Clinical trial NCT03522545: Adjunctive Allogeneic Mesenchymal Stem Cells for Treatment-resistant Bipolar Depression
Official title: Adjunctive Allogeneic Mesenchymal Stem Cells for Treatment-resistant Bipolar Depression
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Treatment-resistant Bipolar Depression
Keywords: treatment-resistant bipolar depression
bipolar disorder
manic depression
Lead sponsor: The University of Texas Health Science Center, Houston
Sponsor class: OTHER
First posted: 2018-05-11
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The overall objective of the investigators 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 MSCs adjunctive to TAU compared to a normal saline solution in patients with TRBD. 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.

MSCs 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, the investigators 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. The investigators 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. Patients will remain on stable psychiatric medications during this period. If patients need to change medications, they will be removed from the study protocol.

Eligibility criteria: 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. Hemodynamic instability at the time of MSCs infusion.
7. Positive pregnancy test (at screening or baseline visits).

Primary outcomes:
measure: Change in depression as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS)
timeFrame: baseline, week 8, week 26
Secondary outcomes:
measure: Change in Functional impairment as assessed by the Functioning Assessment Short Test (FAST)
timeFrame: baseline, week 26
measure: Change in Overall functioning in living as assessed by the Global Assessment of Functioning (GAF)
timeFrame: baseline, week 26
measure: Change in Clinical Global Impression Scale for Bipolar illness (CGI-BP), severity of mania subscale
timeFrame: baseline, week 26
measure: Change in Clinical Global Impression Scale for Bipolar illness (CGI-BP), severity of depression subscale
timeFrame: baseline, week 26
measure: Change in Clinical Global Impression Scale for Bipolar illness (CGI-BP), severity overall subscale
timeFrame: baseline, week 26
measure: Change in neurocognition as assessed by the California Verbal Learning Test
timeFrame: baseline, week 26
measure: Change in problem-solving ability as assessed by the Wisconsin Card Sorting Test (WCST)
timeFrame: baseline, week 26
measure: Number of participants with inflammatory markers as assessed by multiplex biomarker analysis
timeFrame: baseline
measure: Number of participants with inflammatory markers as assessed by multiplex biomarker analysis
timeFrame: week 26
measure: Change in brain-derived neurotrophic factor (BDNF) level as assessed by enzyme-linked immunosorbent assay (ELISA)
timeFrame: baseline, week 26
measure: Change in C-reactive protein (CRP) level as assessed by enzyme-linked immunosorbent assay (ELISA)
timeFrame: baseline, week 26
measure: Number of participants with a change in brain activity between baseline and week 26 as assessed by Magnetic Resonance Imaging (MRI)
timeFrame: baseline, week 26
measure: Number of participants who withdrawal due to Adverse Events (AEs)
timeFrame: week 26
measure: Number of participants with suicidal ideation based on clinical assessment
timeFrame: week 26
measure: Number of participants with treatment emergent mania or hypomania as assessed by the Young Mania Rating Scale (YMRS) and clinical assessment
timeFrame: week 26
Other outcomes:
Locations:
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
Study officials:
affiliation: The University of Texas Health Science Center, Houston
name: Jair C Soares, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: