<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/NCT01692834</url>
  </required_header>
  <id_info>
    <org_study_id>99752</org_study_id>
    <nct_id>NCT01692834</nct_id>
  </id_info>
  <brief_title>A Study to Compare the Bioavailability and Pharmacokinetics of Cyclosporine After Intravenous Administration of NEUROSTAT®, a CREMOPHOR® EL-free Lipid Emulsion, and SANDIMMUNE® Injection (a Suspension of Cyclosporine in CREMOPHOR® EL) in Healthy Volunteers</brief_title>
  <official_title>A Study to Compare the Bioavailability and Pharmacokinetics of Cyclosporine After Intravenous Administration of NEUROSTAT®, a CREMOPHOR® EL-free Lipid Emulsion, and SANDIMMUNE® Injection (a Suspension of Cyclosporine in CREMOPHOR® EL) in Healthy Volunteers ; An Open-label, Subject-blind, Laboratory-blind, Single-dose (5 mg/kg Infusion), Randomised, Two-period Crossover Tolerability Study Carried Out in Healthy Male and Female Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NeuroVive Pharmaceutical AB</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Abliva AB</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To compare the bioavailability, pharmacokinetic profiles and the tolerability of two&#xD;
      formulations of intravenous cyclosporine in healthy volunteers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Participants were randomized into two treatment sequences: the test product followed by the&#xD;
      reference product or vice versa. There was a washout period set to 14-21 days between the&#xD;
      first and second treatment period. Through an indwelling IV cannula, the subjects received&#xD;
      either 5 mg/kg NeuroSTAT® (test) or 5 mg/kg Sandimmune® (reference), infused at a constant&#xD;
      rate over 4 h with a syringe pump. A total of 22 blood samples for Cyclosporine analysis were&#xD;
      obtained pre-dose and at pre specified time points with last sample 48 h after start of&#xD;
      infusion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2009</start_date>
  <completion_date type="Actual">January 2010</completion_date>
  <primary_completion_date type="Actual">January 2010</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>Crossover Assignment</intervention_model>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Bioequivalence between test and reference product.</measure>
    <time_frame>Repeated samplings from pre-dose to 48 hours</time_frame>
    <description>To compare the bioavailability and pharmacokinetics of a single dose of the test product, NeuroSTAT® 5 mg/mL ready-to-use Cremophor® EL-free cyclosporine with the reference product, Sandimmune® Injection 50 mg/mL Cremophor® EL suspension (each 1 mL diluted in 20 mL saline). For this purpose the pharmacokinetics of cyclosporine was compared during and after intravenous (IV) infusion, over 4 hours, of a single dose of 5 mg/kg of each of the two formulations to healthy subjects. The primary parameters are area under the blood concentration-time curves (AUC) from time zero to time of last measurable concentration (AUC0-last), time zero to infinity (AUC0-∞), time 4 h to infinity (AUC4-∞). Point estimates and 90 % Confidence IntervaI (CI) for the NeuroSTAT®/Sandimmune® geometric mean ratios of all variables are calculated. The two products are considered bioequivalent if the 90 % CI for the primary variables are within the FDA and EMA approved range of 0.8 and 1.25.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tolerability comparison of test and reference product</measure>
    <time_frame>From start of study drug administration to last blood sampling at 48 hours</time_frame>
    <description>To compare the tolerability profiles of the test product, NeuroSTAT® 5 mg/mL ready-to-use Cremophor® EL-free cyclosporine USP/Ph. Eur. lipid emulsion, with the reference product, Sandimmune® Injection (cyclosporine injection, USP) 50 mg/mL Cremophor® EL suspension (each 1 mL diluted in 20 mL saline). The proportions of overall adverse events and adverse events per organ class (as defined by the Medical Dictionary for Regulatory Activities) are compared between NeuroSTAT® and Sandimmune® by means of 95 % CI for the difference between paired proportions and p-values.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">65</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Cyclosporine in Cremophor EL®</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Dosing 5 mg/kg infused at a constant rate over 4 h with a syringe pump.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cyclosporine in lipid emulsion</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Dosing 5 mg/kg infused at a constant rate over 4 h with a syringe pump.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sandimmune® Injection</intervention_name>
