xml: <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/NCT05969977</url>
    </required_header>
    <id_info>
      <org_study_id>MLD-CT-1.1</org_study_id>
      <nct_id>NCT05969977</nct_id>
    </id_info>
    <brief_title>A First-in-Human Phase 1 Study of Plasmalogen Precursor PPI-1011 in Healthy Adult Volunteers to Assess Safety, Tolerability, and Pharmacokinetics</brief_title>
    <official_title>A Phase 1, Randomized, Double-blind, Placebo-controlled, Combined Single and Multiple Ascending Dose Study of PPI-1011 in Subjects to Assess Safety, Tolerability, and Pharmacokinetics</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>MED-LIFE DISCOVERIES LP</agency>
        <agency_class>Industry</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>BioPharma Services, Inc</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>MED-LIFE DISCOVERIES LP</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>
    </oversight_info>
    <brief_summary>
      <textblock>
        PPI-1011 is being developed as a docosahexaenoic acid (DHA) containing plasmalogen precursor&#xD;
        with good long-term stability, specifically for the treatment of rhizomelic chondrodysplasia&#xD;
        punctata (RCDP), which is an ultra rare type of peroxisomal biogenesis disorder (PBD). The&#xD;
        goal of treatment with PPI-1011 is to increase the levels of plasmalogens within circulation&#xD;
        and tissues, with the hope that this will normalize plasmalogen levels in the body and result&#xD;
        in clinical improvement to patients. The present study is a first-in-human (FIH), phase 1,&#xD;
        randomized, double-blind, placebo-controlled, dose-escalation study to assess the safety,&#xD;
        tolerability and pharmacokinetics (PK) of single and multiple ascending doses of PPI-1011&#xD;
        administered orally to healthy subjects. The study consists of 5 planned single-dose cohorts&#xD;
        (n = 8 per cohort, total randomized 6 active: 2 placebo) with sentinel design. Following a&#xD;
        review of the safety and PK data by the safety review committee and submission to Health&#xD;
        Canada the study will be expanded to include 2 planned multiple-dose cohorts (n = 8 per&#xD;
        cohort, total randomized 6 active: 2 placebo).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This is a randomized, double-blind, placebo-controlled, first-in-human (FIH) study of&#xD;
        PPI-1011 in healthy male and non-pregnant, non-lactating female volunteers. The study will&#xD;
        consist of two parts: single ascending dose (SAD) and multiple ascending dose (MAD). The&#xD;
        study will evaluate the safety, tolerability and PK in 5 planned SAD cohorts with sentinel&#xD;
        design (n=8 per cohort, total randomized 6 active: 2 placebo) and 2 planned MAD cohorts (n=8&#xD;
        per cohort, total randomized 6 active: 2 placebo). Based on accumulating data, additional&#xD;
        single-dose and/or a multiple-dose cohort(s) (n=8 per cohort) may be added to better assess&#xD;
        the safety, tolerability, or PK profile of PPI-1011 to meet study objectives and try to&#xD;
        determine the maximum tolerated dose.&#xD;
  &#xD;
        A sentinel dose in 2 participants (1:1 PPI-1011: placebo) will be performed in each&#xD;
        single-dose cohort to evaluate the safety and tolerability at planned doses. Additional&#xD;
        cohort(s) will be dosed in case a different dose(s) is required based upon the emerging&#xD;
        safety and PK data from the main cohort(s) to provide better assessment for the safety,&#xD;
        tolerability, or PK of PPI-1011. A sentinel design may not be applicable when a cohort with&#xD;
        the same or a higher drug exposure has already been evaluated.&#xD;
  &#xD;
        Single Ascending Dose (SAD):&#xD;
  &#xD;
        The 5 planned single-dose levels are:&#xD;
  &#xD;
        Cohort A 10 mg/kg PPI-1011 or Placebo Cohort B 25 mg/kg PPI-1011 or Placebo Cohort C 50 mg/kg&#xD;
        PPI-1011 or Placebo Cohort D 75 mg/kg PPI-1011 or Placebo Cohort E 100 mg/kg PPI-1011 or&#xD;
        Placebo&#xD;
  &#xD;
        Dose levels may be changed and/or additional cohorts may be added based on emerging safety&#xD;
        and PK data. Subjects enrolled in the single-dose treatment cohorts will receive a single&#xD;
        dose of the study drug (PPI-1011 or placebo) orally on Day 1.&#xD;
  &#xD;
        A period of at least 24 hours will be required between administering study drug to the first&#xD;
        2 subjects (1 active, 1 placebo) and the 6 remaining subjects (5 active, 1 placebo) in the&#xD;
        cohort. If no major safety concerns are observed following 24 hours of observation, dosing of&#xD;
        the remaining 6 participants in that cohort may proceed. The dose-escalation may proceed&#xD;
        after the Safety Review Committee review of the blinded safety data up to at least Day 3 from&#xD;
        all participants in the preceding single-dose cohort. The dose escalation decision will be&#xD;
