Clinical trial NCT06110546
Conditions: Effect of Methadone on the Duration on Mechanical Ventilation
Keywords: opioids mechanical ventilation
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2024-02-18; Completion date: 2024-02-22
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the effect of methadone on the duration on mechanical ventilation in critically ill patients receiving more than 72 hours of mechanical ventilation (MV) by comparing the number of ventilator free days from enrollment to the time of discharge, to assess the safety of methadone administration in critically ill patients while in the hospital and to determine hospital length of stay from the time of enrollment to the time of discharge

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Methadone group intervention 2: Usual care
Intervention descriptions: intervention 1: Participants will be started on Methadone 5mg, 10mg or 15mg every 8 hours depending on Fentanyl drip rate (0-100mcg/hr, 100-200mcg/hr or \>200mcg/hr) or hydromorphone drip rate (0-1.5mg/hr, 1.5-3mg/hr, or \>3mg/hr). intervention 2: Participants will receive usual care with IV Fentanyl or hydromorphone per hospital protocols

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 65 
Protocol Number / Version No. 2.0 / 5.10.2023 
 
 
 
 
 
 
 
 
 
 
 
Impact of Methadone on prolonged mechanical ventilation in Patients on continuous treatment with 
Opioids, a randomized trial (IMPACTOR Study) 
 
NCT06110546 
 
Version Date: 01/05/2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 2 of 65 
Protocol Number / Version No. 2.0 / 5.10.2023 
 
 
STUDY PROTOCOL 
 
PROTOCOL NUMBER: 
HSC-MS-22-0689 
 
PROTOCOL TITLE: 
Impact of Methadone on prolonged mechanical ventilation in Patients on continuous 
treatment with Opioids, a randomized trial (IMPACTOR Study) 
VERSION: 
3 
DATE: 
08.11.2023 
 
CORRESPONDING PRINCIPAL INVESTIGATOR: 
 
Pascal L Kingah, MD 
Associate Professor Non-Tenure Clinical 
Department of Internal Medicine 
Divisions of Critical Care and Pulmonary Medicine, 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
 
SITE PRINCIPAL INVESTIGATOR: 
 
Pascal L Kingah, MD 
Associate Professor Non-Tenure Clinical 
Department of Internal Medicine 
Divisions of Critical Care and Pulmonary Medicine, 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
 
SITE: 
Memorial Hermann Hospital Texas Medical Center 
6411 Fannin Street, 
Houston Texas USA, 77030 
 
Memorial Hermann Hospital Cypress 
27800 Northwest Fwy, Cypress, TX 77433 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


Page 3 of 65 
Protocol Number / Version No. 2.0 / 5.10.2023 
 
GENERAL INFORMATION 
 
Name and address of the person authorized to sign the protocol and amendments: 
Pascal L Kingah, MD 
Associate Professor Non-Tenure Clinical 
 
Department of Internal Medicine 
Divisions of Critical Care and Pulmonary Medicine, 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
Name and title of the investigator(s) and sub-investigators responsible 
Bela Patel, MD 
Professor NTC, Vice Dean for Healthcare Quality, and Graham Distinguished University Chair 
Department of Internal Medicine, 
Divisions of Critical Care and Pulmonary Medicine, 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
 
Bindu Akkanti, MD 
Associate Professor Non-Tenure Clinical 
Department of Internal Medicine, 
Divisions of Critical Care and Pulmonary Medicine 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
 
Sami Hossri, MD 
Assistant Professor Non-Tenure Clinical 
 
Department of Internal Medicine 
Divisions of Critical Care and Pulmonary Medicine, 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
 
Javier Barreda Garcia, MD 
Assistant Professor Non-Tenure Clinical 
 
Department of Internal Medicine 
Divisions of Critical Care and Pulmonary Medicine, 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
 
Alisha Young, MD 
Assistant Professor Non-Tenure Clinical 
 
Department of Internal Medicine 
Divisions of Critical Care and Pulmonary Medicine, 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


Page 4 of 65 
Protocol Number / Version No. 2.0 / 5.10.2023 
 
Ghazi Rizvi, MD 
Assistant Professor Non-Tenure Clinical 
 
Department of Internal Medicine 
Divisions of Critical Care and Pulmonary Medicine, 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
 
Vishal Demla, MD 
Associate Professor Non-Tenure Clinical 
 
Department of Internal Medicine 
Divisions of Critical Care and Pulmonary Medicine, 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
 
Jennifer Cortes, PharmD, BCPS, BCCP, FCCM 
Clinical Pharmacy Specialist-MICU 
Medical Intensive Care Unit 
Department: EVPARA Research Compliance 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
 
 
Elias Cortez 
Nurse Practitioner - Acute Care 
 
Department of Internal Medicine 
Divisions of Critical Care and Pulmonary Medicine, 
McGovern Medical School at The University of Texas Health Science Center in Houston 
 
 
Katie Beaudoin, PA 
Physician Assistant 
 
 
 
 
Name of Lab &Address 
 
Memorial Hermann Laboratory Services 
6411 Fannin Street, Houston, TX 77030 
 
 
Memorial Hermann Diagnostic Laboratory -Cypress 
27700 Northwest Freeway Cypress, Tx 77433 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


Page 5 of 65 
Protocol Number / Version No. 2.0 / 5.10.2023 
 
TABLE OF CONTENTS 
 
 
 
 
1. 
BACKGROUND AND RATIONALE........................................................................ 6 
1.1. 
GENERAL INTRODUCTION ...................................................................................................... 6 
1.2. 
RATIONALE AND JUSTIFICATION FOR THE STUDY .............................................................. 6 
A. 
RATIONALE FOR THE STUDY PURPOSE ............................................................................... 7 
B. 
RATIONALE FOR DOSES SELECTED ..................................................................................... 7 
C. 
RATIONALE FOR STUDY POPULATION ................................................................................. 7 
D. 
RATIONALE FOR STUDY DESIGN ........................................................................................... 7 
2. 
HYPOTHESIS AND OBJECTIVES ......................................................................... 7 
2.1. 
HYPOTHESIS ............................................................................................................................. 8 
2.4. 
POTENTIAL RISKS AND BENEFITS......................................................................................... 8 
A. 
END POINTS – EFFICACY ....................................................................................................... 8 
B. 
END POINTS – SAFETY ........................................................................................................... 8 
2.5 
Outcome… ...................................................................................................... 9 
A. 
Primary ........................................................................................................... 9 
B 
Secondary… ................................................................................................... 9 
3. 
Study Population… ............................................................................................ 10 
3.1. 
LIST THE NUMBER OF SUBJECTS TO BE ENROLLED ........................................................... 9 
3.2. 
CRITERIA FOR RECRUITMENT ............................................................................................... 9 
3.3. 
INCLUSION CRITERIA ............................................................................................................... 9 
3.4. 
EXCLUSION CRITERIA ............................................................................................................. 9 
3.5. 
WITHDRAWAL CRITERIA ......................................................................................................... 9 
3.6. 
SUBJECT REPLACEMENT ........................................................................................................ 9 
4. 
TRIAL SCHEDULE ............................................................................................... 10 
4.1 
Allocation ..................................................................................................... 11 
4.2 
Interventions .................................................................................................. 11 
5. STUDY DESIGN ..................................................................................................... 10 
5.1. 
SUMMARY OF STUDY DESIGN ............................................................................................. 11 
6. 
METHODS AND ASSESSMENTS ........................................................................ 11 
6.1. 
RANDOMIZATION AND BLINDING ......................................................................................... 12 
7. 
TREATMENT ........................................................................................................ 12 
7.2. 
STUDY DRUG FORMULATIONS ............................................................................................ 12 
7.3. 
STUDY DRUG ADMINISTRATION .......................................................................................... 12 
7.4. 
SPECIFIC RESTRICTIONS / REQUIREMENTS ..................................................................... 12 
7.5. 
BLINDING ................................................................................................................................. 13 
8. 
SAFETY MEASUREMENTS ................................................................................. 13 
8.1. 
DEFINITIONS ........................................................................................................................... 13 
8.2. 
COLLECTING, RECORDING AND REPORTING OF ADVERSE EVENTS ........................... 14 
9. 
DATA ANALYSIS ................................................................................................. 14 
9.1. 
DATA QUALITY ASSURANCE ................................................................................................ 15 
9.2. 
DATA ENTRY AND STORAGE........................................................................I.R...B...N.1UU.5MBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


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Protocol Number / Version No. 2.0 / 5.10.2023 
 
10. SAMPLE SIZE AND STATISTICAL METHODS ................................................... 15 
10.1. 
DETERMINATION OF SAMPLE SIZE ..................................................................................... 15 
10.2. 
STATISTICAL AND ANALYTICAL PLANS .............................................................................. 15 
11. ETHICAL CONSIDERATIONS ............................................................................. 15 
11.1. 
INFORMED CONSENT ............................................................................................................ 15 
11.2. 
IRB REVIEW ............................................................................................................................ 15 
11.3. 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS ..................................................... 15 
12. PUBLICATIONS ................................................................................................... 16 
13. RETENTION OF TRIAL DOCUMENTS ................................................................ 16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


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Protocol Number / Version No. 2.0 / 5.10.2023 
 
STUDY PROTOCOL 
 
1. 
BACKGROUND AND RATIONALE 
 
Our study focus is to identify patients that have been on the ventilator for more than 72 hours 
receiving fentanyl infusions or its equivalents and enroll them into our study, start them on oral 
Methadone in order to wean off Fentanyl. Patients on mechanical ventilation are often 
administered opioids and other sedative medications to control pain, maintain comfort and 
optimize ventilatory support. The use of effective strategies to help wean patients from continuous 
infusions of opioids in an ICU setting that do not predispose them to continuous pain or risk of 
drug withdrawal has been proposed but attaining the above objective remains challenging. 
Based on nomenclature used following 2002 American College of Critical Care Medicine 
sedation consensus guidelines, 72 hours or more on sedation was considered prolonged ICU 
sedation. [1] There has been very few randomized controlled trials on the best strategy to wean 
patients from prolonged infusion of opioids beyond 72 hours and there is no national consensus 
as regards the best strategy. Only a few studies with very small sample sizes have been used to 
guide current management. [2] During COVID-19 pandemic surge periods Massachusetts General 
Hospital published strategies for weaning analgesia using oral methadone which most of our ICU 
physicians are currently using. We do not have evidence of the benefit of this strategy and believe 
designing a study to assess the benefits will be useful for its continuous use. 
 
