Covid-19 living Data

Molnupiravir vs Standard care/Placebo (RCT)

Mild outpatients

FOREST PLOTS -2023-01-27

Studies description

Trial ISRCTN30448031; EudraCT: 2021-005748-31
Publication PANORAMIC - Butler C, SSRN (2022) (preprint)
Dates: 2021-12-08 to 2022-04-27
Funding: Public/non profit (NIHR)
Conflict of interest: No

Trial NCT04575597
Publication MOVe-OUT - Caraco Y, N Engl J Med Evidence (2021) (published paper)

Funding: Private (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA, Brazil, Chile, Colombia, France, Germany, Israel, Russia, South Africa, Spain, Ukraine, UK Follow-up duration (days): 210
Inclusion criteria	Mild or moderate, laboratory confirmed Covid-19 with onset of Covid-19 signs and/or symptoms (hereafter termed “symptom onset”) up to (and including) 7 days before randomization Enrollment of participants with moderate Covid-19 was limited to no more than 50% of the total planned sample size All participants with mild Covid-19, and at least 75% of participants overall, were required to be at increased risk for severe illness from Covid-19. The following characteristics or underlying medical conditions, as adapted from the Centers for Disease Control and Prevention and the WHO,14,15 were protocol-defined factors that qualified a participant as being at increased risk: age older than 60 years, active cancer (other than minor cancers not associated with immunosuppression or significant morbidity/ mortality [e.g., basal cell carcinomas]), chronic kidney disease, chronic obstructive pulmonary disease, immunocompromised status/solid organ transplant recipient, obesity (body mass index 30 kg/m2), serious heart conditions (heart failure, coronary artery disease, and/or cardiomyopathies), diabetes mellitus, and sickle cell disease.
Exclusion criteria	Registry: Is currently hospitalized or is expected to need hospitalization for COVID-19 within 48 hours of randomization Is on dialysis or has reduced estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m^2 by the Modification of Diet in Renal Disease (MDRD) equation Has any of the following conditions: human immunodeficiency virus (HIV) with a recent viral load >50 copies/mL (regardless of CD4 count) or an AIDS-defining illness in the past 6 months, participants with HIV may only be enrolled if on a stable antiretroviral therapy regimen a neutrophilic granulocyte absolute count <500/mm^3 Has a history of hepatitis B virus (HBV) or hepatitis C virus (HCV) with cirrhosis, end-stage liver disease, hepatocellular carcinoma, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3X upper limit of normal at screening Has a platelet count <100,000/μL or received a platelet transfusion in the 5 days prior to randomization Is taking or is anticipated to require any prohibited therapies Is unwilling to abstain from participating in another interventional clinical study through Day 29 with an investigational compound or device, including those for COVID-19 therapeutics Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments including but not limited to: participants who are not expected to survive longer than 48 hours after randomization, or participants with a recent history of mechanical ventilation, or participants with conditions that could limit gastrointestinal absorption of capsule contents.
Interventions
	Treatment Molnupiravir 800 mg twice daily for 5 days Molnupiravir 400 400 mg twice daily for 5 days Molnupiravir 200 200 mg twice daily for 5 days
	Control Placebo
Participants
	Randomized participants : Placebo=74 Molnupiravir=76 Molnupiravir 400=77 Molnupiravir 200=75
	Characteristics of participants N= 302 Mean age : NR 159 males Severity : Mild: n= 282/ Asymptomatic: n=7
Primary outcome
	In the register 1.Percentage of participants who are hospitalized and/or die [ Time Frame: Up to 29 days ] Go to Hospitalization (all cause) is ≥24 hours of acute care in a hospital or similar acute care facility. Death is due to any cause. 2. Percentage of participants with an adverse event (AE) [ Time Frame: Up to ~7 months ] An AE is any untoward medical occurrence in a clinical study participant, temporally associatedwith the use of study intervention, whether or not considered related to the study intervention. 3. Percentage of participants who discontinued study intervention due to an AE [ Time Frame: Up to 6days ] An AE is any untoward medical occurrence in a clinical study participant, temporally associatedwith
	In the report Adverse event (AE) data collection by the investigator from the time of randomization through 14 days after cessation of treatment, physical examinations (including vital signs), and laboratory tests (hematology and chemistry).; The proportion of participants who were hospitalized and/or died from any cause through day 29.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	In addition to the published article, the protocol and study registry were used in data extraction and risk of bias assessment. The study achieved the target sample size specified in the trial registry. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome does reflect the reported primary outcome.

