ABSTRACT
Monoclonal antibodies (mAbs) administered using intramuscular (IM) injections could offer a convenient and accessible therapeutic option. However, there is a paucity of data on IM tolerability by injection site to guide mAb development. This Phase 1, open-label trial randomized healthy adults to receive 62.5 mg/mL sotrovimab IM into each dorsogluteal muscle (2 × 4 mL injections), or 100 mg/mL sotrovimab IM into the dorsogluteal muscle (1 × 5 mL), the anterolateral thigh muscle (1 × 5 mL) or each deltoid muscle (2 × 2.5 mL). Incidence of adverse events (AEs), serious AEs (SAEs) and AEs of special interest (AESIs) were assessed, along with patient-reported outcomes (Perception of Injection version 3 questionnaire and Pain-Numeric Rating Scale [Pain-NRS]). Of 329 participants screened, 215 (65%) received sotrovimab (median age 39 [range 19–65] years; 57% female; mean body mass index 25.4 kg/m2). Overall, 46% (n = 99/215) of participants reported AEs; the most common was injection site pain (30%; n = 65/215). There were no SAEs reported, and all AESIs were Grade 1 or 2. Through Day 8, mean Pain-NRS values were < 1 and similar across injection sites; values were highest on Day 1 at 15 minutes post-dosing and decreased over time through Day 8. Injection site reactions were reported by all participants as ‘not at all’ or ‘a little’ bothersome. No or little impact on sleep and movement was reported. Sotrovimab IM was generally well tolerated at all injection sites, at volumes up to 5 mL (dorsogluteal and anterolateral thigh) and as one 2.5 mL injection into each deltoid muscle. To our knowledge, these are the first data to show that a >2 mL mAb injection into each deltoid muscle is well tolerated.
Trial registration
ClinicalTrials.gov identifier, NCT05280717
KEYWORDS: COVID-19, injection-site reaction, intramuscular, monoclonal antibody, pain, patient-reported outcome, Phase 1, safety, sotrovimab, tolerability
Introduction
Monoclonal antibodies (mAbs) are important treatment options for many diseases.1–3 They are often most effective when used early in the course of a disease with outpatient administration to individuals not requiring hospitalization.4 Intramuscular (IM) administration of mAbs can reduce the burden in healthcare facilities (for example, shortening appointment times, and requiring less infrastructure and infection-control measures compared with intravenous [IV] infusion)2,4 and enable staff in settings without IV facilities to administer treatment, thereby increasing access. However, there is a paucity of data on IM tolerability by injection site to guide mAb development.
Sotrovimab is a dual-action, Fc-engineered human mAb against the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).5–7 Administered as a single 500 mg intravenous (IV) dose, sotrovimab was shown in the pivotal COMET-ICE trial to significantly reduce the risk of all-cause >24-h hospitalization or death compared with placebo in high-risk patients with mild-to-moderate coronavirus disease 2019 (COVID-19).8
Subsequently, sotrovimab was developed for use with alternative non-parenteral routes of administration. Therapeutic mAbs using either subcutaneous (SC) or IM routes of administration have been developed for treatment or prevention of COVID-19.9,10 The developer considered that, on balance, IM was preferable to SC as the route of non-parenteral administration due to the higher absolute bioavailability with this route. Due to this strategic decision, pre-clinical data were not available to support the use of SC administration. Therefore, the Phase 3 COMET-TAIL trial was conducted during the period of Delta variant circulation and evaluated the efficacy, safety and tolerability of IM (administered in deltoid or dorsogluteal muscles) versus IV sotrovimab (62.5 mg/mL) in high-risk patients with mild-to-moderate COVID-19.11 Sotrovimab 500 mg IM (administered as two 4 mL injections in dorsogluteal muscles) was shown to be non-inferior to 500 mg IV, and no clinically meaningful safety or tolerability issues were observed over 36 weeks. Infusion-related reactions were rare, and almost all injection-site reactions (ISRs) were mild and resolved quickly.
To our knowledge, there are currently no data on the tolerability of higher mAb injection volumes (>2 mL) into the deltoid muscle. The aim of the COSMIC study (NCT05280717) was to investigate the relative bioavailability, safety and tolerability of two sotrovimab concentrations administered IM at different injection sites. In addition to the standard 62.5 mg/mL concentration, a 100 mg/mL concentration of sotrovimab was studied to assess a single injection in a dorsogluteal and anterolateral thigh muscle (5 mL) and 2.5 mL injections in the deltoid muscle (one injection in each muscle). Anterolateral thigh and deltoid injection sites were studied in addition to the dorsogluteal site to enable characterization of tolerability as well as rate and extent of absorption at these sites. The deltoid and the anterolateral thigh are both leaner than other IM injection sites, which may result in less variability in pharmacokinetic (PK) profiles. In addition, the deltoid is easily accessible, and a patient is able to receive an injection by exposing only the upper arm.
Methods
Study design
COSMIC was a Phase 1, parallel-group, open-label, randomized, single-treatment trial in healthy adults aged 18–65 years in the USA. The study was designed in three parts: Part A and an optional Part B were open-label and intended to evaluate administration of two sotrovimab concentrations at different IM sites; Part C (also open label) evaluated the safety and tolerability of sotrovimab 3000 mg administered IV. Here, we report results for the safety, tolerability and patient-reported outcomes (up to day 29 after sotrovimab IM administration) from Part A (PK results will be reported separately).
Approximately 190 participants were planned to be enrolled, assuming a 20% rate of non-evaluable participants to achieve approximately 150 evaluable participants across four treatment arms. Sample size calculations were driven by the PK primary endpoint based on assumed between-participant coefficient of variation (CVb) for AUCD1–29 and Cmax of 50%. Therefore, the randomization ratio of 2:2:1:1 was chosen to result in approximately 63 participants randomized to each of the 62.5 mg/mL and 100 mg/mL dorsogluteal arms, and approximately 32 participants randomized to each of the 100 mg/mL anterolateral thigh and deltoid arms (Figure 1). Participants were screened up to 28 days prior to dosing (to allow for eligibility assessments), and sotrovimab was administered on day 1 in each treatment arm as follows: 500 mg of 62.5 mg/mL sotrovimab administered into the dorsogluteal muscles as two 4 mL injections (one in each muscle); 500 mg of 100 mg/mL sotrovimab administered into a dorsogluteal muscle as one 5 mL injection, into an anterolateral thigh muscle as one 5 mL injection or into the deltoid as two 2.5 mL injections (one in each muscle). Participants received treatment with sotrovimab on day 1 and were followed for up to 35 weeks. Since exposure to mAbs after parenteral administration is known to be influenced by body mass index (BMI) and sex, participants were stratified at randomization by BMI category (18 to ≤25 kg/m2 and >25 to 30 kg/m2) and sex to aim for a balance of these characteristics between treatment groups.
Figure 1.
Study design.
aOver-enrollment within the regulatory guidance threshold.
AL anterolateral, BMI body mass index, DG dorsogluteal, IM intramuscular.
Adverse events (AEs), serious AEs (SAEs) and AEs of special interest (AESIs) were collected from dose administration until week 35. AESIs included hypersensitivity reactions occurring any time post-dose, ISRs, immunogenicity and AEs potentially related to antibody-dependent enhancement of disease. Standard toxicity grading according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (version 2.1; July 2017) was used to grade all AEs.
To evaluate the perception of injection and impact of ISRs, participants were required to complete patient-reported outcome (PRO) assessments on days 1, 2, 3, 5 and 8. Perception of Injection (PIN) version 3 – a 20-item questionnaire – was used to assess the participant’s perception of the injection across four dimensions (how bothersome ISRs are, impact on sleep, impact on movement and the acceptability of ISRs) and four individual items (anxiety before injection, bothersomeness during injection, satisfaction with the injection system and willingness to receive as a treatment). Participants provided a response for each PIN item on a 5-point scale (1 = most positive, 5 = least positive), performed before bedtime on day 1 and onsite on days 2, 3, 5 and 8. The Pain-Numeric Rating Scale (Pain-NRS) was used to assess the intensity of pain at the injection site. Participants were asked to rate their pain at the moment of injection on an 11-point scale (0 = no pain, 10 = worst pain imaginable). On day 1, the Pain-NRS was assessed onsite at 15 min, 30 min and 1 h after dosing, and at home before bedtime. Remaining Pain-NRS assessments were performed onsite on days 2, 3, 5 and 8.
Paracetamol/acetaminophen (doses ≤2 g/day) was permitted for use any time during the study. Other concomitant medications could be considered on a case-by-case basis by investigators, in consultation with the medical monitor if required.
Safety laboratory assessments (hematology, clinical chemistry and coagulation) were performed at screening and baseline; days 1 and 5; and weeks 2, 4, 8, 12 and 24. Vital signs (temperature, pulse rate, oxygen saturation, respiratory rate and blood pressure) were taken before each blood collection for laboratory tests.
Study population
Eligible male and female participants were aged 18–65 years and weighed ≥40 kg (BMI range 18–30 kg/m2). Participants were overtly healthy, as determined by medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. In addition, study participants must have received completed dose(s) of SARS-CoV-2 vaccine and were required to have a recent negative test result for COVID-19, determined by two consecutive negative results by any validated SARS-CoV-2 molecular test (e.g., reverse transcriptase polymerase chain reaction on any respiratory type) separated by >24 h. Key eligibility criteria are listed in Supplementary Table S1. All participants provided informed consent.
Study endpoints
The co-primary objectives of Part A of the study were to evaluate the safety and tolerability profile, and relative bioavailability, of 100 mg/mL IM sotrovimab and the 62.5 mg/mL formulation at the dorsogluteal injection site through day 29. Secondary objectives evaluated the safety and tolerability profile and relative bioavailability of 100 mg/mL IM sotrovimab administered at anterolateral thigh and deltoid injection sites and the 62.5 mg/mL formulation administered dorsogluteally through day 29. Here, we report the safety, tolerability and PRO data through day 29. PK data will be reported separately.
Data analysis
A Statistical Analysis Plan included the detailed analysis plan according to the clinical question of interest along with the estimand strategy. This Phase 1 study was not a confirmatory safety study and, therefore, in line with regulatory guidance on statistical principles for clinical trials and as defined in the study protocol, formal statistical hypothesis testing was out of the scope of the study.12 Safety and tolerability assessments, and evaluation of PRO measures (PIN and Pain-NRS), were carried out for all randomized participants who were exposed to the study intervention (safety population). Incidence of all AEs, SAEs and AESIs through day 29 were reported as frequency and percentage of participants. Descriptive statistics were reported for PIN and Pain-NRS through day 8. Missing data were not imputed.
Ethics
The study was conducted in accordance with the ethical principles derived from the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation Good Clinical Practice guidelines, and applicable laws and regulations (including compensation of patient out-of-pocket expenses). Ethics approval was obtained from institutional review boards and ethics committees. Written informed consent was provided prior to the study. This study complies with all applicable laws regarding subject privacy.