 
1.1. 
General Introduction 
 
Methadone is an opioid which binds to opioid receptors to produce analgesia and sedation. It is 
currently in use for treating opioid dependence as well as analgesic for chronic moderate to severe 
pain 
 
1.2. 
Rationale and justification for the Study 
 
Variation in sedation practice may lead to undersedation or over sedation. Over sedation is 
associated with adverse clinical outcomes such as prolonged stay on the ventilator, prolonged 
ICU length of stay, delirium and increased mortality. [ 3] 
We hypothesize that patients who get oral methadone to help wean off opioids will have shorter 
ICU length of stay, shorter duration on the ventilator and potentially improved hospital mortality. 
We hypothesize that we will increase the proportion of patients extubated by day 5. 
 
The use of long-acting opioids by enteral administration to wean mechanically ventilated patients 
from sedation and analgesia has been well documented by Wanzuita et al. They used 10mg of 
methadone every six hours enterally while reducing the rate of fentanyl infusion by 20%. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


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Protocol Number / Version No. 2.0 / 5.10.2023 
 
a. 
Rationale for the Study Purpose 
 
Based on nomenclature used following 2002 American College of Critical Care Medicine sedation 
consensus guidelines, 72 hours or more on sedation was considered prolonged ICU sedation. [1] 
There has been very few randomized controlled trials on the best strategy to wean patients from 
prolonged infusion of opioids beyond 72 hours and there is no national consensus as regards the 
best strategy. Only a few studies with very small sample sizes have been used to guide current 
management. [2] A randomized control trial carried out in Brazil introduced the use of Methadone 
after patients were on ICU sedation for 5 days, compared to Society guidelines, which was two 
days longer. [ 4] Current protocols recommend tapering Fentanyl based on a nursing protocolized 
sedation in which the dose is reduced by 25mcg per hour to bring the patient to a desired RASS 
(Richmond Agitation Sedation Scale score) set by the physician. 
 
In our study, we seek to identify patients on IMV for over 72 hours and randomize them to those 
who will receive methadone and those that will get usual care not receiving methadone. We plan 
to compare any differences in ICU outcomes. 
 
Prior randomized trials introduced the use of methadone after 5 days of ICU sedation which was 
much longer than the ACCM definition of 3 days on prolonged mechanical ventilation. 
 
 
b. 
Rationale for Doses Selected 
Patients will be randomized to either Oral Methadone tablets the interventional group or Control 
group that will receive usual care with IV Fentanyl or hydromorphone per hospital protocols. 
Patients on the methadone group will be started on Methadone 5mg, 10mg or 15mg every 8 hours 
via a feeding tube depending on Fentanyl drip rate (0-100mcg/hr, 100-200mcg/hr or >200mcg/hr) 
or hydromorphone drip rate (0-1.5mg/hr, 1.5-3mg/hr, or >3mg/hr), Appendix3. The rate of Fentanyl 
or hydromorphone will be reduced by 25% initially to bring patient to a desired RASS (Richmond 
Agitation Sedation Scale score) as requested by the physician. While the control group will Not 
get any medication and will be weaned off opioids as per usual care. 
 
 
c. 
Rationale for Study Population 
 
In order to test our hypothesis our population of target needed to be patients admitted to the ICU 
who have been on mechanical ventilation for more the 72 hours on sedation with opioids. This 
gives us the opportunity to be able to compare outcomes between those that will receive 
methadone to those that will not 
 
d. 
Rationale for Study Design 
 
 
A randomized control trial gives us the best tool devoid of selection bias as well as controlling for 
potential confounders. 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


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Protocol Number / Version No. 2.0 / 5.10.2023 
 
2. 
HYPOTHESIS AND OBJECTIVES 
 
 
2.1. 
Hypothesis 
 
The study hypothesizes that patients who get oral methadone to help wean off opioids will 
have shorter ICU length of stay, shorter duration on the ventilator and potentially improved 
hospital mortality. The study hypothesizes that, there will be increase in the proportion of patients 
extubated by day 5. 
 
