SHIELD: Sorafenib Hand-foot Syndrome Inhibition With Pre-Emptive Local Delivery of Topical Indomethacin

SHIELD is a single-center, open-label, single-arm prospective study designed to evaluate whether pre-emptive topical indomethacin can reduce sorafenib-associated hand-foot syndrome (HFS) in patients with advanced hepatocellular carcinoma (HCC). Eligible adult patients with advanced HCC who are planned to initiate sorafenib will receive standard sorafenib treatment together with prophylactic 1% topical indomethacin gel applied to both hands twice daily for up to 12 weeks, or until development of HFS or discontinuation of sorafenib, whichever occurs first. The primary endpoint is the incidence of all-grade HFS during the first 12 weeks of sorafenib treatment. Secondary endpoints include grade 2 or higher HFS rate, grade 3 or higher HFS rate, mean sorafenib dose intensity during the first 12 weeks, adverse events of special interest, and duration of sorafenib treatment. The study will enroll 39 patients and compare outcomes with historical control data.

Study Overview

• Status: Recruiting
• Conditions: Hepato Cellular Carcinoma (HCC); Hand Foot Skin Syndrome
• Intervention / Treatment: Drug: Topical Indomethacin

Detailed Description

This is a single-center, open-label, single-arm prospective study evaluating the prophylactic use of topical indomethacin for prevention of sorafenib-associated hand-foot syndrome (HFS) in patients with advanced hepatocellular carcinoma (HCC). Sorafenib is an established systemic treatment option for advanced HCC, but HFS is a frequent toxicity that may reduce quality of life and interfere with treatment delivery. Historical studies have reported all-grade HFS rates of approximately 45% in patients treated with sorafenib.

Topical NSAIDs have shown preventive activity against chemotherapy-related HFS in prior studies. Based on this rationale, this study will investigate whether pre-emptive administration of 1% topical indomethacin gel can reduce the incidence of sorafenib-related HFS while avoiding the systemic adverse effects associated with oral NSAIDs.

Eligible adult patients with advanced HCC who are planned to start sorafenib will receive sorafenib at an initial dose of 400 mg orally twice daily, with subsequent dose modification according to routine clinical practice. Participants will also apply 1% topical indomethacin gel to the palmar and dorsal surfaces of both hands twice daily (total 4 g/day) for up to 12 weeks, or until development of HFS or discontinuation of sorafenib, whichever occurs first.

The primary endpoint is the incidence of all-grade HFS during the first 12 weeks of sorafenib treatment, defined according to NCI CTCAE version 5.0. Secondary endpoints include the incidence of grade 2 or higher HFS, incidence of grade 3 or higher HFS, mean sorafenib dose intensity during the first 12 weeks, adverse events of special interest, and sorafenib treatment duration. A total of 39 patients will be enrolled. Outcomes will be interpreted against historical control data.

• Study Type: Interventional
• Enrollment (Estimated): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 10002
    • Recruiting
    • National Taiwan University Hospital
    • Contact: Yu-Yun Shao, M.D., Ph.D.; Phone Number: 886-2-2312-3456; Email: yuyunshao@gmail.com
    • Contact: Tsung-Che Wu, M.D.; Phone Number: 886-2-23123456; Email: tsungchewu8825@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Female or male patients, 18 years of age or older, able to understand and give written informed consent.
2. Hepatocellular carcinoma, diagnosed by clinical or pathological diagnosis.
3. Patients with advanced HCC, defined as those with macrovascular invasion, extrahepatic spread, or who failed or are not feasible to locoregional therapy.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
5. Child-Pugh score A-B7.
6. Sorafenib is deemed as an appropriate treatment option for the patient at the discretion of the investigator.
7. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendices.
8. Willing and able to comply with the requirements and restrictions in this protocol.

Exclusion Criteria:

1. Exposure to multikinase inhibitors or capecitabine within 1 week before starting the study treatment.
2. Unresolved HFS.
3. Exposure to oral NSAID, topical NSAID, or topical steroid within 1 week before starting the study treatment.
4. Known allergy to NSAID.
5. Any concurrent systemic chemotherapy, immunotherapy, or biologic for cancer treatment.
6. Recent gastrointestinal bleeding within 12 weeks.
7. Female patients who are pregnant, breast-feeding, or male or female patients of reproductive potential who are not employing an effective method of birth control.
8. Have other concurrent medical or psychiatric conditions that, in the investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
9. Any medical condition that, in the investigator's or sponsor's opinion, poses an undue risk to the patient's participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental; Prophylactic topical indomethacin

Drug: Topical Indomethacin; The participant will be provided with 2 tubes (20 gm each) per week in the first 4 weeks (D1, 8, 15, 22), 4 tubes per 2 weeks at the second 4 weeks (D29, 43), and 4 tubes per 4 weeks for the third 4 weeks (D57) suffice for topical application over 12 weeks. The participant will apply 1 g (1 g = two fingertip units [FTU]: one FTU for one surface of one hand) of 1% topical indomethacin on the palmar and dorsal surface of each hand twice daily (= 4g/day) until discontinuation of sorafenib or 12 weeks or development of HFS, whichever is earlier. If the patient has adequate residual indomethacin gel at the visit, the prescribing amount may be reduced accordingly.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-grade hand-foot skin reaction rate during the first 12 weeks of sorafenib treatment	The proportion of participants who experience any grade of hand-foot skin reaction during the first 12 weeks of sorafenib treatment. Hand-foot skin reaction severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The grading scale ranges from Grade 1 to Grade 5, with higher grades indicating greater severity. For participants who discontinue sorafenib before Week 12, hand-foot skin reaction events will be assessed during the actual sorafenib treatment period.	From initiation of sorafenib treatment through Week 12, assessed up to 12 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grade ≥2 hand-foot skin reaction rate during the first 12 weeks	The proportion of participants who experience Grade 2 or higher hand-foot skin reaction during the first 12 weeks of sorafenib treatment. Hand-foot skin reaction severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The grading scale ranges from Grade 1 to Grade 5, with higher grades indicating greater severity.	From initiation of sorafenib treatment through Week 12, assessed up to 12 weeks.
Grade ≥3 hand-foot skin reaction rate during the first 12 weeks	The proportion of participants who experience Grade 3 or higher hand-foot skin reaction during the first 12 weeks of sorafenib treatment. Hand-foot skin reaction severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The grading scale ranges from Grade 1 to Grade 5, with higher grades indicating greater severity.	From initiation of sorafenib treatment through Week 12, assessed up to 12 weeks.
Mean sorafenib dose intensity during the first 12 weeks of treatment		From initiation of sorafenib treatment through Week 12, assessed up to 12 weeks.
Adverse events of special interest in the first 12 weeks of sorafenib treatment		From initiation of sorafenib treatment through Week 12, assessed up to 12 weeks.
Treatment duration of sorafenib		From initiation of sorafenib treatment until permanent discontinuation of sorafenib, assessed up to 24 weeks.

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Principal Investigator: Yu-Yun Shao, M.D., Ph.D., National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2025
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: April 21, 2026
• First Submitted That Met QC Criteria: April 27, 2026
• First Posted (Actual): May 1, 2026

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Sorafenib; hepatocellular carcinoma; Prophylaxis; Topical NSAID; Hand foot skin syndrome
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indoles; Indomethacin
• Other Study ID Numbers: 202508066MIPC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No