        based on safety evaluation for an acceptable safety profile as determined by the SRC.&#xD;
  &#xD;
        Cohorts A, B, C, D, and E will be dosed in a non-fasting state.&#xD;
  &#xD;
        Multiple Ascending Dose (MAD):&#xD;
  &#xD;
        The 2 planned multiple-dose levels are:&#xD;
  &#xD;
        Cohort AA:&#xD;
  &#xD;
        Study Drug Dose*: TBD mg/kg PPI-1011 or Placebo Dosing Regimen*: 1 x TBD mg/kg every 24 hours&#xD;
        Duration (Days): 14 Total Dose (mg/kg): TBD&#xD;
  &#xD;
        Cohort BB:&#xD;
  &#xD;
        Study Drug Dose*: TBD mg/kg PPI-1011 or Placebo Dosing Regimen*: 1 x TBD mg/kg every 24 hours&#xD;
        Duration (Days): 14 Total Dose (mg/kg): TBD&#xD;
  &#xD;
        Cohorts AA and BB will be dosed in a non-fasting state.&#xD;
  &#xD;
        *MAD dosing levels will be decided after review of the safety and PK data from the SAD&#xD;
        cohorts. The SRC will propose doses, which will be submitted to Health Canada, together with&#xD;
        the safety and PK data from the SAD. Dose levels may be further adjusted based on emerging&#xD;
        safety and PK data from MAD cohorts.&#xD;
  &#xD;
        Subjects enrolled in the multiple-dose treatment cohorts will receive oral doses of the study&#xD;
        drug (PPI-1011 or placebo) once daily at 24-hour intervals. Thus, the total number of doses&#xD;
        subjects will receive in a MAD cohort will be up to 14 doses. The doses for these cohorts&#xD;
        will be selected after review of the blinded safety and PK data by the SRC and submitted to&#xD;
        Health Canada. The dose in the MAD will not exceed the doses tested in the SAD.&#xD;
  &#xD;
        Treatment Phases:&#xD;
  &#xD;
        Single-Dose Cohorts (In-Clinic):&#xD;
  &#xD;
        Participants will check in on Day -1. On Day 1, participants will receive a single dose of&#xD;
        PPI-1011 or placebo. Participants will remain confined in the clinic from Day -1 until Day 2&#xD;
        (at least 36 hours after dosing). Participant can stay longer in the clinic if deemed&#xD;
        necessary upon the Investigator's discretion.&#xD;
  &#xD;
        Single-Dose Cohorts (Outpatient Visits):&#xD;
  &#xD;
        After completing the in-house confinement period, participants will return to the clinic for&#xD;
        an outpatient visit on Day 3, Day 4, Day 5 and Day 6.&#xD;
  &#xD;
        Multiple-Dose Cohorts (In-Clinic):&#xD;
  &#xD;
        Participants will check in on Day -1. Participants will receive oral doses of PPI-1011 or&#xD;
        placebo from Day 1 to Day 14. Participants will remain confined in the clinic from Day -1&#xD;
        through Day 15 (at least 36 hours after the last dose). Participant can stay longer in the&#xD;
        clinic if deemed necessary upon the Investigator's discretion.&#xD;
  &#xD;
        Multiple-Dose Cohorts (Outpatient Visits):&#xD;
  &#xD;
        After completing the confinement period, participants will return to the clinic for an&#xD;
        outpatient visit on Day 16, Day 17, Day 18 and Day 19.&#xD;
  &#xD;
        Study Numbers:&#xD;
  &#xD;
        Fifty-six (56) healthy volunteers are planned to be enrolled in this study. Forty (40)&#xD;
        subjects will be enrolled in the SAD portion of the study and 16 subjects will be enrolled in&#xD;
        the MAD portion (n=8 per cohort). For SAD cohorts, each cohort will enroll a minimum of 3&#xD;
        subjects of each sex, with at least 2 males and 2 females randomized to the active treatment.&#xD;
        The same may be implemented for MAD cohorts based on emerging safety and PK data.&#xD;
  &#xD;
        Additional subjects (in single [n=8] or multiple dose [n=8] cohorts) may be added to better&#xD;
        assess the safety, tolerability, or PK of PPI-1011 to meet study objectives.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">May 29, 2023</start_date>
    <completion_date type="Anticipated">November 30, 2023</completion_date>
    <primary_completion_date type="Anticipated">November 30, 2023</primary_completion_date>
    <phase>Phase 1</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Sequential Assignment</intervention_model>
      <intervention_model_description>The study consists of 5 planned single-dose cohorts (n = 8 per cohort, total randomized 6 active: 2 placebo) with sentinel design followed by 2 multiple-dose cohorts (n = 8 per cohort, total randomized 6 active: 2 placebo).</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Treatment-emergent adverse events as assessed by the CTCAE scale</measure>
      <time_frame>Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the last dose in multiple ascending dose subjects.</time_frame>
      <description>Emergence of adverse events will be documented for incidence, severity and duration and rated according to the CTCAE criteria.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Pharmacokinetics-AUC</measure>
      <time_frame>Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the last dose in multiple ascending dose subjects.</time_frame>
      <description>Characterize the pharmacokinetics of PPI-1011 using the AUC</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pharmacokinetics-Cmax</measure>
      <time_frame>Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the last dose in multiple ascending dose subjects.</time_frame>
      <description>Characterize the pharmacokinetics of PPI-1011 using the peak serum concentration (Cmax)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pharmacokinetics-Tmax</measure>
      <time_frame>Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the last dose in multiple ascending dose subjects.</time_frame>
      <description>Characterize the pharmacokinetics of PPI-1011 by determining the time of the maximum serum concentration (Tmax).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pharmacokinetics-T1/2</measure>
      <time_frame>Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the last dose in multiple ascending dose subjects.</time_frame>
      <description>Characterize the pharmacokinetics of PPI-1011 by determining the terminal half-life in serum (T1/2).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pharmacokinetics-λ</measure>
      <time_frame>Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the lst dose in multiple ascending dose subjects.</time_frame>
      <description>Characterize the pharmacokinetics of PPI-1011 by determining the terminal elimination rate constant (λ) in serum.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pharmacokinetics-CL/F</measure>
      <time_frame>Up to 6 days post-dose in single ascending dose subjects</time_frame>
      <description>Characterize the pharmacokinetics of PPI-1011 by determining the apparent total body clearance calculated after a single extravascular administration (CL/F).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pharmacokinetics-Vd/F</measure>
      <time_frame>Up to 6 days post-dose in single ascending dose subjects</time_frame>
      <description>Characterize the pharmacokinetics of PPI-1011 by determining the apparent volume of distribution after oral administration based on the terminal phase calculated after a single extravascular administration (Vd/F).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pharmacokinetics-Accumulation ratio (AR)</measure>
      <time_frame>Up to 24 hrs after the final dose in multiple ascending dose participants.</time_frame>
      <description>Characterize the pharmacokinetics of PPI-1011 by determining the accumulation ratio of PPI-1011 following 14 days of oral administration.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">56</enrollment>
    <condition>Rhizomelic Chondrodysplasia Punctata</condition>
    <arm_group>
      <arm_group_label>PPI-1011</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Single Ascending: PPI-1011 at 10, 25, 50, 75 and 100 mg/kg. Multiple Dose: PPI-1011 dose to be based on SAD; duration 14 days; one dose daily.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>Placebo arm.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>PPI-1011</intervention_name>
      <description>PPI-1011 is a liquid oil with light yellow to amber color, clear to slightly opalescent and flows readily at room temperature. It is insoluble in water and miscible with dichloromethane and liquid coconut oil. It is a synthetic glycerolipid derivative, comprised of an assembly of naturally-occurring products including glycerol backbone, an ether-linked hexadecyl group at sn1 position, an all-cis-4, 7, 10, 13, 16, 19-docosahexaenoyl group at sn2 position, and a lipoyl group at sn3 position. It was designed as a plasmalogen precursor and is similar in structure to naturally occurring alkyl-diacyl lipids with the primary difference being the presence of a lipoic acid moiety at the sn3 position. PPI-1011 is formulated in liquid coconut oil containing 0.1% 1-thioglycerol as an antioxidant.</description>
      <arm_group_label>PPI-1011</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>Placebo</description>
      <arm_group_label>Placebo</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Healthy, non-smoking (for at least 6 months prior to first study drug administration)&#xD;
               male, and non-pregnant and non-lactating female (including post-menopausal and&#xD;
               surgically sterile female) volunteers, 18-65 years of age, inclusive at the time of&#xD;
               informed consent.&#xD;
  &#xD;
                 -  Post-menopausal for at least 1 year [confirmed by FSH (16-157 IU/L) and&#xD;
                    17β-estradiol (&lt;202 pmol/L) levels]&#xD;
  &#xD;
                      -  Surgically sterile (Partial or total hysterectomy, bilateral oophorectomy,&#xD;
                         bilateral salpingo-oophorectomy) for at least 6 months [confirmed by&#xD;
                         medical/operative report or if medical/operative report is not available by&#xD;
                         FSH and 17β-estradiol tests, if applicable].&#xD;
  &#xD;
            2. Body mass index (BMI) that is within 18.5 - 30.0 kg/m2, inclusive, and subject weighs&#xD;
               no more than 91.0 kg.&#xD;
  &#xD;
            3. Healthy, according to the medical history, ECG, vital signs, laboratory results and&#xD;
               physical examination as determined by the PI/Sub-Investigator.&#xD;
  &#xD;
            4. Systolic blood pressure between 95-140 mmHg, inclusive, and diastolic blood pressure&#xD;
               between 55-90 mmHg, inclusive, oxygen saturation level between 95% and 100%,&#xD;
               inclusive, and heart rate between 55-100 bpm, inclusive, unless deemed otherwise by&#xD;
               the PI/Sub-Investigator.&#xD;
  &#xD;
            5. Clinical laboratory values within BPSI's most recent acceptable laboratory test range,&#xD;
               and/or values are deemed by the PI/Sub-Investigator as &quot;Not Clinically Significant&quot;.&#xD;
  &#xD;
            6. Ability to comprehend and be informed of the nature of the study, as assessed by BPSI&#xD;
               staff. Capable of giving written informed consent prior to any study related&#xD;
               procedure. Must be able to communicate effectively with clinic staff.&#xD;
  &#xD;
            7. Ability to fast for at least 10 hours and consume standard meals.&#xD;
  &#xD;
            8. Availability to volunteer for the entire study duration and willing to adhere to all&#xD;
               protocol requirements.&#xD;
  &#xD;
            9. Agree not to have a tattoo or body piercing until the end of the study.&#xD;
  &#xD;
           10. Agree not to receive COVD-19 vaccination from 7 days prior to first study drug&#xD;
               administration until 7 days after the last study drug administration or the last&#xD;
               procedure in the study, whichever is later.&#xD;
  &#xD;
           11. Agree not to receive a vaccination (live attenuated vaccine) during the study and&#xD;
               until 60 days after the study has ended (last study procedure)&#xD;
  &#xD;
           12. Female subjects must be non-pregnant and non-lactating and fulfil at least one of the&#xD;
               following:&#xD;
  &#xD;
                 -  Be surgically sterile for a minimum of 6 months (achieved through partial or&#xD;
                    total hysterectomy, bilateral oophorectomy, or bilateral salpingectomy; note that&#xD;
                    tubal ligation is not considered a method of permanent sterilization).&#xD;
  &#xD;
                 -  Post-menopausal for a minimum of 1 year [confirmed by FSH (16-157 IU/L) and&#xD;
                    17β-estradiol (&lt;202 pmol/L) levels]) (post-menopausal is defined as 12&#xD;
                    consecutive months with no menses without an alternative medical cause).&#xD;
  &#xD;
                 -  Agree to avoid pregnancy and use an acceptable highly effective method of&#xD;
                    contraception with male sexual partners from at least 30 days prior to the study&#xD;
                    until at least 30 days after the study has ended (last study procedure).&#xD;
  &#xD;
               Medically acceptable methods of contraception include oral contraceptives, hormonal&#xD;
               patch, implant or injection, hormonal or non-hormonal intrauterine device (IUD)&#xD;
               combined with a barrier method (male or female condom, diaphragm with spermicide, or&#xD;
               cervical cap with spermicide) or double barrier methods (male condom in conjunction&#xD;
               with diaphragm and spermicide, male condom in conjunction with cervical cap and&#xD;
               spermicide). Complete abstinence as a method of contraception is acceptable if it is&#xD;
               in line with the preferred and usual lifestyle of the subject.&#xD;
  &#xD;
               If a subject becomes pregnant during her participation in the study and for 30 days&#xD;
               after she has completed her last study study procedure, she must inform BPSI staff&#xD;
               immediately.&#xD;
  &#xD;
           13. Males who are not vasectomized for at least 6 months prior to dosing and are able to&#xD;
               father children must agree to use an acceptable highly effective method of&#xD;
               contraception with female sexual partners of childbearing potential and not donate&#xD;
               sperm during the study and for at least 30 days after the last study drug&#xD;
               administration.&#xD;
  &#xD;
          Medically acceptable methods of contraception include using a condom with a female sexual&#xD;
          partner of childbearing potential who is using oral contraceptives, hormonal patch, implant&#xD;
          or injection, IUD or system, or diaphragm with spermicide. Complete abstinence as a method&#xD;
          of contraception is acceptable if it is in line with the preferred and usual lifestyle of&#xD;
          the subject.&#xD;
  &#xD;
          If a subject's partner becomes pregnant during his participation in the study and for 30&#xD;
