Effects of Atomoxetine in Mild Cognitive Impairment (ATX-001)

• ClinicalTrials.gov Identifier: NCT01522404
• Recruitment Status: Completed
• First Posted: January 31, 2012
• Results First Posted: December 5, 2018
• Last Update Posted: July 23, 2019
• Sponsor: Emory University
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Allan I Levey, MD, Emory University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Basic Science
• Condition: Mild Cognitive Impairment
• Interventions: Drug: Atomoxetine; Drug: Placebo
• Enrollment: 39

Participant Flow

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

Arm/Group Title	Atomoxetine / Inactive Compound	Inactive Compound / Atomoxetine
Arm/Group Description	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.	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.
Period Title: First Intervention (up to Week 29)
Started	20	19
Completed	18	19
Not Completed	2	0
Reason Not Completed
Withdrawal by Subject	1	0
Adverse Event	1	0
Period Title: Second Intervention (up to Week 58)
Started	18	19
Completed	17	19
Not Completed	1	0
Reason Not Completed
Withdrawal by Subject	1	0

Baseline Characteristics

Arm/Group Title		Atomoxetine / Inactive Compound	Inactive Compound / Atomoxetine	Total
Arm/Group Description		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.	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 of all reporting groups
Overall Number of Baseline Participants		20	19	39
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	20 participants	19 participants	39 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	4 20.0%	3 15.8%	7 17.9%
	>=65 years	16 80.0%	16 84.2%	32 82.1%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	20 participants	19 participants	39 participants
		70.2 (5.7)	72.0 (7.5)	71.1 (6.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	20 participants	19 participants	39 participants
	Female	10 50.0%	8 42.1%	18 46.2%
	Male	10 50.0%	11 57.9%	21 53.8%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	20 participants	19 participants	39 participants
	Hispanic or Latino	1 5.0%	0 0.0%	1 2.6%
	Not Hispanic or Latino	19 95.0%	19 100.0%	38 97.4%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	20 participants	19 participants	39 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	20 100.0%	19 100.0%	39 100.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	20 participants	19 participants	39 participants
		20	19	39

Outcome Measures

1. Primary Outcome

Title	Change in Interleukin 1 (IL 1-alpha) in Cerebrospinal Fluid (CSF) in Subjects With Mild Cognitive Impairment (MCI) Treated With Atomoxetine/Inactive Compound Compared to Subjects Treated With Inactive Compound / Atomoxetine
Description	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.
Time Frame	Baseline, Week 29 and Week 58

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Atomoxetine / Inactive Compound	Inactive Compound / Atomoxetine
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

2. Primary Outcome

Title	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
Description	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.
Time Frame	Baseline, Week 29 and Week 58

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Atomoxetine	Inactive Compound / Placebo
Arm/Group Description:	Participants in this group 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.	Participants in this group receive matching placebo that have inactive compound
Overall Number of Participants Analyzed	18	18
Mean (Standard Deviation); Unit of Measure: pg/mL
Baseline	1 (0.4)	0.8 (0.2)
Week 29	1 (0.4)	0.9 (0.2)
Week 58	1.1 (0.7)	0.9 (0.3)

3. Primary Outcome

Title	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
Description	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.
Time Frame	Up to Week 58

Outcome Measure Data

Analysis Population Description

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)

Arm/Group Title	Atomoxetine	Inactive Compound (Placebo)
Arm/Group Description:	Participants in this arm 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	Participants in this arm will receive a matching placebo that have inactive compound.
Overall Number of Participants Analyzed	39	37
Measure Type: Number; Unit of Measure: Adverse events
	142	91

4. Primary Outcome

Title	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)
Description	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% .
Time Frame	Up to Week 58

Outcome Measure Data

Analysis Population Description

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)

Arm/Group Title	Atomoxetine	Inactive Compound/Placebo
Arm/Group Description:	Participants in this group 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.	Participants in this group received Matching placebo that have inactive compound.
Overall Number of Participants Analyzed	39	37
Measure Type: Count of Participants; Unit of Measure: Participants
	2 5.1%	1 2.7%

5. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, Week 29, Week 58

Outcome Measure Data

Analysis Population Description

This analysis includes participants who completed the entire study.

