A total of 156 participants will be enrolled using competitive recruitment. The flowchart is shown in Figure 1.

1. Study design

  1. Sample size calculation
    1. Calculate the required sample size of 71 participants per group using PASS 11.0 software, setting the significance level at α = 0.05 and a power of 1−β = 0.80.
    2. Assume BWAGN reduces the incidence of SREs in lung cancer BM patients from 46% to 26%28,29,30,31, and set the final total sample size at 156 participants after adjustment for a 10% dropout rate.
  2. Randomization and blinding implementation
    1. Use a central dynamic minimization randomization algorithm via the Clinical Research Integrated Service Platform (CRISP) from Shanghai Clinical Research Center.
    2. Stratify randomization based on systemic treatment (chemotherapy/targeted therapy/immunotherapy), duration of BM (newly diagnosed/≤3 months/>3 months), and bone-targeted therapy (zoledronic acid/denosumab).
    3. Adopt a double-blind design where independent statisticians ensure that the study drugs and placebos are identically packed and mask package numbers. Generate drug codes by the CRISP system and allocate them by independent dispensing staff to ensure patients, investigators, monitors, and outcome assessors are blinded throughout the trial.
    4. Perform emergency unblinding only in the event of severe adverse events (SAEs) or complications, with unblinding for efficacy concerns strictly prohibited. Conduct unblinding in the CRISP system to maintain an audit trail and notify the sponsors within 24 hours upon approval by the site principal investigator.

2. Patient recruitment

  1. Screen patients with lung cancer BM in the oncology outpatient clinics and wards of all participating centers by clinical investigators or Clinical Research Coordinator (CRCs).
  2. Enroll eligible patients who meet the inclusion criteria and provide informed consent during the screening visit to ensure compliance with the study protocol.

3. Eligibility criteria

  1. Identify potential participants through hospital databases and clinical consultations at the six participating centers.
  2. To ensure a representative and safe study population, the clinical investigator or CRCs will enroll eligible patients who meet the following inclusion criteria.
    1. A confirmed histological or cytological diagnosis of lung cancer with radiologic evidence of BM.
    2. Age between 18 and 80 years.
    3. Serum calcium levels between 2.26 and 2.9 mmol/L, an ECOG performance status of 0–2, and a TCM syndrome differentiation consistent with spleen-kidney deficiency.
    4. Written informed consent obtained prior to any study-specific procedures.
  3. Conversely, the study will exclude patients who meet any of the following criteria
    1. Presence of multiple primary tumors or severe comorbid cardiovascular, cerebrovascular, hepatic, renal, or hematologic diseases.
    2. Unhealed oral surgical wounds or a history of strontium-89 treatment.
    3. Known allergies to the investigational drug (BWAGN) or its components or plans to receive other TCM or non-protocol bone-targeted therapies during the study period.

4. Study intervention

  1. Experimental group
    1. Administer standard bone-targeted therapy using intravenous zoledronic acid (4 mg diluted in 100 mL solution, infused over >15 min, once every 3–4 weeks) or subcutaneous denosumab (120 mg once every 4 weeks) and concurrently provide daily supplementation with calcium (1200 – 1500 mg/day) and vitamin D3 (400–800 IU/day).
    2. Prescribe BWAGN manufactured by Jiangyin Tianjiang Pharmaceutical Co., Ltd., which consists of the defined eight-herb herbal formula (Astragali Radix - 18 g; Notoginseng Radix et Rhizoma - 6 g; Drynariae Rhizoma - 9 g; Ligustri Lucidi Fructus - 12 g; Moutan Cortex - 9 g; Clematidis Radix et Rhizoma - 9 g; Spatholobi Caulis - 9 g; Phellodendri Chinensis Cortex - 6 g).
    3. Instruct patients to take two sachets twice daily (morning and evening) dissolved in warm water for 6 consecutive months.
  2. Control group
    1. Follow the same bone-targeted therapy and supplement regimen as defined in Step 4.1.1 to ensure baseline treatment consistency between the two study groups.
    2. Prescribe a matching placebo composed of 68.61% maltodextrin (MD20), 28.38% lactose, 2.44% caramel coloring, 0.50% marine extract (as a bitterness agent), 0.06% lemon yellow, and 0.01% sunset yellow to simulate the appearance and slight bitterness of the active drug.
    3. Ensure the brown placebo granules match the investigational product in color and odor through sensory evaluation by five independent evaluators before batch release, maintaining the same dosing schedule of two sachets twice daily for 6 months.
    4. Instruct patients to take two sachets twice daily (morning and evening) dissolved in warm water for 6 consecutive months.