          days after he has completed his last study drug administration, he must inform BPSI staff&#xD;
          immediately.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Known history or presence of any clinically significant hepatic, renal/genitourinary,&#xD;
               gastrointestinal, cardiovascular, cerebrovascular, pulmonary, endocrine,&#xD;
               immunological, musculoskeletal, neurological, psychiatric, dermatological or&#xD;
               hematological disease or condition unless determined as not clinically significant by&#xD;
               the PI/Sub-Investigator.&#xD;
  &#xD;
            2. Clinically significant history or presence of any clinically significant&#xD;
               gastrointestinal pathology (e.g., chronic diarrhea, inflammatory bowel disease),&#xD;
               unresolved gastrointestinal symptoms (e.g., diarrhea, vomiting), or other conditions&#xD;
               known to interfere with the absorption, distribution, metabolism or excretion of the&#xD;
               drug experienced within 7 days prior to first study drug administration, as determined&#xD;
               by the PI/Sub-Investigator.&#xD;
  &#xD;
            3. Presence of any clinically significant illness within 30 days prior to first dosing,&#xD;
               as determined by the PI/Sub-Investigator.&#xD;
  &#xD;
            4. Presence of any significant physical or organ abnormality as determined by the&#xD;
               PI/Sub-Investigator.&#xD;
  &#xD;
            5. A known history or positive test result for human immunodeficiency virus (HIV),&#xD;
               chronic Hepatitis B surface antigen, or Hepatitis C.&#xD;
  &#xD;
            6. A positive test result for drugs of abuse/recreational drugs (marijuana, amphetamines,&#xD;
               barbiturates, cocaine, opiates, phencyclidine and benzodiazepines), alcohol test and&#xD;
               cotinine. Positive pregnancy test for female subjects of childbearing potential.&#xD;
  &#xD;
            7. Known history or presence of:&#xD;
  &#xD;
                 -  Alcohol abuse or dependence within one year prior to first study drug&#xD;
                    administration;&#xD;
  &#xD;
                 -  Drug abuse or dependence;&#xD;
  &#xD;
                 -  Known hypersensitivity or idiosyncratic reaction to PPI-1011, its excipients&#xD;
                    (e.g., liquid coconut oil, 1-thioglycerol etc), and/or related substances;&#xD;
  &#xD;
                 -  Food allergies;&#xD;
  &#xD;
                 -  Presence of any dietary restrictions unless deemed by the PI/Sub-Investigator as&#xD;
                    &quot;Not Clinically Significant&quot;;&#xD;
  &#xD;
                 -  Severe allergic reactions (e.g. anaphylactic reactions, angioedema).&#xD;
  &#xD;
                 -  Intolerance to and/or difficulty with blood sampling through venipuncture.&#xD;
  &#xD;
                 -  Abnormal diet patterns (for any reason) during the four weeks preceding the&#xD;
                    study, including fasting, high protein diets etc.&#xD;
  &#xD;
          10. Individuals who have donated, in the days prior to first study drug administration:&#xD;
  &#xD;
            -  50-499 mL of blood in the previous 30 days;&#xD;
  &#xD;
            -  500 mL or more in the previous 56 days. 11. Donation of plasma by plasmapheresis&#xD;
               within 7 days prior to first study drug administration.&#xD;
  &#xD;
               12. Individuals who have participated in another clinical trial or who received an&#xD;
               investigational drug within 30 days prior to first study drug administration.&#xD;
  &#xD;
               13. Use of any lipid lowering drug/agent including hydroxymethylglutaryl (HMG) CoA&#xD;
               reductase inhibitors (Statins), cholesterol absorbing inhibitors (Ezetimibe), fibric&#xD;
               acid derivatives (Fibrates), bile acid sequestrants, PCSK9 inhibitors, and nicotinic&#xD;
               acid within 30 days prior to first study drug administration and for the duration of&#xD;
               the study.&#xD;
  &#xD;
               14. Use of of any supplements containing DHA, fish oil, krill oil, plasmalogen extract&#xD;
               or scallop extracts within 30 days prior to first study drug administration and for&#xD;
               the duration of the study.&#xD;
  &#xD;
               15. Use of any supplements containing lipoic acid within 30 days prior to first study&#xD;
               drug administration and for the duration of the study.&#xD;
  &#xD;
               16. Use of any prescription medication within 14 days prior to first study drug&#xD;
               administration (except for accepted methods of contraception).&#xD;
  &#xD;
               17. Use of any over-the-counter medications (including oral multivitamins, herbal&#xD;
               and/or dietary supplements) within 14 days prior to first study drug administration&#xD;
               (except for accepted methods of contraception).&#xD;
  &#xD;
               18. Consumption of food or beverages containing grapefruit and/or pomelo within 10&#xD;
               days prior to first study drug administration.&#xD;
  &#xD;
               19. Consumption of food or beverages containing caffeine/methylxanthines, poppy seeds&#xD;
               and/or alcohol within 48 hours before dosing.&#xD;
  &#xD;
               20. Individuals having undergone any major surgery within 6 months prior to the start&#xD;
               of the study, unless deemed otherwise by PI/Sub-Investigator.&#xD;
  &#xD;
               21. Have any other conditions that, in the opinion of the Investigator or Sponsor,&#xD;
               would make the subject unsuitable for inclusion, or could interfere with the subject&#xD;
               participating in or completing the study.&#xD;
  &#xD;
               22. Difficulty with swallowing the study drug (oral solution). 23. Have tongue&#xD;
               piercings and/or mouth jewelry. 24. Women who are pregnant or lactating. 25. Unable or&#xD;
               unwilling to provide informed consent 26. Have had a tattoo or body piercing within 30&#xD;
               days prior to first study drug administration.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>65 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Tara Smith, PhD</last_name>
      <role>Study Director</role>
      <affiliation>MED-LIFE DISCOVERIES LP</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Vaithiegaa Mathanarajan</last_name>
      <phone>+1 437 213 1750</phone>
      <email>vmathanarajan@biopharmaservices.com</email>
    </overall_contact>
    <location>
      <facility>
        <name>Biopharma Services Inc.</name>
        <address>
          <city>Toronto</city>
          <state>Ontario</state>
          <zip>M9L 3A2</zip>
          <country>Canada</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Vaithiegaa Mathanarajan</last_name>
        <phone>1-437-213-1750</phone>
        <email>vmathanarajan@biopharmaservices.com</email>
      </contact>
    </location>
    <location_countries>
      <country>Canada</country>
    </location_countries>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>June 11, 2023</study_first_submitted>
    <study_first_submitted_qc>July 23, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 1, 2023</study_first_posted>
    <last_update_submitted>July 23, 2023</last_update_submitted>
    <last_update_submitted_qc>July 23, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 1, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Phase 1</keyword>
    <keyword>Healthy Adult Volunteer</keyword>
    <keyword>RCDP</keyword>
    <keyword>Plasmalogen</keyword>
    <keyword>Rhizomelic Chondrodysplasia Punctata</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Chondrodysplasia Punctata, Rhizomelic</mesh_term>
      <mesh_term>Chondrodysplasia Punctata</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05969977
  org study id: MLD-CT-1.1
  nct id: NCT05969977
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  PPI-1011 is being developed as a docosahexaenoic acid (DHA) containing plasmalogen precursor
        with good long-term stability, specifically for the treatment of rhizomelic chondrodysplasia
        punctata (RCDP), which is an ultra rare type of peroxisomal biogenesis disorder (PBD). The
        goal of treatment with PPI-1011 is to increase the levels of plasmalogens within circulation
        and tissues, with the hope that this will normalize plasmalogen levels in the body and result
        in clinical improvement to patients. The present study is a first-in-human (FIH), phase 1,
        randomized, double-blind, placebo-controlled, dose-escalation study to assess the safety,
        tolerability and pharmacokinetics (PK) of single and multiple ascending doses of PPI-1011
        administered orally to healthy subjects. The study consists of 5 planned single-dose cohorts
        (n = 8 per cohort, total randomized 6 active: 2 placebo) with sentinel design. Following a
        review of the safety and PK data by the safety review committee and submission to Health
        Canada the study will be expanded to include 2 planned multiple-dose cohorts (n = 8 per
        cohort, total randomized 6 active: 2 placebo).
  This is a randomized, double-blind, placebo-controlled, first-in-human (FIH) study of
        PPI-1011 in healthy male and non-pregnant, non-lactating female volunteers. The study will
        consist of two parts: single ascending dose (SAD) and multiple ascending dose (MAD). The
        study will evaluate the safety, tolerability and PK in 5 planned SAD cohorts with sentinel
        design (n=8 per cohort, total randomized 6 active: 2 placebo) and 2 planned MAD cohorts (n=8
        per cohort, total randomized 6 active: 2 placebo). Based on accumulating data, additional
        single-dose and/or a multiple-dose cohort(s) (n=8 per cohort) may be added to better assess
        the safety, tolerability, or PK profile of PPI-1011 to meet study objectives and try to
        determine the maximum tolerated dose.
  
