article review on management functions

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The Control Function of Management

After strategies are set and plans are made, management’s primary task is to ensure that these plans are carried out.

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After strategies are set and plans are made, management’s primary task is to take steps to ensure that these plans are carried out, or, if conditions warrant, that the plans are modified. This is the critical control function of management. And since management involves directing the activities of others, a major part of the control function is making sure other people do what should be done.

The management literature is filled with advice on how to achieve better control. This advice usually includes a description of some type of measurement and feedback process:

• The basic control process, wherever it is found and whatever it is found and whatever it controls, involves three steps: (1) establishing standards. (2) measuring performance against these standards. and (3) correcting deviations from standards and plans. 1
• A good management control system stimulates action by spotting the significant variations from the original plan and highlighting them for the people who can set things right . 2
• Controls need to focus on results. 3

This focus on measurement and feedback, however, can be seriously misleading. In many circumstances, a control system built around measurement and feedback is not feasible. And even when feasibility is not a limitation, use of a feedback-oriented control system is often an inferior solution. Yet, good controls can be established and maintained using other techniques.

What is needed is a broader perspective on control as a management function: this article addresses such a perspective. The first part summarizes the general control problem by discussing the underlying reasons for implementing controls and by describing what can realistically be achieved. In the second part, the various types of controls available are identified. The last part discusses why the appropriate choice of controls is and should be different in different settings.

Why Are Controls Needed?

If all personnel always did what was best for the organization, control — and even management — would not be needed. But, obviously individuals are sometimes unable or unwilling to act in the organization’s best interest, and a set of controls must be implemented to guard against undesirable behavior and to encourage desirable actions.

One important class of problems against which control systems guard may be called personal limitations. People do not always understand what is expected of them nor how they can best perform their jobs, as they may lack some requisite ability, training, or information.

About the Author

Kenneth A. Merchant is Assistant Professor of Business Administration at Harvard University. Dr. Merchant holds the B.A. degree from Union College, the M.B.A. degree from Columbia University, and the Ph.D. degree from the University of California, Berkeley. His main interests lie in the areas of accounting, information systems, and planning and control. Dr. Merchant has published articles for such journals as The Accounting Review and Accounting, Organizations, and Society.

1. See H. Koontz, C. O'Donnell, and H. Weihrich. Management, 7th ed. (New York: McGraw-Hill, 1980). p. 722.

2. See W. D. Brinckloe and M. T. Coughlin, Managing Organizations (Encino, CA: Glencoe Press. 1977). p. 298.

3. See P. F. Drucker. Management: Tasks, Responsibilities, Practices (New York: Harper & Row. 1974). p. 497.

4. A recent summary of many of the findings in this area (illustrating such cognitive limitations as conservative revision of prior subjective probabilities when new information is provided. and the use of simplifying decision-making heuristics when faced with complex problems) is provided by W. F. Wright, “Cognitive Information Processing Biases: Implications for Producers and Users of Financial Information,” Decision Sciences (April 1980): 284–298.

5. A similar scheme is presented in W. G. Ouchi, “A Conceptual Framework for the Design of Organizational Control Mechanisms,” Management Science (September 1979): 833–848.

6. See H. Klein, “At Harley-Davidson, Life without AMF Is Upbeat but Full of Financial Problems,” Wall Street Journal . 13 April 1982, p. 37.

7. See N. Babchukand W. J. Goode. “Work Incentives in a Self-Determined Group,” American Sociological Review (1951): 679–687.

8. For a summary of criticisms of return-an-investment (ROI) measures of performance, see J. Dearden, “The Case against ROI Control,” Harvard Business Review , May–June 1969, pp. 124–135.

9. See D. Mitchell. Control without Bureaucracy (London: McGraw-Hill Book Company Limited, 1979), p. 6.

Acknowledgments

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What Will Management Look Like in the Next 100 Years?

• Dagny Dukach

In recent years, the practice of management has often felt like an exercise in putting out fires. Facing one social, environmental, and economic crisis after the next, it’s easy to get stuck in a near-singular focus on the short term. But at the same time, it’s critical for leaders to find time to consider the bigger picture as well. To get some new perspectives, we asked a diverse group of researchers from around the world to share their insights on how the practice of management has transformed over the past 100 years — and how we can expect (or hope) it to change in the next 100.

A panel of global experts weigh in on the practices that will — or should — change.

As the era of “unprecedented times” refuses to end, many of us have become accustomed to an almost exclusive focus on the here and now. Recent years have delivered a nonstop crash course in putting out fires as we contend with simultaneous social, environmental, health, and economic crises (not to mention the ordinary frustrations and challenges of everyday life).

Highlights from a century of management insights.

• Dagny Dukach is a former associate editor at Harvard Business Review.

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By Vanessa Leikvoll Leaders Staff

Vanessa Leikvoll

Culture and Personal Success Writer

Vanessa Leikvoll is a culture and personal success writer for Leaders Media. Vanessa is a certified Workplace Wellness Specialist and...

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Aug 9, 2022

How to Lead Using the 4 Functions of Management

The core functions of management, breaking down the 4 functions of management, where leadership and management intersect.

Few leaders have embodied the principles of effective management like Jack Welch, former CEO of General Electric. While General Electric received acclaim publicly, the internal systems Welch inherited in 1981 were anything but admirable. From unorganized processes and poor communication to falling stock value, Welch knew that company growth would only come by changing the bureaucratic structure completely.

So that’s what he did. As the new CEO, his first order of business was to change the systems radically. He called for fewer meetings, decreased layers of management and oversight, and more focus on employee growth and empowerment. Welch even cut about 100,000 GE employees to help streamline roles, earning him the nickname of “Neutron Jack,” according to the New York Times . Despite seeming rash at first, Welch’s management approach worked, and within 20 years, GE grew from a $14 billion company to a $400 billion company.

In Winning , Welch says: “Before you are a leader, success is all about growing yourself. When you become a leader, success is all about growing others.”

By building others up as leaders, demonstrating authenticity, and making purposeful decisions despite external criticisms, you begin to embrace the true power of the functions of management. Welch’s style wasn’t popular at the time, but he maintained his grit and determination to lead GE to unprecedented success. For this, he was named “Ultimate Manager” and “Manager of the Century” by Fortune , according to his obituary .

Analysis from Gallup shows 70% of the variance  in employee engagement and investment is a result of management functions .   This means that the level to which your employees are invested and engaged largely depends on how well the functions of management are practiced. An excellent manager, for example, will cultivate a great corporate culture , which attracts and retains top talent and builds stronger relationships. On the other hand, a manager who doesn’t perform the functions of management well can become a toxic boss who no one wants to work for.

However, if you practice the core functions of management, follow your passion, and model successful  leadership qualities , your team will follow you. 

Key Insights on the Functions of Management

• The functions of management were established in 1908 from the theories of French engineer Henri Fayol.
• Today, the functions consist of four phases: planning, organizing, leading, and controlling.
• Poor management is what drives 50 percent of employees to quit their jobs.
• Business success increases when the four functions of management intersect with servant leadership.

Productivity is never an accident. It is always the result of a commitment to excellence, intelligent planning, and focused effort. paul j. meyer

In 1888, Henri Fayol became the managing director of a French ironmaking company called Boigues Rambourg. The company at that time was on the verge of bankruptcy, but under Fayol’s management, the business turned around. By 1900, it had grown to become one of the country’s most significant steel and iron producers. 

Fayol observed many management problems during his time at Boigues Rambourg, especially at the organizational level. He studied the issues and posed solutions that would prove effective. Then, in 1908, he published his theories and what he had learned to share his knowledge with the world. His theories attracted global attention and respect, earning him the nickname, “The Father of Modern Management.”

Fayol’s theories included five original functions of management: planning, organizing, command, coordination, and control. Today, these functions of management are four phases:  planning, organizing, leading, and controlling. These four functions are the foundation for effective and successful management practice. As Fayol began demonstrating in 1888, integrating these functions of management into your company can save your business. 

Gain more insight into the four functions of management by learning more about how each one of these works below.

1. Planning

Planning means both to assess the future and make provision for it. henri fayol

This stage involves identifying overarching company goals and forming a plan to achieve them. What are the primary thresholds to meet? What is the timeline for completing these thresholds? Which human and physical resources will be needed?

Once these answers are determined, it’s time to craft a strategy. Who will do what tasks? What stages are those tasks broken down into? And what is the priority level of these tasks? These questions are all examined during the planning phase. 

