Hemoporfin Photodynamic Therapy for Port-Wine Stain: A Randomized Controlled Trial

Background and Objectives Photodynamic therapy (PDT) has shown potentially beneficial results in treating port-wine stain, but its benefit–risk profile remains undefined. This study aimed to evaluate the efficacy and safety of PDT conducted with hemoporfin and a 532 nm continuous wave laser to treat port-wine stain clinically. Patients and Methods This randomized clinical trial was conducted in eight hospitals in China. Participants were adolescent and adult patients (age range: 14–65 years old) with port-wine stain. During stage 1 (day 1 to week 8) all patients were randomized at a 3:1 ratio to treatment (532 nm laser irradiation (96–120 J/cm2) with hemoporfin (5mg/kg; PDT-hemoporfin, n = 330)) or placebo groups (irradiation with placebo (PDT-placebo, n = 110)); during stage 2 (week 8 to 16) patients in both groups were offered treatment. Clinician-evaluators, who were blind to the study, classified each case on the following four-level scale according to assessment of before and after standardized pictures of the lesion area: no improvement: <20%; some improvement: 20–59%; great improvement: 60–89%; or nearly completely resolved: ≥90%. The primary efficacy endpoint was proportion of patients achieving at least some improvement at week 8. The secondary efficacy endpoints were proportion of patients achieving nearly completely resolved or at least great improvement at week 8, proportion of patients achieving early completely resolved, at least great improvement, or at least some improvement at week 16, and the corresponding satisfaction of the investigators and the patients (designated as ‘excellent’, ‘good’, ‘moderate’, or ‘ineffective’) at weeks 8 and 16. Results Compared to the PDT-placebo group, the PDT-hemoporfin group showed a significantly higher proportion of patients that achieved at least some improvement (89.7% [n = 295; 95% CI, 85.9%-92.5%] vs. 24.5% [n = 27; 95% CI, 17.4%-33.3%]) at week 8 (P < 0.0001) and higher improvements for all secondary efficacy endpoints. Treatment reactions occurred in 99.5% (n = 731; 95% CI, 98.7%-99.8%) of the PDT-hemoporfin treatments (n = 735). Hyperpigmentation occurred in 22.9 per 100 patient-treatments (n = 168; 95% CI, 20.0–26.0) in the PDT-hemoporfin treated patients. Conclusions Hemoporfin-mediated PDT is an effective and safe treatment option for adolescent and adult patients with port-wine stain. Trial Registration Chinese Clinical Trial Registry ChiCTR-TRC-08000213

A multicenter clinical trial (phase III) to evaluate the efficacy and safety of hemoporfin for injection for the treatment of port-wine stains

