{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T02:01:30Z","timestamp":1772244090816,"version":"3.50.1"},"update-to":[{"DOI":"10.3310\/nihropenres.13275.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T00:00:00Z","timestamp":1682294400000}}],"reference-count":41,"publisher":"National Institute for Health and Care Research","license":[{"start":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T00:00:00Z","timestamp":1682294400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health Research - Research for Patient Benefit Programme","award":["(Project reference: 201031)"],"award-info":[{"award-number":["(Project reference: 201031)"]}]},{"name":"180 Life Sciences will provide funding for the purchase of the study drug","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["openresearch.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["NIHR Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Objectives:<\/ns4:bold>\n                    The Anti-Freaze-F trial will assess the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with pain predominant early stage frozen shoulder.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods and analysis:<\/ns4:bold>\n                    We are conducting a multi-centre, randomised feasibility study, with an embedded qualitative sub-study. We will recruit adults \u226518 years with a new episode of shoulder pain attributable to early stage frozen shoulder, recruited from at least five UK NHS musculoskeletal and related physiotherapy services. Participants (n=84) will be randomised (centralised computer generated 1:1 allocation) to receive either: 1) intra-articular injection of anti-TNF (adalimumab 160mg) or 2) placebo injection (saline [0.9% sodium chloride]), both under ultrasound guidance. A second injection of the allocated treatment (adalimumab 80mg) or equivalent volume of placebo will be administered 2-3 weeks later. All participants will receive a physiotherapy advice leaflet providing education and advice about frozen shoulder and pain management. The primary feasibility objectives are: 1) the ability to screen and identify potential participants with pain predominant early stage frozen shoulder; 2) willingness of eligible participants to consent and be randomised to intervention; 3) practicalities of delivering the intervention, including time to first injection and number of participants receiving second injection; 4) standard deviation of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months from baseline in order to estimate the sample size for a definitive trial. We will also assess follow up rates and viability of patient-reported outcome measures and range of shoulder motion for a definitive trial. \u00a0Research Ethics Committee approval (REC 21\/NE\/0214).\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Trial registration number:<\/ns4:bold>\n                    ISRCTN 27075727; EudraCT number: 2021-003509-23; ClinicalTrials.gov NCT05299242.\n                  <\/ns4:p>","DOI":"10.3310\/nihropenres.13275.2","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T06:45:14Z","timestamp":1682318714000},"page":"28","update-policy":"https:\/\/doi.org\/10.3310\/nihropenres.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Anti-TNF (adalimumab) injection for the treatment of adults with frozen shoulder during the pain predominant stage protocol for a multi-centre, randomised, double blind, parallel group, feasibility trial"],"prefix":"10.3310","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6881-6984","authenticated-orcid":false,"given":"Sally","family":"Hopewell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3113-0305","authenticated-orcid":false,"given":"Nicola","family":"Kenealy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Knight","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amar","family":"Rangan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Dutton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cynthia","family":"Srikesavan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Feldmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Lamb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9579-9411","authenticated-orcid":false,"given":"Jagdeep","family":"Nanchahal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"6221","published-online":{"date-parts":[[2023,4,24]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"232-7","DOI":"10.1111\/j.1758-5740.2010.00067.x","article-title":"An 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We have included our response to each of the reviewer comments below:  \n<b>Reviewer Report 1: <\/b>  \n<i>Hopewell&nbsp;et al.&nbsp;have prepared a clear and compelling protocol for a study assessing the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with pain predominant early stage frozen shoulder. The methods proposed are rigorous and the protocol is reported in enough detail to allow others to replicate the planned methods. I have only a few minor suggestions.  