Effects of Erythropoietin on Cognition and Neural Activity in Mood Disorders

Bipolar Disorder Clinical Trial

— PreTEC-EPO  

Official title:

Effects of Erythropoietin on Cognitive Functions and Neural Activity in Cognitively Impaired Remitted Patients With Bipolar Disorder or Recurrent Depressive Disorder and Healthy People: Study Protocol for a Randomized, Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03315897
• Other study ID #: H-16043370
• Secondary ID: 2016-004023-24RH
• Status: Completed
• Phase: Phase 2
• Start date: July 5, 2017
• Est. completion date: October 1, 2022

Study information

• Verified date: March 2023
• Source: Mental Health Services in the Capital Region, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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) and recurrent unipolar depressive disorder (UD) (defined as minimum 2 treatment-requiring depressive episodes). 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 people with cognitive impairment (substudy 1) and (ii) patients with remitted BD or recurrent UD (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.

Description:

This trial will include healthy people (sub-study 1) and patients with bipolar disorder or recurrent unipolar depressive disorder 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, respectively (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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 103
• Est. completion date: October 1, 2022
• Est. primary completion date: October 1, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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) or recurrent depressive disorder confirmed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview.

• Healthy people 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

Related Conditions & MeSH terms

• Bipolar Disorder
• Cognitive Impairment
• Depressive Disorder
• Disease
• Unipolar Depression

Intervention

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.
• Saline
1 ml NaCl is administered 4 times as intravenous infusions over 15 minutes

Locations

Country	Name	City	State
Denmark	Mental Health Services, Capital Region of Denmark, Copenhagen University Hospital, Rigshospitalet	Copenhagen

Sponsors (3)

Lead Sponsor	Collaborator
Lars Vedel Kessing	Lundbeck Foundation, Mental Health Services in the Capital Region, Denmark

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Rey Auditory Verbal Learning Test	Neuropsychological test assessing verbal memory	Baseline, two weeks of treatment, week 13, and 6-months follow-up
Other	Trail Making Test Part A	Neuropsychological test assessing attention and processing speed	Baseline, two weeks of treatment, week 13, and 6-months follow-up
Other	Trail Making Test Part B	Neuropsychological test assessing executive functions	Baseline, two weeks of treatment, week 13, and 6-months follow-up
Other	Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding	Neuropsychological test assessing attention	Baseline, two weeks of treatment, week 13, and 6-months follow-up
Other	Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Digit Span	Neuropsychological test assessing executive functions	Baseline, two weeks of treatment, week 13, and 6-months follow-up
Other	WAIS-III Letter-Number Sequencing	Neuropsychological test assessing executive functions	Baseline, two weeks of treatment, week 13, and 6-months follow-up
Other	Verbal fluency with the letter "D" and 'S"	Neuropsychological test assessing executive functions	Baseline, two weeks of treatment, week 13, and 6-months follow-up
Other	One Touch Stockings of Cambridge	A computerized neuropsychological test assessing executive functions	Baseline, two weeks of treatment, week 13, and 6-months follow-up
Other	Spatial Working Memory (SWM) from Cambridge Cognition	Neuropsychological test assessing sustained attention	Baseline, two weeks of treatment, week 13, and 6-months follow-up
Other	Brief University of California, San Diego Performance-Based Skills Assessment-B	Objective, performance-based assessment of level of functioning	Baseline, week 13, and 6-months follow-up
Other	Sheehan Disability Scale	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).	Baseline, week 13, and 6-months follow-up
Other	The Assessment of Quality of Life	Questionnaire on quality of life	Baseline, week 13, and 6-months follow-up
Other	World Health Organization Quality of Life	Questionnaire on quality of life	Baseline, week 13, and 6-months follow-up
Other	Cognitive Complaints in Bipolar Disorder Rating Assessment	Questionnaire on subjective cognitive complaints	Baseline, week 13, and 6-months follow-up
Other	Work and Social Adjustment Scale	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).	Baseline, week 13, and 6-months follow-up
Primary	Cognitive composite score	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).	Change from baseline and week 13
Secondary	Rapid Visual Information Processing (RVP) from Cambridge Cognition (CANTAB)	Neuropsychological test assessing sustained attention	Baseline, two weeks of treatment, week 13, and 6-months follow-up
Secondary	Functional Assessment Short Test	A semi-structured interview assessing level of functioning	Baseline, week 13, and 6-months follow-up