Ibudilast + Pentoxifylline for Long COVID

(RECLAIM Trial)

Not currently recruiting at 2 trial locations

Overseen By Angela M Cheung, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University Health Network, Toronto

Disqualifiers: Mechanical ventilation, Organ failure, Transplantation, Hospitalization, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests treatments for Long COVID, characterized by lingering symptoms that persist for months after a COVID-19 infection. Participants will be divided into groups to receive either Ibudilast (a potential treatment for inflammation), Pentoxifylline (a drug that improves blood flow), or a placebo. The goal is to determine which treatment best eases ongoing symptoms. Suitable candidates for this trial are individuals who had COVID-19 and continue to experience symptoms like fatigue or brain fog at least three months later. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering hope for effective relief.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be on standard of care therapies for at least 4 weeks before joining the trial.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that patients should be treated with standard of care therapies for at least 4 weeks before joining the trial, which suggests you may need to continue your current treatments.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier studies tested Ibudilast on patients hospitalized with COVID-19 to assess its effect on severe lung issues. These studies are ongoing, but so far, Ibudilast has generally been well-tolerated, with no major side effects reported. This suggests it might be safe for use.

Research on Pentoxifylline in hospitalized COVID-19 patients showed it did not improve health outcomes. However, it did not cause specific harmful effects, indicating that Pentoxifylline is also likely safe.

Both treatments have shown safety in previous studies, but more research is needed to confirm these results. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments Ibudilast and Pentoxifylline for Long COVID because they offer new approaches compared to standard care options like supportive therapies and symptom management. Ibudilast is unique due to its action as a phosphodiesterase inhibitor, which may reduce inflammation in the brain and nervous system—offering potential relief for neurological symptoms of Long COVID. Pentoxifylline also stands out because it improves blood flow and has anti-inflammatory properties, which could help alleviate some cardiovascular and fatigue-related symptoms. These distinct mechanisms of action provide hope for more targeted relief for Long COVID sufferers.

What evidence suggests that this trial's treatments could be effective for Long COVID?

Research suggests that ibudilast, which participants in this trial may receive, might aid Long COVID recovery by reducing inflammation and supporting nerve health. Some studies have shown it can help COVID-19 patients recover, but more research is needed to confirm its effects specifically for Long COVID.

Pentoxifylline, another treatment option in this trial, has been studied for its ability to reduce inflammation in COVID-19 cases. It has shown promise in shortening hospital stays and improving inflammation levels. However, its exact effects on Long COVID symptoms remain under investigation. This trial tests both treatments to determine their potential in addressing the ongoing effects of the virus. ^{1 6 7 8 9}

Who Is on the Research Team?

Peter Juni, MD, PhD

Principal Investigator

Oxford University, UK

Angela M Cheung, MD,PhD

Principal Investigator

University Health Network, Toronto

George Tomlinson, PhD

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

Adults over 18 with Long COVID symptoms persisting for more than 3 months since the earliest of a positive test or symptom onset, and who have been symptomatic for at least 2 months. Participants must have tried standard care therapies for 4 weeks, be able to consent, follow study rules, and if capable of childbearing, agree to use approved contraception methods. Excludes those who had severe COVID requiring mechanical ventilation or ECMO, current severe organ failure or transplant patients.

Inclusion Criteria

I have had COVID-19 symptoms for more than 3 months since I first got sick.

I have been on standard cancer treatment for at least 4 weeks.

Must be able to provide informed consent and both willing and able to comply with study requirements

Exclusion Criteria

I cannot undergo any of the treatments offered in this study due to health reasons.

I was on a ventilator or ECMO for COVID-19 treatment.

I do not have organ failure, haven't had an organ transplant, and am not in the hospital.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive one of the interventions or placebo for 2 months

8 weeks

Weekly visits (in-person or virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

16 weeks

Monthly visits (in-person or virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Ibudilast
• Pentoxifylline
• Placebo
• Whey Protein Isolate

Trial Overview

The RECLAIM trial is testing Ibudilast and Pentoxifylline against a placebo in Canadian patients with Long COVID. It's an adaptive trial that can modify its arms based on effectiveness results during the process. Treatment lasts two months with four additional months of follow-up to evaluate recovery from lingering symptoms.

How Is the Trial Designed?

Group I: PENTOXIFYLLINE Experimental Treatment 1 Intervention

Participants will receive a 400mg dose (1 pill) 3 times per day taken by mouth.