5. Drug handling & visits

  1. Packaging, distribution, and storage
    1. Store all study drugs in a secure, temperature-controlled environment (15–30 °C, humidity <75%) managed by a designated unblinded pharmacist.
    2. Pack single doses into sachets, distribute study drugs in 3-month supplies, including a 7-day backup window supply.
    3. Document each dispensing and return on dedicated drug accountability forms.
  2. Compliance monitoring
    1. Check compliance using both sachet counts and participant self-reporting; trigger patient education and corrective and preventive action (CAPA) documentation with monthly compliance <80%.
    2. Use SMS (Short Message Service)/text message or telephone reminders to enhance compliance.
  3. Follow-up schedule and windows
    1. Complete baseline examinations and stratification confirmation during screening, followed by randomization.
    2. Include safety assessments and symptom/scale evaluations in monthly follow-up visits during treatment; perform imaging every 12 weeks.
    3. Follow up every 3 months until the event occurs or the study ends after treatment completion.
    4. Allow ±7-day window for scheduled visits; conduct remote follow-up and document if in-person visits are not feasible.

6. Possible risks and discomforts

  1. Safety monitoring and risk mitigation
    1. Monitor participants during monthly follow-up visits for adverse reactions associated with BWAGN and standard bone-directed therapy.
    2. For fever, gastrointestinal discomfort, or suspected allergic reactions, investigators must grade severity according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and document all findings in the electronic case report form (eCRF) safety log.
    3. Once any Grade 3 or higher adverse reactions occur, trial medication must be discontinued immediately and supportive treatment initiated within 24 h.
    4. Evaluate serum calcium and creatinine levels at baseline and prior to each 4-week administration.
    5. Implement a rescue protocol consisting of oral calcium (1200 mg/day) and vitamin D3 (800 IU/day) if serum calcium falls below the 2.0 mmol/L alert threshold.
    6. Suspend zoledronic acid administration if creatinine clearance (CrCl) drops below 35 mL/min, resuming only after recovery and documenting all interventions in the Laboratory Alert & Action Log.
  2. Concomitant therapy management
    1. Ask participants to bring their current medications for each follow-up visit; record their drug name, dose, frequency, and treatment duration in case report form (CRF).
    2. Allow concomitant medications required for comorbidities, prohibit use of other bone-targeted agents inhibiting osteoclast activity.
    3. For patients requiring additional pain control, short-term rescue analgesics may be used as needed, provided that the dosage and morphine equivalents are strictly documented.

