A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects with Treatment-resistant Depression

Study ID
STU 072015-065

Cancer Related
No

Healthy Volunteers
No

Study Sites

  • UT Southwestern-Other

Contact
Jessica Baine
214/648-5020
Jessica.Baine@UTSouthwestern.edu

Principal Investigator
Madhukar Trivedi, M.D.

Summary

Screening/prospective observational phase (4-week duration)
This phase will prospectively assess treatment response to the subject's current oral antidepressant treatment regimen. after 4 weeks of continuing the same treatment regimen (at the same dosage), subjects who are nonresponders to their current oral antidepressant treatment (as assessed by independent, remote raters) may be eligible to proceed to the double-blind induction phase. The site investigators will be blinded to the study criteria for non-response. eligible subjects who are entering the double-blind induction phase will discontinue their current oral antidepressant medication(s). if clinically indicated, a subject's current antidepressant medication(s) may be tapered and discontinued over an additional, optional period of up to 3 weeks per the local prescribing information or clinical judgment.
as a new oral antidepressant will be initiated on Day 1 of the double-blind induction phase, eligible subjects who do not require a tapered discontinuation of their antidepressant medication(s) can proceed immediately into the double-blind induction phase.

Double-blind induction phase (4-week duration)
approximately 196 subjects will be randomly assigned at a 1:1 ratio (n[?]98 per treatment arm) to receive double-blind treatment with either intranasal esketamine or intranasal placebo. The intranasal treatment sessions (esketamine or placebo) will occur twice weekly. in addition, all subjects will initiate a new open-label oral antidepressant on Day 1 that will be taken daily for the duration of this phase. The assigned oral antidepressant will be 1 of 4 oral antidepressant medications (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]), that the subject has not previously had a nonresponse to in the current depressive episode, has not been previously intolerant to (lifetime), and is available in the participating country.

at the end of the induction phase, subjects who are responders (defined as [GreaterThanorequalTo]50% reduction in the
MaDRS total score from baseline [Day 1 pre-randomization] to the end of the 4-week double-blind induction phase) may be eligible to participate in the subsequent study eSKeTinTRD3003 if they meet all other study entry criteria (eSKeTinTRD3003 is a longer-term efficacy maintenance study involving repeated treatment sessions of intranasal esketamine).

Follow-up phase (24-week duration)
This phase will include all subjects who are not eligible or who choose to not participate in the maintenance of effect study eSKeTinTRD3003 and have received at least 1 dose of intranasal study medication in the double-blind induction phase. There will be no intranasal treatment sessions administered during this phase.
The follow-up phase will also allow collection of additional informative data to assess the course of the subject's major depressive episode over a 6-month period.Taking into consideration the optional taper period of up to 3 weeks, the duration of a subject's study participation will be 11 weeks (for subjects continuing into eSKeTinTRD3003) or 35 weeks (for subjects completing the follow-up phase).

Primary efficacy evaluation and endpoint
The primary efficacy evaluation will be the MaDRS total score. The MaDRS will be performed by independent remote raters during the study. The primary efficacy endpoint will be change from baseline in MaDRS total score from Day 1 pre-randomization to the end of the 4-week double-blind induction phase.

Key Secondary efficacy evaluations and endpoints
1. Patient Health Questionnaire 9-item (PHQ-9): The PHQ-9 is a subject-reported outcome measure that will be used to assess depressive symptoms.
2. Sheehan Disability Scale (SDS): The SDS is a subject-reported outcome measure that will be used to assess functional impairment and associated disability.