Fayol describes four components of planning:

• The desired result
• The methods

Example:  A manager is hired to run a new restaurant. One of his goals is to staff the restaurant adequately while remaining financially efficient for overhead and profit. In the planning phase, the manager identifies how many servers, kitchen staff, hostesses, and bussers are needed when the restaurant is open. The manager will consider busy times, like evenings and weekends, and slower times, like mid-week lunch, to form his plan. 

Three types of planning:

• Strategic: With a time frame of usually three years, strategic planning looks at overall company threats and the environment. It examines competition, outliers, consumer markets, and other variables that can help reveal areas of strength and weakness.
• Tactical: Tactical planning focuses on one specific department, like production, human resources, or food and beverage. This kind of planning focuses on tactical goals that will take less than a year to achieve.
• Operational: This planning type leverages tactical planning to conduct strategic planning. By putting a goal defined in strategic planning into practice operationally, a whole company can work towards achieving that goal together.

2. Organizing

To organize means building up the dual structure, material, and human, of the undertaking. To command means binding together, unifying and harmonizing all activity and effort. henri fayol

Once the planning is done, the next function of management is organizing. This phase is about delegation, processes, and expectations. A  manager’s job  at this stage is to coordinate teams, assign tasks to qualified employees, and set clear expectations. The purpose of organizing is to set your employees up for successfully executing the goals   established during planning. 

In the organizing stage, it’s also vital to set contingency plans. Tasks and projects don’t always go as planned. Anticipating potential problems and working through a plan to avoid them ahead of time is key. This will help you and your team stay on track even when things go awry. 

Example:  The new restaurant manager organizes human and physical resources to help the company run smoothly. For instance, they might have their top servers working weekends. Additionally, they schedule prep work in the early morning to avoid long customer wait times during dinner service. They clearly communicate what time people should show up for work, when they can take breaks, how operations run, which tasks should be completed, and who is doing what.

The manner in which the subordinates do their work has incontestably a great effect upon the ultimate result, but the operation of management has a much greater effect. henri fayol

Once a team has clear goals, priorities, processes, and timelines, the following required function of management to ensure success is leading. Leading is inspiring and motivating your team to perform at their best . It means giving praise and constructive criticism —when warranted—so your team knows how they are doing and how they should pivot. Managers who demonstrate a strong sense of direction and clear vision command the most buy-in from their employees.

Leading is also about modeling empathy, showing support, and providing encouragement. Your team members aren’t robots—they’re humans. They have lives, worries, and other things outside of work that affect them. Recognizing this and showing compassion will not only strengthen your relationship with your team but will lead them to do their best work.

Example:  One of the restaurant manager’s servers received excellent reviews for their service on Saturday night. Because of this, the manager takes time to give praise to the server. Additionally, another one of their staff members had a family emergency and had to leave during a busy time. Instead of getting angry, the manager practices servant leadership and covers the remainder of their shift. After work, they also check in on them to make sure everything is okay. 

4. Controlling

To be a good manager of people requires both fairness and bluntness. james cook

The last function of management is the controlling phase. With the controlling phase, the goal is to identify areas of concern and make necessary adjustments. For example, who is performing well or not so well? What areas of weakness or concern are there? Are there any tasks that are off-track? These are all questions managers should ask at this point. 

Under the controlling phase,  make any tweaks and pivots necessary  to make sure the work done in the planning, organizing, and leading phases are all being honored. This might look like meeting with employees who are struggling and assigning them tasks that are better suited to their strengths.

Example:  The restaurant manager reviews the previous quarter’s sales, reservations, and losses. They know examining these areas is key because it reveals potential problems and areas to work on. With this knowledge, they can make decisions and changes to improve during the next quarter. For instance, they realize the business actually loses money by remaining open on Mondays, so they decide to keep the restaurant closed on this day.

Management is doing things right; leadership is doing the right things. peter f. drucker

Bad management can cost a company big time. In a recent poll from GoodHire, 82% of employees  said  they’d consider leaving their company simply because of a bad manager. Furthermore, according to Gallup, 50% of U.S. employees actually do quit their job because of their boss.

While the two terms are often interchangeable,  leadership and management  are different. You can be a good leader but not necessarily a good manager, and vice versa. What many managers lack, and why their employees are disengaged, de-motivated, and uninvested, are good leadership qualities. Traits like emotional intelligence , communication, empathy , passion, and balance are reflective of someone both leading and managing effectively.

Once the  functions of management —that is, planning, organizing, leading, and controlling—intersect with these leadership traits, real business success can occur.

Continue advancing your management knowledge and expertise with  How to Excel at a Manager’s Job . 

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• Study Protocol
• Open access
• Published: 20 April 2024

Self-management including exercise, education and activity modification compared to usual care for adolescents with Osgood-Schlatter (the SOGOOD trial): protocol of a randomized controlled superiority trial

• Kasper Krommes 1 ,
• Kristian Thorborg 1 , 2 ,
• Mikkel Bek Clausen 3 ,
• Michael Skovdal Rathleff 4 , 5 ,
• Jens Lykkegaard Olesen 4 ,
• Thomas Kallemose 3 , 6 &
• Per Hölmich 1 , 2  

BMC Sports Science, Medicine and Rehabilitation volume  16 , Article number:  89 ( 2024 ) Cite this article

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Metrics details

Osgood-Schlatter is the most frequent growth-related injury affecting about 10% of physically active adolescents. It can cause long-term pain and limitations in sports and physical activity, with potential sequela well into adulthood. The management of Osgood-Schlatter is very heterogeneous. Recent systematic reviews have found low level evidence for surgical intervention and injection therapies, and an absence of studies on conservative management. Recently, a novel self-management approach with exercise, education, and activity modification, demonstrated favorable outcomes for adolescents with patellofemoral pain and Osgood-Schlatter in prospective cohort studies.

The aim of this trial is to assess the effectiveness of the novel self-management approach compared to usual care in improving self-reported knee-related function in sport (measured using the KOOS-child ‘Sport/play’ subscale) after a 5-month period.

This trial is a pragmatic, assessor-blinded, randomized controlled trial with a two-group parallel arm design, including participants aged 10–16 years diagnosed with Osgood-Schlatter. Participants will receive 3 months of treatment, consisting of either usual care or the self-management approach including exercise, education, and activity modification, followed by 2 months of self-management. Primary endpoint is the KOOS-child ‘Sport/play’ score at 5 months. This protocol details the planned methods and procedures.

The novel approach has already shown promise in previous cohort studies. This trial will potentially provide much-needed level 1 evidence for the effectiveness of the self-management approach, representing a crucial step towards addressing the long-term pain and limitations associated with Osgood-Schlatter.

Trial registration

Clinicaltrials.gov: NCT05174182. Prospectively registered December 30th 2021. Date of first recruitment: January 3rd 2022. Target sample size: 130 participants.

Peer Review reports

Introduction

Background and rationale.

Osgood-Schlatter affects up to 1 in 10 physically active adolescents and is the most common growth-related injury [ 1 , 2 ]. The condition affects the knee, specifically the proximal tibial apophysis [ 3 ]. Osgood-Schlatter can lead to long-term pain and swelling, decreased quality of life, and limit participation in sports and physical activity [ 4 , 5 , 6 , 7 ]. Even years after diagnosis, adolescents can experience continued pain, discontinuation of sports-participation, impairments in knee function, and sonographic changes can persist [ 5 , 6 , 7 , 8 , 9 ]. Recent systematic reviews identified only low level evidence for surgical intervention and injection therapies for recalcitrant cases, and a complete absence of studies on conservative management [ 10 , 11 ]. The recommended types of conservative management modalities for Osgood-Schlatter is abundant and conflicting in the literature [ 10 , 12 , 13 , 14 ]. The same is evident in studies of clinical practice, in which clinicians and patients report a range of different advice and modalities utilized [ 15 , 16 ]. This reflects the lack of evidence regarding this area for first-line conservative treatments, which leaves clinicians to an experience-based approach to management of Osgood-Schlatter. This highlights the need for an effective evidence-based conservative management approach. In 2020, a promising cohort study was published by Rathleff et al. where adolescents with Osgood-Schlatter received a self-management approach containing gradual exposure to sports and physical activity using a guidance tool based on pain response, and progressive exercise therapy. This was associated with successful outcomes, such as rating of change, pain, and sports participation [ 17 ].

