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Randomized trial of bupropion hydrochloride for fatigue in patients with long COVID (post‑COVID syndrome)

Verified siteRegistered drugNo placebo
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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on Post Covid Syndrome, a condition that can follow a COVID‑19 infection and often includes persistent tiredness and reduced ability to carry out everyday tasks. The medication being tested is the antidepressant and smoking‑cessation drug bupropion, given in tablet form, and it is compared with an inactive tablet known as placebo.

The main aim of the trial is to find out whether bupropion can reduce the level of fatigue and improve physical functioning in people with this condition. Participants are assigned by chance to receive either the active drug or the placebo, take the study tablets for about eight weeks, and attend a few clinic visits: one at the start, one midway through treatment, one at the end of the eight‑week period, and a follow‑up about four weeks later. During these visits, simple questionnaires and short physical tests are completed.

The questionnaires include the Fatigue Severity Scale, which asks the participant to rate how often they feel exhausted during daily activities, and the Short Form-36 Physical Function, which measures how easy it is to perform common tasks such as walking or climbing stairs. Additional brief surveys evaluate mood, anxiety and breathing difficulty, while a quick sit‑to‑stand test checks basic exercise capacity. All assessments are designed to be easy to understand and complete.

The research process

The trial runs in 5 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Baseline assessment (day 1)

    After enrollment, attend the baseline visit. during this visit, complete questionnaires that measure fatigue, physical function, mood, anxiety, and other symptoms.

    A blood sample of about 45 ml is drawn for future research. the sample is divided into serum, plasma, and cells.

    Receive the study medication. the medication is either bupropion (300 mg total, taken as two 150 mg tablets) or a matching placebo capsule. instructions are to take the tablets orally once daily for the next 56 days.

  2. Step 2

    Daily medication intake

    Take the assigned tablets every morning with water. continue this routine for the entire treatment period of 56 days.

  3. Step 3

    Mid‑treatment visit (day 28)

    Return to the study site 28 days after the baseline visit.

    Repeat the questionnaires that evaluate fatigue (fatigue severity scale), physical function, depression, anxiety, somatic symptoms, and stress.

    Perform a 1‑minute sit‑to‑stand test to assess exercise capacity and a simple cognitive test (symbol digit modalities test).

    No new medication is provided; continue taking the same tablets daily.

  4. Step 4

    End‑treatment visit (day 56)

    Attend the visit at the end of the 56‑day medication period.

    Complete the same set of questionnaires as at baseline and day 28, including the fatigue severity scale and physical function assessment.

    Perform the 1‑minute sit‑to‑stand test and the cognitive test again.

    A second blood sample of about 45 ml is drawn for future analysis.

    Stop taking the study medication after this visit.

  5. Step 5

    Follow‑up visit (day 84)

    Return 28 days after the end‑treatment visit (day 84).

    Answer the questionnaires again to evaluate any lasting changes in fatigue, physical function, mood, and other symptoms.

    Repeat the 1‑minute sit‑to‑stand test and the cognitive test.

    No medication is taken at this point.

Who can join the trial?

13 criteria

  • Be 18 years old or older, male or female.
  • Have had a confirmed COVID‑19 infection (shown by a PCR test, antigen test, or documented positive result) at least 3 months before joining the study.
  • Experience significant fatigue, measured by a Fatigue Severity Scale (FSS) score of 45 or higher (the FSS is a questionnaire that rates how tired you feel).
  • Have at least one other symptom that started after COVID‑19, such as:
    • Shortness of breath, defined by a rating of 2 or more on the Modified Medical Research Council (mMRC) scale (a simple breathlessness questionnaire).
    • Reduced ability to exercise, shown by fewer than 29 repetitions in a 1‑minute sit‑to‑stand test (1MSTST).
    • Problems with thinking or memory, indicated by a score lower than 44 on the written version of the Symbol Digit Modalities Test (SDMT).
    • Feeling much worse after physical or mental effort, called post‑exertional malaise (a positive PEM‑Screening result).
    • The fatigue and the additional symptom must have lasted for at least 3 months and no other medical condition should explain them.
    • Show moderate to severe overall disability, measured by a Bell Scale score between 20 and 60 (the Bell Scale rates how much daily activities are limited).
    • Be able to understand what the study involves and follow the study procedures.
    • Agree not to change the type, dose, or frequency of any other medicines you are taking for the first 84 days of the study.
    • Use a highly effective method of contraception correctly and consistently during the study and for 30 days after the last dose (if you could become pregnant or have a partner who could become pregnant). This includes:
      • For women who could become pregnant: a negative pregnancy test at screening, a promise not to try to become pregnant, not to donate eggs, and use of reliable birth control.
      • For men whose partners could become pregnant: agreement to use barrier protection (condoms) while taking the study medication and for 30 days after the final dose.

Who cannot join the trial?

