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Data availability

The pharmacometric reproducibility script (without specifics of clinical data) is available at

PMC10539503

Competing interests

The authors declare no competing interests.

PMC10539503

References

PMC10539503

Main

glioma, tumors, tumor

PROLIFERATION, GLIOMA, TUMORS, TUMOR

Pediatric low-grade glioma (pLGG) is the most common childhood central nervous system (CNS) tumor, representing approximately 30% of pediatric brain tumorsMost pLGGs are driven by genomic alterations affecting components of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, which regulates cell proliferation and survivalA randomized phase 2 trial, which investigated the type I RAF inhibitor dabrafenib plus the MEK inhibitor trametinib versus vincristine and carboplatin as first-line therapy in patients with pLGG with a BRAF V600 mutation, showed the superiority of dabrafenib plus trametinib over vincristine–carboplatin in this settingTovorafenib (previously known as DAY101, TAK-580, MLN2480 or BIIB024) is an investigational, oral, selective, CNS-penetrant type II RAF inhibitor in clinical development for the treatment of patients with tumors harboring an activating The phase 2 FIREFLY-1 (PNOC026;

PMC10803270

Results

PMC10803270

Endpoints

ADVERSE EVENTS, SECONDARY

The primary endpoint in arm 1 was the ORR as assessed by the IRC according to RANO-HGG criteria. Secondary endpoints for arm 1 included ORR by RAPNO criteria per IRC; clinical benefit rate (CBR), progression-free survival (PFS), duration of response (DOR) and time to response (TTR), per IRC by RANO-HGG and RAPNO criteria; and safety and tolerability (primary endpoint in arm 2), assessed by the type, frequency and severity of adverse events (AEs) and laboratory abnormalities. Additional planned secondary endpoints not reported in this manuscript are described in detail in the full trial protocol (confidential information redacted) in the

PMC10803270

Patients and disposition

Between 22 April 2021 and 26 January 2023, 137 patients were enrolled to arms 1 and 2 and received tovorafenib—77 in arm 1 and 60 in arm 2. Seven (9%) patients in arm 1 and 21 (35%) patients in arm 2 received tovorafenib as a liquid formulation; all other patients received the tablet formulation. As of the datacut, 102 patients remained on treatment (Fig.

PMC10803270

Maximal change in tumor size for evaluable patients.

Per RANO-HGG (

PMC10803270

Swimlane plot of TTR and DOT.

Per RANO-HGG (

PMC10803270

RAPNO criteria (secondary endpoints)

tumor, SD, PD, BOR, MR, tumors

MINOR, TUMORS, TUMOR

The ORR per RAPNO criteria was 51% (95% CI: 40–63), including 28 (37%; 95% CI: 26–49) patients with a PR (≥50% reduction from baseline by sum of the product of the perpendicular diameters (SPPD)) and 11 (14%; 95% CI: 8–24) patients with a minor response (MR; 25–49% reduction from baseline by SPPD). Twenty-three (30%) patients had a BOR of SD, resulting in a CBR of 82%. The ORR was similar in patients with tumors harboring Figure Thirteen (17.1%) patients initially had a best overall response of PD according to RAPNO criteria per IRC evaluation but continued tovorafenib treatment due to the absence of PD by RANO-HGG criteria per investigator, consistent with the trial design and primary endpoint assessment. All but two patients had no symptoms or signs of clinical progression. Plots of tumor size (SPPD) over time in several of these patients showed subsequent tumor shrinkage after the initial assessment of PD (Extended Data Fig.

PMC10803270

RANO-LGG criteria (post hoc exploratory endpoints)

tumor, SD, PD, BOR, tumors

TUMOR, TUMORS

The ORR per RANO-LGG criteria was 53% (95% CI: 41–64), including 20 (26%; 95% CI: 17–38) patients with a PR and 20 (26%; 95% CI: 17–38) with an MR. Twenty-three (30%) patients had a BOR of SD, giving a CBR of 83%. ORR was similar in patients with tumors harboring Figure Similar to the RAPNO analysis, there was a subset of patients who initially had PD according to RANO-LGG criteria per IRC evaluation but who continued on treatment due to the absence of PD according to RANO-HGG criteria. Plots of tumor size (SPPD) over time in several of these patients showed a pattern of subsequent tumor shrinkage after the initial PD assessment (Extended Data Fig.

PMC10803270

Response to tovorafenib in patients with PD while on a MAPKi as their most recent prior therapy (post hoc analysis)

crieria

A post hoc analysis was completed using all three radiological criteria to assess responses to tovorafenib in patients who received a MAPKi as their most recent line of therapy and discontinued due to progression. For RANO-HGG criteria, 33% (n = 15) of patients who had progressed on a MAPKi as their most recent prior therapy had a CR or a PR to tovorafenib; similar trends were observed for RAPNO and RANO-LGG crieria, which include MRs: 33% (

PMC10803270

Safety

intercurrent infectious disease, fatigue, seizure, hyponatremia, vomiting, anemia, rash, pyrexia, hemorrhage, tumor hemorrhage, decreased appetite, TRAEs

RTI, CORONAVIRUS DISEASE 2019, EVENT, HYPONATREMIA, ANEMIA, HEMORRHAGE, ADVERSE EVENT, RESPIRATORY TRACT INFECTION, EVENTS

Among 137 patients (arms 1 and 2), 118 (86%) had been treated for at least 6 months and 67 (49%) for at least 1 year. All patients experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs at any grade occurring in ≥20% of patients were hair color changes (76%), anemia (59%) and elevated creatine phosphokinase (CPK) (58%) (Table TEAEs and TRAEs (safety analysis set, TEAEs, TRAEs and laboratory abnormalities in ≥20% of patients and all TRAEs grade ≥3 occurring in ≥1 patient are reported. Patients are counted only once per event and are shown in the worst CTCAE grade that was reported for each event they experienced. MedDRA version 23.1; CTCAE version 5.0. APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; CSF, cerebrospinal fluid; GGT, gamma-glutamyl transferase; LDH, lactate dehydrogenase; RTI, respiratory tract infection; WBC, white blood cell.A decrease in growth velocity was observed in patients treated with tovorafenib. At cycle 13 (Serious TEAEs were reported for 45% of patients, the most common being pyrexia (most cases were confounded by intercurrent infectious disease), seizure and vomiting (each 5%). Serious TRAEs occurred in 15% of patients, the most common being tumor hemorrhage (3%), decreased appetite, hyponatremia and vomiting (each 2%). Two of four patients with serious tumor hemorrhage TRAEs had a history of intratumoral hemorrhage before initiating tovorafenib, and, in all four, the serious events of tumor hemorrhage resolved.Nine (7%) patients had TRAEs leading to tovorafenib discontinuation, the most common being tumor hemorrhage (three patients) and decrease in growth velocity (two patients). TRAEs leading to dose reduction were seen in 33 (24%) patients, the most common being maculopapular rash (4%) and decreased appetite (3%). TRAEs leading to dose interruption occurred in 50 (37%) patients, the most common being maculopapular rash (9%), vomiting, fatigue, increased alanine aminotransaminase (ALT) and elevated CPK (each 4%). The median duration of dose interruption due to any TEAE was 14 d, or two doses.