Trial background
Port-wine stains, also known as nevus flammeus or nevus telangiectasia, can occur in any part of the body, more frequently in the face, neck and scalp, affecting the appearance and psychology of patients. Port-wine stains is malformation of the superficial dermal capillaries, the essential difficulty in treatment is to remove the dilated superficial dermal capillaries to eliminate the abnormal red color of the lesion area without damaging the epidermis and deep dermal tissues in order to achieve a scar-free therapeutic goal. Treatments including cryosurgery, excision followed by skin grafting, X-ray, isotope and laser either leaves scars or is unable to eliminate color of the lesion area completely. Therefore, it is a clinical challenge to develop highly selective therapeutic methods.
Photodynamic therapy (PDT) is a therapeutic method that employs photosensitizers to generate cytotoxic substances after irradiation with visible light of specific wavelengths to act on the target tissues and produce histological effect. The photosensitizers can absorb photons and pass the energy to oxygen molecules to induce chemical reactions producing singlet oxygen and other toxic substances. An important property of photosensitizers is the ability to concentrate preferentially in the lesional tissues to produce specific biological effects with minimal impact on the surrounding normal tissues. Currently, PDT has demonstrated remarkable efficacy in the treatment of condyloma acuminate, actinic keratosis and other diseases.
The mechanism of PDT for the treatment of port-wine stains: because the photosensitizer obtains a plasma concentration peak immediately after its intravenous injection followed by rapid absorption by the vascular endothelial cells with little absorption in the epidermal cells, the distribution of injected photosensitizer forms an apparent concentration gradient between the vascular endothelial cells and the epidermal cells. Then transepidermal laser irradiation using specific wavelengths of selective absorption can activate the photosensitizers to generate singlet oxygen and other phototoxic substances, leading to selective destruction of the dilated and malformed capillary networks containing abundant photosensitizers at the lesion site without damaging the top normal epidermis containing little photosensitizers, the underneath dermal tissues are also protected because the limited laser penetration.
Photosensitizer is one of the key factors of PDT efficacy. Despite the significant results achieved with clinical application of the first generation of photosensitizers (hematoporphyrin derivatives, HpD), the skin phototoxicity reaction still lasts for 1~2 months and up to 3~4 months in some patients because HpD is a mixture of multiple porphyrins with strong affinity with collagen fibers, Hemoporfin for injection for the treatment of port-wine stains Phase III Clinical Trial Protocol Page6/25 its composition and chemical structure are yet to be clarified fully, and its excretion from the body is fairly slow. The patients must be strictly protected from light during this period, which severely affect not only the patient's quality of life and work but also cause great inconvenience in clinical treatment. Therefore, the current issue to be addressed urgently in order to meet the clinical demands on PDT is to develop photosensitizers with single chemical composition, clear structure, stable physicochemical properties, ideal action spectrum, high target tissue selectivity, strong photodynamic effect, low toxicity, and rapid metabolism.
Hemoporfin (hematoporphyrin monomethyl ether, HMME or MHD in short) co-developed by Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. and Chinese PLA General Hospital is a new drug for monomeric porphyrin photodynamic therapy. HMME methanol solution has characteristic absorption peaks at 401, 500, 533, 569 and 613 nm. HMME can be cleared from the tissues rapidly with very low phototoxicity in normal tissues. Both the acute toxicity and long-term toxicity of this compound are lower than the first-generation photosensitizers hematoporphyrin derivatives. The clear structure and rapid metabolism lead to mild adverse reactions, short period of protection from light, and treatments might be repeated within short intervals. Hospital of Central South University. The study purpose is to evaluate the efficacy and safety of hemoporfin for injection co-developed by Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. and Chinese PLA General Hospital for the treatment of port-wine stains using PDT method.
Based on the phase II clinical trial results showing that 5mg/kg hemoporfin and photodynamic irradiation for 20min were safe and effective in the treatment of port-wine stains, the phase III clinical study is to further verify the efficacy and safety of PDT using hemoporfin for port-wine stains.

Trial purpose
This study is to evaluate the efficacy and safety of hemoporfin for injection for the treatment of port-wine stains using placebo as the control in two stages of PDT treatments. Primary endpoint will be established at the first stage, and safety analysis will include both stages.

Design principle:
This is a parallel, placebo-controlled, double-blinded and multicenter clinical trial.
The subjects are randomized into trial group and control group at 3:1 ratio in this phase III clinical trial.
Statistical estimation of the sample size: using two-sided test of the efficacy, α=0.05 and β=0.1 (power=90%) based on phase II clinical trial results, the expert panel estimates the total clinical efficacy rate of hemoporfin for injection to be 75.0% in the treatment of port-wine stains and expects a 40% difference from the placebo group; consequently, the estimated minimal number of subjects is 66 for the trial group and 22 for the control group.
In compliance with the SFDA requirement of minimum sample size of no less than 300 subjects for phase III clinical trial group, and also taking into account of dropout, the sample size of this clinical trial was determined to be 330 subjects for the trial group and 110 subjects for the control group, giving a total of 440 subjects.
The subjects will be assigned into trial group or control group by stratified block randomization to receive not more than 2 courses of treatment. The control group receive placebo during the first course of treatment followed by trial drug during the second course of treatment. Each course of treatment will last for 8 weeks. Based on the phase II clinical trial results, the trial drug dose is set at 5mg/kg. All the patients participating in this clinical study must satisfy all the following criteria: The patients must been clinically diagnosed as port-wine stains; Male or female patients aged 14~65 years; The patients have read the subject's instructions and are willing to receive the treatment per protocol requirements and complete the visits in timely manner; The patients agree to sign the written informed consent form (ICF); For subjects aged<18 years, both the subjects and legal guardians should sign the ICF at the same time.