Review of the literature

Two recent systematic reviews on treatment for adolescents with Osgood-Schlatter found no studies assessing conservative treatments [ 10 , 11 ]. Three studies were identified assessing surgical or injection-based interventions; all exhibited significant methodological flaws, such as selective or shifting of outcomes reported, and lack of blinding of participants and personnel [ 11 ]. The two reviews concluded that there is a paucity of evidence to guide clinical practice, and a need for trials on conservative management [ 11 ]. At this point in time four trials on Osgood-Schlatter are registered on clinicaltrials.gov; 1 trial comparing static stretching vs. active elongation (estimated completion November 2013); 1 trial comparing cast immobilization vs. advice to rest (recruitment completed December 2016); 1 trial comparing myofascial massage vs. usual care (recruitment completed September 2022); and 1 recent trial from a member of our study group comparing some of the different components in the experimental intervention in a 3-armed trial, thus comparing tailored progressive loading and return to sport vs. pain guided activity vs. 4 week rest (recruitment started January 2023). The need for this trial therefore remains.

Choice of comparators

An international study among 251 practitioners with a special interest in Osgood-Schlatter found that, besides patient education and exercise therapy, treatment approaches are highly heterogenous [ 15 ]. In lack of existing knowledge about usual care in the Danish healthcare system, and an absence of an established treatment approach in the literature, we have performed a step-wise sub-study to investigate current standard of care in Denmark, in order to compile a standardized treatment package as comparator [ 16 ]. In Denmark, clinicians who commonly see patients with Osgood-Schlatter disease are Sports Physiotherapists and general practitioners, mainly in private or primary practice, and Orthopedic Surgeons from secondary care orthopedic departments. Among these professions, we conducted interviews with 10 clinicians and surveyed 63 more, asking them about the modalities and advice they most frequently use when treating patients with Osgood-Schlatter [ 16 ]. Results were then combined with reports from patients seen in our outpatient clinic ( n  = 34) who were questioned in detail on what modalities and advice they had previously received [ 16 ]. The resulting list of modalities ordered by frequency where then combined and developed into a standardized treatment package with an accompanying patient-aimed leaflet [ 16 ]. An overview of the two treatments and their timing can be seen in Table 1 .

Aims and primary hypothesis

The primary aim is to investigate whether a self-management approach is superior to usual care in adolescents with Osgood-Schlatter. The primary endpoint is changes in self-reported function in sport from baseline to 5 months. A secondary aim is to investigate changes in secondary outcomes (acceptable symptoms state, frequency of pain flares, pain intensity, sports participation, sonographic severity, pain during knee-loading, rating of change), also at secondary timepoints (weekly from week 0 to 22, and at months 1, 2, and 3). Results on the primary and secondary aims and outcomes, are planned to be included in the primary report. The primary hypothesis, is that the novel self-management approach is superior to usual care after 5 months on improvements in self-reported function in sport, measured on the KOOS-child ‘Sport/play’ subscale, in adolescents with Osgood-Schlatter.

Trial design

The trial is an assessor-blinded randomized controlled superiority trial, with a two-group parallel arm design and 1:1 group allocation ratio. Besides assessor-blinding, we will blind participants and treatment-personnel to the superiority hypothesis and specific contents of the intervention they are not receiving/delivering. This protocol is structured according to the SPIRIT guidelines (Standard Protocol Items: Recommendations for Interventional Trials) [ 18 ]. We chose a superiority framework for two reasons; firstly, due to a preliminary study of the intervention showing promising results for patients having tried other treatments and with a significant duration of symptoms; and secondly, as the current usual care given is based on clinical expertise and experience [ 15 , 16 ]. We found our design to be mostly pragmatic on the Pragmatic-Explanatory Continuum in terms of clinical domains, making the potential results fit for clinical implementation, and the trial will therefore provide evidence on the effectiveness of the intervention [ 19 , 20 ].

Registration and reporting

The reporting of the results will adhere to the Consolidated Standards of Reporting Trials (CONSORT) [ 21 ]. The interventions are described according to current best-practice standards [ 22 , 23 , 24 ]. We have posted a previous version (v1.4) of this protocol and the statistical analysis plan to the ClinicalTrials.gov repository before starting recruitment as a supplementary to the registration (NCT05174182). The embedded statistical analysis plan follows regulatory and academic recommendations and guidelines, as well as open-science practices [ 25 , 26 , 27 , 28 ]. Exercises in the experimental intervention is described by parameters proposed by Toigo & Boutellier [ 24 ], and domains from CERT [ 23 ] (Checklist for Exercise Reporting Template) and TIDieR [ 22 ] (Template for Intervention Description and Replication).

Pilot study: results and amendments

The initial 15 participants acted as pilot-participants. The purpose of the internal pilot [ 29 ] was to assess the feasibility of the larger extensive full-scale study, to avoid any adverse consequences or unforeseen pitfalls during the main trial, and ensure that all trial components worked together [ 30 , 31 ]. This did not incur any additional burden to participants or change their experience or procedures, compared to the intended setup for subsequent participants. Trial personnel recorded extra data during months 0–3 for these participants on specific pilot objectives. We prespecified pilot objectives and criteria for either a success or failure of the pilot study. If the aim and features of the pilot trial is aligned with the main trial and participant data are deemed compatible such that none or minimal amendments are needed for the main trial, their data be included in the analysis of the main trial [ 30 ]. The internal pilot were deemed as successful per pre-specified criteria, as only minor changes to trial-procedures were needed, and participant-data was considered compatible with inclusion in the main trial dataset [ 29 , 30 ]. The following minor changes to procedures was implemented as a result of the internal pilot:

Changes to the REDCap-project, such as removing obsolete fields, fixed validation values, change wrong field values.

Changed sequence of some clinical measures to increase time-efficiency

As one participant performed fewer than the planned 3 attempts of maximal knee extension strength test due to knee pain, the analysis of pain during testing will now consider the most painful attempt during these trials, rather a mean measure of pain across trials.

Four participants experiences (minor) incidents of sensor-adhesive causing skin irritation. We changes the procedures for preventing and handling irritated skin to be more rigorous.

Embedded qualitative study

A qualitative study will be nested in the trial to understand barriers and facilitators to adhering to the interventions and describe the participant-perspective of undergoing the interventions as a whole [ 32 ]. This will support potential implementation and adjustments of the intervention. The interviews will be performed in groups stratified by group allocation and age, across 4–6 sessions in total. Participants from the main trial will be invited to group-sessions after undergoing their visit at 5 months (primary endpoint assessment). They will be provided with a leaflet detailing how the session will take place and what themes are planned. As compensation, participants will receive a voucher for movie theaters (280 dkr. ~ 38 EUR) as well as generous refreshments during the session. The sessions will take place at Hvidovre Hospital in a standard meeting room. An adjacent room with refreshments will be made available for parents. The sessions are planned for 2 × 45 min. Separated by a 45 min. break. As the population are young adolescents, the interviews will be performed as group-interviews to facilitate dialogue and discussions between participants, hopefully inviting participants to openly share their experiences in a safe space, motivated by a mostly shared experience. The planned sample size is based on field-specific guidance [ 33 ]. If sufficient Information Power does not appear to be achieved following this pre-planned number of interviews, more interviews will be conducted to reach sufficient Information Power. The sample size of n  = 16 is based on the following elements:

Aim: The aim of the study is not narrow or specifically around any one or few theoretical constructs. This adds to a larger sample size needed.

Specificity: The sample of participants will be quite homogenous with one strata to (group allocation). This aspect will decrease the sample size needed.

Theory: Our group will apply a theoretical framework to the design and analysis (theoretical domains and component constructs from the field of behavior-change) [ 34 , 35 ]. These specifications will narrow the scope of data collection and analysis and will thus decrease the number of participants needed.

Quality of dialogue: As the researcher conducting the interviews will have no experience, the quality of dialogue will be weak. However, an experienced qualitative researcher will supervise the first few interviews to facilitate a stronger quality of dialogue. Moreover, the interviewing researcher will have extensive knowledge of the subject matter. We therefore expect this aspect will neither require us to increase or lower the needed sample size.

Our analysis will focus on creating understanding across participants with diverse experiences, not just for singular participants. This will increase the needed sample size.

Data will be organized using data derived coding, based on relevance to research questions and the theoretical constructs. Codes will be collapsed into categories and underlying themes based on prevalence of similarities and differences either within respondents or across respondents. Major themes can then be built upon other themes and coding. We will utilize an iterative approach to determine themes and overall interpretations, in line with the epistemology of circular deductive reasoning. Based on known theoretical constructs of behavior change [ 34 , 35 ], we have used theory to comprise the interview-guide within the scope of the research questions. One specific study provides some evidence for choosing which behavior-change constructs to include in our interview guide. The study is a previous investigation of adolescents experiencing non-traumatic anterior knee pain, on how they achieve successful self-management [ 36 ]. This source, combined with clinical experience, has guided the choice and prioritization of domains and constructs.