PMC10803270

Discussion

tumor, seizures, bone marrow failure, Intratumoral hemorrhage, cancer, rash, hemorrhage, heterogenous, fatigue, hypothalamic/chiasmatic gliomas, anemia, pruritus, paronychia, heterogeneous disease, endocrine abnormalities, TRAEs, leptomeningeal disease, intratumoral hemorrhage, PD, tumor hemorrhage, deaths, tumors, dermatitis

TUMOR, BONE MARROW FAILURE, ENDOCRINE DISORDER, CANCER, DISEASE, BLEEDS, ANEMIA, HEMORRHAGE, SECONDARY, PARONYCHIA, TUMORS, DERMATITIS

In this international, multicenter, single-arm phase 2 trial, tovorafenib monotherapy resulted in clinically meaningful, rapid and durable tumor responses in children and young adults with This trial was designed with IRC-assessed ORR as the primary endpoint, evaluated according to RANO-HGG criteria. These criteria assess tumor response based primarily on T1-weighted, contrast-enhanced imaging. At the time the original protocol was initiated, the largest trial in pLGG with published efficacy results in the relapsed/refractory population primarily used T1-weighted, contrast enhancement–based, centrally reviewed assessment criteria to evaluate the treatment effect of vinblastineFor patients with pLGG, decrease in contrast-enhancing tumor may not represent all aspects of anti-tumor activity. The RAPNO working group recommendations highlighted the lack of standard response criteria in clinical trials of pLGG as well as the biologic difference between pediatric and adult gliomasAlthough responses to tovorafenib generally occurred early, the kinetic analysis of tumor size over time per RAPNO and RANO-LGG criteria revealed that some patients who remained on treatment after an initial assessment of radiographic PD subsequently had marked tumor shrinkage, suggestive of a delayed response to treatment. This type of response pattern (that is, tumor flare or pseudoprogression) was previously observed in patients treated with immune checkpoint inhibitors, where some patients experience an initial increase in tumor size, followed later by an objective responseBy using both T1-weighted contrast-enhanced (RANO-HGG) and T2/FLAIR-based (RAPNO and RANO-LGG) approaches, the current trial assessed the impact of tovorafenib on different aspects of pLGG tumor biology and response. Despite the unique challenges of ascertaining an optimal, single set of response assessment criteria for this heterogeneous disease, confirmed responses to tovorafenib over time were observed across three different neuro-oncology response assessment criteria. To our knowledge, this is the first trial to report outcomes for these three criteria for a large, uniformly treated patient group.The main limitation of the current trial is that it is a single-arm clinical trial. However, this design was considered both sufficient and necessary due to the lack of a SOC for most patients with relapsed/refractory pLGG. In addition, there was a lack of diversity in relation to ethnicity/race of the patient population. The efficacy results of tovorafenib in FIREFLY-1 are similar to those in earlier non-registrational studies investigating MAPK inhibitors in this setting. The phase 2 trial of the MEKi selumetinibThe safety and tolerability profile of tovorafenib monotherapy in children and young adults with pLGG was encouraging, with TRAEs being predominantly grade 1 or 2 and only nine (7%) of 137 patients discontinuing due to a TRAE. The most common TRAEs of any grade, excluding laboratory abnormalities, were hair color changes, fatigue, maculopapular rash, dry skin, acneiform dermatitis, pruritus and paronychia. Although grade 1 and 2 laboratory abnormalities were commonly reported as AEs, most were not associated with any clinical symptoms or need for clinical intervention or change in therapy. The most common grade ≥3 TRAEs included elevated CPK, anemia and maculopapular rash. Other common grade ≥3 TEAEs (not assessed as related to tovorafenib), including seizures, were consistent with effects of the underlying disease.Overall, the AEs were consistent with the tovorafenib phase 1 trial in adults dosed once weekly and similar to other targeted agents used as pLGG therapy, including MAPK inhibitors, with some notable exceptionsThere were no on-trial treatment-related deaths, and TRAEs requiring discontinuation were infrequent. Intratumoral hemorrhage was reported in 15 patients and led to discontinuation of therapy in three patients. However, half (eight of 15) of the patients with intratumoral hemorrhage were asymptomatic, with areas of tumor hemorrhage identified on routine trial MRI only. Three of the seven patients with symptomatic tumor hemorrhage had tumor bleeds assessed by the investigator as consistent with the natural history of their underlying tumor and not related to tovorafenib. Of the four patients in which the symptomatic hemorrhage was considered by the investigator to be possibly related to tovorafenib, two patients had a history of tumor hemorrhage before starting the study; the third patient had a disseminated tumor with leptomeningeal disease; and the fourth patient had bone marrow failure secondary to prior treatment with multiple alkylating agents that was diagnosed before the onset of tumor hemorrhage. Although the incidence of intratumoral hemorrhage in this patient population is not well described, case reports suggest that the tumor hemorrhage risk across pLGG tumor types with heterogenous histology, morphology and prior interventions may be underappreciatedDecreases in growth velocity were observed in children treated with tovorafenib. Among patients with complete endocrinology assessments reported, radiographic studies of the wrist supported conservation of growth potential with no advancement of bone age or evidence of premature fusion of growth plates. Furthermore, patients with available data after discontinuation of tovorafenib in the setting of FIREFLY-1 and prior studies show various degrees of recovery of growth velocity, including achievement of catch-up growth. A more detailed analysis of growth during and after treatment with tovorafenib is planned. Notably, children with cancer, and with midline CNS tumors such as pLGG, commonly develop endocrine abnormalities that may impact growth trajectories and the likelihood of achieving genetic potential for height. In one report, nearly half of children with hypothalamic/chiasmatic gliomas developed at least one endocrine disorder, most commonly a growth hormone deficiencyCollectively, these results show that tovorafenib monotherapy was generally well tolerated and demonstrated encouraging evidence of clinically meaningful, rapid and durable clinical activity in children and young adults with

PMC10803270

Methods

PMC10803270

Trial design

FIREFLY-1 (PNOC026; Sex and/or gender were not considered in the trial design as no sex differences have been seen in previous clinical trials in pLGG, although, in line with rates generally seen in childhood cancerTovorafenib was administered at the recommended phase 2 dose of 420 mg mAn independent data safety monitoring board (DSMB) was established before initiation of the trial and was in place for the duration of the trial. Medical monitoring of the trial was provided by the sponsor and used a safety review committee that included the principal investigator (or their designee) from each active clinical site.The protocol, protocol amendments, informed consent form, pediatric assent form, investigator brochure and other relevant documents were approved by an institutional review board/independent ethics committee at each trial site. As applicable according to local regulations, the protocol and all protocol amendments were reviewed and approved by each pertinent competent authority.This trial was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines, including the Declaration of Helsinki, Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, applicable International Council for Harmonization Good Clinical Practice (GCP) guidelines and other applicable laws and regulations. All patients and/or their legally authorized representative provided written informed consent and pediatric assent before enrollment in the trial, according to local regulations. No direct compensation was provided to patients or families for participating in the trial.

PMC10803270

Data collection

CRF

CRF

Clinical data required by the protocol were entered into the electronic case report forms (eCRFs) and used a fully validated secure web-enabled electronic data capture (EDC) system, Medidata Classic Rave 2022.3.2, which is compliant with 21 CRF Part 11 requirements. Automatic validation edit checks in the EDC system and offline listings were programmed to capture data discrepancies in the eCRFs and allowed modification and validation of the entered data. The investigator verified and signed off the eCRFs in the EDC system to confirm that the clinical data captured were complete and accurate. The sponsor can attest that all data and metadata will be archived in perpetuity. The data are in the EDC system and the trial master file (TMF), which are retained in perpetuity. In addition, these data have been filed with the US FDA.

PMC10803270

Eligibility

tumor, ophthalmopathy

CENTRAL SEROUS RETINOPATHY, TUMOR, CARDIOVASCULAR DISEASE, OPHTHALMOPATHY, DISEASE, NEUROFIBROMATOSIS TYPE 1

Full inclusion and exclusion criteria are listed in the trial protocol, located in the Patients were excluded if their tumor harbored an additional previously known or expected to be activating molecular alteration; if they had symptoms of clinical progression without radiographically recurrent or radiographically progressive disease; if they had a known or suspected diagnosis of neurofibromatosis type 1 by genetic testing or current diagnostic criteria; if they had a history or current evidence of central serous retinopathy, retinal vein occlusion or ophthalmopathy present at baseline that would be considered a risk factor for either; if they had clinically significant active cardiovascular disease; or if they were neurologically unstable despite adequate treatment.

