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Adjunctive Allogeneic Mesenchymal Stem Cells for Treatment-resistant Bipolar Depression

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03522545
Recruitment Status : Not yet recruiting
First Posted : May 11, 2018
Last Update Posted : May 11, 2018
Sponsor:
Information provided by (Responsible Party):
Jair Soares, The University of Texas Health Science Center, Houston

Tracking Information
First Submitted Date  ICMJE March 29, 2018
First Posted Date  ICMJE May 11, 2018
Last Update Posted Date May 11, 2018
Estimated Study Start Date  ICMJE June 1, 2018
Estimated Primary Completion Date June 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 30, 2018)
Change in depression as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) [ Time Frame: baseline, week 8, week 26 ]
The Montgomery-Åsberg Depression Rating Scale (MADRS) is a short and reliable scale devised to be sensitive to change. Patients are rated on ten items, each of which has value ranges from 0 (the least pathology) to 6 (the most sever pathology). Sum scores range from 0 to 60, with a scoring of 20 indicating moderate and 30 severe depression. The scale is sensitive to change and covers many, but not all, symptom domains in depression.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2018)
  • Change in Functional impairment as assessed by the Functioning Assessment Short Test (FAST) [ Time Frame: baseline, week 26 ]
    The Functioning Assessment Short Test (FAST) assesses functional impairment. FAST is a 24-item scale and assesses six functional domains: autonomy, occupational functioning, cognitive, financial issues, interpersonal relationships, and leisure time. Higher scores indicate higher degrees of functional impairment.
  • Change in Overall functioning in living as assessed by the Global Assessment of Functioning (GAF) [ Time Frame: baseline, week 26 ]
    The Global Assessment of Functioning (GAF) is a numeric scale (1 through 100) used to rate subjectively the social, occupational, and psychological functioning of adults, e.g., how well or adaptively one is meeting various problems-in-living. The scale is presented and described in the DSM-IV-TR on page 34.
  • Change in Clinical Global Impression Scale for Bipolar lllness (CGI-BP), severity of mania subscale [ Time Frame: baseline, week 26 ]
    The Clinical Global Impression Scale for bipolar lllness (CGI-BP) is a modification of the CGI specifically for use in assessing global illness severity and change in patients with bipolar disorder (BD). The revised scale and manual provide a focused set of instructions to facilitate the reliability of these ratings of mania, depression, and overall bipolar illness during treatment of an acute episode or in longer-term illness prophylaxis. The clinician forms a global judgment both of the severity of the illness as compared to other cases with the same diagnosis and the global degree of change during treatment. There are 3 subscales (severity of mania, severity of depression, severity overall); and each subscale has a range of values from 1 (best) to 7 (worst).
  • Change in Clinical Global Impression Scale for Bipolar lllness (CGI-BP), severity of depression subscale [ Time Frame: baseline, week 26 ]
    The Clinical Global Impression Scale for bipolar lllness (CGI-BP) is a modification of the CGI specifically for use in assessing global illness severity and change in patients with bipolar disorder (BD). The revised scale and manual provide a focused set of instructions to facilitate the reliability of these ratings of mania, depression, and overall bipolar illness during treatment of an acute episode or in longer-term illness prophylaxis. The clinician forms a global judgment both of the severity of the illness as compared to other cases with the same diagnosis and the global degree of change during treatment. There are 3 subscales (severity of mania, severity of depression, severity overall); and each subscale has a range of values from 1 (best) to 7 (worst).
  • Change in Clinical Global Impression Scale for Bipolar lllness (CGI-BP), severity overall subscale [ Time Frame: baseline, week 26 ]
    The Clinical Global Impression Scale for bipolar lllness (CGI-BP) is a modification of the CGI specifically for use in assessing global illness severity and change in patients with bipolar disorder (BD). The revised scale and manual provide a focused set of instructions to facilitate the reliability of these ratings of mania, depression, and overall bipolar illness during treatment of an acute episode or in longer-term illness prophylaxis. The clinician forms a global judgment both of the severity of the illness as compared to other cases with the same diagnosis and the global degree of change during treatment. There are 3 subscales (severity of mania, severity of depression, severity overall); and each subscale has a range of values from 1 (best) to 7 (worst).
  • Change in neurocognition as assessed by the California Verbal Learning Test [ Time Frame: baseline, week 26 ]
    California Verbal Learning Test (second edition (CVLT-II)). The adult version was chosen because it is one of the most widely used neuropsychological tests. This test consists of verbal list learning and memory test.
  • Change in problem-solving ability as assessed by the Wisconsin Card Sorting Test (WCST) [ Time Frame: baseline, week 26 ]
    The Wisconsin Card Sorting Test (WCST) assesses problem-solving ability and is thought to be an index of functioning of the prefrontal cortex. The task requires subjects to match cards to one of four target cards according to a certain sorting rule (color, shape or number) without explicit instructions regarding the nature of the sorting rule. After 10 consecutive matches, the sorting rule changes without warning, and the subject needs to determine the new principle. Perseverative errors and number of categories achieved will be used as dependent measures.
  • Number of participants with inflammatory markers as assessed by multiplex biomarker analysis [ Time Frame: baseline ]
    The Bioplex 200 (Bio-Rad) will be usedfor multiplex biomarker analysis.
  • Number of participants with inflammatory markers as assessed by multiplex biomarker analysis [ Time Frame: week 26 ]
    The Bioplex 200 (Bio-Rad) will be usedfor multiplex biomarker analysis.
  • Change in brain-derived neurotrophic factor (BDNF) level as assessed by enzyme-linked immunosorbent assay (ELISA) [ Time Frame: baseline, week 26 ]
  • Change in C-reactive protein (CRP) level as assessed by enzyme-linked immunosorbent assay (ELISA) [ Time Frame: baseline, week 26 ]
  • Number of participants with a change in brain activity between baseline and week 26 as assessed by Magnetic Resonance Imaging (MRI) [ Time Frame: baseline, week 26 ]
  • Number of participants who withdrawal due to Adverse Events (AEs) [ Time Frame: week 26 ]
  • Number of participants with suicidal ideation based on clinical assessment [ Time Frame: week 26 ]
  • Number of participants with treatment emergent mania or hypomania as assessed by the Young Mania Rating Scale (YMRS) and clinical assessment [ Time Frame: week 26 ]
    The YMRS is an 11-item scale that is used to assess the severity of mania. Each item is given a severity rating--four items are graded on a 0 to 8 scale (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale. These four items (irritability, speech, thought content, and disruptive/aggressive behavior) are given twice the weight of the others to compensate for poor cooperation from severely ill patients.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Adjunctive Allogeneic Mesenchymal Stem Cells for Treatment-resistant Bipolar Depression
Official Title  ICMJE Adjunctive Allogeneic Mesenchymal Stem Cells for Treatment-resistant Bipolar Depression
Brief Summary Our overall objective is to assess the therapeutic efficacy and tolerability of Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal Cells (MSCs) isolated from hematogenous bone marrow for treatment of treatment-resistant bipolar depression patient (TRBD).
Detailed Description

This clinical trial is a randomized, double-blind, placebo-controlled study aiming to study the efficacy and side effects of BMMNCs adjunctive to TAU compared to a normal saline solution in patients with TRBD. A flow chart of the study design is shown in Fig. 1. Relevant patients with bipolar depression will be addressed in order to establish whether they are willing to be screened for the study. The patients must be assigned a patient number and sign the consent form after receiving oral and written information about the study prior to undergoing any study procedures.

BMMNCs will be infused as a single dose up to one week after the inclusion of the patient. The treatment trial lasts eight weeks. Of note, we will assess patients also at week 26 with a neurocognitive and clinical battery. It will not be allowed changes in psychiatric medication during this period. If a patient or the treating clinician decides that the patient could receive better treatment outside of the study, the patient may leave the study at all times, as specified in the informed consent. Patients were not allowed to take nonsteroidal or steroidal anti-inflammatory medications during the study. Medications for hypertension, diabetes, hypothyroidism, allergies, infections, or other medical conditions were allowed as dictated by the patients' treating physicians. We defined refractory bipolar depression as depression that failed to respond to two trials (during lifetime) with antidepressants and/or mood stabilizer with proven efficacy in bipolar depression (lithium, lamotrigine, quetiapine, lurasidone, olanzapine) in adequate doses for at least 6 weeks or until cessation of treatment due to side effects (Schoeyen et al., 2015).

