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Effects of Erythropoietin on Cognition and Neural Activity in Bipolar Disorder (PRETEC-EPO)

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ClinicalTrials.gov Identifier: NCT03315897
Recruitment Status : Recruiting
First Posted : October 20, 2017
Last Update Posted : October 23, 2017
Sponsor:
Collaborators:
Mental Health Services in the Capital Region, Denmark
Lundbeck Foundation
Information provided by (Responsible Party):
Lars Vedel Kessing, Mental Health Services in the Capital Region, Denmark

Brief Summary:

The present trial consists of 2 sub-studies that investigate important novel aspects of treatment with erythropoietin (EPO) on cognitive dysfunction in bipolar disorder (BD). The aims of the trial are three-fold. We aim to investigate the effects of 12 weekly recombinant human EPO infusions on cognition in (i) healthy first-degree relatives of BD patients (substudy 1) and (ii) remitted BD patients (substudy 2), and (iii) explore early treatment-associated neural activity changes that may predict subsequent cognitive improvement.

It is hypothesized that:

i. 12 weekly EPO infusions improve cognition in healthy first-degree relatives and remitted BD patients in comparison with saline.

ii. EPO vs. saline-treated participants will display early cognition-related neural activity in the frontal lobes, which will correlate with cognitive improvement.


Condition or disease Intervention/treatment Phase
Bipolar Disorder Cognitive Impairment Drug: Erythropoietin Drug: Saline Phase 2

Detailed Description:

This trial will include healthy first-degree relatives (sub-study 1) and bipolar disorder (BD) patients in partial or full remission (defined as a score of ≤14 on the Hamilton Depression Rating Scale 17-items and the Young Mania Rating Scale (sub-study 2) with objectively-verified cognitive dysfunction. Participants will be recruited from Psychiatric Centres in The Mental Health Services in the Capital Region of Denmark, consultant psychiatrists in the Capital Region of Denmark, as well as through advertisements on relevant websites.

The study design comprises 4 major assessments (baseline, week 3, week 13, and a 6 month follow-up after treatment completion) and weekly safety monitoring and study medication infusions during a 12 week treatment period. The baseline assessment is divided into 2 days, 1-3 days apart for practical reasons and to avoid attrition. On the first day of the baseline assessment, participants will perform an fMRI scan. On the second baseline day, participants complete an assessment comprising neuropsychological testing, verbal IQ assessment, and filling in questionnaires concerning subjective cognitive complaints, quality of life, level of functioning, and functional capacity, as well as mood symptom severity ratings. Functional capacity is assessed using a clinician-rated interview and a performance-based task. After 2 weeks of treatment (i.e., 2 doses of EPO or saline) an fMRI scan, neuropsychological testing, mood ratings, and questionnaires on subjective cognitive difficulties are repeated. After treatment completion (week 13) and at the 6 month follow-up, the neuropsychological tests, questionnaires concerning subjective cognitive complaints, quality of life, and functional capacity (self-reported and performance-based) are repeated. Sleep quantity and quality in the past three days is assessed before each of the 4 major assessment time point. Blood samples are collected at baseline, week 3 and 13 for assessment of potential blood-based biomarkers of pro-cognitive effects.

Pharma Consulting Group AB (www.pharmaconsultinggroup.com) has conducted block randomization for each sub-study group, stratified for gender and age (sub-study 1: < or >=30 years; sub-study 2: < or >=35 years). Power calculation was also carried out by Pharma Consulting Group based on findings from a previous RCT in our group assessing the effect of 8 weeks of EPO treatment on the same cognitive composite score. In this trial, the clinically relevant differential change between EPO and saline groups following 12 weeks of treatment is assumed to be at least 0.4 SD (corresponding to a moderate effect size) on the primary outcome with SD of the change of 0.5. Assuming a 10% drop-out rate, we plan to recruit up to n=58 for each sub-study to achieve complete data sets for n=52 participants per sub-study.

Data from the primary, secondary, and tertiary outcomes will be analyzed using Mixed Models Design and Intention to Treat (ITT) analyses. Functional MRI data are pre-processed and analyzed with FMRIB Expert Analysis Tool (FEAT) and the 'randomize' algorithm implemented in FSL (FMRIB Software Library; www.fmrib.ox.ac.uk/fsl). Functional MRI data is analysed using region of interest (ROI) analyses to assess potential differences in neural activity within the dorsal prefrontal cortex and the hippocampi between EPO and placebo groups after 2 weeks of treatment. Exploratory whole-brain analyses are conducted to assess treatment-related activity change in other brain regions. Any differences in neural activity between treatment groups are correlated with potential changes in the primary cognitive composite measure after 2 weeks of treatment (week 3) and after treatment completion (week 13). If this correlation is significant, multiple regression analyses will be performed with adjustment for mood symptoms, age, and gender to assess the potential predictive value of early neural activity change for potential pro-cognitive efficacy after 12 weeks of EPO treatment.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 116 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Erythropoietin on Cognitive Functions and Neural Activity in Cognitively Impaired Remitted Bipolar Disorder Patients and Healthy First-degree Relatives: Study Protocol for a Randomized, Controlled Trial
Actual Study Start Date : July 5, 2017
Estimated Primary Completion Date : February 1, 2021
Estimated Study Completion Date : February 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bipolar Disorder