PMC10803270

Trial endpoints

tumor

DISEASE, TUMOR

The assessment of response was undertaken using three different radiological response assessment criteria: RANO-HGG criteria, which assess tumor response primarily based on T1-weighted, contrast-enhanced imaging, and RAPNO-LGG and RANO-LGG criteria, both of which assess tumor response based primarily on non-enhancing disease by T2/FLAIR. The characteristics of these different response criteria are summarized in Extended Data Table The primary endpoint in arm 1 was ORR, defined as the proportion of patients with a confirmed response of CR or PR according to RANO-HGG criteria, as assessed by an IRC. Secondary endpoints for arm 1 included CBR, PFS, DOR and TTR, as assessed by the IRC using RANO-HGG criteria. CBR is defined as the proportion of patients with a confirmed response or SD lasting any length of time, 6 months or more or 12 months or more. ORR, CBR, PFS, DOR and TTR were also assessed by the IRC according to RAPNO criteria. Secondary endpoints for safety included evaluation of AEs, laboratory abnormalities and cardiac function assessments (change from baseline in QTcF, PR interval, QRS interval, heart rate or ECG waveform morphology). Post hoc exploratory endpoints for arm 1 included ORR and CBR according to RANO-LGG criteria by IRC assessment. For RAPNO and RANO-LGG ORR assessments, patients with confirmed MRs were considered responders in accordance with published guidelines. Changes in quality of life and health utilities measures were exploratory objectives.

PMC10803270

Assessments

intraspinal disease, primary malignancy, optic pathway glioma, IE, disability

ADVERSE EVENT, DISEASE, DISEASE, EVENT

Disease assessments in arm 1 were conducted by MRI of the brain and spine and were performed at screening up to 28 d before first dose, at the end of cycle 3 and then at the end of every three cycles thereafter. Spinal scans were only required to be repeated after screening in patients with known or clinically suspected intraspinal disease. Patients who had an optic pathway glioma (OPG) or underlying visual function deficit related to the primary malignancy had a visual acuity examination every time they had a radiographic disease assessment.A central imaging laboratory was used. Imaging Endpoints (IE) is a research and imaging core laboratory providing blinded independent central review of response assessments with dual reader plus adjudication paradigm using neuro-radiologists trained in all three response assessment criteria as readers for the following assessments: RANO-HGG criteria, RAPNO-LGG criteria and RANO-LGG criteria. All activities at IE meet or exceed GCP standards, and IE underwent a GCP audit by the sponsor. A prospectively designed imaging charter was developed for the FIREFLY-1 study before the initiation of the study. This outlined the processes for initial imaging review, data transfers and data review, and queries were followed throughout the study. IE functions as the centralized imaging core laboratory responsible for the collection, quality control, archiving and blinded independent central review (BICR) of imaging for the FIREFLY-1 trial. IE is responsible for management of the image analysis system, reporting methods, implementation of the analysis criteria and reader management, including qualification, training and oversight.Reader performance was assessed by evaluating reader variability at defined and prespecified milestones during ongoing imaging interpretation. Variability metrics included inter-reader and intra-reader variability to monitor for consistency of reads. If the reader acceptance rate fell outside the caution or alert limits, IE determined the appropriate unbiased action(s).For this report, safety was assessed in the arm 1 and 2 safety analysis set, which comprised all enrolled patients who received at least one dose of trial treatment. The assessment period for AEs was from the first dose of tovorafenib until 30 d after the last dose. For the current trial, an AE was defined as treatment emergent if it occurred at any time after the first dose of trial drug until 30 d after the last dose of trial drug. A TRAE was any treatment-emergent event that the investigator assessed had at least a reasonable possibility of having a causal relationship with the trial drug based on temporal association with initiation of treatment and assessment of other potential etiologies. An AE was considered serious if it met one of the following criteria: required or prolonged hospitalization, was life-threatening, caused disability or was considered a medically important event by the investigator (regardless of symptoms or Common Terminology Criteria for Adverse Events (CTCAE) grade).Routine laboratory tests were performed locally and included pregnancy tests for female patients of childbearing potential (at screening and on day 1 of every cycle); assessments of hematology parameters and serum chemistries (at screening, days 1 and 15 of cycle 1, day 1 of cycle 2 and every cycle thereafter); and thyroid function (at screening, on day 1 of cycles 1–3 and every other cycle thereafter). Scheduled cardiac function assessments included independently centrally reviewed 12-lead resting ECGs (performed in triplicate at baseline, on days 1 and 15 of cycle 1, on day 1 of cycles 2 and 4 and on day 1 of every third cycle thereafter) and ECGs or MUGA scans (conducted throughout by the same technique, on day 1 of cycles 2 and 4 and on day 1 of every third cycle thereafter). CPK level was assessed at screening, on day 1 of cycles 2 and 4 and on day 1 of every fourth cycle thereafter.In patients 2 years of age or older, health-related quality of life was assessed using the PedsQL-Core, PedsQL-Cancer and PROMIS assessments for the patient or their parent/caregiver every third cycle. The PROMIS questionnaire was administered only to English-speaking patients enrolled in the United States, Australia and the United Kingdom.

PMC10803270

Statistical considerations

Cancer

DISEASE, CANCER

In terms of the ‘evaluable’ population, patients ‘evaluable for efficacy’ were all patients enrolled in the trial who received at least one dose of trial treatment and met the definition for the prespecified efficacy analyses criteria (RANO-HGG, RAPNO and RANO-LGG)The primary endpoint analysis was performed in the arm 1 evaluable population, which included all enrolled patients who received at least one dose of tovorafenib and had measurable disease at baseline per RANO-HGG criteria as determined by the IRC. A sample size of 60 patients in the evaluable population was considered to provide 88% power to reject the null hypothesis ORR of 21%, at the two-sided 0.05 level, assuming that the true underlying ORR of tovorafenib was 40% in this disease population. An exact binomial test was used for hypothesis testing. Responses per RAPNO and RANO-LGG criteria were evaluated in evaluable populations, which included all enrolled patients who received at least one dose of tovorafenib and had measurable disease at baseline per RAPNO and RANO-LGG criteria, respectively, as determined by the IRC.Prespecified subgroup analysis of the uniformity of the treatment effects for ORR in arm 1 was planned for subgroups defined by The ORR and CBR were calculated with 95% CIs determined using the Clopper–Pearson method. PFS and DOR were estimated by the Kaplan–Meier method and were summarized along with the corresponding two-sided 95% CI. Waterfall plots were generated for each patient’s best percentage change in sum of perpendicular diameters of measurable lesions.Safety endpoints were analyzed using descriptive statistics based on the safety population in arms 1 and 2. AEs were coded by system organ class and preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.1 and graded according to the National Cancer Institute CTCAE version 5.0.Statistical analyses were carried out using SAS version 9.4.

PMC10803270

Management of cutaneous AEs

pruritus, erythema, ulcerative or bullous dermatitis, rash/dermatitis

EVENT, ERYTHEMA, ERUPTION, VESICULAR ERUPTION, GENERALIZED ERYTHRODERMA

Guidance for the management of rash/dermatitis was included in the trial protocol, in line with the stepwise approach proposed by Song et al.In the event of grade 2 macular or papular eruption, erythema with pruritus or other associated symptoms, localized desquamation or other lesions covering less than 50% of body surface area (BSA), tovorafenib dose reduction by one dose level once weekly could be considered. In the event of grade 3 or higher severe, generalized erythroderma or macular, papular or vesicular eruption, desquamation covering ≥50% of BSA or generalized exfoliative, ulcerative or bullous dermatitis, tovorafenib dosing was to be delayed until the condition improved, a dermatologist was consulted and a dose reduction by two dose levels or holding tovorafenib administration until resolution to grade 1 or baseline could be considered.

