Trial Outcomes & Findings for Effects of Atomoxetine in Mild Cognitive Impairment (NCT NCT01522404)

Last Updated: 2019-07-23

Results Overview

This study will examine the effects of Atomoxetine and Inactive compound on biomarkers of inflammation by measuring and comparing the levels of Interleukin 1 (IL 1-alpha) using the assay of CSF at Baseline, Week 29 and Week 58 among the two groups. The study hypothesizes that the period that participants are treated with atomoxetine will have reductions in levels of these pro-inflammatory biomarkers among the two groups.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

39 participants

Primary outcome timeframe

Baseline, Week 29 and Week 58

Results posted on

2019-07-23

Participant Flow

Participants were recruited between March 2012 and October 2017. The study is conducted at Emory University Hospital in Atlanta.

Participant milestones

Participant milestones
Measure	Atomoxetine / Inactive Compound Participants in this group are randomized to Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 1/ Matching placebo that have inactive compound during period 2.	Inactive Compound / Atomoxetine Participants in this group are randomized to matching placebo that have inactive compound during period 1/ Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 2.
First Intervention (up to Week 29) STARTED	20	19
First Intervention (up to Week 29) COMPLETED	18	19
First Intervention (up to Week 29) NOT COMPLETED	2	0
Second Intervention (up to Week 58) STARTED	18	19
Second Intervention (up to Week 58) COMPLETED	17	19
Second Intervention (up to Week 58) NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Atomoxetine / Inactive Compound Participants in this group are randomized to Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 1/ Matching placebo that have inactive compound during period 2.	Inactive Compound / Atomoxetine Participants in this group are randomized to matching placebo that have inactive compound during period 1/ Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 2.
First Intervention (up to Week 29) Withdrawal by Subject	1	0
First Intervention (up to Week 29) Adverse Event	1	0
Second Intervention (up to Week 58) Withdrawal by Subject	1	0

Baseline Characteristics

Effects of Atomoxetine in Mild Cognitive Impairment

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Atomoxetine / Inactive Compound n=20 Participants Participants in this group are randomized to Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 1/ Matching placebo that have inactive compound during period 2.	Inactive Compound / Atomoxetine n=19 Participants Participants in this group are randomized to matching placebo that have inactive compound during period 1/ Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 2.	Total n=39 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Age, Categorical >=65 years	16 Participants n=5 Participants	16 Participants n=7 Participants	32 Participants n=5 Participants
Age, Continuous	70.2 years STANDARD_DEVIATION 5.7 • n=5 Participants	72.0 years STANDARD_DEVIATION 7.5 • n=7 Participants	71.1 years STANDARD_DEVIATION 6.6 • n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants	8 Participants n=7 Participants	18 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	11 Participants n=7 Participants	21 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	19 Participants n=5 Participants	19 Participants n=7 Participants	38 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	20 Participants n=5 Participants	19 Participants n=7 Participants	39 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	20 participants n=5 Participants	19 participants n=7 Participants	39 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 29 and Week 58

Population: Only 15.1 % of the samples were above the limit of detection for Interleukin 1 (IL 1-alpha) alpha in CSF, precluding the planned analysis and comparing the mean and standard deviation of Interleukin 1 (IL 1-alpha) alpha levels in treatment versus placebo groups. Hence the analysis was not done and the outcome was not measured.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Baseline, Week 29 and Week 58

Population: Only 49.1 % of the samples were above the limit of detection for TECK in CSF among the groups that are included in the analysis below. The levels for only 18 participants in Atomoxetine group and 18 participants in Inactive compound were analyzed

This study will examine the effect of Atomoxetine and Inactive Compound on biomarkers of inflammation by measuring and comparing the mean levels of Thymus-Expressed Chemokine (TECK). These levels are measured using the assay of CSF at Baseline, Week 29 and Week 58. The study hypothesizes that the period that participants are treated with atomoxetine will have reduction in levels of these markers among both groups.

Outcome measures

Outcome measures
Measure	Atomoxetine / Inactive Compound n=18 Participants Participants in this group are randomized to Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 1/ Matching placebo that have inactive compound during period 2.	Inactive Compound / Atomoxetine n=18 Participants Participants in this group are randomized to matching placebo that have inactive compound during period 1/ Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 2.
Change in Mean Level of Thymus-Expressed Chemokine (TECK) in Cerebrospinal Fluid (CSF) in Participants With Mild Cognitive Impairment (MCI) Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine Baseline	1 pg/mL Standard Deviation 0.4	0.8 pg/mL Standard Deviation 0.2
Change in Mean Level of Thymus-Expressed Chemokine (TECK) in Cerebrospinal Fluid (CSF) in Participants With Mild Cognitive Impairment (MCI) Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine Week 29	1 pg/mL Standard Deviation 0.4	0.9 pg/mL Standard Deviation 0.2
Change in Mean Level of Thymus-Expressed Chemokine (TECK) in Cerebrospinal Fluid (CSF) in Participants With Mild Cognitive Impairment (MCI) Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine Week 58	1.1 pg/mL Standard Deviation 0.7	0.9 pg/mL Standard Deviation 0.3

