Optimizing DMF and MMF Clinical Trials: Managing Flushing with Aspirin

Dimethyl fumarate (DMF) is a medication used primarily to treat relapsing forms of multiple sclerosis (MS). Monomethyl fumarate (MMF) is a derivative of fumaric acid that contains a single methyl group attached to the fumarate backbone. They belong to a class of drugs known as fumaric acid esters. DMF works by modulating the immune system, although its exact mechanism of action in treating MS is not fully understood. MMF itself has been explored for potential therapeutic use, but it is primarily significant as a metabolite of DMF in the context of pharmacokinetics and pharmacodynamics, and MMF showed improved gastrointestinal (GI) tolerability in terms of incidence, severity, and duration.

The major challenge in DMF and MMF clinical trials is the dropouts due to adverse events (AEs). DMF and MMF are noted with flushing (e.g., warmth, redness, itching, and/or burning sensation) and gastrointestinal symptoms which is observed in up to 40% of patients treated with DMF and causes the discontinuation of 3% of patients. Managing AEs like flushing in DMF/MMF clinical trials is crucial for the success of clinical trials Co-administration with food seems to reduce flushing events for DMF but not with MMF. Alternatively, administration of non-enteric coated aspirin (ASA) (up to a dose of 325 mg) 30 minutes before DMF and MMF dosing may reduce the incidence or severity of flushing.

At BioPharma Services, we understand the challenges sponsors face in ensuring patient comfort and trial efficiency. This blog explores how aspirin co-administration can mitigate flushing, enhancing patient retention and data quality in your studies.

Aspirin (ASA) inhibits cyclooxygenase enzymes (COX-1 and COX-2), leading to reduced prostaglandin production. DMF-induced flushing is thought to be mediated by prostaglandins, particularly (PGE2), which cause vasodilation and flushing; clinical trial results indicated that ASA pretreatment may mitigate flushing associated with DMF, with no adverse effect on GI events. Moreover, ASA is widely used for its antiplatelet effects in preventing cardiovascular events such as heart attacks and strokes. If a patient with multiple sclerosis (MS) treated with DMF also has cardiovascular risk factors, co-administration of ASA might provide additional cardiovascular protection. Many neurologists and healthcare providers may consider using aspirin as part of a strategy to manage DMF-induced flushing, especially in patients who experience significant discomfort or intolerance to flushing. Administration ASA about 30 minutes before DMF/MMF dosing were included to the product labels.

Multiple studies have suggested that aspirin pretreatment reduces flushing associated with DMF dosing. John G. et al in an 8-week study that included 173 healthy volunteers reported ASA reduced the incidence, severity, and number of flushing events while dose titration had no significant effect on flushing or GI events. In another study by Sarah S. and colleagues evaluating the tolerability and pharmacokinetic (PK) of DMF with and without ASA in 56 healthy volunteers confirmed the same effect of ASA in reduction the flushing events.

BioPharma Services Experience in DMF Studies

In past years, BioPharma Services (BPSI) had conducted over 20 single-dose (SD) and multiple-dose (MD) clinical trials on DMF and MMF which included phase 1 clinical trials, 505(b)(2), and bioequivalence/bioavailability studies in 980 healthy volunteers. In the Phase 1 clinical trial involving 423 healthy volunteers, BioPharma Services explored the approach of using food to minimize adverse events, and in some bioequivalence/bioavailability clinical trials, ASA was used for adverse events mitigation in accordance with the agencies’ specific product guidance, BioPharma Services gained extensive experience with clinical trials on DMF and MMF products. The major adverse events such as flushing and GI events on DMF and MMF are shown in Table 1, and the comparison of incidence rate of major AEs from different type of studies is shown in Figure 1.

Table 1. Summary of adverse events from DMF and MMF in-house Clinical Trials

For flushing, in SD DMF and MMF clinical trials, ASA significantly reduced the incidence rate under fasting conditions. The ASA co-administration is generally not recommended for the fed conditions as label indicated that food may reduce the incidence of flushing caused by DMF4. However, from in-house clinical trials data, without ASA, the incidence rate of flushing from fed studies were even higher than fasting studies. It should be noted that such observation might be bias by the total studies represented each condition and different study population variability. Without ASA, the incidence rate of flushing was lower in MD than in SD studies, as flushing is the most common reaction and especially happened at the initiation of therapy, and decrease over time per product label.

For GI events, the incidence rate is overall lower than flushing events (≤ 0.7), thus the differences between conditions are also minimum. The incidence rate of MD is much lower than SD studies, which match the description in labels that the incidence of GI events was higher early during treatment and usually decreased over time.

Further Discussion on DMF and MMF Clinical Trials

Despite the advantages of ASA in increasing the patient’s tolerance to DMF and MMF and the evidence prof discussed above, many researchers suggested that ASA should not be used long-term for the management of flushing.

Both ASA and DMF and MMF can independently increase the risk of GI bleeding. ASA is a non-steroidal anti-inflammatory drug (NSAID) known to irritate the GI tract and potentially cause ulcers and bleeding. DMF and MMF, while not directly causing GI bleeding, might exacerbate this risk if taken concurrently with ASA. Serious gastrointestinal reactions, including perforation, ulceration, hemorrhage, and obstruction, some with fatal outcomes, have been reported with the use of fumaric acid esters, with and without ASA co-administration. Patients should be monitored closely for signs of GI bleeding if they are on both medications.

Adding ASA to a treatment regimen that already includes DMF can increase the complexity and pill burden for patients. Compliance might become an issue if the patient finds it difficult to adhere to multiple medications.

The Potential Benefit of Co-administering ASA with DMF

All in all, the potential benefit of co-administering ASA with DMF lies primarily in the theoretical reduction of flushing associated with DMF treatment, along with potential cardiovascular protection in at-risk patients. However, this must be weighed against the increased risk of GI bleeding and other potential adverse effects. The decision to co-administer ASA with DMF should be individualized based on the patient’s overall health status, cardiovascular risk, and tolerance to both medications. Factors such as history of bleeding disorders, renal function, and concurrent medications should be carefully evaluated.

Based on BioPharma Services’ experience, for clinical trials under fasting conditions, although the MMF and MMF is generally tolerable, ASA pretreatment might be benefit for the participants, especially for single-dose study under fasting conditions to improve the tolerability by reducing the incidence rate of flushing and GI events. BioPharma Services research clinic can close monitor and individualized during study and make appropriate decision to keep volunteers’ safety and integrity of clinical trial.

Why Choose BioPharma Services for Your Next Drug Development Project?

BioPharma Services has extensive experiences in executing DMF/MMF studies from difference stage, our Phase 1 clinical trials are designed to proactively manage adverse events like flushing and GI adverse events, ensuring minimal impact on study timelines, for 505(b)2 and bioequivalence studies. We tailor our approaches to the specific needs of your compound and study objectives, whether it’s a 505(b)(2) pathway or bioequivalence assessment, BioPharma Services experience across different regulatory agencies ensures your DMF and MMF studies meet all compliance requirements.

If you are interested in an DMF and MMF study or any other compounds and would like to discuss further to customize a design for the objective, please visit our Contact page and an expert Pharmacometrics team member will be happy to discuss our capabilities with you.

Find out why BioPharma might be the right partner for you! Learn more about BioPharma Services and the wide array of bioanalytical services we provide.

Written By:

David Yu

Sr. Pharmacokinetic Scientist

BioPharma Services, Inc., a HEALWELL AI and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a, Human Abuse Liability(HAL) and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma Services conducts clinical research operations from its Canadian facility, with access to healthy volunteers and special populations.