PMC10803270

Key protocol amendments

PMC10803270

Current version 3.0, 21 October 2021

The protocol was amended primarily to add two new arms to the trial, to add a powder for reconstitution formulation of tovorafenib and to incorporate other changes based on feedback from regulatory authorities. This version of the full trial protocol (some confidential information redacted) is in the

PMC10803270

Version 2.0, 23 October 2020

The protocol was amended primarily to change the recommended phase 2 dose of tovorafenib from 530 mg m

PMC10803270

Clinical trial registration

The study is registered on ClinicalTrials.gov as

PMC10803270

Reporting summary

Further information on research design is available in the

PMC10803270

Online content

Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02668-y.

PMC10803270

Supplementary information

Supplementary Tables 1 and 2 and trial protocol.Reporting Summary

PMC10803270

Extended data

PMC10803270

Tumor kinetics.

Fig.

PMC10803270

Swimlane plot of time to response and duration of therapy per RANO-LGG criteria.

MR, glioma

MINOR, GLIOMA

In patients with response, symbols indicate the start of response (MR or PR). If initial response improved with continued treatment (from MR to confirmed PR), both the timepoint of the initial response and the timepoint that response initially improved are marked accordingly. BRAFi, BRAF inhibitor; LGG, low-grade glioma; MEKi, MEK inhibitor; MR, minor response; PR, partial response; RANO, Response Assessment in Neuro-Oncology.

PMC10803270

Extended data

is available for this paper at 10.1038/s41591-023-02668-y.

PMC10803270

Supplementary information

The online version contains supplementary material available at 10.1038/s41591-023-02668-y.

PMC10803270

Acknowledgements

D.H., Cancer

WRIGHT, CANCER

This trial was funded by Day One Biopharmaceuticals. We thank the patients, families, caregivers and clinical investigators for their participation in the FIREFLY-1 trial. We are deeply grateful for the site coordinators and trial staff who are instrumental in making this work possible. The authors would like to thank the Pacific Pediatric Neuro-Oncology Consortium (PNOC) for their partnership in the conduct of this trial. We also would like to acknowledge and thank the PNOC014 investigators and trial team (principal investigator: K. Wright) for generating the initial observation of the activity of tovorafenib in pLGG in their phase 1 trial. We also thank M. C. Cox for his contribution to protocol development and trial management. Medical writing support was provided by M. Hoke and S. Govinda Raju of Day One Biopharmaceuticals and J. Heighway and A. Cleasby of Cancer Communications and Consultancy Ltd., funded by Day One Biopharmaceuticals. D.S.Z. is supported by grants from the National Health and Medical Research Council (Synergy Grant 2019056 and Leadership Grant APP2017898) and Cancer Institute New South Wales Program Grant TPG2037. D.H. is supported by funding from the National Institute for Health and Care Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health and Social Care.

PMC10803270

Author contributions

All authors had access to primary clinical trial data. All authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. All authors contributed substantially to the concept and design of the manuscript, data analysis and interpretation and writing of the manuscript. All authors approved the final version of the manuscript.

PMC10803270

Peer review

PMC10803270

Data availability

The trial protocol (confidential information redacted) is provided in the

PMC10803270

Competing interests

D.H.

L.B.K. has received consulting fees from Blueprint Medicine as DSMB Chair and has contracted institutional research with Novartis, Regeneron Pharmaceuticals, Day One Biopharmaceuticals, Spring Works Therapeutics, Bristol Myers Squibb and SonALAsense. L.B.K. also owns stock in Onconova Therapeutics. J.R.H. has received honoraria for consultation from Bayer, Alexion Pharma and Boxer Capital. P.H.D. is on an advisory board with Alexion and is part of the Alexion ICI Sprinkle Study. S.P. is on advisory boards with Bayer, Alexion and Esai and has received research support from Novartis, Bayer and Roche. D.S.Z. has received consulting/advisory board fees from Bayer, AstraZeneca, Accendatech, Novartis, Day One Biopharmaceuticals, FivePhusion, Amgen, Alexion and Norgine and has received research support from Accendatech. O.W. is on advisory boards with Novartis, Janssen, Roche, Bristol Myers Squibb and AstraZeneca and has received research grants from Day One Biopharmaceuticals, Biomed Valley Discovery, Bristol Myers Squibb, Syndax and PreComb. H.J.K. is on advisory boards with Novartis, Jazz Pharmaceuticals, Takeda, Cartexell and GPCR. D.H. is on advisory boards with Alexion/AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Day One Biopharmaceuticals, Janssen, Novartis and Roche and has received research grants from Alexion/AstraZeneca and Roche. V.L. is on an advisory board with Alexion. C.K. is a study chair of an investigator-sponsored trial for which Day One Biopharmaceuticals provides drug and research support; she also has research relationships with other industry partners. D.S. is on an advisory board with Alexion. L.M., X.Z., A.W., D.D., P.M., I.C. and S.C.B. are employees of Day One Biopharmaceuticals and have received Day One Biopharmaceuticals stock and stock options. K.N. has received advisory board or consulting fees from Y-mAbs, EUSA Pharma, Bayer and Eli Lilly. All remaining authors declare no competing interests.

PMC10803270

References

PMC10803270

Background

gynecologic cancer

GYNECOLOGIC CANCER

Patients with gynecologic cancer receiving chemotherapy often report unmet supportive care needs. Compared with traditional face-to-face clinical interventions, mobile health can increase access to supportive care and may address patients’ needs. Although app-based support programs have been developed to support patients with gynecologic cancer, their efficacy has not been adequately tested.

PMC10682921

Objective

gynecologic cancer

GYNECOLOGIC CANCER

The aim of this study was to examine the efficacy of a mobile app for gynecologic cancer support (MGCS) for patients with gynecologic cancer receiving chemotherapy in China.

PMC10682921

Methods

gynecologic cancer, Mishel

SECONDARY, GYNECOLOGIC CANCER

A multicenter randomized controlled trial was conducted in 2 university-affiliated hospitals in China. A total of 168 Chinese patients with gynecologic cancer were recruited and randomized to receive routine care or MGCS program plus routine care for 24 weeks. The Mishel uncertainty in illness theory guided the development of MGCS program, which has 4 modules: weekly topics, emotional care, discussion center, and health consultation. The primary outcome of this program was the assessment of the uncertainty in illness. The secondary outcomes were quality of life, symptom distress, and social support. All health outcomes were evaluated at baseline (T0), 12 weeks (T1), and 24 weeks (T2). Repeated measures analysis of covariance was used to assess the efficacy of the MGCS program.

PMC10682921

Results

In this trial, 67 patients in the control group and 69 patients in the intervention group completed 2 follow-up assessments (response rate, 136/168, 81%). At 12 weeks, no significant differences were observed in any of the health outcomes between the 2 groups. At 24 weeks, compared to patients in the control group, those in the intervention group reported significant decreased uncertainty in illness (

PMC10682921

Conclusions

cancer, gynecologic cancer

CANCER, GYNECOLOGIC CANCER

The MGCS program demonstrated efficacy in supporting patients with gynecologic cancer receiving chemotherapy. This trial illustrates that an app-based program can be incorporated into routine care to support patients with cancer and suggests that allocation of more resources (grants, manpower, etc) to mobile health in clinics is warranted.

PMC10682921

Trial Registration

Chinese Clinical Trial Registry ChiCTR2000033678; https://www.chictr.org.cn/showproj.html?proj=54807

PMC10682921

Introduction

PMC10682921

Background

cancer, ovarian cancers

CANCER, OVARIAN CANCER

Gynecologic cancer (GC) is a global public health concern, with cervical, endometrial, and ovarian cancers being the 3 most common GCs [

PMC10682921

Conceptual Framework

gynecologic cancer, Mishel

GYNECOLOGIC CANCER

Many patients with GC receiving chemotherapy experience high levels of uncertainty in illness [We developed the mobile app for gynecologic cancer support (MGCS) program under the conceptualization of Mishel uncertainty in illness theory. The primary aim of this trial was to examine whether the MGCS program can effectively target uncertainty in illness. We hypothesized that MGCS plus routine care is superior to routine care alone in reducing uncertainty in illness. The subhypotheses were that MGCS plus routine care would improve QoL, reduce symptom distress, and promote social support for patients with GC.

