Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia

ABSTRACTNew prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for 2 months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated, without any serious adverse events. Four adverse events (transient and slight elevations of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, againstPlasmodium falciparuminfections, whereas both offered 100% prophylactic efficacy againstPlasmodium vivaxandPlasmodium ovale. These trials showed that NQAZ had a good safety profile, and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species.

Download Full-text

Efficacy of Phenazone in the Treatment of Acute Migraine Attacks: A Double-Blind, Placebo-Controlled, Randomized Study

Cephalalgia ◽

10.1111/j.1468-2982.2004.00764.x ◽

2004 ◽

Vol 24 (10) ◽

pp. 888-893 ◽

Cited By ~ 15

Author(s):

H Göbel ◽

A Heinze ◽

U Niederberger ◽

T Witt ◽

V Zumbroich

Keyword(s):

Adverse Events ◽

Randomized Study ◽

Controlled Study ◽

Acute Migraine ◽

Serious Adverse Events ◽

Double Blind ◽

Double Blind Placebo ◽

Number Of Patients ◽

Significant Difference ◽

Main Target

In this study we compared the efficacy of 1000 mg phenazone with that of placebo in the treatment of acute migraine attacks in a randomized double-blind, placebo-controlled study of 208 patients. The main target criterion was the number of patients with a pain reduction from severe or moderate to slight or no pain 2 h after taking the pain medication. The percentage of patients satisfying the main target criterion was 48.6% for phenazone and 27.2% ( P < 0.05) for placebo. Freedom from pain after 2 h was reported by 27.6% with phenazone treatment and 13.6% ( P < 0.05) with placebo. Compared with placebo, the phenazone treatment also resulted in a significant improvement in the associated migraine symptoms of nausea, phonophobia and photophobia. Of patients treated with phenazone 11.4%, and 5.8% of those treated with placebo reported adverse events. There was no significant difference between the groups with regard to numbers of patients with adverse events. No serious adverse events occurred. The results show that phenazone at a dosage of 1000 mg is effective and well tolerated in the treatment of acute migraine attacks.

Download Full-text

Safety, Tolerability and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02329-20 ◽

2021 ◽

Author(s):

J. T. Guptill ◽

S. M. Raja ◽

V. C. Juel ◽

E. B. Walter ◽

M Cohen-Wolkowiez ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Adverse Events ◽

Clinical Laboratory ◽

Human Study ◽

Post Exposure Prophylaxis ◽

Serious Adverse Events ◽

Dose Escalation Study ◽

Double Blind ◽

Time Curve ◽

Post Exposure

Objective Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given post-exposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. Methods This double-blind, single-center, placebo-controlled dose escalation study, randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at pre-specified time points for PK and immunogenicity analyses. Results Twenty-four subjects received study product (18 NTM-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life >20 days for the 0.330 mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent anti-drug antibody responses in the low and middle dosing groups and none at the highest dose. Interpretation NTM-1632 is well-tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and post-exposure prophylaxis.

Download Full-text

OC 8582 A PHASE IA/B STUDY TO ASSESS SAFETY AND IMMUNOGENICITY OF PLACENTAL MALARIA VACCINE CANDIDATE: PRELIMINARY RESULTS OF THE PRIMALVAC TRIAL

BMJ Global Health ◽

10.1136/bmjgh-2019-edc.35 ◽

2019 ◽

Vol 4 (Suppl 3) ◽

pp. A14.3-A15

Author(s):

Amadou Konate ◽

Laura Richert ◽

Arnaud Chêne ◽

Jean-Philippe Semblat ◽

Gwenaelle Roguet ◽

...

Keyword(s):