        A sentinel dose in 2 participants (1:1 PPI-1011: placebo) will be performed in each
        single-dose cohort to evaluate the safety and tolerability at planned doses. Additional
        cohort(s) will be dosed in case a different dose(s) is required based upon the emerging
        safety and PK data from the main cohort(s) to provide better assessment for the safety,
        tolerability, or PK of PPI-1011. A sentinel design may not be applicable when a cohort with
        the same or a higher drug exposure has already been evaluated.
  
        Single Ascending Dose (SAD):
  
        The 5 planned single-dose levels are:
  
        Cohort A 10 mg/kg PPI-1011 or Placebo Cohort B 25 mg/kg PPI-1011 or Placebo Cohort C 50 mg/kg
        PPI-1011 or Placebo Cohort D 75 mg/kg PPI-1011 or Placebo Cohort E 100 mg/kg PPI-1011 or
        Placebo
  
        Dose levels may be changed and/or additional cohorts may be added based on emerging safety
        and PK data. Subjects enrolled in the single-dose treatment cohorts will receive a single
        dose of the study drug (PPI-1011 or placebo) orally on Day 1.
  
        A period of at least 24 hours will be required between administering study drug to the first
        2 subjects (1 active, 1 placebo) and the 6 remaining subjects (5 active, 1 placebo) in the
        cohort. If no major safety concerns are observed following 24 hours of observation, dosing of
        the remaining 6 participants in that cohort may proceed. The dose-escalation may proceed
        after the Safety Review Committee review of the blinded safety data up to at least Day 3 from
        all participants in the preceding single-dose cohort. The dose escalation decision will be
        based on safety evaluation for an acceptable safety profile as determined by the SRC.
  
        Cohorts A, B, C, D, and E will be dosed in a non-fasting state.
  
        Multiple Ascending Dose (MAD):
  
        The 2 planned multiple-dose levels are:
  
        Cohort AA:
  
        Study Drug Dose*: TBD mg/kg PPI-1011 or Placebo Dosing Regimen*: 1 x TBD mg/kg every 24 hours
        Duration (Days): 14 Total Dose (mg/kg): TBD
  
        Cohort BB:
  
        Study Drug Dose*: TBD mg/kg PPI-1011 or Placebo Dosing Regimen*: 1 x TBD mg/kg every 24 hours
        Duration (Days): 14 Total Dose (mg/kg): TBD
  
        Cohorts AA and BB will be dosed in a non-fasting state.
  
        *MAD dosing levels will be decided after review of the safety and PK data from the SAD
        cohorts. The SRC will propose doses, which will be submitted to Health Canada, together with
        the safety and PK data from the SAD. Dose levels may be further adjusted based on emerging
        safety and PK data from MAD cohorts.
  
        Subjects enrolled in the multiple-dose treatment cohorts will receive oral doses of the study
        drug (PPI-1011 or placebo) once daily at 24-hour intervals. Thus, the total number of doses
        subjects will receive in a MAD cohort will be up to 14 doses. The doses for these cohorts
        will be selected after review of the blinded safety and PK data by the SRC and submitted to
        Health Canada. The dose in the MAD will not exceed the doses tested in the SAD.
  
        Treatment Phases:
  
        Single-Dose Cohorts (In-Clinic):
  
        Participants will check in on Day -1. On Day 1, participants will receive a single dose of
        PPI-1011 or placebo. Participants will remain confined in the clinic from Day -1 until Day 2
        (at least 36 hours after dosing). Participant can stay longer in the clinic if deemed
        necessary upon the Investigator's discretion.
  
        Single-Dose Cohorts (Outpatient Visits):
  
        After completing the in-house confinement period, participants will return to the clinic for
        an outpatient visit on Day 3, Day 4, Day 5 and Day 6.
  
        Multiple-Dose Cohorts (In-Clinic):
  
        Participants will check in on Day -1. Participants will receive oral doses of PPI-1011 or
        placebo from Day 1 to Day 14. Participants will remain confined in the clinic from Day -1
        through Day 15 (at least 36 hours after the last dose). Participant can stay longer in the
        clinic if deemed necessary upon the Investigator's discretion.
  
        Multiple-Dose Cohorts (Outpatient Visits):
  
        After completing the confinement period, participants will return to the clinic for an
        outpatient visit on Day 16, Day 17, Day 18 and Day 19.
  
        Study Numbers:
  
        Fifty-six (56) healthy volunteers are planned to be enrolled in this study. Forty (40)
        subjects will be enrolled in the SAD portion of the study and 16 subjects will be enrolled in
        the MAD portion (n=8 per cohort). For SAD cohorts, each cohort will enroll a minimum of 3
        subjects of each sex, with at least 2 males and 2 females randomized to the active treatment.
        The same may be implemented for MAD cohorts based on emerging safety and PK data.
  