Name of the trial:&nbsp;This is extremely minor, but every time I read \u201cAnti-Freaze-F trial\u201d I wondered why it was not called the \u201cAnti-Freeze-F trial\u201d. Perhaps a brief explanation for the name would help.<\/i>  RESPONSE: The acronym is derived from ANTI-tnF for the tREAtment of froZEn shoulder \u2013 Feasibility  \n<i>Plain language summary:&nbsp;Overall, this section is very clear and informative. However, I think there needs to be a clearer link between the first and second paragraph. The first paragraph ends with the claim that there is no evidence that current treatments, including rest, painkillers, anti-inflammatories, physiotherapy and steroid injections lead to significant benefit in the long term, and that steroid injections only help in the short term. Then in the second paragraph the authors claim that the aim of the study is to find out if it is feasible to \u201crun a larger trial to test whether an injection of adalimumab can reduce pain and prevent the disease from getting worse\u201d. However, it\u2019s not clear why the authors are investigating the effects of adalimumab, nor what adalimumab even is (is it a type of one of the interventions described as ineffective in the first paragraph, or something else entirely?). Postscript:&nbsp;Oh, I see a rationale for the choice of adalimumab appears at the end of the third paragraph. Hmm, I think it would flow better if this text were moved earlier.<\/i>  RESPONSE: We have now added the explanation for the use of adalimumab before the description of the trial.  \n<i>Eligibility:&nbsp;By specifying that \u201cMen and women aged 18 years and above\u201d were eligible for this study, does this mean that non-binary people and those who do not identify with either of those genders are ineligible? If not, perhaps it's more inclusive to just write \u201cPeople aged 18 years and above\u201d.<\/i>  RESPONSE: We have reworded this as suggested to be more inclusive.  \n<i>Figure 1:&nbsp;It might help to clarify that the second injections will be delivered 2-3 weeks after the first injection. It would also help to specify if follow-up is at 3-months from randomisation, or 3-months after receiving the second injection.<\/i>  RESPONSE: We have changed Figure 1 to clarify the second injection is given 2-3 weeks after the first injection. We have also clarified that follow up is 3 months (i.e. 12 weeks) post-randomisation.  \n<i>Informed consent, baseline assessment and trial specific screening tests:&nbsp;It is not immediately clear to me why \u201cParticipants will undergo serological testing to check for latent Tuberculosis (TB) and Hepatitis B surface antigen\u201d.<\/i>  RESPONSE: Continuous administration of anti-TNF is associated with reactivation of latent TB or hepatitis B. Whilst the risk is extremely low following a single injection, to ensure participant safety we specified that participants will undergo serological testing before the second injection. Those testing positive will be referred to their local infectious diseases service and will not receive the second injection  \n<i>Table 2:&nbsp;Love this table, really helpful!<\/i>  RESPONSE: Thank you!  \n<i>Outcomes:&nbsp;The authors claim that \u201cThe choice of outcome measures is based on Outcome Measures in Rheumatology (OMERACT) 2016 core outcome set for shoulder disorder\u201d. However, the core outcome set cited is a preliminary core outcome set, which was finalised and endorsed by OMERACT in 2019. So I suggest the final core outcome set be cited - Ramiro&nbsp;et al.&nbsp;(2019)<\/i>\n<i><sup>1<\/sup><\/i>\n<i>.<\/i>  RESPONSE: We have updated this reference.","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/2-28\/v2#referee-comment-3242","order":1,"name":"referee-comment-3242","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.3310\/nihropenres.14394.r29120, Stefan Siebert, School of Infection and Immunity, University of Glasgow, Glasgow, Scotland, 03 Apr 2023, version 1, indexed","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/2-28\/v1#referee-response-29120","order":2,"name":"referee-response-29120","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Sally Hopewell<\/b>; \n<i>Posted: 14 Apr 2023<\/i>; Thank you for the positive comments and suggestions for improving the protocol for the Anti-Freaze-F trial. We have included our response to each of the reviewer comments below:  \n<b>Reviewer Report 2: <\/b>  \n<i>The authors present a protocol for multi-centre, randomised, double-blind feasibility study of intra-adalimumab adalimumab injections for early frozen shoulder. The protocol is very well written, with clear justification and methods that address the primary objectives. Importantly for a feasibility study, the progression criteria for the main study are clearly pre-defined. I have a few comments, relating to some aspects where the protocol is slightly unclear or not specific:  1.