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Taltz ® (ixekizumab)
This information is intended for UK registered healthcare professionals only in response to your search for information. For current information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).
Are injection site reactions with Taltz® (ixekizumab) frequent?
ISRs were more frequently reported with ixekizumab compared with placebo in patients with PsO, PsA, or axSpA. In healthy participants, ISRs were reported less frequently with citrate-free ixekizumab than with original ixekizumab.
Table of Contents
Original Ixekizumab Formulation and Citrate-Free Ixekizumab Formulation
Injection Site Reactions in Clinical Trials Using Citrate-Free Ixekizumab
Injection Site Reactions in Clinical Trials Using the Original Formulation of Ixekizumab
Original Ixekizumab Formulation and Citrate-Free Ixekizumab Formulation
The original formulation of ixekizumab that contained citrate was used in clinical trials conducted in patients with moderate-to-severe plaque psoriasis, active psoriatic arthritis, ankylosing spondylitis (AS), and nonradiographic axial spondyloarthritis (nr-axSpA). Information is available in Injection Site Reactions in Clinical Trials Using the Original Formulation of Ixekizumab.
The currently marketed citrate-free ixekizumab formulation was studied in clinical trials conducted in healthy participants. Information is available in Injection Site Reactions in Clinical Trials Using Citrate-Free Ixekizumab.
Note that multiple, different dosing regimens, including unapproved doses, as well as an unapproved formulation are included in this response. Please refer to Taltz summary of product characteristics for full prescribing information.
Injection Site Reactions in Clinical Trials Using Citrate-Free Ixekizumab
The aim of the citrate-free formulation program was the reduction in injection site pain and to ensure the same bioavailability and bioequivalence of the original commercial ixekizumab formulation.1
Erythema, pain, and pruritus were injection site reactions (ISRs) reported in trials of citrate-free ixekizumab. While reductions in ISRs other than injection pain were noted, the studies were not designed to make comparisons across the formulations for ISRs other than pain. Information on spontaneous reports of erythema, pain, and pruritus in the bioequivalence study is available in Summary of Injection Site Reactions in Ixekizumab Citrate-Free Bioequivalence Study in Healthy Participants. Until more data are available in patients, the impact of the citrate-free formulation on types of ISRs other than pain is to be determined.
Trial RHCS was a trial conducted in healthy participants to determine the reduction in injection site pain for 2 test citrate-free formulations compared to the original commercial formulation of ixekizumab.1
In addition, ISRs were reported as treatment-emergent adverse events in a trial of ixekizumab conducted in healthy participants as part of the new formulation program (trial RHCU).1
The RHCU trial assessed the bioequivalence of citrate-free ixekizumab to the original commercial ixekizumab formulation.1
Injection Pain Study - Solicited Data
In a single-blinded, randomized cross-over study in 45 healthy subjects comparing the original formulation with the revised, citrate-free formulation, statistically significantly lower visual analog scale (VAS) pain scores were obtained with the citrate-free vs. the original formulation during injection (difference in LS Mean VAS score - 21.69) and 10 min after injection (difference in LS Mean VAS score -4.47).2
The primary objective of the injection site pain study was to evaluate pain intensity on a single injection administered using a prefilled syringe with the
- original commercial ixekizumab formulation
- citrate-free ixekizumab formulation 1, and
- citrate-free ixekizumab formulation 2.1
All participants in the injection pain study were exposed to the 3 formulations listed above using a cross-over study design.1
Based on the relative bioavailability results of the test formulations, one formulation was selected for the pivotal bioequivalence study.1