Exclusion criteria
The patients who meet any one of the following criteria must be excluded from this clinical study: The affected area has other concomitant skin diseases (e.g. severe acne, contact dermatitis, or purulent infection) that may affect the efficacy evaluation; The treatment area has been treated with isotope therapy, PDT or other therapies that may affect the efficacy evaluation; The patients are currently suffering from allergic diseases; the patients have known photosensitive dermatitis and porphyria or known history of allergies to the trial drug (porphyrins) and drugs with similar chemical structure; The patients have allergic constitutions, scarring constitutions or scarring tendency; The patients used known photosensitive drugs such as griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulfonamides, retinoic acids, quinolones and tetracyclines within 1 month The patients have known severe immunocompromised conditions or require long-term use of corticosteroids and immunosuppressants; The patients have ECG abnormalities and organic heart diseases; Hemoporfin for injection for the treatment of port-wine stains Phase III Clinical Trial Protocol Page9/25 Abnormal liver function (ALT and AST exceed the upper limit of normal (ULN), TBIL exceeds 1.5xULN) or severe renal dysfunction (renal function index exceeds 1.5xULN); The patients have hereditary or acquired coagulation disorders or are using anticoagulants; The patients have severe neurological, mental and endocrine disorders; The patients received systemic therapies to treat port-wine stains within 4 weeks prior to this treatment; The patients received topical therapies to treat port-wine stains within 2 weeks prior to this treatment; 2) The injection site skin is sterilized routinely.
3) Intravenous infusion of the drug solution should be at a constant speed using an infusion pump, and be completed within 20min. The relatively large veins easily protected from exposure to light should be selected (the largest vein in the arm such as the median cubital vein is preferred and small veins in the back of the hand should be avoided); 1ml physiological saline is injected for confirmation prior to drug infusion to prevent drug leakage into the extravascular space. Additional 2~4ml physiological saline should be infused at ending of drug infusion to decrease the intravascular drug concentration in order to prevent Hemoporfin for injection for the treatment of port-wine stains Phase III Clinical Trial Protocol Page10/25 photosensitive reactions at the injection site. The photosensitizers should be protected from light during the preparation and injection process to avoid efficacy decline. Measures should be taken to protect the subjects from light after drug infusion.
4) The target lesions are irradiated with 532nm laser and irradiation power density of 80-100 mW/cm 2 .
Irradiation time: the laser irradiation begins 10min after beginning of drug infusion and ends 20min later. The total irradiation time is 20 mintues.
Precautions during laser irradiation: ① depending on the lesion size and site, the selected treatment areas should be as flat as possible; the hair-covered areas (eyebrow, beard and hairline) need to be shaved clean to avoid affecting laser irradiation. The non-treatment area surrounding the lesion, especially the nasolabial fold and other weak areas should be carefully covered with adhesive tapes and double-layer red-black clothing; ② the output power at the fiber terminal should be adjusted and measured according to the therapeutic regimen prior to irradiation, the beam expander should be maintained perpendicular to the irradiation surface; in addition, it is necessary to pay attention to the size of the beam spot, closely observe the changes in the irradiated areas, and accurately control the irradiation time; ③ the output power need to be monitored before, after and during the irradiation process.

5) Precautions
: the patients should be instructed to observe the photoreaction after drug infusion and pay attention to photo protection. The photoreaction is expected to disappear completely in approximately 10 days after drug infusion. During the light protection period (2 weeks), the subjects should pay attention to protection of the exposed skin and eyes, avoid irradiation of sunlight or strong indoor lights. In case of drug extravasation during the infusion, the extravasation area must be kept completely away from light for a fairly long time until local swelling and discoloration disappears completely, otherwise severe local skin photoinjury may occur.
6) PDT may cause the following treatment reactions: the patients may experience itching, burning sensation, pain, swelling, blisters and scabs at the irradiated and surrounding area.
These therapeutic responses are usually transient and self-healing without special treatment.

Drug packaging and blinding
Because the drug used in this trial is powder for injection and the doses for the control group and trial group are different, stimulant is inappropriate for the double-blinded design; considering the fact that the trial drugs are prepared by nurses, the sponsor will prepare the drugs for each group per the double-blinded requirement during the drug preparation period.
Identical drug outer packaging are used for both groups; each patient needs an independent large packaging that contains two medium packaging marked with "drugs for the first course of treatment or drugs for the second course of treatment". Each medium packaging includes drugs for trial group (5 bottles of drugs in each medium packaging) and control group (each medium packaging contains 5 empty bottles for the first course of treatment and 5 bottles of drugs for the second course of treatment).
The statisticians will provide the random number table generated using DAS software simulation and provide it for random blinding of the drugs. Stratified block randomization is carried out by trial centers. Drug coding is completed by personnel unrelated to this clinical trial.
During the trial period, each center assigns a special person to manage the trial drugs and a nurses will prepare the trial drugs, keeping the investigators and subjects blinded.

