A Study of MELT-300 (Midazolam and Ketamine Sublingual Tablets) for Sedation and Intraoperative Ocular Analgesia in Participants Undergoing Cataract Extraction With Lens Replacement (CELR)

A Phase 2, Factorial-Designed, Randomized, Double-Blind, Placebo-Controlled, Parallel- Cohort Study to Evaluate Efficacy and Safety of MELT-300 and the Contribution of Midazolam and Ketamine Components to Sedation and Intraoperative Ocular Analgesia in Subjects Undergoing Cataract Extraction With Lens Replacement (CELR)

The primary purpose of the study is to evaluate the efficacy and safety of MELT-300 (Midazolam and Ketamine Sublingual Tablets) and the contribution of midazolam and ketamine components to sedation and during the surgery or ocular analgesia in participants undergoing cataract surgery with lens replacement.

Study Overview

• Status: Completed
• Conditions: Cataract
• Intervention / Treatment: Drug: Placebo; Drug: MELT-300; Drug: Midazolam alone; Drug: Ketamine alone

Detailed Description

This is a Phase 2, factorial-designed, randomized, double-blind, placebo-controlled, parallel-cohort study to be conducted in 324 adult male and female participants who are ≥ 55 years of age and undergoing cataract extraction with lens replacement. An additional 3 participants per site (first 3 participants enrolled per site) will be considered sentinel participants for the purpose of ensuring safety and that logistical and operational challenges that may occur during the study are identified and mitigated. Sentinel participants will be evaluated for safety but not for efficacy. The study aims to evaluate the efficacy and safety of MELT-300 and the contribution of midazolam and ketamine components for procedural sedation prior to cataract surgery. In the study, eligible study participants will be randomly assigned (1:1:1:1 ratio) to one of the following treatments: MELT-300 (3 mg/50 mg), midazolam 3 mg, ketamine 50 mg, and placebo sublingual tablet 30 (± 5) minutes prior to the anticipated start of surgery (defined as instillation of topical ocular anesthetic drops [i.e., proparacaine]) without food or water in the operating room. At the time of dosing, participants will be instructed to hold the tablet under their tongue until it is completely dissolved and to not swallow or chew the tablets. The study duration will be up to 35 days, including 28 days for screening and 7 ± 2 days after surgery.

Efficacy assessments will be performed after study medication administration before surgery, intraoperatively, and postoperatively on Day 1 (end of surgery defined as drape removal). Efficacy assessments will include assessments of sedation and intraoperative pain, the need for rescue medication for sedation or pain, and the ability to complete the surgery. Safety will be monitored at baseline, intraoperatively, postoperatively on Day 1, on the day after surgery (Day 2, via a phone call), and at 1 week (Day 8 ± 2 days) after dosing of study medication. Safety assessments will include monitoring of AEs, vital sign measurements, physical examinations, and 12-lead ECGs. Exploratory endpoints are postoperative pain as measured by the NPRS prior to discharge, 6 hours +/- 30 minutes after the end of surgery on Day 1 and on Days 2 (the day after surgery), the percentage of participants with concomitant medication opioid use, and average opioid consumption on Day 2 and participant likelihood of wanting study drug again for second cataract surgery as measured by an 11-point Likert scale on Day 2.

• Study Type: Interventional
• Enrollment (Actual): 338
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Rancho Cordova, California, United States, 95670
      • Martel Eye Medical Group
  • Florida
    • Jacksonville, Florida, United States, 32204
      • Levenson Eye Associates
  • North Dakota
    • W. Fargo, North Dakota, United States, 58078
      • Vance Thompson Vision

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 53 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Are to undergo unilateral primary uncomplicated CELR under topical anesthesia, with a phacoemulsification device and insertion of an intraocular lens.

Exclusion Criteria:

1. Participants scheduled for simultaneous bilateral or 2nd-eye cataract surgery (note, subjects scheduled for a future 2nd eye cataract study are eligible for the study).
2. Known sensitivity to benzodiazepines or ketamine.
3. Known sensitivity to -caines (including proparacaine), benzalkonium chloride (BAK).
4. Intraocular pressure (IOP) ≥ 23 mmHg in the study eye and/or ≥ 30 mmHg in the fellow eye at screening. This IOP exclusion requirement will only need to be re-confirmed on the day of surgery if it has been > 14 days since the screening visit.
5. History of iritis, or any ocular trauma with iris damage in the study eye.
6. Presence of active corneal pathology other than corneal pathology per slit lamp and an external eye exam at screening in either eye.
7. Presence of extraocular/intraocular inflammation in either eye.
8. Presence of active bacterial and/or viral infection in either eye.
9. History of intraocular non-laser surgery in the study eye within the 3 months prior to day of surgery, or intraocular laser surgery in the study eye within 30 days prior to the day of surgery.
10. Require or are planning other additional ocular surgery during the cataract surgery.

12. Have a history or clinical manifestations (e.g., signs, symptoms, laboratory values, diagnostic imaging, etc.) of significant gastrointestinal, cardiovascular, hepatic, renal, hematological, endocrine, neurological, psychiatric, respiratory, or other medical condition that in the opinion of the investigator might confound the study results or pose additional risk in administering the study procedures.