Participant Eligibility

1. At the time of signing the informed consent form (ICF), subject must be a man or woman 18 (or older if the minimum legal age of consent in the country in which the study is taking place is >18) to 64 years of age, inclusive. 2. At the start of the screening/prospective observational phase, subject must meet the DSM-5 diagnostic criteria for single-episode MDD (if single-episode MDD, the duration must be >=2 years) or recurrent MDD, without psychotic features, based upon clinical assessment andconfirmed by the MINI. 3. Criterion modified per amendment 1 3.1. Criterion modified per amendment 2 3.2. At the start of the screening/prospective observational phase, subject must have had non-response (<=25% improvement) to >=1 but <=5 (if current episode is >2 years, upper limit is applicable to only the last 2 years) oral antidepressant treatments in the current episode of depression, assessed using the MGH-ATRQ and confirmed by documented records (eg, medical/pharmacy/prescription records or a letter from a treating physician, etc.). In addition, the subject is taking a different oral antidepressant treatment (on the MGH-ATRQ) for at least the previous 2 weeks at or above the minimum therapeutic dose. --For specific tricyclic antidepressants which are ongoing and being taken at a dose below the MGH-ATRQ minimum therapeutic dose, a blood level that is within the therapeutic (antidepressant) range, is acceptable to establish the adequacy of the antidepressant treatment. --Subjects must be adherent to the continued oral antidepressant treatment medication(s) through the screening/prospective observational phase, as documented on the PAQ. Missing >=4 days of antidepressant medication in the prior 2-week period will be considered as inadequate adherence. --Subjects who are non-responders to their current oral antidepressant medication(s) from the screening/prospective observational phase (as assessed by independent, remote raters) may be eligible for randomization if all other entry criteria are met. Nonresponse at the end of the screening/prospective observational phase is defined as <=25% improvement in the MADRS total score from Week 1 to Week 4 and a MADRS total score of >=28 on Week 2 and Week 4. 4. At the start of the screening/prospective observational phase, subject must have an IDS-C30 total score of >=34. 5. Criterion modified per amendment 1 5.1. The subject[Single Quote]s current major depressive episode, depression symptom severity (Week 1 MADRS total score >=28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using a Site Independent Qualification Assessment. 6. Subject must be medically stable on the basis of physical examination, medical history, vital signs (including blood pressure), pulse oximetry, and 12-lead ECG performed in the screening/prospective observational phase. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, the determination of their clinical significance must be determined by the investigator and recorded in the subject's source documents and initialed by the investigator. 7. Criterion modified per amendment 1 7.1. Criterion modified per amendment 2 7.2. Subject must be medically stable on the basis of clinical laboratory tests performed in the screening/prospective observational phase. 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 or to be appropriate and reasonable for the population under study. This determination must be recorded in the subject's source documents and initialed by the investigator. - Subjects with a pre-existing history of thyroid disease/disorder who are treated with thyroid hormones must be on a stable dosage for 3 months prior to the start of the screening/prospective observational phase. - For any subject (regardless of thyroid history), if the thyroid-stimulating hormone (TSH) value is out of range, a free thyroxine (FT4) will be conducted. If the FT4 value is abnormal and considered to be clinically significant (after discussion with the medical monitor), the subject is not eligible. 8. Subject must be comfortable with self-administration of intranasal medication and be able to follow the intranasal administration instructions provided. 9. Criterion modified per amendment 1 9.1. Criterion modified per amendment 2 9.2. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. A woman must be either: a. Not of childbearing potential defined as: -- postmenopausal: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy, however in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. --permanently sterile: Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy. 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 hormonereleasing 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. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. -- 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 (eg, woman who is not heterosexually active becomes active), a woman must begin a highly effective method of birth control, as described throughout the inclusion criteria. 10. Criterion modified per amendment 1 10.1 A woman of childbearing potential must have a negative highly sensitive serum ([BETA]- human chorionic gonadotropin [[BETA]-hCG]) at the start of the screening/prospective observational phase and a negative urine pregnancy test must be obtained before the first dose of study drug on Day 1 of the double-blind induction phase prior to randomization. 11. Criterion modified per amendment 1 11.1. Criterion modified per amendment 2 11.2. During the study (ie, from Day 1 of the double-blind induction phase, prior to randomization) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of intranasal study medication, 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. 12. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol. 13. Each subject must sign an ICF indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study. 