Nejmoa2108447 Protocol
Nejmoa2108447 Protocol
Nejmoa2108447 Protocol
Protocol for: Myhrvold SB, Brouwer EF, Andresen TKM, et al. Nonoperative or surgical treatment of acute
Achilles’ tendon rupture. N Engl J Med 2022;386:1409-20. DOI: 10.1056/NEJMoa2108447
This trial protocol has been provided by the authors to give readers additional information about the work.
This supplement contains the original protocol, final protocol and summary of changes.
The original statistical analysis plan (Version 1.0) was not changed.
Original protocol of January 29th 2013:
Supervisor
Sigurd Erik Hoelsbrekken MD, PhD (1)
Co-supervisors
Kjetil Hvaal MD, PhD (2)
Lars Engebretsen MD, PhD (2)
Øivind Paulsrud MD,(2)
1. Background
Ruptures of the Achilles tendon can be treated by surgical repair or by immobilization using a
cast or a brace allowing the tendon to heal without surgery. Even though such ruptures
represent a common injury, there is no consensus regarding the best treatment protocol3. In
general, the Norwegian orthopedic community has recommended surgical repair based on
studies published the past thirty years showing that surgical repair conveys a significantly
lower risk of rerupture compared to non-operative treatment. Moreover, the comparatively
low number of reruptures has been used to justify the risk of infections and nerve injuries
inferred by surgical treatment4. To reduce the number of complications associated with
operative treatment, mini-invasive surgical techniques have been developed thereby
significantly reducing the number of wound problems while retaining good functional result5.
This has led to an increasing popularity of the mini-invasive approach and a growing number
of patients are treated by mini-invasive surgery. The use of different suture materials and
techniques has also been investigated, but none have proven to be consistently better than
other alternatives and there are no clear recommendations6. There is also uncertainty as to
what time point reruptures tend to occur, and if reruptures happens when the healing tendon
carries most of the tensile strength, regardless of suture techniques and material used.
Mechanical loading stimulates bone healing and bone formation. This correlation was
deduced by the German surgeon Julius Wolff during the late eighteen century and has later
been known as Wolff’s law7. Similar to the relationship dictated by Wolff’s law, mechanical
loading of tendons stimulates increased tensile strength over time8,9. Awareness centered on
Figure 1
this biomechanical trait has led to the development of new rehabilitation protocols10,
especially concerning non-operative treatment. In analogue to Woffs law, by allowing early
controlled loading of the ruptured Achilles tendon, the presumed healing process is
accelerated thereby increasing tensile strength. If true, this approach would reduce the risk of
reruptures and several recent papers have shown that early mobilization actually do improve
the prognosis10-12. Furthermore, if non-operative treatment and surgery yield similar treatment
results, it would be of considerable importance since surgery is inherently associated with the
risk of infections and paresthesia. However, the studies carried out this far have included a
relatively small number of patients and no firm conclusions have been made13. It is therefore
of great interest to conclusively determine treatment results by conducting a prospective
randomized study comprising a sufficient number of patients, potentially altering current
treatment recommendations.
2. Study design
Figure 3
2.4 Postoperative treatment regiment
All patients included in the study will be immobilized in equinus position for the first two
weeks using a below-the-knee cast. Following the first two weeks the cast is replaced with a
brace maintaining ∼12° plantar flexion (three heel lifts). We have chosen to use standardized
heel lifts because it eases weightbearing compared to a hinged brace. After two weeks (four
weeks from injury) the ankle position is adjusted to ∼8° plantar flexion (two heel lifts) and
following additional two weeks the ankle position is adjusted to ∼4° plantar flexion (one heel
lift. The last week of the orthosis treatment (the 8th week after treatment initiation) the heel
lifts are completely removed. Hence, the brace is retained for a total of six weeks, and patients
are allowed full weight bearing as tolerated during the entire time period. The brace is worn
day and night for the first two weeks, but is removed during nighttime for the last four weeks.
Importantly, the immobilization regimen is identical for the three treatment groups. To ensure
identical rehabilitation following immobilization, physical therapy has to adhere to a
standardized protocol supervised by an experienced physiotherapist at the Norwegian Sport
Medicine Clinic (NIMI) as outlined in table 1.
Figure 4 Lateral radiographic evaluations of the ankle brace depicting the angle
between the longitudinal axis of the first metatarsal and the base of the brace using
none (A), one (B) or three (C) standardized heel lifts.