Participants were asked to rate their injection pain using a visual analog scale (VAS)-100 at 0, 10, 20, 30, and 60 minutes after injection.1
Pain was rated as
- no pain (VAS 0)
- mild pain (VAS ≤30)
- moderate pain (VAS >30 and ≤70), and
- severe pain (VAS >70).1
The study demonstrated a significant difference in injection site pain immediately after injection between the original commercial formulation of ixekizumab and citrate-free ixekizumab. Pain was reported as
- 25.21 on VAS with the original commercial formulation of ixekizumab, and
- 3.52 on VAS with citrate-free ixekizumab, based on least squares mean (LSM) analysis (LSM difference of -21.7; p<.0001).1
Unsolicited Injection Site Reactions in Bioequivalence Study
In a bioequivalence study, healthy participants received a single dose of either
- ixekizumab 80 mg (original commercial formulation) or
- citrate-free ixekizumab 80 mg, both administered using an autoinjector.1
Injection site reactions were reported as unsolicited treatment-emergent adverse events more frequently in participants who received the original commercial formulation of ixekizumab (23.8%) compared with citrate-free ixekizumab (9.2%).1
Injection site erythema was the most frequently reported ISR from unsolicited reports overall for both formulations in the bioequivalence study. Summary of Injection Site Reactions in Ixekizumab Citrate-Free Bioequivalence Study in Healthy Participants shows the severity of reported ISRs reported during the bioequivalence study.1 Summary of Erythema in Ixekizumab Citrate-Free Bioequivalence Study in Healthy Participants presents additional details on the timing and size of erythema during trial RHCU.3
Treatment-Emergent Adverse Eventsa |
Original Commercial IXE |
Citrate-Free IXE |
Participants reporting ISRs, n (%) |
30 (23.8) |
11 (9.2) |
Number of reported ISRs (n) |
58 |
25 |
Pain severity, n (%) |
|
|
Mild |
5 (8.6) |
2 (8.0) |
Moderate |
8 (13.8) |
0 |
Severe |
1 (1.7) |
0 |
Pruritus severity, n (%) |
|
|
Mild |
6 (10.3) |
2 (8.0) |
Moderate |
0 |
0 |
Severe |
0 |
0 |
Erythema severity, n (%) |
|
|
Noticeable but mild |
11 (19.0) |
7 (28.0) |
Clearly red |
4 (6.9) |
2 (8.0) |
Bright red |
7 (12.1) |
1 (4.0) |
Unknown |
1 (1.7) |
0 |
Abbreviations: ISRs = injection site reactions; IXE = ixekizumab.
aPercentages are based on number of reported ISRs by treatment. Only maximum severity of each adverse event is reported.
Original Commercial IXE |
Citrate-Free IXE |
|
Number of participants reporting erythema (% of N) |
23 (18.3) |
9 (7.6) |
Total number of events of erythema |
23 |
10 |
Size of erythema (diameter), n (% of events) |
||
Barely noticeable (less than 25 mm) |
2 (8.7) |
1 (10.0) |
Slight (25-50 mm) |
11 (47.8) |
6 (60.0) |
Moderate (51-100 mm) |
6 (26.1) |
3 (30.0) |
Severe (more than 100 mm) |
3 (13.0) |
0 |
Unknown |
1 (4.3) |
0 |
Time of onset relative to study drug administration, n (% of events) |
||
During administration |
0 |
0 |
Within 30 minutes |
5 (21.7) |
2 (20.0) |
More than 30 minutes to 6 hours |
1 (4.3) |
3 (30.0) |
More than 6 hours to 24 hours |
6 (26.1) |
1 (10.0) |
More than 24 hours to 14 days |
11 (47.8) |
4 (40.0) |
Abbreviation: IXE = ixekizumab.
No participants discontinued from the bioequivalence study due to ISRs in either formulation group.3
Injection Site Reactions in Clinical Trials Using the Original Formulation of Ixekizumab
The majority of reported ISRs in pivotal phase 3 psoriasis trials
- occurred after the initial 160-mg starting dose
- were mild-to-moderate in severity
- decreased over time, and
- did not lead to discontinuation.3,4
A similar safety profile was observed with ISRs in psoriasis and psoriatic arthritis clinical trials.3
Injection Site Reactions in Patients with Psoriasis
Psoriasis Integrated Data
Injection site reactions were reported as an adverse event in 15.3% (1056/6892) (incidence rate [IR]=5.9 per 100 patient-years [PYs] of exposure) of patients exposed to ixekizumab across 17 adult psoriasis trials as of March 2022.5Of these, Incidence of Injection Site Reactions in All Patients Exposed to Ixekizumab Across 17 Adult Psoriasis Clinical Trials summarizes the most commonly reported types of ISRs.