PMC10682921

Methods

PMC10682921

Study Design

A multicenter randomized controlled trial was conducted. This trial was registered in the Chinese Clinical Trial Registry (ChiCTR2000033678). The protocol for this trial was published and strictly followed at all stages [

PMC10682921

Participants and Settings

cancers

CANCERS, OVARIAN CANCERS

Trial participants included patients who were (1) aged 18 years and older, (2) first diagnosed with GC (including cervical, endometrial, and ovarian cancers), (3) starting the first cycle of chemotherapy, (4) able to access the internet via a mobile phone, (5) contactable, and (6) able to read and write Chinese. Patients were excluded if they had (1) other major health conditions, including other cancers and (2) other major mental health conditions, which may prevent them from participating in the MGCS program. Patients were excluded if they were not aware of their diagnoses of a GC. Although not common, this does occur in China when families seek to protect patients from bad news. Participants were recruited from the Department of Gynecology in 2 Chinese university-affiliated hospitals. The hospitals administer chemotherapy to approximately 500 (400 and 100 in each hospital, respectively) patients with GC each year. Patients with GC need to stay overnight in the hospital on the first day of each cycle of chemotherapy. Approximately 50% of patients with GC were eligible to participate in this trial.

PMC10682921

Sample Size Calculation and Sample Randomization

The primary health outcome of uncertainty was used to calculate the sample size. Previous research on a face-to-face uncertainty management intervention reduced uncertainty in illness for patients with HIV with an effect size of 0.53 [

PMC10682921

Ethics Approval

Ethics approval was obtained from the ethics committees of the School of Medicine in Xiamen University (XDYX2019013) and 2 university-affiliated hospitals (Zhongshan Hospital: XMZSYYKY2020-113 and First Affiliated Hospital: FA2020-037). All participants were informed that their participation was voluntary. Participants needed to complete informed consent before participation. All collected data were kept confidential and anonymous. Participants received a gift compensation (approximately US $4) after each evaluation.

PMC10682921

Intervention

gynecologic cancer, Mishel

EFFECTS OF CHEMOTHERAPY, GYNECOLOGIC CANCER

A health care team consisting of 3 gynecologic oncologists, 1 psychologist, and 2 oncology nursing specialists designed the MGCS program. An information technology company technically developed and subsequently maintained the MGCS program. The Mishel theory outlines 4 main components of uncertainty in illness: antecedents (stimuli frame and structure providers), appraisal (danger and opportunity), coping, and adaptation [The MGCS program has 4 modules: weekly topics, emotional care, discussion center, and health consultation [Four modules of the mobile app for gynecologic cancer support program.Different strategies were provided to make MGCS content easy to understand, such as the use of graphics, images, short videos, emoticon pictures, and plain language. The perceived usefulness and perceived ease of use of the MGCS program were assessed by 8 patients with GC receiving chemotherapy, and they all found that this program provided useful information and was easy to use. No major components and contents were changed during the implementation of the program.Participants in the intervention group were given a QR code to download the MGCS onto their mobile phones (Android and iOS versions available). Once access to the app was approved by the researchers, participants could use their mobile phone number and a self-set password to access the MGCS program when and where needed. The researchers offered 30-minute individual face-to-face training to participants on how to use the 4 modules. Training included assisting participants to explore the content in the modules of weekly topic and emotional care as well as to write their first message in the modules of discussion center and health consultation. When participants logged into the app for the first time, a tutorial guide video was displayed initially. Once viewed, the video was automatically saved in the tutorial section of the individual center for future reference. Participants could seek technical assistance in the help section in the individual center. Access to the app automatically expired 24 weeks after activation.Participants in both groups received routine care from health care workers during their stay in the hospitals for each cycle of chemotherapy. Before the first chemotherapy cycle, the patient’s oncologist offered information regarding chemotherapy and chemotherapy-related side effects. The ward nurse provided written information on how to manage the side effects of chemotherapy and answered any question. Currently, there are no app-based programs to help patients with GC to cope with uncertainty and the side effects of chemotherapy at the participating hospitals.

PMC10682921

Outcome Measures

primary disease, cancer

CANCER

Self-reported demographic and clinical characteristics questionnaires were designed by the research team. Demographic characteristics consist of age, marital status, educational level, current employment, monthly family income (in USD), and payment methods. Clinical characteristics include primary disease site, stage of cancer, treatment before chemotherapy, cycles of chemotherapy, and chemotherapy regimen. Clinical characteristics were confirmed through the participants’ electronic medical records.

PMC10682921

Primary Outcome

Participants’ uncertainty in illness was assessed with the Chinese version of the 25-item Mishel Uncertainty in Illness Scale for Adults (MUIS-A) [

PMC10682921

Secondary Outcomes

Cancer

CANCER

Participants’ QoL was measured with the Chinese version of the 27-item Functional Assessment of Cancer Therapy-General (FACT-G, version 4) [

PMC10682921

Data Collection

BLIND

Data were collected between February 2021 and March 2022. The oncologist informed eligible patients with GC about the MGCS program. Patients with GC who expressed an interest in this study were approached by a member of the research team to provide more detailed information. After signing the paper consent form, all participants completed paper-based demographic and baseline health outcomes questionnaires before randomization (T0). Participants were notified of their group allocations in the trial. Following the protocol of the participating hospitals, patients with GC received 4-8 cycles of chemotherapy (3 weeks/cycle). Chemotherapy was usually completed within 24 weeks. Participants in both groups completed the paper questionnaires at 12 (T1) and 24 weeks (T2). The researchers who collected questionnaires were not blind to group allocation. If the participants did not return to the hospital at either time point, a researcher contacted them by phone and mailed them the questionnaires.

PMC10682921

Statistical Analysis

SPSS (version 25; IBM Corp) was applied to analyze all the data [

PMC10682921

Results

PMC10682921

Efficacy of the MGCS Program

PMC10682921

Secondary Outcomes

gynecologic cancer, Cancer

GYNECOLOGIC CANCER, CANCER

At 12 weeks (T1), there was no significant difference in the QoL between the 2 groups. At 24 weeks (T2), after adjusting for the baseline scores, participants who received the MGCS program plus routine care exhibited a significant improvement in QoL compared with participants who only received routine care (Mean change in the measurement outcomes at baseline (T0), 12 weeks (T1), and 24 weeks (T2) (N=168). FACT-G: Functional Assessment of Cancer Therapy-General; MDASI: MD Anderson Symptom Inventory; MGCS: mobile app for gynecologic cancer support; MSPSS: Multidimensional Scale of Perceived Social Support; MUIS-A: Mishel Uncertainty in Illness Scale for Adults.

PMC10682921

Usage Data of the MGCS Program

gynecologic cancer

GYNECOLOGIC CANCER

The MGCS program usage varied considerably. During the 24-week intervention, the mean of the total usage duration was 85.23 minutes (SD 196.24; maximum 1144.60; median 16.53, IQR 2.12-75.20), and the mean of the total log-in frequency was 67.90 times (SD 106.01; maximum 565; median 21, IQR 4-94). The weekly topics and discussion center modules were most commonly used by participants. The health consultation module was the least used module in our study. Usage duration and log-in frequency of the mobile app for gynecologic cancer support program for participants during the 24-week intervention (n=84).