Table 1
3. Secondary studies
The prospective randomized trial embodies many different disciplines and will spur off
follow-up studies. As part of the main project we will conduct a treatment-cost analysis in
relation to individual results. We will also perform an investigation based on ultrasound
grading of Achilles tendon ruptures according to a classification system established by
Michael Amlang and colleagues. Previous studies have provided evidence suggesting that
treatment results may depend on the extension of the injury, and that treatment
recommendations should be based on type of rupture sustained22,23. This is of particular
interest as it may facilitate individualized treatment. Together with the prospective
randomized trial and the treatment-cost analysis, the ultrasound investigation will constitute
the core of the PhD project. Additionally, The Norwegian School of Sport Sciences has
established a method to assess tendon elasticity by ultrasound examinations, which would
enable us to evaluate the healing process qualitatively24,25. A biomechanical analysis
including three-dimensional gait analysis and pedographic measurements of patients treated
for Achilles tendon ruptures matched with a healthy control group will be carried out in
collaboration with the Norwegian School of Sport Sciences (Pedography registers the
distribution of the plantar pressure load during walking). These examinations may provide a
biomechanical understanding of the pathomechanical changes induced following treatment.
Reduced function in patients treated for Achilles tendon ruptures, regardless of choice of
treatment, is well documented19, but the orthopedic community has largely ignored the casual
relationships.
The study will be carried out as part of a PhD project under supervision of Sigurd Erik
Hoelsbrekken employed at the orthopedic department, Akershus University Hospital. Lars
Engebretsen, Kjetil Hvaal and Øyvind Paulsrud at Oslo University Hospital, Ullevål, will
serve as co-supervisors. Knut Melhuus and Agathe Rønning will be responsible for the
implementation and follow-up at the Emergency Department of Oslo University Hospital.
Asbjørn Sorteberg and Lars Fredrik Høifødt will organize the implementation at Fredrikstad
hospital whereas Finnur Snorrasson and Faisal Butt are responsible for carrying out the study
at Drammen hospital. Karin Rydevik at the Norwegian Sport Medicine Clinic (NIMI)
supervises the physical therapy program as well as overseeing functional testing and
examinations at follow-up. Two master students in physical therapy under the supervision of
Jens Bojsen-Møller will execute the physical examinations at the Norwegian School of Sport
Sciences. The Dresden group under the leadership of Hans Zwipp has generously allowed us
to share some of their vast knowledge, and has also invited us to visit the university clinic at
Dresden. We have also been in contact with Professor Jon Karlsson at the University Hospital
in Gothenburg and Katarina Nilsson Helander visited Ahus earlier this year to deliver a
lecture on Achilles tendon ruptures. Hopefully the study will facilitate cooperation across
different institutions, and an axis of collaboration has already been established along the Oslo
Fiord. Furthermore, we are in the process of founding an international research network
(Figure 5).
5. Study progress and planning
During the final work on the study protocol, we organized an achilles day at Ahus in
conjunction with a visit by Dr. Amlang from Dresden in May 2012. He held a lecture and
performed two surgical procedures that were streamed by Internet to the participating
hospitals. We were also fortunate enough to welcome Dr. Nilsson Helander to Ahus 2012-06-
14 for another presentation on ruptures of the achilles tendon. By sharing their own
experiences in conducting similar projects, our international collaborators have proven
invaluable in the process of developing the study protocol. The start date of the prospective
randomized trial is set to 2013-02-15, and the study was approved by the Regional Ethics
Committee for Medical Research 2012-05-11 (REK Helseregion Øst, approval number
2012/530 D). For the time being, we are in the process of finishing a trial period aimed at
assessing the planned implementation and to ease cooperation across the different institutions.
Furthermore, the trial period has allowed us to identify and rectify potential problems and the
start date has been pushed forward to 2013-02-15. The inclusion period is planned to last until
31.12.15, and collection, analysis and preparation of data will be completed by the end of
2016. Publication of results and writing of the PhD thesis is set to 2017.
Figure 5
Literature
1. Giddings, V. L.; Beaupre, G. S.; Whalen, R. T.; and Carter, D. R.: Calcaneal loading during walking and
running. Med Sci Sports Exerc, 32(3): 627-34, 2000.
2. Jarvinen, T. A.; Kannus, P.; Maffulli, N.; and Khan, K. M.: Achilles tendon disorders: etiology and
epidemiology. Foot and ankle clinics, 10(2): 255-66, 2005.
