Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD
Condition: Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
Study type: Interventional
Phase: Phase 2

Summary: 
      This a Phase 2a, multicenter, randomized, double-blind, placebo controlled 3 arm study to
      assess the safety and tolerability of multiple oral doses of REL-1017 25 mg and 50 mg as
      adjunctive therapy in the treatment of patients diagnosed with major depressive disorder
      (MDD). The patients will be adults with MDD who are diagnosed with a current MDE who have
      experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant
      medication. This population will provide the opportunity to compare the safety and efficacy
      effects of treatment with an approved antidepressant in conjunction with REL-1017 versus the
      effects of an antidepressant alone. This study includes in-patient and out-patient periods.
    

Detailed description: 
      Currently available medications have proven to be useful for the treatment of depression, but
      also have limitations including low response rates, a significant number of treatment
      resistant patients, and time-lag for response, which emphasizes a major unmet need for more
      efficacious and faster-acting antidepressants. Recent studies have demonstrated that
      ketamine, a non-competitive glutamate-N-methyl-D-Aspartate (NMDA) receptor antagonist,
      produces rapid onset (2 hours) and long-lasting (7 days) antidepressant actions in treatment
      resistant patients. This rapid action, by a mechanism completely different from typical
      monoamine reuptake inhibitors, represents a significant finding in the field of depression.

      Racemic methadone, the 50/50 combination of d-methadone and l-methadone, has been in
      widespread use for decades and has been studied extensively. Methadone is currently approved
      for use in the management of severe pain, detoxification treatment of opioid addiction, and
      maintenance treatment of opioid addiction.

      The results of a study evaluating the receptor binding profiles of racemic methadone and its
      stereoisomers suggest that d-methadone does not essentially contribute to the opioid effect
      of racemic methadone and that it has a 10 times lower affinity for the mu1, mu2, and delta
      opioid receptors compared to l-methadone. Racemic methadone and its d- and l isomers exhibit
      similar affinities for the non-competitive binding site of the NMDA receptor and are
      non-competitive NMDA receptor antagonists.

      In the forced swim test, a rodent behavioral model of antidepressant activity, both ketamine
      and d-methadone at all doses tested significantly decreased the immobility of the rats
      compared to the vehicle suggesting antidepressant like activity. Neither drug increased
      spontaneous locomotor activity.

      Relmada has conducted 2 clinical studies to identify the dose levels of REL-1017
      (d-methadone) that have little to no opioid effects and that are expected to possess NMDA
      antagonistic properties for the evaluation of oral REL-1017 in the treatment of MDD and
      neuropathic pain conditions. Initial Phase 1 single ascending dose and multiple ascending
      dose clinical studies of REL-1017 were designed to evaluate the safety and tolerance of the
      pure d methadone isomer in healthy opioid-naïve subjects and identify a safe and potentially
      effective dose range in this population. These studies showed that REL-1017 was safe and
      well-tolerated at single oral doses up to 150 mg (maximum tolerated dose) and up to 75 mg
      administered once daily for 10 days in healthy opioid-naïve subjects.

      The pre-clinical and previous clinical experience with REL-1017 (d-methadone) provided the
      basis for the initiation of the present study, which will extend the evaluation of the
      safety, tolerability, and PK of REL-1017 at 2 doses with repeated administration to depressed
      patients. Since REL-1017 is proposed for use as adjunctive therapy in the treatment of
      patients diagnosed with major depressive disorder (MDD), the patients will be male adults
      with MDD who are diagnosed with a current depressive episode who have experienced an
      inadequate response to 1 to 3 courses of treatment with an antidepressant medication.

      Based on the safety data from Protocol REL-1017-111, single doses of 5 mg, 20 mg, 60 mg, 100
      mg, and 150 mg of REL-1017 or placebo were well tolerated. The results of Protocol
      REL-1017-112 evaluated 10 days of dosing with 25 mg, 50 mg and 75 mg of REL-1017 or placebo,
      and no impact on safety was observed. In spite of the confirmed dose proportionality, the
      comparison of concentration and exposure between the 50 mg and 75 mg REL-1017 treatment
      groups demonstrated only slight differences. Consequently, 25 mg and 50 mg doses were chosen
      for administration in Protocol REL-1017-202 as single daily doses over a period of 7 days.

      Thus, as a single isomer of racemic methadone, d-methadone has been shown to possess NMDA
      antagonist properties with virtually no opioid activity or ketamine-like toxicities at the
      expected therapeutic doses.

      In this study, adult male patients with MDD who are diagnosed with a current MDE and who have
      experienced an inadequate response to 1 to 3 courses of treatment with an antidepressant
      medication will be randomized to study drug in a 1:1:1 ratio. Approximately 15 patients each
      will receive REL-1017 25 mg, REL-1017 50 mg, or placebo once daily for 7 days. Endpoints
      include assessments of safety, tolerability, efficacy and pharmacokinetics of REL-1017.
      Patients will be required to stay in the clinic for 10 days and will then be followed as an
      outpatient for 12 additional days.
    

Intervention name(s): REL-1017; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): REL-1017 will be administered as an oral solution. Patients will continue to take the same, stabilized antidepressant medication that they were taking at screening throughout the course of the study.; Placebo will be administered as an oral solution. Patients will continue to take the same, stabilized antidepressant medication that they were taking at screening throughout the course of the study.
Other intervention name(s): d-Methadone
Intervention MeSH terms: Methadone; D-methadone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: REL-1017; d-Methadone; Methadone; Depression; Refractory Depression; Antidepressant; Adjunctive Treatment; NMDA Receptor Antagonist; Excitatory Amino Acid Antagonist; Glutamate Antagonist