2.2. 
Primary Objectives 
 
To determine the effect of methadone on the duration on mechanical ventilation in critically 
ill patients receiving more than 72 hours of MV by comparing the number of ventilator free days 
form enrolment to the time of discharge 
 
2.3. 
Secondary Objectives 
 
To assess the safety of methadone administration in critically ill patients while in the 
hospital. 
To determine hospital length of stay from the time of enrollment to the time of discharge 
 
 
2.4. 
Potential Risks and Benefits: 
 
a. 
End Points – Efficacy 
 
The study might show the efficacy and potency of methadone in decreasing the length of stay in 
ICU and duration of mechanically intubation in critically ill patients. 
 
b. 
End Points – Safety 
Adverse events that could be anticipated during the study include signs of opioid withdrawal, 
elevated liver enzymes, ileus, hypotension and QTC prolongation. Adverse events will be 
reported in the adverse events registry. 
 
The only two adult studies reported on the use of methadone to wean opioids on mechanical 
ventilation showed that the much-anticipated risk of QTC prolongation was similar in both patients 
who received methadone and those that did not receive methadone as shown in the study by 
Wanzuita et al and Al-Qadheeb et al. [5] Methadone was well tolerated in both studies. 
 
2.5 
Outcomes 
 
a. 
Primary 
Proportion of patients on methadone that get extubated by day number 5 from the date of 
intubation 
b. 
Secondary 
Proportion of patients that develop prolonged QTC after administration of methadone. Others will 
be ICU length of stay, ICU mortality, hospital length of stay and hospital mortality. 
 
 
 
 
 
3. 
STUDY POPULATION 
 
3.1. 
List the number of subjects to be enrolled. 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


Page 10 of 65 
Protocol Number / Version No. 2.0 / 5.10.2023 
 
All patients admitted to the medical ICU of Memorial Hermann Cypress and to the medical ICU of 
Memorial Hermann at the Texas medical Center will be screened for eligibility. There will be no 
restrictions based on the race of subjects. The study will not involve children as the investigators 
are only credentialed to treat adults aged 18 years and older. 
 
 
3.2. 
Criteria for Recruitment 
 
Patient will be screened to confirm they meet study criteria. Consent will be obtained from the legal 
authorized representative. 
 
3.3. 
Inclusion Criteria 
 
Patients will be enrolled only if they consented and they meet all of the inclusion criteria listed 
below. 
1. Patients 18 years or older 
2. Patients on IMV for more than 72 hours 
3. Patients infused Fentanyl or Hydromorphone for more than 72 hours 
4. Patients with evidence of reversal of process that caused respiratory failure, adequate 
oxygenation (PaO2/FIO2>200; Positive end expiratory pressure (PEEP)≤8 and Ph≥7.2 
5. Patients hemodynamically stable 
6. Patients with a failed single or multiple attempts at spontaneous breathing trials 
 
3.4. 
Exclusion Criteria 
All subjects meeting any of the exclusion criteria at baseline will be excluded from participation. 
 
1. Patients with history of opioid drug abuse 
2. Patients receiving schedule II narcotics on a chronic basis for longer than 6 months prior to 
ICU admission or on other analgesic infusions other than Fentanyl or Hydromorphone 
3. Patients with cervical spinal cord injury or neuromuscular disease 
4. Patients with end stage liver disease at ICU admission (ie, International normalized ratio 
≥2and not taking warfarin and/or a total serum bilirubin ≥1.5 times above normal limits 
5. Patients with prolonged QTc interval ≥500 
6. Patients with prior history of cardiac conduction defects or sudden death 
7. Patients with QTc increase of ≥60 milliseconds above the value of prior EKGs measured 
during current ICU admission 
8. 
Patients with more than 5 days on IV analgesia 
9. 
Patients intubated for more than 30 days 
10. Patients without feeding tubes 
11. Patients not receiving enteral feeding 
12. Exclusion of patients in a comatose state 
13. Exclusion of patients in Status Epilepticus 
14. Exclusion of post-operative patients 
 
 
3.5. 
Withdrawal Criteria 
The study will be discontinued after completion or upon recommendation from Data Safety and 
Monitoring board DSMB and with help from IRB. 
 
3.6. 
Subject Replacement 
Yes, Subjects who drop out will be replaced. 
 
 
4. 
TRIAL SCHEDULE 
 
 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


Page 11 of 65 
Protocol Number / Version No. 2.0 / 5.10.2023 
 
4.1 
Allocation 
 
All patients admitted to the medical ICU will be screened for eligibility. Group assignment will be 
done using the randomization module of the Research Electronic Data Capture (REDCap) 
platform. Patients will be randomized in a 1 to 1 ratio, using permuted blocks of 4 or 6, into one of 
two groups: methadone group and the Non-Methadone group. The randomization will be stratified 
based on location where patients will be recruited. 
 
4.2 
Interventions 
 
Pre-intervention period (1 month) 
 
The objective of this period is to standardize the process to improve familiarity to the investigators. 
Study procedures will be presented to the nurses by oral presentations, printed material, and by 
email. The information will include detailed explanation of the process of tapering methadone and 
weaning patients off opiates as stipulated in the study. It will also elaborate more on the process 
of managing patients that develop clinical opiate withdrawal symptoms. 
 