Trial drug distribution and dispensing
Both the trial drug and light source are provided by Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. and delivered to all study centers periodically per the protocol by the company's clinical study monitors. The drugs are distributed by a special person at each study center. The observation doctors should dispense the drugs by the order of each patient's visit and the sequence of drug numbers without choosing the drugs intentionally. The drug numbers remain unchanged throughout the trial process. After successful enrollment, the patients will be offered with sufficient dose of trial drug of identical labels.
The drug managers should fill out the drug dispensing/recovery registration form timely and accurately.
An emergency letter should accompany each of the trial drugs and the letters will be maintained by the principal investigator of the participating institution. 7.2 typing type of port-wine stains in the lesion area should be assessed at enrollment Based on the erythema color and skin hyperplasia, port-wine stains can be divided into three types: Red type: the lesion is flat, not raised, similar to normal skin, the color is light pink to dark red and fades completely on finger pressing.
Purple type: the lesion is flat, not raised, similar to normal skin, the lesion is pale to dark purple and the color can fade completely or incompletely.
Hypertrophictype: the lesion is thickening and raised above normal skin with nodular hyperplasia, the color is dark purple-red and fades completely or incompletely. Evidence of using the trial drug; AE is more likely caused by other reasons; drug withdrawal reaction is negative or plausible; drug rechallenge test is negative or plausible.

Not related to the trial drug
The subject did not use the trial drug; the time relationship between the occurrence of AE and the use of trial drug is not plausible; or some other obvious reason causes the AE.

Severity evaluation
The intensity or severity of AE falls into the following categories: Mild: easily tolerated AE, subjects can feel it occasionally.
Moderate: AE is significantly discomfort and interfere with the daily activities; the subjects felt significantly but still can tolerate the symptoms without need to discontinue drug treatment.
Severe: AE significantly interferes with normal daily activities; the subjects felt significant intolerable symptoms and discontinuation of drug treatment is required.

AE report
The investigators need to fill out the AE record form in CRF.
The data retained in CRF will be forwarded to the clinical trial monitors by the end of this trial.

Handling of AE during and after the trial period
The investigators should observe and record the outcomes of all AEs and follow up with the subjects who withdraw from this trial due to AE until the AE is resolved completely. The investigators must determine whether the AE is related to the study drug and provide evidence to support the opinion.  In the investigator's opinion, continuing the treatment is not to the patient's best interests (e.g. pregnancy) The efficacy can't be evaluated or the efficacy or safety evaluation is affected by reasons like data incompleteness, etc Unblinding or emergency unblinding It is inappropriate for the subjects to continue this trial due to AE or SAE

Withdrawal decided by subjects
The subjects have rights to withdraw during this trial, or although the subjects did not explicitly request to withdraw from this trial, they will be regarded as "withdrawal" (or "dropout") cases if they no longer take the study drug or examination and consequently lost to follow-up. Efforts should be made to find out and record the reasons of withdrawal such as subjective perception of poor efficacy; finding it difficult to tolerate certain adverse reactions; too busy to continue this clinical study; economic reasons; or lost to follow-up for unexplained reasons.

Handling of the withdrawal cases
The investigators should fill in the CRF with the withdrawal reasons, try best to contact the patients to complete the assessment items, fill in the last visit form, and record the last dosing time. For withdrawals due to AEs that have been eventually judged to be related to the trial drug through follow-ups, the investigators must record them in the CRF and notify the sponsor. CRF of the withdrawal cases must be retained regardless of their withdrawal reasons; the last assessment results will be carried forward to serve as the final results for full data analysis of the efficacy and adverse reactions.

Discontinuation of the trial
Trial discontinuation refers to stop of this whole clinical trial without completion per the trial protocol. The major purposes of trial discontinuation are to protect the subject's interests, ensure trial quality and avoid unnecessary financial loss. Trial discontinuation during the study can result from the following reasons: The investigators identify serious safety issues Hemoporfin for injection for the treatment of port-wine stains Phase III Clinical Trial Protocol Page20/25 Very poor efficacy makes it unnecessary to continue this trial There are major defects in protocol design or major deviations during the implementation process The sponsor has budget or management difficulties The state's administrative department revokes this trial The trial discontinuation can be temporary or permanent. When the trial is discontinued, all the trial records should be retained for future supervision.