Setting and personnel

All trial-related procedures will take place at Hvidovre Hospital, Capital Region, Denmark, at either the Department of Orthopedic Surgery or Department of Physiotherapy. Intervention personnel will be 8–10 physiotherapists. Outcome assessors will be 3–4 physiotherapists. Personnel responsible for diagnosis, inclusion, end-of-study visit will be one physiotherapist (KK) and a potential trained replacement, who will not be blinded to either group allocation or outcome measures. The Medical Advisor will be a Chief Orthopedic Surgeon (PH), who will examine participants in need of a second opinion regarding initial diagnosis, AEs, or other sudden health deterioration in participants. A biostatistician (TK) blinded to group allocation in the dataset will perform the analyses.

Interventions and implementation

Experimental intervention: self-management and activity modification.

Based on previous work by Rathleff et al. for adolescents with patellofemoral pain and Osgood-Schlatter [ 17 , 37 ], the experimental intervention will contain a self-management approach to activity modification of sports and physical activity, and progressive exercise therapy, delivered through 4 one-on-one visits lasting approximately 20 minutes (at months 0, 1, 2, 3) over 3 months with a physiotherapist and an accompanying leaflet with written and illustrated exercise description, self-management tools, and advice and information.

Exercises: For targeting the insertion site of the patella tendon, the tibial tubercle, exercises at around 75° knee flexion will be performed, starting with the mild “knee-press” exercise during the first month, after which participants will be instructed to proceed to heavier weight-bearing wall-squats at appx 90° knee flexion, followed by unilateral lunges at approximately 125° knee flexion (Fig. 1 ). The tensile force on the patella tendon is approximately half that during a bodyweight squat compared to a lunge with high range of motion [ 38 , 39 ]. The regression/progression of exercises will depend upon the pain experienced during and until the morning after performing the exercise – if pain has not exceeded NPRS 2, the standardized exercise-dose should be progressed. Alternatively, the exercise dose should be maintained or regressed until NPRS ≤2 is achieved. Besides knee-dominant exercises, the hip abductor bridge will be prescribed, with the same dose throughout months 0–3.

Depiction of hip- and knee exercises

Loading from sport and physical activity

Participants will be asked to take a complete break from weight-bearing sports and rigorous physical activity during the first month. After month 1, gradual exposure to sport will begin, using the same pain-model to progress or regress loading, as well as sport-specific advice from a physiotherapist based on load-markers such as intensity, frequency, duration. Once full or maximum-possible sports participation has been achieved, progression of load from rigorous physical activity will follow in the same manner.

Advice and education: The leaflet and conversations during visits will contain information and advice regarding the following domains: 1) Aetiology 2) Pain management 3) Effects of exercise and knee loading activities 4) Prognosis 5) Self-management decision-making tools and addressing real-world challenges for the participant. From month 3 to 5, the participants will completely self-manage their condition and is encouraged to maintain some level of self-chosen exercise dose (advice of 1–3 sets of lunges and hip abductor bridge, 2–3 times weekly).

Comparator intervention: usual care

We have comprised a usual care treatment package encompassing the most common advice and modalities (see "Choice of comparators"). The treatment package includes a patient-aimed leaflet, which contains vignettes and elaborations of the multimodal approaches included in the usual care package, which will be implemented through four visits (at months 0, 1, 2, 3) with a physiotherapist (mirroring the plan of care of the experimental group). The modalities include: 1) Progressive balance and alignment exercises every other day on one of 6 progressing levels; 2) Stretching of the quadriceps muscle of the symptomatic leg(s), consisting of 2 daily sets of 30 seconds; 3) Use of a patella strap if participants find relief in its use, particularly during sport or physical activity; 4) Advice on cryotherapy and taping; and 5) Advice on load, pain, and prognosis.

Progressive balance and alignment exercises

Participants will be performing one exercise incorporating balance and alignment every other day. The exercise can be one of 6 exercises on progressively more challenging levels (Fig. 2 ). The exercise levels has been sourced or inspired by sections from a leading sports rehabilitation textbook [ 13 ] and subsequently adjusted and refined with an experienced clinician utilizing this type of modality with Osgood-Schlatter patients (23 years practiced, seeing appx. 40 Osgood-Schlatter patients/year).

Depiction of progressive balance and alignment exercise levels

If a participant continuously experience pain during any of the exercises, the participant is advised to stop performing the exercises and regress to a previous pain-free level of exercise. If participants have bilateral Osgood-Schlatter, the exercises will be performed unilaterally, with each leg as the supporting leg interchangeably. For all the exercise levels, the participant must focus on stability/balance and hip-knee-foot alignment on the supporting/landing leg, defined as the symptomatic leg. When each exercise can be performed with a sufficient level of alignment and stability, the participant can progress to the next level. The participants will be instructed through their leaflet and visits with a physiotherapist on how to evaluated exercise quality and when to progress exercises. During each visit, the physiotherapists will also evaluate the current exercise level. All exercises levels are depicted in Fig. 2 .

Alignment in this context is defined as the ability to

keep the pelvis horizontal in the coronal plane, neutral in the sagittal plane, and not twist around the center of mass in the axial plane

keep the knee from going into varus or valgus, and

keep the foot and midfoot arch from going into pronation or supination

Stability and balance in this context are defined as the ability to perform movement or holds without excessive perturbations, corrections, or otherwise inability to perform the movement with intended form or tempo.

Level 1 exercise “Standing on one leg”: The exercise is performed by standing upright on one leg for 2 repetitions of 30 seconds.

Level 2 exercise “Side lifts”: Standing upright on one leg, participants slowly and controlled lifts their contralateral straight sideways out in the coronal plane into hip abduction, and then back again, without the foot touching the ground. The exercise is performed for 2 sets of 10 repetitions in a slow controlled movement.

Level 3 exercise “Half moons”: Standing upright on one leg, participants slowly and controlled tracks their contralateral foot just off the floor, drawing half-circles around themselves. The exercise is performed for 2 sets of 10 repetitions in a slow controlled movement.

Level 4 exercise “Side twists”: Standing upright on one leg, the participant lifts the contralateral leg by grabbing their knee with one hand, tucks it toward their abdomen, and then rotates in the hip around their center of mass in the axial plane. Thereby the leg is slowly rotated to the side, all while keeping sufficient alignment on the supporting leg and sufficient stability and balance. The exercise is performed for 2 sets of 10 repetitions.

Level 5 exercise “Standing Superman”: Standing upright on one leg with both arms flexed at the shoulder, and positioned straight in front them, they slowly and controlled lean forward with stretched arms while also lifting the other (asymptomatic) leg up behind themselves. The exercise is performed for 2 sets of 10 repetitions.

Level 6 exercise: Participants perform hops by setting off on the asymptomatic leg and landing on the symptomatic leg, and alignment and balance/stability are then evaluated during landing. The hop is performed in three different directions; straight forward, sideways, and diagonally. After each hop, participants takes a step back to the starting position. The exercise is performed for 3 repetitions of 8 hops to each direction, totaling 24 hops.

Criteria for discontinuing or modifying allocated interventions

If scheduling or the availability of equipment (surface, chair) hinders the participant from following the exercise dosage, the treating physiotherapist will, together with the participant, try to amend the programme to better suit the preferences and context of the participant while still aiming for the correct dose and form in accordance with the original approach to the fullest extent possible.

Adherence strategy and monitoring

Making exercises enjoyable, social, and convenient, has been identified as the most likely facilitators to exercise adherence in adolescents with musculoskeletal pain [ 40 ]. In line with this, the exercises prescribed in both groups are designed to be performed with only little if any exercise-equipment and are time-efficient (1–20 minutes per day/every other day). We also encourage the participants to attend their regular sports team practices and perform the exercises in that environment, thereby gaining a social aspect of performing the exercises rather than potentially skipping practice altogether [ 41 ]. Through weekly text-based monitoring from week 0 to 22, participants are asked about their adherence to exercise the past week. Participants will be asked at visits at months 1, 2 and 3 about their current exercise dose and to demonstrate the exercises (month 1 and 3), which will then be rated by the observing therapist on a standardized form. Participants will be encouraged only to receive treatment as outlined in their allocated group. Concomitant treatment will not be course for exclusion, but will be recorded at visits months 1, 2, 3, and 5. Adherence to the 4-week break from weight-bearing sports and rigorous physical activity is monitored through accelerometry with a compliance-criteria of ≤15 min of VPA (vigorous physical activity) and ≤ 30 min of MPA (moderate physical activity) every day.