    <arm_group_label>Cyclosporine in Cremophor EL®</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>NeuroSTAT®</intervention_name>
    <arm_group_label>Cyclosporine in lipid emulsion</arm_group_label>
    <other_name>CicloMulsion® (ready-to-use lipid emulsion of Cyclosporine A)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Healthy male and female subjects 18 to &lt; 56 years of age.&#xD;
&#xD;
          2. Caucasian and Non-Caucasian subjects.&#xD;
&#xD;
          3. Body mass within 15% of the ideal mass in relation to height and age (this relates to&#xD;
             a Body Mass Index [BMI] of 19 - 33 kg/m2).&#xD;
&#xD;
          4. Body mass not less than 60 kg and not more than 100 kg.&#xD;
&#xD;
          5. Findings within the range of clinical acceptability in medical history and physical&#xD;
             examination, and laboratory results within the laboratory reference ranges for the&#xD;
             relevant laboratory tests (unless the investigator considered the deviation to be&#xD;
             irrelevant for the purpose of the study).&#xD;
&#xD;
          6. Normal 12-lead ECG and vital signs, or abnormalities which the investigator did not&#xD;
             consider a disqualification for participation in the study.&#xD;
&#xD;
          7. Willingness to undergo pre-, interim- and post-study physical examinations, vital&#xD;
             signs and laboratory investigations.&#xD;
&#xD;
          8. Ability to comprehend and willingness to have signed both statements of informed&#xD;
             consent (for screening and period-related procedures).&#xD;
&#xD;
          9. Non-smoker or past smoker who had stopped the use of any form of tobacco, including&#xD;
             snuff or similar products, at least 3 months before the first administration of study&#xD;
             medication.&#xD;
&#xD;
         10. Female subjects of childbearing potential, but who were not pregnant, not lactating&#xD;
             and who were either abstaining from sexual activity or using medically acceptable and&#xD;
             reliable methods of contraception for the duration of the study. Examples of reliable&#xD;
             methods of contraception included tubal ligation, hysterectomy, intrauterine device,&#xD;
             or a barrier method combined with a spermicide. The use of hormonal contraceptives&#xD;
             (including a hormonal intrauterine device) was not allowed. Females not of&#xD;
             childbearing potential may have been included if they had no menstrual period for one&#xD;
             year and were considered as post-menopausal. A pregnancy test was performed prior to&#xD;
             each cyclosporine dosing to all women of childbearing potential.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional&#xD;
             or intellectual problems likely to have limited the validity of consent to participate&#xD;
             in the study or limited the ability to comply with protocol requirements.&#xD;
&#xD;
          2. History of, or current compulsive alcohol abuse (&gt; 10 drinks weekly), or regular&#xD;
             exposure to other substances of abuse.&#xD;
&#xD;
          3. Use of any medication, prescribed or over-the-counter, within 2 weeks prior to the&#xD;
             first administration of study medication (within 2 weeks prior to dosing in Treatment&#xD;
             period 2 for Cohort 2) except if this would not have affected the outcome of the study&#xD;
             in the opinion of the investigator.&#xD;
&#xD;
          4. Females taking oral or transdermal hormonal contraceptives within 14 days preceding&#xD;
             dosing or having used implanted or injected hormonal contraceptives within 6 months&#xD;
             prior to dosing.&#xD;
&#xD;
          5. Participation in another study with an experimental drug, where the last&#xD;
             administration (of previous study medication) was within 12 weeks before the first&#xD;
             administration of study medication.&#xD;
&#xD;
          6. Treatment within the previous 3 months with any drug with a well-defined potential for&#xD;
             adversely affecting a major organ or system.&#xD;
&#xD;
          7. A major illness during the 3 months before commencement of the screening period.&#xD;
&#xD;
          8. History of hypersensitivity to the study medication, carrier substances, or any&#xD;
             related medication.&#xD;
&#xD;
          9. History of any type of malignancy.&#xD;
&#xD;
         10. Tendency toward recurrent infections, known untreated parasitic infection, or history&#xD;
             of primary or secondary immunodeficiency.&#xD;
&#xD;
         11. History of allergy to soybeans or soy products.&#xD;
&#xD;
         12. History of allergy to eggs or egg products.&#xD;
&#xD;
         13. History of bronchial asthma or any other bronchospastic diseases.&#xD;
&#xD;
         14. History of epilepsy.&#xD;
&#xD;
         15. History of porphyria.&#xD;
&#xD;
         16. History of psoriasis.&#xD;
&#xD;
         17. History of atopic dermatitis.&#xD;
&#xD;
         18. History of elevated cholesterol levels of above 6.5 mmol/L.&#xD;
&#xD;
         19. History of gout.&#xD;
&#xD;
         20. History of rheumatoid arthritis.&#xD;
&#xD;
         21. History or evidence of kidney disease or renal failure.&#xD;
&#xD;
         22. Relevant history or laboratory or clinical findings indicative of acute or chronic&#xD;
             disease, likely to have influenced study outcome.&#xD;
&#xD;
         23. Total bilirubin concentration, which exceeds 10% of normal laboratory ranges (4-30&#xD;
             μmol/L).&#xD;
&#xD;
         24. Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the&#xD;
             first administration of study medication.&#xD;
&#xD;
         25. Diagnosis of hypotension made during the screening period.&#xD;
&#xD;
         26. Diagnosis of hypertension made during the screening period or current diagnosis of&#xD;
             hypertension.&#xD;
&#xD;
         27. Resting pulse rate of &gt; 100 beats per minute or &lt; 40 beats per minute during the&#xD;
             screening period, either supine or standing.&#xD;
&#xD;
         28. Positive testing for HIV and Hepatitis B and/or Hepatitis C.&#xD;
&#xD;
         29. Positive urine screen for drugs of abuse.&#xD;
&#xD;
         30. Positive urine screen for tobacco use.&#xD;
&#xD;
         31. A serum pregnancy test for females (beta human chorionic gonadotropin [β-HCG]) either&#xD;
             positive or not performed or lactation.&#xD;
&#xD;
         32. Vaccination with any vaccine (including live, attenuated virus or bacterial vaccines)&#xD;
             within 4 weeks of first dose or planning to have had a vaccination within 3 months&#xD;
             after the second dose.&#xD;
&#xD;
         33. Subjects with close family members (spouse/partner/children) receiving a live vaccine&#xD;
             during the study, or within 3 months after the second dose.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eduard FW Krantz, Dr</last_name>
    <role>Principal Investigator</role>
    <affiliation>Parexel</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>PAREXEL</name>
      <address>
        <city>Bloemfontein</city>
        <zip>9301</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>South Africa</country>
  </location_countries>
  <link>
    <url>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586182/pdf/40261_2012_Article_29.pdf</url>
    <description>Ehinger KH, Hansson MJ, Sjövall F, Elmér E. Bioequivalence and tolerability</description>
  </link>
  <link>
    <url>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079516/pdf/40261_2012_Article_50.pdf</url>
    <description>Errata to publication</description>
  </link>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>September 11, 2012</study_first_submitted>
  <study_first_submitted_qc>September 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 25, 2012</study_first_posted>
  <last_update_submitted>July 31, 2014</last_update_submitted>
  <last_update_submitted_qc>July 31, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 1, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>bioequivalence</keyword>
  <keyword>pharmacokinetics</keyword>
  <keyword>tolerability</keyword>
  <keyword>safety</keyword>
  <keyword>ciclosporin</keyword>
  <keyword>cyclosporine</keyword>
  <keyword>cyclosporine A</keyword>
  <keyword>Sandimmune</keyword>
  <keyword>Sandimmun</keyword>
  <keyword>CicloMulsion</keyword>
  <keyword>NeuroSTAT</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclosporine</mesh_term>
    <mesh_term>Cyclosporins</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01692834
org study id: 99752
nct id: NCT01692834
lead sponsor: 
has dmc: No
To compare the bioavailability, pharmacokinetic profiles and the tolerability of two
      formulations of intravenous cyclosporine in healthy volunteers.
