Incomplete Response in Late-Life Depression: Getting to Remission With Buprenorphine
Phase: PHASE2
Conditions: Depression, Major Depressive Disorder
Sponsor: Jordan F. Karp

 
Incomplete Response in Late-Life Depression: Getting to Remission With Buprenorphine 
NCT02176291 
Study Protocol 
11/20/17 
 
Study Protocol:  100 subjects, of both sexes and all races, will be asked to participate in this 
project. 
This study has 2 phases.  The core of this project is in the second phase: a randomized, 
placebo controlled, double blind parallel group comparison of venlafaxine XR plus 
buprenorphine with venlafaxine XR plus placebo for Treatment Resistant Late Life Depression 
(TRLLD). 
 
Phase 1: We will prospectively determine treatment resistance by initially treating participants 
with a 12-week course (up to 16 weeks) of open-label venlafaxine XR. This is the same lead-in 
treatment as in our completed IRL-GREY multi-site R01 for TRLLD, and we have found it to be 
highly successful. We will have up to 100 participants start venlafaxine XR 37.5 mg daily and 
will rapidly (2 weeks) titrate to 150 mg/d. Then, at week 6, those who inadequately respond to 
this dose will have venlafaxine titrated (as tolerated) further, up to a maximum dose of 300 
mg/day. At the end of 12 weeks, those who achieve remission with venlafaxine will exit the 
study; non-remitters will be eligible for the RCT of BPN vs. placebo augmentation. Visits and 
assessments during open-label lead-in are weekly for the first two weeks and then every 2 
weeks. Assessments may be completed by phone if necessary. If assessment is done by 
phone, vitals will not be collected at that timepoint. 
 
In patients who are already on venlafaxine when they start the protocol, the titration can be 
faster with an increase to 300 mg/day after only 4 weeks. To assess remission status, we want 
to be able to follow subjects for at least 4 weeks on 300 mg/day or the maximum tolerated dose 
(because less than that will have been an inadequate exposure to rigorous first line 
antidepressant pharmacotherapy. Subjects who enter the study on venlafaxine and are already 
on their highest tolerated dose need to be maintained on this dose for at least 4 weeks before 
they are eligible for RCT (phase 2).  
 
Phase 1 can be extended up to 16 weeks to assure we have prospectively documented 
treatment non-response. Patients must have at least 4 weeks at the highest tolerated dose in 
order to have been declared a non-responder (because less than that will have been an 
inadequate exposure to rigorous first line antidepressant pharmacotherapy). They need to have 
2 weeks of MADRS less than or equal to 10 in order to be declared a responder (thus the 
flexibility to extend phase 1 to 16 weeks to assure true treatment resistance). 

 
Phase 2, RCT Overview: In the 8-weeks of BPN vs. placebo, thirty subjects will be randomized 
(using permuted block randomization) 2:1 to receive venlafaxine XR (at the dose they reached 
and tolerated in the open-label lead-in) plus either BPN or placebo. The reasons for using a 2:1 
random allocation include: 1) collection of more data about plasma levels of BPN and its 
metabolites, and 2) gaining further clinical experience with the molecule. Both of these reasons 
are consistent with the developmental nature of the R34 grant mechanism (the NIH grant 
mechanisms supporting this project). We will use independent evaluators (who are blind to 
treatment assignment) at the end of phase 2 for the last two assessments to determine if the 
participant has met response. The reason for using independent evaluators at this pivotal 
timepoint is that clinicians may become unblinded because they are also assessing side effects. 
 
At the beginning of phase 2, participants will be asked to review and sign the phase 2 contract 
(attached under other attachments in OSIRIS). This contract outlines safety precautions and 
directions for taking and storing the medication. This contract will be signed with all participants 
who are moving into phase 2. 
 
BPN will be started at 0.2 mg/d and will be titrated weekly by 0.2 mg, based on tolerability 
(assessed with the FIBSER) and depression severity (assessed with MADRS). The minimum 
target dose is 0.6 mg/d (based on our pilot work) with an allowed maximum of 1.2 mg/d. The 
primary outcome will be remission at the end of the 8-week period (defined by a MADRS score 
of 10 or lower for two consecutive weeks, as in the IRL GREY study). The first dose of 
buprenorphine will be taken while in the office while under the supervision of the PI, Co-I, and 
study personnel. They will wait in the office for 60 minutes after taking the initial buprenophine 
dose. 
 
Since the analgesic effects of BPN may obscure the antidepressant effects, we will exclude 
subjects with severe pain. This will be defined as a score of greater than 7 on a 0-10 Numeric 
Rating Scale for Pain. The time assessed for pain will be the previous month (note: we are not 
trying to diagnose a chronic pain syndrome, but exclude those with recent clinically significant 
pain).  
 
Assessing durability of clinical response: While a relapse prevention study would require a 
different design, we aim to collect data on the durability of clinical effect. Blinded independent 
assessors will be used to confirm treatment response. The rationale for this is described above. 
 
Titration schedule of BPN: Dosing increases will be guided by antidepressant response (e.g., 2 
consecutive MADRS scores less than 10) and our protocolized use of the Frequency, Intensity, 
and Burden of Side Effect Rating (FIBSER) Scale score. This individualized dosing regimen 
accommodates both antidepressant response and tolerability. We have used it successfully in 
our BPN pilot work, an ongoing study of the pharmacotherapy of complicated grief, and it was 
used in the STAR*D project (Steffens et al, 2010). We will increase the dose by 0.2 mg/week up 
to 1.2 mg/day based on MADRS and FIBSER scores. Our rationale for selecting this dosing 
schedule is based on other small open-label trials using BPN for treatment resistant depression 

in younger patients in which the initial dose ranged from 0.15 mg/day (intranasal formulation) – 
0.4 mg/day (sublingual), and was increased to 1.8 mg/day (intranasal) – 2 mg/day (sublingual). 
The duration of previous studies has ranged from 1 week to 4 weeks, with the dose increased 
by 0.4 mg/day every 1-2 days or according to tolerance and clinical benefit. In our recently 
completed work, the duration of exposure to BPN has been 8 weeks with a maximum dose of 
1.6 mg/day.  
 
Consistent with the developmental aim to learn more about dosing ranges and plasma levels, 
we will extend phase 2 to eight weeks with a maximum dose of 1.2 mg/d.). With this approach, 
we expect to clarify the range of efficacious and tolerable doses for BPN, ultimately resulting in 
a more parsimonious dose titration schedule. This is of great importance, as the appropriate 
dose range is not yet established. In order to ensure that subjects do not experience withdrawal, 
we will taper the study drug at the end of phase 3. The study drug will be tapered by 20% every 
3 days until discontinued. We will use the Clinical Opiate Withdrawal Scale (COWS) to assess 
any symptoms of withdrawal and adjust the discontinuation as needed to assure a comfortable 
discontinuation for subjects. In our pilot work, we have not encountered ANY discontinuation 
symptoms during the cessation of BPN. This may be due to the relatively short duration of 
exposure and the very low doses used in the project. 
 
Breaking the blind: The blind will be broken for all participants at the end of phase 2.