PMC10682921

Discussion

PMC10682921

Principal Results

colorectal cancer

COLORECTAL CANCER

The strengths of this study include the clinical importance of an app for supporting patients with GC and the theory-derived intervention as well as the methodological rigor in collecting and analyzing data. The MGCS program is the first expert-led app-based program designed in China for patients with GC receiving chemotherapy. The MGCS program illustrates how an app-based support program can be incorporated into routine care to promote health outcomes for patients with GC receiving chemotherapy.Our trial shows that the MGCS program significantly decreased the uncertainty in patients with GC at 24 weeks. This is consistent with that reported in another study, which found that a mobile navigation program significantly decreased the uncertainty in patients with colorectal cancer [Our results show that the MGCS program significantly improved the QoL of patients with GC at 24 weeks. Minimally important clinical differences with values over 3-7 in the FACT-G scale have been established as clinically meaningful improvements in QoL [Our trial shows that the MGCS program did not significantly improve the symptom distress and social support of patients with GC at 24 weeks. In the MGCS program, symptom management strategies were provided, but the practices of the strategies were not tracked or monitored. Patients with GC may not practice these strategies or may get tired of doing the same exercises strategies over time [We found no significant differences in any of the health outcomes between the intervention and control groups at 12 weeks. During early chemotherapy cycles, patients with GC experience high levels of physical and psychological distress, which may limit their ability or desire to read, interact with others, and practice coping strategies [

PMC10682921

Limitations

VULVAR CANCER

This trial has several limitations. We only recruited patients with 3 types of GCs, while those with other GCs (eg, vulvar cancer) were excluded. Patients with GC recruited from the 2 participating university-affiliated hospitals may not represent those in the hospitals located in rural or remote areas. Implementing the intervention may exclude patients who were unfamiliar with technology and not comfortable with technology, which might further hinder generalizability. The evaluation data are more likely to reflect only those patients with a strong interest in psychosocial interventions, which may lead to positive bias. Additionally, the information on patients' treatment regimen changes during the trial were not collected, and its impacts on the outcomes could not be known. We only followed up patients with GC until the completion of our intervention at 24 weeks. Some researchers have shown that web-based cognitive behavioral therapy interventions have a positive effect on the improvement of QoL and decrease of symptoms at 1-year and 3-year follow-ups [

PMC10682921

Conclusions

cancer, Cancer

CANCER, CANCER

This trial demonstrates the efficacy of an app-based program to decrease uncertainty in illness and improve the QoL of patients with GC receiving chemotherapy. This trial illustrates how an app-based support program can be incorporated into clinical practice. Translating the intervention into clinical practice can be strengthened by establishing optimal dosage or by adapting for the larger cancer population online. This trial suggests that allocation of greater resources to mobile health interventions in clinics is warranted.This study received support from the National Natural Science Foundation of China (71974162). The grant body had no role in the design of this study, data collection, data analysis, and data interpretation. The authors thank Kate White and Louise Acret (Cancer Care Research Unit, Susan Wakil School of Nursing and Midwifery, Faculty of Medicine and Health, The University of Sydney) for their support in editing and reviewing this manuscript.Authors' Contributions: HL contributed to conceptualization, data curation, formal analysis, investigation, methodology, resources, software, and writing the original draft. MY contributed to conceptualization, data curation, formal analysis, investigation, methodology, resources, software, and writing the original draft. YL contributed to conceptualization, data curation, formal analysis, investigation, methodology, and writing the original draft. SC contributed to project administration, supervision, validation, and manuscript reviewing and editing. HC contributed to data curation, investigation, and resources. FC contributed to project administration, supervision, validation, and manuscript reviewing and editing. JZ contributed to conceptualization, data curation, formal analysis, investigation, methodology, funding acquisition, project administration, resources, software, supervision, validation, and manuscript reviewing and editing.Conflicts of Interest: None declared.CONSORT-EHEALTH (V1.6.1) checklist.

PMC10682921

Abbreviations

cancer, Cancer

CANCER

Consolidated Standards of Reporting Trials of Electronic and Mobile Health Applications and Online TelehealthFunctional Assessment of Cancer Therapy-Generalgynecologic cancerMD Anderson Symptom Inventorymobile app for gynecologic cancer supportMultidimensional Scale of Perceived Social SupportMishel Uncertainty in Illness Scale for Adultsquality of life

PMC10682921

Data Availability

The data sets generated and analyzed during this study are available in the Mendeley repository: 10.17632/cmn7zfbwby.2

PMC10682921

BACKGROUND:

ABI, brain injury

ORCID: 0000-0003-1772-2037ORCID: 0000-0002-6889-4552Sleep disturbances are common after acquired brain injury (ABI) and have a negative impact on functioning.

PMC10657700

OBJECTIVE:

sleep disturbances, ABI

This study examines whether a short add-on therapy for sleep disturbances in individuals with ABI is effective in addition to rehabilitation treatment as usual.

PMC10657700

METHODS:

ABI, fatigue, anxiety, insomnia, depression

In the randomized-controlled study, 54 adults with ABI and self-reported sleep disturbances receiving outpatient rehabilitation services were randomized in two groups: one receiving a sleep intervention (based on cognitive behavioural therapy for insomnia (CBT-I)) in addition to their rehabilitation treatment (CBT-I + TAU group) and one receiving treatment as usual (TAU). The primary outcome was sleep quality, measured with the Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included measures of anxiety, depression, fatigue and dysfunctional beliefs and attitudes about sleep.

PMC10657700

RESULTS:

fatigue

The short add-on sleep therapy resulted in improvements in sleep quality in the CBT-I + TAU group as compared to the TAU group (ES = 0.924). Furthermore, the CBT-I + TAU group reported less dysfunctional beliefs and attitudes about sleep and were better able to cope with fatigue compared to the TAU group.

PMC10657700

CONCLUSIONS:

The application of this short add-on sleep intervention could be implemented in neuropsychological rehabilitation settings.

PMC10657700

Introduction

ABI, mood disorders, decline in cognitive abilities, fatigue, sleep disturbances, anxiety, brain injury, insomnia, depression

Individuals with acquired brain injury (ABI) often have a wide range of impairments which may result in long-term difficulties in everyday life (Sleep disturbances negatively affect health, resulting in a lower quality of life, decline in cognitive abilities and a higher risk of mood disorders (According to the European Sleep Research Society (ESRS), the preferred treatment of sleep disturbances in the healthy population consists of non-pharmacological treatments, such as cognitive behavioural therapy for insomnia (CBT-I) (While studies in healthy individuals have thus provided clear evidence for CBT-I as the treatment of choice for sleep disturbances, there is to date limited evidence for the effectiveness of CBT-I following ABI. Based on several systematic reviews, CBT interventions are most promising for improving sleep following ABI (The aim of the present study is to examine whether a short add-on therapy for sleep disturbances in individuals with ABI is effective in an outpatient rehabilitation setting. The add-on sleep therapy was developed based on CBT-I components, which have shown to be effective in previous studies (The main hypothesis of the present study is that the sleep quality significantly improves in the group who received the short add-on sleep therapy in addition to treatment as usual (CBT-I + TAU) compared to the group that received rehabilitation treatment as usual only (TAU only). We also hypothesize that the treatment group (CBT-I + TAU) will demonstrate less fatigue and dysfunctional beliefs and attitudes about sleep, and less feelings of anxiety and depression. In addition to a group analysis, the effectiveness of the short add-on sleep therapy will also be studied at the individual level. Reliable change indices (RCI) for the primary outcome measure (reported sleep quality) will be calculated for each patient to determine whether the short add-on therapy resulted in clinically significant changes in sleep quality. The short add-on therapy may lead to a valuable contribution to neuropsychological rehabilitation in clinical practice.