 
Intervention period 
 
 
Following randomization patients will be assigned to the MG or the NG group. For patients 
randomized to the MG a “non-formulary medication” order will be placed in the electronic medical 
record to alert nurses to follow the protocol for patients started on Methadone. For those in the 
NG group usual hospital protocol of weaning opioids will be followed. 
The study is completed for each patient once extubated or discharged from ICU, death, comfort 
care measures, or after 30 days of participation in the study. 
We will collect data regarding participants demographic characteristics, comorbidities, main 
admission diagnosis, use of mechanical ventilation and vasopressors, ICU and hospital LOS, ICU 
and hospital mortality. Vital signs, focused general examination, LFTs, with normal ICU standard 
of care will done. However, EKG will be done at baseline and on day 30 if patient is still on 
methadone. LFTs are only done at baseline. The duration of use of the medication is not expected 
to cause an increase in LFTs. The listed labs are the only additional labs other than what is usually 
ordered for standard care in ICU. The information will be collected by reviewing medical records 
and will be recorded in electronic form only, using REDCap. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


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Protocol Number / Version No. 2.0 / 5.10.2023 
 
5. 
STUDY DESIGN 
 
 
5.1. 
Summary of Study Design 
The study is randomized clinical trial. The duration of the study is 2 years. Patients will be 
screened to confirm they meet study criteria. Consent will be obtained from the legal authorized 
representative. Initial demographic data will be obtained using REDCap Database. Patients will 
be randomized to either Oral Methadone tablets or Non-Methadone group. The control group will 
receive usual care with IV Fentanyl or hydromorphone per hospital protocols as on appendix 1. 
Patients on the methadone group will be started on Methadone 5mg, 10mg or 15mg every 8 hours 
depending on Fentanyl drip rate (0-100mcg/hr, 100-200mcg/hr or >200mcg/hr) or hydromorphone 
drip rate (0-1.5mg/hr, 1.5-3mg/hr, or >3mg/hr). The rate of Fentanyl or hydromorphone will be 
reduced by 25% initially. If patients require additional sedation later, this will be administered per 
usual care and the total amount of additional opioids will be documented and used for analysis as 
morphine milligram equivalents (MME). Likewise, patients could be weaned more than 25% if they 
showed signs of tolerance to lesser sedation. 
At Subsequent encounters: Rate of Fentanyl or Hydromorphone drip will be reduced by 
25% every 24 hours until the patient is extubated from the ventilator. 
Continuous IV opioids for analgesia for patients on mechanical ventilation is routine clinical care 
and will not be denied to patients. Once patients are extubated oral methadone will be 
discontinued and patient monitored for any opioid withdrawal symptoms and treated per protocol 
as shown on appendix 2 based on their clinical opiate withdrawal scale (COWS) appendix 4. For 
those with a score of less than 25 oral methadone will no longer be required. For those with a 
COWS score of >25 methadone will be resumed for a short taper of 3 days. The above can be 
illustrated as on study protocol flow on Appendix 5 and details on methadone taper as on Appendix 
2. 
 
 
6. 
METHODS AND ASSESSMENTS 
 
Based on the assumptions of successful extubation by day 5 of 50% of patients in the 
methadone group and 20% of patients in the control group and using a two tailed alpha level of 
5%, a power of 80% our sample size calculation comparing proportions of two groups yielded 76. 
A 5% fallout as correction factor was 4 leaving us with a sample size of 80 patients. Statistical 
methods will include descriptive statistics and time to event analysis. Baseline characteristics will 
be reported. Data will be collected on a data collection sheet prior to transfer to REDCAPs 
database (Appendix 6). We will generate Kaplan-Meier curves and for comparison of hazard 
between groups we will use Cox regression (Cox proportional hazards model). Patients who die 
will be censored at time of death. Time of weaning will take into consideration only patients who 
were permanently disconnected from the ventilator. QTc values will be obtained from patient 
monitors and documented on data collection tool daily. 
Randomization tables will be generated using REDCAPs database by study statistician. 
At the end of the study recorded information from REDCAPs will be exported to STATA for 
statistical analysis. 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


Page 13 of 65 
Protocol Number / Version No. 2.0 / 5.10.2023 
 
6.1. 
Randomization and Blinding 
 
Patients will be randomized between two groups, the Methadone group (MG) and the Non- 
Methadone group (NG). Randomization tables will be generated using REDCap database. 
Randomization will be stratified by Center of data collection. The investigators evaluating the 
primary and secondary outcomes will be blinded to the group assignments. The study participants, 
pharmacists, physicians and nurses taking care of the patients will not be blinded. 
Assignment of patients to study groups will be by random allocation by randomization tables. 
There will be two randomization tables, one for Memorial Hermann Cypress and the other for 
Memorial Hermann Texas Medical Center. Patients predetermined to receive methadone will 
receive oral methadone which comes in 5mg tablets. Tablets will be crushed and administered via 
the feeding tube if patients are still on enteral feeding at the time the medication is administered. 
Patients predetermined not to receive methadone will continue treatment following usual care per 
hospital weaning protocols. 
 