Group II: IBUDILAST Experimental Treatment 1 Intervention

Participants will receive 20 mg dose (2 pills) twice per day taken by mouth.

Group III: PLACEBO Placebo Group 1 Intervention

Participants will receive 2 placebo pills twice per day taken by mouth OR 1 placebo pill 3 times a day taken by mouth.

Ibudilast is already approved in Japan, United States for the following indications:

Approved in Japan as Ibudilast for:

• Bronchial asthma
• Cerebral vasospasm following subarachnoid hemorrhage

Approved in United States as MN-166 for:

• Multiple sclerosis
• Amyotrophic lateral sclerosis (ALS)
• Progressive multiple sclerosis
• Neuropathic pain

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

Sarcopenia and muscle wasting are expected to increase in older adults due to COVID-19 hospitalizations and lockdowns, driven by factors like physical inactivity and poor diet.

Supplementing meals with whey protein-enriched enteral products, which provide 3-5 g of leucine, can effectively stimulate muscle protein synthesis in older adults, potentially helping to mitigate the risk of sarcopenia during prolonged periods of inactivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mTOR1c Activation with the Leucine "Trigger" for Prevention of Sarcopenia in Older Adults During Lockdown. Mai, K., Cando, P., Trasino, SE.[2022]

Whey protein concentrate significantly improved lung damage caused by methotrexate in rats and inhibited key interactions related to SARS-CoV-2, suggesting its potential as a protective agent against COVID-19-related lung injury.

The study indicates that whey proteins may enhance treatment strategies for COVID-19, especially in patients with pre-existing lung conditions, due to their various health benefits including antiviral and immunomodulating properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibitory effect of whey protein concentrate on SARS-CoV-2-targeted furin activity and spike protein-ACE2 binding in methotrexate-induced lung damage. Tufan, E., Sivas, GG., Gürel-Gökmen, B., et al.[2022]

The combination of fluticasone furoate (FF) and vilanterol trifenatate (VI) offers a once-daily dosing option for asthma management, which may improve patient adherence compared to traditional twice-daily inhalers.

Clinical studies show that FF/VI at doses of 100/25µg and 200/25µg provide similar improvements in lung function and asthma control as the twice-daily combination of fluticasone propionate and salmeterol, with comparable side effect rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluticasone furoate and vilanterol trifenatate combination therapy for the treatment of asthma. Gray, EL., Chang, V., Thomas, PS.[2022]

The combination of umeclidinium bromide and vilanterol, administered as a once-daily inhaled therapy, was found to be safe and well-tolerated in a study involving healthy Japanese volunteers, with no significant adverse effects compared to individual treatments.

Both drugs were rapidly absorbed and eliminated, with umeclidinium showing a Tmax of 5 minutes and vilanterol also at 5 minutes, indicating quick onset of action, although pharmacokinetic interactions between the two drugs were inconclusive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability, pharmacodynamics and pharmacokinetics of umeclidinium and vilanterol alone and in combination: a randomized crossover trial. Kelleher, DL., Mehta, RS., Jean-Francois, BM., et al.[2021]

Combining interferon-beta1b (IFN-beta1b) with the phosphodiesterase inhibitor pentoxifylline (PTX) may reduce early side effects in patients with relapsing-remitting multiple sclerosis (RRMS), as patients receiving both treatments reported fewer side effects compared to those on IFN-beta1b alone.

The combination therapy also showed a synergistic effect in regulating cytokine levels, leading to increased interleukin-10 (IL-10) expression, which could help restore the immune balance in MS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic immunomodulatory effects of interferon-beta1b and the phosphodiesterase inhibitor pentoxifylline in patients with relapsing-remitting multiple sclerosis. Weber, F., Polak, T., Günther, A., et al.[2015]

In a study involving 70 patients with cancer-associated anorexia and cachexia, pentoxifylline did not improve appetite or weight gain, indicating it may not be effective for this condition.

The drug was well-tolerated and did not cause any toxicity, suggesting it is safe to use, but ultimately, it did not provide the expected therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pentoxifylline for treatment of cancer anorexia and cachexia? A randomized, double-blind, placebo-controlled trial. Goldberg, RM., Loprinzi, CL., Mailliard, JA., et al.[2022]

In a study of 22 patients with COPD over 16 weeks, pressurized whey supplementation significantly improved exercise tolerance, as evidenced by increased cycle endurance test times after combining with exercise training.

