Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2019

Open Access 01-12-2019 | Methodology

An adaptive two-arm clinical trial using early endpoints to inform decision making: design for a study of sub-acromial spacers for repair of rotator cuff tendon tears

Authors: Nick Parsons, Nigel Stallard, Helen Parsons, Philip Wells, Martin Underwood, James Mason, Andrew Metcalfe

Published in: Trials | Issue 1/2019

Login to get access

Abstract

Background

There is widespread concern across the clinical and research communities that clinical trials, powered for patient-reported outcomes, testing new surgical procedures are often expensive and time-consuming, particularly when the new intervention is shown to be no better than the standard. Conventional (non-adaptive) randomised controlled trials (RCTs) are perceived as being particularly inefficient in this setting. Therefore, we have developed an adaptive group sequential design that allows early endpoints to inform decision making and show, through simulations and a worked example, that these designs are feasible and often preferable to conventional non-adaptive designs. The methodology is motivated by an ongoing clinical trial investigating a saline-filled balloon, inserted above the main joint of the shoulder at the end of arthroscopic debridement, for treatment of tears of rotor cuff tendons. This research question and setting is typical of many studies undertaken to assess new surgical procedures.

Methods

Test statistics are presented based on the setting of two early outcomes, and methods for estimation of sequential stopping boundaries are described. A framework for the implementation of simulations to evaluate design characteristics is also described.

Results

Simulations show that designs with one, two and three early looks are feasible and, with appropriately chosen futility stopping boundaries, have appealing design characteristics. A number of possible design options are described that have good power and a high probability of stopping for futility if there is no evidence of a treatment effect at early looks. A worked example, with code in R, provides a practical demonstration of how the design might work in a real study.

Conclusions

In summary, we show that adaptive designs are feasible and could work in practice. We describe the operating characteristics of the designs and provide guidelines for appropriate values for the stopping boundaries for the START:REACTS (Sub-acromial spacer for Tears Affecting Rotator cuff Tendons: a Randomised, Efficient, Adaptive Clinical Trial in Surgery) study.

