RECLAIM: Recovering From COVID-19 Lingering Symptoms Adaptive Integrative Medicine (RECLAIM)

• ClinicalTrials.gov Identifier: NCT05513560
• Recruitment Status: Recruiting
• First Posted: August 24, 2022
• Last Update Posted: October 2, 2023
• Sponsor: University Health Network, Toronto
• Information provided by (Responsible Party): University Health Network, Toronto

Tracking Information

• First Submitted Date: August 22, 2022
• First Posted Date: August 24, 2022
• Last Update Posted Date: October 2, 2023
• Actual Study Start Date: May 31, 2023
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 22, 2022)

SF-36 physical component score (PCS) [ Time Frame: from baseline to two months ]

mean change in the SF-36 (v.1) physical component score (PCS)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 12, 2022)

• Symptoms scale [ Time Frame: Baseline/Randomization weekly to 2 months, then once monthly to 6 months. ]
  Three point Likert scale assessing how bothersome symptoms are on a weekly basis for two months then monthly until end of study, as reported by the participant: to provide a granular, detailed picture of the symptom trajectory.
• Symptom Checklist [ Time Frame: Baseline/Randomization weekly to 2 months, then once monthly to 6 months. ]
  Symptom Checklist (adapted from the De Paul Symptom Questionnaire (DSQ2), the World Health Organization Global COVID-19 Clinical Platform's Post COVID-19 CRF and the Symptom Burden Questionnaire for Long COVID): to track symptom trajectory.
• Six Minute Walking Test (6MWT) with oximetry [ Time Frame: Baseline/Randomization and 2 months ]
  Subjects walk as far as they can in six minutes while receiving maximum encouragement. It is simple to execute, inexpensive, standardized and gives a tangible measure of functional exercise capacity. It has been validated in many different populations. The 6MWT will be conducted according to American Thoracic Society standards.
• TestMyBrain cognitive testing [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  TestMyBrain was developed as a tool to collect large, population-based samples for understanding the relationship between cognition, emotion, social functioning, and health. This test battery will take about 20 minutes to complete and will assess: verbal, episodic and working memory, attention, processing speed, basic psychomotor response speed, and cognitive control.
• Post COVID19 functional status scale [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The post-COVID-19 functional status (PCFS) scale focuses on relevant aspects of daily life during follow-up after the infection. The scale is intended to help users become aware of current functional limitations in COVID-19 patients, whether or not as a result of the specific infection, and to objectively determine this degree of disability. The scale is ordinal, has 6 steps ranging from 0 (no symptoms) to 5 (death), and covers the entire range of functional outcomes by focusing on limitations in usual duties/activities either at home or at work/study, as well as changes in lifestyle. The PCFS demonstrates good construct validity.
• Reintegration to Normal Living Index (RNLI) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  This short self-administered assessment tool will determine the degree to which participants reintegrate into normal social activities such as recreation, mobility in the community and interaction in family and other relationships. This tool has been validated in community living adults with mobility limitations.
• Fatigue Scale [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The Fatigue Scale was adapted from the De Paul Symptom Questionnaire (DSQ2)'s 38 questions assessing medical history of Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS), comorbidities, medications, impact on quality of life and daily activities, etc.
• Brief Fatigue inventory [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The self-administered Brief Fatigue Inventory is composed of 9 items evaluated on a 10-point scale, assessing severity of fatigue and impact of fatigue on daily life. It takes approximately 2-3 minutes to complete.
• Post-Exertional Malaise [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The self-administered DPEMQ is comprised of three sections assessing post-exertional malaise (PEM): (i) onset and triggers of PEM (9 questions), (ii) consequences and symptoms (14 questions), (iii) duration, recovery and pacing (7 questions).
• Mental Health - Post-traumatic Stress Disorder Checklist (PCL-5) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The PCL-5 is a validated, reliable, 20-item self-report measure that assesses the 20 Diagnostic and Statistical Manual 5 (DSM-5) symptoms of Post-Traumatic Stress Disorder (PTSD). It takes approximately 5-10 minutes to complete.
• Mental Health - General Anxiety Assessment Form (GAD-7) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The GAD-7 is a valid and efficient tool for screening for generalized anxiety disorder and assessing its severity in clinical practice and research. It is an easy-to-use, self-administered patient questionnaire that can be completed in minutes.
• Mental Health - Patient Health Questionnaire (PHQ-9) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The PHQ-9 is a validated, multipurpose instrument for screening, diagnosing, monitoring and measuring the severity of depression. It incorporates Diagnostic and Statistical Manual 1V (DSM-IV) depression diagnostic criteria with other leading major depressive symptoms into a brief self-report tool. The PHQ-9 is brief and useful in clinical practice. The PHQ-9 is completed by the patient in minutes and is rapidly scored by the clinician. The PHQ-9 can also be administered repeatedly, which can reflect improvement or worsening of depression in response to treatment.
• Mental Health Composite score (MCS) of the SF-36 [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The self-administered SF-36 evaluates eight health concepts: physical functioning, role functioning-physical, bodily pain, general health, vitality, social functioning, role functioning-emotional, and mental health. Previous studies have used this instrument in many different populations and it takes approximately 15 minutes to complete.
• Dyspnea [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  Assessed using the Borg Dyspnea scale. This short assessment tool assesses perceived shortness of breath on exertion using a 10 point scale as assessed by the patient.
• Blood samples [ Time Frame: Baseline/Randomization and 2 months ]
  Blood samples will be used in correlative studies using advanced multi-omic and machine learning methods to better understand our results so as to identify phenotypes that will benefit from specific therapies

