A study to assess the efficacy and safety of combination of Dextromethorphan and Bupropion Tablets in patients with depression.

Phase 3

Completed

• Conditions: Major depressive disorder, singleepisode, unspecified,

• Registration Number: CTRI/2023/06/053474
• Lead Sponsor: Exemed Pharmaceuticals

Brief Summary

Thistrial is a phase III, randomized, double blind, active controlled, prospective,parallel group, comparative, multicentric clinical study to evaluate theefficacy, safety and tolerability of fixed dose combination of DextromethorphanHydrobromide plus Bupropion Hydrochloride Extended Release Tablets versusBupropion Hydrochloride Sustained Release Tablets in adult patients with majordepressive disorder (MDD).

 Patientswho are willing and able to participate in the study will sign and date theInformed Consent Form on the day of screening visit (Visit 1). During this screeningperiod, patients who are willing to give consent will be evaluated for all theeligibility criteria. Eligible patients (male or female) aged between 18 to 65years (both inclusive) and fulfil the inclusion criteria and none of theexclusion criteria considered for the study.

 Thestudy will be divided into 3 segments: an up to four-week screening period(Screening); a 6-week treatment period; and a 1-week follow-up period.

 After confirming the inclusion/exclusion criteria thesubject will be randomized and provided with study medication at randomizationvisit. Subjects will be provided with patient diary at randomization visit,which need to be brought along with in each subsequent visit till the lastvisit. Follow up visits will be done on telephonic visit/day 4, week 1/day 7(±2),week 2/day 14(±2), week 3/day 21(±2), week 4/day 28(±2), week 6/day 42(±2) and week7/day 49(±2) of treatment to assess efficacy, safety and tolerability.

 Patientswill be assigned to either of the two arms i.e., Arm A or Arm B consisting of FDCof Dextromethorphan Hydrobromide 45 mg + Bupropion Hydrochloride 105 mgExtended Release Tablets or Bupropion Hydrochloride Sustained Release Tablets150 mg.

Detailed Description

Not available

Study Timeline

• Study Start: 2023-06-16
• Study Completion: 2023-09-11
• Last Update Posted: 2023-12-25

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 192

Inclusion Criteria

• Male or female patients aged between 18 to 65 years (both inclusive).
• Patients currently meets the DSM-5 criteria for MDD without psychotic features, with a current major depressive episode of at least 4 weeks in duration at visit 1.
• Patients with MADRS score of ≥ 25 and CGI-S ≥ 4 at screening (visit 1) and baseline (visit 2).
• Patients with normal physical examination findings and clinical laboratory test results from screening (visit 1) or abnormal results that are judged not clinically significant by the investigator.
• Patients with body mass index (BMI) between 18 and 40 kg/m2 (both inclusive).
• Women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study.
• WOCBP must have a negative urine pregnancy test at screening (visit 1) and baseline (visit 2).
• Patient with ability to understand and provide written informed consent form, which must have been obtained prior to screening.
• Patients willing to comply with the protocol requirements.