3. Movin, T.; Ryberg, A.; McBride, D. J.; and Maffulli, N.: Acute rupture of the Achilles tendon. Foot and ankle
clinics, 10(2): 331-56, 2005.
4. Khan, R. J.; Fick, D.; Brammar, T. J.; Crawford, J.; and Parker, M. J.: Interventions for treating acute
Achilles tendon ruptures. Cochrane Database Syst Rev, (3): CD003674, 2004.
5. McMahon, S. E.; Smith, T. O.; and Hing, C. B.: A meta-analysis of randomised controlled trials comparing
conventional to minimally invasive approaches for repair of an Achilles tendon rupture. Foot and ankle surgery :
official journal of the European Society of Foot and Ankle Surgeons, 17(4): 211-7, 2011.
6. Maquirriain, J.: Achilles tendon rupture: avoiding tendon lengthening during surgical repair and rehabilitation.
Yale J Biol Med, 84(3): 289-300, 2011.
7. Wolff, J.: Das Gesetz der Transformation der Knochen. Edited, Hirschwald, 1892.
8. Palmes, D.; Spiegel, H. U.; Schneider, T. O.; Langer, M.; Stratmann, U.; Budny, T.; and Probst, A.: Achilles
tendon healing: long-term biomechanical effects of postoperative mobilization and immobilization in a new mouse
model. J Orthop Res, 20(5): 939-46, 2002.
9. Pneumaticos, S. G.; Phd, P. C. N.; McGarvey, W. C.; Mody, D. R.; and Trevino, S. G.: The effects of early
mobilization in the healing of achilles tendon repair. Foot Ankle Int, 21(7): 551-7, 2000.
10. Twaddle, B. C., and Poon, P.: Early motion for Achilles tendon ruptures: is surgery important? A randomized,
prospective study. Am J Sports Med, 35(12): 2033-8, 2007.
11. Gwynne-Jones, D. P.; Sims, M.; and Handcock, D.: Epidemiology and outcomes of acute Achilles tendon
rupture with operative or nonoperative treatment using an identical functional bracing protocol. Foot Ankle Int,
32(4): 337-43, 2011.
12. Nilsson-Helander, K.; Silbernagel, K. G.; Thomee, R.; Faxen, E.; Olsson, N.; Eriksson, B. I.; and Karlsson,
J.: Acute achilles tendon rupture: a randomized, controlled study comparing surgical and nonsurgical treatments
using validated outcome measures. Am J Sports Med, 38(11): 2186-93, 2010.
13. Tengberg, P. T.; Barfod, K.; Krasheninnikoff, M.; Ebskov, L.; and Troelsen, A.: Promising conservative
treatment using dynamic mobilisation after Achilles tendon rupture. Ugeskr Laeger, 173(44): 2778-84, 2011.
14. Amlang, M. H.; Christiani, P.; Heinz, P.; and Zwipp, H.: Percutaneous technique for Achilles tendon repair
with the Dresden Instruments. Unfallchirurg, 108(7): 529-36, 2005.
15. Nilsson-Helander, K.; Thomee, R.; Silbernagel, K. G.; Thomee, P.; Faxen, E.; Eriksson, B. I.; and Karlsson,
J.: The Achilles tendon Total Rupture Score (ATRS): development and validation. Am J Sports Med, 35(3): 421-6,
2007.
16. Garratt, A. M.; Ruta, D. A.; Abdalla, M. I.; Buckingham, J. K.; and Russell, I. T.: The SF36 health survey
questionnaire: an outcome measure suitable for routine use within the NHS? BMJ, 306(6890): 1440-4, 1993.
17. Melzack, R.: The short-form McGill Pain Questionnaire. Pain, 30(2): 191-7, 1987.
18. Silbernagel, K. G.; Gustavsson, A.; Thomee, R.; and Karlsson, J.: Evaluation of lower leg function in patients
with Achilles tendinopathy. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA,
14(11): 1207-17, 2006.
19. Olsson, N.; Nilsson-Helander, K.; Karlsson, J.; Eriksson, B. I.; Thomee, R.; Faxen, E.; and Silbernagel, K.
G.: Major functional deficits persist 2 years after acute Achilles tendon rupture. Knee surgery, sports traumatology,
arthroscopy : official journal of the ESSKA, 19(8): 1385-93, 2011.
20. Carmont, M. R.; Silbernagel, K. G.; Nilsson-Helander, K.; Mei-Dan, O.; Karlsson, J.; and Maffulli, N.:
Cross cultural adaptation of the Achilles tendon Total Rupture Score with reliability, validity and responsiveness
evaluation. Knee Surg Sports Traumatol Arthrosc, 2012.