Arm Intervention/treatment
Active Comparator: Erythropoietin
12 intravenous infusions of recombinant human erythropoietin (EPO)
Drug: Erythropoietin
40.000 IU/ml Erythropoietin (Epoetin alpha; Eprex) diluted with 100 ml saline (0.9% NaCl) is administered 12 times as intravenous infusions over 15 minutes.
Other Names:
  • Eprex
  • EPO

Placebo Comparator: Saline
12 intravenous infusions of saline (1 ml NaCl)
Drug: Saline
1 ml NaCl is administered 4 times as intravenous infusions over 15 minutes
Other Name: Placebo




Primary Outcome Measures :
  1. Cognitive composite score [ Time Frame: Change from baseline and week 13 ]
    A cognitive composite based on an average of the Rey Auditory Verbal Learning Test (RAVLT), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding, verbal fluency with the letter "D", WAIS-III Letter-Number Sequencing, Trail Making Test B (TMT B) and Rapid Visual Information Processing (RVP) from Cambridge Cognition (CANTAB).


Secondary Outcome Measures :
  1. Rapid Visual Information Processing (RVP) from Cambridge Cognition (CANTAB) [ Time Frame: Baseline, two weeks of treatment, week 13, and 6-months follow-up ]
    Neuropsychological test assessing sustained attention

  2. Functional Assessment Short Test [ Time Frame: Baseline, week 13, and 6-months follow-up ]
    A semi-structured interview assessing level of functioning


Other Outcome Measures:
  1. Rey Auditory Verbal Learning Test [ Time Frame: Baseline, two weeks of treatment, week 13, and 6-months follow-up ]
    Neuropsychological test assessing verbal memory

  2. Trail Making Test Part A [ Time Frame: Baseline, two weeks of treatment, week 13, and 6-months follow-up ]
    Neuropsychological test assessing attention and processing speed

  3. Trail Making Test Part B [ Time Frame: Baseline, two weeks of treatment, week 13, and 6-months follow-up ]
    Neuropsychological test assessing executive functions

  4. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding [ Time Frame: Baseline, two weeks of treatment, week 13, and 6-months follow-up ]
    Neuropsychological test assessing attention

  5. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Digit Span [ Time Frame: Baseline, two weeks of treatment, week 13, and 6-months follow-up ]
    Neuropsychological test assessing executive functions

  6. WAIS-III Letter-Number Sequencing [ Time Frame: Baseline, two weeks of treatment, week 13, and 6-months follow-up ]
    Neuropsychological test assessing executive functions

  7. Verbal fluency with the letter "D" and 'S" [ Time Frame: Baseline, two weeks of treatment, week 13, and 6-months follow-up ]
    Neuropsychological test assessing executive functions

  8. One Touch Stockings of Cambridge [ Time Frame: Baseline, two weeks of treatment, week 13, and 6-months follow-up ]
    A computerized neuropsychological test assessing executive functions

  9. Spatial Working Memory (SWM) from Cambridge Cognition [ Time Frame: Baseline, two weeks of treatment, week 13, and 6-months follow-up ]
    Neuropsychological test assessing sustained attention

  10. Brief University of California, San Diego Performance-Based Skills Assessment-B [ Time Frame: Baseline, week 13, and 6-months follow-up ]
    Objective, performance-based assessment of level of functioning

  11. Sheehan Disability Scale [ Time Frame: Baseline, week 13, and 6-months follow-up ]
    Visual analogue scale assessing level of functioning (i.e., the magnitude to which social, professional, and everyday life is impaired by symptoms). Each of the three subscale items have numerical scores that range from 0 to 10 with higher scores representing worse outcomes. These subscale items can be summed into a total dimensional measure reflecting global functional impairment with scores that range from 0 (no functional impairment at all) to 30 (severe functional impairment).