Trial NCT04405570
Publication Fischer W, Sci Transl Med (2021) (published paper)
Dates: 2020-06-19 to 2021-01-21
Funding: Mixed (Ridgeback Biotherapeutics, Wayne and Wendy Holman, Merck, Drug Innovations at Emory (DRIVE) LLC, US government)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA Follow-up duration (days): 28
Inclusion criteria	Able to provide informed consent prior to initiation of any study procedures ≥18 years of age at Screening Study treatment is expected to begin within ≤168 hours from first symptom onset Ability to swallow pills Documentation of confirmed active SARS-CoV-2 infection, as determined by a molecular test conducted at any US clinic or laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent from an NP swab collected ≤96 hours prior to study entry Experiencing at least one of the following SARS-CoV-2 infection symptoms: fever (can be subjective including feeling feverish or having chills) OR signs/symptoms of respiratory illness (including but not limited to upper respiratory congestion, loss of sense of smell or taste, sore throat OR lower respiratory illness - cough, shortness of breath) Agrees to not participate in another interventional clinical trial for the treatment of SARS-CoV-2 during the study period (28 days) unless hospitalized Agrees to not obtain investigational medications outside of the EIDD-2801 study Agrees to the sampling detailed in the schedule of evaluations (SOE) and to comply with study requirements including contraception requirements Female participants of childbearing potential must meet the following criteria to be enrolled: i. Have a negative pregnancy test at Day 1, prior to randomization. ii. Must agree to undergo a follow-up pregnancy test on Study Day 28. iii. Must agree to use at least 2 forms of contraception during the study and for at least 50 days after dosing of the study drug is complete, as discussed with and approved by the investigator, OR Must have an azoospermic partner (vasectomized or due to a to medical cause). Note: azoospermic partner is acceptable provided that the partner is the sole sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed Male participants must refrain from donating sperm during the study and for 100 days after dosing of the study drug is complete Male participants with female partners must have either Surgical sterilization (vasectomy ≥1 month before screening) OR Female partner must be of not be of childbearing potential OR Agree to use 2 forms of contraception during the study and for 100 days after dosing of the study drug is complete, as discussed with and approved by the investigator
Exclusion criteria	Need for hospitalization or immediate medical attention in the clinical opinion of the study investigator Hemoglobin <10 g/dL in men and <9 g/dL in women Platelet count <125,000/L Estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73m2 Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥3x upper limit normal (ULN) History of or current hospitalization for COVID-19 History of significant kidney disease in the opinion of the site investigator History of significant liver disease in the opinion of the site investigator or active Hepatitis B or active Hepatitis C Human immunodeficiency virus (HIV) that is advanced (CD4<200/mm3) and/or on treatment with nucleoside analogues History of known blood dyscrasia Use of therapeutic interventions with possible anti-SARS-CoV-2 activity within 30 days prior to study entry, e.g., remdesivir, lopinavir/ritonavir fixed dose combination, ribavirin, chloroquine, hydroxychloroquine, convalescent plasma, or participation in a clinical trial involving any of these drugs whether for treatment or prophylaxis Receipt of a SARS-CoV-2 vaccination prior to study entry Known allergy/sensitivity or any hypersensitivity to components of EIDD-2801, or its formulation Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements History of recent hemorrhagic cerebrovascular accident (CVA) or major bleed Presence of a condition, that in the opinion of the investigator, would place the subject at increased risk from study participation
Interventions
	Treatment Molnupiravir 200 200 mg orally twice daily for 5 days Molnupiravir 800 mg orally twice daily for 5 days Molnupiravir 400 400 mg orally twice daily for 5 days
	Control Placebo
Participants
	Randomized NR Analyzed 202 participants Molnupiravir 200=23 Placebo=62 Molnupiravir=55 Molnupiravir 400=62
	Characteristics of participants N= 202 Mean age : NR 98 males Severity : Mild: n= 202/ Asymptomatic: n=0
Primary outcome
	In the register 1. Virologic Efficacy [ Time Frame: 28 days ]; 2. Number of Participants with any Adverse Events (AEs) as Assessed by Kaplan Meier Approach [ Time Frame: 28 days ]
	In the report Time to viral RNA clearance; Adverse events that were Grade 3 or higher and those that led to early treatment discontinuation
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: N
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to the published report, the preprint article, the trial registry (dated May 28 2020) was used for data extraction and risk of bias assessment. The study achieved the target sample size as reported in the registry. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome, but timepoints were not specified in the registry. Additional outcomes are reported in the article, including mortality, antibody detection, self-reported health, and symptom duration. This study was updated on the March 2nd, 2022 with data from the published report.

