A randomised, multi-centre, double-blind, Phase 3 study to observe the effectiveness, safety and tolerability of molnupiravir compared to placebo administered orally to high- risk adult outpatients with mild COVID-19 receiving local standard of care in South Africa
Rationale
Recurring waves and outbreaks of COVID-19 driven by the highly transmissible Delta (B.1.617.2) variant and most recently by the Omicron variant first described in South Africa, are exacerbating the global public health crisis. Vaccines have substantially reduced the morbidity and mortality rates in those infected with SARS-CoV-2, and several therapeutic agents, including steroids, have been shown to impact on severe disease1–3. However, individuals who have been infected or vaccinated still run the risk of recurrent infection. These infections are often symptomatic, with occasional severe morbidity and even mortality in those with similar risk factors for severe disease to those without immunity.
Several oral, injectable and infusion agents have been tested for use as early treatment, and several promising oral agents have recently emerged. These include fluvoxamine, molnupiravir and nirmatrelvir, and all have an impact on hospitalization and severe outcomes. Multiple other agents are being investigated. While study design varied for these new agents, all appear to have maximum impact if administered soon after symptom onset (within 3-5 days), and for several days. This aligns with the current understanding of the development of SARS-CoV-2 infection: an initial viral infection and dissemination phase is followed by an immunological phase (during which immunomodulation contributes significantly) in certain high-risk patients with associated severe morbidity and mortality. Current thinking is that new agents play a role in early disease by limiting viral replication and potentially preventing or limiting the subsequent immunological phase. The effectiveness of these agents relies on early presentation of patients to a relevant health care facility, rapid confirmation of SARS-CoV-2 infection, and prompt initiation of therapy.
South Africa, like many countries, has endured several waves of SARS-CoV-2, with some estimates suggesting that 80% of the population have been infected. Excess mortality due to the virus is recorded at just over 300 000 since the first cases in March 2020 4, in a population of 50 million. Currently, only 48% of the population have been vaccinated (68% in those over 60 years)5. Accurate comparisons with elsewhere on the continent, or even with high income countries are difficult, although there are some suggestions that South African mortality is particularly high. This may be due to the very high levels of obesity and diabetes, both significant risk factors for poor COVID-19 outcomes, as well as high levels of HIV, also somewhat associated with poorer outcomes6,7m. Access to agents with a demonstrated ability to impact hospitalisation and severe outcomes related to COVID-19 will have clear benefits in the South African context but is limited by the time to registration of new drugs, or caveats attached to the use and monitoring of unregistered products through the Section 21 mechanism.
Rapid access to molnupiravir in South Africa will be facilitated for a large number of COVID-19 patients through this Phase 3 clinical trial while awaiting registration applications and procedures. The LumiraDx point of care diagnostic platform for diagnosis of SARS-CoV-2 infection through antigen detection, will enable rapid confirmation of COVID-19 in patients with recent onset of symptoms and mild disease. Patients who meet the enrolment criteria will have same-day initiation of a five-day treatment course of molnupiravir, and will be followed to monitor tolerability, adverse drug reactions, effectiveness through time to resolution of symptoms and progression to severe disease (requiring hospitalisation and/or resulting in death), and adherence.
Design
This is a multi-centre, double-blind, Phase 3 study to observe the effectiveness, safety, and tolerability of molnupiravir 800 mg administered 12-hourly for five days to adult patients with mild COVID-19 at the time of enrolment who are at risk of progression to severe disease, compared to a placebo.
Patients with recent onset of COVID-19 symptoms will be screened to assess eligibility for enrolment. Confirmation of SARS-CoV-2 infection will be performed through rapid antigen detection using the LumiraDx point of care diagnostic platform. Eligible patients will be enrolled and will be randomised in a 1:1 manner to start treatment with either molnupiravir or a placebo on the same day. Patients will record their symptoms (through a self-administered questionnaire) and self-observed vital signs daily for 10 days from the time of enrolment and will be contacted by study team personnel on Days 3, 6 and 10 to monitor their well-being. Adverse event and concomitant medication data will be collected. A final end-of-study follow-up visit will be conducted on Day 29.
An independent Data and Safety Monitoring Board (DSMB) will be convened for this study with expertise in COVID-19 or respiratory viruses, and emerging epidemics. The purpose of the DSMB is to monitor the study for safety and operational futility.
In addition to the usual, regular, required reporting to SAHPRA, we anticipate that additional reporting may be required, noting the severity of the 3rd and 4th waves, the level of ‘’breakthrough’’ infections in the context of high background comorbidities, and the urgent interest in this class of drugs.
Population
Adults ≥50 years of age with self-reported symptoms of COVID-19 for no more than five days prior to screening, and who test positive for SARS-CoV-2 antigen on the day of screening or have a documented positive SARS-CoV-2 RT-PCR within 2 days prior to screening, and who are at risk of progression to severe disease, will be enrolled.
The following eligibility criteria will be used to select study participants. Inclusion criteria:
- Able and willing to provide written or electronic informed consent prior to any study-specific procedure.
- Age ≥50 at the time of signing the informed consent form.
- Women of reproductive potential must have a negative pregnancy test at screening and be using a highly effective method of contraception. Highly effective methods of contraception include:
-
- Hormonal methods of contraception for at least 14 days prior to screening (including oral contraceptive pills, injectables, or implants)
- Intrauterine devices from at least 7 days prior to screening (including hormone-releasing, and non-hormone-releasing devices)
- Bilateral tubal ligation
- Engaging exclusively single-sex relationships
- Sexual abstinence
-
- A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another while taking the investigational product. Male participants should also be advised of the benefit for a female partner to use a highly effective method of contraception as condom may break or leak
- Self-reported symptoms of COVID-19 with onset no more than five days prior to screening informed consent including at least one of, fever or chills, cough, sore throat, rhinorrhoea or rhinitis or sinusitis, shortness of breath, headache, myalgia, new onset anosmia or ageusia, nausea, diarrhoea, or extreme fatigue, or other symptoms recognized in local and international guidelines as typical of mild COVID-19.
- SARS-CoV-2 infection confirmed through a positive LumiraDx rapid antigen test on the day of screening or a positive RT-PCR within two days prior to screening.
- Participant is at high risk for progression to severe COVID-19, this defined as either:
-
- Age ≥50 with at least one of the following background or medical conditions: diabetes mellitus, obesity (BMI 30 kg/m2), hypertension, HIV, or active or previous TB.
- Age ≥65
-
- Participant agrees to comply with study procedures, including the completion of a daily diary for 10 days from the time of enrolment, and to be available for study contacts and visits.
Exclusion criteria:
- Pregnant or breastfeeding women, or women planning/desiring to become pregnant during the 28 days following enrolment into the study.
- Duration of self-reported symptoms of COVID-19 for more than five days prior to screening.
- Signs of respiratory distress or severe disease prior to enrolment, including:
- respiratory rate >24 breaths/min
- SpO2 <95% in room air
- heart rate 120 bpm
- abnormal mental status
- inability to walk due to COVID-19 symptoms
- inability to talk in full sentences due to COVID-19 symptoms
- a requirement for hospitalisation.
- Inability/unlikely to be in the study area for the duration of the 28-day follow- up period.
- Inability to tolerate oral medications.
- Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the safety of the patient or the objectives of the study. The Investigator should make this determination in consideration of the volunteer’s medical history.
- The volunteer is assessed to be clinically unstable in the Investigator’s opinion.
- Participation in another investigational study involving an investigational product within 30 days, or 5 half-lives, whichever is longer, prior to screening.
- Personnel (e.g., investigator, sub-investigator, research assistant, pharmacist, study coordinator or anyone mentioned in the delegation log) directly involved in the conduct of the study.
- Any physical, mental, or social condition, drug/alcohol use, history of illness or
laboratory abnormality that, in the Investigator’s judgment, might jeopardise the safety of the patient in the context of this study, or might interfere with study procedures or the ability of the subject to adhere to and complete the study. The Investigator should make this determination in consideration of the volunteer’s medical history.
Volunteers may be re-screened if they are found not to have COVID-19 at the time of the initial screening, but develop a further, and distinct, acute illness suggestive of COVID-19 at a later stage.
Investigational Medicinal Product
Molnupiravir 800 mg 12-hourly or placebo administered orally for five days.