Exclusion Criteria

• Psychiatric Criteria: 1.
• Patients with history of: a.
• Any depressive episode with psychotic or catatonic features b.
• Any manic, hypomanic or mixed episode, including bipolar disorder (Type 1 or Type 2) and substance-induced (e.g., antidepressant-induced) manic, hypomanic/mixed episode c.
• Bipolar depression d.
• Schizophrenia, schizoaffective, or other psychotic disorder e.
• Panic disorder, with or without agoraphobia f.
• Obsessive-compulsive disorder g.
• Bulimia or anorexia nervosa h.
• Any persistent neurocognitive disorder i.
• Any other anxiety disorder which has been the primary focus of clinical attention for the six months prior to screening, while MDD was a secondary focus of attention 2.
• Patients with history of treatment resistant depression defined as 2 or more failed treatments of adequate dose and duration in the current depressive episode.
• Patients with Improvement in MADRS score of ≥ 25% between visit 1 and visit 2.
• Patients with borderline or antisocial personality disorder or other disorder of sufficient severity to interfere with participation in this study.
• Patients with alcohol/substance use disorder (other than nicotine or caffeine), active within 1 year of visit 1.
• Patients with psychiatric hospitalization within current depressive episode.
• Psychiatric symptoms secondary to any other general medical condition.
• Patients with clinically significant risk of suicide or harm to self or others.
• Risk of suicide is determined by meeting any of the following criteria: a.
• In the judgment of the investigator, the patient may be a significant risk for suicide as judged by the psychiatric interview or information collected in the Columbia-Suicide Severity Rating Scale (C-SSRS) at visit 1 or visit 2 (e.g., The patient responded “yes†to question 4 or question 5 on the screening CSSRS, and the most recent episode occurred within the current depressive episode).
• The patient has attempted suicide within the current depressive episode.
• MADRS Item 10 score ≥ 5 at visit 1 or visit 2.
• Treatment-Related Criteria: 9.
• Patients with the use of drugs that are strong inhibitors of CYP2D6 (e.g., Fluoxetine, Paroxetine, Quinidine).
• Patients with the use of drugs that are inhibitors of CYP2B6, the primary enzyme that metabolizes Bupropion (e.g., Clopidogrel, Ticlopidene, Prasugrel), or that are inducers of CYP2B6 (e.g., Ritonavir, Lopinavir, Efavirenz).
• Patients with current use, or use within 14 days before visit 1, of monoamine oxidase inhibitors (MAOIs), or Linezolid, or intravenous Methylene Blue.
• Patients with the use of opioids (e.g., Codeine, Oxycodone, Morphine) within 14 days before visit 1.
• Patients having received any prohibited medications, supplements or herbal products including any antipsychotic, anticonvulsant/mood stabilizer, anxiolytic, Benzodiazepine, ADT, or ADT augmentation agent (e.g., T3 [except as treatment for thyroid condition], 2nd antidepressant, etc.) within 1 week or 5 half- lives of the medication, whichever is longer, prior to visit 2; however, 4 weeks is required for T3, 2 weeks is required for MAOIs. Lithium must be tapered and followed by a 1-week washout.
• The safe withdrawal from benzodiazepine treatment should be decided by the patient’s treating clinician and also monitored by the principal investigator.
• Patients with history of electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, or any experimental central nervous system treatment during the current episode or in the 6 months before visit 1 (whichever is longer).
• Patients requiring concomitant treatment with any of the prohibited medications, supplements, or herbal products including any psychotropic drug or any drug with psychotropic activity or with a potentially psychotropic component, except for the following: a.
• Eszopiclone, Zolpidem, Zolpidem extended-release, Zopiclone or Zaleplon for insomnia may be continued provided the medication has been used in a consistent manner for 4 weeks prior to enrolment and at doses that do not exceed the maximum labelled amounts.
• Patients with initiation or termination of psychotherapy for depression within 3 months of visit 1, or plans to initiate, terminate, or change such therapy during the study (Support meetings or counseling (e.g., marital counseling) are allowed provided they are no more frequent than weekly and do not have treatment of depression as their objective).
• Patients with ongoing, initiation or termination of phototherapy within 1 month of visit 1.
• Other Medical Criteria: 18.
• Patients with history of seizure disorder; undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates or antiepileptic drugs; or any other condition that increases the risk of seizure such as stroke, significant head injury, tumor or infection of the central nervous system, arteriovenous malformation, neuroleptic malignant syndrome/serotonin syndrome, or clinically significant, as deemed by the investigator, metabolic disorders (e.g., clinically significant hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia).
• Patients with a positive serum ethanol test or urine drug screen (UDS) for any prohibited medication or drugs of abuse (cocaine, marijuana, PCP, opioid or other agent that in the opinion of the investigator is being abused) at visit 1.
• Patients with any current or recent medical, psychiatric, or social condition that, in the investigator’s opinion, is likely to interfere with the conduct of the study, confounds the interpretation of study results, or endangers the subject’s well-being.
• This includes (but is not limited to) any clinically significant oncologic, hematologic, endocrine/metabolic, cardiovascular, respiratory, renal, hepatic, gastrointestinal, infectious or neurologic disease or has a chronic disease which is unstable or progressive.
• Patients with hypertension defined as resting, sitting systolic blood pressure (BP) ≥150 mm Hg or diastolic blood pressure ≥ 95 mm Hg. 22.
• Patients with hypo- or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no change in dosage for at least 1 month before visit 1 (Serum TSH must be > 0.75 × the LLN and < 1.25 × ULN).
• Patients with a history of allergy or hypersensitivity to Bupropion, Dextromethorphan, opiate drugs (e.g., Codeine, etc.), or any other ingredient in the study medication.
• Patients who have received Dextromethorphan co-administered with Quinidine within the past four weeks.
• Patients with gastric bypass or any condition that would be expected to affect drug absorption (lap band procedures are acceptable if there is no problem with absorption).
• Patients with known case of infection with hepatitis B, hepatitis C or HIV.
• Patients with clinically significant impaired hepatic function (SGOT & SGPT ≥ 2X the ULN and/or Total bilirubin ≥ 1.2X the ULN) at screening visit.
• Patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 [using the Modification of Diet in Renal Disease (MDRD) equation] at screening visit.
• Pregnant or breast-feeding or expecting to conceive within the projected duration of the study.
• Female patients who are of childbearing potential and who are neither surgically sterilized nor willing to use reliable contraceptive methods (like hormonal, barrier methods or intrauterine device).

