<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04416113</url>
  </required_header>
  <id_info>
    <org_study_id>Cu-NILES/16/20</org_study_id>
    <nct_id>NCT04416113</nct_id>
  </id_info>
  <brief_title>Photodynamic Therapy for the Treatment of COVID-19</brief_title>
  <official_title>Photobiomodulation and Photodynamic Therapy for the Treatment of COVID-19 A Randomized Controlled Clinical Trials</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cairo University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cairo University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Until now there is no vaccine or reliable treatment for the COVID-19 pandemic. The&#xD;
      fundamental mechanisms of non-invasive low-level laser in photobiomodulation (PBM) and&#xD;
      photodynamic therapy is to stimulate the mitochondrial respiratory chain where a transient&#xD;
      release of non-cytotoxic levels of reactive oxygen species (ROS) will lead to positive&#xD;
      modulation of the immune response. As previous studies mentioned that the most important&#xD;
      strategy for COVID-19 management is oxygenation and faster rehabilitation of the damaged&#xD;
      tissue, antiviral effects, and, ﬁnally, reduction or controlling the cytokine storm by&#xD;
      reducing inﬂammatory agents. PBM may be used as adjuvant therapy or even an alternative&#xD;
      therapy in all these mechanisms without side effects and drug interactions.&#xD;
&#xD;
      Objectives The objective of this clinical trial is to use the photobiomodulation therapy&#xD;
      (PBMT), and photodynamic therapy as adjuvant therapy or even an alternative therapy for&#xD;
      Covide-19.&#xD;
&#xD;
      Patients and methods A randomized controlled study will be conducted on 60 patients of&#xD;
      positive COVID 19. The patients will be divided into 3 equal groups. Group, I will receive a&#xD;
      low-level laser (diode laser 980nm) from laser watch for 30 minutes, 20 J for 3 to 5 days,&#xD;
      and laser acupuncture. Group 2 will be treated with photodynamic therapy by injecting the&#xD;
      methylene blue as a photosensitizer and irradiated with laser watch (diode laser 670 nm).&#xD;
      Group 3 will serve as a control. Evaluation methods will include laboratory investigations&#xD;
      and CT chest.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Treatment protocol:&#xD;
&#xD;
      This clinical study was conducted following the approval of the research ethics committee for&#xD;
      experimental and clinical studies at the National Institute of Laser Enhanced Sciences, Cairo&#xD;
      University, Egypt (approval number CU-NILES/16/20 May 2020) with the principles outlined in&#xD;
      the Declaration of Helsinki for human subject experimentation being followed. Informed&#xD;
      consent will be obtained from the patients, and the privacy rights will be continuously&#xD;
      observed.&#xD;
&#xD;
      This study will be conducted on 60 patients with COVID 19 of all ages and both sex.&#xD;
&#xD;
      Patients will be divided into 3 groups:&#xD;
&#xD;
      Group 1: photobiomodulation This group included the use of laser watch and laser acupuncture&#xD;
&#xD;
      Laser watch Patients will be subjected to low level laser (diode laser 980nm) for 30 minutes,&#xD;
      the recommended dose based on previous study is 20 J for 3 to 7 days.&#xD;
&#xD;
      The laser device:&#xD;
&#xD;
      Laser watched applied at the wrist on the radial artery.&#xD;
&#xD;
      Laser acupuncture Patients will receive laser acupuncture using pulsed infra- red laser,&#xD;
      wavelength 880 / 905/980 nm, spot size diameter of 5 mm frequency 2500 Hz, average power 15&#xD;
      W, energy of 225 mJ applied for 2 min per point and pulse width of 100 ns and area = 0.2 cm2.&#xD;
      Patients will receive one session daily for 7 days.&#xD;
&#xD;
      Laser acupuncture was applied at the following points (World Health Organization 2008). The&#xD;
      points where the laser acupuncture will be applied are demonstrated in the following figures:&#xD;
&#xD;
        -  For cough and chest tightness, wheezes and congestion: LU1, 2, 5, 7, 9, 14 (fig.1) For&#xD;
           improving immunity and blood circulation, also for dyspnea and GIT manifestation also,&#xD;
           breaks up blood stagnation in the chest: ST36&#xD;
&#xD;
        -  Affects the throat, chest, lungs: CV12, CV4 Sore throat, coughing, &amp; asthma: KI3 Fig&#xD;
&#xD;
        -  Laser acupuncture device could be applied simultaneously on all points same time by&#xD;
           special multi-channel device (fig3)&#xD;
&#xD;
      Group 2 (photodynamic therapy) Methylene blue injection USP 1% will be used as a&#xD;
      photosensitizer in PDT.&#xD;
&#xD;
        -  0.1 to 0.2 mL of 1% solution per kilogram of body weight Methylene Blue (methylene blue&#xD;
           injection) will be injected intravenously very slowly over a period of several minutes&#xD;
           to prevent local high concentration of the compound from producing methemoglobin (low&#xD;
           concentrations will convert methemoglobin to hemoglobin and will be activated by light).&#xD;
&#xD;
        -  After one hour apply Light dose: 100 - 200 J/cm2 50-100 mW/cm2. (50 mW/cm2 increased the&#xD;
           phototoxic response as well as fractionated light application).&#xD;
&#xD;
        -  Session will be done twice per week&#xD;
&#xD;
      The laser device:&#xD;
&#xD;
      Laser watched applied at the wrist on the radial artery. Group 3: positive control This group&#xD;
      will include patients who are subjected to conventional treatment Evaluation and assessment&#xD;
      All patients will be subjected to thorough examination with complete personal and clinical&#xD;
      history and will do the following before and after treatment: PCR, CBC, CRP, ESR, D dimers,&#xD;
      liver enzymes, and Ferritin, CT chest&#xD;
&#xD;
      Endpoint Treatment will be stopped if no improvement occurred after one week&#xD;
&#xD;
      Statistical analysis&#xD;
&#xD;
      All statistical calculations were done using computer programs SPSS (Statistical Package for&#xD;
      the Social Science; SPSS Inc., Chicago, IL) v.16 for Microsoft Windows. Continuous variables&#xD;
      were tested for normality by the Shapiro-Wilk normality test. Values are presented as mean ±&#xD;
      standard deviation, or in the case of non-normally distributed data as median and&#xD;
      inter-quartile range. For comparison between paired parameters (before and after treatment),&#xD;
