52 week OLE study of Pimavanserin in depression
Research type
Research Study
Full title
A 52-Week Open-Label Extension Study of Pimavanserin in Subjects With Major Depressive Disorder and Inadequate Response to Antidepressant Treatment
IRAS ID
264881
Contact name
Aliya Asher
Contact email
Sponsor organisation
ACADIA Pharmaceuticals Inc
Eudract number
2018-003252-20
Duration of Study in the UK
2 years, 11 months, 10 days
Research summary
Research Summary:
This study will be a 52-week open-label extension study to evaluate the long-term safety and tolerability of pimavanserin in subjects with major depressive disorder and inadequate response to antidepressant treatment.
The study will have two periods:
• Open-label treatment period (52 weeks)
• Safety follow-up period (at least 30 days)
The end of treatment (EOT) visit for the antecedent study, Study ACP-103-054 or Study ACP-103-059, is the Baseline visit for this study.
The duration of participation for individual study subjects will be up to approximately 56 weeks. The total duration of exposure to pimavanserin may be greater than 52 weeks as subjects may have been treated with pimavanserin in the antecedent studies, ACP-103-054 and ACP-103-059.
Approximately 80 sites will participate in this study.Lay Summary of Results:
: Study results are available here: https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agba4yu73OCS9U-2BkKS40W1kfZLMhYNSL6uAQ3D-2BHysQkrDGoVPUfVSVQRFhJA8y41gnOUEgCMHF6xJ92vu17-2F-2Fx0o6R5cMuydqSKvtcQ97R-2FYOBco0l-2FJjyVD7Wik-2B3AUY6Q-3D-3DMTVM_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YKqNV-2FcuJaiy6reZsHms3Y-2B2jje1SWprKW4Xe0MT2oL8fmqw5XilYHBuKMBEfE04Q6H1VqZjyZBQey23ztSBXXiD3ejQ31yaObT5ObKzqmLtYm3poNwpKD5Rw-2BFEdfExaCUZ7bQyruyI80t7Jj3ltfJ90A6-2BxmIa5qYlp2T9IWUrw-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7C1e16c2203104494cc74808da16623b8c%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637846908397577715%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=UGqL6rP1YxMpPA8lAXdRSr6PXJoijNRXa%2FzN0a24o7k%3D&reserved=0Results:
This study was ultimately terminated early by the Sponsor for business reasons due to the COVID-19 pandemic; there were no safety concerns contributing to study termination. Subjects were discontinued from the study and completed safety follow-up procedures.
Subject Disposition, Demographics, and Other Baseline Characteristics:
The study enrolled 236 subjects in 69 study sites, of which 235 subjects comprised the Safety Analysis Set (119 subjects who took placebo in one of the double-blind antecedent studies and 116 subjects who took pimavanserin in one of the double-blind antecedent studies). Overall, 70 subjects (29.8%) completed the study and 165 subjects (70.2%) were terminated early by the Sponsor. The most common reason for early termination was that the study was terminated by the Sponsor (98 subjects [41.7%]). Other reasons for early termination included subject withdrawal (22 subjects [9.4%]) and adverse events (13 subjects [5.5%]).
Overall, the mean age was 45.5 years, and the mean BMI was 27.30 kg/m2. The majority of subjects were female (70.2%), and in terms of race, the majority of subjects were White (93.2%). Overall, for open-label baseline disease characteristics, the mean HAMD-17 total score was 13.7, the mean SDS score was 4.448, the mean CGI-S score was 3.5, the mean CSFQ-14 total score was 38.5, and the mean KSS score was 5.4. A majority of subjects (74.5%) were concomitantly receiving selective serotonin reuptake inhibitors (SSRIs), while 25.5% of subjects were concomitantly receiving SNRIs. Generally, demographics and baseline characteristics at open-label baseline were similar between subjects who received placebo in one of the antecedent studies and subjects who received pimavanserin in one of the antecedent studies.
Efficacy Results:
Key exploratory efficacy findings for this open-label extension study include the following:
• Improvements (i.e., decreases) in the mean HAMD-17 total score, the mean CGI-S score, and the SDS mean score from open-label Baseline and double-blind Baseline were observed at each visit.
o For the HAMD-17 total score, the overall mean changes from open-label Baseline to Weeks 12 and 52 were -5.5 and -7.2, respectively; and the overall mean changes from double-blind Baseline to open-label Weeks 12 and 52 were -15.2 and -16.3, respectively.
o For the CGI-S score, the overall mean changes from open-label Baseline to Weeks 12 and 52 were -1.1 and -1.5, respectively; and the overall mean changes from double-blind Baseline to open-label Weeks 12 and 52 were -2.4 and -1.5, respectively.
o For the SDS mean score, the overall mean changes from open-label Baseline to Weeks 12 and 52 were -1.271 and -2.058, respectively; and the overall mean changes from double-blind Baseline to open-label Weeks 12 and 52 were -3.803 and -4.341, respectively.
• Improvements (i.e., increases) in the mean CSFQ-14 total score from open-label Baseline and double-blind Baseline were observed at each visit. The overall mean changes from open-label Baseline to Weeks 12 and 52 were 2.6 and 4.6, respectively; and the overall mean changes from double-blind Baseline to open-label Weeks 12 and 52 were 6.3 and 7.9, respectively.