27 criteria

  • Pregnancy or breastfeeding: If you are currently pregnant, planning to become pregnant, or are nursing a baby, you cannot join the study.
  • Using bupropion products: Taking any medication that contains bupropion (such as Zyban® or Elontril®) now or planning to start it prevents participation.
  • Allergy to bupropion: If you have a known allergy or cannot tolerate bupropion, you are excluded.
  • Postural Orthostatic Tachycardia Syndrome (POTS) or fast resting heart rate: A history of POTS or a resting heart rate consistently above 100 beats per minute disqualifies you.
  • Eating‑disorder or brain cancer history: Past or current anorexia nervosa, bulimia nervosa, or any cancer of the brain or central nervous system excludes you.
  • Seizure history: If you have ever had epileptic seizures or have ongoing seizure disorders, you cannot enroll.
  • Use of prohibited medications: Taking any of the following types of medicines stops you from joining:   • Monoamine oxidase inhibitors (MAOIs) such as phenelzine or tranylcypromine,   • Any other bupropion‑containing drug,   • Selective serotonin reuptake inhibitors (SSRIs) or serotonin‑norepinephrine reuptake inhibitors (SNRIs) such as sertraline or duloxetine,   • Drugs that affect the liver enzyme CYP2D6 (e.g., tamoxifen, certain beta‑blockers, codeine, tramadol),   • Medicines that lower the seizure threshold (e.g., certain antipsychotics, quinolone antibiotics, high‑dose antihistamines, tricyclic antidepressants, stimulants). These medicines must be stopped at least 14 days before screening.
  • Current moderate or severe substance‑use disorder: If you have a substance‑use problem that has not been abstinent for at least six months, you are excluded.
  • Positive urine drug test: Detection of illegal drugs such as amphetamines, cocaine, opioids, or benzodiazepines in your urine at screening prevents enrollment.
  • Planned abrupt stop of alcohol or certain drugs: Planning to suddenly stop drinking more than two standard alcoholic drinks per day, or stopping benzodiazepines, barbiturates, or antiepileptic drugs during the trial, excludes you.
  • Severe liver disease: Includes advanced cirrhosis (Child‑Pugh Class C), liver enzymes (ALT or AST) more than three times the normal limit, total bilirubin (a breakdown product of red blood cells) more than two times normal (unless you have Gilbert’s syndrome), or a combination of high enzymes and high bilirubin.
  • Severe kidney disease: Includes an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² (stage 4‑5 chronic kidney disease), needing dialysis, a sudden doubling of serum creatinine within a week, or an acute kidney decline needing urgent treatment.
  • Electrolyte imbalance: Low sodium (<130 mmol/L) or high sodium (>150 mmol/L), and low potassium (<3.0 mmol/L) or high potassium (>5.5 mmol/L) exclude you.
  • Uncontrolled high blood pressure: Systolic pressure ≥160 mmHg or diastolic pressure ≥100 mmHg after at least five minutes of rest (confirmed on two separate occasions) prevents participation.
  • Active major psychiatric illness: Includes schizophrenia, schizoaffective disorder, depression with psychotic features, bipolar disorder, or severe depression that is not well‑controlled, as defined by recent hospitalizations, medication changes, or severe symptoms.
  • Recent suicide attempt or current suicidal thoughts: Any suicide attempt in the past 12 months or current thoughts of harming yourself (PHQ‑9 item 9 score ≥ 2) exclude you.
  • Severe heart disease: Includes advanced heart failure (NYHA Class III‑IV), dangerous heart rhythm problems (e.g., uncontrolled atrial fibrillation with fast ventricular rate, ventricular tachycardia/fibrillation), prolonged QT interval on ECG (>480 ms), Brugada syndrome, a heart attack within the last six months, unstable chest pain, or a weak heart pump (ejection fraction <40%).
  • Current COVID‑19 infection: Ongoing SARS‑CoV‑2 infection or a positive test within 14 days before enrollment disqualifies you.
  • Active cancer: Any currently active malignancy (except localized basal cell skin cancer or adequately treated cervical cancer) prevents participation.
  • History of chronic fatigue syndrome or other disease‑related fatigue: Having pre‑COVID chronic fatigue syndrome or fatigue caused by conditions like cancer or autoimmune disease excludes you.
  • Recent participation in another clinical trial: Being in another interventional trial within the past 30 days (or within five drug half‑lives of that trial’s medication) makes you ineligible.
  • Simultaneous participation in conflicting trials: Being enrolled in another interventional study that could interfere with this one is not allowed (non‑interventional registries are permitted).
  • Lack of legal capacity: If you are unable to understand the nature and consequences of the study, you cannot enroll.
  • Previous enrollment in this same trial: Anyone who has already been randomized in this study before is excluded.
  • Dependent relationship with study staff: If you are employed by, financially dependent on, or otherwise in a relationship of dependence with the sponsor or investigators, you cannot take part.
  • Incarceration or institutional confinement: Persons who are imprisoned or placed in a facility by a court order are excluded.
  • Other disease that interferes with study measurements: Any additional serious medical condition that the investigator believes would make it difficult to assess the study’s outcomes also excludes you.
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Investigated drugs

bupropion is an oral tablet taken by mouth. In this study it is being tested to see if it can reduce the extreme tiredness that many people feel after having COVID‑19. The drug is thought to help improve energy levels and overall physical ability, so researchers are measuring how much it can lower fatigue scores and increase physical function compared with a placebo.

What is already known about the treatment

Bupropion - The medication is taken as an oral tablet that releases the drug slowly after swallowing. It is an approved medicine that is used for depression, to help people stop smoking, and is now being studied for fatigue after COVID‑19. It works by raising the levels of the brain chemicals dopamine and norepinephrine, which can improve energy and mood. Bupropion belongs to the class of norepinephrine‑dopamine reuptake inhibitors.

Investigated diseases

Post COVID-19 condition - A condition that appears after the acute phase of a COVID-19 infection, marked by ongoing symptoms such as tiredness, shortness of breath, and difficulty thinking clearly. These symptoms can start a few weeks after the initial illness and may come and go over months. The pattern of symptoms often changes, with some improving while others persist or fluctuate. It is recognized as a continuation of the body’s response to the original virus rather than a new infection.
Trial detailsLast updated 2 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-524443-12-00Protocol code2025-03997Estimated enrolment250 patientsSponsorGoethe University Frankfurt

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