Results
Participant characteristics
Participants were enrolled at ten clinical centers in the USA between April and September 2022. Of 329 screened participants, 216 (65.7%) were randomized to treatment (62.5 mg/mL sotrovimab dorsogluteal, n = 72; 100 mg/mL sotrovimab dorsogluteal, n = 72; 100 mg/mL sotrovimab anterolateral thigh, n = 36; 100 mg/mL sotrovimab deltoid, n = 36) (Figure 2). One participant randomized to 62.5 mg/mL sotrovimab (dorsogluteal) did not receive study treatment (randomized later than 28 days after providing informed consent) and was excluded from the analyses. Two participants both randomized to receive a 100 mg/mL injection in the anterolateral thigh or dorsogluteal muscles instead received an injection in the deltoid. These participants were included in, and analyzed as part of, the treatment group that matched the treatment they actually received. Three participants withdrew consent during the study (two on day 16 and one on day 91). No participants withdrew due to AEs. The median (minimum, maximum) duration on study post-dose was 90 (16, 186) days. The majority (n = 213/215; 99.1%) of participants remained in the study for >29 days.
Figure 2.
Participant disposition (safety population).
aParticipants may have had more than one reason for screen failure.
bPer protocol randomization did not occur within 28 days of screening.
cOne participant randomized to 62.5 mg/mL sotrovimab (dorsogluteal) did not receive study treatment (randomized later than 28 days after providing informed consent) and was excluded from the analyses.
cOne participant randomized to 62.5 mg/mL sotrovimab (dorsogluteal) did not receive study treatment (randomized later than 28 days after providing informed consent) and was excluded from the analyses.
dTwo participants both randomized to 100 mg/mL anterolateral thigh or dorsogluteal arm instead received an injection in the deltoid. These participants were included in, and analyzed as part of, the treatment group that matched the treatment they actually received.
AE adverse event.
Demographic characteristics of the safety population are shown in Table 1. Median age was 39 years (range 19–65 years) and 57% of participants were female. The majority of participants were White (n = 179/211; 85%) and non-Hispanic/Latino (n = 176/212; 83%). Mean (standard deviation) overall BMI was 25.43 (2.874). Of note, a numerically lower proportion of participants who received deltoid administration had BMI in the range 18 to ≤25 kg/m2 compared with other groups (37% vs. 44–49%), although mean BMI appeared to be similar across all groups.
Table 1.
Participant characteristics (safety population).
| Characteristics | 62.5 mg/mL sotrovimab (dorsogluteal) (n = 71) |
100 mg/mL sotrovimab (dorsogluteal) (n = 71) |
100 mg/mL sotrovimab (anterolateral thigh) (n = 35) |
100 mg/mL sotrovimab (deltoid) (n = 38) |
Total (N = 215) |
|---|---|---|---|---|---|
| Age (years) | |||||
| Median (range) Mean (SD) |
38.0 (21–65) 39.0 (11.8) |
40.0 (19–62) 38.5 (10.9) |
38.0 (19–61) 37.6 (12.8) |
41.5 (19–61) 40.3 (12.9) |
39.0 (19–65) 38.8 (11.8) |
| Female, n (%) | 42 (59) | 39 (55) | 21 (60) | 20 (53) | 122 (57) |
| Male, n (%) | 29 (41) | 32 (45) | 14 (40) | 18 (47) | 93 (43) |
| Race, n | 71 | 70 | 33 | 37 | 211 |
| Black or African American, n (%) | 6 (8) | 2 (3) | 3 (9) | 4 (11) | 15 (7) |
| White, n (%) Asian, n (%) Other,a n (%) |
60 (85) 2 (3) 3 (4) |
63 (90) 3 (4) 2 (3) |
25 (76) 2 (6) 3 (9) |
31 (84) 1 (3) 1 (3) |
179 (85) 8 (4) 9 (4) |
| Ethnicity, n | 70 | 70 | 34 | 38 | 212 |
| Hispanic/Latino, n (%) | 10 (14) | 12 (17) | 9 (26) | 5 (13) | 36 (17) |
| Non-Hispanic/Latino, n (%) | 60 (86) | 58 (83) | 25 (74) | 33 (87) | 176 (83) |
| BMI (kg/m2), mean (SD) | 25.72 (2.751) | 25.22 (3.214) | 25.00 (2.235) | 25.70 (2.967) | 25.43 (2.874) |
| BMI category (kg/m2), n (%) | |||||
| 18 to ≤ 25 | 31 (44) | 35 (49) | 16 (46) | 14 (37) | 96 (45) |
| >25 to 30 | 40 (56) | 36 (51) | 19 (54) | 24 (63) | 119 (55) |
| Tobacco-use history, n (%) | |||||
| Never Former Current |
64 (90) 5 (7) 2 (3) |
61 (86) 8 (11) 2 (3) |
27 (77) 4 (11) 4 (11) |
32 (84) 5 (13) 1 (3) |
184 (86) 22 (10) 9 (4) |
| Alcohol-use history, n (%) | |||||
| Never Former Current Units per week, mean (SD) |
24 (34) 2 (3) 45 (63) 1.96 (1.39) |
26 (37) 5 (7) 40 (56) 3.03 (2.53) |
14 (40) 2 (6) 19 (54) 3.16 (2.57) |
13 (34) 3 (8) 22 (58) 2.45 (2.32) |
77 (36) 12 (6) 126 (59) 2.56 (2.19) |