Outcomes and harms

Assessment of outcomes.

In Table 2 we have outlined the schedule of data collection for all outcomes. Weekly monitoring will be performed using a text-based service (SMS-track®, Esbjerg, Denmark) starting the following Monday after the baseline visit, and continue for 22 weeks. We will continue data collection irrespective of adherence to interventions. No biological samples will be collected. We have reported our outcomes in a prioritized order in addition to designations as primary and secondary (Table 3 ), which also reflects the order of hypothesis-testing, analyses, and intentional order of reporting, with the primary outcome, secondary outcomes no. 2–10, and adverse events (AEs), intended for the primary report [ 42 ].

Primary outcome measure

The primary between-group difference will be evaluated using the self-reported outcome measure KOOS-child (Knee injury and Osteoarthritis Outcome Score – Child), designed specifically for adolescents aged 10–18 years experiencing knee problems [ 43 ]. The questions are answered on 5-point Likert scales and pertains to the prior week. The scoring of each subscale is normalized to a 0–100 score, 0 being extreme symptoms and 100 being no symptoms. Four subscales (‘Symptoms’, ‘Pain’, Sport/play’, and ‘Quality of Life’) will be recorded and presented, and one omitted (‘Activities of Daily Living’ due to low responsiveness [ 44 , 45 ]). The subscale ‘Sport/play’ will be prioritized and used as primary outcome, based on its ability to capture self-reported difficulties in performing sports-related activities and movements, and also due to its alignment with study aims, responsiveness in the target population [ 44 , 45 ], and preferences from patient representatives. The ‘Sport/play’ subscale will thus provide properties for sample size calculation. The KOOS-child has low detectable change on the group level (1–3 points, n  = 70) and substantial/near-perfect test-retest reliability (ICC 0.78–91) [ 43 ]. For the KOOS-child ‘Sport/play’ subscale, the smallest detectable group-level change is 3 points and the standard error of measurement are 8 points [ 43 ].

Secondary outcomes

Remaining outcomes are outlined in Table 3 , and includes self-reported measures, clinical tests, and ultrasound imaging.

Adverse events and harms

In our published cohort-study [ 17 ] and during pilot-testing of the intervention in the clinic [ 44 ], we have not observed any AEs related to undergoing the treatment, imaging or clinical tests. As part of the accelerometry-based monitoring of physical activity, adhesive patches are used to fix the sensor to the skin. Skin irritation due to sensor-patches was observed in four participants during piloting. The manufacturer has since provided adhesives made of a new FDA-approved breathable woven material to mitigate this issue. Adverse events during trial-participation will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) grading (grade 1–5) [ 46 ]. To probe for potential any suspected harms or AEs, participants will be asked during all clinical visits and the telephone consultation at month 2, through open-ended questioning about any new symptoms or illnesses, accidents, reasons for care-seeking. In addition, serious (grade 3–5) unexpected side effects or AEs will be reported to the Capital Regional Ethics Committee in Denmark within 7 days after the study director has become aware of the incident. All serious adverse events will be assessed by the study director and the Medical Advisor (PH) for possible relations with the assessments and/or intervention.

Study schedule and post-trial care

After baseline, participants have visits at months 1, 2, 3, 5 and 8, and electronical long-term follow-up after 10, 12, 24 and 48 months (Fig. 3 ).

The primary and secondary fixed endpoints are chosen based on the fact that our previous cohort had trajectories of pain, knee-function, and sports participation that were not fully recovered at 12 weeks [ 17 ], and that some participants had not progressed fully through the exercise regime. Thus, we decided to add a period of complete self-management by adding 2 months to the timeline before the primary endpoint. We have found this alteration to be feasible in clinical practice [ 44 ]. No participants will receive reimbursement for their travel expenses related to participation in the study, nor will participants be offered compensation of any kind for their participation. No post-trial treatment is planned, but will be implemented on a case by case evaluation. During treatment at Hvidovre Hospital, the participants will be covered under the Danish Patient Compensation Act (LBK no 995 of 14/06/2018, chapter 3 §19) (In Danish: Patienterstatningen), which is a scheme that deals with compensation claims of patients treated in the public health system in Denmark who has sustained an unintended or unexpected injury or harm.

Inclusion criteria

The diagnosis of Osgood-Schlatter and eligibility for trial participants will be made according to the following criteria: 1) Pain or swelling of the tibial tubercle for ≥6 weeks with a primary insidious onset, which is provoked by at least 2 of the following positions or activities; prolonged sitting or kneeling, squatting, running, hopping/jumping, stair walking, or during multidirectional sports; 2) Tenderness on palpation of the tibial tubercle or pain during resisted isometric knee extensions. Adolescents aged 10–16 fulfilling these criteria at enrollment and confirm when asked during clinical examination that they either 1) “ have markedly reduced sports participation”, or 2) “are severely affected by pain during participation during the past (representative) 6 weeks?”, will be eligible for inclusion. Any other primary pathology or complaints from other structures of the knee will disqualify the participant from inclusion but will be allowed providing that primary complaints during the preceding ≥6 weeks are from the tibial tubercle. Previous fractures or avulsions of the tibial tubercle will disqualify patients.

Sample size estimation

In the absence of minimal important change thresholds for KOOS-child ‘Sport/play’ scale, specific in terms of diagnosis, severity, intervention, and length of follow [ 47 ], we have performed a clinical case series accounting for these factors, providing specific and relevant estimates of change on the different KOOS-Child subscales. In this clinical case series, 16 out of 33 patients met eligible criteria for inclusion in the current trial at their baseline visit, received the intervention in question, and attended follow-up at 6 months. The subscales most affected at baseline which also showed high responsiveness to change were ‘QoL’ and ‘Sport/play’. Furthermore, patients preferred the ‘Sport/play’ subscale, and we therefore decided to use the ‘Sport/play’ subscale as the primary outcome measure. We will utilize a 9 point difference as a threshold for determining superiority. We consider this to be a meaningful longitudinal change, a relevant between-group difference, and is within the recommended range of 8–10 points ( heartbeat-med.com/resources/knee-injury-and-osteoarthritis-outcome-score-koos ). All 16 patients from the case series reported their global rating of improvement on a 7-point Likert scale ranging from ‘much worse (7) ‘to ‘much better (1)‘. Patients who reported ‘much better (1)’ or ‘better (2)’ had a mean improvement on KOOS-child ‘sport/play’ subscale of 12.7 ± 16 points, whereas patients reporting less improvement (‘little’ improvement or ‘no change’) only had a 3.6 point increase. Thus, the 9 point difference also distinguished patients in our case series who reported meaningful improvements, from those who did not. To detect this 9 point difference with a standard deviation of 16 points, at an α-level (type I/false positive error rate) of 5 and 90% power (β-1, or probability of avoiding type II/false negative error rate), n  = 55 participants per group would be needed based on an independent one-sided t-test (R 4.0.2, Foundation for Statistical Computing, Vienna, Austria; RStudio 1.0.153, power.t.test package). To account for a potential 15% dropout rate [ 37 ] a total of 130 participants will be included. This will correspond to a 0.56 Cohens d ‘medium’ effect size at 90% power. The smallest effect size reliably detectable will thus be > 0.482 (Cohens d ‘small’ effect size) at ≥80% power (Jamovi 1.2.25, jpower module), surpassing the trivial (< 0.2) and small (> 0.2) effect size thresholds.

Group allocation

Allocation concealment.

The sequence will be implemented using sequentially numbered sealed opaque envelopes, sealed and prepared by a person not otherwise involved in the trial. During the trial, only the person responsible for including participants will unseal envelopes when a participant is included in the trial.

Sequence generation and implementation of group allocation

Participants will be allocated to either group with a 1:1 allocation ratio. To perform adequate sequence generation, we will use The Robust Randomization App [ 48 ] (RRApp v3.0.1, https://clinicalresearch-apps.shinyapps.io/rrapp/ ) for a computer-generated sequence in random sized blocks with no stratifications, extracted by a person not otherwise involved in the trial. During the study period, all staff involved in including participants, treatment, data collection, and analysis will be blinded to randomization sequence and block size.

