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High quality RWE - Registry based randomized clinical trials
31 Aug 2022

There is an increasing need to develop high-quality evidence to support decision makers. There are many important improvements that require such big trials that they are never done. In the recent decade there has been a development to different types of pragmatic trial designs to optimize the cost-effectiveness of the trials.

In the spectrum of pragmatic trials, one of the more interesting methods is the utility of registry based randomized clinical trials. The foundation with established high-quality data-collection and longitudinal follow-up is essential.

With the rich datasets in Sweden, the ease of linkage and longitudinal quality it provides one the of the best locations for this type of research.

There are several completed and on-going R-RCT’s in Sweden that has demonstrated the ability to develop high-quality evidence. They are particularly helpful in trials to evaluate therapeutic options available in routine clinical trial.

In the previous blogpost about the fracture registry, we provided an insight to the high quality of the data. Below is a summary of the ongoing R-RCT’s within this registry. They cover from 200 up to 7000 patients and some with follow up to 10 years. This at a fraction of what a traditional trial, one of the trials has a cost of approximately 240 €/patient enrolled.

With the focus on evaluating options in clinical practice, one could argue that this is the most optimal approach for such study. There are other questions, where the traditional RCT is the favorable or even the only option.

In the DAISY trial they evaluate the role of antibiotic loaded cement vs standard of care in 7 000 patients, a trial that probably never would be carried out as a traditional trial due to the significant cost. With the R-RCT, there will be an answer at a very low cost (@1,7 million €).

  • Will the HTA-evaluators and other decision makers use these types of trials to guide decisions?

Summary table comparing the trials:

Trial name

Start

Duration

Number of patients

HipSTHeR

2019

10 years

1440

Duality trial

2020

5 years

1600

SUNBURST

2021

4 years

202

Fragility Fracture

2021

6 years (4 years)

2900

DAICY

2022

5 years

7000

 

For full information about the trials, see the links to the respective protocols at the end.

Trial: DAICY

Indication 

Dual-impregnated antibiotic loaded cement and lower incidence of periprosthetic joint infection.

Start 

2022

Estimated duration 

5 years

Number of participants 

 7000 patients / participants

Standard of care 

Cemented hemiarthroplasty with low dose single antibiotic cement Replacement of the femoral head and neck with choice of femoral head and stem

Comparator 

Cemented hemiarthroplasty with high dose dual-impregnated antibiotic cement Replacement of the femoral head and neck with choice of femoral head and stem.

Allocation 

Randomization

Intervention model 

Parallel assignment

Primary outcome 

Periprosthetic joint infection of the index joint within one year (re-operation, or suppressive antibiotics, or combinations thereof)

Secondary outcome 

  • Any re-operation
  • Antibiotic suppression at 120 days and 1-year post-surgery.
  • 90-day and 1-year mortality
  • Resistance patterns of infections
  • Cost-effectiveness (procedural cost for the intervention, control treatment and reoperation costs)

Follow up 

 120 days -1-year follow-up

Budget  

 @17 million SEK (1,7 million €)

Cost per patient included 

 @2 400 SEK (240 €)

 

Trial: SUNBURST

Indication

Thoracolumbar burst fractures without neurological deficit or complete rupture of the posterior ligament complex (PLC)

Start

2021

Estimated duration

4 years

Number of participants

202

Standard of care

Non-surgical

Comparator

Surgical intervention

Allocation

Randomized

Intervention model

Parallel assignment

Primary outcome

  • Oswestry Disability Index
  • (PRO for spinal disorders)

Secondary outcome

Many including the following at 5&10 years:

  • EQ-5D-DL
  • Sick leave
  • Social cost

Follow up

3-4 months

1 year

5-10 years

Budget

Not possible to identify.

Cost per patient included

Not possible to identify.

 

Trial: The Fragility Fracture Trial (FFT)

Indication 

 Zoledronic acid reduction of the risk of new clinical fractures

Start 

 First quarter of 2021-starting with participant recruitment.

Estimated duration 

6 years (4 years)

Number of participants 

 2900 Participants

Standard of care 

Placebo (normal saline)

Comparator 

Zoledronic acid (5 mg)

Allocation 

Randomized, double-blind

Intervention model 

Parallel assignment 

Primary outcome 

Time to first new clinical fracture

Secondary outcome 

  • Time to first cardiovascular event and cancer diagnosis.
  • In the 10-year follow-up, deaths, cancer events, myocardial infarction and stroke will be traced.
  • And more.