| Most common past medical conditions (≥10% in any group; SOC, PT), n (%) | |||||
| Infections and infestations COVID-19 Surgical and medical procedures Caesarean section Injury, poisoning and procedural complications |
21 (30) 17 (24) 19 (27) 2 (3) 3 (4) |
21 (30) 17 (24) 19 (27) 5 (7) 4 (6) |
16 (46) 16 (46) 11 (31) 4 (11) 2 (6) |
6 (16) 4 (11) 15 (39) 3 (8) 4 (11) |
64 (30) 54 (25) 64 (30) 14 (7) 13 (6) |
| Most common current medical conditions (≥10% in any group; SOC, PT), n (%) | |||||
| Immune system disorders Seasonal allergy Drug hypersensitivity |
23 (32) 16 (23) 8 (11) |
16 (23) 13 (18) 4 (6) |
10 (29) 7 (20) 3 (9) |
15 (39) 10 (26) 8 (21) |
64 (30) 46 (21) 23 (11) |
| Psychiatric disorders Anxiety |
12 (17) 5 (7) |
13 (18) 8 (11) |
6 (17) 3 (9) |
5 (13) 1 (3) |
36 (17) 17 (8) |
| Nervous system disorders Migraine |
8 (11) 4 (6) |
13 (18) 7 (10) |
4 (11) 1 (3) |
4 (11) 2 (5) |
29 (13) 14 (7) |
| Respiratory, thoracic and mediastinal disorders Rhinitis perennial |
9 (13) 6 (8) |
6 (8) 4 (6) |
5 (14) 4 (11) |
4 (11) 3 (8) |
24 (11) 17 (8) |
| Skin and subcutaneous tissue disorders | 2 (3) | 8 (11) | 4 (11) | 1 (3) | 15 (7) |
| Social circumstances Post-menopause |
5 (7) 5 (7) |
2 (3) 1 (1) |
2 (6) 2 (6) |
4 (11) 4 (11) |
13 (6) 12 (6) |
aAmerican Indian or Alaska Native; Native Hawaiian or other Pacific Islander; or mixed race.
BMI body mass index, COVID-19 coronavirus disease 2019, PT Preferred Term, SD standard deviation, SOC System Organ Class.
Just over half of participants (n = 121/215; 56%) had any past medical conditions, mostly ‘infections and infestations’ and ‘surgical and medical procedures’ (Table 1). A quarter of participants (n = 54/215; 25%) had a history of COVID-19 infection. Most participants (n = 184/215; 86%) had no tobacco-use history and 59% (n = 126/215) had current history of any alcohol intake (median two units per week, range 0–10).
Safety and tolerability
Overall, 46% (n = 99/215) of participants reported any AE through day 29 post-dosing (Table 2). The most common AE overall was injection-site pain (n = 65/215; 30%) followed by confirmed COVID-19 infection/positive SARS-CoV-2 test result (n = 12/215; 6%).
Table 2.
AE overview at day 29 (safety population).
| 62.5 mg/mL sotrovimab (dorsogluteal) (n = 71) |
100 mg/mL sotrovimab (dorsogluteal) (n = 71) |
100 mg/mL sotrovimab (anterolateral thigh) (n = 35) |
100 mg/mL sotrovimab (deltoid) (n = 38) |
Total (N = 215) |
|
|---|---|---|---|---|---|
| Any AE, n (%) | 36 (51) | 25 (35) | 17 (49) | 21 (55) | 99 (46) |
| AEs related to study treatment | 25 (35) | 16 (23) | 13 (37) | 18 (47) | 72 (33) |
| AEs leading to permanent discontinuation of study treatment | 0 | 1 (1) | 0 | 0 | 1 (<1) |
| Any max Grade 3–4 AE, n (%) | 1 (1) | 1 (1) | 0 | 0 | 2 (<1) |
| AEs related to study treatment | 0 | 1 (1) | 0 | 0 | 1 (<1) |
| AEs leading to permanent discontinuation of study treatment |
0 | 1 (1) | 0 | 0 | 1 (<1) |
| Most common (≥5%) AEs, n (%) | |||||
| Injection-site pain | 24 (34) | 14 (20) | 9 (26) | 18 (47) | 65 (30) |
| Positive COVID-19 or SARS-CoV-2 test result |
8 (11) | 1 (1) | 0 | 3 (8) | 12 (6) |
| Injection-site induration | 2 (3) | 2 (3) | 4 (11) | 1 (3) | 9 (4) |
| Headache | 0 | 6 (8) | 1 (3) | 1 (3) | 8 (4) |
| Urinary tract infection | 2 (3) | 0 | 2 (6) | 0 | 4 (2) |
AE adverse event, COVID-19 coronavirus disease 2019, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.
AEs related to study treatment were reported in one-third of participants (n = 72/215; 33%) (Table 3). Among participants receiving dorsogluteal administration, treatment-related injection-site pain was reported in 32% (n = 23/71) of the 62.5 mg/mL (2 × 4 mL injections) group and 17% (n = 12/71) of the 100 mg/mL (1 × 5 mL injection) group. Injection-site pain was numerically most common in the 100 mg/mL deltoid group (n = 17/38; 45%); however, injection-site hemorrhage, bruising, erythema, pruritus or swelling were not observed in any participant after deltoid administration. Two (<1%) participants had Grade 3 AEs: COVID-19 infection (62.5 mg/mL dorsogluteal group) and presyncope (100 mg/mL dorsogluteal group). The presyncope event was considered by the investigator to be drug-related and resulted in permanent discontinuation of study treatment (participant not given full dose amount). The incidence of other treatment-related AEs was low across all treatment groups.
Table 3.