7. Outcomes and assessments

  1. Baseline and general records
    1. Collect patient demographics, including name, contact information, date of birth, sex, age, height, weight, and smoking history, to establish a foundational participant profile.
    2. Simultaneously, document the clinical history—encompassing the date of pathological diagnosis, prior therapies (chemotherapy, targeted therapy, immunotherapy, radiotherapy, or surgery), tumor type, tumor-node-metastasis (TNM) staging, genetic testing results, comorbidities, and current medications—to evaluate baseline disease burden and potential confounding factors.
    3. Evaluate the patient's performance status using the Karnofsky Performance Status (KPS) and Eastern Cooperative Oncology Group (ECOG) scales to ensure treatment tolerance and study eligibility.
    4. Additionally, perform baseline laboratory tests, including tumor markers and other relevant biochemical indices, to provide a physiological reference point for assessing the subsequent efficacy and safety of the intervention.
  2. Primary endpoint
    1. Define the incidence of SREs (pathological fracture, radiotherapy for bone pain, spinal cord compression, bone surgery, or malignant hypercalcemia) within 1 year as the proportion of patients experiencing their first SRE within 1 year after enrollment.
    2. Identify SREs through regular imaging and patient reporting of clinical interventions. Cross-check all suspected events against the predefined SREs event dictionary to ensure standardized classification before submission for adjudication.
  3. Secondary endpoints
    1. Time to first SRE
      1. Record the time from enrollment to the first SRE, censor at the last follow-up for patients without events.
      2. Conduct verification at baseline (21 ± 7 days before treatment) and at study end (28 ± 7 days after last treatment); update event status at routine follow-ups.
    2. Quality of life
      1. Assess quality of life using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and Lung Cancer Module (QLQ-LC13) questionnaires; calculate raw scores (RS) and standardized scores (SS) according to the scoring manual.
      2. Define improvement as higher SS in functional or global health domains, or lower SS in symptom domains.
      3. Perform assessments within 7 ± 1 days prior to treatment, monthly during treatment, and at 28 ± 7 days after the last treatment.
    3. TCM symptom score
      1. Follow the NMPA Guidelines for Clinical Research on New Chinese Medicines for Primary Bronchogenic Carcinoma (2002) for symptom scoring. Specific core symptoms related to lung cancer BM, such as cough, expectoration, chest pain, shortness of breath, and fatigue, will be graded on a 4-point scale: absent (0), mild (1), moderate (2), or severe (3).
      2. Categorize clinical improvement as: significant improvement (≥70% score reduction), partial improvement (≥30% reduction), no improvement (<30% change), or worsening (≥30% increase).
      3. Perform assessments within 7 ± 4 days before treatment and monthly thereafter until 28 ± 7 days after the last treatment. Reliability analysis will be performed to validate the internal consistency of the TCM symptom assessments.
    4. Pain assessment (numerical rating scale, NRS)
      1. Assess pain severity using the 0–10 NRS (0 = no pain, 1–3 = mild, 4–6 = moderate, 7–10 = severe).
      2. Categorize responses as: CR (pain disappearance or ≥2 grade reduction), PR (≥1 grade reduction), MR (mild improvement with reduced analgesic use but <1 grade reduction), or NR (no change or worsening). Total effective rate = CR + PR.
      3. Assess pain within 7 ± 4 days prior to treatment and monthly thereafter until 28 ± 7 days after last treatment.
    5. Progression-Free Survival (PFS)
      1. Define PFS as the time from enrollment to documented disease progression or death from any cause.
      2. Complete baseline imaging and laboratory tests within 1 month prior to treatment; repeat assessments every 3 months during treatment and follow-up.
    6. Overall Survival (OS)
      1. Define OS as the time from enrollment to death from any cause.
      2. Follow up with participants monthly during treatment and every 3 months after treatment until death.
    7. Biochemical and bone turnover markers
    8. To evaluate the impact of BWAGN on bone homeostasis and tumor-induced bone destruction, assess several biochemical markers reflecting the status of bone remodeling.
      1. Bone resorption markers: urinary pyridinoline (uPYD), urinary deoxypyridinoline (uDPD).
      2. Bone formation markers: serum bone-specific alkaline phosphatase (sBAP), serum osteocalcin (sBGP).
      3. Bone lysis-related factors: interleukin-11 (IL-11), receptor activator of nuclear factor-κB ligand (RANKL), parathyroid hormone-related protein (PTHrP), Dickkopf-1 (DKK1).
      4. Collect samples within 7 ± 4 days before treatment and at 28 ± 7 days after last treatment, and analyze using the test kit purchased from AMOY LUNCHANGSHUO BIOTECH, CO., LTD.
  4. Safety endpoints
    1. Grade adverse events (AEs) and toxicities according to CTCAE v5.0, including complete blood count, urinalysis, stool tests, liver/kidney function, and electrocardiogram (ECG).
    2. Pay special attention to bisphosphonate-related AEs (fever, arthralgia, renal impairment, osteonecrosis of the jaw) and denosumab-related AEs (allergy, hypocalcemia, osteonecrosis of the jaw).
    3. Record AEs/SAEs monthly during treatment and every 3 months after treatment until outcome events occur and submit all recorded AEs/SAEs to the Clinical Endpoint Committee (CEC) for blind review.
    4. Assess serum calcium and creatinine levels before each bone-targeted therapy cycle; trigger the intervention protocol if serum calcium falls below 2.0 mmol/L.
  5. Event adjudication
    1. Submit all suspected SREs, PFS, and OS events to the independent CEC for blinded review.
    2. Assign two senior oncologists to independently adjudicate each event based on eCRF data, source documents, and DICOM images. Resolve any discrepancies through a third senior reviewer whose decision shall be final.
    3. Conduct centralized imaging reviews based on RECIST 1.1 criteria to ensure consistency and eliminate inter-site observation bias.