21. Metz, R.; van der Heijden, G. J.; Verleisdonk, E. J.; Kolfschoten, N.; Verhofstad, M. H.; and van der
Werken, C.: Effect of complications after minimally invasive surgical repair of acute achilles tendon ruptures:
report on 211 cases. Am J Sports Med, 39(4): 820-4, 2011.
22. Kotnis, R.; David, S.; Handley, R.; Willett, K.; and Ostlere, S.: Dynamic ultrasound as a selection tool for
reducing achilles tendon reruptures. Am J Sports Med, 34(9): 1395-400, 2006.
23. Thermann, H.; Zwipp, H.; Milbradt, H.; and Reimer, P.: [Ultrasound sonography in the diagnosis and follow-
up of Achilles tendon rupture]. Unfallchirurg, 92(6): 266-73, 1989.
24. Bojsen-Moller, J.; Hansen, P.; Aagaard, P.; Svantesson, U.; Kjaer, M.; and Magnusson, S. P.: Differential
displacement of the human soleus and medial gastrocnemius aponeuroses during isometric plantar flexor
contractions in vivo. J Appl Physiol, 97(5): 1908-14, 2004.
25. Fukashiro, S.; Itoh, M.; Ichinose, Y.; Kawakami, Y.; and Fukunaga, T.: Ultrasonography gives directly but
noninvasively elastic characteristic of human tendon in vivo. Eur J Appl Physiol Occup Physiol, 71(6): 555-7,
1995.
The final protocol of February 5th 2014:
Supervisor
Sigurd Erik Hoelsbrekken MD, PhD (1)
Co-supervisors
Kjetil Hvaal MD, PhD (2)
Lars Engebretsen MD, PhD (2)
Øivind Paulsrud MD,(2)
1. Background
Ruptures of the Achilles tendon can be treated by surgical repair or by immobilization using
a cast or a brace allowing the tendon to heal without surgery. Even though such ruptures
represent a common injury, there is no consensus regarding the best treatment protocol3.
In general, the Norwegian orthopedic community has recommended surgical repair based
on studies published the past thirty years showing that surgical repair conveys a
significantly lower risk of rerupture compared to non-operative treatment. Moreover, the
comparatively low number of reruptures has been used to justify the risk of infections and
nerve injuries inferred by surgical treatment4. To reduce the number of complications
associated with operative treatment, mini-invasive surgical techniques have been
developed thereby significantly reducing the number of wound problems while retaining
good functional result5. This has led to an increasing popularity of the mini-invasive
approach and a growing number of patients are treated by mini-invasive surgery. The use of
different suture materials and techniques has also been investigated, but none have proven
to be consistently better than other alternatives and there are no clear recommendations6.
There is also uncertainty as to what time point reruptures tend to occur, and if reruptures
happens when the healing tendon carries most of the tensile strength, regardless of suture
techniques and material used. Mechanical loading stimulates bone healing and bone
formation. This correlation was deduced by the German surgeon Julius Wolff during the
late eighteen century and has later been known as Wolff’s law7. Similar to the relationship
dictated by Wolff’s law, mechanical loading of tendons stimulates increased tensile strength
over time8,9. Awareness centered on
Figure 1
this biomechanical trait has led to the development of new rehabilitation protocols10,
especially concerning non-operative treatment. In analogue to Woffs law, by allowing early
controlled loading of the ruptured Achilles tendon, the presumed healing process is
accelerated thereby increasing tensile strength. If true, this approach would reduce the risk
of reruptures and several recent papers have shown that early mobilization actually do
improve the prognosis10-12. Furthermore, if non-operative treatment and surgery yield
similar treatment results, it would be of considerable importance since surgery is inherently
associated with the risk of infections and paresthesia. However, the studies carried out this
far have included a relatively small number of patients and no firm conclusions have been
made13. It is therefore of great interest to conclusively determine treatment results by
conducting a prospective randomized study comprising a sufficient number of patients,
potentially altering current treatment recommendations.