      paired t-test or the Wilcoxon matched-pairs signed-rank test were used according to data&#xD;
      normality. For comparison between independent groups, the chi-squared test was used to&#xD;
      compare percentages between different groups of patients. Normally distributed data were&#xD;
      analyzed using independent samples t-test. Non-normally distributed data were analyzed using&#xD;
      the Mann-Whitney U-test. p values &lt;.05 were considered statistically significant.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">August 5, 2021</start_date>
  <completion_date type="Anticipated">February 2022</completion_date>
  <primary_completion_date type="Anticipated">December 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>A randomized controlled study will be conducted on 60 patients of positive COVID 19. The patients will be divided into 3 equal groups. Group I will receive low level laser (diode laser 980nm) from laser watch for 30 minutes, 20 J for 3 to 5 days and laser acupuncture. Group 2 will be treated with photodynamic therapy by injecting the methylene blue as a photosensitizer and irradiated with laser watch (diode laser 670 nm). Group 3 will serve as a control. Evaluation methods will include laboratory investigations and CT chest.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Participants Achieving Either a Major Clinical Response or Partial Clinical Response (PCR) Defined by WHO</measure>
    <time_frame>2 weeks</time_frame>
    <description>Molecular-based assays:&#xD;
N COV 2019&#xD;
Antigen assays:&#xD;
SARS (COV) antigen, Serology assays:&#xD;
N COV 2019 antibodies medical respiratory clearance questionnaire</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Photodynamic Therapy&amp; Low Level Laser in Management of COVID 19</condition>
  <arm_group>
    <arm_group_label>photobiomodulation group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Laser watch Patients will be subjected to low-level laser (diode laser 980nm) for 30 minutes, the recommended dose based on the previous study is 20 J for 3 to 7 days.&#xD;
The laser device:&#xD;
Laser watched applied at the wrist on the radial artery.&#xD;
Laser acupuncture</description>
  </arm_group>
  <arm_group>
    <arm_group_label>photodynamic group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Methylene blue injection USP 1% will be used as a photosensitizer in PDT.&#xD;
0.1 to 0.2 mL of 1% solution per kilogram of body weight Methylene Blue (methylene blue injection) will be injected intravenously very slowly over a period of several minutes to&#xD;
After one hour apply Light dose: 100 - 200 J/cm2 50-100 mW/cm2. (50 mW/cm2 increased the phototoxic response as well as the fractionated light application).&#xD;
The session will be done twice per week&#xD;
Laser watched applied at the wrist on the radial artery.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>positive control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This group will include patients who are subjected to conventional treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>photobiomodulation and photodynamic therapy</intervention_name>
    <description>antiviral treatment</description>
    <arm_group_label>photobiomodulation group</arm_group_label>
    <arm_group_label>photodynamic group</arm_group_label>
    <arm_group_label>positive control</arm_group_label>
    <other_name>conventional</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Hospitalized patients with Positive COVID 19 test suffering from Fever, cough,&#xD;
             shortness of breath, chills, muscle pain, the new loss of taste or smell, vomiting or&#xD;
             diarrhea, and/or sore throat&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients in critical cases who admitted to the ICU, bacterial pneumonia, and&#xD;
             respiratory distress grade III, IV, and patients on a mechanical ventilator.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Abeer Attia Tawfik</name>
      <address>
        <city>Giza</city>
        <zip>11236</zip>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <reference>
    <citation>Mahase E. Covid-19: what treatments are being investigated? BMJ. 2020 Mar 26;368:m1252. doi: 10.1136/bmj.m1252. No abstract available.</citation>
    <PMID>32217607</PMID>
  </reference>
  <reference>
    <citation>Fekrazad R. Photobiomodulation and Antiviral Photodynamic Therapy as a Possible Novel Approach in COVID-19 Management. Photobiomodul Photomed Laser Surg. 2020 May;38(5):255-257. doi: 10.1089/photob.2020.4868. Epub 2020 Apr 23. No abstract available.</citation>
    <PMID>32326830</PMID>
  </reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>May 24, 2020</study_first_submitted>
  <study_first_submitted_qc>June 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>August 5, 2021</last_update_submitted>
  <last_update_submitted_qc>August 5, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 6, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cairo University</investigator_affiliation>
    <investigator_full_name>Abeer Attia Tawfik</investigator_full_name>
    <investigator_title>professor of dermatology and laser at national institute of laser enhanced sciences</investigator_title>
  </responsible_party>
  <keyword>photodynamic therapy</keyword>
  <keyword>low level laser therapy</keyword>
  <keyword>COVID 19 virus</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>if the results are positive we will invite other researchers to share</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04416113
org study id: Cu-NILES/16/20
nct id: NCT04416113
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Until now there is no vaccine or reliable treatment for the COVID-19 pandemic. The
      fundamental mechanisms of non-invasive low-level laser in photobiomodulation (PBM) and
      photodynamic therapy is to stimulate the mitochondrial respiratory chain where a transient
      release of non-cytotoxic levels of reactive oxygen species (ROS) will lead to positive
      modulation of the immune response. As previous studies mentioned that the most important
      strategy for COVID-19 management is oxygenation and faster rehabilitation of the damaged
      tissue, antiviral effects, and, ﬁnally, reduction or controlling the cytokine storm by
      reducing inﬂammatory agents. PBM may be used as adjuvant therapy or even an alternative
      therapy in all these mechanisms without side effects and drug interactions.

      Objectives The objective of this clinical trial is to use the photobiomodulation therapy
      (PBMT), and photodynamic therapy as adjuvant therapy or even an alternative therapy for
      Covide-19.

      Patients and methods A randomized controlled study will be conducted on 60 patients of
      positive COVID 19. The patients will be divided into 3 equal groups. Group, I will receive a
      low-level laser (diode laser 980nm) from laser watch for 30 minutes, 20 J for 3 to 5 days,
      and laser acupuncture. Group 2 will be treated with photodynamic therapy by injecting the
      methylene blue as a photosensitizer and irradiated with laser watch (diode laser 670 nm).
      Group 3 will serve as a control. Evaluation methods will include laboratory investigations
      and CT chest.
Treatment protocol:

      This clinical study was conducted following the approval of the research ethics committee for
      experimental and clinical studies at the National Institute of Laser Enhanced Sciences, Cairo
      University, Egypt (approval number CU-NILES/16/20 May 2020) with the principles outlined in
      the Declaration of Helsinki for human subject experimentation being followed. Informed
      consent will be obtained from the patients, and the privacy rights will be continuously
      observed.

      This study will be conducted on 60 patients with COVID 19 of all ages and both sex.

      Patients will be divided into 3 groups:

      Group 1: photobiomodulation This group included the use of laser watch and laser acupuncture

      Laser watch Patients will be subjected to low level laser (diode laser 980nm) for 30 minutes,
      the recommended dose based on previous study is 20 J for 3 to 7 days.

      The laser device:

      Laser watched applied at the wrist on the radial artery.

      Laser acupuncture Patients will receive laser acupuncture using pulsed infra- red laser,
      wavelength 880 / 905/980 nm, spot size diameter of 5 mm frequency 2500 Hz, average power 15
      W, energy of 225 mJ applied for 2 min per point and pulse width of 100 ns and area = 0.2 cm2.
      Patients will receive one session daily for 7 days.

      Laser acupuncture was applied at the following points (World Health Organization 2008). The
      points where the laser acupuncture will be applied are demonstrated in the following figures:

        -  For cough and chest tightness, wheezes and congestion: LU1, 2, 5, 7, 9, 14 (fig.1) For
           improving immunity and blood circulation, also for dyspnea and GIT manifestation also,
           breaks up blood stagnation in the chest: ST36

        -  Affects the throat, chest, lungs: CV12, CV4 Sore throat, coughing, & asthma: KI3 Fig

        -  Laser acupuncture device could be applied simultaneously on all points same time by
           special multi-channel device (fig3)

      Group 2 (photodynamic therapy) Methylene blue injection USP 1% will be used as a
      photosensitizer in PDT.