Arm/Group Title	Atomoxetine / Inactive Compound	Inactive Compound / Atomoxetine
Arm/Group Description:	Participants in this arm 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 for up to weeks 29 and are then crossed over to Inactive compound group	Subjects in this arm received a matching placebo that have inactive compound for up to weeks 29 and then are crossed over to receive active treatment of Atomoxetine
Overall Number of Participants Analyzed	17	19
Mean (Standard Deviation); Unit of Measure: mL/100 g/min
Baseline	42.4 (8.6)	42.6 (7.5)
Week 29	39.3 (5.6)	38.8 (6.2)
Week 58	40.2 (7.1)	39.6 (8.0)

6. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, Week 29 and Week 58

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Atomoxetine / Inactive Compound	Inactive Compound / Atomoxetine
Arm/Group Description:	Participants in this arm 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 for up to weeks 29 and are then crossed over to Inactive compound group	Subjects in this arm received a matching placebo that have inactive compound for up to weeks 29 and then are crossed over to receive active treatment of Atomoxetine
Overall Number of Participants Analyzed	17	19
Mean (Standard Deviation); Unit of Measure: ratio
Baseline	0.69 (0.07)	0.68 (0.08)
Week 29	0.72 (0.08)	0.67 (0.10)
Week 58	0.74 (0.09)	0.73 (0.08)

Adverse Events

Time Frame	All Adverse events were collected from Baseline to week 58 among the participants in both groups.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Atomoxetine		Inactive Compound
Arm/Group Description	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.		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.
All-Cause Mortality
	Atomoxetine		Inactive Compound
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/39 (0.00%)		0/37 (0.00%)
Serious Adverse Events
	Atomoxetine		Inactive Compound
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/39 (12.82%)		1/37 (2.70%)
Gastrointestinal disorders
Appendicitis *	0/39 (0.00%)	0	1/37 (2.70%)	1
General disorders
Hypothermia/dizziness *	1/39 (2.56%)	1	0/37 (0.00%)	0
Headache Pain *	1/39 (2.56%)	1	0/37 (0.00%)	0
Musculoskeletal and connective tissue disorders
Fracture of Right Leg/Hip (Pelvis) *	1/39 (2.56%)	1	0/37 (0.00%)	0
Nervous system disorders
Dysautonomia *	1/39 (2.56%)	1	0/37 (0.00%)	0
Vascular disorders
Severe Elevated Blood Pressure *	1/39 (2.56%)	1	0/37 (0.00%)	0
* Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Atomoxetine		Inactive Compound
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/39 (100.00%)		37/37 (100.00%)
Gastrointestinal disorders
Constipation *	4/39 (10.26%)	4	1/37 (2.70%)	1
Irritable Stomach *	11/39 (28.21%)	14	5/37 (13.51%)	5
General disorders
Falls *	6/39 (15.38%)	7	2/37 (5.41%)	2
Dizziness *	9/39 (23.08%)	11	8/37 (21.62%)	8
Back Pain *	1/39 (2.56%)	1	3/37 (8.11%)	3
Loss of Appetite *	3/39 (7.69%)	3	0/37 (0.00%)	0
Dry Mouth *	10/39 (25.64%)	10	2/37 (5.41%)	2
Suicide *	2/39 (5.13%)	2	1/37 (2.70%)	1
Injury to Head and Ear *	1/39 (2.56%)	1	2/37 (5.41%)	2
Fatigue *	3/39 (7.69%)	3	3/37 (8.11%)	3
Body Cramps *	0/39 (0.00%)	0	2/37 (5.41%)	2
Metabolism and nutrition disorders
Hypokalemia *	1/39 (2.56%)	1	2/37 (5.41%)	2
Musculoskeletal and connective tissue disorders
Fracture *	2/39 (5.13%)	3	0/37 (0.00%)	0
Tremor *	3/39 (7.69%)	3	0/37 (0.00%)	0
Psychiatric disorders
Anxiety *	2/39 (5.13%)	2	1/37 (2.70%)	1
Respiratory, thoracic and mediastinal disorders
Upper respiratory infection *	4/39 (10.26%)	4	7/37 (18.92%)	8
Skin and subcutaneous tissue disorders
Rash *	2/39 (5.13%)	2	2/37 (5.41%)	2
Vascular disorders
Headache *	5/39 (12.82%)	7	2/37 (5.41%)	2
Hypertension *	2/39 (5.13%)	3	1/37 (2.70%)	2
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

Sample size is small leading to some analytical limitations

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Allan I. Levey, MD, PhD
• Organization: Emory University
• Phone: 404-727-7220
• EMail: alevey@emory.edu

• Responsible Party: Allan I Levey, MD, Emory University
• ClinicalTrials.gov Identifier: NCT01522404
• Other Study ID Numbers: IRB00054397; 5U01AG010483 ( U.S. NIH Grant/Contract ); ATX-001 ( Other Identifier: Other )
• First Submitted: January 25, 2012
• First Posted: January 31, 2012
• Results First Submitted: October 31, 2018
• Results First Posted: December 5, 2018
• Last Update Posted: July 23, 2019