Trial NCT04575597
Publication Jayk Bernal A, N Engl J Med (2021) (published paper)
Dates: 2021-05-06 to 2021-10-02
Funding: Private (Merck Sharp and Dohme)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Argentina, Brazil, Canada, Chile, Colombia, Egypt, France, Germany, Guatemala, Italy, Japan, Mexico, Philippines, Russian Federation, South Africa, Sp Follow-up duration (days): 28
Inclusion criteria	Non-hospitalized adults with mild or moderate Covid-19 SARS-CoV-2 infection that had been laboratory-confirmed no more than 5 days earlier Onset of signs or symptoms no more than 5 days earlier At least one sign or symptom of Covid-19 At least one risk factor for development of severe illness from Covid-19 (age >60 years, active cancer, chronic kidney disease, chronic obstructive pulmonary disease, obesity, defined by a body-mass index [the weight in kilograms divided by the square of the height in meters] ≥30, serious heart conditions [heart failure, coronary artery disease, or cardiomyopathies], or diabetes mellitus)
Exclusion criteria	An anticipated need for hospitalization for Covid-19 within the next 48 hours Dialysis or estimated glomerular filtration rate less than 30 ml per minute per 1.73 m2 Pregnancy Unwillingness to use contraception during the intervention period and for at least 4 days after completion of the regimen Severe neutropenia (absolute neutrophil count of <500 per milliliter) Platelet count below 100,000 per microliter SARS-CoV-2 vaccination
Interventions
	Treatment Molnupiravir 800 mg orally twice a day for 5 days
	Control Placebo
Participants
	Randomized participants : Molnupiravir=716 Placebo=717
	Characteristics of participants N= 1433 Mean age : NR 698 males Severity : Mild: n= 785/ Asymptomatic: n=0
Primary outcome
	In the register 1) Percentage of participants who are hospitalized and/or die [ Time Frame: Up to 29 days ] Hospitalization (all cause) is ≥24 hours of acute care in a hospital or similar acute care facility. Death is due to any cause. 2) Percentage of participants with an adverse event (AE) [ Time Frame: Up to ~7 months ] An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. 3) Percentage of participants who discontinued study intervention due to an AE [ Time Frame: Up to 6 days ] An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
	In the report 1) the incidence of hospitalization for any cause (defined as ≥24 hours of acute care in a hospital or any similar facility) or death through day 29 2) the incidence of adverse events
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	In addition to the published article, the trial registry, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. There is no change from the trial registration in the intervention and control treatments. The primary outcomes described in the article generally reflect those in the registry, with the omission of the percentage of participants who discontinued study intervention due to an AE. Recruitment was terminated on the basis of positive efficacy results from a planned interim analysis performed when 50% of target enrollment had been followed through day 29, and thus the study (n = 1433) did not achieve its target sample size (n = 1550).

