Limonene for Pulmonary Nodule Chemoprevention

A Randomized Phase II Trial of Limonene for Pulmonary Nodule Chemoprevention

The prevention and treatment of lung nodules involves many fields in preventive medicine and clinical medicine. A nodule is a growth or lump that may be malignant (cancer) or benign (not cancer). This study is aim to investigate the chemopreventive effect of limonene in inhibiting the occurrence/progression of ground glass pulmonary nodules. It is expected that limonene can be used as a safe and effective chemopreventive agent for preventing the development/progress of pulmonary nodules as well as expanding the indications of limonene.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Nodules
• Intervention / Treatment: Drug: Limonene capsules(Placebo); Drug: Limonene capsule

Detailed Description

Early prevention, early detection and early treatment of lung cancer can help reduce the incidence and improve the survival rate.Chemoprevention is known to have an important role in high-risk people because it has the potential to prevent or reverse the progression of lung cancer.Lung nodules are good targets for testing the efficacy of chemopreventive agents.So far，none of the chemopreventive agents have been shown to be effective.

Limonene is widely found in the essential oils of traditional Chinese medicine tangerine peel, green peel and other plants. Its taste is sour, sweet and pungent. It has an aromatic odor effect. Limonene Capsule, a Chinese patent medicine, has been on the market, which is suitable for the treatment of cholecystitis, cholangitis, cholelithiasis, and postoperative biliary syndrome.Preliminary studies of the research group suggest that it has a potential anti-cancer effect.

This randomized, double-blind, controlled trial studied limonene compared with placebo in treating high-risk patients with pure ground glass pulmonary nodules，so as to expand indications.

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ziyi Sheng, Master; Phone Number: 5452 22200000; Email: shxkcru@163.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200030
      • Recruiting
      • Shanghai Chest Hospital
      • Contact: Sheng Zi Yi, Master; Phone Number: 5452 22200000; Email: shxkcru@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Non-smokers (those who have smoked less than 100 cigarettes in their lifetime, including those who have never smoked in their lifetime).
• Subjects must have positive nodules detected by high-resolution CT（HRCT）: longest diameter > 6 mm and < 20 mm; pure ground glass nodule; according to the judgment of the clinician, follow-up can be performed, and surgical excision is not recommended for the time being; the nodules did not disappear or were not significantly reduced by more than 2 mm after six months follow-up; subjects should have at least one positive nodule when had multiple nodules.
• ECOG performance status 0-1.
• Those who accept and are willing to sign the informed consent.

Exclusion Criteria:

• Subjects with the history of autoimmune diseases and severe gastrointestinal diseases;
• Subjects suffering from malignant tumor, severe heart disease, severe liver or kidney disease currently or within the past 5 years;
• Within 6 weeks since prior herbal supplements, non-steroidal anti-inflammatory drugs, or antibiotics
• Subjects who are allergic to limonene capsules or citrus foods;
• Use of any other investigational agents at time of enrollment in the study during the three months preceding study enrollment
• Pregnant or lactating females, or those who disagreeing with contraception;
• Subjects who have a history of mental illness and cannot cooperate with this project;
• HIV-positive subjects should be excluded.

• Subjects whose organ and bone marrow function indexes exceeded the following range of normal value were excluded:

  1. Leukocytes: 3.5-9.5 109/L;
  2. Absolute neutrophil count: 1.8-6.3 109/L;
  3. Platelets: 125-350 109/L;
  4. Total bilirubin: 5.0-21.0 µmol /L;
  5. AST (SGOT)/ALT (SGPT): 0.8-1.5;
  6. Serum creatinine: 41-81 μmol/L;
• Other situations where the researcher thinks it is inappropriate to participate in this research.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Limonene capsules(marketed product in China); Limonene capsules(marketed product in China) donate by pharmaceutical company.	Drug: Limonene capsule; Citrus foods rich in D-limonene were forbiden 2 days before taking the drug (washout period), which was maintained after taking the drug.Limonene capsules group and placebo group were used for treatment. The random number is generated by the central randomization system. All the recruiters were divided into placebo control group and limonene capsule administration group. The numbers will be assigned according to random numbers. In this study, qualified subjects were randomly assigned to the treatment group and the placebo control group at a ratio of 1:1. The drug was administered for 12 weeks, 3 times a day, 5 capsules each time.; Other Names: DAN LENING capsule
PLACEBO_COMPARATOR: Limonene capsules(Placebo); Same smell, color and shape as limonene capsules(marketed product in China), without limonene in capsules.	Drug: Limonene capsules(Placebo); Limonene capsules(Placebo); Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the sum of longest diameters of target nodules (multiple nodules) between the drug group and the placebo group.	Difference in the sum of longest diameters of target nodules	at baseline, three months and six months after administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate of participants as measured by RECIST criteria between the two groups	Difference in the overall response rate of participants	at baseline, three months and six months after administration
Changes in the sum of longest diameters of baseline target nodules (multiple nodules) between the drug group and the placebo group	Difference in the sum of longest diameters of target nodules	at baseline and twelve months after administration
Change in diameters of baseline target nodules (single nodule) detected by CT between the two groups.	Difference in the longest diameters of baseline target nodules	at baseline, three months and six months after administration
Change in density of baseline target nodules between the two groups.	Difference in density of baseline target nodules	at baseline, three months and six months after administration
Change in the longest diameters size of baseline non-target nodules between the two groups	Difference in the longest diameters of baseline non-target nodules	at baseline, three months and six months after administration
Change in numbers of baseline non-target nodules between the two groups	Difference in numbers of baseline non-target nodules	at baseline, three months and six months after administration
Change in density of baseline non-target nodules between the two groups	Difference in density of baseline non-target nodules	at baseline, three months and six months after administration
Adverse events	Incidence of adverse events	at baseline, three months and six months after administration
Value of serum miRNA	Value of serum miRNA	at baseline, three months and six months after administration
Cytokine detection	Value of cytokine detection	at baseline, three months and six months after administration
Plasma metabolomics	Analysis of plasma metabolomics	at baseline, three months and six months after administration
Proportion of circulating blood immune cells	Analysis of the proportion of circulating blood immune cells	at baseline, three months and six months after administration

Collaborators and Investigators

• Sponsor: Shanghai Jiao Tong University School of Medicine
• Collaborators: Shanghai Chest Hospital

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): February 1, 2023
• Primary Completion (ANTICIPATED): February 1, 2024
• Study Completion (ANTICIPATED): December 1, 2025

Study Registration Dates

• First Submitted: August 9, 2022
• First Submitted That Met QC Criteria: August 30, 2022
• First Posted (ACTUAL): September 1, 2022

Study Record Updates

• Last Update Posted (ACTUAL): February 6, 2023
• Last Update Submitted That Met QC Criteria: February 2, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Multiple Pulmonary Nodules
• Other Study ID Numbers: DISH-pGGO

Drug and device information, study documents

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