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Bioavailability of Disulfiram and Metformin in Glioblastomas (INSIDE)

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ClinicalTrials.gov Identifier: NCT03151772
Recruitment Status : Recruiting
First Posted : May 12, 2017
Last Update Posted : April 4, 2019
Sponsor:
Information provided by (Responsible Party):
Asgeir S. Jakola, Sahlgrenska University Hospital, Sweden

Tracking Information
First Submitted Date  ICMJE May 9, 2017
First Posted Date  ICMJE May 12, 2017
Last Update Posted Date April 4, 2019
Actual Study Start Date  ICMJE January 29, 2018
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 10, 2017)
  • Bioavailabilty disulfiram [ Time Frame: At time of surgery ]
    Concentration of disulifram-copper complex available in glioblastoma compared to blood
  • Bioavailabilty of metformin [ Time Frame: At time of surgery ]
    Concentration of metformin available in glioblastoma compared to blood
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03151772 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bioavailability of Disulfiram and Metformin in Glioblastomas
Official Title  ICMJE Drug Level and Investigation of Novel Substances Indicated Downstream Effect in Glioblastoma
Brief Summary

Neuro-oncological trials may fail due to the drug never getting to the intended target (i.e. within the tumor micro environment). Also, changes' occurring in tumor cells when removed from patients and grown in-vitro is another limiting factor influencing the clinical success.

Important questions are therefore:

  1. Does the drug get there?
  2. Does the drug do what it is intended to do?

To improve chances of clinical success there is a need for rational and intelligent selection of potential drugs in future trials. This is an initiative for analyzing tumor concentration of preoperative administered repurposed drugs

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Bioavailability study with an adaptive design (evaluation after 5 patients up to a total maximum of 20 patients in each arm). Experimental therapy not to be combined and not any comparison between therapies
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • Drug: Disulfiram
    200 mg disulfiram two times daily and 2,5 mg copper once daily taken preoperatively
  • Drug: Metformin
    Metformin 850 mg x 3 taken preoperatively
Study Arms  ICMJE
  • Experimental: Disulfiram
    Disulfiram 200 mg twice daily and copper 2,5 mg once daily. For bioavailability purpose only, treatment is withdrawn postoperatively
    Intervention: Drug: Disulfiram
  • Experimental: Metformin
    Metformin 850 mg x 3 daily. For bioavailability purpose only, treatment is withdrawn postoperatively
    Intervention: Drug: Metformin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 10, 2017)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

The subjects must fulfill all the following inclusion criteria to be eligible for participation in the study, unless otherwise specified:

  1. A suspected glioblastoma (based on MRI) or recurrent glioblastoma undergoing surgical resection.
  2. Elective surgical indication
  3. Age 18 years or older.
  4. Karnofsky performance status of 60 - 100 (see attachment 3).
  5. Not receiving another experimental treatment for glioblastoma at the moment of inclusion.
  6. Able to take oral medications.
  7. No known allergy to substance
  8. Absolute neutrophil count ≥ 1,500/mcL and platelets ≥ 100,000/mcL

Exclusion Criteria:

General

  1. Other likely diagnosis than glioblastoma based on MRI.
  2. Pregnant and/or breastfeeding.
  3. Women of childbearing potential who do not have a negative pregnancy test (not older than 14 days) before inclusion.
  4. History of active liver disease, including chronic active hepatitis, viral hepatitis (hepatitis B, C and CMV), cholestatic jaundice of any etiology or toxic hepatitis or inadequate hepatic function, defined as baseline ASAT and ALAT > 1.5 X upper institutional limit and/or bilirubin > 1.5 X upper institutional limit.
  5. Suspected significant raised intracranial pressure or other indication for emergent surgery
  6. Unfit for participation for any other reason judged by the including physician.

Specific additional exclusions criteria for disulfiram

  1. History of uncontrolled hypertension (i.e. systolic BP > 180 mmHg) and a diagnosis of congestive heart failure
  2. History of psychiatric conditions (e.g. depression, psychosis, schizophrenia) or dementia.
  3. History of Wilson's disease or family member with Wilson's disease (unless excluded as a carrier by genetic test).
  4. History of hemochromatosis or family member with hemochromatosis (unless excluded as a carrier by genetic test).
  5. Nickel hypersensitivity (disulfiram mobilize nickel causing a brief increase in nickel concentrations before excretion. The initial increase may lead to hepatitis and predisposed patients).7
  6. Need for metronidazole, warfarin and/or theophylline medication (the metabolism may be influenced by disulfiram).
  7. Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives (phenytoin, phenobarbital, chlordiazepoxide, imipramine, diazepam, isoniazid, metronidazole, warfarin, amitriptyline within 14 days prior to the first dose of disulfiram. Of note, lorazepam and oxazepam are not affected by the P450 system and are not contraindicated with disulfiram).
  8. Addiction to alcohol or drugs. Alcohol must be avoided.
  9. Serum/plasma copper and serum ceruloplasmin outside institutional limits. a. However increased levels are seen together with ongoing acute phase reaction as determined by elevated C-reactive protein (ceruloplasmin is elevated as part of the same process) it is possible to retest after normalization of C-reactive protein.

Specific additional exclusions criteria for metformin

  1. Diabetic patients or other patients where treating physician and/or anesthesiologist consider may have an increased risk for lactic acidosis per- and postoperatively
  2. Known renal failure, renal risk factors (including single kidney, donor kidney, polycystic kidneys) or estimated glomerular filtration rate below 80 ml/min.
  3. Congestive heart failure
  4. Scheduled diagnostic work-up where contrast medium containing iodine is indicated
  5. Concomitant use of NSAIDs (risk of renal injury)
  6. Risk of dehydration judged by the treating physician (e.g. when symptoms include vomiting)
  7. Alcohol must be avoidance during treatment (increased risk of lactic acidosis)
  8. Treatment with diuretics as they may increase risk of lactic acidosis.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Asgeir S Jakola, MD, PhD +46313421000 asgeir.jakola@vgregion.se
Contact: Louise Carstam, MD +46313421000 louise.carstam@vgregion.se
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03151772
Other Study ID Numbers  ICMJE 1144-16
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Asgeir S. Jakola, Sahlgrenska University Hospital, Sweden
Study Sponsor  ICMJE Sahlgrenska University Hospital, Sweden
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Asgeir S Jakola, MD, PhD Sahlgrenska University Hospital, Sweden
PRS Account Sahlgrenska University Hospital, Sweden
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP