Roflumilast Plus Antipsychotics Proof of Mechanism Study in Schizophrenia

Schizophrenia Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo Controlled, 3-period, Proof of Mechanism, Cross-Over Study of Roflumilast Administered up to Steady State to Evaluate the Effects of Add-on Roflumilast to Second Generation Antipsychotics on Cognitive Impairment as Well as Brain Imaging (ie, fMRI) and Electrical Activity (ie, EEG) Changes Observed in Subjects With Stable Schizophrenia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02079844
• Other study ID #: ROF-SCHZ_106
• Secondary ID: 2012-002091-13U1
• Status: Completed
• Phase: Phase 1
• First received: March 4, 2014
• Last updated: July 16, 2015
• Start date: March 2014
• Est. completion date: June 2015

Study information

• Verified date: July 2015
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: Department of HealthUnited Kingdom: National Health ServiceUnited Kingdom: Research Ethics Committee
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether cognitive impairment associated with schizophrenia is attenuated by add-on roflumilast administration to second generation antipsychotics (SGA) in participants with stable schizophrenia.

Description:

The drug being tested in this study is called roflumilast. Roflumilast is being tested as an add-on treatment to second generation antipsychotics (SGA) to treat cognitive impairment in people with stable schizophrenia. This study will look at improvement in cognitive impairment associated with schizophrenia in people who take roflumilast as an add-on to SGA.

The study will enroll approximately 22 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of three treatment groups—which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need) All participants will receive the following treatments at different periods throughout the study:

• Roflumilast Dose A + SGA

• Roflumilast Dose B +SGA

• Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient + SGA.

All participants will be asked to take one tablet at the same time each day throughout the study.

This single-centre trial will be conducted in the United Kingdom. The overall time to participate in this study is up to 64 days. Participants will make 2 screening visits to the clinic and then must be brought to the clinic every day for dosing during each of 3 Treatment Periods. Each Treatment Period will be 8 days in duration. All participants will also make 1 final visit 14 days after last dose of study drug for a follow-up assessment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.

2. Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. Meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) by the Mini International Neuropsychiatric Interview (MINI).

4. On a stable dose of second generation antipsychotics (SGA) for at least 2 months as documented by medical history and assessed by site staff.

5. Meets the following symptom criteria: (a) Positive and Negative Syndrome Scale (PANSS) Conceptual Disorganization item score =4 (b) PANSS Hallucinatory Behavior or Unusual Thought Content item scores =4 (c) PANSS Negative Subscale scores on all items =4.

6. Has cognitive impairment as per investigator judgment.

7. Is aged 18 to 55 years, inclusive, at the time of informed consent.

8. Weighs at least 60 kg and has a body mass index (BMI) between 18 and 32 kg/m^2 inclusive at Screening.

9. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose.

10. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use acceptable methods of contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose.

11. Has clinical laboratory evaluations (including clinical chemistry, hematology and complete urinalysis) within the reference range for the testing laboratory, unless the results are deemed not to be clinically significant (NCS) by the investigator at screening and Day 1 of Period 1.

Exclusion Criteria:

1. Has received any investigational compound within 30 days prior to the first dose of study medication.

2. Has received roflumilast in a previous clinical study or as a therapeutic agent.

3. Is an immediate family member, study site employee, or in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

4. Has uncontrolled, clinically significant neurological, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality which may impact the ability of the participant to participate or potentially confound the study results.

5. History of claustrophobia or inability to tolerate mock scanner environment during habituation/screening session.

6. Fulfillment of any of the magnetic resonance imaging (MRI) contraindications on the standard radiography screening questionnaire at the Centre for Neuroimaging Sciences, Institute of Psychiatry, King's College London (ie, history of surgery involving metal implants, metal body piercing, dentures, dental plates or bridges, any implanted device that is electrically, magnetically, and mechanically activated).

7. Has a known hypersensitivity to any component of the formulation of roflumilast.

8. Has a positive urine drug result for drugs of abuse at Screening or Day 1 for each treatment period.

9. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 6 months prior to the screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.

10. The participant with a history in the last year or currently receiving treatment with clozapine.

11. Has taken any excluded medication, supplements, or food products.

12. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.

13. Has evidence of current cardiovascular, hepatic, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the participant's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking roflumilast or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias.

14. Has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, or erosive esophagitis frequent occurrence [more than once per week] of heartburn).

15. History of any surgical intervention known to impact absorption (eg, bariatric surgery or bowel resection).

16. Has a history of cancer within the past 5 years prior to the first dose of study medication. This criterion does not include those participants with basal cell or stage I squamous cell carcinoma of the skin who are eligible.

17. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV), human immunodeficiency virus (HIV) antibody/antigen at Screening.

18. Has poor peripheral venous access.

19. Has donated or lost 450 mL or more of his or her blood volume (including plasmapheresis), or had a transfusion of any blood product within 3 months prior to Day 1.

20. Has a Screening or Day 1 of Period 1 abnormal (clinically significant) electrocardiogram (ECG). Entry of any participant with an abnormal (not clinically significant) ECG must be approved, and documented by signature by the principal investigator.

21. Has abnormal Screening or Day 1 of Period 1 laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1.5 the upper limits of normal.

22. Has abnormal Screening or Day 1 of Period 1 vital sign values that suggest a clinically significant underlying disease.

23. Has a risk of suicide according to the Investigator's clinical judgment (eg, per Columbia-Suicide Severity Rating Scale [C-SSRS] or has made a suicide attempt within 6 months prior to screening visit).

24. Has a current diagnosis of a significant psychiatric illness other than schizophrenia, per DSM-V and is in an acute phase/episode.

25. In the opinion of the investigator or sponsor, the participant is unsuitable for inclusion in the study.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Schizophrenia

Intervention

Drug:
• Roflumilast
Roflumilast tablets
• Placebo
Roflumilast placebo-matching tablets
• Second generation antipsychotic

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from Baseline in Spatial Span Test Score	The Spatial Span test assesses the participants working memory. During this task, participants are presented with a board containing blue blocks randomly arranged. The rater first taps out a pattern of blocks, beginning with two blocks and increasing with participant proficiency, and the participant is tasked with tapping the same pattern. After discontinuation of this part of the subtest, the participant is then tasked with tapping out the reverse pattern after the rater's demonstration. These patterns also begin with two blocks and increase with participant proficiency. The total score for this subtest ranges from 0 to 32.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Primary	Change from Baseline in Hopkins Verbal Learning Test Score	The Hopkins Verbal Learning Test assesses the participant's verbal learning. The test consists of a list of 12 words from three taxonomic categories which are presented orally, and the respondent is asked to recall as many as possible after each of three learning trials. The key outcome variable for this task is the total correct responses in the three learning trials.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Primary	Dorsolateral Prefrontal Cortex Activation During the Rewarded Delayed Response Working Memory Task Compared to the Inter-Trial-Interval as Measured by Functional MRI Blood-Oxygen-Level-Dependent (BOLD) Signal Imaging	Functional magnetic resonance imaging (fMRI) changes in the blood-oxygen-level-dependent (BOLD) - signal, which changes in response to neural activity. Baseline fMRI measurements will be followed by rewarded delayed response Working Memory (WM) task measurements in which participants are required to remember the spatial location of a target stimulus (a dot) relative to a fixation cross. Participants are given feedback indicating success or failure.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Change from Baseline in the Continuous Performance Test Mean D-Prime Value for the 2-Digit, 3-Digit, and 4-Digit Trials	The Continuous Performance Test is a computerized test that assesses the patient's attention and vigilance.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Change from Baseline in Brief Assessment of Cognition in Schizophrenia: Symbol-Coding	The Brief Assessment of Cognition in Schizophrenia (BACS): Symbol-Coding assesses the participant's speed of processing. The test is a timed paper-and-pencil test in which the respondent uses a key to write digits that correspond to nonsense symbols. The key outcome variable for this task is the total number of correct, valid symbols in 90 seconds.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Change from Baseline in Category Fluency Test	The Category Fluency test assesses the participant's speed of processing. The test is administered orally, with the respondent naming as many animals as he can in 1 minute. The key outcome variable for the test is the total number of correct, valid category words in 60 seconds.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Dorsolateral prefrontal cortex activation during the Rewarded Delayed Response Working Memory Task	Baseline fMRI arterial spin labeling (ASL) measurements will be followed by rewarded delayed response Working Memory (WM) task measurements in which participants are required to remember the spatial location of a target stimulus (a dot) relative to a fixation cross. Participants are given feedback indicating success or failure.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Ventro-lateral prefrontal cortex and orbitofrontal cortex activation during the shift trials versus the control trials	Measured by fMRI BOLD and ASL imaging.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Ventral striatum activation during the reward trials versus the control trials	Measured by fMRI BOLD and ASL imaging.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Multivariate pattern recognition analysis in the whole brain	Measured by fMRI BOLD and ASL imaging.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	P300 amplitude at the midline parietal electrode (Pz)	Brain electrical activity changes will be quantified with electroencephalogram (EEG) battery tests.; The P300 occurs after the presentation of a novel, behaviorally relevant target stimulus embedded among irrelevant stimuli. It reflects allocation of attention and activation of immediate memory.; The amplitude of P300 indexes brain actions when the mental representation of the stimulus environment is updated, while its latency indexes stimulus classification speed unrelated to response selection processes. The participants are instructed to push a button when hearing the target stimulus, but not when hearing the standard. They are asked to press the button as fast as possible.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Mis Match Negativity (MMN) amplitude at the midline frontal electrode (Fz)	The MMN is an auditory event related potential that is elicited by any discriminable change in auditory stimulation irrespective of the participant or participant's attention. The response to stimuli is being recorded by EEG electrodes while participants read a book.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Amplitude of the C1 component of the Visual Evoked Potentials at the midline occipital electrode (Oz)	Participants will undergo a baseline Visual Evoked Potentials (VEP) recording (2 minute checkerboard VEP) followed by a period of high frequency stimulation (2 minutes 9 Hz checkerboard stimulation). The VEP will be repeated 2 minutes after the end of high frequency stimulation.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Beta/gamma power during resting EEG	Participants are asked to open and close their eyes in 30 second alternating blocks to maintain an approximately constant level of arousal. The eyes closed EEG is dominated by alpha (8-14Hz) and the eyes open EEG dominated by beta (14-30Hz eyes open) with the two states analyzed separately to increase sensitivity to drug effects in these bands.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Frontal theta power (EEG) in an N-back Working Memory Task	In the n-back task participants are required to monitor a series of letters and report when the current letter matches the letter n integers back, where n=1 (1-back) or n=2 (2-back), the latter requiring a greater working memory resources. The task requires continuous updating of information stores. In the 0-back condition (which does not require manipulation of material in working memory), participants respond to the appearance of a pre-specified letter. The task consists of alternating 30-s blocks of 0-back with 1-back, and 2-back conditions, with letters displayed every 2 s for 1 s within each block.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Change from Baseline in Positive and Negative Syndrome Scale (PANSS) total score	The Positive and Negative Syndrome Scale was developed and standardized for typological and dimensional assessment of schizophrenic phenomena.	Baseline and Day 8 of Treatment Periods 1, 2 and 3	No
Secondary	Percentage of participants who experience at least 1 treatment emergent adverse event		From Day 1 until Day 63	Yes
Secondary	Percentage of participants who meet the markedly abnormal criteria for safety laboratory tests		From Day 1 until Day 63	Yes
Secondary	Percentage of participants who meet the markedly abnormal criteria for vital sign measurements		From Day 1 until Day 63	Yes