 
6.2. 
Contraception and Pregnancy Testing 
Patients that are pregnant or have a positive pregnancy test or are on oral contraception will not 
be enroll into the study since they are a vulnerable population screened for eligibility. 
 
 
 
6.3. 
Storage and Drug Accountability 
Neither the Pharmacy nor the nursing staff will be accountable for the drugs. Pharmacy will 
dispense medication as normal physician order for drugs administered. Information on drug 
administered will be retrieved from patient records. 
 
 
 
 
7. 
TREATMENT 
 
7.1. 
Rationale for Selection of Dose 
Dose selection will be based on currently approved protocol which is attached as an appendix 2. 
 
 
 
 
 
7.2. 
Study Drug Formulations 
Drug will be dispensed to patients in form of oral tablets appendix 3. 
 
 
7.3. 
Study Drug Administration 
Drug to be used is Methadone. Warnings not to use the drug in patients with asthma, GI 
obstruction, paralytic ileus, renal impairment, hepatic impairment, pregnancy, debilitated patients, 
QT prolongation, Congestive heart failure, Seizures, alcohol abuse and CNSdepression. 
 
7.4. 
Specific Restrictions / Requirements 
Not applicable. 
 
 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


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Protocol Number / Version No. 2.0 / 5.10.2023 
 
7.5. 
Blinding 
 
The investigators evaluating the primary and secondary outcomes will be blinded to the 
group assignments. The study participants, pharmacists, physicians and nurses taking 
care of the patients will not be blinded. 
 
 
8. 
SAFETY MEASUREMENTS 
 
Any adverse events encountered will be documented in the patients’ chart once it is noted. These 
include QTc >500, high grade arrhythmias such as ventricular tachycardia, hypotension and 
elevated Liver function testing more than 2.5 times the upper limit of normal. 
 
8.1. 
Definitions 
Serious adverse events include persistent hypotension, persistently prolonged QTc, ileus, 
anaphylaxis and death. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-22-0689 
IRB APPROVAL DATE: 01/05/2024 


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8.2. 
Collecting, Recording and Reporting of Adverse Events 
The principal investigator will be responsible for accurate documentation, investigation and follow- 
up as well as timely reporting of the following: 
1- 
Any adverse event at the study site which in the opinion of the principal investigator is 
both unexpected and related and places subjects or others at risk of harm 
2- 
Information that indicates a change to the risks or potential benefits of the research 
3- 
An interim analysis or safety monitoring report indicates that frequency or magnitude of 
harms or benefits may be different than initially presented to the IRB 
4- 
A paper is published from another study that shows that the risks or potential benefits of 
the research may be different than initially presented to the IRB 
5- 
A breach of confidentiality 
6- 
Change in FDA labelling or withdrawal from marketing of a drug, device or biologic used 
in a research protocol 
7- 
Change to the protocol taken without prior IRB review to eliminate an apparent 
immediate hazard to a research participant 
8- 
Incarceration of a participant in a protocol not approved to enroll prisoners 
9- Event that requires prompt reporting to the sponsor 
10- Sponsor imposed suspension 
11- Complaint by a participant when the complaint indicates unexpected risks or cannot be 
resolved by the research team 
12- Protocol deviation meaning an accidental or unintentional change to IRB approved 
protocol) that harmed participants or others or that indicates that participants or others 
may be at increased risk of harm 
13- Unanticipated adverse device effect 
 
Nursing staff and physicians will be notified to look out for the above. Any identified adverse event 
will be reported to the study PI who will discuss and inform the study coordinator aboutit. 
 
The Principal investigator shall make a judgement about the expectedness of a problem. If the 
problem is an adverse event, the investigator shall make a judgement about the causality of the 
adverse event with respect to study intervention. The Principal investigator shall also evaluate 
whether protocol consent forms are needed. 
 
The Principal investigator shall state whether the problem is expected or unexpected. 
 
For adverse events the Principal Investigator shall evaluate the event and assess causality. He 
shall reveal evidence or arguments to suggest causal relationship 
 
The Principal Investigator shall report the reportable events described above to CPHS via iRIS 
as follow: All problems involving local deaths shall be reported immediately, within 24 hours after 
first knowledge by the investigator. All other problems shall be reported as soon as possible but 
not later than 7 calendar days after first knowledge by the investigator. 
 
Safety Monitoring Plan 
 
The research team will meet once every 3 months to review adverse events, protocol deviations 
and other problems encountered. We will work with IRB to create a data and safety monitoring 
board. A data safety monitoring board will be created and will meet once every quarter to assess 
study conduct and progress and determine continuity of the study. 
 