Original Secondary Outcome Measures (submitted: August 22, 2022)

• Global Symptom Scale [ Time Frame: Baseline/Randomization weekly to 2 months, then once monthly to 6 months. ]
  Three point Likert scale assessing whether symptoms are improved, no change or worsened from baseline.
• Symptom Checklist [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  Adapted from the De Paul Symptom Questionnaire (DSQ2), the World Health Organization Global COVID-19 Clinical Platform's Post COVID-19 case report form and the Symptom Burden Questionnaire for Long COVID.
• Six Minute Walking Test (6MWT) with oximetry [ Time Frame: Baseline/Randomization and 2 months ]
  Subjects walk as far as they can in six minutes while receiving maximum encouragement. It is simple to execute, inexpensive, standardized and gives a tangible measure of functional exercise capacity. It has been validated in many different populations. The 6MWT will be conducted according to American Thoracic Society standards.
• TestMyBrain cognitive testing [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  TestMyBrain was developed as a tool to collect large, population-based samples for understanding the relationship between cognition, emotion, social functioning, and health. This test battery will take about 20 minutes to complete and will assess: verbal, episodic and working memory, attention, processing speed, basic psychomotor response speed, and cognitive control.
• Post COVID19 functional status scale [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The post-COVID-19 functional status (PCFS) scale focuses on relevant aspects of daily life during follow-up after the infection. The scale is intended to help users become aware of current functional limitations in COVID-19 patients, whether or not as a result of the specific infection, and to objectively determine this degree of disability. The scale is ordinal, has 6 steps ranging from 0 (no symptoms) to 5 (death), and covers the entire range of functional outcomes by focusing on limitations in usual duties/activities either at home or at work/study, as well as changes in lifestyle. The PCFS demonstrates good construct validity.
• Reintegration to Normal Living Index (RNLI) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  This short self-administered assessment tool will determine the degree to which participants reintegrate into normal social activities such as recreation, mobility in the community and interaction in family and other relationships. This tool has been validated in community living adults with mobility limitations.
• Fatigue Scale (adapted from the De Paul Symptom Questionnaire (DSQ2)) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The Fatigue Scale was adapted from the De Paul Symptom Questionnaire (DSQ2)'s 38 questions assessing medical history of Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS), comorbidities, medications, impact on quality of life and daily activities, etc.
• DePaul Post-Exertional Malaise Questionnaire (DPEMQ) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The self-administered DPEMQ is comprised of three sections assessing post-exertional malaise (PEM): (i) onset and triggers of PEM (9 questions), (ii) consequences and symptoms (14 questions), (iii) duration, recovery and pacing (7 questions).
• Brief Fatigue Inventory [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The self-administered Brief Fatigue Inventory is composed of 9 items evaluated on a 10-point scale, assessing severity of fatigue and impact of fatigue on daily life. It takes approximately 2-3 minutes to complete.
• Post-traumatic Stress Disorder Checklist (PCL-5) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The PCL-5 is a validated, reliable, 20-item self-report measure that assesses the 20 Diagnostic and Statistical Manual 5 (DSM-5) symptoms of Post-Traumatic Stress Disorder (PTSD). It takes approximately 5-10 minutes to complete.
• General Anxiety Assessment Form (GAD-7) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The GAD-7 is a valid and efficient tool for screening for generalized anxiety disorder and assessing its severity in clinical practice and research. It is an easy-to-use, self-administered patient questionnaire that can be completed in minutes.
• Patient Health Questionnaire (PHQ-9) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The PHQ-9 is a validated, multipurpose instrument for screening, diagnosing, monitoring and measuring the severity of depression. It incorporates Diagnostic and Statistical Manual 1V (DSM-IV) depression diagnostic criteria with other leading major depressive symptoms into a brief self-report tool. The PHQ-9 is brief and useful in clinical practice. The PHQ-9 is completed by the patient in minutes and is rapidly scored by the clinician. The PHQ-9 can also be administered repeatedly, which can reflect improvement or worsening of depression in response to treatment.
• BORG Dyspnea scale [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  This short assessment tool assesses perceived shortness of breath on exertion using a 10 point scale as assessed by the patient.
• Medical Outcomes Study Short Form -36 Questionnaire (SF-36) [ Time Frame: Baseline/Randomization to 1, 2 months 3 and 6 months ]
  The self-administered SF-36 evaluates eight health concepts: physical functioning, role functioning-physical, bodily pain, general health, vitality, social functioning, role functioning-emotional, and mental health. Previous studies have used this instrument in many different populations and it takes approximately 15 minutes to complete.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: August 22, 2022)