Adverse Events ◽

Burkina Faso ◽

Malaria Vaccine ◽

Clinical Laboratory ◽

Placental Malaria ◽

Safety Data ◽

Vaccine Trial ◽

Adult Women ◽

Serious Adverse Events ◽

Double Blind

BackgroundAdhesion of P. falciparum-infected erythrocytes (PEs) to placental chondroitin-4-sulfate (CSA) has been linked to severe placental malaria (PM) outcomes. Evidence strongly supports the VAR2CSA variant surface antigen mediating PEs CSA-binding phenotype as the leading candidate for a PM vaccine. This study was conducted to assess the safety and immunogenicity of 3 different dosages (20 µg, 50 µg and 100 µg) of the recombinant VAR2CSA protein (PRIMVAC), formulated with Alhydrogel or GLA-SE administered at days 0, 28 and 56.MethodsA randomised double-blind phase Ia/Ib dose-escalation vaccine trial was conducted in healthy adult women. Within 4 sequential cohorts, volunteers were randomised to 2 arms (PRIMVAC adjuvanted with Alhydrogel or GLA-SE) in the first phase conducted in France and then to 3 arms (PRIMVAC with Alhydrogel or GLA-SE or placebo) in Burkina Faso. Enrolled volunteers were observed for at least 1 hour following each vaccination then seen at 1 day and 7 days later for safety evaluations. Serious adverse events (SAE) were recorded throughout the study duration. Routine clinical laboratory safety analyses were performed prior to first injection and at each subsequent visit.ResultsA total of 68 subjects were recruited in the four study cohorts. No SAE was reported in any of the cohort A volunteers and enrolment in cohort B was started. A Data Safety Monitoring Board (DSMB) reviewed the safety data for cohorts A (20 µg) and B (50 µg) before the trial was initiated in Burkina Faso. The DSMB also reviewed the safety data in Burkina to authorise the progression from the cohort C (50 µg) to cohort D (100 µg). The last vaccination of the last subject occurred in September 2017.ConclusionThis was the first placental malaria vaccine phase Ia/b clinical trial conducted in France and Burkina Faso. No serious adverse events have been recorded. Preliminary safety and immunogenicity results will be presented.

Download Full-text

Safety and efficacy of glycopyrrolate as a premedication for endoscopic submucosal dissection: a randomized, double-blind, placebo-controlled study

Endoscopy ◽

10.1055/s-0043-112491 ◽

2017 ◽

Vol 49 (10) ◽

pp. 949-956 ◽

Cited By ~ 1

Author(s):

Eui Kim ◽

Min Um ◽

Kyoung Kim ◽

Jung Kim ◽

Su Kim ◽

...

Keyword(s):

Adverse Events ◽

Endoscopic Submucosal Dissection ◽

Medical Center ◽

Controlled Trial ◽

Controlled Study ◽

Research Information ◽

Serious Adverse Events ◽

Double Blind ◽

Double Blind Placebo ◽

Submucosal Dissection

Abstract Background and study aims Anticholinergic premedication has not been validated for endoscopic submucosal dissection (ESD). In this randomized, double-blind, placebo-controlled trial, we investigated the efficacy and safety of glycopyrrolate as a premedication for ESD. Methods A total of 196 patients undergoing ESD at a single tertiary medical center between December 2014 and February 2016 were randomly allocated to receive one of the following two premedications: glycopyrrolate (0.004 mg/kg intramuscularly [IM]) or placebo (2.0 mL normal saline solution IM). All patients received the premedication 30 minutes prior to ESD in a double-blind manner. The endoscopists reported the ease of performing the procedure and the incidence of secretion-induced hypoxemia, cough, and other procedure-related adverse events. Results Glycopyrrolate and placebo were received by 96 and 100 patients, respectively. ESD was successfully performed in all patients without any serious adverse events related to sedation or ESD. The median visual analog scale for procedure ease was higher in the glycopyrrolate group at 8 (interquartile range [IQR] 7 – 9) vs. 7 (IQR 6 – 8.25); P < 0.001. The proportions of patients with secretion-induced hypoxemia (4.4 % vs. 14.3 %; P = 0.03) and cough (16.7 % vs. 35.7 %; P = 0.005) were lower in the glycopyrrolate group. Conclusions The use of glycopyrrolate as a premedication for ESD significantly improved the ease of performing the procedure and reduced the incidence of secretion-induced hypoxemia and cough during ESD. Glycopyrrolate may be a promising premedication to ensure safe and stable ESD procedures.Trial registration: Clinical Research Information Service (CRIS): KCT0001540.

Download Full-text

Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00717-19 ◽

2019 ◽

Vol 63 (9) ◽

Cited By ~ 4

Author(s):

Nadine G. Rouphael ◽

Selwyn J. Hurwitz ◽

Mari Hart ◽

Allison Beck ◽

Evan J. Anderson ◽

...

Keyword(s):

Adverse Events ◽

Clinical Laboratory ◽

Subcutaneous Tissue ◽

Phase 1 ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Plasma Exposure ◽

Serious Adverse Events ◽

Double Blind ◽

Time Curve

ABSTRACT Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro. (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.)