Recruitment and participant retention

Participants will be recruited through a combination of convenience sampling from the uptake area of the Capital Region of Copenhagen, Denmark (1.8 M inhabitants), through two different approaches; 1) postings to our website encouraging parents of adolescents with confirmed Osgood-Schlatter or anterior knee pain below the knee to contact the study director, which will also be shared with sports clubs in the uptake area through our organizational network and social media; and 2) patients referred to specialized outpatient clinic at the Orthopedic Department. Based on historical patient flow and past studies in this population, the planned recruitment rate is expected to be around 10–15 participants per month. Thus, inclusion is expected to last no more than 2 years, from January 1st 2022 to December 31st 2023.

To yield valid results from the trial and in lieu of clinical equipoise in usual care (see Choice of comparators section), we will blind participants to the superiority hypothesis and specific contents of the intervention they are not receiving. This will be done by providing minimal information to participants about the contents of either intervention until after group allocation. The written and verbal information prior to inclusions will state that the two groups both contain first line treatment modalities such as different advice and exercises and that it is unknown if any treatment is superior. Information on which of the two treatments are hypothesized to be superior, will be withheld. This blinding aspect will reduce the risk of performance bias. To further minimize performance- and verification bias, the intervention personnel will not be aware which, or if any, of the two treatments is the experimental or the comparator, or if the trial is investigating superiority/non-inferiority/equivalence. Intervention personnel will need to engage participants in conversations about their current pain and symptoms, and will therefore not be blinded to outcomes as such. Outcome assessors and the statistician performing analysis will be blinded to group allocation. As the study director and the Medical Advisor is unblinded to group allocation, unblinding is not expected to be necessary during the trial.

Data management and confidentially

The study director will manage and curate data in collaboration with the blinded statistician (TK). Written consent forms and other hardcopy data will be stored in locked steel cabinets in a locked room and will be stored for 3 years after completion of the long-term follow-up of the study. All outcome data, besides text-messages, ultrasound images, and sensor-data, will be entered into REDCap. We will keep standard confidential electronic health records in accordance with local laws and healthcare regulations. In addition, our plans (and sub-contractors) for use and handling of patient-data have been reviewed and approved by the Capital Region Data Protection Agency (P-2021-818) after the protocol was approved by the Capital Region Committee on Health Research Ethics (H-21028912). We plan for only the study director to hold access to the de-identifier key. As per usual care, information regarding clinical findings, treatment plans, and delivery, will be noted in the participants regular electronic medical records to support potential post-trial care. All statistical code and fully anonymized dataset will be shared in an open-access repository once all planned publications are accepted or published as pre-print [ 49 , 50 ].

Statistical analysis

A statistical analysis plan is embedded in the full protocol (NCT05174182). Analyses will be performed by a statistician (TK) blinded to group allocation. Change scores for KOOS-child ‘Sport/play’ score ( △ KOOS-child) from baseline to month 5 will be calculated for all participants. We will fit a linear regression model for △ KOOS-child as the outcome variable, and group allocation as the predictor variable. Potential covariates are described in Table 4 .

The linear model will be evaluated for linearity, multicollinearity, homogeneity of variance, distortion of outliers, homoskedasticity, and distribution of residuals using plots and scripts for model-checks. If these model assumptions are not met, non-parametric bootstrap estimation and tests will be used instead. To examine the effect of adherence we will perform sensitivity analyses of subgroups according to pre-specified compliance criteria. No interim analyses or stopping rules are planned, due to very low safety concerns and to preserve statistical power. Assuming that data will be missing at random, multiple imputations using chain equations will be used to handle missing data. Imputation models for missing variables will be fitted using linear, logistic or polytomous regression models. All available variables will be included in the imputation models, unless a specific reason is given for exclusion. Imputation will only be performed for variables included in the analysis. Multiple imputation will be done using R-package mice [ 74 ] Table 5 .

Data sharing, authorship, and dissemination

All members of the study group will be invited as co-authors on the specific publications according to the International Committee of Medical Journal Editors (ICMJE) recommendations and The Danish Code of Conduct for Research Integrity codec [ 75 , 76 ]. All findings and results are planned to be published in international peer-reviewed scientific journals. The results will be posted to ClinicalTrials.gov once the results have been published. The results will be published regardless of positive, negative, or inconclusive findings. No trial conduct audit is planned. Kasper Krommes and Per Hölmich will enforce publications as first and senior authors respectively, unless other publication-specific contributions warrants.

Protocol amendments and versions

The protocol have been published in several version. Version 1.0 was approved by ethics review board. Version 1.1 and 1.2 included all SPIRIT items, the embedded SAP, and was posted to ClinicalTrials.gov before recruitment started without details of the interventions, in order to preserve blinding of potential participants and staff. The subsequent versions (v1.3 01-MAR-2023 and v1.4 05-APR-2024) had updates on pilot-results, qualitative study, mediation analysis, and details on the interventions as blinding was no longer an issue. This version (v1.5) is formatted for journal publication.

Trial audit, steering committee, and contact details

The Sports Orthopedic Research Center – Copenhagen (SORC-C), specifically PhD-fellow Kasper Krommes (Study Director), Professor Per Hölmich (Main Supervisor and Medical Advisor), and Professor Kristian Thorborg (Co-supervisor) at the Department of Orthopedic Surgery at Amager-Hvidovre Hospital has initiated and will manage the trial. Together, they also form the steering- and writing committee, which will oversee the trial and assume stewardship of the data. No specific data monitoring committee is convened.

Availability of data and materials

Protocol-related materials are available at open-access repository ( doi.org/10.6084/m9.figshare.c.5730008.v1 ).

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Acknowledgements

Patients and their parents attending meetings regarding objectives, design, and the practical implementation of the trial. Pre-graduate students that have assisted in performing studies and other preparational work for this protocol: Frederikke Villumsen, Amalie Bjerre Jørgensen, Oliver Olsen, Nickoline Andersen, Line Holm, Caroline Schad, Hjalte Nørremark. Ph.d. Candidate Marie Skov Breum and Professor Torben Martinussen for valuable input and review of prespecified approach to mediation analysis. Senior Researcher Jeanetter Wassar Kirk is acknowledged for methodological guidance in designing and planning qualitative substudy.

Contact details

Email: [email protected] , Tel: + 45 21 75 72 60. Visiting address: Hvidovre Hospital, Orthopedic Department (section 333), Kettegaard Alle 30, DK-2650, Hvidovre, Denmark. ClinicalTrials.gov registration and protocol repository: NCT05174182. Protocol identifier and IRB approval number: H-21028912 Supplementary materials: doi.org/10.6084/m9.figshare.c.5730008.v1 . Licensing: CC-BY-NC-ND 4.0: Anyone can share this material, provided it remains unaltered in any way, this is not done for commercial purposes, and the original authors are credited and cited.

Trial status

We have currently (27-SEP-2023) enrolled 124 of 130 (95%) participants and expect enrollment to finish by 31-DEC-2023.

Open access funding provided by Copenhagen University The Department of Orthopedic Surgery, and the Department for Physiotherapy will provide facilities and imaging capabilities. The research unit SORC-C will provide 100% funding for statistical support. The following funders have provided grants for other project costs: Fysioterapipraksisfonden (dkr. 678.200), Østifterne (dkr. 599.958), Helsefonden (dkr. 350.000), Købmand Ferdinand Sallings Mindefond (dkr. 219.480), Hvidovre Hospitals Frie Forskningsmidler (dkr. 100.000), Beckett Fund (dkr. 70.000), FLSmidth Donation Fund (dkr. 50.000), Frimodt-Heineke Fonden (dkr. 50.000), Danish Association of Physiotherapists Research Fund (dkr. 36.600) and the Danish Society of Sports Physical Therapy (dkr. 6.000). No funding body will have any control or involvement in data collection, analyses, interpretation, writing the report, or deciding whether to publish.

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Sports Orthopedic Research Center – Copenhagen (SORC-C), Department of Orthopedic Surgery, Amager-Hvidovre, Copenhagen University Hospital, Kettegaard Allé 30, Hvidovre, DK-2650, Denmark

Kasper Krommes, Kristian Thorborg & Per Hölmich

Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark

Kristian Thorborg & Per Hölmich

Department of Midwifery, Physiotherapy, Occupational Therapy and Psychomotor Therapy, Faculty of Health, University College Copenhagen, Sigurdsgade 26, DK-2200, Copenhagen N, Denmark

Mikkel Bek Clausen & Thomas Kallemose

Center for General Practice at Aalborg University, Aalborg. Fyrkildevej 7, DK-9220, Aalborg, Denmark

Michael Skovdal Rathleff & Jens Lykkegaard Olesen

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Michael Skovdal Rathleff

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K.K. drafted the manuscript text and prepared all figures and tables. All authors (K.T., M.B.C., M.S.R., J.L.O., T.K., and P.H.) reviewed and approved the final submitted manuscript. All contributions are listed in Table 5 . 