Follow up 

Every 6 months until 48 months

4 years of follow-up

10-year follow-up.

Budget  

 52,1 million SEK (5,2 million €)

Cost per patient included 

18 000 sek / patient (1,800 €)

 

 

Trial: HipSTHeR

Indication 

Internal fixation (hip screws) or (Hip Arthroplasty) hip replacement for undisplaced femoral neck fractures.

Start 

2019 to 2029 (inclusion period 2019–2022).

Estimated duration 

10 years

Number of participants 

1440 older patients

Standard of care 

Internal fixation

Comparator 

Surgical intervention (Hip Arthroplasty)

Allocation 

Randomization and no blinding

Intervention model 

Parallel assignment

Primary outcome 

A composite variable (reoperation rate and mortality).

Secondary outcome 

  • Reoperation rates
  • Mortality
  • Disease specific PROM
  • Other adverse events such as suffering, physical harm or disease
  • Death

Follow up 

2 years

5 years

10 years

Budget  

Not possible to identify.

Cost per patient included 

Not possible to identify.

 

Trial:  DUALITY

Indication 

Dual mobility cups and the reduced risk of dislocation amongst patients with displaced femoral neck fractures.

Start 

The DUALITY trial started recruiting patients in January 2020 and will continue for approximately 5 years.

Estimated duration 

5 years

Number of participants 

1,600 patients

Standard of care 

a standard cup

Comparator 

dual mobility cups (DMC)

Allocation 

Randomization

Intervention model 

Parallel assignment

Primary outcome 

the occurrence of any dislocation of the index joint treated with closed or open reduction within 1 year after surgery,

Secondary outcome 

  • the relative risk of any reoperation of the index joint,
  • PJI (periprosthetic joint infection) of the index joint,
  • mortality within 90 days and 1 year in the intervention compared with the control group.
  • Patient-reported outcomes and health economics (EQ-5D domain scores (5 levels) at 1 year after index surgery and EQ5D-visual analogue scale (VAS) on a 0–100 numeric scale at 1 year after index surgery)

Follow up 

90 days and 1 year after surgery

Budget  

Not possible to identify.

Cost per patient included 

Not possible to identify.

 

  • Blixt, Simon, Sebastian Mukka, Peter Försth, Olof Westin, Paul Gerdhem, and on behalf of the SunBurst study Group. ‘Study Protocol: The SunBurst Trial—a Register-Based, Randomized Controlled Trial on Thoracolumbar Burst Fractures’. Acta Orthopaedica 93 (24 January 2022): 256–63. https://doi.org/10.2340/17453674.2022.1614.
  • ‘Study Protocol: DAICY Trial – Dual vs. Single-Antibiotic Impregnated Cement in Hemiarthroplasty for Femoral Neck Fracture: A Registerbased Cluster-Randomized Cross-over Controlled Trial’. Accessed 10 August 2022. https://registercentrum.blob.core.windows.net/sfr/r/StudyProtocol_DAICY_220101-Sygv5OCrf9.pdf.
  • ‘Study Protocol: The Fragility Fracture Trial (FFT): A Randomized, Doubleblind, Placebo-Controlled Trial to Investigate Whether Zoledronic Acid Prevents New Fractures in Older Adults with a Recent Nonhip, Non-Vertebral Fragility Fracture’. Accessed 10 August 2022. https://www.fftstudy.com/_files/ugd/3ac01b_481b5842c23640df946b27700a3e8819.pdf.
  • Wolf, Olof, Sebastian Mukka, Maja Notini, Michael Möller, and Nils P Hailer. ‘Study Protocol: The DUALITY Trial—a Register-Based, Randomized Controlled Trial to Investigate Dual Mobility Cups in Hip Fracture Patients’. Acta Orthopaedica 91, no. 5 (2 September 2020): 506–13. https://doi.org/10.1080/17453674.2020.1780059.
  • Wolf, Olof, Pontus Sjöholm, Nils P. Hailer, Michael Möller, and Sebastian Mukka. ‘Study Protocol: HipSTHeR - a Register-Based Randomised Controlled Trial – Hip Screws or (Total) Hip Replacement for Undisplaced Femoral Neck Fractures in Older Patients’. BMC Geriatrics 20, no. 1 (2020). https://doi.org/10.1186/s12877-020-1418-2.

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High quality RWE - Registry based randomized clinical trials | Synergus

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