Download Full-text

Safety and Pharmacokinetics of CD101 IV, a Novel Echinocandin, in Healthy Adults

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01627-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 45

Author(s):

Taylor Sandison ◽

Voon Ong ◽

Jonathan Lee ◽

Dirk Thye

Keyword(s):

Adverse Events ◽

Vital Signs ◽

High Plasma ◽

Primary Objective ◽

Healthy Adults ◽

Serious Adverse Events ◽

Double Blind ◽

Content Type

ABSTRACT CD101 IV is a novel echinocandin with distinctive pharmacokinetic properties that is being developed as a once-weekly treatment for candidemia and invasive candidiasis. CD101 has potent in vitro activity and in vivo efficacy against a broad range of Candida and Aspergillus species. The primary objective of two randomized, double-blind, placebo-controlled, dose-escalation studies in healthy adults was to determine the safety and tolerability of CD101 IV. Sequential cohorts of 8 subjects (n = 6, active; n = 2, placebo) were administered single (50, 100, 200, 400 mg) or multiple once-weekly (100 mg given once weekly for two weeks [×2], 200 mg ×2, 400 mg ×3) doses of CD101 IV infused over 1 h. There were no deaths, serious adverse events (SAEs), severe adverse events (AEs), or withdrawals from the study due to an AE. The majority of AEs were mild, and all completely resolved. There was a higher incidence of total AEs and mild transient infusion reactions in the 400-mg ×3 dose group. There were no clinically meaningful trends in postbaseline laboratory abnormalities and no safety issues related to electrocardiograms, vital signs, or physical exams. CD101 showed dose-proportional plasma exposures, minor accumulation (30% to 55%), low apparent clearance (<0.28 liter/h), long half-life (t 1/2) (>80 h), and minimal urine excretion. CD101 IV was safe and well tolerated at single and multiple doses of up to 400 mg given once weekly for 3 weeks and exhibited a long t 1/2, minimal accumulation over several weeks, negligible renal excretion, and high plasma exposures enabling once-weekly dosing.

Download Full-text

Randomized, Double-Blind, Placebo-Controlled Clinical Trial of a Two-Day Regimen of Dihydroartemisinin-Piperaquine for Malaria Prevention Halted for Concern over Prolonged Corrected QT Interval

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02667-14 ◽

2014 ◽

Vol 58 (10) ◽

pp. 6056-6067 ◽

Cited By ~ 37

Author(s):

Jessica Manning ◽

Pattaraporn Vanachayangkul ◽

Chanthap Lon ◽

Michele Spring ◽

Mary So ◽

...

Keyword(s):

Qt Interval ◽

Protective Efficacy ◽

Day Treatment ◽

Armed Forces ◽

Malaria Prevention ◽

Controlled Clinical Trial ◽

Double Blind ◽

Content Type ◽

Double Blind Placebo ◽

Qt Interval Prolongation

ABSTRACTDihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused byPlasmodium falciparumandPlasmodium vivaxin Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericia's formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (Cmax) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered atClinicalTrials.govunder registration no. NCT01624337.)

Download Full-text

Safety and tolerance of three probiotic strains in healthy infants: a multi-centre randomized, double-blind, placebo-controlled trial

Beneficial Microbes ◽

10.3920/bm2017.0009 ◽

2017 ◽

Vol 8 (4) ◽

pp. 569-578 ◽

Cited By ~ 5

Author(s):

S. Manzano ◽

J. De Andrés ◽

I. Castro ◽

J.M. Rodríguez ◽

E. Jiménez ◽

...

Keyword(s):

Adverse Events ◽

Head Circumference ◽

Controlled Trial ◽

Bifidobacterium Longum ◽

Lactobacillus Helveticus ◽

Serious Adverse Events ◽

Double Blind ◽

Double Blind Placebo ◽

Healthy Infants ◽

Probiotic Strains

Some strains of species belonging to the genera Bifidobacterium and Lactobacillus are used in order to maintain health. Although these organisms have a long record of safe use, it is important to assess their safety and tolerance in potentially vulnerable populations, such as infants. The objective of this study was to evaluate the safety and tolerance of three probiotic strains (Bifidobacterium longum subsp. infantis R0033, Bifidobacterium bifidum R0071 and Lactobacillus helveticus R0052) in healthy infants aged 3 to 12 months. A multi-centre randomized, double-blind, placebo-controlled intervention study with 221 healthy full-term infants was conducted. Infants received either a placebo or one of the 3 probiotic strains (3×109 cfu) daily during an 8 week intervention period. Growth (weight, height and head circumference), adverse events (AEs)/serious adverse events (SAEs), concentrations of D-lactic acid in urine samples, characteristics of the stools and use of medication were collected for safety evaluation. All 4 groups were homogeneous with respect to age, gender, feeding type, ethnicity, height, weight and head circumference at the start of the study. The results showed that changes in growth (weight, height and head circumference) were equivalent in all 4 groups. No SAEs were reported. Total number of AEs recorded was equivalent in all groups. Thus, the use of B. infantis R0033, L. helveticus R0052 and B. bifidum R0071 in infancy is safe, and well tolerated.