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The protocol was approved by the Capital Region Committee on Health Research Ethics (H-21028912). The study director will obtain consent from parents/guardians to participate in the trial. Participants over the age of 15 will also be asked to sign a written consent form themselves. Written and verbal information will be supplied to participants and their parents prior to consent. Verbal information will be delivered in an undisturbed setting, similar to a usual medical consultation. If participants wish to drop out of the study, they will be given the opportunity to only complete digital self-reported follow-up. The consent form, written information, and the review board approval has been uploaded to the open access figshare repository: https://doi.org/10.6084/m9.figshare.c.5730008.v1 .

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Krommes, K., Thorborg, K., Clausen, M.B. et al. Self-management including exercise, education and activity modification compared to usual care for adolescents with Osgood-Schlatter (the SOGOOD trial): protocol of a randomized controlled superiority trial. BMC Sports Sci Med Rehabil 16 , 89 (2024). https://doi.org/10.1186/s13102-024-00870-0

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DOI : https://doi.org/10.1186/s13102-024-00870-0

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• Osgood-Schlatter
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• Study Protocol
• Open access
• Published: 30 April 2024

Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial

• Matthew R. Lammi 1 , 2 , 3 , 9 ,
• Monica Mukherjee 4 ,
• Lesley Ann Saketkoo 3 , 5 ,
• Kyle Carey 6 ,
• Laura Hummers 7 ,
• Steven Hsu 4 ,
• Amita Krishnan 1 , 2 ,
• Marie Sandi 1 ,
• Ami A. Shah 7 ,
• Stefan L. Zimmerman 8 ,
• Paul M. Hassoun 9 &
• Steven C. Mathai 9  

BMC Pulmonary Medicine volume  24 , Article number:  211 ( 2024 ) Cite this article

Metrics details

Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21–24 mmHg).

The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks.

The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP.

Trial registration

ClinicalTrials.gov Identifier NCT04797286.

Peer Review reports

Pulmonary hypertension (PH) is a hemodynamic condition defined by directly measured pulmonary arterial pressures from right heart catheterization (RHC). Until recently, an individual was considered to have PH when their mean pulmonary artery pressure (mPAP) was ≥ 25 mmHg at rest. In 2018, the 6th World Symposium on Pulmonary Hypertension (WSPH) lowered the threshold for a diagnosis of PH to a mPAP > 20 mmHg on resting RHC [ 1 ]. This recommendation was based on prior data describing the normal mPAP as 14 ± 6 mmHg [ 2 ], with 20mmHg therefore representing the 95th percentile of mPAP. Additionally, multiple large epidemiological studies demonstrated that there is a continuum of risk whereby a mPAP ≥ 19 mmHg is strongly associated with worse survival [ 3 , 4 ]. A meta-analysis of 8 studies comprising almost 12,000 patients found that there is a 34–78% increased risk of death in those with a mPAP of 19–24 mmHg compared to those with a normal mPAP [ 5 ].

The updated definition of PH is most relevant to populations at high-risk for pulmonary hypertension who undergo routine screening. One such group of patients are those with systemic sclerosis (SSc, also known as scleroderma), who suffer from a severe autoimmune disease characterized by exaggerated fibrosis, vasculopathy, and dysregulation of the immune system that can affect the skin and internal organs. The prevalence of mild increases in mPAP (21–24 mmHg) in SSc, hereafter referred to as SSc with mildly elevated pulmonary pressures (SSc-MEP), is 10–15% [ 6 , 7 , 8 , 9 ]. This prevalence is similar to the prevalence of pulmonary arterial hypertension (PAH) in SSc, a form of group 1 PH with significant morbidity and mortality, when defined using the mPAP ≥ 25 mmHg cut-off [ 10 ]. Application of evidence-based PH early detection strategies such as the DETECT algorithm led to an increase in the identification of SSc patients with a mildly increased mPAP [ 11 ]. Therefore, improved early detection strategies and the changed definition of PH may significantly increase the number of SSc patients who now have PH. Compared to SSc patients with a mPAP < 21 mmHg, SSc-MEP patients have worse exercise capacity with a lower six-minute walk distance (6MWD) and peak exercise workload, along with impaired right ventricular (RV) output reserve during exercise [ 8 ], demonstrating that SSc-MEP patients have significant functional limitations.

While epidemiologic data show increased morbidity and mortality for persons with mildly elevated pulmonary artery pressures and guidelines now support lower thresholds for establishing the diagnosis of PH, there are no approved therapies for treatment of patients with this form of PH, which may substantially impact survival and progression to more severe PH. Only one prior trial has attempted to address this patient population. The EDITA study was a randomized controlled trial (RCT) of an endothelin receptor antagonist (ERA), ambrisentan versus placebo in 38 SSc subjects who either had SSc-MEP or an exercise-induced increase in mPAP [ 12 ]. Although the primary endpoint, change in mPAP after 6 months of treatment, was not different between the groups, the ambrisentan-treated participants had an improvement in resting pulmonary vascular resistance (PVR) and cardiac index (CI) change during exercise. Change in 6MWD also favored the ambrisentan group, with a 39-meter (m) improved compared to placebo [ 12 ]. This trial demonstrated the potential for a PAH medication to improve outcomes in SSc patients with mildly elevated mPAP but was limited by the mixed nature of the cohort and the selection of their primary endpoint, since mPAP is unlikely to change significantly due to the narrow range of pressures in SSc-MEP.

The lack of data examining the utility of vasodilator therapy in the management of SSc-MEP motivated the “ S ildenafil Versus Placebo for E arly P ulmonary V ascular D isease I n S cleroderma” (SEPVADIS) Study. This study is a RCT of sildenafil versus placebo in SSc-MEP patients to investigate the following aims: (1) To determine whether sildenafil affects the 6MWD in SSc-MEP patients at 16 weeks and 1 year; (2) To determine if sildenafil affects RV function in SSc-MEP patients at 16 weeks; (3) To determine whether sildenafil affects health-related quality of life (HRQoL) in SSc-MEP patients at 16 weeks and 1 year.

Design and setting

SEPVADIS is a bicentric randomized, placebo-controlled, double-masked, parallel group superiority trial that is being conducted at two academic PH and SSc referral centers in the United States: Johns Hopkins University (Baltimore, MD) and Louisiana State University Health Sciences Center (New Orleans, LA).

Participant selection

Recruitment is occurring at each study site, drawing from patient referrals and each center’s existing SSc population. The selection criteria are displayed in Fig.  1 . The main inclusion criteria are a diagnosis of SSc and a diagnosis of pre-capillary PH with a mPAP 21–24 mmHg and a pulmonary artery wedge pressure (PAWP) ≤ 15mmHg. Of note, we did not include a PVR > 3 Wood units [ 1 ], which has been supported by the latest European guidelines, which lowered the PVR threshold for PAH to > 2 Wood units [ 13 , 14 ]. Exclusion criteria are listed in Fig.  1 and focus on the exclusion of participants in whom sildenafil would be contraindicated, such as severe systemic hypotension, use of nitrates [ 15 ], and sickle cell disease [ 16 ].

Selection criteria. SSc = systemic sclerosis; ACR = American College of Rheumatology; EULAR = European League Against Rheumatism; RHC = right heart catheterization; mPAP = mean pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; TLC = total lung capacity; ILD = interstitial lung disease; HRCT = high resolution computed tomography; VQ = ventilation-perfusion scan; CTA = chest CT angiography; 6MWT = six-minute walk test; PAH = pulmonary arterial hypertension; WHO = World Health Organization; FC = functional class; LVEF = left ventricular ejection fraction; BP = blood pressure

Interventions

Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor that was originally FDA-approved for the treatment of erectile dysfunction, but was later investigated for PAH in the SUPER trial, in which sildenafil led to improvements in 6WMD, mPAP, and functional class [ 17 ]. In a sub-group of connective tissue disease PAH, most of whom had SSc, significant benefit was seen with sildenafil [ 18 ]. This medication is used for SSc-related Raynaud’s phenomenon and digital ulcers and has been proven to be safe in a group of SSc patients with a mPAP < 25mmHg [ 19 ]. We chose a PDE-5 inhibitor rather than an ERA due to an RCT that demonstrated improved 6MWD, RV mass, and HRQoL in PAH patients who received sildenafil compared to an ERA [ 20 ]. Additionally, in patients with SSc-PAH initial treatment with PDE-5 inhibitor monotherapy was associated with less clinical worsening compared to ERA [ 21 ].

