Long Covid is a multisystem condition comprising often severe symptoms that follow asevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Long COVID oftenmanifests as fatigue and neurocognitive impairment (also referred to as 'brain fog').Based on two systematic reviews of Covid-19 cases in neonates, children and adolescentsunder 19 years of age, fatigue caused by Long Covid can persist for years and can lead towork disability and labour shortages, posing a public health emergency with lastinghealth, mental, and economic impacts. To date, no treatment has shown to be broadlyeffective for the treatment of Long Covid. An experimental study has demonstrated thatmetformin, a common diabetes drug, might reduce the incidence of long COVID if givenduring the acute phase of COVID-19. The study, however, did not look at whether metforminwould be effective as a treatment for those who already have long COVID. It also did notreport the results by age groups, so it is not clear if the effect of metformin differsfor people younger than 35 years of age. Therefore, a pilot, adaptive randomizedcontrolled trial, which will evaluate the feasibility of conducting a large platformtrial and will also evaluate the efficacy and safety of using metformin (versus placebo,a look-alike substance with no active ingredient) in managing fatigue in long COVIDadolescent patients with persistent (long term) features of fatigue (chronic fatiguesyndrome) has been proposed.
Shortly after the beginning of the COVID-19 global pandemic, reports emerged showing that
some individuals infected with SARS-CoV-2 developed persistent symptoms and new health
problems that arose long after the acute phase of infection and could not be explained by
other factors. The patient community who first recognized and reported this new syndrome
used the term 'long COVID' to describe the post-acute and chronic sequelae of SARS-CoV-2
infection. Long COVID (sometimes referred to as 'post-acute sequelae of COVID-19') is a
multisystem condition comprising often severe symptoms that follow a severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This condition affects all
individuals ubiquitously regardless of their race, age, gender, baseline health status
and the severity of their initial COVID infection. As reported by the two systematic
reviews of the total COVID-19 cases of neonates, children, and adolescents aged less than
19 years since the start of the pandemic, the persistent clinical features spectrum of
long COVID is wide with fatigue having the second highest percentage of persistent long
COVID symptoms within this age group. Long COVID symptoms can last for years,
particularly in cases for chronic fatigue syndrome/dysautonomia which can be lifelong.
Therefore, significant proportions of individuals have been unable to return to work
which has even to led to labour shortages. Consequently, long COVID is considered a
public health emergency that can have lasting health, mental health, and economic
sequelae.
Since, the clinical trials done so far have not been prioritized to understand the
diagnosis, treatment, and prevention in marginalized populations such as adolescents and
because of the high disability associated with this condition, research targeting this
age group for the management of long COVID is needed. There are currently no approved
therapies for long COVID; however, treatments for certain components have been effective
for subsets of populations. Metformin has been proposed in this study as a potential
avenue for the management of chronic fatigue that is associated with long COVID. It has
clinical benefits when used as an outpatient treatment for COVID-19 and is globally
available, has a low-cost, and is safe. A study that was conducted recently had reported
that its use in patients infected with COVID could reduce the incidence of long COVID.
However, since this study had only focused on older individuals who were already infected
with COVID, a pilot trial evaluating the efficacy and safety of metformin in younger
individuals with long COVID is warranted.
Therefore, a pilot, adaptive randomized controlled trial has been proposed, which will
evaluate the feasibility of conducting a large platform trial and will also evaluate the
efficacy and safety of using metformin versus placebo, (since there's no approved therapy
for it) in managing fatigue in long COVID adolescent patients with persistent features of
fatigue (chronic fatigue syndrome).
Drug: Metformin
Metformin is an FDA-approved antidiabetic agent that manages high blood sugar levels in
type 2 diabetes patients. However, emerging evidence may suggest a benefit to COVID
recovery.
Other: Placebo
Patients will receive matching placebo control twice daily.
Inclusion Criteria:
- Age 10 to 18 years at time of screening
- Willing and able to provide written informed consent, or with a legal representative
who can provide informed consent (where locally and nationally approved)
- Previous confirmed case of SARS-CoV-2 infection (e.g., communicates that they
previously had a positive nucleic acid amplification test or had a positive
professional use or self-test SARS-CoV-2 rapid antigen diagnostic test)
- New or worsening symptoms since acute COVID-19 illness that have persisted for a
duration of at least 90 days but less than 365 days
- Not currently hospitalized or requiring hospitalization
- Patients with childbearing potential or with partners of childbearing potential must
agree to use adequate methods of contraception during the trial and through 90 days
of follow-up
- Able to complete the questionnaires
- Reports moderate to severe fatigue, defined as a score of 75 or lower on the
PedsQL-MFS
- Fatigue symptoms have been present for at least 90 days since time of COVID-19
infection
- Fatigue symptoms are not attributable to another cause (in opinion of investigator)
- Willingness to follow the trial procedures
Exclusion Criteria:
- Known active acute SARS-CoV-2 infection
- Known prior diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome, not
related to SARS-CoV-2 infection
- Known pre-existing dysautonomia, not related to SARS-CoV-2 infection
- Diabetes
- Known stroke within 3 months of screening
- Known severe anemia, defined as < 8 g/dL21
- Known diagnosis of Lyme disease
- Any non-marijuana illicit drug use within 30 days prior to informed consent
- Pregnancy or breastfeeding
- Current co-morbid psychiatric disorder (e.g. clinical depression, anxiety, sleep
disorder, eating disorder, substance abuse) that is uncontrolled and associated with
significant symptoms or that requires a prohibited medication
- Taking medications with known side effect of chronic fatigue
- Contraindications to metformin
- Patients with a history of seizures may participate if they have not occurred in the
last 60 days and are stable, under pharmacological control
- Any condition that would make the patient, in the opinion of the investigator,
unsuitable for the trial
Suite No 301, Al-Sehat Centre, Adj Regent Plaza Hotel Rafiqui Shaheed Road
Karachi, Sindh, Pakistan
Zamir Hussain Suhag, MBBS, FCPS
(+92)-300-2018880
zamir.suhag@tvi.org.pk
Zamir Hussain Suhag, MBBS, FCPS, Principal Investigator
Technical Director of Trust in Vaccines & Immunization, Pakistan