A Trial of the Effect of CVL-865 on Panic Symptoms Induced by Carbon Dioxide Inhalation in Healthy Subjects

NCT04592536 | Completed Phase 1 FDA Drug

• 1 other identifier: CVL-865-HV-001
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine anxiolytic effect of multiple doses of CVL-865 using an experimental medicine model of carbon dioxide (CO2) inhalation in healthy volunteers.

Conditions

Panic Disorder

Keywords

Anxiety; Panic; CVL-865; PF-06372865; Hypercapnia; CO2 challenge; Healthy Subjects

Outcome Measures

Primary Outcomes (1)

• PSL-IV score

  Change in Panic Symptom List -IV (PSL-IV), a questionnaire including 13 symptoms, each with intensity rating from 0 (not at all) to 4 (very intense), from pre-CO2 to Post CO2 challenge value

  up to Day 8

Secondary Outcomes (7)

• VAS Fear score

  up to Day 8

• CO2 challenge

  Screening, Day 1, Day 8

• Treatment-emergent AEs

  From screening to Follow-up Visit

• Suicidality assessed using Columbia - Suicide Severity Rating Scale (C-SSRS)

  Screening, Day -1, Day 8

• CVL-865 (and alprazolam, if appropriate) concentrations

  Day 8

Study Arms (3)

CVL-865

EXPERIMENTAL

High dose CVL-865 (25mg) Low dose CVL-865 (7.5mg)

Drug: CVL-865 High dose; Drug: CVL-865 low dose

Alprazolam

ACTIVE COMPARATOR

Active Comparator Alprazolam with extended release oral tablets; 1 tablet BID

Drug: Alprazolam 1mg XR

Placebo

PLACEBO COMPARATOR

Placebo Comparator matching oral tablets for CVL-865, capsule for Alprazolam

Drug: Placebo

Interventions

CVL-865 High dose DRUG

High dose CVL-865: Will be administered as 5mg BID for 2 days followed by 12.5mg BID for another 2 days during the Titration Phase. 25mg will be administered during the Maintenance Phase (3 days of BID and morning dose only on the 4th day)

CVL-865

Alprazolam 1mg XR DRUG

Alprazolam 1mg XR will be administered for 8 days BID (morning dose only on 8th day)

Alprazolam

Placebo DRUG

Placebo, oral tablet/capsule will be administered for 8 days BID (morning dose only on 8th day)

Placebo

CVL-865 low dose DRUG

Low dose CVL-865, oral tablets. Will be administered as 2.5mg BID for 2 days followed by 5mg BID for another 2 days during the Titration Phase. 7.5mg BID will be administered during the Maintenance Phase (3 days of BID and morning dose only on 4th day)

CVL-865

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male and female subjects, ages 18 to 55 years, inclusive, at the time of signing the ICF. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and heart rate measurement, 12-lead ECG, and clinical laboratory tests, as evaluated by the investigator.
• Body mass index of 18.5 to 30.0 kg/m2, inclusive, and a total body weight \>50 kg (110 lbs)
• A female subject of childbearing potential who is sexually active with a nonsterilized male partner must agree to use a highly effective method of contraception from signing of informed consent and for 30 days post last dose. A male subject with a pregnant or a nonpregnant partner of childbearing potential must agree to use condom during treatment and until the end of relevant systemic exposure in the male subject for 94 days following the last dose with IMP.
• Capable of giving signed informed consent
• Ability, in the opinion of the investigator, to understand the nature of the trial and comply with protocol requirements, including the prescribed dosage regimens, scheduled visits, laboratory tests, and other trial procedures.
• Defined as sensitive to the anxiogenic effects of double-breath CO2 inhalation

You may not qualify if:

• Subjects with a current history of clinically significant cardiovascular pulmonary, gastrointestinal, renal, hepatic, metabolic, hematological, immunological, or neurological disease.
• Subjects with a current or past history of clinically significant respiratory conditions
• Subject with a personal or family history of sickle cell anemia
• Subject with a personal or family history of cerebral aneurysm
• Subjects with a clinically significant current or past personal or family history of any psychiatric disorder as classified by DSM-4 or DSM-5 criteria
• Subjects with epilepsy or a history of seizures except for a single seizure episode
• Subjects with a history of substance or alcohol-use disorder (DSM-5 criteria)
• Subjects who answer "Yes" on the C-SSRS Suicidal Ideation Item 4, 5 and whose most recent episode meeting criteria for this C-SSRS Item 4, 5 occurred within the last 6 months
• Subjects who, in the opinion of the investigator, present a serious risk of suicide
• Subjects with human immunodeficiency virus seropositive status or acquired immunodeficiency syndrome, chronic hepatitis B or C (defined as positive serology and aspartate aminotransferase or alanine aminotransferase elevated to \>2 × ULN)
• Subject with a positive drug screen for illicit drugs
• Subjects with a 12-lead ECG demonstrating either of the following:
• QT interval corrected for heart rate using Fridericia's formula \>450 msec (average of 3 ECGs obtained at the Screening Visit)
• QRS interval \>120 msec at the Screening Visit
• Subjects with any of the following abnormalities in clinical laboratory tests at the Screening Visit, as assessed by the local laboratory and confirmed by a single repeat measurement, if deemed necessary:

Sponsors & Collaborators

• Cerevel Therapeutics, LLC: lead

Study Sites (1)

Centre for Human Drug Research

Leiden, Zernikedreef 8, 2333 CL, Netherlands

Location

Related Publications (25)

• Atack JR. GABAA receptor alpha2/alpha3 subtype-selective modulators as potential nonsedating anxiolytics. Curr Top Behav Neurosci. 2010;2:331-60. doi: 10.1007/7854_2009_30.

  PMID: 21309116 BACKGROUND

• Atack JR, Hallett DJ, Tye S, Wafford KA, Ryan C, Sanabria-Bohorquez SM, Eng WS, Gibson RE, Burns HD, Dawson GR, Carling RW, Street LJ, Pike A, De Lepeleire I, Van Laere K, Bormans G, de Hoon JN, Van Hecken A, McKernan RM, Murphy MG, Hargreaves RJ. Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist. J Psychopharmacol. 2011 Mar;25(3):329-44. doi: 10.1177/0269881109354928. Epub 2010 Feb 15.

  PMID: 20156926 BACKGROUND

• Atack JR, Hutson PH, Collinson N, Marshall G, Bentley G, Moyes C, Cook SM, Collins I, Wafford K, McKernan RM, Dawson GR. Anxiogenic properties of an inverse agonist selective for alpha3 subunit-containing GABA A receptors. Br J Pharmacol. 2005 Feb;144(3):357-66. doi: 10.1038/sj.bjp.0706056.

  PMID: 15655523 BACKGROUND

• Atack JR, Wafford KA, Tye SJ, Cook SM, Sohal B, Pike A, Sur C, Melillo D, Bristow L, Bromidge F, Ragan I, Kerby J, Street L, Carling R, Castro JL, Whiting P, Dawson GR, McKernan RM. TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for alpha2- and alpha3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates. J Pharmacol Exp Ther. 2006 Jan;316(1):410-22. doi: 10.1124/jpet.105.089920. Epub 2005 Sep 23.

  PMID: 16183706 BACKGROUND

• Bailey JE, Dawson GR, Dourish CT, Nutt DJ. Validating the inhalation of 7.5% CO(2) in healthy volunteers as a human experimental medicine: a model of generalized anxiety disorder (GAD). J Psychopharmacol. 2011 Sep;25(9):1192-8. doi: 10.1177/0269881111408455.