Both groups showed improvements in quality of life measures, but the whey group had additional benefits in reducing fatigue and enhancing emotional control, suggesting that whey supplementation can enhance the effects of exercise training in COPD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined effect of dietary supplementation with pressurized whey and exercise training in chronic obstructive pulmonary disease: a randomized, controlled, double-blind pilot study. Laviolette, L., Lands, LC., Dauletbaev, N., et al.[2022]

New ultra-long-acting β-agonists (ultra-LABAs) like indacaterol, vilanterol, olodaterol, and abediterol have been developed to provide over 24 hours of bronchodilation for asthma patients, potentially improving treatment adherence.

These ultra-LABAs have shown a good safety profile, but currently, there is insufficient data to recommend any specific ultra-LABA combined with inhaled corticosteroids as a preferred treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next generation beta adrenoreceptor agonists for the treatment of asthma. Crisafulli, E., Frizzelli, A., Fantin, A., et al.[2018]

Beta-lactoglobulin (BLG), derived from bovine whey, is considered safe for consumption as a novel food ingredient, with no adverse effects observed in toxicity studies at doses up to 1,000 mg/kg body weight per day.

The nutritional profile of BLG is similar to whey protein isolate, and its intake levels for children are below the recommended protein intake, indicating it can be safely included in various food products without raising health concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Beta-lactoglobulin as a Novel food pursuant to Regulation (EU) 2015/2283. Turck, D., Bohn, T., Castenmiller, J., et al.[2022]

In a double-blind, placebo-controlled crossover study involving 48 patients with bronchospastic disease, the long-acting bronchodilator 'Nethaprin Dospan' significantly improved lung function, as measured by FEV1 and vital capacity (VC).

Patients reported better sleep, improved appetite, and reduced cough symptoms while using the active medication compared to the placebo, indicating its efficacy in enhancing overall quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind trial of a long-acting bronchodilator preparation ("Nethaprin Dospan") in bronchospastic disease. Kagan, G., Rose, R.[2019]

The EFSA Panel concluded that whey basic protein isolate from skimmed cow's milk is safe for human consumption, including its use in infant formulas and food supplements, based on a review of its safety in 2018.

The Panel determined that extending the use of whey basic protein isolate in infant formulas and food supplements would not increase the potential intake beyond previously assessed levels, confirming its safety at these new proposed uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of whey basic protein isolate for extended uses in foods for special medical purposes and food supplements for infants pursuant to Regulation (EU) 2015/2283. Turck, D., Castenmiller, J., de Henauw, S., et al.[2020]

Olodaterol is a long-acting beta2 agonist (LABA) approved for once-daily use as a maintenance treatment for chronic obstructive pulmonary disease (COPD), making it the third LABA available in the UK for this purpose.

The review evaluates whether olodaterol provides any advantages over existing LABAs like indacaterol and vilanterol, which are used in combination therapies for COPD management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

▼Olodaterol--another LABA for COPD. [2016]

Pentoxifylline (PTX) effectively prevents muscle atrophy and reduces protein breakdown in cancer cachexia by inhibiting the activation of the ubiquitin-proteasome pathway, as demonstrated in a study with Yoshida sarcoma-bearing rats.

PTX is a well-tolerated drug in humans that could be valuable for cachectic patients, as it suppresses the effects of tumor necrosis factor, which is linked to muscle wasting in conditions like cancer, sepsis, and trauma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of 20S and 26S proteasomes in muscles from tumor-bearing rats. Combaret, L., Rallière, C., Taillandier, D., et al.[2019]

In a study of 50 patients undergoing long-term pentoxifylline therapy, 27 patients successfully weaned off the medication without experiencing symptomatic deterioration, indicating that long-term therapy can be safely reduced.

However, 60% of those who weaned successfully showed asymptomatic declines in walking performance, suggesting that while patients may not feel worse, their objective measures of claudication could still decline, which does not necessarily require resuming therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pentoxifylline therapy for chronic claudication: are patients dependent on therapy? Johnson, WC., Watkins, MT., Hamilton, J., et al.[2013]

In a study of 40 metastatic colon cancer patients undergoing chemotherapy, those treated with pentoxifylline (PTX) experienced significant weight gain and reduced stomatitis, leading to improved quality of life.

The beneficial effects of PTX were linked to significant decreases in inflammatory cytokines and tumor markers, suggesting that PTX may help mitigate cancer-related cachexia and inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PTX Treatment of Colon Cancer: Mode of Action Based on Tumor Marker and Cytokine Kinetics. Meirovitz, A., Baider, L., Peretz, T., et al.[2022]

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