2. Study design
Figure 3
3. Secondary studies
The prospective randomized trial embodies many different disciplines and will spur off
follow-up studies. As part of the main project we will conduct a treatment-cost analysis in
relation to individual results. We will also perform an investigation based on ultrasound
grading of Achilles tendon ruptures according to a classification system established by
Michael Amlang and colleagues. Previous studies have provided evidence suggesting that
treatment results may depend on the extension of the injury, and that treatment
recommendations should be based on type of rupture sustained22,23. This is of particular
interest as it may facilitate individualized treatment. Together with the prospective
randomized trial and the treatment-cost analysis, the ultrasound investigation will
constitute the core of the PhD project. Additionally, The Norwegian School of Sport Sciences
has established a method to assess tendon elasticity by ultrasound examinations, which
would enable us to evaluate the healing process qualitatively24,25. A biomechanical analysis
including three-dimensional gait analysis and pedographic measurements of patients
treated for Achilles tendon ruptures matched with a healthy control group will be carried
out in collaboration with the Norwegian School of Sport Sciences (Pedography registers the
distribution of the plantar pressure load during walking). These examinations may provide a
biomechanical understanding of the pathomechanical changes induced following
treatment. Reduced function in patients treated for Achilles tendon ruptures, regardless of
choice of treatment, is well documented19, but the orthopedic community has largely
ignored the casual relationships.
Figure 5 Sonographic classifications of achilles tendon ruptures. Type 1 ruptures have complete adaptation of the
tendon ends whereas type 2 only displays partial adaptation with (2a) or without (2b) hematoma. In type 3
ruptures there is a diastasis between the tendon ends with (3a) or without (3b) an organized hematoma. Type 4 is
a proximal rupture at the muscle/tendon intersection while type 5 represents distal ruptures near the insertion.
The study will be carried out as part of a PhD project under supervision of Sigurd Erik
Hoelsbrekken employed at the orthopedic department, Akershus University Hospital. Lars
Engebretsen, Kjetil Hvaal and Øyvind Paulsrud at Oslo University Hospital, Ullevål, will serve
as co-supervisors. Knut Melhuus and Agathe Rønning will be responsible for the
implementation and follow-up at the Emergency Department of Oslo University Hospital.
Asbjørn Sorteberg and Lars Fredrik Høifødt will organize the implementation at Fredrikstad
hospital whereas Finnur Snorrasson and Faisal Butt are responsible for carrying out the
study at Drammen hospital. Karin Rydevik at the Norwegian Sport Medicine Clinic (NIMI)
supervises the physical therapy program as well as overseeing functional testing and
examinations at follow-up. She has also organized a group of centers providing
physiotherapy (Figure 2), and participants of the group hold regular meetings. Its members
treat all patients included in the study, and centers are located in Drammen and Sande
(Vestfold); Fredrikstad, Sarpsborg and Moss (Østfold); Oslo, Frogner and Lillestrøm (Oslo
and Akershus). Two master students in physical therapy under the supervision of Jens
Bojsen-Møller will execute the physical examinations at the Norwegian School of Sport
Sciences. The Dresden group under the leadership of Hans Zwipp has generously allowed us
to share some of their vast knowledge, and has also invited us to visit the university clinic at
Dresden. We have also been in contact with Professor Jon Karlsson at the University
Hospital in Gothenburg and Katarina Nilsson Helander visited Ahus earlier this year to
deliver a lecture on Achilles tendon ruptures. Hopefully the study will facilitate cooperation
across different institutions, and an axis of collaboration has already been established along
the Oslo Fiord. Furthermore, we are in the process of founding an international research
network (Figure 5).
During the final work on the study protocol, we organized an achilles day at Ahus in
conjunction with a visit by Dr. Amlang from Dresden in May 2012. He held a lecture and
performed two surgical procedures that were streamed by Internet to the participating
hospitals. We were also fortunate enough to welcome Dr. Nilsson Helander to Ahus in June
2012 for another presentation on ruptures of the achilles tendon. By sharing their own
experiences in conducting similar projects, our international collaborators have proven
invaluable in the process of developing the study protocol. The start date of the prospective
randomized trial is set to 15.02.2013, and the study was approved by the Regional Ethics
Committee for Medical Research 11.05.2012 (REK Helseregion Øst, approval number
2012/530 D). For the time being, we are in the process of finishing a trial period aimed at
assessing the planned implementation and to ease cooperation across the different
institutions. Furthermore, the trial period has allowed us to identify and rectify potential
problems and challenges. The inclusion period is planned to last until 31.12.15, and
collection, analysis and preparation of data will be completed by the end of 2016.
Publication of results and writing of the PhD thesis is set to 2017.
Figure 5
Literature
1. Giddings, V. L.; Beaupre, G. S.; Whalen, R. T.; and Carter, D. R.: Calcaneal loading during walking and
running. Med Sci Sports Exerc, 32(3): 627-34, 2000.
2. Jarvinen, T. A.; Kannus, P.; Maffulli, N.; and Khan, K. M.: Achilles tendon disorders: etiology and
epidemiology. Foot and ankle clinics, 10(2): 255-66, 2005.
3. Movin, T.; Ryberg, A.; McBride, D. J.; and Maffulli, N.: Acute rupture of the Achilles tendon. Foot and ankle
clinics, 10(2): 331-56, 2005.
4. Khan, R. J.; Fick, D.; Brammar, T. J.; Crawford, J.; and Parker, M. J.: Interventions for treating acute
Achilles tendon ruptures. Cochrane Database Syst Rev, (3): CD003674, 2004.
5. McMahon, S. E.; Smith, T. O.; and Hing, C. B.: A meta-analysis of randomised controlled trials comparing
conventional to minimally invasive approaches for repair of an Achilles tendon rupture. Foot and ankle surgery :
official journal of the European Society of Foot and Ankle Surgeons, 17(4): 211-7, 2011.
6. Maquirriain, J.: Achilles tendon rupture: avoiding tendon lengthening during surgical repair and rehabilitation.
Yale J Biol Med, 84(3): 289-300, 2011.
7. Wolff, J.: Das Gesetz der Transformation der Knochen. Edited, Hirschwald, 1892.
8. Palmes, D.; Spiegel, H. U.; Schneider, T. O.; Langer, M.; Stratmann, U.; Budny, T.; and Probst, A.: Achilles
tendon healing: long-term biomechanical effects of postoperative mobilization and immobilization in a new
mouse model. J Orthop Res, 20(5): 939-46, 2002.
9. Pneumaticos, S. G.; Phd, P. C. N.; McGarvey, W. C.; Mody, D. R.; and Trevino, S. G.: The effects of early
mobilization in the healing of achilles tendon repair. Foot Ankle Int, 21(7): 551-7, 2000.
10. Twaddle, B. C., and Poon, P.: Early motion for Achilles tendon ruptures: is surgery important? A randomized,
prospective study. Am J Sports Med, 35(12): 2033-8, 2007.
11. Gwynne-Jones, D. P.; Sims, M.; and Handcock, D.: Epidemiology and outcomes of acute Achilles tendon
rupture with operative or nonoperative treatment using an identical functional bracing protocol. Foot Ankle Int,
32(4): 337-43, 2011.
12. Nilsson-Helander, K.; Silbernagel, K. G.; Thomee, R.; Faxen, E.; Olsson, N.; Eriksson, B. I.; and Karlsson,
J.: Acute achilles tendon rupture: a randomized, controlled study comparing surgical and nonsurgical treatments
using validated outcome measures. Am J Sports Med, 38(11): 2186-93, 2010.
13. Tengberg, P. T.; Barfod, K.; Krasheninnikoff, M.; Ebskov, L.; and Troelsen, A.: Promising conservative
treatment using dynamic mobilisation after Achilles tendon rupture. Ugeskr Laeger, 173(44): 2778-84, 2011.
14. Amlang, M. H.; Christiani, P.; Heinz, P.; and Zwipp, H.: Percutaneous technique for Achilles tendon repair
with the Dresden Instruments. Unfallchirurg, 108(7): 529-36, 2005.
15. Nilsson-Helander, K.; Thomee, R.; Silbernagel, K. G.; Thomee, P.; Faxen, E.; Eriksson, B. I.; and Karlsson,
J.: The Achilles tendon Total Rupture Score (ATRS): development and validation. Am J Sports Med, 35(3): 421-6,
2007.
16. Garratt, A. M.; Ruta, D. A.; Abdalla, M. I.; Buckingham, J. K.; and Russell, I. T.: The SF36 health survey
questionnaire: an outcome measure suitable for routine use within the NHS? BMJ, 306(6890): 1440-4, 1993.
17. Melzack, R.: The short-form McGill Pain Questionnaire. Pain, 30(2): 191-7, 1987.
18. Silbernagel, K. G.; Gustavsson, A.; Thomee, R.; and Karlsson, J.: Evaluation of lower leg function in patients
with Achilles tendinopathy. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA,
14(11): 1207-17, 2006.
