Avanir Pharmaceuticals, a subsidiary of Otsuka, has initiated both arms of the phase 3 clinical trial for Alzheimer's Agitation termed TRIAD, and the Long Term Extension Study for patients who have completed 12 weeks of either TRIAD 1 or 2. Patients will be enrolled into the long term extension NCT02446132 study based on the following criteria:
- Patient has successfully completed Studies 15-AVP-786-301, 15-AVP-786-302, or 12-AVR-131.
- Patients will be enrolled in the study for approximately 52 weeks.
- Approximately 550 patients will be enrolled at approximately 110 centers in the US.
- All patients enrolled will receive AVP-786, the treatment dose assigned will be masked to the patient, investigator, study staff, and the sponsor.
The long term extension study is scheduled to complete in July of 2019, approximately 52 weeks after TRIAD 1 and 2 have completed dosing with AVP-786. This long term extension study may be important for the drug label the FDA assigns during the approval process, for agitation in patients with dementia of the Alzheimer's type.
AVP-786 (AVP-923) has exhibited a consistent and mild safety profile, making the drug a unique candidate for elderly patients with behavioral problems due to Alzheimer's or other dementia related diseases. A mild safety profile, compared to current anti-psychotics could also promote off-label prescribing potential, for the drug. The safety profile of AVP-923 was written about in a post here Rexulti & AVP-923 Safety Profile Comparison. Thank you for reading.
Assessing
the success of a clinical trial depends on many factors. Trial design, primary endpoint, prior drug trials, safety and tolerability, competitor
success with similar drug, and what is deemed successful by FDA standards, are just a few factors to consider.
Avanir Pharmaceuticals is nearing the end of a phase 2 clinical trial
for AVP-786 as Adjunctive Therapy in
Patients with Major Depressive Disorder With Inadequate Response to Anti-Depressant Treatment in clinical trial NCT02153502.
The first important factor to consider is that AVP-786
is the deutered version of AVP-923. Both
drugs were tested in a Phase 1,
Single-center, Randomized, Double-blind, Double-dummy, 2-way Crossover Study
Comparing AVP-786 with AVP-923 here NCT02336347. The two drugs exhibited a similar PK and safety profile. This is important because we will be using data
from two AVP-923 clinical studies that had a subset of patients tested for
depression, with either the BDI-2 (Beck Depression
Inventory-II) or the Cornell Depression Scale.
Avanir ran a phase
3 clinical trial with AVP-923 evaluating the safety and efficacy of AVP-923 in
PBA (Pseudobulbar Affect) patients with ALS or MS, trial named (STAR) here NCT00573443. The mean change from baseline at day 84 in the Beck
Depression Inventory (BDI-II) Total Score was used as a secondary endpoint. Patients with moderate depression on the BDI-II scale, greater than 18, scored a significant p=0.03
while taking AVP-923, 30mg dextromethorphan / 10mg quinidine. Below is the Avanir, JP Morgan Healthcare Conference presentation in January 2014.
2014 JP Morgan Healthcare Conference
Treatment-Resistant MDD Clinical Rationale
The Beck Depression Inventory-II (BDI-II) was included as a secondary efficacy endpoint in the pivotal phase 3 trial in PBA patients
Major Depression Excluded
Among patients with baseline BDI-II scores >10, AVP-923 treatment was associated with a reduction in depression symptoms
STAR Trial; Avanir data on file
Endpoint BDI-II
(n=50) -3.36 AVP-923 30/10
(n=55) -2.3 AVP-923 20/10
(n=52) -1.1 Placebo
P Value
0.065 AVP-923 30/10
0.378 AVP-923 20/10
"Among a subset of patients with baseline BDI-II scores > 18, AVP-923 30/10 was
associated with statistically significant improvement (p=0.03)".
Using the description below for the (p=0.03) subset, the trial had patients classified primarily in the moderate depression range, as the presentation listed major depression as excluded. The following is a breakdown of the BDI-II, which is a 21-item self-report
instrument intended to assess the existence and severity of symptoms of
depression, summed to give a single score. The BDI-II uses a 4-point for each item ranging from 0 to 3.
BDI-II Depression Scale
0-13 is considered minimal range
14
to 19 mild depression
20 to 28 moderate depression
29 to 63 severe depression
In a phase 2 clinical trial for Alzheimer's patients experiencing agitation. Trial NCT01584440 utilized a secondary
endpoint called the Cornell Scale for
Depression in Dementia (CSDD): which a statistical p=0.02 was observed.
Bottom Line:
Although the number of patients were relatively small in the two above trials showing benefits of AVP-923 for depression, it does give us some guidelines to the probabilities for potential success in the current clinical trial coming to completion. Thank you for reading.