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Results

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At present, this study remains in the follow-up phase. While complete efficacy and safety outcomes cannot yet be formally analyzed without compromising the study’s double-blind integrity and GCP standards, we present descriptive observations from a representative participant to illustrate the currently available protocol-specified data. Formal, comprehensive results will be reported after data lock and statistical unblinding.

Study enrollment status

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Discussion

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This study employed a prospective, multicenter, randomized, double-blind, placebo-controlled design, with the incidence of SREs within one year as the primary endpoint. Secondary endpoints encompassed multiple dimensions, including quality of life, pain control, lung cancer-related symptoms, survival outcomes, and bone turnover markers. This design was intended to minimize selection and observation biases and to provide a rigorous methodological framework for the eventual evaluation of trial outcomes32<...

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Disclosures

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The authors have nothing to disclose.

Acknowledgements

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This study was supported by grants from Shanghai Top Priority Research Center construction project (2022ZZ01009) and National Nature Science Foundation (82174408, 82374477, and 82474535).

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Materials

List of materials used in this article
NameCompanyCatalog NumberComments
Bawei Aiguning GranulesJiangyin Tianjiang Pharmaceutical Co., Ltd2312306
Bawei Aiguning Granules PlaceboJiangyin Tianjiang Pharmaceutical Co., Ltd230368
Bone-Specific Alkaline Phosphatase (sBAP)AMOY LUNCHANGSHUO BIOTECH,CO.,LTDED-16329
CRISP (Clinical Research Integrated Service Platform)Shanghai Clinical Research Center2022ZZ01009
Dickkopf-related protein 1 (DKK1)AMOY LUNCHANGSHUO BIOTECH,CO.,LTDED-10124
Human Parathyroid Hormone Related Protein (PTHrP)AMOY LUNCHANGSHUO BIOTECH,CO.,LTDED-14237
Interleukin-11(IL-11)AMOY LUNCHANGSHUO BIOTECH,CO.,LTDED-10335
Osteocalcin/R-hydroxy glutamic acid protein (sBGP;OCN)AMOY LUNCHANGSHUO BIOTECH,CO.,LTDED-10658
Receptor Activator of Nuclear Factor-κB Ligand (RANKL)AMOY LUNCHANGSHUO BIOTECH,CO.,LTDED-10694

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Tags

Lung CancerBone MetastasesBawei Aiguning GranulesRandomized TrialDouble Blind StudyPlacebo ControlledBone Targeted TherapySkeletal Related EventsPain AssessmentQuality Of Life

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