 
 
9. 
DATA ANALYSIS 
 
9.1. 
Data Quality Assurance 
 
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After physician or advanced care practitioner entry of information into patient database, research 
coordinator will verify information for accuracy and correctness. There will be no plans to have 
ongoing third-party monitoring. 
 
9.2. 
Data Entry and Storage 
Data will be entered electronically on REDCAPs data base. All information will be stored on 
UTHealth computers. 
 
10. 
SAMPLE SIZE AND STATISTICAL METHODS 
 
10.1. 
Determination of Sample Size 
Based on the assumptions of successful extubation by day 5 of 50% of patients in the methadone 
group and 20% of patients in the Non Methadone group and using a two tailed alpha level of 5%, 
a power of 80% our sample size calculation comparing proportions of two groups yielded 76. A 
5% fall out as correction factor was 4 leaving us with a sample size of 80 patients. 
 
10.2. 
Statistical and Analytical Plans 
 
Methadone when used at appropriate doses is considered safe and is an FDA approved 
medication. We will not be performing safety analysis. We will perform interim analysis after 
randomizing up to 50%(40) patients. Categorial variable will be compared using the student Chi- 
squared test and continuous variables will be compared using the T-test. Interim analysis will be 
performed by an independent statistician blinded for the treatment allocation. The statistician will 
report to the data safety and monitoring committee. The DSMB will discuss the results of the 
interim analysis with the statistician and a steering committee and in a joint meeting will decide on 
continuation of the trial. 
 
11. 
ETHICAL CONSIDERATIONS 
11.1. 
Informed Consent 
 
Consent will be obtained from legal authorized representatives while the patient in on mechanical 
ventilation and will be confirmed by the patient once extubated and sedation weaned in order for 
the patient to continue in the study. Consent forms and non-electronic data will be stored in 
protected locked storage in the office of the ICU Director while the research office will keep copies 
of the regulatory binders. A hospital translation phone will be used for communication with non- 
English speakers. 
 
 
 
11.2. 
IRB review 
Consent forms will be sent to IRB. 
 
11.3. 
Confidentiality of Data and Patient Records 
 
Patients records that will Include procedures for maintaining subject confidentiality, or any special 
data security requirements, and record retention will be kept secured. 
 
 
 
 
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12. 
PUBLICATIONS 
 
After Principal investigator or the Co-investigators enter the patients information into the 
patient database, research coordinator will verify information for accuracy and correctness. There 
will be no plans to have ongoing third-party monitoring. 
 
13. 
RETENTION OF TRIAL DOCUMENTS 
Records will be stored in ICU Directors office for Memorial Hermann Cypress and Dr. Sami 
Hossri's office in the Medical school will store documents for Memorial Hermann Texas Medical 
Center in secured case. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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List of Possible Attachments 
 
 
Reference 
 
Appendix 1 
 
Appendix 2 
ICU Sedation Weaning Protocol 
 
The Massachusetts General sedation weaning strategies 
 
 
 
Appendix 3 
 
Appendix 4 
 
Appendix 5 
 
Appendix 6 
Methadone tablet Packet insert 
Clinical Opiate Withdrawal Score 
Protocol Flow Diagram 
Data Collection Sheet 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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REFERENCE 
 
[1] A. Nasa, Impact of Enteral Methadone on the Ability to Wean Off Continuously Infused Opioids in Critically 
Ill, Mechanically Ventilated Adults: A Case-Control Study, vol. 46, The Annals of Pharmacotherapy, 
2012. 
[2] J. Jacobi, "Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill 
adult," Critical Care Medicine, pp. 119-41, 2002. 
[3] R. Chang, "COVID-19 ICU and mechanical ventilation patient characteristics and outcomes-A systematic 
review and meta-analysis," PloS One, vol. 16, no. 2, 2021. 
 
[4] R. Wanzuita, "Replacement of Fentanyl infusion by enteral methadone decreases the weaning time from 
mechanical ventilation: a randomized controlled trial," Critical Care, vol. 16, no. R49,2012. 
 
[5] Al-Qadheeb, Nada S, et al. “Impact of Enteral Methadone on the Ability to Wean off Continuously Infused 
Opioids in Critically Ill, Mechanically Ventilated Adults: A Case-Control Study.” Annals of 
Pharmacotherapy, vol. 46, no. 9, 2012, pp. 1160–1166, doi:10.1345/aph.1r132. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1 
 
ICU Sedation Weaning Protocol 
 
 
Fentanyl 1000microgram in 20mls of Normal saline 
 
Start dose: 50microgram per hour, 
 
Titration: 25microgram per hour every 15minutes, maximum dose: 200microgram per hour 
 
Route: Intravenous 
 
May Rebolus fentanyl 25micrograms IV addition to each infusion increase 
Notify the physician when the dose of 200 micrograms per hour is reached. 
 
 
Hydromorphone 50mg in NS 50ml Titrate Intravenous 
50mg, 50ml, Start Dose: 0.2mg/hr. 
Titration: 0.2mg/hr. every 15min, 
 
Maximum Dose: 5mg/hr. 
 