13. History of or presence of any connective tissue disorder (i.e., lupus, rheumatoid arthritis, fibromyalgia).

14. Use of disallowed medications, including the following:

1. Pain medication (opioids, non-steroidal anti-inflammatory drugs [NSAIDs], cyclooxygenase-2 [COX-2] inhibitors, tramadol, ketamine, clonidine, gabapentin, pregabalin, or cannabinoids) within 3 days prior to Day 1, or routine, daily opioid therapy within the past 30 days.
2. Central nervous system (CNS) active drugs such as benzodiazepines, tricyclic antidepressants, serotonin, and norepinephrine reuptake inhibitors (SNRIs), or selective serotonin reuptake inhibitors (SSRIs) for pain within 7 days prior to Day 1. These drugs are permitted for non-pain indications if the dose has been stable for at least 30 days prior to Day 1 and is planned to remain stable throughout the study. The use of lorazepam and other sleep medications, except those containing analgesic properties, is permitted.
3. Use of parenteral or oral corticosteroid(s) within 14 days prior to Day 1.

4. Antihypertensive agent or diabetic regimen at a dose that has not been stable for at least 30 days, or which is not expected to remain stable throughout the study.

   15. Chronic pain rated moderate to severe within the past week (4-pt categorical scale, 0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain). 17. Hospital Depression and Anxiety Scale (HADS) score > 10

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: MELT-300; Participants will receive a single dose of MELT-300 sublingual, rapidly dissolving tablet containing 3 mg of midazolam and 50 mg of ketamine.	Drug: MELT-300; Sublingual tablet
Active Comparator: Midazolam alone; Participants will receive a single dose of midazolam 3 mg sublingual tablet.	Drug: Midazolam alone; Sublingual tablet
Active Comparator: Ketamine alone; Participants will receive a single dose of ketamine 50 mg sublingual tablet.	Drug: Ketamine alone; Sublingual tablet
Placebo Comparator: Placebo; Participants will receive a single dose of a matching placebo sublingual tablet.	Drug: Placebo; Sublingual tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants with Success for Procedural Sedation by Using Ramsay Sedation Scale	The Ramsay Sedation Scale (RSS) was the first scale to be defined for the sedated participants and was designed as a test of arousability. The Ramsay Scale provides three levels of 'awake' states (score 1-3) and three levels of 'asleep' states (score 4-6). A score of 2 (participant is cooperative, orientated, and tranquil) best fits an optimum sedation level based on the criteria of calm, comfortable, communicative, and cooperative participants. Ramsay Sedation Scale; =Participant is anxious and agitated or restless, or both; =Participant is cooperative, oriented, and tranquil; =Participant responds to commands only; =Participant exhibits brisk response to a light glabellar tap or loud auditory stimulus; =Participant exhibits a sluggish response to a light glabellar tap or loud auditory stimulus; =Participants exhibits no response RSS score will be assessed pre-operatively, intra-operatively, and post-operatively on Day 1	Day 1
Mean Intraoperative Analgesia as Measured by the Numeric Pain Rating Scale	The Numeric Pain Rating Scale (NPRS) is a segmented numeric version of the visual analog scale (VAS) in which a respondent selects a whole number (0-10 integers) that best reflects the intensity of his/her pain. The 11-point numeric scale ranges from '0' representing one pain extreme (e.g. "no pain") to '10' representing the other pain extreme (e.g. "pain as bad as you can imagine" or "worst pain imaginable")	Intraoperatively on Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Pre-operative Target Sedation Responders by Ramsay Sedation Scale (level 2 or 3)	The Ramsay Sedation Scale (RSS) was the first scale to be defined for the sedated participants and was designed as a test of arousability. The Ramsay Scale provides three levels of 'awake' states (score 1-3) and three levels of 'asleep' states (score 4-6). A score of 2 (participant is cooperative, orientated, and tranquil) best fits an optimum sedation level based on the criteria of calm, comfortable, communicative, and cooperative participants. Ramsay Sedation Scale; =Participant is anxious and agitated or restless, or both; =Participant is cooperative, oriented, and tranquil; =Participant responds to commands only; =Participant exhibits brisk response to a light glabellar tap or loud auditory stimulus; =Participant exhibits a sluggish response to a light glabellar tap or loud auditory stimulus; =Participants exhibits no response	Pre-operatively (at baseline), intra-operatively and post-operatively on Day 1
Percentage of Analgesia Responders Using Numeric Pain Rating Scale	The Numeric Pain Rating Scale (NPRS) is a segmented numeric version of the visual analog scale (VAS) in which a respondent selects a whole number (0-10 integers) that best reflects the intensity of his/her pain. The 11-point numeric scale ranges from '0' representing one pain extreme (e.g. "no pain") to '10' representing the other pain extreme (e.g. "pain as bad as you can imagine" or "worst pain imaginable").	Pre-operatively (at baseline), intra-operatively and post-operatively on Day 1
Number of Participants with Sedation Scores	The Ramsay Sedation Scale (RSS) was the first scale to be defined for the sedated participants and was designed as a test of arousability. The Ramsay Scale provides three levels of 'awake' states (score 1-3) and three levels of 'asleep' states (score 4-6). A score of 2 (participant is cooperative, orientated, and tranquil) best fits an optimum sedation level based on the criteria of calm, comfortable, communicative, and cooperative participants. Ramsay Sedation Scale; =Participant is anxious and agitated or restless, or both; =Participant is cooperative, oriented, and tranquil; =Participant responds to commands only; =Participant exhibits brisk response to a light glabellar tap or loud auditory stimulus; =Participant exhibits a sluggish response to a light glabellar tap or loud auditory stimulus; =Participants exhibits no response	After study medication administration before surgery (baseline), intraoperatively, and postoperatively on Day 1 (end of surgery defined as drape removal)
Number of Participants with Pain Scores		Before dosing on the day of surgery (Day 1)
Number of Participants-rated Worst Pain Following Completion of Surgery		Pre-operatively (at baseline), intra-operatively, and post-operatively on Day 1
Percentage of Participants Able to Complete Surgery		Pre-operatively (at baseline), intra-operatively and post-operatively on Day 1
Percentage of Participants Without Interruption of Surgery for Intervention (Other Than Rescue Medication) Due to Pain or Anxiety		Pre-operatively (at baseline), intra-operatively, and post-operatively on Day 1
Percentage of Participants Requiring Rescue Sedative Medication	The preoperative target level of sedation for this trial is Ramsay Sedation Scale (RSS) 2 or 3. If a participant does not achieve this level of sedation prior to the start of surgery (administration of topical local anesthesia), rescue sedation medication (i.e., intravenous midazolam only, at a dose determined by Investigator or anesthesiologist) may be given. Use of rescue sedation medication during surgery will be allowed if a participant's RSS score is <2.	Pre-operatively (at baseline) and Intra-operatively on Day 1
Percentage of Participants Requiring Rescue Analgesic Medication	Intraoperative pain assessments using the Numeric Pain Rating Scale (NPRS) scale, from 0 (no pain) to 10 (extreme pain), will be assessed. The NPRS is a segmented numeric version of the visual analog scale (VAS) in which a respondent selects a whole number (0-10 integers) that best reflects the intensity of his/her pain. The 11-point numeric scale ranges from '0' representing one pain extreme (e.g. "no pain") to '10' representing the other pain extreme (e.g. "pain as bad as you can imagine" or "worst pain imaginable").	After study medication administration before surgery (baseline) and intraoperatively
Number of Participants Reported with At least One Treatment Emergent Adverse Event (TEAE)	A treatment-emergent adverse event is defined as any event not present prior to the initiation of the drug treatment or any event already present that worsens in either intensity or frequency following exposure to the drug treatment.	Pre-operatively (at baseline), intra-operatively post-operatively on Day 1, on the day after surgery (Day 2, via a phone call), and at 1 week (Day 8 ± 2 days) after dose of study medication