PMC10657700

Method

PMC10657700

Participants

drug abuse or dependence, sleep disorder, fatigue, brain injury, psychosis, brain damage, Parkinson, Multiple Sclerosis), ideations, disability

NEURODEGENERATIVE DISORDERS, RESTLESS LEGS SYNDROME, OBSTRUCTIVE SLEEP APNOEA

Participants were recruited from the outpatient department of the Rehabilitation Medical Centre Klimmendaal in Arnhem, The Netherlands. To be eligible for inclusion, participants (1) had to have an acquired brain injury (≥3 months post-injury), (2) had self-reported sleep problems which are associated with disability in daily life (not confirmed by a self-reported questionnaire measuring sleep disturbances) (3) were aged between 18 and 75 and (4) received outpatient rehabilitation services. Exclusion criteria were (1) severe brain damage, (2) neurodegenerative disorders (e.g., Parkinson, Multiple Sclerosis), (3) were diagnosed with a sleep disorder prior to injury (e.g., obstructive sleep apnoea, restless legs syndrome), (4) alcohol or drug abuse or dependence, (5) had serious psychopathology (e.g., risk for psychosis) or expressed suicidal ideations and (6) recently started taking sleep medication (less than a month ago). All participants voluntarily participated in this study. Sleep disturbances refer to sleep problems that occur at night and are characterized by the inability to initiate and maintain sleep and are associated with fatigue during daytime.For the calculation of the required sample size, G*Power for ANOVA was used (The present study was registered at The Dutch Trial Register; registration number NL9368;

PMC10657700

Outcome measures

Anxiety, fatigue, DMFS, depressive, Depression, Fatigue

For evaluation of the effects of the short add-on sleep therapy, validated Dutch versions of four self-reported questionnaires were administered, including the Pittsburg Sleep Quality Index (PSQI), the Dutch Multi-Factor Fatigue Scale (DMFS), the Hospital Anxiety and Depression Scale (HADS) and the Dysfunctional Beliefs and Attitudes about Sleep Scale brief version (DBAS-16). All self-report questionnaires were administered at baseline and post-treatment.The primary outcome measure was the self-report Pittsburg Sleep Quality Index (PSQI) questionnaire (Secondary outcome measures included the DMFS, the HADS and the DBAS-16. The Dutch Multi-Factor Fatigue Scale (DMFS) is a self-report questionnaire and considered to be a subjective measure of fatigue (Anxiety and depressive symptoms were examined using the Hospital Anxiety and Depression Scale (HADS) (The Dysfunctional Beliefs and Attitudes about Sleep Scale brief version (DBAS-16) was administered to assess dysfunctional beliefs and attitudes about sleep (

PMC10657700

Intervention

sleep-related

The add-on sleep intervention comprised four sessions over six weeks and is based on CBT-I principles. The sleep intervention was added to the regular rehabilitation program, which varied between individuals based on their rehabilitation goals. Thus, the add-on sleep intervention is a short variant of CBT-I which is in addition to the rehabilitation treatment as usual. All therapists were trained in CBT-I. Furthermore, individual supervision by an experienced CBT-I therapist was available during the study. During the COVID-19 pandemic lockdown in 2020, treatment sessions were delivered online through video calls and assessments were sent by post.The first session started with the baseline assessment. During a structured interview, participants were asked to address their sleep-related problems. Subsequently, a daily homework assignment was given to the participants that involved completing a sleep-wake diary for one week. This sleep-wake diary provided information about several (sleep) parameters, including sleep duration, time spent in bed, wake time, sleep quality, nighttime activities, caffeinated drinks and alcohol consumption.The second session (one week later) consisted of psychoeducation about sleep and recommendations were made to change sleep behaviour. Psychoeducation and recommendations were somewhat personalized based on information gathered from the sleep assessment (interview, questionnaires and sleep diary). Behavioural techniques consisted of discussing sleep hygiene, such as caffeine intake and activities before bedtime, stimulus control and sleep restriction. Stimulus control aims to improve the association between bed and sleep-behaviour by solely using the bed for sleeping (and not for other activities such as reading or watching TV). In addition, an adapted form of sleep restriction was used in which participants were instructed to shorten the time spent in bed to a maximum of 7 hours in order to consolidate sleep. It is important to note that regular CBT-I treatments instruct participants to spent only 5 hours in bed. Since research demonstrated that individuals with ABI need more sleep as compared to individuals without ABI (After two weeks, the third session took place in which the adjustments in sleep behaviour and its effect on sleep quality were evaluated and, if necessary, extended or adapted. Possible additional elements contained relaxation exercises, strategies to cope with worrying (e.g., ‘worry postponement’) or increasing physical activities during daytime. Participants were instructed to maintain their changes in sleep behaviour for another two weeks.During the final session, which took place two weeks after the third session, changes in sleep behaviour and its impact on sleep were evaluated. Furthermore, the therapist and participant jointly developed a relapse prevention plan which also included an overview of the most important sleep recommendations. The session ended with the post-treatment assessment (T6: PSQI, HADS, DMFS, DBAS-16). Throughout the treatment, participants were encouraged to follow the program strictly to develop a regular sleep pattern. A summary of the content of the sleep intervention is presented in Summary of the short add-on sleep therapy

PMC10657700

Procedure

ABI

This randomized controlled trial was conducted between September 2018 and February 2022, with the first patient included on 10 September 2018. Potential participants were referred by their neuropsychologists in the first weeks of their rehabilitation program. Neuropsychologists screened possible participants for inclusion and exclusion criteria and gave information about the study. All ABI patients who met the inclusion criteria were able to receive the add-on sleep therapy, regardless of their participation in the study. When participants were interested in participation in the study, the researcher (LP) was informed. A final check on inclusion- and exclusion criteria was performed by the researcher. After obtaining the signed informed consents, participants were randomly allocated to either the CBT-I + TAU or TAU only group using a computer-generated randomization program (Research Randomizer; The CBT-I + TAU group started with the six-week sleep intervention, in addition to their rehabilitation treatment as usual. Patients in the TAU only group were placed on a wait-list for six weeks, while receiving rehabilitation treatment as usual (based on indication, which consisted of physiotherapy, occupational therapy, neuropsychological treatment, speech therapy). Demographic and injury-related information was obtained and the self-report measures (PSQI, HADS, DMFS, DBAS-16) were filled in (T0 for the treatment group) during the first session. Note that results of the baseline measures were not discussed with the participants during the first session. At the end of the sleep intervention, pre-and post- assessments were discussed with patients during the last session.A follow-up measurement took place in the CBT-I + TAU group to examine whether the effects of the add-on sleep intervention were maintained. The CBT-I + TAU group completed the follow-up assessment 3 months after completing the intervention. Note that the follow-up assessment was limited to the CBT-I + TAU group, as the TAU only group also received the intervention following the 6-week waiting period.Assessments for the CBT-I + TAU group were built in the treatment sessions, with T0 in the first session and T6 after six weeks in the fourth session and administered by the therapists. At the start of the waiting period, a baseline assessment (T0) was administered by one of the researchers. T6 was carried out in the first session of the intervention. Patients and therapists were aware of the group allocation as the CBT-I + TAU group received the therapy in addition to their rehabilitation treatment as usual, while the TAU only group received the intervention after six weeks. The researcher was not blinded, since her role was to communicate with the planning staff to ensure patients started the intervention at the appropriate timepoint. A CONSORT flow diagram showing the content of the interventions is presented in

PMC10657700

Statistical analyses

For all variables the assumption of normality was checked and corrected for, if necessary. IBM SPSS 27 was used for the statistical analyses (IBM Corp., Armonk, USA). Demographic and baseline data of the two groups were analyzed using two-tailed independent To determine the efficacy of the short add-on therapy, per protocol analyses were performed (see The Dutch Trial Register; registration number NL9368; Individual-level change scores were calculated using Reliable Change Indices (RCI; (In order to assess whether the effects of the add-on sleep intervention were maintained from post-treatment to 3-month follow-up, paired sample

PMC10657700

Discussion

ABI, fatigue, anxiety, sleep disturbances, sleep-related cognitions, depressive

This randomized controlled trial (RCT) investigated the effectiveness of a short add-on CBT-I-based therapy for sleep disturbances in individuals with ABI in addition to rehabilitation treatment as usual. The CBT-I + TAU group improved more on self-reported sleep quality, dysfunctional beliefs and attitudes about sleep and partially on fatigue relative to the TAU only group. Specifically, the CBT-I + TAU group significantly improved on sleep quality with large effect sizes over time relative to the TAU only group. Furthermore, sleep-related cognitions significantly improved in the CBT-I + TAU group, with small effect sizes (ES = 0.375), as compared to the TAU only group, and participants in the CBT-I + TAU group were better able to cope with fatigue. No significant treatment effects were found regarding impact, consequences or symptoms of fatigue, mental and physical fatigue, or in anxiety and depressive symptoms. Our results also showed that the post-treatment improvement (e.g. sleep quality, sleep related cognitions and coping with fatigue) were maintained at 3-month follow-up in the group that received the add-on treatment.These results corroborate and extend previous findings showing that CBT is effective in improving sleep in individuals with ABI (