Download Full-text

Effect of scheduled antimicrobial and nicotinamide treatment on linear growth in children in rural Tanzania: A factorial randomized, double-blind, placebo-controlled trial

PLoS Medicine ◽

10.1371/journal.pmed.1003617 ◽

2021 ◽

Vol 18 (9) ◽

pp. e1003617

Author(s):

Mark D. DeBoer ◽

James A. Platts-Mills ◽

Sarah E. Elwood ◽

Rebecca J. Scharf ◽

Joann M. McDermid ◽

...

Keyword(s):

Adverse Events ◽

Maternal Education ◽

Linear Growth ◽

Controlled Trial ◽

Enteric Pathogen ◽

Mean Difference ◽

Double Blind ◽

Double Blind Placebo ◽

Intention To Treat ◽

High Prevalence

Background Stunting among children in low-resource settings is associated with enteric pathogen carriage and micronutrient deficiencies. Our goal was to test whether administration of scheduled antimicrobials and daily nicotinamide improved linear growth in a region with a high prevalence of stunting and enteric pathogen carriage. Methods and findings We performed a randomized, 2 × 2 factorial, double-blind, placebo-controlled trial in the area around Haydom, Tanzania. Mother–child dyads were enrolled by age 14 days and followed with monthly home visits and every 3-month anthropometry assessments through 18 months. Those randomized to the antimicrobial arm received 2 medications (versus corresponding placebos): azithromycin (single dose of 20 mg/kg) at months 6, 9, 12, and 15 and nitazoxanide (3-day course of 100 mg twice daily) at months 12 and 15. Those randomized to nicotinamide arm received daily nicotinamide to the mother (250 mg pills months 0 to 6) and to the child (100 mg sachets months 6 to 18). Primary outcome was length-for-age z-score (LAZ) at 18 months in the modified intention-to-treat group. Between September 5, 2017 and August 31, 2018, 1,188 children were randomized, of whom 1,084 (n = 277 placebo/placebo, 273 antimicrobial/placebo, 274 placebo/nicotinamide, and 260 antimicrobial/nicotinamide) were included in the modified intention-to-treat analysis. The study was suspended for a 3-month period by the Tanzanian National Institute for Medical Research (NIMR) because of concerns related to the timing of laboratory testing and the total number of serious adverse events (SAEs); this resulted in some participants receiving their final study assessment late. There was a high prevalence of stunting overall (533/1,084, 49.2%). Mean 18-month LAZ did not differ between groups for either intervention (mean LAZ with 95% confidence interval [CI]: antimicrobial: −2.05 CI −2.13, −1.96, placebo: −2.05 CI −2.14, −1.97; mean difference: 0.01 CI −0.13, 0.11, p = 0.91; nicotinamide: −2.06 CI −2.13, −1.95, placebo: −2.04 CI −2.14, −1.98, mean difference 0.03 CI −0.15, 0.09, p = 0.66). There was no difference in LAZ for either intervention after adjusting for possible confounders (baseline LAZ, age in days at 18-month measurement, ward, hospital birth, birth month, years of maternal education, socioeconomic status (SES) quartile category, sex, whether the mother was a member of the Datoga tribe, and mother’s height). Adverse events (AEs) and SAEs were overall similar between treatment groups for both the nicotinamide and antimicrobial interventions. Key limitations include the absence of laboratory measures of pathogen carriage and nicotinamide metabolism to provide context for the negative findings. Conclusions In this study, we observed that neither scheduled administration of azithromycin and nitazoxanide nor daily provision of nicotinamide was associated with improved growth in this resource-poor setting with a high force of enteric infections. Further research remains critical to identify interventions toward improved early childhood growth in challenging conditions. Trial registration ClinicalTrials.gov NCT03268902.

Download Full-text

Human Safety, Tolerability, and Pharmacokinetics of a Novel Broad-Spectrum Oral Antiviral Compound, Molnupiravir, with Activity Against SARS-CoV-2

10.1101/2020.12.10.20235747 ◽

2020 ◽

Author(s):

Wendy P. Painter ◽

Wayne Holman ◽

Jim A. Bush ◽

Firas Almazedi ◽

Hamzah Malik ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Adverse Events ◽

Clinical Laboratory ◽

Phase 1 ◽

Influenza Viruses ◽

Controlled Study ◽

Serious Adverse Events ◽

Double Blind ◽

Antiviral Compound ◽

Multiple Doses

AbstractMolnupiravir, EIDD-2801/MK-4482, the prodrug of the ribonucleoside analog ß-d-N4-hydroxycytidine (NHC), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, seasonal and pandemic influenza viruses, and respiratory syncytial virus.Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics.EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure.Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.Clinical trial identifierThis study was registered at ClinicalTrials.gov with the identifier NCT04392219.

Download Full-text