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Change in MADRS total score from baseline to week 6.	At Baseline or Randomization Visit (Day 0), | Follow up Visit (Week 1 / Day 7±2), | Follow up Visit (Week 2 / Day 14±2), | Follow up Visit (Week 3 / Day 21±2), | Follow up Visit (Week 4 / Day 28±2) and | End of the Treatment Visit (Week 6 / Day 42±2).

Secondary Outcome Measures

Name	Time	Method
Clinical Global Impression of Improvement of Illness (CGI-I) at week 1, week 2, week 3, week 4 and week 6.	At Follow up Visit (Week 1 / Day 7±2),
Change in SDS total score from baseline to week 6.	At Baseline or Randomization Visit (Day 0),
Change in Q-LES-Q-SF score from baseline to week 6.	At Baseline or Randomization Visit (Day 0),
Changes in clinical laboratory parameters.	At Screening Visit and
Clinical response (≥ 50% reduction in MADRS total score) at week 1, week 2, week 3, week 4 and week 6.	At Follow up Visit (Week 1 / Day 7±2),
Patient Global Impression-Improvement (PGI-I) at week 6.	At End of the Treatment Visit (Week 6 / Day 42±2).
Remission (MADRS total score ≤ 10) at week 1, week 2, week 3, week 4 and week 6.	At Follow up Visit (Week 1 / Day 7±2),
Change in QIDS-SR-16 score from baseline to week 6.	At Baseline or Randomization Visit (Day 0),
Change in CGI-S from baseline to week 6.	At Baseline or Randomization Visit (Day 0),
Adverse events and Serious adverse events reported during the study.	Throughout the study.

Trial Locations

Locations (12)

Aatman Hospital; 🇮🇳 Ahmadabad, GUJARAT, India

Apex Hospitals Private Limited; 🇮🇳 Jaipur, RAJASTHAN, India

Chandani Hospital Pvt. Ltd.; 🇮🇳 Nagar, UTTAR PRADESH, India

College of Medicine & Sagore Dutta Hospital; 🇮🇳 Kolkata, WEST BENGAL, India

Great Eastern Medical School and Hospital; 🇮🇳 Srikakulam, ANDHRA PRADESH, India

GSVM Medical College; 🇮🇳 Nagar, UTTAR PRADESH, India

Indira Gandhi Institute of Medical Sciences (IGIMS); 🇮🇳 Patna, BIHAR, India

Jawahar Lal Nehru (J.L.N) Medical College; 🇮🇳 Jaipur, RAJASTHAN, India

Prakash Institute of Medical Sciences & Research (PIMS&R); 🇮🇳 Sangli, MAHARASHTRA, India

Ruby General Hospital Ltd.; 🇮🇳 Kolkata, WEST BENGAL, India

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Aatman Hospital

🇮🇳Ahmadabad, GUJARAT, India

Dr Fenil Shah

Principal investigator

9409009484

cr.aatman@gmail.com