Minocycline for Treatment of Posttraumatic Stress Disorder in Veterans

• Sponsor: Sriram Ramaswamy (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT03340350
• Collaborator: Creighton University (Other)
• Enrollment: 10
• Location: 1
• Arm: 1
• Actual Duration (Months): 12.7
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The study will evaluate the safety and efficacy of adjunctive minocycline treatment in veterans with PTSD.

Condition or Disease	Intervention/Treatment	Phase
PTSD	Drug: Minocycline	Phase 4

Detailed Description

This is a 12-week, open-label pilot study in which adjunctive minocycline will be administered to approximately 15 veterans diagnosed with PTSD.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Minocycline for Treatment of Posttraumatic Stress Disorder in Veterans
• Actual Study Start Date: May 10, 2017
• Actual Primary Completion Date: Jun 1, 2018
• Actual Study Completion Date: Jun 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Minocycline Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12	Drug: Minocycline; Minocycline capsule; Other Names: Minocycline hydrochloride capsule

Outcome Measures

Primary Outcome Measures

1. PTSD Symptom Severity [Baseline and Week 12]

   PTSD symptom severity was assessed using total scores on the Past Month version of the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (CAPS-5). Total scores on the CAPS-5 range from 0 to 80, with higher scores indicating greater severity of PTSD symptoms.

2. Change in C-reactive Protein (CRP) Level [Screening and Week 12]

   Measure of inflammation

3. Change in Interleukin 6 (IL-6) Level [Screening and Week 12]

   Measure of inflammation

4. Change in Tumor Necrosis Factor Alpha (TNF-α) Level [Screening and Week 12]

   Measure of inflammation

Secondary Outcome Measures

1. Depression Symptom Severity [Screening and Week 12]

   Depression symptom severity was assessed using total scores on the Beck Depression Inventory-II (BDI-II). Total scores on the BDI-II range from 0 to 63, with higher scores indicating greater severity of depression symptoms.

2. Clinical Status (Severity) [Baseline and Week 12]

   The Clinical Global Impressions Severity scale (CGI-S) was used to assess severity of illness. Scores on the CGI-S range from 0 to 7, with higher scores reflecting greater severity of illness.

3. Clinical Status (Improvement) [Baseline and Week 12]

   The Clinical Global Impressions Improvement scale (CGI-I) was used to assess global improvement in clinical status. Scores on the CGI-I range from 0 to 7, with lower scores reflecting greater improvement in clinical status.

4. Executive Functioning (Set Shifting) [Baseline and Week 12]

   The Trail Making Test (TMT) is a scale used to measure a type of executive functioning (i.e., higher-order cognitive function) called set shifting. The TMT is scored as time (in seconds) to complete Parts A and B of this task. A difference score was calculated (time to complete Part B minus time to complete Part A) to subtract the motor component of this task and provide a better estimate of executive functioning. Lower difference scores on the TMT indicate better set shifting.

5. Executive Functioning (Verbal Fluency) [Baseline and Week 12]

   The Controlled Oral Word Association (COWA) is a scale used to measure a type of executive functioning (i.e., higher-order cognitive function) called verbal fluency. The COWA is scored as the total number of valid words produced in one minute for each of three letters, with 1 point scored for each valid word (score range: 0-no upper limit). Higher scores on the COWA indicate greater verbal fluency.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Veterans between the ages of 19 and 65 who meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for chronic PTSD.

2. Patients who have been taking an adequate dose of selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) medication, bupropion, or mirtazapine for a minimum of 8 weeks at the time of study entry.

3. PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PCL-5) score of > 33 at the Screening Visit. Eligible persons will be allowed to have other symptoms that are commonly comorbid with PTSD (e.g., anxiety, somatic symptoms). This strategy will provide a feasible and generalizable sample of those with chronic PTSD.

Exclusion Criteria:

1. Patients with a concurrent DSM-5 diagnosis in any of the following categories:

1.1. Major Neurocognitive Disorder (NCD) 1.2. Lifetime Schizophrenia and other Psychotic Disorders 1.3. Lifetime Bipolar Disorder 1.4. Alcohol Dependence or Abuse in 3 months prior to the Screening Visit 1.5. Any other Substance Dependence or Abuse (excluding nicotine) in 12 months prior to the Screening Visit 1.6. Any other concurrent Axis I Disorder (including Major Depressive Disorder) must be secondary to the primary diagnosis of PTSD.