• Improvements (i.e., decreases) in the mean KSS score from open-label Baseline and double-blind Baseline were observed at each visit, with the exception of the mean changes from open-label Baseline to Week 2 for subjects who received pimavanserin in one of the antecedent studies (0.2). The overall mean changes in the KSS score from open-label Baseline to Weeks 12 and 52 were -0.6
and -1.3, respectively; and the overall mean changes from double-blind Baseline to open-label Weeks 12 and 52 were -1.7 and -2.2, respectively.
• From open-label Baseline, the treatment response and remission rates were 46.0% and 56.5%, respectively, at Week 12 and 58.2% and 67.3%, respectively, at Week 52. From double-blind Baseline, the treatment response and remission rates were 76.5% and 56.5%, respectively, at Week 12 and 81.6% and 67.3%, respectively, at Week 52.
Safety Results:
Key safety findings for this open-label extension study include the following:
• The mean (SE) duration of exposure to open-label pimavanserin was 264.2 (7.39) days. Across the double-blind and open-label treatment periods, the mean (SE) duration of total exposure to pimavanserin was 285.4 (7.62) days.
• Overall, 137 subjects (58.3%) reported at least one TEAE in the study, including 59.5% of subjects who received pimavanserin in one of the antecedent studies and 57.1% of subjects who received placebo in one of the antecedent studies.
• The most frequently reported TEAEs (experienced by at least 5% of subjects overall) included headache (12.3%), nasopharyngitis (6.4%), weight increased (6.0%), and diarrhea and UTI (5.1%
each).
• COVID-19-related TEAEs included COVID-19 and SARS-CoV-2 test positive (1.7% of subjects each) and suspected COVID-19 and SARS-CoV-2 test negative (0.4% of subjects each); none of the events were considered a serious TEAE or related to study drug by the Investigator.
• The majority of TEAEs were considered mild or moderate in severity (29.3% and 25.9% of subjects who received pimavanserin in one of the antecedent studies, respectively, and 23.5% and 30.3% of subjects who received placebo in one of the antecedent studies, respectively).
• Overall, 46 subjects (19.6%) reported a related TEAE, including 21.6% of subjects who received pimavanserin in one of the antecedent studies and 17.6% of subjects who received placebo in one of the antecedent studies.
• No deaths were reported during this study.
• Serious TEAEs were reported in 5 subjects (2.1%) overall, including 1 subject who received pimavanserin in one of the antecedent studies (gastrointestinal obstruction) and 4 subjects who received placebo in one of the antecedent studies (cholangiocarcinoma, diverticular perforation, nasal septum deviation, and pulmonary embolism; 1 subject each). The TEAE of pulmonary embolism was considered by the Investigator to be related to study drug, and the event led to withdrawal of study drug. The TEAEs of diverticular perforation and gastrointestinal obstruction led to withdrawal of study drug.
• Treatment-emergent AEs leading to discontinuation (i.e., leading to study drug discontinuation or study termination) were reported in 13 subjects (5.5%) overall, including 4.3% of subjects who received pimavanserin in one of the antecedent studies and 6.7% of subjects who received placebo in one of the antecedent studies.
• Changes from open-label and double-blind Baseline to post-open-label Baseline visits in laboratory parameters (including metabolic parameters), vital signs, and ECG parameters were generally small and not clinically meaningful. The percentages of subjects with PCI values in laboratory parameters, vital signs, and ECG parameters were generally low.
• No subjects had QTcF >500 ms post-open-label Baseline or double-blind Baseline. One subject (0.4%) had a change in QTcF value from open-label Baseline of >60 ms, and 3 subjects (1.3%) had a change in QTcF value from double-blind Baseline of >60 ms. These cases of reported QTcF changes were all asymptomatic.
• Based on categorical analysis of the QTcF observed values and changes from open label and double-blind Baseline, pimavanserin was generally well tolerated in combination with other antidepressants (citalopram, escitalopram, and venlafaxine).
• Overall, post-open-label Baseline, 14.2% of subjects had a weight increase ≥7% and 5.6% of subjects had a weight decrease ≥7% from open-label Baseline; post-double-blind Baseline, 22.6% of subjects had a weight increase ≥7% and 5.1% of subjects had a weight decrease ≥7% from double-blind
Baseline. Treatment-emergent AEs of weight increased and weight decreased were reported in 6.0% and 2.1% of subjects, respectively.
• Pimavanserin did not appear to worsen suicidal ideation or behavior, extrapyramidal symptoms, or sexual dysfunction.
• No subjects expressed suicidal behavior; self-injurious behavior without suicidal intent; active suicidal ideation with some intent to act, without specific plan; or active suicidal ideation with specific plan and intent based on the C-SSRS assessment. One subject experienced a TEAE of suicidal ideation.
Conclusions:
In summary, improvements were observed in the exploratory efficacy endpoints with open-label adjunctive pimavanserin treatment in this extension study. Pimavanserin was generally well tolerated in this extension study in subjects with MDD and inadequate response to antidepressant treatment who completed one of the antecedent studies; no new safety signals were observed.REC name
North East - Newcastle & North Tyneside 2 Research Ethics Committee
REC reference
19/NE/0153
Date of REC Opinion
11 Jun 2019
REC opinion
Further Information Favourable Opinion