PMID- 38019356
OWN - NLM
STAT- MEDLINE
DCOM- 20231216
LR  - 20240419
IS  - 1179-1934 (Electronic)
IS  - 1172-7047 (Print)
IS  - 1172-7047 (Linking)
VI  - 37
IP  - 12
DP  - 2023 Dec
TI  - Effect of BI 1358894 on Cholecystokinin-Tetrapeptide (CCK-4)-Induced Anxiety, 
      Panic Symptoms, and Stress Biomarkers: A Phase I Randomized Trial in Healthy 
      Males.
PG  - 1099-1109
LID - 10.1007/s40263-023-01042-3 [doi]
AB  - INTRODUCTION: Depression, anxiety, and/or panic disorder are often comorbid and 
      have a complex etiology mediated through the same neuronal network. 
      Cholecystokinin-tetrapeptide (CCK-4), a synthetic analog of the endogenous 
      neuropeptide cholecystokinin (CCK), is thought to be implicated in this network. 
      The CCK-4 challenge model is an accepted method of investigating the 
      pathophysiology of panic and has been shown to mediate neuronal activation via 
      the transient receptor potential canonical (TRPC) ion channels. OBJECTIVES: This 
      study aimed to assess the pharmacodynamic effects of BI 1358894, a small-molecule 
      inhibitor of TRPC ion channel members 4 and 5 (TRPC4/5), on CCK-4-induced 
      anxiety/panic-like symptoms and evaluate circuit engagement. METHODS: Twenty 
      healthy male CCK-4-sensitive volunteers entered a Phase I, double blind, 
      randomized, two-way cross-over, single dose, placebo-controlled trial. 
      Randomization was to oral BI 1358894 100 mg in the fed state followed by oral 
      placebo in the fed state, or vice versa. Treatments were administered 5 h prior 
      to intravenous CCK-4 50 microg. The primary endpoint was maximum change from baseline 
      of the Panic Symptom Scale (PSS) sum intensity score after CCK-4 injection. 
      Further endpoints included the emotional faces visual analog score (EVAS), the 
      Spielberger State-Trait Anxiety Inventory (STAI), plasma adrenocorticotropic 
      hormone (ACTH), and serum cortisol values. The safety and tolerability of BI 
      1358894 was assessed based on a number of parameters including occurrence of 
      adverse events (AEs). All pharmacodynamic, pharmacokinetic, and safety endpoints 
      were analyzed using descriptive statistics. RESULTS: Single oral doses of BI 
      1358894 were generally well tolerated by the healthy male volunteers included in 
      this study. Adjusted mean maximum change from baseline in PSS sum intensity score 
      was 24.4 % lower in volunteers treated with BI 1358894 versus placebo, while 
      adjusted mean maximum change from baseline of EVAS was reduced by 19.2 % (BI 
      1358894 vs placebo). The STAI total score before CCK-4 injection was similar in 
      both groups (placebo: 25.1; BI 1358894: 24.3). Relative to placebo, BI 1358894 
      reduced CCK-4-induced mean maximum plasma ACTH and serum cortisol values by 58.6 
      % and 27.3 %, respectively. Investigator-assessed drug-related AEs were reported 
      for 13/20 participants (65.0 %). There were no serious or severe AEs, AEs of 
      special interest, AEs leading to discontinuation of trial medication, or deaths. 
      CONCLUSIONS: Overall, BI 1358894 reduced psychological and physiological 
      responses to CCK-4 compared with placebo, as measured by PSS, subjective EVAS and 
      objectively measured stress biomarkers. BI 1358894 had a positive safety profile, 
      and single oral doses were well tolerated by the healthy volunteers. This trial 
      (NCT03904576/1402-0005) was registered on Clinicaltrials.gov on 05.04.19.
CI  - (c) 2023. The Author(s).
FAU - Goettel, Markus
AU  - Goettel M
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400, Biberach 
      an der Riss, Germany. markus.goettel@boehringer-ingelheim.com.
FAU - Fuertig, Rene
AU  - Fuertig R
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400, Biberach 
      an der Riss, Germany.
FAU - Mack, Salome Rebecca
AU  - Mack SR
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400, Biberach 
      an der Riss, Germany.
FAU - Just, Stefan
AU  - Just S
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400, Biberach 
      an der Riss, Germany.
FAU - Sharma, Vikas
AU  - Sharma V
AD  - Boehringer Ingelheim International GmbH, Ingelheim-am-Rhein, Germany.
FAU - Wunder, Andreas
AU  - Wunder A
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400, Biberach 
      an der Riss, Germany.
FAU - den Boer, Johan
AU  - den Boer J
AD  - PRA Health Sciences, Groningen, The Netherlands.
LA  - eng
SI  - ClinicalTrials.gov/NCT03904576
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20231129
PL  - New Zealand
TA  - CNS Drugs
JT  - CNS drugs
JID - 9431220
RN  - 0OL293AV80 (Tetragastrin)
RN  - WI4X0X7BPJ (Hydrocortisone)
RN  - 9002-60-2 (Adrenocorticotropic Hormone)
RN  - 0 (Biomarkers)
SB  - IM
MH  - Humans
MH  - Male
MH  - *Tetragastrin/adverse effects
MH  - *Hydrocortisone
MH  - Adrenocorticotropic Hormone
MH  - Anxiety/drug therapy
MH  - Double-Blind Method
MH  - Biomarkers
PMC - PMC10703963
COIS- MG, RF, SRM, SJ and AW are employees of Boehringer Ingelheim Pharma GmbH & Co. 
      KG. VS is an employee of Boehringer Ingelheim International GmbH. JdB is an 
      employee of PRA Health Sciences. All authors did not receive any direct 
      compensation relating to the development of the manuscript.
EDAT- 2023/11/29 12:43
MHDA- 2023/12/17 09:46
PMCR- 2023/11/29
CRDT- 2023/11/29 11:08
PHST- 2023/09/26 00:00 [accepted]
PHST- 2023/12/17 09:46 [medline]
PHST- 2023/11/29 12:43 [pubmed]
PHST- 2023/11/29 11:08 [entrez]
PHST- 2023/11/29 00:00 [pmc-release]
AID - 10.1007/s40263-023-01042-3 [pii]
AID - 1042 [pii]
AID - 10.1007/s40263-023-01042-3 [doi]
PST - ppublish
SO  - CNS Drugs. 2023 Dec;37(12):1099-1109. doi: 10.1007/s40263-023-01042-3. Epub 2023 
      Nov 29.