  12. The Assessment of Quality of Life [ Time Frame: Baseline, week 13, and 6-months follow-up ]
    Questionnaire on quality of life

  13. World Health Organization Quality of Life [ Time Frame: Baseline, week 13, and 6-months follow-up ]
    Questionnaire on quality of life

  14. Cognitive Complaints in Bipolar Disorder Rating Assessment [ Time Frame: Baseline, week 13, and 6-months follow-up ]
    Questionnaire on subjective cognitive complaints

  15. Work and Social Adjustment Scale [ Time Frame: Baseline, week 13, and 6-months follow-up ]
    Questionnaire on occupational functioning (work and social adjustment). The questionnaire consists of five subscale items with numerical scores that range from 0 (reflecting no impairment at all) to 8 (reflecting severe impairment). These subscale items can be summed into a total dimensional measure assessing global work and social adjustment with scores that range from 0 to 40 (with higher scores reflecting worse outcomes).



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Fluent Danish skills and objective cognitive impairment (a total score below cutoff, or scores below cutoff on a minimum of two out of the five subtests (Verbal Learning Test - Immediate, Working Memory Test, Verbal Fluency Test, Verbal Learning Test - Delayed and Processing Speed Test) on the Screen for Cognitive Impairment in Psychiatry - Danish version (SCIP-D).
  • Patients must meet the ICD-10 diagnosis of BD (type I and II) confirmed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview.
  • Healthy first-degree relatives are eligible even when diagnosed with a less severe mental disorder defined as ICD-10 codes ≥F40.

Exclusion Criteria:

  • Schizophrenia or schizoaffective disorder
  • Current alcohol or substance misuse disorder (3 months prior to inclusion)
  • Daily use of benzodiazepines > 22.5 mg oxazepam
  • Diabetes
  • Kidney disease
  • Renal failure
  • Untreated/insufficiently treated arterial hypertension
  • Heart diseases (previously diagnosed or abnormal ECG findings during screening)
  • Previous serious head trauma
  • Neurological illness (including dementia)
  • Previous or current epilepsy in patient or first degree family
  • Malignancies or thromboses
  • Known allergy or antibodies against erythropoietin
  • Initial hematocrit > 50% (males) or > 48% (females)
  • Initial thrombocyte numbers over normal (>400 billions/L)
  • Initial reticulocyte numbers <1‰
  • Contraindications against prophylactic thrombosis treatment
  • Myeloproliferative disorder, polycythemia
  • Pregnancy or breast feeding
  • Use of contraceptive medication or other hormonal contraceptives
  • Sexually active women in the fertile age, who do not or do not want to use double barrier anticontraceptive methods
  • Previous or current history of thromboembolic events or thromboses in patient or first degree family (increased risk of thromboembolic events)
  • Overweight (BMI>30) or body weight <45 or >95 kg.
  • Previous electroconvulsive therapy (ECT) treatment within last 3 months
  • Dyslexia
  • Claustrophobia
  • Having a pacemaker or other metal implants inside the body
  • Reluctance or inability to comply with the protocol requirements

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03315897


Contacts
Layout table for location contacts
Contact: Kamilla W. Miskowiak, Prof. +45 38647087 ext +45 38647087 kamilla.woznica.miskowiak@regionh.dk
Contact: Jeff Z. Petersen, MSc +45 21947368 ext +45 21947368 jeff.zarp.petersen@regionh.dk

Locations
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Denmark
Mental Health Services, Capital Region of Denmark, Copenhagen University Hospital, Rigshospitalet Recruiting
Copenhagen, Denmark, 2100
Contact: Kamilla W. Miskowiak, Prof.    +45 38647087 ext +45 38647087    kamilla.woznica.miskowiak@regionh.dk   
Sponsors and Collaborators
Lars Vedel Kessing
Mental Health Services in the Capital Region, Denmark
Lundbeck Foundation
Investigators
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Principal Investigator: Lars V. Kessing, Prof. Mental Health Services, Capital Region of Denmark, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 2100
Study Director: Kamilla W. Miskowiak, Prof. Mental Health Services, Capital Region of Denmark, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 2100

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Lars Vedel Kessing, Professor, MD, DMSc, Mental Health Services in the Capital Region, Denmark
ClinicalTrials.gov Identifier: NCT03315897     History of Changes
Other Study ID Numbers: H-16043370
2016-004023-24 ( EudraCT Number )
RHP-2017-020 ( Other Identifier: Danish Data Protection Agency )
First Posted: October 20, 2017    Key Record Dates
Last Update Posted: October 23, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Lars Vedel Kessing, Mental Health Services in the Capital Region, Denmark:
bipolar disorder
cognition
cognitive dysfunction
erythropoietin
pro-cognitive efficacy
prefrontal cortex
functional magnetic resonance imaging
biomarker
Additional relevant MeSH terms:
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Disease
Cognitive Dysfunction
Bipolar Disorder
Pathologic Processes
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Bipolar and Related Disorders
Epoetin Alfa
Hematinics