19. Olsson, N.; Nilsson-Helander, K.; Karlsson, J.; Eriksson, B. I.; Thomee, R.; Faxen, E.; and Silbernagel, K.
G.: Major functional deficits persist 2 years after acute Achilles tendon rupture. Knee surgery, sports
traumatology, arthroscopy : official journal of the ESSKA, 19(8): 1385-93, 2011.
20. Carmont, M. R.; Silbernagel, K. G.; Nilsson-Helander, K.; Mei-Dan, O.; Karlsson, J.; and Maffulli, N.:
Cross cultural adaptation of the Achilles tendon Total Rupture Score with reliability, validity and responsiveness
evaluation. Knee Surg Sports Traumatol Arthrosc, 2012.
21. Metz, R.; van der Heijden, G. J.; Verleisdonk, E. J.; Kolfschoten, N.; Verhofstad, M. H.; and van der
Werken, C.: Effect of complications after minimally invasive surgical repair of acute achilles tendon ruptures:
report on 211 cases. Am J Sports Med, 39(4): 820-4, 2011.
22. Kotnis, R.; David, S.; Handley, R.; Willett, K.; and Ostlere, S.: Dynamic ultrasound as a selection tool for
reducing achilles tendon reruptures. Am J Sports Med, 34(9): 1395-400, 2006.
23. Thermann, H.; Zwipp, H.; Milbradt, H.; and Reimer, P.: [Ultrasound sonography in the diagnosis and
followup of Achilles tendon rupture]. Unfallchirurg, 92(6): 266-73, 1989.
24. Bojsen-Moller, J.; Hansen, P.; Aagaard, P.; Svantesson, U.; Kjaer, M.; and Magnusson, S. P.: Differential
displacement of the human soleus and medial gastrocnemius aponeuroses during isometric plantar flexor
contractions in vivo. J Appl Physiol, 97(5): 1908-14, 2004.
25. Fukashiro, S.; Itoh, M.; Ichinose, Y.; Kawakami, Y.; and Fukunaga, T.: Ultrasonography gives directly but
noninvasively elastic characteristic of human tendon in vivo. Eur J Appl Physiol Occup Physiol, 71(6): 555-7,
1995.
Summary of changes to the trial protocol:
Local anesthesia was the preferred choice of anesthesia, however surgical procedures were
not limited to local anesthesia, and other types of anesthesia were used dependent upon
indication.
Open surgical repair of the Achilles tendon was performed with a three-knot double layer
Krakow whip suture. Sutures were tightened so that the ankle joint demonstrated an
equinus position comparable to the non-injured foot. A slight overcorrection was also
accepted.
Three Ethibond 0 sutures with straight cutting needles were used for minimal invasive
surgery. Sutures were tightened so that the ankle joint demonstrated an equinus position
comparable to the non-injured foot. A slight overcorrection was also accepted.
Administrative information:
Sponsor name Akershus University Hospital
Protocol SAP Section number Description and reason for change Date changed
version version changed
1 INTRODUCTION ...................................................................................................................... 27
1.1 Background and rationale .................................................................................................. 27
1.2 Trial Objectives .................................................................................................................. 27
2 TRIAL METHODS .................................................................................................................... 27
2.1 Trial Design ........................................................................................................................ 27
2.2 Randomisation ................................................................................................................... 27
2.3 Sample size........................................................................................................................ 27
2.4 Statistical Framework ......................................................................................................... 28
2.5 Statistical Interim Analyses and Stopping Guidance ......................................................... 29
2.6 Timing of Final Analysis ..................................................................................................... 29
2.7 Timing of Outcome Assessments ...................................................................................... 29
3 STATISTICAL PRINCIPLES .................................................................................................... 30
3.1 Confidence Intervals and p-values .................................................................................... 30
3.2 Adherence and Protocol Deviations .................................................................................. 30
3.3 Analysis Populations .......................................................................................................... 30
4 TRIAL POPULATION ............................................................................................................... 31
4.1 Screening Data, Eligibility and Recruitment....................................................................... 31
4.2 Withdrawal/Follow-up ......................................................................................................... 31
4.3 Baseline Patient Characteristics ........................................................................................ 31
5 ANALYSIS ................................................................................................................................ 32
5.1 Outcome Definitions ........................................................................................................... 32
5.2 Analysis Methods ............................................................................................................... 34
6 SAFETY ANALYSES................................................................................................................ 39
6.1 Adverse Events .................................................................................................................. 39
6.2 Clinical Laboratory Parameters.......................................................................................... 39
6.3 Vital Signs .......................................................................................................................... 39
7 STATISTICAL SOFTWARE ..................................................................................................... 39
8 REFERENCES ......................................................................................................................... 40
8.1 Literature References ........................................................................................................ 40
8.2 Reference to Data Management Plan ............................................................................... 19
1 Introduction
2 Trial Methods
2.2 Randomisation
Eligible patients were allocated in a 1:1:1 ratio between CT, OR and MIS. Treatment
allocation was done by block randomization, stratified by hospital, with 6, 9 or 12 patients in
each block. Details of allocation sequence generation was provided in a separate document
unavailable to those who enrolled patients or assigned treatment.