3. Criterion modified per amendment 1 3.1. At the start of the screening/prospective observational phase, subject must have had non-response (<=25% improvement) to >=2 but <=5 (if current episode is >2 years, upper limit applicable to only the last 2 years) oral antidepressant treatments in the current episode of depression, assessed using the MGH-ATRQ and confirmed by documented records (eg, medical/pharmacy/prescription records) or a letter from a treating physician. Subject must be taking one of the oral antidepressant treatment(s) with non-response that is documented on the MGH-ATRQ (i.e. this oral antidepressant treatment must have been taken for at least 6 weeks at the minimum therapeutic dose with a lack of clinically meaningful improvement) at the start of the screening/prospective observational phase. - For specific tricyclic antidepressants which are being taken at a dose below the MGH-ATRQ minimum therapeutic dose, a blood level that is within the therapeutic (antidepressant) range, is acceptable to establish the adequacy of the antidepressant treatment. - Subjects must have been adherent to the continued oral antidepressant treatment medication(s) (without adjustment in dosage) through the screening/prospective observational phase, as documented on the PAQ. Missing >=4 days of antidepressant medication in the prior 2-week period will be considered as inadequate adherence. - Subjects who are non-responders to their current oral antidepressant medication(s) from the screening/prospective observational phase (as assessed by independent, remote raters) may be eligible for randomization if all other entry criteria are met. 4. At the start of the screening/prospective observational phase, subject must have an IDS-C30 total score of >= 34. 5. Criterion modified per amendment 1 5.1. The subject[Single Quote]s current major depressive episode, depression symptom severity (Week 1 MADRS total score >=28 required), and antidepressant treatment response in the current depressive episode, must be confirmed using a Site Independent Qualification Assessment. 6. Subject must be medically stable on the basis of physical examination, medical history, vital signs (including blood pressure), pulse oximetry, and 12-lead ECG performed in the screening/prospective observational phase. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, the determination of their clinical significance must be determined by the investigator and recorded in the subject's source documents and initialed by the investigator. 7. Criterion modified per amendment 1 7.1. Subject must be medically stable on the basis of clinical laboratory tests performed in the screening/prospective observational phase. 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 or to be appropriate and reasonable for the population under study. This determination must be recorded in the subject's source documents and initialed by the investigator. - Subjects with a pre-existing history of thyroid disease/disorder who are treated with thyroid hormones must be on a stable dosage for 3 months prior to the start of the screening/prospective observational phase and must have thyroid-stimulating hormone (TSH) within normal range in the screening/prospective observational phase. - For any subject (regardless of thyroid history), if the TSH value is out of range, a free thyroxine (FT4) will be conducted. If the FT4 is normal, the subject can be enrolled. If the FT4 value is out of range, the subject is not eligible. 8. Subject must be comfortable with self-administration of intranasal medication and be able to follow the intranasal administration instructions provided. 9. Criterion modified per amendment 1 9.1. A woman must be either: a. Not of childbearing potential defined as: -postmenopausal. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy, however in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. - permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy. 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. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. - 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 (eg, woman who is not heterosexually active becomes active), a woman must begin a highly effective method of birth control, as described throughout the inclusion criteria. 10. Criterion modified per amendment 1 10.1 A woman of childbearing potential must have a negative highly sensitive serum ([BETA]- human chorionic gonadotropin [[BETA]-hCG]) at the start of the screening/prospective observational phase and a negative urine pregnancy test must be obtained before the first dose of study drug on Day 1 of the double-blind induction phase prior to randomization. 11. Criterion modified per amendment 1 11.1. During the study (ie, from Day 1 of the double-blind induction phase, prior to randomization) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of intranasal study medication, in addition to the user independent highly effective method of contraception, a man - who is sexually active with a woman of childbearing potential must agree to use a double-barrier method of contraception (eg, diaphragm or cervical/vault caps plus condom with spermicidal foam/gel/film/cream/suppository) - who is sexually active with a woman who is pregnant must use a condom - must agree not to donate sperm Alternatively female partners of childbearing potential may be practicing a highly effective method of birth control, eg, established use of oral, injected, or implanted hormonal methods of contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); or male partner sterilization. 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. 12. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol. 13. Each subject must sign an ICF indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study.