PRIMARY outcome

Timeframe: Up to Week 58

Population: In Atomoxetine/Placebo group 20 participants got Atomoxetine during period 1 and 18 got Placebo during period 2. In Placebo/ Atomoxetine group 19 participants got Placebo during period 1 and 19 participants got Atomoxetine during period 2. Total for Atomoxetine (20 in period 1 + 19 in period 2) Total for Placebo (19 in period 1+ 18 in period 2)

Safety was assessed by number of all adverse events among the participants treated with Atomoxetine compared to the participants treated with Placebo throughout the study. The Adverse Event assessment was done at each study visit through their participation in the study.

Outcome measures

Outcome measures
Measure	Atomoxetine / Inactive Compound n=39 Participants Participants in this group are randomized to Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 1/ Matching placebo that have inactive compound during period 2.	Inactive Compound / Atomoxetine n=37 Participants Participants in this group are randomized to matching placebo that have inactive compound during period 1/ Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 2.
Number of All Adverse Events Among the Participants With Mild Cognitive Impairment (MCI) Treated With Atomoxetine Compared to the Participants Treated With Placebo/Inactive Compound	142 Adverse events	91 Adverse events

PRIMARY outcome

Timeframe: Up to Week 58

Tolerability is measured by comparing the drop out rate among the participants treated with Atomoxetine to the participants treated with inactive compound (Placebo). Study predicts that treatment-associated (Atomoxetine Group) drop out rate will be \< 15% .

Outcome measures

Outcome measures
Measure	Atomoxetine / Inactive Compound n=39 Participants Participants in this group are randomized to Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 1/ Matching placebo that have inactive compound during period 2.	Inactive Compound / Atomoxetine n=37 Participants Participants in this group are randomized to matching placebo that have inactive compound during period 1/ Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 2.
Number of Participants That Drop Out of the Study Among the Participants Treated With Atomoxetine When Compared to the Participants Treated With Inactive Compound (Placebo)	2 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline, Week 29, Week 58

Population: This analysis includes participants who completed the entire study.

Change in rate of cerebral blood flow is assessed by arterial spin labeling Magnetic Resonance Imaging (ASL-MRI) in subjects with Mild Cognitive Impairment MCI treated with Atomoxetine / Inactive Compound compared to participants treated with Inactive compound / Atomoxetine. The rates from the Baseline are compared to week 29 and week 58 among the participants treated with Atomoxetine / Inactive Compound compared to participants treated with Inactive compound / Atomoxetine. All MRIs will be reviewed by the investigators and the investigator.

Outcome measures

Outcome measures
Measure	Atomoxetine / Inactive Compound n=17 Participants Participants in this group are randomized to Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 1/ Matching placebo that have inactive compound during period 2.	Inactive Compound / Atomoxetine n=19 Participants Participants in this group are randomized to matching placebo that have inactive compound during period 1/ Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 2.
Rate of Cerebral Blood Flow in Subjects With Mild Cognitive Impairment MCI Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine Baseline	42.4 mL/100 g/min Standard Deviation 8.6	42.6 mL/100 g/min Standard Deviation 7.5
Rate of Cerebral Blood Flow in Subjects With Mild Cognitive Impairment MCI Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine Week 29	39.3 mL/100 g/min Standard Deviation 5.6	38.8 mL/100 g/min Standard Deviation 6.2
Rate of Cerebral Blood Flow in Subjects With Mild Cognitive Impairment MCI Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine Week 58	40.2 mL/100 g/min Standard Deviation 7.1	39.6 mL/100 g/min Standard Deviation 8.0

SECONDARY outcome

Timeframe: Baseline, Week 29 and Week 58

Population: This analyses includes participants that completed 58 weeks of follow up.

Cerebral metabolic rate for glucose as measured by Fluoro Deoxy Glucose (FDG) uptake will be obtained by Positron Emission Tomography (PET) scan. The rates from the Baseline are compared to week 29 and week 58 among the subjects treated with Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine. . Cerebral glucose metabolism is reduced in early stages of AD. The ratio of hippocampal FDG-PET uptake to the whole brain average are presented below.

Outcome measures

Outcome measures
Measure	Atomoxetine / Inactive Compound n=17 Participants Participants in this group are randomized to Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 1/ Matching placebo that have inactive compound during period 2.	Inactive Compound / Atomoxetine n=19 Participants Participants in this group are randomized to matching placebo that have inactive compound during period 1/ Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose during period 2.
Change in FluoroDeoxyGlucose (FDG) Uptake in Participants With Mild Cognitive Impairment (MCI) Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine Week 58	0.74 ratio Standard Deviation 0.09	0.73 ratio Standard Deviation 0.08
Change in FluoroDeoxyGlucose (FDG) Uptake in Participants With Mild Cognitive Impairment (MCI) Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine Baseline	0.69 ratio Standard Deviation 0.07	0.68 ratio Standard Deviation 0.08
Change in FluoroDeoxyGlucose (FDG) Uptake in Participants With Mild Cognitive Impairment (MCI) Treated With Atomoxetine / Inactive Compound Compared to Participants Treated With Inactive Compound / Atomoxetine Week 29	0.72 ratio Standard Deviation 0.08	0.67 ratio Standard Deviation 0.10

Adverse Events

Atomoxetine

Serious events: 5 serious events

Other events: 39 other events

Deaths: 0 deaths

Inactive Compound

Serious events: 1 serious events

Other events: 37 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Atomoxetine n=39 participants at risk Participants in this arm included all the participants that received Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose. The group includes 20 participants on Atomoxetine during period 1 and 19 participants on Atomoxetine during period 2.	Inactive Compound n=37 participants at risk Participants in this arm included all the participants from both groups that received a matching placebo that have inactive compound. 19 participants on inactive compound during period 1 and 18 participants on inactive compound during period 2.
Musculoskeletal and connective tissue disorders Fracture of Right Leg/Hip (Pelvis)	2.6% 1/39 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	0.00% 0/37 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Nervous system disorders Dysautonomia	2.6% 1/39 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	0.00% 0/37 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Hypothermia/dizziness	2.6% 1/39 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	0.00% 0/37 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Headache Pain	2.6% 1/39 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	0.00% 0/37 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Gastrointestinal disorders Appendicitis	0.00% 0/39 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	2.7% 1/37 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Vascular disorders Severe Elevated Blood Pressure	2.6% 1/39 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	0.00% 0/37 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.

Other adverse events

Additional Information

Allan I. Levey, MD, PhD

Emory University

Phone: 404-727-7220

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Atomoxetine n=39 participants at risk Participants in this arm included all the participants that received Atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose. The group includes 20 participants on Atomoxetine during period 1 and 19 participants on Atomoxetine during period 2.	Inactive Compound n=37 participants at risk Participants in this arm included all the participants from both groups that received a matching placebo that have inactive compound. 19 participants on inactive compound during period 1 and 18 participants on inactive compound during period 2.
Vascular disorders Headache	12.8% 5/39 • Number of events 7 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	5.4% 2/37 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Skin and subcutaneous tissue disorders Rash	5.1% 2/39 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	5.4% 2/37 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Falls	15.4% 6/39 • Number of events 7 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	5.4% 2/37 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Respiratory, thoracic and mediastinal disorders Upper respiratory infection	10.3% 4/39 • Number of events 4 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	18.9% 7/37 • Number of events 8 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Dizziness	23.1% 9/39 • Number of events 11 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	21.6% 8/37 • Number of events 8 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Back Pain	2.6% 1/39 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	8.1% 3/37 • Number of events 3 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Vascular disorders Hypertension	5.1% 2/39 • Number of events 3 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	2.7% 1/37 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Loss of Appetite	7.7% 3/39 • Number of events 3 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	0.00% 0/37 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Dry Mouth	25.6% 10/39 • Number of events 10 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	5.4% 2/37 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Gastrointestinal disorders Constipation	10.3% 4/39 • Number of events 4 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	2.7% 1/37 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Musculoskeletal and connective tissue disorders Fracture	5.1% 2/39 • Number of events 3 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	0.00% 0/37 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Suicide	5.1% 2/39 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	2.7% 1/37 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Gastrointestinal disorders Irritable Stomach	28.2% 11/39 • Number of events 14 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	13.5% 5/37 • Number of events 5 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Injury to Head and Ear	2.6% 1/39 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	5.4% 2/37 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Fatigue	7.7% 3/39 • Number of events 3 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	8.1% 3/37 • Number of events 3 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Musculoskeletal and connective tissue disorders Tremor	7.7% 3/39 • Number of events 3 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	0.00% 0/37 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
General disorders Body Cramps	0.00% 0/39 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	5.4% 2/37 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Psychiatric disorders Anxiety	5.1% 2/39 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	2.7% 1/37 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Metabolism and nutrition disorders Hypokalemia	2.6% 1/39 • Number of events 1 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.	5.4% 2/37 • Number of events 2 • All Adverse events were collected from Baseline to week 58 among the participants in both groups.