Refractory Major Depressive Disorder

Use R-107 for the treatment of refractory major depressive disorder

R-107

Ketamine

Tablet

30 mg,60 mg

Primary endpoint:
The primary efficacy evaluation for the study will be the change in MADRS total score as measured by the change from baseline (Day 1 pre-dose) to the end of the doubleblind randomised phase, planned at Day 92.

Secondary Endpoints:
• Change from baseline (Day 1 pre-dose) in MADRS total score to Day 36 and Day 64;
• Proportion of subjects with response at Day 36, Day 64, and Day 92, where response is defined as ≥50% reduction from baseline in MADRS total score;
• Proportion of subjects in remission at Day 36, Day 64, and Day 92, where remission is defined as MADRS total score of ≤10;
• Change from baseline to the final drug administering visit (Day 92) of the CGI-S;
• Change from baseline to the final drug administering visit (Day 92) of the PGI-S;
• PK parameters (CL/F; Vd/F) from the population PK analysis of sparse plasma samples obtained on Days 8-9, 64-65, and 92-93.

1) Provision of written informed consent prior to any study specific procedures;
2) Female or male subjects aged 21-80 years inclusive for the Singapore sites and 20-80 years inclusive for the Taiwan sites, at the time of enrolment (screening visit);
3) Diagnosed with MDD as per Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and Mini-International Neuropsychiatric Interview (MINI) 7.0.2 without psychotic features for at least three months prior to screening (comorbid anxiety disorders are also acceptable);
4) Montgomery Asberg Depression Rating Scale (MADRS) total score of ≥20 at screening and baseline;
5) Treatment resistance in major depression (TRD) defined as lack of clinically meaningful improvement despite the use of adequate doses of at least two antidepressant agents, derived from the group(s) of commonly used first line treatment, prescribed for adequate duration with adequate affirmation of treatment adherence
6) Montreal Cognitive Assessment (MoCA) score ≥26 assessing cognitive function;
7) Psychotropic medication and/or psychotherapy is stable (i.e. no change of drugs or drug dose or visit schedule within 4 weeks prior to study entry);
8) Subjects must weigh at least 50kg and have a Body Mass Index (BMI) between 18 and 40 kg/m2 inclusive;
9) Women of childbearing potential (WOCBP) must use a highly effective form of birth control (confirmed by the Investigator). Highly effective forms of birth control include:
• True sexual abstinence (defined as refraining from heterosexual intercourse for the duration of the study and a minimum of 30 days following the last dose of study drug);
• Oral, intravaginal, or transdermal combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation;
• Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation;
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS);
• Bilateral tubal occlusion;
• Vasectomised partner (provided that the partner is the sole sexual partner of the female participant with childbearing potential and that the vasectomised partner has received medical assessment of the surgical success).
WOCBP are defined as women who are NOT either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are NOT postmenopausal. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative medical cause.
The following age-specific requirements apply:
• Women <50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range (FSH level > 40 mIU/mL);
• Women ≥50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
Rhythm methods will not be considered as highly effective methods of birth control.
10) Male subjects must use an adequate method of contraception (condom or condom with spermicide depending on local regulations) from the first dose of Investigational Medicinal Product (IMP) until 30 days after their last dose. Men with a partner or partners who is (are) not of childbearing potential are exempt of these requirements;
11) Male subjects must not donate sperm for at least 30 days post‐dose of the last study treatment;
12) A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 3 months after receiving the last dose of study drug;
13) Ability and willingness to attend the necessary visits to the study centre;
14) Ability to read and write (for Singapore sites only, ability to read and write English; for Taiwan sites only, ability to read and write English or Traditional Chinese);
15) Subject must be willing and able to adhere to the prohibitions and restrictions specified in the protocol;
16) Able to swallow tablets.
Entry to Double-blind phase of the study at Day 8
Subjects with a clinical response as demonstrated by ≥50% reduction of their MADRS total score which is ≤12 will enter into Part 2 of the study.

