IRLGREY-B: Incomplete Response in Late-Life Depression: Getting to Remission With Buprenorphine

• Sponsor: Jordan F. Karp (Other)
• Overall Status: Completed
• CT.gov ID: NCT02176291
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 31
• Location: 1
• Arms: 2
• Duration (Months): 42.1
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purposes of this project are to examine the feasibility, safety, tolerability and clinical effect of low-dose buprenorphine as a novel treatment for late-life treatment-resistant depression and to develop preliminary data about mechanism of action.

Condition or Disease	Intervention/Treatment	Phase
Depression; Major Depressive Disorder	Drug: Buprenorphine; Drug: Placebo	Phase 2

Detailed Description

Up to one half of older patients with major depression develop Late-Life Treatment Resistant Depression (LL-TRD). Consequences of LL-TRD include suicide, worsened medical conditions, increased caregiver burden, and higher all-cause mortality. The development and testing of novel-mechanism pharmacotherapies is a public health priority embraced by National Institute of Mental Health (NIMH). Among the neuropeptidergic transmitters, opioids are known to modulate mood, and this system is often altered in patients with major depression. Targeting the opiate system in LL-TRD may positively modulate a system in which there is age-associated imbalance between circulating opiates and the density and binding affinity of mu and kappa opiate receptors. Buprenorphine (BPN) is an antagonist at the kappa opiate receptor and a partial agonist at the mu opiate receptor. Either, or both, of these pharmacodynamic actions may underlie its putative antidepressant effects. Our research group has open pilot data from 15 older adults with prospectively demonstrated treatment resistance to venlafaxine who were exposed to low-dose BPN, suggesting a clinically meaningful antidepressant effect. In addition, since BPN: 1) is available in sublingual formulation and 2) has a favorable safety and pharmacokinetic profile, it is an attractive candidate to re-purpose as a molecule for LL-TRD. Thus, the overarching aims of this project are to examine the feasibility, safety, tolerability and clinical effect of low-dose BPN as a novel treatment for LL-TRD and to develop preliminary data about mechanism of action (MOA).

The overarching aims are to examine the feasibility, safety, and tolerability of buprenorphine (BPN) as a novel treatment for late-life treatment resistant depression (LL-TRD). This also involves using translational tools of modern neurobiology (fMRI) to rapidly obtain proof-of-concept support for further clinical development. Formal dosing schedules in the use of buprenorphine have yet to be thoroughly established. This study hopes to determine optimal dosing strategies to improve acceptability.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Incomplete Response in Late-Life Depression: Getting to Remission With Buprenorphine
• Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Apr 1, 2017
• Actual Study Completion Date: Feb 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Buprenorphine Buprenorphine	Drug: Buprenorphine; low-dose buprenorphine (range 0.2 mg/day -- 2.0 mg/day); Other Names: suboxone buprenex temgesic subutex
Placebo Comparator: Placebo Placebo	Drug: Placebo; matched placebo

Outcome Measures

Primary Outcome Measures

1. Montgomery-Asberg Depression Rating Scale (MADRS) [baseline and 8 weeks]

   Measure of depression severity, range of 0-60 We calculated the mean change in depression severity for both groups using baseline MADRS and week 8 MADRS scores. Greater mean change represents better outcome.

Secondary Outcome Measures

1. Brief Symptom Inventory--Anxiety Subscale (BSI) [Baseline and 8 weeks]

   Measure of Anxiety Theoretical Range 0-2.4 with lower numbers indicating a better outcome. We calculated the mean change in anxiety for both groups using Phase 1 week 12 time point (baseline) and Phase 2 week 8 time point (final time point).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age >/= to 50 years.

2. Major depressive disorder (MDD), single or recurrent, as diagnosed by the Structured Clinical Interview for the DSM IV (SCID-IV).

3. Montgomery-Åsberg Depression Rating Scale (MADRS) >/= to 15.

4. Has or agrees to establish a clinical relationship with primary care physician (PCP).

5. Availability of an informant (e.g., emergency contact).

Exclusion Criteria:

1. Inability to provide informed consent.

2. Depressive symptoms not severe enough i.e.,Montgomery-Åsberg Depression Rating Scale ( MADRS) < 15 at the baseline assessments.

3. Dementia, as defined by The Modified Mini-Mental State (3MS) examination < 84 and clinical evidence of dementia (e.g., memory impairment, executive dysfunction, agnosia, apraxia, aphasia, with functional impairment).

4. Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms, as diagnosed by the Structured Clinical Interview for DSM (SCID).

5. Abuse of or dependence on alcohol or other substances within the past 3 months as determined by SCID, and confirmed by study physician interview.

6. Alcohol use amounting to 15 or more drinks per week or drinking 5 or more drinks on one occasion during any given week.

7. High risk for suicide (e.g., active suicidal ideation (SI) and/or current/recent intent or plan) AND unable to be managed safely in the clinical trial (e.g., unwilling to be hospitalized). Urgent psychiatric referral will be made in these cases.

8. Contraindication to venlafaxine extended release (XR) or BPN as determined by study physician including history of intolerance of either venlafaxine XR or BPN in the study target dosage range (venlafaxine XR at up to 300 mg/day; BPN at up to 2 mg/day).

9. Inability to communicate in English (i.e., interview cannot be conducted without an interpreter; subject largely unable to understand questions and cannot respond in English).

10. Non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview).

11. Unstable medical illness, including delirium, uncontrolled diabetes mellitus, hypertension, or cerebrovascular or cardiovascular risk factors that are not under medical management. This will be determined based on information from the patient's personal physician and study physician's clinical judgment. Referral to the patient's personal physician or to a general practitioner will be made in these cases. Sodium and glucose levels done in the past 6 months are also reviewed before a subject begins study medication to determine if an illness is stable or uncontrolled. Individual lab parameters may deviate from normal without any associated pathophysiology or negative clinical affect; therefore we will follow the guide below before beginning starting any study medication.

Sodium value of 135 but asymptomatic= consider to be normal and proceed without further testing.

Sodium value of 134= repeat sodium. If value continues to be at 134 or higher and subject is asymptomatic, continue study participation but recheck sodium level after one week of exposure to study medication to confirm it has stayed stable.

Sodium value of 133 or less= will evaluate subject's medication list to suggest possibly removing other medications which may be contributing to low sodium (in collaboration with their PCP), suggest fluid restriction and require repeat sodium that is normal range prior to commencing study.

Glucose < 275 and asymptomatic= stable to proceed but will communicate value to PCP with participants permission.

(see exclusion #17 for information on hepatic function lab parameters)

1. Subjects taking psychotropic medications that cannot be safely tapered and discontinued prior to study initiation. The following exceptions are allowed if they have been taken at a stable dose for at least 4 weeks prior to study entry and there is not a plan to change the dose during the next 28 weeks: benzodiazepines up to 2 mg/d lorazepam equivalent; other sedative-hypnotics (e.g., zolpidem, zaleplon, eszopiclone); gabapentin if prescribed for non-psychiatric indication (e.g., neuropathy).

2. History of opiate abuse or dependence.

3. Severe pain, defined as >/= 7 on 0-10 numeric rating scale for pain.

4. Concomitant use of strong or moderate CYP3A4 inhibitor (indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketonazole, nefazodone, saquinovir, telithromycin, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem)

5. Refusal to stop all opioids (to avoid precipitating opioid withdrawal).

6. Hepatic impairment- aspartate aminotransferase (AST) /alanine aminotransferase (ALT) > 1.5 times upper normal. If AST and ALT are within 1.5 times the upper limit, and subjects are asymptomatic, they will be considered medically stable to participate

7. Estimated Glomerular Filtration Rate (GFR) < 20 ml/min.

8. Inability/refusal to identify a person as an emergency contact.

9. Pregnancy

10. Contraindications to MRI

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Western Psychiatric Institute and Clinic, University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• Jordan F. Karp
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Jordan F. Karp, M.D., University of Pittsburgh

Study Documents (Full-Text)

• Study Protocol - Nov 20, 2017
• Statistical Analysis Plan - Nov 20, 2017

More Information

Publications

None provided.

• Responsible Party: Jordan F. Karp, Associate Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02176291
• Other Study ID Numbers: PRO13120236; R34MH101371
• First Posted: Jun 27, 2014
• Last Update Posted: Aug 29, 2018
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Jordan F. Karp, Associate Professor, University of Pittsburgh: Buprenorphine; Receptors, opioid; Receptors, opioid kappa and mu
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major; Buprenorphine

Study Results

Participant Flow

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	Buprenorphine Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 2.0 mg/day)	Placebo Placebo: matched placebo
Period Title: Overall Study
STARTED	20	11
COMPLETED	15	11
NOT COMPLETED	5	0

Baseline Characteristics

Arm/Group Title	Buprenorphine	Placebo	Total
Arm/Group Description	Buprenorphine Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 2.0 mg/day)	Placebo Placebo: matched placebo	Total of all reporting groups
Overall Participants	20	11	31
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.7 (9.7)	65.6 (7.5)	65.0 (8.9)
Sex: Female, Male (Count of Participants)
Female	8 40%	3 27.3%	11 35.5%
Male	12 60%	8 72.7%	20 64.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 20%	0 0%	4 12.9%
White	16 80%	11 100%	27 87.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	20 100%	11 100%	31 100%

Outcome Measures

1. Primary Outcome

Title	Montgomery-Asberg Depression Rating Scale (MADRS)
Description	Measure of depression severity, range of 0-60 We calculated the mean change in depression severity for both groups using baseline MADRS and week 8 MADRS scores. Greater mean change represents better outcome.
Time Frame	baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.2 mg/day)	Placebo: matched placebo
Measure Participants	15	11
Change in MADRS	3.47 (8.94)	4.09 (8.06)
Final MADRS score	16.93 (8.68)	14.64 (9.41)

2. Secondary Outcome

Title	Brief Symptom Inventory--Anxiety Subscale (BSI)
Description	Measure of Anxiety Theoretical Range 0-2.4 with lower numbers indicating a better outcome. We calculated the mean change in anxiety for both groups using Phase 1 week 12 time point (baseline) and Phase 2 week 8 time point (final time point).
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buprenorphine	Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.2 mg/day)	Placebo: matched placebo
Measure Participants	18	11
Change in BSI	0.07 (1.39)	0.06 (0.80)
Final BSI Score	0.74 (0.94)	0.64 (0.48)

Adverse Events

Time Frame	Adverse events were collected over a period of 1 year and six months.
Arm/Group Title	Buprenorphine		Placebo
Arm/Group Description	Buprenorphine: low-dose buprenorphine (range 0.2 mg/day -- 1.2 mg/day)		Placebo: matched placebo
All Cause Mortality
	Buprenorphine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		0/11 (0%)
Serious Adverse Events
	Buprenorphine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/20 (10%)		2/11 (18.2%)
Cardiac disorders
death	1/20 (5%)		0/11 (0%)
Gastrointestinal disorders
severe abdominal pain	0/20 (0%)		1/11 (9.1%)
General disorders
nausea and hypertension	1/20 (5%)		0/11 (0%)
Respiratory, thoracic and mediastinal disorders
pneumonia	0/20 (0%)		1/11 (9.1%)
Other (Not Including Serious) Adverse Events
	Buprenorphine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/20 (60%)		8/11 (72.7%)
Cardiac disorders
Increased Blood Pressure	2/20 (10%)		2/11 (18.2%)
Endocrine disorders
Increased plasma glucose level	1/20 (5%)		0/11 (0%)
Gastrointestinal disorders
Constipation	5/20 (25%)		2/11 (18.2%)
Nausea	1/20 (5%)		1/11 (9.1%)
Diarrhea	0/20 (0%)		1/11 (9.1%)
General disorders
Lightheadedness	4/19 (21.1%)		1/11 (9.1%)
Insomnia	3/20 (15%)		2/11 (18.2%)
Drowsiness	4/20 (20%)		0/11 (0%)
Dry Mouth	4/20 (20%)		0/11 (0%)
Increased pulse	1/20 (5%)		1/11 (9.1%)
Falls	1/20 (5%)		1/11 (9.1%)
Increased Sleep	0/20 (0%)		1/11 (9.1%)
Sweating	0/20 (0%)		1/11 (9.1%)
Blurred vision	0/20 (0%)		1/11 (9.1%)
Decreased Libido	1/20 (5%)		0/11 (0%)
Headache	1/20 (5%)		0/11 (0%)
Coughing	0/20 (0%)		2/11 (18.2%)
Yawning	1/20 (5%)		0/11 (0%)
Weight gain	0/20 (0%)		1/11 (9.1%)
Myalgia	1/20 (5%)		0/11 (0%)
Nervous system disorders
Myoclonus	1/20 (5%)		0/11 (0%)
Tremor	1/20 (5%)		0/11 (0%)
Psychiatric disorders
Anxiety	0/20 (0%)		1/11 (9.1%)
Renal and urinary disorders
urinary frequency	2/20 (10%)		0/11 (0%)
Reproductive system and breast disorders
Erectile dysfunction	0/20 (0%)		1/11 (9.1%)

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.