Clinical trial quality control
During this study, all the clinical trial participants should implement the GCP principles and strictly follow the clinical protocol in observation and evaluation. The sponsor will dispatch clinical study monitors to inspect the trial progresses and CRF quality and give advice on the drugs and study-emerged issues.
The participating investigators must receive uniform training and use uniform recording style and determination criteria.
The entire clinical trial process should proceed under strict blinded condition.
The investigators should record the contents of all raw data items accurately, carefully and in sufficient details, and fill in the CRF items accurately.
All the observation results and findings in this clinical trial should be verified to guarantee the data reliability and ensure that all the conclusions of this clinical trial are derived from the raw data. Corresponding data management procedures should be in place in all stage of clinical trial and data processing.
Active measures should be taken in case of potential dropout cases. The dropout rate should be controlled within 10%.
All the study hospitals should maintain their quality control standards stringently, and the clinical monitors will carry out periodical monitoring.

Data management
See "data management plan" for details of data management. Before database lock, the data manager, principal investigator and sponsor will carry out blind review and discussion, and come into a final data management report. This protocol will only provide the general requirements for data management. The completed CRF will be reviewed by the clinical investigators and monitors before transferring to the data statistical processing institution for data entry and management. All the processes should be documented properly.

Data entry and modification
The data managers of the statistical institution are responsible for data entry and management using excel or EpiData2.1 database. The data are required to be double entered by two independent data managers and verified to ensure data accuracy.
The data manager will fill out the DRQ in response to any doubts in the CRF and send queries to the investigators through clinical monitors; the investigators should answer the questions promptly and respond back. The data manager will modify the data per the investigator's response, verify and enter the modifications, and re-issue the DRQ if necessary.

Blind review and database lock
The principal investigator, sponsor and statistical analyst will lock the database after completing the blind review and confirming correctness of the constructed database.

Unblinding
Once all the study data have been reviewed and locked, the principal investigator (PI), statisticians and sponsor will jointly discuss the statistical plan, unblind this study and co-sign the blind codes.
Any modifications of the database after unblinding must be approved by the principal investigator, biostatisticians and data manager in written prior to implementation.
Once received the blind codes, the statistical analysts will carry out statistical analysis per the statistical plan and eventually write the statistical analysis report based on which the principal investigator will write the clinical trial summary report.

Statistical analysis
See the "statistical analysis plan" for details of statistical analysis. Before database lock, the statisticians, principal investigator and sponsor will jointly discuss and finalize the statistical plan in accordance with the data characteristics. This protocol only provides the general statistical requirements.

Primary Populations
The primary efficacy variable will be summarized and analyzed in ITT and PP populations, the secondary efficacy variables will be summarized and analyzed in ITT populations. ITT population will be the primary analysis population.
Full analysis set (FAS): refers to the set of eligible cases and dropout cases excluding the rejected cases. The ITT population will be defined as all randomised patients having received at least one dose of either the tested or the reference treatments.
Per protocol set (PPS): The PP population will be defined as all the subjects who completed the treatment period without any major deviation from the protocol.
Safety set (SS): Safety population will be defined as all the subjects who received at least one treatment and have actual data of safety indexes.
14.2 Statistical Analysis Method

Demographic Characteristics
(1) Consistency with normal distribution: Because this is a randomized and blinded trial with a large sample size, the data is acceptable when close to normal distribution. Appropriate statistical methods or data transformation will be adopted for non-normal distributed data, D method, W method or moment method will be used.
(2) Presence of outliers: statistical and clinical analysis should be carried out to determine the acceptation and rejection.
(3) Handling of the missing values of primary efficacy index: if the primary efficacy data of an individual subjects is missing, missing data were imputed as non-responses.
(4) Analysis of the subjects who did not complete this trial: the cause of each dropout case should be analyzed.

Statistical inference method
(1) Measurement data: t-test, paired t-test, rank sum test, paired rank sum test, median test method, etc.
(2) Numeration data: chi-square test, Fisher's exact test, etc.; Ridit analysis and CMH method can be used to test the ranked data.
(3) Primary efficacy: The response rate will be analyzed using Cochran-Mantel-Haenszel test.
Logistic regression analysis, with center and PWS type as covariates will be used to compare treatment group versus placebo group on primary efficacy. If baseline variables are not balanced between groups, non-balanced variable will be also included as covariates in the model. For response rate at week 8, missing data were imputed as non-responses.
(4) Difference analysis: in primary efficacy analysis, a 40% difference between the treatment and placebo group in response rate is expected to be detected.