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative Pain as measured by the Numeric Pain Rating Scale Scores	The Numeric Pain Rating Scale (NPRS) is a segmented numeric version of the Visual Analog Scale (VAS) in which a respondent selects a whole number (0-10 integers) that best reflects the intensity of his/her pain. The 11-point numeric scale ranges from '0' representing one pain extreme (e.g. "no pain") to '10' representing the other pain extreme (e.g. "pain as bad as you can imagine" or "worst pain imaginable").	Prior to discharge, 6 hours +/- 30 minutes, and on Day 2 (the day after surgery)
Percentage of Participants with Concomitant Medication Opioid Use and Average Opioid Consumption	Concomitant medication is a medication, a person is taking that is not being studied in the clinical trial he or she is taking part in.	Day 2
Participant Likelihood of Wanting Study Drug Again for Second Cataract Surgery as Measured by 11-point Likert Scale	A Likert Scale is a Psychometric Scale commonly involved in research that employs questionnaires. A Likert scale is the sum of responses on several Likert items. A Likert item is simply a statement that the respondent is asked to evaluate by giving it a quantitative value on any kind of subjective or objective dimension, with the level of agreement/disagreement being the dimension most commonly used. Study participants will be asked to rate their likelihood that they would want the same study medication again if they had second cataract surgery on an 11-point Likert scale of 0 (not likely at all) to 10 (extremely likely)	Day 2

Collaborators and Investigators

• Sponsor: Melt Pharmaceuticals
• Collaborators: Worldwide Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2021
• Primary Completion (Actual): October 26, 2022
• Study Completion (Actual): November 3, 2022

Study Registration Dates

• First Submitted: November 12, 2021
• First Submitted That Met QC Criteria: November 12, 2021
• First Posted (Actual): November 24, 2021

Study Record Updates

• Last Update Posted (Actual): December 19, 2022
• Last Update Submitted That Met QC Criteria: December 15, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Cataract surgery; Intraocular pressure; Sedation; Cataract extraction; Intraoperative ocular pain; Lens replacement; MELT-300
• Additional Relevant MeSH Terms: Eye Diseases; Lens Diseases; Cataract; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Ketamine; Midazolam
• Other Study ID Numbers: MELT-2-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No