Non-serious drug-related adverse events at day 29 (safety population).
| Preferred Term | 62.5 mg/mL sotrovimab (dorsogluteal) (n = 71) | 100 mg/mL sotrovimab (dorsogluteal) (n = 71) | 100 mg/mL sotrovimab (anterolateral thigh) (n = 35) |
100 mg/mL sotrovimab (deltoid) (n = 38) | Total (N = 215) |
|---|---|---|---|---|---|
| Any event, n (%) | 25 (35) | 16 (23) | 13 (37) | 18 (47) | 72 (33) |
| Injection-site pain | 23 (32) | 12 (17) | 9 (26) | 17 (45) | 61 (28) |
| Injection-site induration | 2 (3) | 2 (3) | 3 (9) | 1 (3) | 8 (4) |
| Headache | 0 | 2 (3) | 0 | 1 (3) | 3 (1) |
| Injection-site hemorrhage | 1 (1) | 1 (1) | 1 (3) | 0 | 3 (1) |
| Fatigue | 1 (1) | 1 (1) | 0 | 0 | 2 (1) |
| Injection-site erythema | 0 | 2 (3) | 0 | 0 | 2 (1) |
| Injection-site pruritus | 0 | 1 (1) | 1 (3) | 0 | 2 (1) |
| Diarrhoea | 0 | 1 (1) | 0 | 0 | 1 (<1) |
| Ecchymosis | 0 | 0 | 1 (3) | 0 | 1 (<1) |
| Gastritis | 1 (1) | 0 | 0 | 0 | 1 (<1) |
| Injection-site swelling | 1 (1) | 0 | 0 | 0 | 1 (<1) |
| Pain | 1 (1) | 0 | 0 | 0 | 1 (<1) |
| Palpitations | 0 | 0 | 1 (3) | 0 | 1 (<1) |
| Peripheral swelling | 0 | 0 | 1 (3) | 0 | 1 (<1) |
| Presyncope | 0 | 1 (1) | 0 | 0 | 1 (<1) |
| Procedural dizziness | 1 (1) | 0 | 0 | 0 | 1 (<1) |
| Pruritus | 0 | 0 | 1 (3) | 0 | 1 (<1) |
No Grade 4 AEs, SAEs or fatal SAEs were reported in any treatment group, and there were no renal, cardiac or pulmonary events.
All AESIs were Grade 1 or 2. ISRs were the most common AESI, occurring in 32% (n = 69/215) of participants (Table 4). Injection-site induration was reported by ten participants across the study; all such events were Grade 1, and most (in 7/10 participants) resolved during day 1. Hypersensitivity reaction (contact dermatitis after exposure to Poison Oak) was reported in one participant on study day 4 in the 100 mg/mL anterolateral thigh group.
Table 4.
AESIs: ISRs and hypersensitivity reactions at day 29 (safety population).
| Preferred Term | 62.5 mg/mL sotrovimab (dorsogluteal) (n = 71) |
100 mg/mL sotrovimab (dorsogluteal) (n = 71) |
100 mg/mL sotrovimab (anterolateral thigh) (n = 35) |
100 mg/mL sotrovimab (deltoid) (n = 38) |
Total (N = 215) |
|---|---|---|---|---|---|
| Any AESI, n (%) | 24 (34) | 15 (21) | 13 (37) | 18 (47) | 70 (33) |
| Injection-site reactions, n (%) | |||||
| Any event | 24 (34) | 15 (21) | 12 (34) | 18 (47) | 69 (32) |
| Injection-site pain | 24 (34) | 14 (20) | 9 (26) | 18 (47) | 65 (30) |
| Injection-site induration | 2 (3) | 2 (3) | 5 (14) | 1 (3) | 10 (5) |
| Injection-site hemorrhage | 1 (1) | 1 (1) | 1 (3) | 0 | 3 (1) |
| Injection-site bruising | 2 (3) | 0 | 0 | 0 | 2 (1) |
| Injection-site erythema | 0 | 2 (3) | 0 | 0 | 2 (1) |
| Injection-site pruritus | 0 | 1 (1) | 1 (3) | 0 | 2 (1) |
| Injection-site swelling | 1 (1) | 0 | 0 | 0 | 1 (<1) |
| Hypersensitivity reactions, n (%) | |||||
| Dermatitis contact | 0 | 0 | 1 (3) | 0 | 1 (<1) |
AESI adverse event of special interest, ISR injection-site reaction.
Results of the local injection-site tolerability assessments through day 8 are shown in Supplementary Figure S1. Consistent with AESIs, most ISRs were mild, and the maximum severity was Grade 2 (reported in 1–3% of participants). Mild pain and tenderness were observed in each of the treatment groups but generally declined over time. A numerically larger proportion of participants in the deltoid administration group reported Grade 1 pain at early time points (34% at 15 min post-dose, 26% at 1 h post-dose) than in other groups (9–13% at 15 min post-dose, 1–8% at 1 h post-dose), but the pain resolved over time. Grade 1 induration was numerically more common with 100 mg/mL anterolateral thigh administration (11% at 15 min post-dose) than at other administration sites (0–3% at 15 min post-dose) but declined within 30 min post-dose and was not observed by day 5.
Post day 29, two (<1%) participants reported SAEs (of which all but one event resolved through week 35) and the events were not considered by the investigator as related to study intervention. Immunogenicity findings demonstrated that a total of 210 participants were classified as anti-drug antibody (ADA)-negative post-baseline and a total of two (<1%) were considered treatment-emergent ADA. No study participant tested positive for neutralizing antibodies through week 35.