Trial registration

ISRCTN Registry, ISRCTN17825590. Registered on 5 March 2018.
Appendix
Available only for authorised users
Literature
1.
McCulloch P, Cook JA, Altman DG, Heneghan C, Diener MK, Group I. Ideal framework for surgical innovation 1: the idea and development stages. BMJ. 2013; 346:3012.CrossRef
2.
Ergina PL, Barkun JS, McCulloch P, Cook JA, Altman DG, Group I. Ideal framework for surgical innovation 2: observational studies in the exploration and assessment stages. BMJ. 2013; 346:3011.CrossRef
3.
Cook JA, McCulloch P, Blazeby JM, Beard DJ, Marinac-Dabic D, Sedrakyan A, Group I. Ideal framework for surgical innovation 3: randomised controlled trials in the assessment stage and evaluations in the long term study stage. BMJ. 2013; 346:2820.CrossRef
4.
Bauer P, Bretz F, Dragalin V, Konig F, Wassmer G. Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls. Stat Med. 2016; 35(3):325–47.CrossRefPubMed
5.
Pallmann P, Bedding AW, Choodari-Oskooei B, Dimairo M, Flight L, Hampson LV, Holmes J, Mander AP, Odondi L, Sydes MR, Villar SS, Wason JMS, Weir CJ, Wheeler GM, Yap C, Jaki T. Adaptive designs in clinical trials: why use them, and how to run and report them. BMC Med. 2018; 16(1):29.CrossRefPubMedPubMedCentral
6.
7.
8.
Bauer P, Brannath W. The advantages and disadvantages of adaptive designs for clinical trials. Drug Discov Today. 2004; 9(8):351–7.CrossRefPubMed
9.
Stallard N. A confirmatory seamless phase II/III clinical trial design incorporating short-term endpoint information. Stat Med. 2010; 29(9):959–71.PubMed
10.
11.
Galbraith S, Marschner IC. Interim analysis of continuous long-term endpoints in clinical trials with longitudinal outcomes. Stat Med. 2003; 22(11):1787–805.CrossRefPubMed
12.
Kukkonen J, Joukainen A, Lehtinen J, Mattila KT, Tuominen EK, Kauko T, Aarimaa V. Treatment of non-traumatic rotator cuff tears: a randomised controlled trial with one-year clinical results. Bone Joint J. 2014; 96(1):75–81.CrossRefPubMed
13.
Rangan A, Upadhaya S, Regan S, Toye F, Rees JL. Research priorities for shoulder surgery: results of the 2015 James Lind Alliance patient and clinician priority setting partnership. BMJ Open. 2016; 6(4):010412.CrossRef
14.
15.
Burks RT, Crim J, Brown N, Fink B, Greis PE. A prospective randomized clinical trial comparing arthroscopic single- and double-row rotator cuff repair: magnetic resonance imaging and early clinical evaluation. Am J Sports Med. 2009; 37(4):674–82.CrossRefPubMed
16.
17.
18.
Constant C, Murley A. A clinical method of functional assessment of the shoulder. Clin Orthop Relat Res. 1987; 214:160–4.
19.
Constant C, Gerber C, Emery R, Sojbjerg J, Gohlke F, Boileau P. A review of the Constant score: modifications and guidelines for its use. J Should Elb Surg. 2008; 17(2):355–61.CrossRef
20.
Roy J, MacDermid J, Woodhouse L. A systematic review of the psychometric properties of the Constant-Murley score. J Should Elb Surg. 2010; 19(1):157–64.CrossRef
21.
Blonna D, Scelsi M, Bellato EME, Tellini A, Rossi R, Bonasia D, Castoldi F. Can we improve the reliability of the Constant-Murley score?. J Should Elb Surg. 2012; 21(1):4–12.CrossRef
22.
Ban I, Troelsen A, Christiansen D, Svendsen S, Kristensen M. Standardised test protocol (Constant score) for evaluation of functionality in patients with shoulder disorders. Dan Med J. 2013; 60(4):4608.
23.
Christiansen D, Frost P, Falla D, Haahr J, Frich L, Svendsen S. Responsiveness and minimal clinically important change: comparison between 2 shoulder outcome measures. J Orthop Sports Phys Ther. 2015; 45(8):620–5.CrossRefPubMed
24.
Khatri C, Ahmed I, Parsons H, Smith N, Lawrence T, Modi C, Drew S, Bhabra G, Parsons N, Underwood M, Metcalfe A. The natural history of full-thickness rotator cuff tears in randomized controlled trials: a systematic review and meta-analysis. Am J Sports Med. 2018; 47(1):1–1.
25.
Haahra J, Ostergaard S, Dalsgaard J, Norup K, Frost P, Lausen S, Holm E, Andersen J. Exercises versus arthroscopic decompression in patients with subacromial impingement: a randomised, controlled study in 90 cases with a one year follow up. Ann Rheum Dis. 2005; 64(5):760–4.CrossRef
26.
Karthikeyan S, Kwong H, Upadhyay P, Parsons N, Drew S, Griffin D. A double blind randomised controlled study comparing subacromial NSAID (tenoxicam) injection with steroid (methylprednisolone) injection in patients with subacromial impingement syndrome. J Bone Joint Surg (British). 2010; 92(1):77–82.CrossRef
27.
Senekovic V, Poberaj B, Kovacic L, Mikek M, Adar E, Dekel A. Prospective clinical study of a novel biodegradable sub-acromial spacer in treatment of massive irreparable rotator cuff tears. Eur J Orthop Surg Traumatol. 2013; 23(3):311–16.CrossRefPubMed
28.
Whitehead J.Overrunning and underrunning in sequential clinical trials. Control Clin Trials. 1992; 13:106–21.CrossRefPubMed
29.
Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials. Boca Raton: Chapman & Hall/CRC; 2000, p. 390.
30.
Barnard K, Dent L, Cook A. A systematic review of models to predict recruitment to multicentre clinical trials. BMC Med Res Methodol. 2010;10(63).
31.
32.
33.
Bretz F, Koenig F, Brannath W, Glimm E, Posch M. Adaptive designs for confirmatory clinical trials. Stat Med. 2009; 28(8):1181–217.CrossRefPubMed
Metadata
Title
An adaptive two-arm clinical trial using early endpoints to inform decision making: design for a study of sub-acromial spacers for repair of rotator cuff tendon tears
Authors
Nick Parsons
Nigel Stallard
Helen Parsons
Philip Wells
Martin Underwood
James Mason
Andrew Metcalfe
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Trials / Issue 1/2019
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-019-3708-6

Other articles of this Issue 1/2019

Trials 1/2019 Go to the issue

Study protocol

Metabolic follow-up at one year and beyond of women with gestational diabetes treated with insulin and/or oral hypoglycaemic agents: study protocol for the identification of a core outcomes set using a Delphi survey

Study protocol

MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis

Research

Ambassadors of hope, research pioneers and agents of change—individuals’ expectations and experiences of taking part in a randomised trial of an innovative health technology: longitudinal qualitative study

Correction

Correction to: Contributions of Vitamin D in the management of depressive symptoms and cardiovascular risk factors: study protocol for a randomized, double-blind, placebo-controlled clinical trial

Review

What happens to intimate partner violence studies registered on clinicaltrials.gov? A systematic review of a clinical trials registry

Commentary

SWATted away: the challenging experience of setting up a programme of SWATs in paediatric trials