|
All Ixekizumab Exposures Across 17 Adult Psoriasis Trials |
Injection site reactions |
1056 (15.3) [5.9] |
Injection site reaction (unspecified) |
698 (10.1) [3.9] |
Injection site erythema |
203 (2.9) [1.1] |
Injection site pain |
117 (1.7) [0.6] |
Abbreviations: IR = incidence rate per 100 patient-years of exposure; PY = patient-year.
The incidence of ISRs decreased over time in psoriasis trials with an IR of 16.5 per 100 patient-years (PYs) during the first year to 1.7 per 100 PYs during year 4-5.5
In the adult plaque psoriasis studies, injection site reactions were more common in subjects with a body weight < 60 kg compared with the group with a body weight ≥ 60 kg (25 % vs. 14 % for the combined Q2W and Q4W groups).2
Data From 12-Week, Double-Blind, Placebo-Controlled Induction Period
Most ISRs (≥95%) were mild-to-moderate in severity. Of patients who reported an ISR, 0.2% discontinued ixekizumab due to ISR.7,8
Frequency of Injection Site Reactions During 12-Week Induction Periods of UNCOVER-1, -2, and -3 Psoriasis Trials summarizes the most commonly reported types of ISRs during the 12-week induction periods of UNCOVER-1, -2, and -3 for the ixekizumab 80 mg every 2 weeks (Q2W) and every 4 weeks (Q4W) dosing groups and placebo.
IXE Q2W |
IXE Q4W |
PBO |
|
Injection site reaction (unspecified) |
117 (10.0)a |
89 (7.7)a |
9 (1.1) |
Injection site erythema |
52 (4.5)a |
32 (2.8)a |
2 (0.3) |
Injection site pain |
28 (2.4) |
17 (1.5) |
14 (1.8) |
Abbreviations: IXE Q2W= ixekizumab 80 mg every 2 weeks; IXE Q4W = ixekizumab 80 mg every 4 weeks; PBO = placebo.
ap<.001 vs PBO.
Additional Patient Follow-Up on Injection Site Reactions
Patients who reported an ISR of any type during psoriasis trials were given a follow-up form to collect additional information. Follow-up forms of patients who spontaneously reported an ISR of any type showed that 51% reported pain, the majority (>90%) of which were categorized by the patient as mild-to-moderate in severity.3
- The majority of reported ISRs in UNCOVER-1, -2, and -3 occurred following the initial 160-mg starting dose.3 Median time to onset was 7 days for the first 160-mg dose. For those with multiple ISRs reported, subsequent doses had earlier median time to onset of 1.5 days for weeks 2 and 4 injections.4
- The median duration of ISRs was 2 days.9
- Generally, injection site pain was typically reported to occur during injection and erythema onset was delayed.4
- Timing of ISRs varied depending on treatment group (ixekizumab 80 mg Q2W and Q4W dosing groups, etanercept, or placebo) and symptom reported.10
Injection Site Reactions in Patients with Psoriatic Arthritis
Psoriatic Arthritis Integrated Data
Injection site reactions were reported as an adverse event in 18.6% (260/1401) (IR=11.6 per 100 PYs of exposure) of patients exposed to ixekizumab across 4 psoriatic arthritis trials (SPIRIT-P1, SPIRIT-P2, SPIRIT-P3, and SPIRIT-H2H) as of March 2022.11,12 Of these, Incidence of Injection Site Reactions in All Patients Exposed to Ixekizumab Across 4 Psoriatic Arthritis Trials summarizes the most commonly reported types of ISRs.
|
All Ixekizumab Exposures Across 4 Psoriatic Arthritis Trials |
Injection site reactions |
260 (18.6) [11.6] |
Injection site reaction (unspecified) |
156 (11.1) [6.9] |
Injection site erythema |
60 (4.3) [2.7] |
Injection site pain |
22 (1.6) [1.0] |
Abbreviations: IR = incidence rate per 100 patient-years of exposure; PY = patient-year.
The incidence of ISRs decreased over time in psoriatic arthritis trials with an IR of 21.3 per 100 PYs during year 0-1 to 2.3 per 100 PYs during year 2-3.5
In the psoriatic arthritis studies, injection site reactions were more common in subjects with a body weight < 100 kg compared with the group with a body weight ≥ 100 kg (24 % vs. 13 % for the combined Q2W and Q4W groups).2
Data From 24-Week Double-Blind Treatment Periods of SPIRIT-P1 and SPIRIT-P2 Trials
Most ISRs (>95%) were mild-to-moderate in severity.3,14 Of patients who reported an ISR, 1.1% discontinued ixekizumab due to ISR.14,15
Frequency of Injection Site Reactions During 24-Week Placebo-Controlled Periods of SPIRIT-P1 and SPIRIT-P2 Psoriatic Arthritis Trials summarizes the most commonly reported types of ISRs during the 24-week placebo-controlled periods of SPIRIT-P1 and SPIRIT-P2 for the ixekizumab 80 mg Q2W and Q4W dosing groups and placebo.
IXE Q2W |
IXE Q4W |
PBO |
|
Injection site reaction (unspecified) |
32 (14.2)a |
22 (9.6)a |
1 (0.4) |
Injection site erythema |
17 (7.6)a |
9 (3.9)b |
0 |
Injection site hypersensitivity |
6 (2.7)c |
1 (0.4) |
0 |
Abbreviations: IXE Q2W = ixekizumab 80 mg every 2 weeks; IXE Q4W = ixekizumab 80 mg every 4 weeks; PBO = placebo.
ap<.001 vs PBO.
bp<.005 vs PBO.
cp<.05 vs PBO.
In addition to the most commonly reported types of ISRs, as listed in Frequency of Injection Site Reactions During 24-Week Placebo-Controlled Periods of SPIRIT-P1 and SPIRIT-P2 Psoriatic Arthritis Trials, injection site pain was reported in
- 0.9% of patients in both the ixekizumab 80 mg Q2W and Q4W groups, and
- 2.2% of patients in the placebo group.3
The first occurrence of ISRs was most often within the first 6 weeks of treatment in the SPIRIT-P1 and SPIRIT-P2 studies. The median duration of ISRs was 3 days.3
Additional Patient Follow-Up on Injection Site Reactions
Patients who reported an ISR of any type during trials were given a follow-up form to collect additional information. Follow-up of patients who spontaneously reported an ISR of any type treated with ixekizumab 80 mg Q4W showed that 32.5% reported pain, the majority (>90%) of which were categorized by the patient as mild-to-moderate in severity.3
Injection Site Reactions in Patients with Axial Spondyloarthritis
Axial Spondyloarthritis Integrated Data
Injection site reactions were reported as an adverse event in 16.7% (156/932) [IR=7.4 per 100 PYs of exposure] of patients across 4 axial spondyloarthritis (axSpA) trials (including AS/r-axSpA and nr-axSpA trials) as of March 2022.5 Of these, Incidence of Injection Site Reactions in All Patients Exposed to Ixekizumab Across 4 Axial Spondyloarthritis Trials summarizes the most commonly reported types of ISRs.
|
All Ixekizumab Exposures Across 4 axSpA Trials |
Injection site reactions |
156 (16.7) [7.4] |
Injection site reaction (unspecified) |
93 (10.0) [4.4] |
Injection site erythema |
33 (3.5) [1.6] |
Injection site swelling |
16 (1.7) [0.8] |
Abbreviations: axSpA = axial spondyloarthritis; IR = incidence rate per 100 patient-years; PY = patient-year.
The incidence of ISRs decreased over time in axSpA trials with an IR of 18.2 per 100 PYs during year 0-1 to 1.9 per 100 PYs during ≥2 years.5
In the axial spondyloarthritis studies, injection site reactions were similar in subjects with a body weight < 100 kg compared with the group with a body weight ≥ 100 kg (14 % vs. 9 % for the combined Q2W and Q4W groups).2
Data From 16-Week Double-Blind, Placebo-Controlled Treatment Periods of COAST-V and COAST-W AS/r-axSpA Trials
Most ISRs (>95%) were mild-to-moderate in severity.3,16,17 Of patients who reported an ISR, 1.1% discontinued ixekizumab due to ISR.16,17
Frequency of Injection Site Reactions During 16-Week Placebo-Controlled Periods of COAST-V and COAST-W AS/r-axSpA Trials summarizes the most commonly reported types of ISRs during the 16-week placebo-controlled periods of COAST-V and COAST-W for the ixekizumab 80 mg Q2W and Q4W dosing groups and placebo.
|
IXE Q2W |
IXE Q4W |
PBO |
Injection site reaction (unspecified) |
15 (8.3) |
3 (1.5) |
3 (1.6) |
Injection site pain |
5 (2.8) |
4 (2.1) |
4 (2.1) |
Injection site erythema |
4 (2.2) |
3 (1.5) |
1 (0.5) |
Abbreviations: IXE Q2W = ixekizumab 80 mg every 2 weeks; IXE Q4W = ixekizumab 80 mg every 4 weeks; PBO = placebo.
Data From 52-Week Double-Blind, Placebo-Controlled Treatment Period of COAST-X nr-axSpA Trial
Injection site reactions were reported in 21.7% (43/198) of patients with nr-axSpA treated with ixekizumab during the 52-week double-blind treatment period of COAST-X.18
Most ISRs (>95%) were mild-to-moderate in severity. Of patients who reported ISR, 1.6% discontinued due to ISR.18
Incidence of Injection Site Reactions During 52-Week Placebo-Controlled Period of COAST-X Clinical nr-axSpA Trial summarizes the most commonly reported types of ISRs during the 52-week placebo-controlled period of COAST-X for the ixekizumab 80 mg Q2W and Q4W dosing groups and placebo.
|
IXE Q2W |
IXE Q4W |
PBO |
Injection site reaction (unspecified) |
17 (16.7)b |
11 (11.5) |
4 (3.8) |
Injection site erythema |
4 (3.9) |
3 (3.1) |
1 (1.0) |
Injection site swelling |
2 (2.0) |
2 (2.1) |
0 |
Abbreviations: IXE Q2W = ixekizumab 80 mg every 2 weeks; IXE Q4W = ixekizumab 80 mg every 4 weeks; PBO = placebo; TEAE = treatment-emergent adverse event.
aTEAEs were summarized using the safety population, defined as all patients who received at least 1 dose of the trial drug, per the assigned treatment. TEAEs were summarized before any switch to open-label ixekizumab.
bp<.001 vs PBO.
In addition to the most commonly reported types of ISRs, as listed in Incidence of Injection Site Reactions During 52-Week Placebo-Controlled Period of COAST-X Clinical nr-axSpA Trial, injection site pain was reported in 1 patient (1.0%) each in the ixekizumab 80 mg Q2W and Q4W and placebo groups.3
References
1Chabra S, Gill BJ, Gallo G, et al. Ixekizumab citrate-free formulation: results from two clinical trials. Adv Ther. 2022;39(6):2862-2872. https://doi.org/10.1007/s12325-022-02126-0
2Taltz [summary of product characteristics]. Eli Lilly and Company (Ireland) Limited, Ireland
3Data on file, Eli Lilly and Company and/or one of its subsidiaries.
4Shear NH, Paul C, Blauvelt A, et al. Safety and tolerability of ixekizumab: integrated analysis of injection-site reactions from 11 clinical trials. J Drugs Dermatol. 2018;17(2):200-206. http://jddonline.com/articles/dermatology/S1545961618P0200X
5Deodhar A, Blauvelt A, Lebwohl M, et al. Long-term safety of Ixekizumab in adults with psoriasis, psoriatic arthritis, or axial spondyloarthritis: a post-hoc analysis of final safety data from 25 randomized clinical trials. Arthritis Res Ther. 2024;26(1):49. https://doi.org/10.1186/s13075-023-03257-7
6Griffiths CEM, Gooderham M, Colombel JF, et al. Safety of ixekizumab in adult patients with moderate-to-severe psoriasis: data from 17 clinical trials with over 18,000 patient-years of exposure. Dermatol Ther (Heidelb). 2022;12(6):1431-1446. https://doi.org/10.1007/s13555-022-00743-9
7Griffiths CEM, Reich K, Gooderham M, et al. Long-term safety of ixekizumab in patients with moderate-to-severe psoriasis up to 5 years: pooled data from 16 clinical trials. Poster presented at: 29th Annual Meeting of the European Academy of Dermatology and Venereology (EADVirtual); October 29-31, 2020.
8Gordon KB, Blauvelt A, Papp KA, et al; UNCOVER-1, UNCOVER-2, and UNCOVER-3 Study Groups. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4):345-356. http://dx.doi.org/10.1056/NEJMoa1512711
9Reich K, Leonardi C, Ohtsuki M, et al. Safety and tolerability of ixekizumab: integrated analysis of injection-site reactions in patients with moderate-to-severe psoriasis treated with ixekizumab compared with placebo or etanercept from three phase 3 trials. Poster presented at: 25th European Academy of Dermatology and Venereology Congress; September 28-October 2, 2016; Vienna, Austria.
10Sheth P, Muram T, Lin C, et al. Patient perspectives on injection site reactions in 2 phase 3 trials of ixekizumab versus etanercept and placebo in psoriasis. Poster presented at: 77th Annual Meeting of the American Academy of Dermatology; March 1-15, 2019; Washington, D.C.
11Deodhar AA, Combe B, Accioly AP, et al. Safety of ixekizumab in patients with psoriatic arthritis: data from four clinical trials with over 2000 patient-years of exposure. Ann Rheum Dis. 2022;81(7):944-950. https://doi.org/10.1136/annrheumdis-2021-222027
12Deodhar A, Blauvelt A, Schwartzman S, et al. Long-term safety of ixekizumab in adult patients with psoriasis, psoriatic arthritis, and axial spondyloarthritis. Poster presented at: American College of Rheumatology/ARP - 2022 Annual Scientific Meeting; November 10-14, 2022; Philadelphia, Pennsylvania.
13Schwartzman S, Deodhar A, Combe B, et al. Safety profile of ixekizumab for the treatment of psoriatic arthritis and axial spondyloarthritis up to 3 years: an updated integrated safety analysis. Poster presented at: Annual Meeting of the America College of Rheumatology (ACR Convergence Virtual); November 1-10, 2021.
14Mease PJ, van der Heijde D, Ritchlin CT, et al; SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76(1):79-87. http://dx.doi.org/10.1136/annrheumdis-2016-209709
15Nash P, Kirkham B, Okada M, et al; SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389(10086):2317-2327. http://dx.doi.org/10.1016/S0140-6736(17)31429-0
16Deodhar A, Poddubnyy D, Pacheco-Tena C, et al; COAST-W Study Group. Efficacy and safety of ixekizumab in the treatment of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors. Arthritis Rheumatol. 2019;71(4):599-611. http://dx.doi.org/10.1002/art.40753
17van der Heijde D, Cheng-Chung Wei J, Dougados M, et al; COAST-V Study Group. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392(10163):2441-2451. http://dx.doi.org/10.1016/s0140-6736(18)31946-9
18Deodhar A, van der Heijde D, Gensler LS, et al; COAST-X Study Group. Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet. 2020;395(10217):53-64. http://dx.doi.org/10.1016/S0140-6736(19)32971-X
Date of Last Review: 25 October 2022