Trial NCT04746183; ISRCTN27106947; EudraCT 2020-001860-2
Publication AGILE CST-2 - Khoo SH, Lancet Infect Dis (2022) (published paper)
Dates: 2020-10-18 to 2022-03-16
Funding: Mixed (Ridgeback Biotherapeutics; Medical Research Council; the Wellcome Trust; UK National Institute of Healthcare Research; NIHR Health Protection Research Unit in Emerging and Zoonotic Infections; UK Medical Research Council. Molnupiravir was provided by Ridgeback Biotherapeutics as 200mg capsules (with matching placebo).)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / UK Follow-up duration (days): 28
Inclusion criteria	Men and women Aged ≥18 years PCR-confirmed SARS-CoV-2 infection Within five days of symptom onset Free of uncontrolled chronic conditions Ambulant in the community Mild or moderate disease Women of childbearing potential and men were required to use two effective methods of contraception, one of which should be highly effective, throughout the study and for 50 and 100 days thereafter, respectively Participants were eligible irrespective of whether they were unvaccinated or had received one or multiple UK approved vaccines
Exclusion criteria	Pregnant or breastfeeding women Stage 4 and 5 (severe) chronic kidney disease Clinically significant liver dysfunction SpO2 <95% by oximetry or lung disease requiring supplementary oxygen ALT and/or AST >5 times upper limit of normal Platelets <50 × 109/L Experiencing any grade 3 or above Common Terminology Criteria for Adverse Events (CTCAE version 5) Previously reported hepatitis C infection Known allergy to any study medication Having received any other experimental agents within 30 days of first dose of study drug (use of other co-medications was allowed)
Interventions
	Treatment Molnupiravir 800 mg orally twice a day for 5 days
	Control Placebo
Participants
	Randomized participants : Placebo=90 Molnupiravir=90
	Characteristics of participants N= 180 Mean age : NR 77 males Severity : Mild: n= 180/ Asymptomatic: n=0
Primary outcome
	In the register EudraCT 2020-001860-27 - Master Protocol Co-primary endpoint: Pharmacodynamics of drug defined as time to negative viral titres in nose and/or throat swab, measured up to 29 days from randomisation. For CST-2 (EIDD-2801): To determine the safety and tolerability of multiple ascending doses of EIDD-2801. Efficacy Objective: To determine the ability of EIDD-2801 to improve viral clearance (time to negative PCR).
	In the report Time from randomisation to a negative SARS-CoV-2 PCR test
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	In addition to the pre-print, the three trial registries, protocol and statistical analysis plan were used in data extraction and risk of bias assessment. The supplementary figures and tables referred to in the article were not available through the medRxiv pre-print webpage. The article reports on the molnupiravir sub-study of a platform trial. The primary and secondary outcomes in the article reflect those in the registry. The trial (n = 180) achieved its target sample size (n = 180). This study was updated on January 19th, 2023 with data extracted from the published report.

Trial CTRI/2021/07/034588
Publication Koudinya Tippabhotla S, SSRN (2022) (preprint)
Dates: 2021-07-01 to 2021-08-24
Funding: Private (Aurobindo Pharma Limited )
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / India Follow-up duration (days): 28
Inclusion criteria	Non-hospitalized, adults aged ≥ 18 and ≤ 60 years laboratory-confirmed (RT-PCR positive) SARSCoV-2 infection presenting with uncomplicated upper respiratory tract symptoms like fever, cough, sore throat, nasal congestion, malaise, headache or any other COVID-19 symptoms without breathlessness or hypoxia (normal saturation).
Exclusion criteria	Respiratory rate ≥ 24/min breathlessness SpO2 ≤ 93% on room air pulse rate < 50 beats per minute positive for hepatitis B or C virus with cirrhosis end-stage liver disease hepatocellular carcinoma elevated liver enzymes absolute Neutrophil Count (ANC) < 500 mm3 platelet count <100,000/μL, or received a platelet transfusion in the previous 5 days immunosuppressive treatments in the previous 30 days or systemic corticosteroids.
Interventions
	Treatment Molnupiravir 800 mg (200mg x 4 capsules orally every 12 hours) for 5 days.
	Control Standard care
Participants
	Randomized participants : Molnupiravir=610 Standard care=610
	Characteristics of participants N= 1220 Mean age : NR 752 males Severity : Mild: n= 1220/ Asymptomatic: n=0
Primary outcome
	In the register Rate of hospitalization of patients from randomization up to Day 14.
	In the report Rate of hospitalization of patients from randomization till day 14.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the preprint article, the study registry was used in data extraction and risk of bias assessment. Neither the protocol or statistical analysis plan were available. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome. Some outcomes (e.g. viral negative conversion, WHO Score 7 and above, adverse events) are reported in the paper, but were not pre-specified in the trial registry/protocol. The study (n=1220) achieved the target sample size (n=1220) specified in the trial registry.

Trial CTRI/2021/06/033938
Publication Kumarasamy N, CROI (2022) (unpublished results)