  PMID: 21994314 BACKGROUND

• Bandelow B, Zohar J, Hollander E, Kasper S, Moller HJ; WFSBP Task Force on Treatment Guidelines for Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disoders; Zohar J, Hollander E, Kasper S, Moller HJ, Bandelow B, Allgulander C, Ayuso-Gutierrez J, Baldwin DS, Buenvicius R, Cassano G, Fineberg N, Gabriels L, Hindmarch I, Kaiya H, Klein DF, Lader M, Lecrubier Y, Lepine JP, Liebowitz MR, Lopez-Ibor JJ, Marazziti D, Miguel EC, Oh KS, Preter M, Rupprecht R, Sato M, Starcevic V, Stein DJ, van Ameringen M, Vega J. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - first revision. World J Biol Psychiatry. 2008;9(4):248-312. doi: 10.1080/15622970802465807.

  PMID: 18949648 BACKGROUND

• Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Med Psychol. 1974;47:211-8

  BACKGROUND

• Borland RG, Nicholson AN. Visual motor co-ordination and dynamic visual acuity. Br J Clin Pharmacol. 1984;18 Suppl 1(Suppl 1):69S-72S. doi: 10.1111/j.1365-2125.1984.tb02583.x.

  PMID: 6525331 BACKGROUND

• Borland RG, Nicholson AN. Comparison of the residual effects of two benzodiazepines (nitrazepam and flurazepam hydrochloride) and pentobarbitone sodium on human performance. Br J Clin Pharmacol. 1975 Feb;2(1):9-17. doi: 10.1111/j.1365-2125.1975.tb00465.x.

  PMID: 10941 BACKGROUND

• Dias R, Sheppard WF, Fradley RL, Garrett EM, Stanley JL, Tye SJ, Goodacre S, Lincoln RJ, Cook SM, Conley R, Hallett D, Humphries AC, Thompson SA, Wafford KA, Street LJ, Castro JL, Whiting PJ, Rosahl TW, Atack JR, McKernan RM, Dawson GR, Reynolds DS. Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines. J Neurosci. 2005 Nov 16;25(46):10682-8. doi: 10.1523/JNEUROSCI.1166-05.2005.

  PMID: 16291941 BACKGROUND

• Hidalgo RB, Davidson JR. Generalized anxiety disorder. An important clinical concern. Med Clin North Am. 2001 May;85(3):691-710. doi: 10.1016/s0025-7125(05)70336-9.

  PMID: 11349480 BACKGROUND

• Leibold NK, van den Hove DL, Viechtbauer W, Buchanan GF, Goossens L, Lange I, Knuts I, Lesch KP, Steinbusch HW, Schruers KR. CO2 exposure as translational cross-species experimental model for panic. Transl Psychiatry. 2016 Sep 6;6(9):e885. doi: 10.1038/tp.2016.162.

  PMID: 27598969 BACKGROUND

• Low K, Crestani F, Keist R, Benke D, Brunig I, Benson JA, Fritschy JM, Rulicke T, Bluethmann H, Mohler H, Rudolph U. Molecular and neuronal substrate for the selective attenuation of anxiety. Science. 2000 Oct 6;290(5489):131-4. doi: 10.1126/science.290.5489.131.

  PMID: 11021797 BACKGROUND

• Morris HV, Dawson GR, Reynolds DS, Atack JR, Stephens DN. Both alpha2 and alpha3 GABAA receptor subtypes mediate the anxiolytic properties of benzodiazepine site ligands in the conditioned emotional response paradigm. Eur J Neurosci. 2006 May;23(9):2495-504. doi: 10.1111/j.1460-9568.2006.04775.x.

  PMID: 16706856 BACKGROUND

• Nickolls SA, Gurrell R, van Amerongen G, Kammonen J, Cao L, Brown AR, Stead C, Mead A, Watson C, Hsu C, Owen RM, Pike A, Fish RL, Chen L, Qiu R, Morris ED, Feng G, Whitlock M, Gorman D, van Gerven J, Reynolds DS, Dua P, Butt RP. Pharmacology in translation: the preclinical and early clinical profile of the novel alpha2/3 functionally selective GABAA receptor positive allosteric modulator PF-06372865. Br J Pharmacol. 2018 Feb;175(4):708-725. doi: 10.1111/bph.14119. Epub 2018 Jan 18.