Participants were randomized into two treatment sequences: the test product followed by the
      reference product or vice versa. There was a washout period set to 14-21 days between the
      first and second treatment period. Through an indwelling IV cannula, the subjects received
      either 5 mg/kg NeuroSTAT® (test) or 5 mg/kg Sandimmune® (reference), infused at a constant
      rate over 4 h with a syringe pump. A total of 22 blood samples for Cyclosporine analysis were
      obtained pre-dose and at pre specified time points with last sample 48 h after start of
      infusion.
allocation: Randomized
intervention model: Crossover Assignment
masking: Single (Participant)
measure: Bioequivalence between test and reference product.
time frame: Repeated samplings from pre-dose to 48 hours
description: To compare the bioavailability and pharmacokinetics of a single dose of the test product, NeuroSTAT® 5 mg/mL ready-to-use Cremophor® EL-free cyclosporine with the reference product, Sandimmune® Injection 50 mg/mL Cremophor® EL suspension (each 1 mL diluted in 20 mL saline). For this purpose the pharmacokinetics of cyclosporine was compared during and after intravenous (IV) infusion, over 4 hours, of a single dose of 5 mg/kg of each of the two formulations to healthy subjects. The primary parameters are area under the blood concentration-time curves (AUC) from time zero to time of last measurable concentration (AUC0-last), time zero to infinity (AUC0-∞), time 4 h to infinity (AUC4-∞). Point estimates and 90 % Confidence IntervaI (CI) for the NeuroSTAT®/Sandimmune® geometric mean ratios of all variables are calculated. The two products are considered bioequivalent if the 90 % CI for the primary variables are within the FDA and EMA approved range of 0.8 and 1.25.
measure: Tolerability comparison of test and reference product
time frame: From start of study drug administration to last blood sampling at 48 hours
description: To compare the tolerability profiles of the test product, NeuroSTAT® 5 mg/mL ready-to-use Cremophor® EL-free cyclosporine USP/Ph. Eur. lipid emulsion, with the reference product, Sandimmune® Injection (cyclosporine injection, USP) 50 mg/mL Cremophor® EL suspension (each 1 mL diluted in 20 mL saline). The proportions of overall adverse events and adverse events per organ class (as defined by the Medical Dictionary for Regulatory Activities) are compared between NeuroSTAT® and Sandimmune® by means of 95 % CI for the difference between paired proportions and p-values.
arm group label: Cyclosporine in Cremophor EL®
arm group type: Active Comparator
description: Dosing 5 mg/kg infused at a constant rate over 4 h with a syringe pump.
arm group label: Cyclosporine in lipid emulsion
arm group type: Active Comparator
description: Dosing 5 mg/kg infused at a constant rate over 4 h with a syringe pump.
intervention type: Drug
intervention name: Sandimmune® Injection
arm group label: Cyclosporine in Cremophor EL®
intervention type: Drug
intervention name: NeuroSTAT®
arm group label: Cyclosporine in lipid emulsion
other name: CicloMulsion® (ready-to-use lipid emulsion of Cyclosporine A)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Eduard FW Krantz, Dr
role: Principal Investigator
affiliation: Parexel
facility: 
country: South Africa
url: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586182/pdf/40261_2012_Article_29.pdf
description: Ehinger KH, Hansson MJ, Sjövall F, Elmér E. Bioequivalence and tolerability
url: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079516/pdf/40261_2012_Article_50.pdf
description: Errata to publication
responsible party type: Sponsor
mesh term: Cyclosporine
mesh term: Cyclosporins