Funding: Private (Dr Reddys Laboratories Limited)
Conflict of interest: *

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / India Follow-up duration (days): 14
Inclusion criteria	Patients willing and able to provide voluntary written informed consent and to follow the protocol requirements Male or female patients between 18 and 60 years of age (both inclusive) Patients with positive RT-PCR test for SARS-CoV-2 in nasopharyngeal or oropharyngeal swabs (sample collected â?¤5 days prior to randomization). Note: If rapid antigen test has been performed and patient found positive then RT-PCR will be performed prior to randomization Patients with mild COVID-19 and have following symptoms and signs prior to randomization â?¤5 days prior to randomization: Upper respiratory tract symptoms (&/or fever) without shortness of breath or hypoxia. As defined by AIIMS/ ICMR-COVID-19 National Task Force/Joint Monitoring Group (Directorate General Of Health Services) Ministry of Health & Family Welfare, Government of India- clinical guidance for management of adult COVID-19 patients, dated 22-Apr-2021 Is willing and able to take oral medication Willingness to comply with study instructions for its duration as indicated by written informed consent from the patient
Exclusion criteria	Is currently hospitalized or is expected to need hospitalization for COVID-19 within 48 hours of randomization Pregnancy or lactation History of allergy or hypersensitivity to Molnupiravir or any other treatment component based on investigators assessment Patients on dialysis or having reduced glomerular filtration rate (eGFR) <30 mL/min/1.73m2 by the Modification of Diet in Renal Disease (MDRD) equation Tested positive for Human immunodeficiency virus (HIV), Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection Abnormal laboratory findings at screening: Aspartate aminotransferase (AST) >3X upper limit of normal, Alanine aminotransferase (ALT) >3X upper limit of normal, Absolute neutrophil count <500/mm3 or per microliter, Platelet count <100,000 per microliter or /mm3 Patients who received a platelet transfusion in the 5 days prior to randomization Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments including but not limited to: Participants who are not expected to survive longer than 48 hours at the time of randomization, or Participants with a recent history of mechanical ventilation, or Participants with conditions that could limit gastrointestinal absorption of capsule contents Receipt of following medication/treatment: Ongoing Remdesivir, Favipiravir or any other anti-viral drug, for COVID-19 treatment, Biological therapy (especially, monoclonal antibody, interferon alpha) or convalescent plasma (for COVID-19 treatment) in the 90 days (prior to baseline visit) Participation in any clinical study with an investigational drug, biologic, or device within 1 month prior or within 5 half-lives (of the drug/ biologic) prior to the randomization (whichever is longer)
Interventions
	Treatment Molnupiravir 800 mg orally twice daily for 5 days
	Control Standard care
Participants
	Randomized participants : Molnupiravir=608 Standard care=610
	Characteristics of participants N= 1218 Mean age : NR 0 males Severity : Mild: n= 1218/ Asymptomatic: n=0
Primary outcome
	In the register Rate of hospitalization Timepoint: Randomization up to Day 14
	In the report Rate of hospitalization up to day 14
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	The conference abstract and the trial registry were used in data extraction and risk of bias assessment. The registry primary outcome reflects the reported primary outcome. The study (N =1218) achieved the target sample size specified in the trial registry (N =1218). This trial is still ongoing. Results on incidence of viral negative conversion and clinical improvement are reported with percentages only; we were unable to calculate the number of events since the denominators for the outcomes are unclear.

Trial ChiCTR2200056817
Publication Zou R, Front Pharm (2022) (published paper)
Dates: 2022-03-03 to 2022-03-21
Funding: Mixed (National Key Research and Development Project, Shenzhen Science and Technology Research and Development Project, and in part from the National Science and Technology Major Projects. Molnupiravir was provided by HUAHAI Pharmaceutical. Carelink Pharmaceutical Co., Ltd. provided statistical analysis. )
Conflict of interest: No

Methods
	RCT
	Location : Single center / China Follow-up duration (days): 21
Inclusion criteria	Confirmed mild/moderate COVID-19 Male or nonpregnant females Aged ≥18 years and ≤80 years Tested positive for SARS-CoV-2 Omicron variant Had initial onset of symptoms for ≤5 days prior to the day of treatment
Exclusion criteria	Severe vomiting or intolerance of oral drugs for other reasons Pregnancy or lactation Patients retesting positive for COVID-19 Those who had received antibody therapy, plasma therapy, or other investigational drugs for SARS-CoV-2
Interventions
	Treatment Molnupiravir 800 mg orally twice per day for 5 days
	Control Standard care
Participants
	Randomized participants : Molnupiravir=80 Standard care=36
	Characteristics of participants N= 116 Mean age : NR 60 males Severity : Mild: n= */ Asymptomatic: n=0
Primary outcome
	In the register Percentage of negative nucleic acid tests (Nasopharyngeal swabs/respiratory secretions). Measure time point of outcome: 10 days after the first dose. Measure method: RT-PCR.
	In the report time of viral RNA clearance measured using RT-PCR analysis of pharyngeal swab.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article and its supplement, the study registry was used in data extraction and risk of bias assessment. The study did not achieve the target sample size (N=150) specified in the trial registry. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome does not reflect the reported primary outcome.