1) Any significant disease or disorder (e.g., cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or may influence the results of the study, or the subject’s ability to participate in the study;
2) Contraindication to the use of R‐107, e.g., any condition in which a significant elevation of blood pressure would be hazardous, such as decompensated heart failure, severe or poorly controlled hypertension (blood pressure systolic ≥160 or diastolic ≥90, tested on 2 or more occasions); within last 3 months, recent myocardial infarction, stroke, cerebral haemorrhage; myasthenia gravis; known allergy, hypersensitivity, or intolerance to ketamine or its excipients;
3) History of neurodegenerative disorder e.g. Alzheimer’s disease, vascular dementia or Parkinson's disease;
4) Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening and at baseline, which in the opinion of the Investigator, may put the subject at risk because of his/her participation in the study, or may influence the results of the study, or the subject’s ability to complete entire duration of the study.
5) Any electrocardiogram (ECG) abnormality obtained during the screening period that in Investigator’s judgement may put the subject at risk or negatively affect the outcome of the study;
6) Subjects are excluded if they have any of the following:
• A history of known immunodeficiency disorder including a positive test for human immunodeficiency virus, HIV-1 or HIV-2;
• Positive hepatitis B surface antigen, or positive hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Subjects with a history of hepatitis B vaccination without history of hepatitis B are allowed to enrol.
7) Hepatic Insufficiency: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2 times the upper limit of normal (ULN) confirmed by repeated testing during screening period;
8) Pregnant, breastfeeding, or lactating women (Females of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1);
9) Significant current risk of suicide:
• As assessed by eC‐SSRS (baseline), or
• Serious risk for suicide, as assessed by the evaluating study clinician; a serious suicide risk will be considered:
(a) an inability to control suicide impulses or imminent or unacceptably high risk of suicide in the Investigator's judgment; or
(b) a recent history of suicidal behaviour, which is defined as either one or more suicide attempts (or interrupted suicide attempts) in the 12 months before study entry; or
(c) history of serious suicidal behaviour, defined as one or more suicide attempts (or interrupted attempts) in the last 3 years with a potential lethality judged by the evaluating study clinician to have possibly resulted in serious injury or death.
10) History of alcohol or drug abuse within the past year, which may compromise the study data interpretation as judged by Investigator or Study Physician;
11) Subject has a positive test result(s) for drugs of abuse (including barbiturates, methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) at screening or pre-dose on Day 1. In addition to the drugs of abuse previously mentioned, cannabinoids will also be tested on Day 1;
• Subjects that have a positive test result at screening due to prescribed opiates or amphetamines may be permitted to continue the screening phase if the prohibited medication is discontinued at least 1 week or 5 half-lives, whichever is longer, before the first dose of study medication. Provided the Day 1 pre-dose test for drugs of abuse result is negative, the subject may be enrolled. Retesting is not permitted for positive test result(s) from non-prescription use of drugs of abuse.
• A positive test result for cannabinoids pre-dose on Day 1 is exclusionary.
12) Any clinically significant infection or febrile illness in the five days prior to dosing Day 1;
13) Past or current history of schizophrenia, bipolar disorder, ongoing severe personality disorder, ongoing post-traumatic stress disorder, intellectual disability or severe obsessive-compulsive disorder;
14) History of abuse of ketamine or phencyclidine;
15) Electroconvulsive therapy, transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation or other brain stimulation treatment within the past 4 weeks or currently used as either an acute or maintenance treatment of depression;
16) Receipt of any investigational product within 30 days or 5 half-lives prior to dosing;
17) Subject has a history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the Investigator, with concurrence with the Sponsor's medical monitor, is considered cured with minimal risk of recurrence);
18) Subjects should not consume grapefruit, grapefruit juice or Seville oranges for 72 hours before R-107 administration and during the study;
19) Subject has received any disallowed therapies as noted in the protocol (Restricted Medication), Pre-study and Concomitant Therapy before the specific time relative to the planned first dose of study drug;
20) Subject has had major surgery, (e.g., requiring general anaesthesia) within 2 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Note: subjects with planned surgical procedures to be conducted under local anaesthesia may participate;
21) Employees of the clinical study centre or family members (first-degree relatives) of such individuals or anyone involved in the planning and/or conduct of the study;
22) Subjects who do not consent to their General Practitioner being contacted prior to the commencement of the study, if necessary, about their medical history or after the study about any adverse results or reactions;
23) Subjects who, in the opinion of the Investigator, do not understand the information and procedures of the study, or would not be compliant with them (in particular the study restrictions and risks involved).