Route: Intravenous 
 
Final Concentration =1mg/ml 
 
Total volume=50ml 
 
Contact the physician if the dose of 5mg/hr. is reached. 
Use similar dosing for titrating up or down 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2 
The Massachusetts General sedation weaning strategies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2 
 
 
 
 
 
 
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Appendix 2 
 
 
 
 
 
 
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2.6 Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction 
2.7 Titration and Maintenance Treatment of Opioid Dependence 
2.8 Medically Supervised Withdrawal after a Period of Maintenance Treatment for Opioid Addiction 
2.9 Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction 
2.10 Considerations for Management of Acute Pain during Methadone Maintenance Treatment 
2.11 Dosage Adjustment during Pregnancy 
 
3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 
5 WARNINGS AND PRECAUTIONS 
 
5.1 Addiction, Abuse and Misuse 
5.2 Life-Threatening Respiratory Depression 
5.3 Life-Threatening QT Prolongation 
5.4 Neonatal Opioid Withdrawal Syndrome 
5.5 Risks of Concomitant Use of Cytochrome P450 3A4, 2B6, 2C19, 2C9, or 2D6 Inhibitors or Discontinuation of P450 3A4, 2B6, 2C19, or 2C9 Inducers 
5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants 5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary 
Disease or in Elderly, Cachectic, or Debilitated Patients 
5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs 
 
FULL PRESCRIBING INFORMATION 
 
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide 
Revised: 02/2018 
5.9 Adrenal Insufficiency 
5.10 Severe Hypotension 
5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness 
5.12 Risks of Use in Patients with Gastrointestinal Conditions 
5.13 Increased Risk of Seizures in Patients with Seizure Disorders 
5.14 Withdrawal 
5.15 Risks Driving and Operating Machinery 
5.16 Laboratory Test Interactions 
 
6 ADVERSE REACTIONS 
7 DRUG INTERACTIONS 
8 USE IN SPECIFIC POPULATIONS 
 
8.1 Pregnancy 
8.2 Lactation 
8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 
8.5 Geriatric Use 
8.6 Hepatic Impairment 
8.7 Renal Impairment 
 
9 DRUG ABUSE AND DEPENDENCE 
 
9.1 Controlled Substance 9.2 Abuse 
9.3 Dependence 
 
10 OVERDOSAGE 
11 DESCRIPTION 
12 CLINICAL PHARMACOLOGY 
 
12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 
 
13 NONCLINICAL TOXICOLOGY 
 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
 
16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION MEDICATION GUIDE 
PACKAGE/LABEL PRINCIPAL DISPLAY PANEL PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 
 
*Sections or subsections omitted from the full prescribing information are not listed. 
 
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Appendix 4 
 
 
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Initiate Oral Methadone dosing 
as on appendix 2 
Patient Extubated 
Opiate infusion discontinued 
Wean Fentanyl or 
Hydromorphone per usual care 
as on appendix 1 
Patient Extubated 
Discontinue Opiate infusion 
Evaluate for signs of Clinical 
Opiate Withdrawal (COWS) 
Appendix 4 
Appendix 5 
 
 
Protocol Flow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 6 
IRB NUMBER: HSC-MS-22-0689 
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COWS<25 
Continue 
Usual Care 
COWS>25 
then start 
methadone 
taper as on 
Appendix 2 
Control Group 
Patient Enrolled and 
Randomized in Study 
Methadone Group 


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Data Collection Tool 
 
Patient Identification Code (MRN): 
 
Baseline Characteristics 
Age (years) 
Sex 
Race 
Weight (Kg) 
Duration on ventilator at time of 
randomization (Hours) 
Cause of Lung injury 
Pneumonia = 1 
Aspiration = 2 
Non-Pulmonary Sepsis = 3 
COPD Exacerbation = 4 
Other Causes = 5 
Assessments and Measurements 
APACHE II Score 
Total SOFA Score 
Tidal Volume ml/kg of predicted 
body weight 
Peep at time of enrollment (cm H2O) 
PaO2: FIO2 ratio (mmHg) 
FiO2 at time of enrollment 
Duration on mechanical ventilation 
before start of weaning(hours) 
Last recorded Ph prior to enrollment 
Duration in ICU stay after enrollment 
(Hours) 
Mean QTc while on Methadone 
Clinical Opiate Withdrawal Scale 
(COWS) after extubation 
Adverse Event 
Medication Parameters 
Fentanyl Initial Dose (mcg/hour) 
Fentanyl accumulated dose(mcg) 
Days on Fentanyl before start of 
weaning 
Hydromorphone initial Dose 
(mg/hour) 
Hydromorphone accumulated 
dose(mg) 
Days on Hydromorphone before 
start of weaning 
Dexmedetomidine accumulated 
dose(mcg) 
Midazolam accumulated dose(mg) 
Propofol accumulated dose (mg) 
Ketamine accumulated dose (mg) 
 
 
 
 
 
 
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