After the initial injection, patients will continue maintenance treatment with their current psychiatrist. During this time, they will not receive additional injections but will receive treatment as usual per their clinician's choice. We will ask patients to remain on stable psychiatric medications during this period. If patients need to change medications, they will be removed from the study protocol.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Treatment-resistant Bipolar Depression
Intervention  ICMJE
  • Biological: Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal Cells (MSCs)
    Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal Cells (MSCs) isolated from hematogenous bone marrow
  • Biological: Placebo
    Placebo for Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal Cells (MSCs)
Study Arms  ICMJE
  • Experimental: Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal
    Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal Cells (MSCs) isolated from hematogenous bone marrow
    Intervention: Biological: Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal Cells (MSCs)
  • Placebo Comparator: Placebo
    Placebo for Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal Cells (MSCs)
    Intervention: Biological: Placebo
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 Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 30, 2018)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2020
Estimated Primary Completion Date June 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  1. Diagnosis of DSM-IV-TR of Bipolar I or Bipolar II disorder as verified by the semi-structured diagnostic interviews SCID. The diagnosis may be supported by information from significant others, and from hospital records.
  2. Age: 18-65 years
  3. Severity: meet DSM-IV-TR criteria of depressive episode and MADRS of 25 or above
  4. Treatment resistance: None response to two trials (during lifetime) with mood stabilizers with proven efficacy in bipolar depression (lithium, lamotrigine, quetiapine, olanzapine) and/or antidepressants.

    a A trial is defined as at least 6 weeks in adequate or tolerated dose as reported by the patient, or patients that have been unable to comply with 6 weeks trials of mood stabilizer or an antidepressant.

    b None response: Less than 50% reduction in MADRS values or still meet DSM-IV-TR criteria of depressive episode

  5. CRP concentration greater than 5 mg/L
  6. Female subjects whom are not pregnant, not breastfeeding, and not planning on becoming pregnant during the study. Female patients of childbearing potential must be using a reliable method of contraception.
  7. Patient competent to give informed consent according to the judgment of the clinician
  8. Written informed consent
  9. Patient sufficiently fluent in English language to ensure valid responses to psychometric testing (needed for validated neurocognitive outcomes testing)

Exclusion criteria:

  1. MSCs transplant within the last six months
  2. Inability to comply with study protocol
  3. Patient at high suicidal risk according to clinicians' judgement
  4. History of previous brain injury; neurologic impairment and/or deficit; seizure disorder requiring anti-convulsant therapy; renal disease or altered renal function as defined by serum creatinine 2x ULN at admission; hepatic disease or altered liver function as defined by SGPT > 2 x ULN (non-contusion related), and/or T. Bilirubin 1.5 x ULN at admission; immunosuppression as defined by WBC<3,000 cells/ml at admission; HIV, splenectomy or cancer
  5. Unstable serious medical conditions, including clinically relevant laboratory abnormalities. Conditions that affect neuropsychological assessment such as Parkinson's Disease, Multiple sclerosis, stroke, alcohol and substance abuse or dependence (according to SCID or DSM-IV-TR). Other serious medical illness that is not adequately controlled and, in the investigator's opinion, would not permit the subject to be managed according to the protocol.
  6. Hemodinamic instability at the time of MSCs infusion.
  7. Positive pregnancy test (at screening or baseline visits).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jair C Soares, MD, PhD 7134862627 Jair.C.Soares@uth.tmc.edu
Contact: Kathryn Durkin, BS 7134862627 kathryn.durkin@uth.tmc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03522545
Other Study ID Numbers  ICMJE HSC-MS-16-0657
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jair Soares, The University of Texas Health Science Center, Houston
Study Sponsor  ICMJE The University of Texas Health Science Center, Houston
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jair C Soares, MD, PhD The University of Texas Health Science Center, Houston
PRS Account The University of Texas Health Science Center, Houston
Verification Date April 2018

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