1. Chronic pain levels requiring use of any opiate medications with the exception of Tramadol. Patients are allowed the use of Tramadol at 25-50 mg per day dosing.

2. Any condition or disorder that may cause neuropsychiatric sequelae (e.g., Parkinson's disease, stroke, seizures, or TBI).

3. Past chronic PTSD, meaning PTSD that preceded the incident traumatic event responsible for the current PTSD. Other traumatic life events will not be exclusionary unless they resulted in previous PTSD.

4. Patients with a history of intolerance or hypersensitivity to minocycline or other tetracycline antibiotics, or prior tetracycline use 2 months prior to the Screening Visit.

5. Concomitant treatment with penicillin or other antibiotics, or treatment with antibiotics for greater than 7 days in the past month.

6. Use of aspirin, non-steroidal anti-inflammatory agents (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors for < 6 months prior to study entry or dose changes after study entry. Limited as-needed use is permitted prior to study entry but not during the study.

7. Use of statins will not be permitted during the study as they have been shown to reduce levels of pro-inflammatory cytokines.

8. Use of concomitant anti-coagulant drugs (except low-dose aspirin) as minocycline has been shown to depress plasma prothrombin activity.

9. Any degree of hepatic or renal failure that in the Investigator's judgement would pose a safety risk for treatment with minocycline.

10. Conditions which may be negatively affected by minocycline treatment, such as active inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease).

11. A history of C. difficile colitis.

12. Patients who based on history or mental status examination have a significant risk of committing suicide, or who are homicidal or violent and who are in the Investigator's opinion in significant imminent risk of hurting others.

13. Patients who have a medical condition that, in the Investigator's opinion, would expose them to an increased risk of a significant adverse event or interfere with assessments of safety and efficacy during the course of the trial.

14. Women who are pregnant or plan to become pregnant during the study. All women of childbearing potential must have a negative urine pregnancy test at the Screening Visit and throughout the study. Sexually active women participating in the study must use a medically acceptable form of contraception.

15. Patients with a current known infection or who are acutely ill.

16. Patients with an autoimmune disease (i.e., Lupus, Rheumatoid Arthritis).

17. Immunocompromised patients (i.e., HIV).

18. Patients with thyroid disorders unless euthyroid at screening.

19. Patients with cancer not in remission.

20. Patients with cardiovascular disease, such as myocardial infarction and arrhythmias.

21. Patients with diabetes.

22. History of significant esophagitis.

23. Patients who plan to initiate or terminate any psychotropic medication during the study. Patients taking any psychotropic medication should be on a stable dose for at least 6 weeks prior to the Screening Visit (except for the SSRI, SNRI or mirtazapine used to treat their PTSD) AND agree not to discontinue or otherwise alter treatment during the study.

24. Patients who plan to initiate or terminate any form of psychotherapy or behavior therapy during the study with the exception of PTSD Orientation Group. Subjects may be in supportive psychotherapy if it was initiated at least three months prior to the Screening Visit AND subject agrees not to discontinue or otherwise alter therapy during the study. Subjects receiving evidence-based psychotherapies such as Prolonged Exposure or Cognitive Processing Therapy will be excluded.

25. Patients who are unable to speak, read, and understand English or are judged by the Investigator to be unable or unlikely to follow the study protocol and complete all scheduled visits.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Nebraska-Western Iowa Health Care System	Omaha	Nebraska	United States	68105

Sponsors and Collaborators

• Sriram Ramaswamy
• Creighton University

Investigators

• Principal Investigator: Sriram Ramaswamy, MD, VA Nebraska Western Iowa Health Care System

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 10, 2018

More Information

Publications

None provided.

• Responsible Party: Sriram Ramaswamy, Staff Psychiatrist, VA Nebraska Western Iowa Health Care System
• ClinicalTrials.gov Identifier: NCT03340350
• Other Study ID Numbers: RAM-01068
• First Posted: Nov 13, 2017
• Last Update Posted: Jul 9, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Sriram Ramaswamy, Staff Psychiatrist, VA Nebraska Western Iowa Health Care System: Minocycline; PTSD
• Additional relevant MeSH terms: Stress Disorders, Post-Traumatic; Minocycline

Study Results

Participant Flow

Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Period Title: Overall Study
STARTED	10
COMPLETED	4
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.9 (11.2)
Sex: Female, Male (Count of Participants)
Female	1 10%
Male	9 90%
Race/Ethnicity, Customized (Count of Participants)
White	6 60%
Black	1 10%
Hispanic or Latino	2 20%
Other	1 10%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	PTSD Symptom Severity
Description	PTSD symptom severity was assessed using total scores on the Past Month version of the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (CAPS-5). Total scores on the CAPS-5 range from 0 to 80, with higher scores indicating greater severity of PTSD symptoms.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	Participants received minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Measure Participants	4
Baseline	31.5 (7.23)
Week 12	23 (7.62)

2. Primary Outcome

Title	Change in C-reactive Protein (CRP) Level
Description	Measure of inflammation
Time Frame	Screening and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Measure Participants	4
Screening	1.25 (0.35)
Week 12	0.90 (0.14)

3. Primary Outcome

Title	Change in Interleukin 6 (IL-6) Level
Description	Measure of inflammation
Time Frame	Screening and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Measure Participants	4
Screening	1.27 (0.49)
Week 12	1.64 (0.67)

4. Primary Outcome

Title	Change in Tumor Necrosis Factor Alpha (TNF-α) Level
Description	Measure of inflammation
Time Frame	Screening and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Measure Participants	4
Screening	1.14 (0.31)
Week 12	1.13 (0.14)

5. Secondary Outcome

Title	Depression Symptom Severity
Description	Depression symptom severity was assessed using total scores on the Beck Depression Inventory-II (BDI-II). Total scores on the BDI-II range from 0 to 63, with higher scores indicating greater severity of depression symptoms.
Time Frame	Screening and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Measure Participants	4
Screening	24.5 (12.71)
Week 12	20.75 (5.19)

6. Secondary Outcome

Title	Clinical Status (Severity)
Description	The Clinical Global Impressions Severity scale (CGI-S) was used to assess severity of illness. Scores on the CGI-S range from 0 to 7, with higher scores reflecting greater severity of illness.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Measure Participants	4
Baseline	4.25 (0.50)
Week 12	4.00 (0.00)

7. Secondary Outcome

Title	Clinical Status (Improvement)
Description	The Clinical Global Impressions Improvement scale (CGI-I) was used to assess global improvement in clinical status. Scores on the CGI-I range from 0 to 7, with lower scores reflecting greater improvement in clinical status.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Measure Participants	4
Baseline	4.00 (0.00)
Week 12	3.25 (0.96)

8. Secondary Outcome

Title	Executive Functioning (Set Shifting)
Description	The Trail Making Test (TMT) is a scale used to measure a type of executive functioning (i.e., higher-order cognitive function) called set shifting. The TMT is scored as time (in seconds) to complete Parts A and B of this task. A difference score was calculated (time to complete Part B minus time to complete Part A) to subtract the motor component of this task and provide a better estimate of executive functioning. Lower difference scores on the TMT indicate better set shifting.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Measure Participants	4
Baseline	43.75 (11.62)
Week 12	23.00 (1.92)

9. Secondary Outcome

Title	Executive Functioning (Verbal Fluency)
Description	The Controlled Oral Word Association (COWA) is a scale used to measure a type of executive functioning (i.e., higher-order cognitive function) called verbal fluency. The COWA is scored as the total number of valid words produced in one minute for each of three letters, with 1 point scored for each valid word (score range: 0-no upper limit). Higher scores on the COWA indicate greater verbal fluency.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
Measure Participants	4
Baseline	31.00 (4.00)
Week 12	32.25 (6.65)

Adverse Events

Time Frame	12 weeks
Arm/Group Title	Minocycline
Arm/Group Description	Minocycline 100 mg/day 1 to 7 and 200 mg/day 8 to end of week 12 Minocycline: Minocycline capsule
All Cause Mortality
	Minocycline
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Serious Adverse Events
	Minocycline
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Other (Not Including Serious) Adverse Events
	Minocycline
	Affected / at Risk (%)	# Events
Total	4/10 (40%)
General disorders
Hospitalization	1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Shortness of breath	1/10 (10%)
Skin and subcutaneous tissue disorders
Rash/hives	2/10 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.