  PMID: 29214652 BACKGROUND

• Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. doi: 10.1176/appi.ajp.2011.10111704.

  PMID: 22193671 BACKGROUND

• Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Mohler H. Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature. 1999 Oct 21;401(6755):796-800. doi: 10.1038/44579.

  PMID: 10548105 BACKGROUND

• Salvadore G, Brooks S, Bleys C, Tatikola K, Remmerie B, Jacobs G, et al. The selective Orexin-1 receptor inhibitor JNJ-61393215 decreases subjective anxiety evoked by 35% CO2 inhalation in healthy subjects. Poster presentation at ASCP 2019 Annual Meeting, May 28-31, Scottsdale, Arizona, USA.

  BACKGROUND

• Simen A, Whitlock M, Qiu R, Miceli J, Zumpano L, Du Metz M, Dua P, Binneman B. An 8-Week, Randomized, Phase 2, Double-Blind, Sequential Parallel-Group Comparison Study of Two Dose Levels of the GABAA Positive Allosteric Modulator PF-06372865 Compared With Placebo as an Adjunctive Treatment in Outpatients With Inadequate Response to Standard of Care for Generalized Anxiety Disorder. J Clin Psychopharmacol. 2019 Jan/Feb;39(1):20-27. doi: 10.1097/JCP.0000000000000997.

  PMID: 30531477 BACKGROUND

• Struzik L, Vermani M, Coonerty-Femiano A, Katzman MA. Treatments for generalized anxiety disorder. Expert Rev Neurother. 2004 Mar;4(2):285-94. doi: 10.1586/14737175.4.2.285.

  PMID: 15853570 BACKGROUND

• Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe--a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol. 2005 Aug;15(4):357-76. doi: 10.1016/j.euroneuro.2005.04.012.

  PMID: 15961293 BACKGROUND

• Wright BM. A simple mechanical ataxia-meter. J Physiol. 1971 Oct;218 Suppl:27P-28P. No abstract available.

  PMID: 5130616 BACKGROUND

• van Steveninck AL, Schoemaker HC, Pieters MS, Kroon R, Breimer DD, Cohen AF. A comparison of the sensitivities of adaptive tracking, eye movement analysis and visual analog lines to the effects of incremental doses of temazepam in healthy volunteers. Clin Pharmacol Ther. 1991 Aug;50(2):172-80. doi: 10.1038/clpt.1991.122.

  PMID: 1868679 BACKGROUND

• van Steveninck AL, van Berckel BN, Schoemaker RC, Breimer DD, van Gerven JM, Cohen AF. The sensitivity of pharmacodynamic tests for the central nervous system effects of drugs on the effects of sleep deprivation. J Psychopharmacol. 1999;13(1):10-7. doi: 10.1177/026988119901300102.

  PMID: 10221355 BACKGROUND

• Yonkers KA, Bruce SE, Dyck IR, Keller MB. Chronicity, relapse, and illness--course of panic disorder, social phobia, and generalized anxiety disorder: findings in men and women from 8 years of follow-up. Depress Anxiety. 2003;17(3):173-9. doi: 10.1002/da.10106.

  PMID: 12768651 BACKGROUND

MeSH Terms

Conditions

Panic Disorder; Anxiety Disorders; Hypercapnia

Interventions

Alprazolam

Condition Hierarchy (Ancestors)

Mental Disorders; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Gabriel Etienne Jacobs, PhD, MD

  Centre for Human Drug Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2020
• First Posted: October 19, 2020
• Study Start: October 6, 2020
• Primary Completion: November 14, 2021
• Study Completion: December 13, 2021
• Last Updated: January 11, 2022

Record last verified: 2022-01

Locations

NL (1)