Blood samples [ Time Frame: Baseline/Randomization and 2 months ]

Blood samples will be used in correlative studies using advanced multi-omic and machine learning methods to better understand our results so as to identify phenotypes that will benefit from specific therapies

Descriptive Information

• Brief Title: RECLAIM: Recovering From COVID-19 Lingering Symptoms Adaptive Integrative Medicine
• Official Title: REcovering From COVID-19 Lingering Symptoms Adaptive Integrative Medicine (RECLAIM)

Brief Summary

The researchers propose to develop a Canada-wide, adaptive randomized clinical platform trial to assess the effectiveness of various interventions in patients with lingering symptoms of COVID-19 ("Long COVID"). Participants will be randomized initially to 1 of 3 arms, including placebo (control) and 2 interventions. Because this is an adaptive trial, arms can be dropped if found to be ineffective and new arms can be added.

Interventions will last for 2 months and participants will be followed for an additional 4 months (6 months total). Approximately 800-1000 patients with Long COVID will be recruited across Canada. Results from this trial will accelerate the availability of high-quality, real-time evidence and solutions to enable Canada to improve the clinical care of patients with Long COVID.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

RECLAIM is a Canada-wide phase ll/lll, prospective, adaptive randomized controlled platform trial that is intended to study various interventions for patients with long COVID. Interventional arms may be discontinued based on interim analysis results and new interventions may be selected and included as part of the platform as the trial progresses. As such, the protocol and consent documents are a modular design including;

• Master Protocol and informed consent documents: Contain information applicable to the whole platform.
• Interventional Sub-Protocols: Contain additional information, specific to the interventional arm.

Interventional Sub-Protocols may be modified, discontinued, or added without revisions to the Master Protocol.

Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:

Participants are blinded to intervention in so far as the labelling of the study intervention. However, it is possible that the participant may figure out allocation arm, by the mode of administration, dosing frequency (once a day versus 3 times per day), and treatment form (pill, powder, intervention) etc.

Primary Purpose: Treatment

Condition

• Long COVID
• Post COVID Condition
• Post Acute Sequelae of COVID-19

Intervention

• Drug: Ibudilast
  10mg pills, 2 pills twice per day
  Other Name: MN-166
• Drug: Pentoxifylline
  400mg pill 3 times per day
• Other: Placebo
  Placebo matching ibudilast, 2 pills twice per day OR placebo matching pentoxifylline 1 pill 3 time per day.

Study Arms

• Experimental: IBUDILAST
  Participants will receive 20 mg dose (2 pills) twice per day taken by mouth.
  Intervention: Drug: Ibudilast
• Experimental: PENTOXIFYLLINE
  Participants will receive a 400mg dose (1 pill) 3 times per day taken by mouth.
  Intervention: Drug: Pentoxifylline
• Placebo Comparator: PLACEBO
  Participants will receive 2 placebo pills twice per day taken by mouth OR 1 placebo pill 3 times a day taken by mouth.
  Intervention: Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 22, 2022): 1000
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age ≥18 years;
2. Positive COVID-19 test by nasopharyngeal swab RT-PCR (reverse transcription polymerase chain reaction) test, antibody or antigen tests at least 3 months prior to randomization; OR Presumed COVID-19 assessed by the site investigator (no positive COVID-19 test) with acute illness after October 15, 2019.
3. Patients should be treated with standard of care therapies (as discussed in the study manual) for at least 4 weeks prior to entry into trial.
4. Lingering COVID-19 symptoms beyond 3 months from onset of acute COVID and symptoms have lasted at least 2 months. The onset of COVID is considered the earliest of two dates: the date of positive test or the date of first symptoms;
5. Lingering symptoms from COVID-19 present at the time of randomization.
6. Female patients of childbearing potential (as assessed by the overseeing Investigator) who are sexually active must agree to practice true abstinence or use effective methods of contraception while on study treatment. Effective methods of contraception must be discussed and approved by the overseeing Investigator.
7. Must be able to provide informed consent and both willing and able to comply with study requirements.

Exclusion Criteria:

1. Patients who had mechanical ventilation or extracorporeal membrane oxygen (ECMO) for COVID-19;
2. Current end-organ failure, organ transplantation, or current hospitalization in acute care hospital;
3. Contraindications to all of the study interventions;
4. Co-enrolment in another interventional trial (co-enrolment in an observational study is permitted);
5. Currently pregnant or breastfeeding.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Judy Scher, MSc, CCRC; 416-340-4841; RECLAIM@uhn.ca

Contact: Jeevitha Srighanthan, BSc, MSc; 416-340-4841; RECLAIM@uhn.ca

• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT05513560
• Other Study ID Numbers: 21-6203
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: University Health Network, Toronto
• Original Responsible Party: Same as current
• Current Study Sponsor: University Health Network, Toronto
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Angela M Cheung, MD,PhD; University Health Network, Toronto
• Principal Investigator: George Tomlinson, PhD; University Health Network, Toronto
• Principal Investigator: Peter Juni, MD, PhD; Oxford University, UK

• PRS Account: University Health Network, Toronto
• Verification Date: September 2023