        -  0.1 to 0.2 mL of 1% solution per kilogram of body weight Methylene Blue (methylene blue
           injection) will be injected intravenously very slowly over a period of several minutes
           to prevent local high concentration of the compound from producing methemoglobin (low
           concentrations will convert methemoglobin to hemoglobin and will be activated by light).

        -  After one hour apply Light dose: 100 - 200 J/cm2 50-100 mW/cm2. (50 mW/cm2 increased the
           phototoxic response as well as fractionated light application).

        -  Session will be done twice per week

      The laser device:

      Laser watched applied at the wrist on the radial artery. Group 3: positive control This group
      will include patients who are subjected to conventional treatment Evaluation and assessment
      All patients will be subjected to thorough examination with complete personal and clinical
      history and will do the following before and after treatment: PCR, CBC, CRP, ESR, D dimers,
      liver enzymes, and Ferritin, CT chest

      Endpoint Treatment will be stopped if no improvement occurred after one week

      Statistical analysis

      All statistical calculations were done using computer programs SPSS (Statistical Package for
      the Social Science; SPSS Inc., Chicago, IL) v.16 for Microsoft Windows. Continuous variables
      were tested for normality by the Shapiro-Wilk normality test. Values are presented as mean ±
      standard deviation, or in the case of non-normally distributed data as median and
      inter-quartile range. For comparison between paired parameters (before and after treatment),
      paired t-test or the Wilcoxon matched-pairs signed-rank test were used according to data
      normality. For comparison between independent groups, the chi-squared test was used to
      compare percentages between different groups of patients. Normally distributed data were
      analyzed using independent samples t-test. Non-normally distributed data were analyzed using
      the Mann-Whitney U-test. p values <.05 were considered statistically significant.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A randomized controlled study will be conducted on 60 patients of positive COVID 19. The patients will be divided into 3 equal groups. Group I will receive low level laser (diode laser 980nm) from laser watch for 30 minutes, 20 J for 3 to 5 days and laser acupuncture. Group 2 will be treated with photodynamic therapy by injecting the methylene blue as a photosensitizer and irradiated with laser watch (diode laser 670 nm). Group 3 will serve as a control. Evaluation methods will include laboratory investigations and CT chest.
primary purpose: Treatment
masking: Single (Participant)
measure: Participants Achieving Either a Major Clinical Response or Partial Clinical Response (PCR) Defined by WHO
time frame: 2 weeks
description: Molecular-based assays:
N COV 2019
Antigen assays:
SARS (COV) antigen, Serology assays:
N COV 2019 antibodies medical respiratory clearance questionnaire
arm group label: photobiomodulation group
arm group type: Active Comparator
description: Laser watch Patients will be subjected to low-level laser (diode laser 980nm) for 30 minutes, the recommended dose based on the previous study is 20 J for 3 to 7 days.
The laser device:
Laser watched applied at the wrist on the radial artery.
Laser acupuncture
arm group label: photodynamic group
arm group type: Active Comparator
description: Methylene blue injection USP 1% will be used as a photosensitizer in PDT.
0.1 to 0.2 mL of 1% solution per kilogram of body weight Methylene Blue (methylene blue injection) will be injected intravenously very slowly over a period of several minutes to
After one hour apply Light dose: 100 - 200 J/cm2 50-100 mW/cm2. (50 mW/cm2 increased the phototoxic response as well as the fractionated light application).
The session will be done twice per week
Laser watched applied at the wrist on the radial artery.
arm group label: positive control
arm group type: Active Comparator
description: This group will include patients who are subjected to conventional treatment
intervention type: Procedure
intervention name: photobiomodulation and photodynamic therapy
description: antiviral treatment
arm group label: photobiomodulation group
arm group label: photodynamic group
arm group label: positive control
other name: conventional
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
facility: 
country: Egypt
citation: Mahase E. Covid-19: what treatments are being investigated? BMJ. 2020 Mar 26;368:m1252. doi: 10.1136/bmj.m1252. No abstract available.
PMID: 32217607
citation: Fekrazad R. Photobiomodulation and Antiviral Photodynamic Therapy as a Possible Novel Approach in COVID-19 Management. Photobiomodul Photomed Laser Surg. 2020 May;38(5):255-257. doi: 10.1089/photob.2020.4868. Epub 2020 Apr 23. No abstract available.
PMID: 32326830
responsible party type: Principal Investigator
investigator affiliation: Cairo University
investigator full name: Abeer Attia Tawfik
investigator title: professor of dermatology and laser at national institute of laser enhanced sciences
mesh term: COVID-19
sharing ipd: No
ipd description: if the results are positive we will invite other researchers to share