2. If the overall test shows that there is a significant difference on the 5% level, then
tests of a difference in the change from baseline to 1-2 years ATRS score will be
performed pairwise between the treatment arms. The null hypotheses in these tests
will be that there is no difference between the treatment arms. The alternative
hypotheses are that there is a difference between the two treatment arms being
compared. These tests will be performed at the (two sided) 5% significance level.
The hierarchical testing procedure abides by the closed testing procedure, allowing a 5%
significance level to be used in each test, while at the same time maintaining a family-wise
error rate at 5%.
All other tests than described in step 1 and 2 above, will be regarded as supportive or
exploratory.
Note that if the test in step 1 shows that there is no significant difference between
treatment groups, a pairwise comparison between treatment groups will still be reported,
but these are to be considered as secondary analyses.
3. Superiority of the MIS group over the CT group will be claimed if the two-sided p-
value in the test comparing the change from baseline to 1-2 years ATRS score is less
than 5%, and if the effect goes in favour of the MIS group. Superiority of the CT group
will be claimed if the effect goes in favour of this group.
The number (and percentage) of patients with major protocol deviations will be summarised
by treatment group with details of type of deviation provided. All randomized patients will
be used as the denominator to calculate the percentages. No formal statistical testing will be
undertaken.
The FAS will be used for the primary analysis, while the PPS and the CCS will be used for
sensitivity analyses.
4 Trial Population
4.2 Withdrawal/Follow-up
The status of eligible and randomised patients at trial end will be tabulated by treatment
group according to whether they
• completed intervention, but not assessments.
• completed assessments, but not intervention.
• withdrew consent.
• lost to follow-up.
• excluded due to delay from injury to surgery (>7 days).
• excluded due to protocol deviations after randomisation but occurring prior to surgery.
• Unable to measure the primary endpoint due to:
o comorbidity that compromise rehabilitation or testing.
o death during follow up.
o re-rupture on the contralateral side during follow up.
o other surgery on the lower extremities during follow up.
5.1.3.2 Re-rupture
Re-rupture is here defined as a total rupture of the same Achilles tendon as treated in the
trial within the 12-month visit. Re-rupture will be treated as a dichotomous outcome. The
diagnosis is done clinically without any need of imaging techniques. Re-ruptures were
continuously reported to the principal investigator of the study. Patients suffering from
either a re-rupture of the same Achilles tendon or a new rupture of the contralateral Achilles
tendon were excluded from further testing and questionnaires.
Linear regression models will be fitted to each of these outcomes, for each physical test. The
treatment variable will be adjusted by study centre (the stratification variable used in the
randomization). Note that for each of the 6 physical tests at each visit, a test is also
performed in the healthy foot. The ratio between the performance in the treated foot and
the healthy foot, multiplied with 100, (the LSI) is also considered an outcome variable for
each physical test.
The analyses will be conducted in the FAS.
The multiple imputation in point 2 and 3 will be done simultaneously, after point 1 has been
performed. The following variables will be used to impute the test scores at 6 months and 1-
2 years: Sex, Age, Weight at baseline, weight at the time of the test, study centre, results in
the other 5 physical tests, results from all 6 physical test in the healthy foot, and ATRS scores
at 6 and 1-2 years.
Note that the LSI variables, which is the ratio between the injured and the healthy foot
multiplied by 100, will not be imputed as described above. For the threshold imputation, the
value in the injured and healthy foot will be imputed separately, and the LSI value is
obtained from these. In the multiple imputation procedure, the LSI variables for the
different tests will be imputed by passive imputation.
6 Safety Analyses
Complications and adverse events were continuously registered. For instance, thromboembolic
events, wound healing problems, infections and nerve-damage.
7 Statistical Software
All statistical analyses will be done using R version 3.6.3 (R Core Team (2020). R: A language
and environment for statistical computing. R Foundation for Statistical Computing, Vienna,
Austria. URL https://www.R-project.org/).
8 References