PMC10657700

Limitations and future directions

sleep disturbances

Although our findings provide valuable information on treatment efficacy of a short CBT-I treatment for sleep disturbances in the ABI population, some limitations should be noted. First, the present study aimed to examine the effectiveness of an add-on sleep intervention in individuals with ABI. The Consolidated Standards of Reporting Trials (CONSORT) statement recommends that a RCT study reports detailed information about adherence to treatment (

PMC10657700

Conclusions

depressive, ABI, fatigue, anxiety

Sleep disturbances are common following ABI and have a negative impact on emotional well-being and cognitive functioning. The present study shows that a short CBT-I based sleep intervention produced significant improvements in sleep quality and fatigue in people with ABI in addition to rehabilitation treatment as usual. Furthermore, participants who received the sleep therapy were better able to cope with fatigue compared to the TAU only group. No significant improvements were observed regarding impact and consequences of fatigue, symptoms of physical and mental fatigue, nor in anxiety and depressive symptoms. It is also important to note that some potentially burdensome elements in the add-on sleep intervention, such as stimulus control and sleep restriction, did not increase fatigue during treatment. This study shows that psychoeducation combined with behavioural recommendations to change sleep behaviour seems to be sufficient and confirms the shortening of the regular CBT-I protocol in this ABI population. The application of this short add-on sleep intervention could be implemented in neuropsychological rehabilitation settings.

PMC10657700

Conflict of interest

None to report.

PMC10657700

References

PMC10657700

Background

ANTERIOR

Anterior cruciate ligament (ACL) reconstruction aims to restore anteroposterior and rotatory stability to the knee following ACL injury. This requires the graft to withstand the forces applied during the process of ligamentisation and the rehabilitative period. We hypothesise that the use of suture tape augmentation of single bundle ACL reconstruction (ACLR) will reduce residual knee laxity and improve patient-reported outcomes at 2-year follow-up. We will conduct a 1:1 parallel arm single-centre randomised controlled trial comparing suture tape augmented ACLR to standard ACLR technique.

PMC10037835

Methods

arthrometer, ACL rupture

STERILE, EFFUSION, PATHOLOGY, COMPLICATION

The study design will be a parallel arm 1:1 allocation ratio randomised controlled trial. Sixty-six patients aged 18 and over waitlisted for primary ACLR will be randomised. Patients requiring osteotomy and extra-articular tenodesis and who have had previous contralateral ACL rupture or repair of meniscal or cartilage pathology that modifies the post-operative rehabilitation will be excluded. The primary outcome measure will be the side-to-side difference in anterior tibial translation (measured on the GNRB arthrometer) at 24 months post-surgery. GNRB arthrometer measures will also be taken preoperatively, at 3 months and 12 months post-surgery. Secondary outcomes will include patient-reported outcome measures (PROMs) collected online, including quality of life, activity and readiness to return to sport, complication rates (return to theatre, graft failure and rates of sterile effusion), examination findings and return to sport outcomes. Participants will be seen preoperatively, at 6 weeks, 3 months, 12 months and 24 months post-surgery. Participants and those taking arthrometer measures will be blinded to allocation.

PMC10037835

Discussion

COMPLICATION

This will be the first randomised trial to investigate the effect of suture-tape augmentation of ACLR on either objective or subjective outcome measures. The use of suture-tape augmentation in ACLR has been associated with promising biomechanical and animal-level studies, exhibiting equivalent complication profiles to the standard technique, with initial non-comparative clinical studies establishing possible areas of advantage for the technique. The successful completion of this trial will allow for an improved understanding of the in situ validity of tape augmentation whilst potentially providing a further platform for surgical stabilisation of the ACL graft.

PMC10037835

Trial registration

Australia New Zealand Clinical Trial Registry ACTRN12621001162808. Universal Trial Number (UTN): U1111-1268-1487. Registered prospectively on 27 August 2021

PMC10037835

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-023-07127-0.

PMC10037835

Keywords

PMC10037835

Introduction

PMC10037835

Background and rationale {6a}

arthrometer, knee laxity

KNEE OSTEOARTHRITIS, COMPLICATION

The anterior cruciate ligament (ACL) acts as the primary static constraint to anterior translation and internal rotation of the tibia [Recently, the use of suture tape (a modified suture composed of non-absorbable, braided polyethylene/polyester suture) acting as a ‘seatbelt’ for in situ autograft has been proposed [The primary research objective is to determine whether the use of suture-tape augmentation of a primary hamstring autograft ACLR improves post-operative residual knee laxity. At present, the literature surrounding suture tape augmentation of ACLR is primarily biomechanical and animal model-based, with two retrospective cohort, non-randomised studies reporting subjective outcomes published. This study aims to collect a higher level of evidence, as well as objective measures of post-operative knee laxity among suture tape ACLR patients.The null hypothesis of this study is that there will be no significant difference in side-to-side residual anterior knee laxity, as measured with the GNRB arthrometer, as compared with the contralateral knee at 2 years post-operatively. Secondary outcomes will be graft failure, complication rates, clinical examination findings and patient-reported outcome measures (PROMs) including Knee Osteoarthritis and Outcomes Score Quality of Life subscale (KOOS-QOL) [The study aims to investigate whether suture-tape augmented anterior cruciate ligament reconstruction has superior results to non-augmented reconstructions.

PMC10037835

Objectives {7}

PMC10037835

Primary objective

arthrometer

The objective of this study is to compare residual anterior knee laxity after primary hamstring autograft ACLR with or without suture tape (ST) augmentation, as measured by the GNRB ligament arthrometer at 2 years post-operatively. The primary outcome measure will be the difference between operative and non-operative limbs (side-to-side), between groups, at 2 years.

PMC10037835

Secondary objectives

knee ACL rupture, synovitis, pain, effusion, arthrofibrosis

RSI, SYNOVITIS, COMPLICATION, STERILE, SECONDARY, EFFUSION, COMPLICATIONS, ARTHROFIBROSIS

The secondary objectives are to compare PROMs, complication rates, return to sport rates and examination findings between SA and ST ACLR. The PROMs assessed will include the Marx activity scale, ACL RSI, IKDC, the KOOS QOL and the EQ5D-5L scale. Complications assessed will include post-operative pain levels, graft failure rates, contralateral knee ACL rupture, return to theatre and findings including rates of particulate-related synovitis, sterile effusion, persistent effusion and symptomatic arthrofibrosis of the knee. Return to sport data will include rates of return to sport, timing of return to sport and rates of return to the previous level of the sport. Examination findings assessed will include the presence of effusion, knee range of motion and the presence and grade of the Lachman test, anterior drawer and pivot shift tests.

PMC10037835

Trial design {8}

This study is a randomised controlled single-blind interventional 2-arm parallel-group superiority trial utilising 1:1 allocation ratio comparing ACLR with suture tape augmentation (ST-ACLR) to standard hamstring ACLR technique (ACLR) with femoral adjustable cortical fixation and tibial interference screw. This study is a superiority study with the hypothesis that ACL reconstruction with suture tape augmentation is superior to standard ACL reconstruction technique. All patients meeting inclusion criteria will be randomised to a treatment arm in the operating room following confirmation of exclusion criteria at arthroscopy. All components of the study will be undertaken at a single institution. All patients will be followed up to 2 years post-operatively.

PMC10037835

Methods: participants, interventions and outcomes

PMC10037835