        Additional subjects (in single [n=8] or multiple dose [n=8] cohorts) may be added to better
        assess the safety, tolerability, or PK of PPI-1011 to meet study objectives.
  allocation: Randomized
  intervention model: Sequential Assignment
  intervention model description: The study consists of 5 planned single-dose cohorts (n = 8 per cohort, total randomized 6 active: 2 placebo) with sentinel design followed by 2 multiple-dose cohorts (n = 8 per cohort, total randomized 6 active: 2 placebo).
  primary purpose: Treatment
  masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  measure: Treatment-emergent adverse events as assessed by the CTCAE scale
  time frame: Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the last dose in multiple ascending dose subjects.
  description: Emergence of adverse events will be documented for incidence, severity and duration and rated according to the CTCAE criteria.
  measure: Pharmacokinetics-AUC
  time frame: Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the last dose in multiple ascending dose subjects.
  description: Characterize the pharmacokinetics of PPI-1011 using the AUC
  measure: Pharmacokinetics-Cmax
  time frame: Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the last dose in multiple ascending dose subjects.
  description: Characterize the pharmacokinetics of PPI-1011 using the peak serum concentration (Cmax)
  measure: Pharmacokinetics-Tmax
  time frame: Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the last dose in multiple ascending dose subjects.
  description: Characterize the pharmacokinetics of PPI-1011 by determining the time of the maximum serum concentration (Tmax).
  measure: Pharmacokinetics-T1/2
  time frame: Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the last dose in multiple ascending dose subjects.
  description: Characterize the pharmacokinetics of PPI-1011 by determining the terminal half-life in serum (T1/2).
  measure: Pharmacokinetics-λ
  time frame: Up to 6 days post-dose in single ascending dose subjects and up to 7 days post the lst dose in multiple ascending dose subjects.
  description: Characterize the pharmacokinetics of PPI-1011 by determining the terminal elimination rate constant (λ) in serum.
  measure: Pharmacokinetics-CL/F
  time frame: Up to 6 days post-dose in single ascending dose subjects
  description: Characterize the pharmacokinetics of PPI-1011 by determining the apparent total body clearance calculated after a single extravascular administration (CL/F).
  measure: Pharmacokinetics-Vd/F
  time frame: Up to 6 days post-dose in single ascending dose subjects
  description: Characterize the pharmacokinetics of PPI-1011 by determining the apparent volume of distribution after oral administration based on the terminal phase calculated after a single extravascular administration (Vd/F).
  measure: Pharmacokinetics-Accumulation ratio (AR)
  time frame: Up to 24 hrs after the final dose in multiple ascending dose participants.
  description: Characterize the pharmacokinetics of PPI-1011 by determining the accumulation ratio of PPI-1011 following 14 days of oral administration.
  arm group label: PPI-1011
  arm group type: Experimental
  description: Single Ascending: PPI-1011 at 10, 25, 50, 75 and 100 mg/kg. Multiple Dose: PPI-1011 dose to be based on SAD; duration 14 days; one dose daily.
  arm group label: Placebo
  arm group type: Placebo Comparator
  description: Placebo arm.
  intervention type: Drug
  intervention name: PPI-1011
  description: PPI-1011 is a liquid oil with light yellow to amber color, clear to slightly opalescent and flows readily at room temperature. It is insoluble in water and miscible with dichloromethane and liquid coconut oil. It is a synthetic glycerolipid derivative, comprised of an assembly of naturally-occurring products including glycerol backbone, an ether-linked hexadecyl group at sn1 position, an all-cis-4, 7, 10, 13, 16, 19-docosahexaenoyl group at sn2 position, and a lipoyl group at sn3 position. It was designed as a plasmalogen precursor and is similar in structure to naturally occurring alkyl-diacyl lipids with the primary difference being the presence of a lipoic acid moiety at the sn3 position. PPI-1011 is formulated in liquid coconut oil containing 0.1% 1-thioglycerol as an antioxidant.
  arm group label: PPI-1011
  intervention type: Drug
  intervention name: Placebo
  description: Placebo
  arm group label: Placebo
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 65 Years
  healthy volunteers: Accepts Healthy Volunteers
  last name: Tara Smith, PhD
  role: Study Director
  affiliation: MED-LIFE DISCOVERIES LP
  last name: Vaithiegaa Mathanarajan
  phone: +1 437 213 1750
  email: vmathanarajan@biopharmaservices.com
  facility: 
  status: Recruiting
  contact: 
  country: Canada
  responsible party type: Sponsor
  mesh term: Chondrodysplasia Punctata, Rhizomelic
  mesh term: Chondrodysplasia Punctata
  sharing ipd: No