Vital signs and laboratory results
Worst-case post-baseline changes in vital signs and laboratory results through day 29 are shown in Supplementary Table S2. Overall, 5% and 3% of participants had a Grade 1 increase in alanine aminotransferase and aspartate aminotransferase, respectively. One participant each had a post-baseline increase to Grade 2 in alanine and aspartate aminotransferase, both from the 100 mg/mL sotrovimab (dorsogluteal) group. One participant, who had a history of Gilbert’s syndrome, had a Grade 2 post-baseline increase in total bilirubin; no participant met Hy’s Law quadrant thresholds.13
Perception of injection and pain rating
Day 1 PIN questionnaire results showed that the majority of participants across each treatment group felt that ISRs were ‘not at all’ bothersome (≥66%), and local reactions (≥91%) and pain (≥94%) were ‘totally’ or ‘very acceptable’ (Table 5). No or little impact on sleep and movement was reported, and most participants in each treatment group stated that they were ‘satisfied/very satisfied’ with the injection system (≥86%) and would ‘definitely/probably’ use the injection if it were available as a treatment (≥89%) (Table 5). In general, the impact and bothersomeness of ISRs reduced over time (Supplementary Figure S2; Table 5).
Table 5.
PIN questionnaire results (day 1; safety population).
| Participants responding, n (%) |
|||||
|---|---|---|---|---|---|
| Domain | Item, response | 62.5 mg/mL sotrovimab (dorsogluteal) (n = 71) |
100 mg/mL sotrovimab (dorsogluteal) (n = 71) |
100 mg/mL sotrovimab (anterolateral thigh) (n = 35) | 100 mg/mL sotrovimab (deltoid) (n = 38) |
| How bothered were you by this symptom at your injection site? | Pain | ||||
| Not at all A little |
55 (77) 16 (23) |
64 (90) 7 (10) |
28 (80) 5 (14) |
25 (66) 13 (34) |
|
| Redness | |||||
| Not at all A little |
70 (99) 1 (1) |
68 (96) 3 (4) |
33 (94) 2 (6) |
38 (100) – |
|
| Swelling | |||||
| Not at all A little Moderately |
66 (93) 5 (7) – |
71 (100) – – |
31 (89) 3 (9) 1 (3) |
36 (95) 2 (5) – |
|
| Itching | |||||
| Not at all A little Moderately |
66 (93) 5 (7) – |
69 (97) 2 (3) – |
32 (91) 2 (6) 1 (3) |
37 (97) 1 (3) – |
|
| Hardening (a bump) | |||||
| Not at all A little Moderately Extremely |
68 (96) 3 (4) – – |
68 (96) 3 (4) – – |
32 (91) 1 (3) 2 (6) – |
33 (87) 4 (11) – 1 (3) |
|
| Bruising | |||||
| Not at all A little Moderately Very |
69 (97) 2 (3) – – |
70 (99) 1 (1) – – |
33 (94) 1 (3) 1 (3) – |
36 (95) 1 (3) – 1 (3) |
|
| Impact on sleep: How much did the local reactions bother you when … | Falling asleep | ||||
| Not at all A little No answer provided |
69 (97) 2 (3) – |
68 (96) 2 (3) 1 (1) |
33 (94) 2 (6) – |
36 (95) 2 (5) – |
|
| Changing sleep positions during the night | |||||
| Not at all A little No answer provided |
69 (97) 2 (3) – |
69 (97) 1 (1) 1 (1) |
30 (86) 5 (14) – |
36 (95) 2 (5) – |
|
| Pain when falling asleep | |||||
| Not at all A little Moderately Very |
66 (93) 4 (6) – 1 (1) |
69 (97) 2 (3) – – |
32 (91) 2 (6) 1 (3) – |
36 (95) 2 (5) – – |
|
| Pain when changing sleep positions | |||||
| Not at all A little Moderately |
67 (94) 3 (4) 1 (1) |
70 (99) 1 (1) – |
30 (86) 5 (14) – |
34 (89) 4 (11) – |
|
| Impact on movement: How much do the local reactions cause you difficulties when … | Moving/walking | ||||
| Not at all A little Moderately |
69 (97) 2 (3) – |
71 (100) – – |
31 (89) 3 (9) 1 (3) |
38 (100) – – |
|
| Picking up/carrying | |||||
| Not at all A little Moderately |
70 (99) 1 (1) – |
71 (100) – – |
33 (94) 1 (3) 1 (3) |
36 (95) 2 (5) – |
|
| Pain caused moving/walking | |||||
| Not at all A little Moderately |
70 (99) 1 (1) – |
70 (99) 1 (1) – |
31 (89) 2 (6) 2 (6) |
38 (100) – – |
|
| Pain caused picking up/carrying | |||||
| Not at all A little Moderately |
70 (99) 1 (1) – |
71 (100) – – |
34 (97) – 1 (3) |
36 (95) 2 (5) – |
|
| Acceptability | Acceptability of local reactions | ||||
| Totally acceptable Very acceptable Moderately acceptable No answer provided |
62 (87) 8 (11) 1 (1) – |
67 (94) 4 (6) – – |
31 (89) 1 (3) 3 (9) – |
34 (89) 3 (8) – 1 (3) |
|
| Acceptability of pain | |||||
| Totally acceptable Very acceptable Moderately acceptable No answer provided |
61 (86) 8 (11) 2 (3) – |
64 (90) 6 (8) 1 (1) – |
27 (77) 6 (17) 2 (6) – |
33 (87) 4 (11) – 1 (3) |
|
| Anxiety before injection | Anxious before injection | ||||
| Not at all A little Moderately Very Extremely |
29 (41) 35 (49) 6 (8) 1 (1) – |
30 (42) 33 (46) 7 (10) 1 (1) – |
11 (31) 17 (49) 5 (14) 2 (6) – |
17 (45) 14 (37) 4 (11) 2 (5) 1 (3) |
|
| Bothersomeness during injection | Pain during injection | ||||
| Not at all A little Moderately Very |
37 (52) 26 (37) 5 (7) 3 (4) |
40 (56) 25 (35) 4 (6) 2 (3) |
11 (31) 18 (51) 5 (14) 1 (3) |
16 (42) 17 (45) 3 (8) 2 (5) |
|
| Satisfaction with the injection system (needle, syringe) | Administration (injection system) satisfaction | ||||
| Very satisfied Satisfied Neither satisfied or dissatisfied Dissatisfied |
58 (82) 10 (14) 2 (3) 1 (1) |
51 (72) 11 (15) 8 (11) 1 (1) |
22 (63) 8 (23) 5 (14) – |
25 (66) 12 (32) – 1 (3) |
|
| Would you use this study injection if it were available as a treatment? |
Re-use intention | ||||
| Yes, definitely Yes, probably I don’t know Probably not |
51 (72) 17 (24) 3 (4) – |
49 (69) 15 (21) 5 (7) 2 (3) |
21 (60) 10 (29) 4 (11) – |
30 (79) 5 (13) 3 (8) – |
|
PIN Perception of Injection version 3.
Mean Pain-NRS values on day 1 through day 8 were < 1 and similar across injection sites. Mean values were highest on day 1 at 15 min post-dosing and then generally decreased rapidly through 60 min post-dosing (Figure 3). Mean Pain-NRS scores decreased for all treatment groups over time, with five participants reporting any pain on or after day 3. Pain-NRS scores were generally numerically lower in the 62.5 mg/mL dorsogluteal treatment group compared with the 100 mg/mL groups.
Figure 3.
Pain-NRS score over time (day 1 and through day 8) by treatment group (safety population).
Pain-NRS is scored from 0–10, where 0 = no pain and 10 = worst pain imaginable. Solid lines represent 5th to 95th percentile; dots represent outliers.
AL anterolateral, DG dorsogluteal, Pain-NRS Pain-Numeric Rating Scale.
Discussion
Access to treatment with mAbs can be limited due to logistical challenges of IV administration; an IM route of administration could allow delivery of mAb treatments in a wider range of clinical settings, thereby improving patient access.11 This large Phase 1 study evaluated the safety and tolerability of sotrovimab administered via IM injection at different body sites and concentrations in healthy adults using comprehensive, validated PRO measures. Sotrovimab 500 mg IM injection had a favorable safety profile and was generally well tolerated at all injection sites, at volumes of up to 5 mL at dorsogluteal and anterolateral thigh sites or given as one 2.5 mL injection into each deltoid muscle. Data from PRO measures were also favorable, with pain rating scores low through day 8 and the majority of participants reporting that ISRs were not bothersome.
Although tolerability data are available for IM injections of mAbs in the dorsogluteal and thigh muscles, COSMIC is the first study (to our knowledge) to report data for IM administration of >2 mL in each deltoid muscle. Injection-site pain AEs were most commonly reported with administration in deltoid muscles (two 2.5 mL injections). However, this group was also the most likely to answer ‘yes, definitely’ to the question on re-use intention. It is possible that the greater convenience of deltoid administration compared with the other sites outweighs the short-lived and mild injection-site pain. Although several reviews have suggested that the upper limit of IM injection volume for deltoid muscles is 2 mL,14–16 there is at least one small-molecule treatment with an option for a single 2.4 mL injection in the deltoid or gluteal muscle (albeit for an acute indication).17 In addition, deltoid muscle volumes of approximately 380 mL (in young healthy participants) and 219 mL (in a cadaveric study) have been reported,18,19 implying sufficient residual capacity to absorb the additional 0.5 mL volume above the conventional upper limit of 2 mL.
In the current study, a single 5 mL dorsogluteal injection of 100 mg/mL sotrovimab was associated with numerically fewer reports of injection-site pain AEs than two 4 mL injections of 62.5 mg/mL; however, re-use intention was similar, and two participants in the single 5 mL injection group answered ‘probably not’. This may reflect the low grade and rapid resolution of pain episodes, such that both groups found that their injections were overall tolerable. Injection-site induration was most commonly reported with administration in the anterolateral thigh muscle (single 5 mL injection), although numbers were small across all groups. The proportion of participants who reported ‘very bothersome’ pain was also low (3–5%) across all groups.
Typical sites for IM injections include those tested in the current study (deltoid, anterolateral thigh and dorsogluteal muscles) along with ventrogluteal muscles, although dorsogluteal injection is now less frequently used due to potential injury to the sciatic nerve.20 As mentioned previously, IM injection volumes are relatively low, necessitating a more concentrated product compared with that required for IV administration.20 Our finding that volumes of up to 5 mL are feasible for injection in deltoid (two 2.5 mL injections) and anterolateral (one 5 mL injection) muscle may have positive implications for future development of mAb treatments.
No new or unexpected safety concerns were observed with IM sotrovimab. Two participants reported SAEs (neither was considered to be treatment related) and no deaths occurred. No renal, cardiac or pulmonary events were reported in any treatment group. There were no drug-related hypersensitivity reactions. Rates of study withdrawal were low, and none were related to AEs or COVID-19 infection.
The safety and tolerability findings from this study are similar to those observed in the COMET-TAIL and COMET-PEAK trials, which assessed the efficacy and safety of sotrovimab 500 mg IM injection in the dorsogluteal and deltoid muscles in adults with early mild-to-moderate COVID-19.11,21 In COMET-TAIL, participants were randomized 1:1:1 to receive sotrovimab 500 mg IV, 500 mg IM or 250 mg IM.11 For the 250 mg dose, participants were to receive either one 4 mL injection in the dorsogluteal muscle or 2 × 2 mL injections in each deltoid. Local tolerability assessments were solicited on the day of administration (15- and 30-min post-dose), day 3, day 5 and day 8. There were 25 participants randomized to receive sotrovimab 250 mg IM who received their dose in the deltoids. Of these, nine participants experienced a Grade 1 ISR and one experienced Grade 2 ISRs (pain and tenderness), with the majority occurring at 15–30 min post-dose. The most common ISR reported was pain (6/25, 24%), which was mild and of short duration. In COMET-PEAK Part C, participants randomized to the 250 mg IM treatment group were assessed for local ISRs at 1 h post-dose, as well as on days 2 and 3.21 Similar to COMET-TAIL, participants in the IM group could receive either deltoid (2 × 2 mL) or dorsogluteal injection (1 × 4 mL). In total, 12 participants received deltoid injection. Of these, two participants reported local ISRs: one participant experienced a Grade 1 deltoid injection-site nodule (swelling) at the 1-h post-dose assessment that resolved by the 2-h post-dose assessment on day 1, and one participant experienced Grade 1 pain on day 2 only.
Treatment acceptability is a key consideration in the implementation and effectiveness of healthcare interventions.22,23 If a treatment is acceptable, with a good tolerability profile, patients are more likely to be adherent to, and benefit from, treatment recommendations.23,24 Patients typically have concerns and experience anxiety when starting on a new medication, especially injections. Understanding patients’ perceptions of injectables, and identifying barriers to their use, is important for improving uptake and facilitating medication adherence.22 ISRs have been cited as a common barrier to uptake of injectable therapies22; however, participant responses to the PIN questionnaire in our study indicate that ISRs associated with IM injection of sotrovimab are not burdensome and have little impact on sleep or movement. Mean Pain-NRS scores were low across each of the treatment groups, indicating little pain associated with IM administration, which decreased over time. The tolerability of sotrovimab IM was further endorsed by the positive response of participants regarding their willingness to receive sotrovimab IM as a treatment and satisfaction with the mode of injection.
This study has some limitations that should be considered. Although the study aimed to enroll a diverse population, the majority of participants (85%) were White and 83.0% were non-Hispanic/Latino. COSMIC is an open-label study, typical of Phase 1 trials, and did not include a placebo control group. Conclusions drawn will require further prospective validation in larger, randomized controlled trials enrolling participants with a broad demographic profile. Since COSMIC was a healthy volunteer study, additional research will be needed to understand if the findings translate into patient populations. Depending on the disease area, patients may be older and have smaller muscle mass than healthy volunteers, which could impact tolerability of IM injection in smaller muscles such as the deltoid. This study nevertheless provides important precursor data for drug developers when considering IM injection site and injection volume.
Conclusion
In this large (n = 215) Phase 1 study, sotrovimab 500 mg IM was generally well tolerated at all injection sites, at volumes of up to 5 mL at dorsogluteal and anterolateral thigh sites and as one 2.5 mL injection into each deltoid muscle. To our knowledge, these are the first detailed data reporting across a number of validated assessment tools to show that a >2 mL (2.5 mL) mAb injection into each deltoid muscle is well tolerated. These data from healthy volunteers could provide the basis for further research into the use of 2.5 mL injection volumes of mAbs in the deltoid muscle.
Supplementary Material
Acknowledgments
Medical writing, editorial and other assistance. Editorial support (in the form of writing assistance, including preparation of the draft manuscript under the direction and guidance of the authors, collating and incorporating authors’ comments for each draft, assembling tables, grammatical editing and referencing) was provided by Tony Reardon of Luna, OPEN Health Communications, and funded by GSK and Vir Biotechnology, Inc.™, in accordance with Good Publication Practice (GPP) guidelines (www.ismpp.org/gpp-2022).
Funding Statement
Study sponsored by GSK [study 218128] in collaboration with Vir Biotechnology, IncTM.
Disclosure statement
Jennifer Moore (at time of study conduct), Alicia Aylott, Wen-Hung Chen, Jerzy Daniluk, Ian A. Hawes (at time of study conduct), Prosenjit Sakar, Yasmin Sanchez-Pearson, Megan Turner, Amanda Peppercorn and Andrew Skingsley are employees of, and/or hold financial equities in, GSK. Sergio Parra is an employee of, and holds stocks/shares in, Vir Biotechnology, Inc™.
Authors’ contributions
All authors made a significant contribution to the work reported, whether that was in the conception, study design, execution, acquisition of data, analysis and interpretation or in all these areas; took part in drafting, revising or critically reviewing the manuscript; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Data availability statement
Anonymized individual participant data and study documents can be requested for further research from https://www.gsk-studyregister.com/en/.
Ethics approval
The study was conducted in accordance with the ethical principles derived from the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation Good Clinical Practice guidelines, and applicable laws and regulations. Ethics approval was obtained from institutional review boards and ethics committees. Written informed consent was provided prior to study. This study complies with all applicable laws regarding subject privacy.
Prior presentation
This manuscript is based on work that has been previously presented at IDWeek, October 11–15, 2023, Boston, MA, USA.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19420862.2025.2456467
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Anonymized individual participant data and study documents can be requested for further research from https://www.gsk-studyregister.com/en/.