Statistical presentation
Hemoporfin for injection for the treatment of port-wine stains Phase III Clinical Trial Protocol Page23/25 (1) The report mainly uses the self-evident tables that include title, notes and number of cases.
(2) The results of repetitively measured data use both tables and the annexed statistical charts at the same time to improve readability.
(3) Difference analysis is represented by the two-sided 95% confidence interval for the intergroup difference in efficacy; all the general statistical tests are two-sided tests, P≤0.05 is considered to have statistical significance.
14.3 Statistical software All statistical analyses will be carried out by the SAS statistical software package (version 9.1.3).

Interim analysis
This study does not have interim analysis. If special circumstances including uncertain efficacy or safety issues emerge during this trial, the sponsor, investigators and statisticians will jointly discuss the issues and make decisions.
14.5 Contents of statistical analysis 1. Case distribution: provide the sizes of different data sets of all groups, distribution of the cases among all centers, comparison of the total dropout rate, and a detailed listing of the reasons for termination.
2. Comparability analysis: demographic data and other baseline indexes are compared to measure the intergroup comparability.
3. Compliance analysis: (1) Drug compliance analysis: compare whether the patients of the two groups have taken the correct doses of trial drugs in timely manner without using the prohibited drugs and food as described in this protocol.
(2) Drug combination analysis: count the number of subjects receiving drug combination in each group and provide a detailed list.
4. Efficacy analysis: PP and ITT analysis of the primary efficacy should be carried out at the same time; because this study is a multicenter clinical trial, the impact of center effect on the efficacy should be considered during analysis.
5. Analysis of the efficacy influencing factors: if there are significant differences in age, gender, disease types, disease conditions and other factors between the two groups before drug treatment or relevant factors significantly affecting the efficacy (e.g. drug combination) during the trial process, these factors should be used as covariates for analysis of covariance or logistic regression analysis during intergroup efficacy comparison.
6. Safety analysis: based on the requirements for correlation of adverse reactions, use listings to describe the AEs and adverse reactions in both groups (including the number of cases of various AEs, the number of cases with "normal shift to abnormal" or "exacerbation of the abnormality" of the laboratory test indexes and abnormal conversion rate before and after this trial), list the causes and explain. Chi-square test is used for statistical analysis of the adverse reactions.

Ethics committee
The trial protocol and ICF must be approved by the "Medical Ethics Committee of Peking University First Hospital"; the approval notice issued by the ethics committee must be obtained before initiating this trial.

GCP guideline
Implementation of this trial complies with the national GCP guidance to protect the subject's rights, safety and interests effectively and ensure the reliability of clinical trial data.

Subject's ICF
The investigators must explain all the ICF contents approved by the ethics committee to the subjects before initiating this trial and obtain the written informed consent signed and dated by the subjects or their legal representatives; a copy of the ICF must be made available to the subjects after obtaining the informed consent.
If both the subjects and their legal representatives are illiterate, a witness should be present throughout the informed process. After a detailed explanation of the ICF, the subjects or their legal representatives can give verbal consent and the witnesses should sign and date the consent form.
When it is impossible to obtain the subject's consent in advance in case of specialty (e.g. emergency), it is necessary to obtain consent from the legal representatives and inform the subjects or their legal representatives of the relevant trial situation as early as possible; the trial can proceed if they give their consent.

Data storage
For purpose of evaluation and supervision by the SFDA and sponsor, the investigators should save all the study data including all the patient's ICF and CRFs, detailed drug dispensing records and other materials with confirmation by the participating subjects (for effective verification of different recorded data such as CRF and hospital's original records) and the original signatures. The investigators should maintain the above data for 5 years after the ending of this clinical trial.
The ownership of all data of this clinical trial belongs to the sponsor Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd.; unless required by the SFDA, the investigators should not disclose Hemoporfin for injection for the treatment of port-wine stains Phase III Clinical Trial Protocol Page25/25 these data to any third party by any means without written approval of the sponsor. Approval by the sponsor in advance is required when the investigators publish the study results in scientific journals or present them at academic conferences. The sponsor has the rights to use these reports for academic promotion purposes.