A Double-blind, Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Adult Subjects Assessed to be at Imminent Risk for Suicide
- CTRC Outpatient
- UT Southwestern-Other
- Zale Lipshy University Hospital
Madhukar Trivedi, M.D.
Ketamine and esketamine (the S-enantiomer of ketamine) are approved and widely used for the induction and maintenance of anesthesia via intramuscular (iM) or intravenous (iV) administration. The anesthetic effects of esketamine are attributed to the blockade of ionotropic n-methyl-D-aspartate (nMDa) glutamate receptors. Janssen Research and Development (JRD) is developing intranasal esketamine as an antidepressant therapy. The mechanism of action of esketamine is distinct from conventional monoaminergic antidepressant treatments, and esketamine profoundly affects fast excitatory glutamate transmission, increases brain-derived neurotrophic factor (BDnF) release, and stimulates synaptogenesis. in addition, a higher nMDa receptor binding affinity of esketamine compared to ketamine allows a lower volume of medication to be administered via the non-invasive and rapidly-absorbed intranasal route.
The current study is being conducted to evaluate the efficacy and safety of intranasal esketamine in addition to comprehensive standard of care in subjects with MDD who are at imminent risk for suicide as a pivotal Phase 3 study in support of regulatory agency requirements for registration of intranasal esketamine.
Subjects will remain in the inpatient psychiatry unit for a recommended duration of 5 days, with shorter or longer hospitalizations permitted if clinically warranted. Following discharge from the inpatient psychiatric unit, subsequent visits for the double-blind treatment phase will be conducted twice-weekly at an outpatient psychiatric facility through Day 25. During the follow-up phase, subjects will have visits conducted weekly through Day 53, then on Day 67, and a final visit on Day 90. The study will consist of a screening evaluation performed within 48 hours prior to the Day 1 intranasal dose (if possible, screening should occur within 24 hours prior to the Day 1 intranasal dose), immediately followed by a 25-day double-blind treatment phase (Day 1 to 25), and a 65-day follow-up phase (Day 26 to Day 90). The total study duration for each subject will be approximately 13 weeks.
on Day 1 of the double-blind treatment phase, approximately 224 subjects will be randomized in a 1:1 ratio to 1 of 2 treatments: intranasal esketamine 84 mg (n [?] 112) or intranasal placebo (n [?] 112), administered two times per week for 4 weeks (Days 1, 4, 8, 11, 15, 18, 22, and 25). The first dose of study medication will be administered in the eR or other permitted setting, including the inpatient psychiatric unit. after the first dose (ie, starting with the Day 4 dose or later), a one-time dose reduction to intranasal esketamine 56 mg or intranasal placebo is allowed if a subject is unable to tolerate the intranasal esketamine 84 mg or placebo dose assigned at randomization. no further dose adjustment is allowed during the double-blind treatment phase.
The primary efficacy endpoint will be the change from baseline (Day 1, predose) to 24 hours post first dose in depressive symptoms, as measured by the MaDRS total score.
The key secondary efficacy endpoint will be the change from baseline (Day 1, predose) at 24 hours post first dose in severity of suicidality, as measured by the CGi-SS-R. The other secondary endpoints are: MaDRS, CGi-SS-R, CGi-SR-i, BHS, eQ-5D-5L, QLDS, TQSM-9, SiBaT, pharmacokinetics.
Safety endpoints will be evaluated throughout the study: Teaes, SiBaT, Moaa/S, CaDSS, pulse oximetry, clinical laboratory tests, physical exam, nasal exam, 12-lead electrocardiogram (eCG), and vital signs.
The exploratory endpoints include: Change from baseline in MaDRS, CGi-SS-R, CGi-SR-i, BHS, QLDS, and eQ-5D-5L through the end of the follow-up phase (Day 90). TSQM-9 scores, medical resource utilization, and biomarkers through the end of the follow-up phase (Day 90)
1. Subject must be a man or woman, 18 to 64 years of age, inclusive.
2. Subject must meet Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) diagnostic criteria for MDD, without psychotic features, based upon clinical assessment and confirmed by the MINI.
3. Subjects must have current suicidal ideation with intent, confirmed by a
* response to Question B3 [Think (even momentarily) about harming or of hurting or of injuring yourself: with at least some intent or awareness that you might die as a result; or think about suicide (ie, about killing yourself)?] AND Question B10 [Intend to act on thoughts of killing yourself?] obtained from the MINI. Note: the response to B3 must refer to the present, whereas the response to B10 may reflect the past 24 hours. If the screening period is longer than 24 hours, assessment of B3 and B10 of MINI must be repeated prior to randomization to confirm eligibility.
4. In the physician[Single Quote]s opinion, acute psychiatric hospitalization is clinically warranted due to subject[Single Quote]s imminent risk of suicide.
5. Subject has a MADRS total score of >28 predose on Day 1.
6. As part of standard of care treatment, subject agrees to be hospitalized voluntarily for a recommended period of 5 days after randomization (may be shorter or longer if clinically warranted in the investigator[Single Quote]s opinion) and take prescribed non-investigational antidepressant therapy (ies) for at least the duration of the double-blind treatment phase (Day 25).
7. Subject is comfortable with self-administration of intranasal medication and able to follow instructions provided.
8. Subject must be medically stable on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening. If there are abnormalities, the subject may be included only if the investigator judges the abnormalities to be not clinically significant. This determination must be recorded in the subject's source documents and initialed by the investigator.
Note: Subjects recovering from a recent suicide attempt may be eligible provided they are medically stable.
9. Subject must be medically stable on the basis of clinical laboratory tests performed by the local laboratory at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant. This determination must be recorded in the subject's source documents and initialed by the investigator.
-Incidental exclusionary laboratory values ("incidental" refers to duplicate results from a separate blood sample analyzed at the central laboratory that become available after the subject has satisfied the inclusion and exclusion criteria based on the local laboratory values) will be handled on a case-by-case basis to determine if the subject should be withdrawn from the study.
10. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subject participating in clinical studies. Before randomization, a woman must be either:
a. Not of childbearing potential defined as:
-postmenopausal (>45 years of age with amenorrhea for at least 12 months), permanently sterilized (eg, bilateral tubal occlusion/ligation procedures, hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy
b. Of childbearing potential and
- practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly)
Examples of highly effective contraceptives include
- user-independent methods: implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); vasectomized partner; sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.)
- user-dependent methods: combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.
-agrees to use a highly effective method throughout the study and for at least 6 weeks after the last dose of study drug.
Note: If the childbearing potential changes after start of the study or the risk of pregnancy changes (eg, a woman who is not heterosexually active becomes active), a woman must begin a highly effective method of contraception, as described throughout the inclusion criteria.
11. A woman of childbearing potential must have a negative urine pregnancy test at screening.
12. During the study (ie, from Day 1 of the double-blind phase) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of study drug, a man who is sexually active with a woman of childbearing potential
- must be practicing a highly effective method of contraception with his female partner from those listed above (see examples of highly effective methods of contraception provided for female subjects).
- must use a condom if his partner is pregnant.
-must agree not to donate sperm.
Note: If the childbearing potential changes after start of the study, a female partner of a male study subject must begin a highly effective method of birth control, as described above.
13. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
14. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study.
Note: Subjects with acute alcohol intoxication should not be screened (but can be screened once sober).
15. Each subject must sign a separate informed consent form if he or she agrees to provide an optional DNA sample for research (where local regulations permit). Refusal to give consent for the optional DNA research sample does not exclude a subject from participation in the study.