&nbsp;Timing of follow-up\/final outcome and Table 2: The final assessment is at 3 months but it appears from Table 2 that this is 3 months from screening rather than first injection. I would have expected the latter in light of the variable timing from screening to 1<sup>st<\/sup>&nbsp;injection (meaning some participants may only have 10 weeks from injection) and this may be what is intended, although I note assessments are only done at screening. Either way, the authors should clearly indicate the timepoint for screening in order for others to be able to replicate this work: i.e. either [\u201cScreening week 0\u201d] or [\u201cScreening week -2 to 0\u201d and \u201c1<sup>st<\/sup>&nbsp;injection = week 0\u201d].<\/i>  RESPONSE: Timing of follow up\/final outcome is at 3 months (i.e. 12 weeks) post randomisation. We have clarified this through the protocol.  \n<i>It would also be more typical and helpful to express this final outcome timing in weeks (i.e. 12 weeks) rather than months in order to avoid potential confusion relating to whether this is 3 calendar months or 12 weeks.<\/i>  RESPONSE: &nbsp;Reporting of the outcome measures is at 3 months (i.e. 12 weeks). We have clarified this in the protocol.  \n<i>2. It is also unclear from the protocol what would occur if &gt;2 weeks passed from screening to 1<sup>st<\/sup>&nbsp;injection. This is particularly import as ITT analysis based on randomization so need to know if would be withdrawn, rerandomized etc. The same applies to what would occur if &gt;3 weeks between 1<sup>st<\/sup>&nbsp;and 2<sup>nd<\/sup>&nbsp;injection visit \u2013 I assume no injection would be given but actions for both scenarios should be clearly stated.<\/i>  RESPONSE: This is a feasibility study and so one of our main feasibility objectives is to assess the practicalities for trial sites to deliver the intervention, including the time to first injection and number of participants receiving second injection. This information would then be used to inform any future definitive trial. Therefore, we would respectfully submit that the issue of ITT analysis is not applicable here.  \n<i>3. As a CT-IMP, I would have expected standard adverse event reporting requirements to apply.<\/i>  RESPONSE: Procedures for recording adverse events are described in the protocol in the section \u201cAdverse events\u201d. We will record clinician assessed adverse events, graded 3 and above, occurring during the trial for each participant, from their consent until the three month (i.e. 12 weeks) follow up and that are considered related to the trial medication (adalimumab\/placebo).&nbsp;  \n<i>4.&nbsp;Eligibility criteria \u2013 timing from symptom onset: It is unusual to include an \u201capproximate\u201d cut-off in inclusion criteria as this introduces potential variability, both within this study and with replication studies. I presume this was included to facilitate recruitment, and may be acceptable for this feasibility study (provided clearly and rigorously recorded), but it is largely meaningless without some upper limit (is 4 months ok, what about 5 months?) and would not be acceptable for the main study.<\/i>  RESPONSE: Recruitment will be based on the participant\u2019s predominant symptom being pain rather than limitation of movement or function. The duration of the pain-predominant phase can be very variable, usually between 3 \u2013 9 months and, therefore it is difficult to precisely stipulate inclusion based on a precise time period. We have now clarified this in the protocol.  \n<i>5.&nbsp;Eligibility criteria \u2013 frozen shoulder diagnosis: I found the inclusion criteria slightly vague and open to interpretation. I would have expected more formal diagnostic criteria for frozen shoulder for an RCT. While I accept this study may be intended to reflect real-world-practice, if the authors propose to use results from this and\/or the subsequent main study to obtain approvals for this treatment (adalimumab is not currently licensed for intra-articular injection), I would recommend early discussions with the relevant regulatory bodies to ensure they would accept these criteria for licensing purposes.<\/i>  RESPONSE: We used the BESS (British Elbow and Shoulder Society) criteria for diagnosis of pain predominant early phase frozen shoulder, which is widely used by physiotherapists and shoulder specialists within the NHS. In the protocol we state that imaging, including plain radiographs, may be used to confirm the diagnosis of frozen shoulder and rule out other pathology such as glenohumeral arthritis as would happen as per standard NHS care (i.e. not as part of trial procedures). Regulatory approval from the MHRA was successfully obtained for the trial.","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/2-28\/v2#referee-comment-3243","order":3,"name":"referee-comment-3243","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This research is funded by the National Institute of Health Research - Research for Patient Benefit Programme (Project reference: 201031). 180 Life Sciences will provide funding for the purchase of adalimumab, the investigational medicinal product to be used in this trial. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}