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A Study for Assessing the Efficacy and Safety of Tetrahydrobiopterin in Radiation-Induced Skin Injury

Primary Purpose

Radiation-Induced Dermatitis

Status
Not yet recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
Tetrahydrobiopterin
Sponsored by
West China Second University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Radiation-Induced Dermatitis focused on measuring Tetrahydrobiopterin, Radiation-Induced Skin Injury, Phase I Clinical Study, Vulvar Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age: ≥ 18years old female patients.
  2. The subjects of the study were pathologically diagnosed vulvar cancer patients, who needed postoperative supplemental radiotherapy, patients who received radical radiotherapy and chemotherapy (unresectable locally advanced tumors, including some stage II with tumor diameter > 4 cm or tumor invading vagina, urethra, and anus), and early-stage patients with possible serious postoperative complications or serious complications, where in the option of undergoing a surgery was not appropriate.
  3. The Eastern Cooperative Oncology GroupPerformance Status (ECOG PS) score: 0-1.
  4. Expected survival ≥12 months.
  5. The main organs functioned normally, which meant that they met the following criteria:

1) Blood routine examination results:

  • Hemoglobin (Hb) ≥90g/L. ② Absolute neutrophil count (ANC)≥1.5×109/L. ③ Platelet count (PLT) ≥50×109/L. 2) Biochemical examination results:
  • Total bilirubin (TBIL)<1.5×upper limit of normal (ULN).

    • Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)<2.5×ULN,for patients with liver metastasis<5×ULN.

      ③ Blood urea nitrogen (BUN) and Creatinine ratio (CR) ≤1×ULN or Endogenous creatinine clearance≥50ml/min(by Cockcroft-Gault equation).

      6. The subjects willingly participated inthe study, signed an informed consent form, were medication-compliant, and cooperated with the follow-ups.

Exclusion Criteria:

  1. Patients with hypertension and could not control the blood pressure within the normal range after treating with antihypertensive medications (systolic blood pressure>140 mmHg and diastolic blood pressure>90 mmHg).
  2. Patients with a history of severe cardiovascular diseases, including myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmia (QTc interval ≥470 ms in women), grade III~IV cardiac insufficiencyaccording to the New York Heart Association (NYHA) standards, orthe left ventricular ejection fraction (LVEF) < 50%shown by the heart color Doppler ultrasound.
  3. Patients with coagulation disorders (international normalized ratio (INR) >1.5, activated partial thromboplastin time (aPTT) >1.5 ULN), with bleeding tendency.
  4. Patients with a history of psychotropic medication abuse and unable to quit, and patients with mental disorders.
  5. Patients participatingin another drug trial.
  6. Patients with concomitant diseases that seriously endangered the safety of the patient or affected the completion of the study from the investigators' opinion.
  7. Not suitable for enrollment in the investigators' opinion.

Sites / Locations

  • est China Second Hospital of Sichuan University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

experimental group (BH4 solvent 50 ug/ml)

experimental group (BH4 solvent 100 ug/ml)

experimental group(BH4 solvent 200 ug/ml)

experimental group(BH4 solvent 400 ug/ml)

experimental group(BH4 solvent 600 ug/ml)

experimental group(BH4 solvent 800 ug/ml)

experimental group(BH4 solvent 1000 ug/ml)

Arm Description

A sterile gauze was soaked with BH4 solvent (50 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (100 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (200 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (400 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (600 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (800 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

A sterile gauze was soaked with BH4 solvent (1000 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.

Outcomes

Primary Outcome Measures

Acute radiation dermatitis incidence
incidence that was evaluated every week (according to RTOG radiation morbidity scoring criteria)

Secondary Outcome Measures

progression-free survival (PFS)
Follow-up until the death of the patient or withdraw from the clinical study
overall survival (OS)
Follow-up until the death of the patient or withdraw from the clinical study
cancer remission rate assessed by imaging
It was evaluated one month and three months after the end of treatment

Full Information

First Posted
October 12, 2021
Last Updated
February 25, 2022
Sponsor
West China Second University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05114226
Brief Title
A Study for Assessing the Efficacy and Safety of Tetrahydrobiopterin in Radiation-Induced Skin Injury
Official Title
Clinical Professor
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
March 1, 2022 (Anticipated)
Primary Completion Date
November 1, 2023 (Anticipated)
Study Completion Date
January 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
West China Second University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
This study was a single-center prospective phase I clinical study to evaluate the effectiveness and safety of BH4 in the treatment of radiation-induced skin injury during vulvar cancer radiotherapy.
Detailed Description
Vulvar Cancer is a type of rare gynecological malignant tumor, accounting to2~5% of all the female reproductive system malignancies, and mostly occurs in the postmenopausal women. The incidence of vulva cancer is on the rise, especially in the elderly women, with age 75 years and above. It may be related to non-neoplastic epithelial lesions such as lichen sclerosus of the vulva and atypical hyperplasia of the epithelial cells caused by advanced age. Radiotherapy plays a key role in the treatment of vulvar cancer. High risk factors for postoperative recurrence include positive surgical margin, adjacent surgical margin (<8 mm), lymphovascular space invasion (LVSI), lymph node metastasis (especially more than two metastatic nodes), and extracapsular invasion of lymph nodes. Patients with high risk factors for postoperative recurrence can benefit from radiotherapy. Radical radiotherapy and chemotherapy could be provided to patients with unresectable locally advanced tumors, including part of stage II (tumor diameter> 4 cm or tumor invading vagina, urethra, and anus), and to early-stage patients with possible serious postoperative complications or serious complications that do not allow surgery as an option. Due to the dampness of the vulva and the poor tolerance of the skin and mucous membranes to radiation, most patients with vulvar cancer have severe skin damage during radiotherapy, significantly affecting their treatment process, worsening their prognosis, and impairing their quality of life. Seeking safe and effective prevention and treatment measures for radiation-induced skin injury is particularly important to improve the prognosis of patients and improve their quality of life. Free radicals generated by the indirect action of ionizing radiation on skin cells are considered to be the primary cause of radiation skin injury. Tetrahydrobiopterin (BH4), also known as Sapropterin, is an important cofactor of the nitric oxide synthase (NOS) enzyme. Under normal physiological conditions, guanosine triphosphate cyclohydrolase 1 (GCH1) is the key enzyme for the synthesis of BH4. Reduced GCH1 activity lowers the production of BH4, causing NOS uncoupling, thereby leading to a raised level of oxygen free radicals (reactive oxygen species, ROS). Studies have shown that GCH1 overexpression restores the BH4 level and NO products in irradiated skin cells, reversed and inhibited the NOS uncoupling caused by ionizing radiation, thereby eliminating the ROS induced by ionizing radiation, reducing DNA damage, and postponing the cell apoptosis and cell aging. In animal experiments, direct injection of BH4 under the skin did not only reduce the degree of acute radiation skin injury, but also promoted the repair of the skin damage, lowered the occurrence of radiation-induced skin fibrosis, and maintained the normal physiological functions of the skin. This study was a single-center prospective phase I clinical study. The phase I clinical trial included 21 patients. Given satisfactory results, the cases appropriate for the study of drug concentration were expanded to 25, with a total of 45 subjects included eventually. The subjects of the study were pathologically diagnosed vulvar cancer patients, who needed postoperative supplemental radiotherapy, patients who received radical radiotherapy and chemotherapy (unresectable locally advanced tumors, including some stage II with tumor diameter > 4 cm or tumor invading vagina, urethra, and anus), and early-stage patients with possible serious postoperative complications or serious complications, wherein the option of undergoing a surgery was not appropriate. Intensity-modulated radiation therapy (IMRT) was employed, using the conventional split mode, (1.8~2.0) Gy/day, 5 times/week. The vulva and pelvic clinical target volume (CTV) was (45~50) Gy/25 times. The boost applied for primary visible lesions and metastaticlocal lymph nodes was (60~70) Gy. The techniques for boost regarding residual tumor and tumor bed area were determined based on the tumor location and the radiation dose limit of the surrounding organs. The electron beam vertical irradiation was applied for tumors located superficially. For residual tumors good for brachytherapy, techniques such as near-distance post-implantation were adopted to give a radiation boost. The specific dose and type of the radiation was determined according to the tumor location, size, treatment response, acute side effects, and whether chemotherapy was accompanied or not. For late-stage, metastatic vulvar cancer patients and those received radical chemotherapy and radiotherapy, systemic chemotherapy was provided, with unrestricted chemotherapy regimens. The degree of the skin injury during the radiotherapy was assessed according to the radiation morbidity scoring criteria of the Radiation Therapy Oncology Group (RTOG). After the start of radiotherapy, the degree of the damage to the patient's skin was assessed every week. BH4 was applied when skin damage≥ Grade I occurred. A sterile gauze was soaked with BH4 solvent, wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment. BH4 gradient: 50, 100, 200, 400, 600, 800, and 1,000 ug/ml.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Radiation-Induced Dermatitis
Keywords
Tetrahydrobiopterin, Radiation-Induced Skin Injury, Phase I Clinical Study, Vulvar Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
The degree of the skin injury during the radiotherapy was assessedaccording to the radiation morbidity scoring criteria of the Radiation Therapy Oncology Group (RTOG).After the start of radiotherapy, the degree of the damage to the patient's skin was assessed every week. BH4 was applied when skin damage≥ Grade I occurred. A sterile gauze was soaked with BH4 solvent, wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment. BH4 gradient: 50, 100, 200, 400, 600, 800, and 1,000 ug/ml.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
experimental group (BH4 solvent 50 ug/ml)
Arm Type
Experimental
Arm Description
A sterile gauze was soaked with BH4 solvent (50 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.
Arm Title
experimental group (BH4 solvent 100 ug/ml)
Arm Type
Experimental
Arm Description
A sterile gauze was soaked with BH4 solvent (100 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.
Arm Title
experimental group(BH4 solvent 200 ug/ml)
Arm Type
Experimental
Arm Description
A sterile gauze was soaked with BH4 solvent (200 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.
Arm Title
experimental group(BH4 solvent 400 ug/ml)
Arm Type
Experimental
Arm Description
A sterile gauze was soaked with BH4 solvent (400 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.
Arm Title
experimental group(BH4 solvent 600 ug/ml)
Arm Type
Experimental
Arm Description
A sterile gauze was soaked with BH4 solvent (600 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.
Arm Title
experimental group(BH4 solvent 800 ug/ml)
Arm Type
Experimental
Arm Description
A sterile gauze was soaked with BH4 solvent (800 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.
Arm Title
experimental group(BH4 solvent 1000 ug/ml)
Arm Type
Experimental
Arm Description
A sterile gauze was soaked with BH4 solvent (1000 ug/ml), wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.
Intervention Type
Drug
Intervention Name(s)
Tetrahydrobiopterin
Intervention Description
BH4 was applied when skin damage≥ Grade I occurred. A sterile gauze was soaked with BH4 solvent, wringed out, and applied to the treated skin area for 15 minutes. It was applied three times a day (morning, noon, and evening), until three months after the end of treatment.
Primary Outcome Measure Information:
Title
Acute radiation dermatitis incidence
Description
incidence that was evaluated every week (according to RTOG radiation morbidity scoring criteria)
Time Frame
up to 12 weeks
Secondary Outcome Measure Information:
Title
progression-free survival (PFS)
Description
Follow-up until the death of the patient or withdraw from the clinical study
Time Frame
up to 5 years
Title
overall survival (OS)
Description
Follow-up until the death of the patient or withdraw from the clinical study
Time Frame
up to 5 years
Title
cancer remission rate assessed by imaging
Description
It was evaluated one month and three months after the end of treatment
Time Frame
up to 12 weeks
Other Pre-specified Outcome Measures:
Title
adverse events
Description
Follow-up until the death of the patient or withdraw from the clinical study
Time Frame
up to 12 weeks

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age: ≥ 18years old female patients. The subjects of the study were pathologically diagnosed vulvar cancer patients, who needed postoperative supplemental radiotherapy, patients who received radical radiotherapy and chemotherapy (unresectable locally advanced tumors, including some stage II with tumor diameter > 4 cm or tumor invading vagina, urethra, and anus), and early-stage patients with possible serious postoperative complications or serious complications, where in the option of undergoing a surgery was not appropriate. The Eastern Cooperative Oncology GroupPerformance Status (ECOG PS) score: 0-1. Expected survival ≥12 months. The main organs functioned normally, which meant that they met the following criteria: 1) Blood routine examination results: Hemoglobin (Hb) ≥90g/L. ② Absolute neutrophil count (ANC)≥1.5×109/L. ③ Platelet count (PLT) ≥50×109/L. 2) Biochemical examination results: Total bilirubin (TBIL)<1.5×upper limit of normal (ULN). Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)<2.5×ULN,for patients with liver metastasis<5×ULN. ③ Blood urea nitrogen (BUN) and Creatinine ratio (CR) ≤1×ULN or Endogenous creatinine clearance≥50ml/min(by Cockcroft-Gault equation). 6. The subjects willingly participated inthe study, signed an informed consent form, were medication-compliant, and cooperated with the follow-ups. Exclusion Criteria: Patients with hypertension and could not control the blood pressure within the normal range after treating with antihypertensive medications (systolic blood pressure>140 mmHg and diastolic blood pressure>90 mmHg). Patients with a history of severe cardiovascular diseases, including myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmia (QTc interval ≥470 ms in women), grade III~IV cardiac insufficiencyaccording to the New York Heart Association (NYHA) standards, orthe left ventricular ejection fraction (LVEF) < 50%shown by the heart color Doppler ultrasound. Patients with coagulation disorders (international normalized ratio (INR) >1.5, activated partial thromboplastin time (aPTT) >1.5 ULN), with bleeding tendency. Patients with a history of psychotropic medication abuse and unable to quit, and patients with mental disorders. Patients participatingin another drug trial. Patients with concomitant diseases that seriously endangered the safety of the patient or affected the completion of the study from the investigators' opinion. Not suitable for enrollment in the investigators' opinion.
Facility Information:
Facility Name
est China Second Hospital of Sichuan University
City
Chengdu
State/Province
Sichuan
ZIP/Postal Code
610041
Country
China

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28596000
Citation
Xue J, Yu C, Sheng W, Zhu W, Luo J, Zhang Q, Yang H, Cao H, Wang W, Zhou J, Wu J, Cao P, Chen M, Ding WQ, Cao J, Zhang S. The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade. J Invest Dermatol. 2017 Oct;137(10):2059-2068. doi: 10.1016/j.jid.2017.05.019. Epub 2017 Jun 6.
Results Reference
result

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A Study for Assessing the Efficacy and Safety of Tetrahydrobiopterin in Radiation-Induced Skin Injury

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