Sildenafil is being purchased from Teva Pharmaceuticals, who are not involved in the planning or conduct of this trial. Participants are randomized to either sildenafil (20 mg) or matching placebo taken three times per day. Sildenafil and placebo tablets are being over-encapsulated by the Research Pharmacy at the Johns Hopkins University (JHU) School of Medicine Research Pharmacy. At the Research Pharmacy, capsules are being packaged into bottles with a liner, cotton, and childproof cap. One bottle of drug product is dispensed to study subjects at the baseline study visit and at the 16-week visit during the treatment phase. Subjects are asked to return bottles at the 16-week and 52-week visits to allow for tracking of adherence and medication control. Randomization to drug or placebo is done in a 1:1 fashion blocked and stratified by center. All study personnel, subjects, and the statistician are blinded for the duration of the study until the last subject completes follow-up assessments. The JHU Research Pharmacist is unblinded. In the rare event that unmasking is necessary for clinical care, the Chair of the Steering Committee will make the decision to unmask, and the treating physician will call the research pharmacy to obtain the participant’s treatment assignment. Subjects will be withdrawn from the trial if the participant withdraws consent or if the principal investigator determines that the subject should be withdrawn for safety. One specific scenario in which this could occur is if the participant has a mPAP > 25mmHg and a PAWP ≤ 15mmHg on their week 16 RHC; they would be withdrawn from the trial and given guideline-based PAH treatment.

The primary outcome of this trial is 6MWD measured at 16 weeks. Six-minute walk distance reflects peak oxygen consumption [ 22 ] in PAH and is associated with changes in HRQoL [ 23 ], with a minimal important difference (MID) of 33 m for PAH and 24 m for SSc-PAH [ 23 ]. The 16-week timepoint was chosen since nearly every proprietary drug for PAH has been approved based on changes in 6MWD at 3–4 months as this is considered a clinically important intermediate endpoint [ 17 , 24 , 25 , 26 , 27 ]. Second, improvement in 6MWD in SSc-PAH patients can be seen in as few as 8 weeks in treatment-naïve patients [ 28 ]. We are following patients for one year and collecting 6MWD along with other data to assess the durability of the effect of sildenafil in SSc-MEP.

Secondary endpoints include change in pulmonary arterial compliance (PAC) and RV function by cardiac magnetic resonance imaging (CMR) and echocardiography, serum N-terminal probrain natriuretic peptide (NT-proBNP), and HRQoL at 16 weeks. Six-minute walk distance, NT-proBNP, HRQoL, and echocardiography are also obtained at 52 weeks. PAC is a measure of pulmonary arterial stiffness and a contributor to RV afterload which, due to the inverse hyperbolic relationship of PVR and PAC [ 29 ], may be modifiable early in the course of PAH. This is of significant relevance in SSc-PAH, since PAC is an independent predictor of survival [ 30 ]. Echocardiographic measures of RV function include tricuspid annular planar systolic excursion (TAPSE) [ 31 ] and speckle tracking echocardiography (STE), a quantitative measurement of regional and global contractility that is responsive to PAH treatment and correlates strongly with functional capacity and hemodynamics [ 32 ]. CMR, the gold standard for RV function assessment, is being employed to quantify RV ejection fraction and RV volumes. HRQoL is assessed using the Medical Outcomes Survey Short Form-36 (SF-36) [ 33 ] and emPHasis-10, a disease-specific tool developed specifically for PAH [ 34 ]. Testing protocols were standardized between the two enrolling sites; RHC, echocardiography, and CMR done at LSU will be interpreted centrally at Johns Hopkins.

Data collection and participant timeline

The participant timeline is displayed in Fig.  2 . Subject retention is being addressed through the following methods: extensive contact information will be recorded for each participant and the research coordinator will call before each study visit to encourage attendance. Additionally, participants are contacted and encouraged by the research coordinator to report any serious adverse events as they occur, while any other adverse event reporting occurs at the next available study visit or scheduled phone check in. Participants are being reimbursed for their time and reasonable travel expenses necessary for their participation. Non-adherence with therapy is being minimized by emphasizing the importance of compliance with study drug treatment and performing pill counts at study visits. If a participant wishes to drop-out from the treatment phase of the study or has a serious adverse event, we will continue to follow-up with the subject for study assessments to assist with safety monitoring and to avoid the problems introduced by missing data. Any missing data that will be reported as a protocol deviation to the single IRB and any other relevant monitoring authorities.

Participant timeline and schedule of events. SF-36 = Short Form 36 questionnaire; MRI = magnetic resonance imaging; NT-proBNP = N-terminal pro B-type natriuretic peptide. * : The right heart catheterization that is used for inclusion into the trial was done prior to enrollment as part of clinical care

Specimen collection and storage

In addition to the laboratory tests to be run locally at each visit, research blood is being collected and processed by the research coordinator at each site. Those research collections are processed the same day as the visit and are stored initially at -80 degrees Celsius in freezers at the local site. The processed samples are then transported at a later date to the central JHU Scleroderma Biorepository for long term storage.

Statistical methods

Sample size.

We have based our effect size estimate of 45 m upon our preliminary data (not shown) demonstrating a difference in mean 6MWD between SSc patients with normal mPAP and SSc-MEP of ∼  50 m with a standard deviation of 75 m. As such, we will have > 80% power to detect this difference at significance level of 0.05 with 27 subjects. To account for a 10% drop-out rate, we are enrolling 30 subjects. Even if our actual drop-out rate nearly doubles our expected rate (17% vs. 10%), we maintain adequate power to detect a difference of 45 m with 80% power (Fig. 3 ). While this estimate of change in 6MWD exceeds the MID for the 6MWD in PAH, the MID for this test in SSc-MEP is unknown. Further, if differences in 6MWD observed in the study do not reach the predefined detectable alternative, clinical relevance of the effect on 6MWD may be reflected by comparing the proportion of patients who exceeded the MID for 6MWD between arms. Based upon a sample size of 27 subjects completing the trial, we also have adequate power (80% or greater) to detect differences in the proposed secondary outcome measures. For instance, we have 80% power to detect a mean difference in PAC of 0.6 mL/mmHg (SD 1.1) between treatment arms; this difference was the average difference between these SSc-MEP and SSc-normal pressures found in our preliminary studies (data not shown). Further, we will have sufficient power to detect differences of 0.23 cm (SD 0.5) in TAPSE between groups which is close to the estimated MID for TAPSE in SSc-PAH (0.22 cm) from prior work from our group [ 28 ]. For global RV strain measured by STE, we have more than 85% power to detect a difference of 4.8% (SD 8%); this is the difference detected in our ATPAHSS Study of ambrisentan and tadalafil in treatment naïve SSc-PAH patients after therapy [ 28 , 32 ]. Similarly, we have adequate power to detect a difference of 5% (SD 9%) in RVEF between arms; this difference is the MID for RVEF in PAH [ 35 ]. For HRQoL outcomes, we also have adequate power to detect clinically relevant changes in SF-36 of 5 units (SD 7 units) and emPHasis-10 of 6 units (SD 10) [ 36 ].

Power estimates and detectable alternatives by sample size in the SEPVADIS trial

Data analysis plan

The intent-to-treat analysis will include all randomized subjects. Hypothesis testing will use two-sided α = 0.05 without correction for multiplicity. We will characterize subjects regarding baseline and follow-up 6MWD and other endpoints. We will summarize demographics and other predictors of clinical status. Continuous variables will be summarized by the mean, median, standard deviation, and range, as appropriate. The distribution of the outcome measures of interest will be assessed for normality. If the distribution is normal, we will use independent t-tests to compare by treatment assignment. If the distribution is not normal, we will transform the data to meet the assumption of normality. If transformation does not achieve normality, comparisons between groups will be made using the Wilcoxon rank-sum test. We will use contingency tables for discrete and dichotomous variables.

The primary analysis will compare the absolute change in 6MWD from baseline with adjustment for baseline 6MWD, age, and sex in linear regression models. We chose sex as a potential confounder of the relationship between 6WMD and treatment based upon prior work demonstrating there may be worse survival for men with SSc-PAH compared to women [ 37 ], but men may have improved 6MWD and HRQoL compared to women in response to PDE-5 inhibitors [ 38 ]. Given the small sample size of our study, we will be sensitive to overfitting our model with covariates but will use the univariate analyses to inform the inclusion of additional covariates in the final model. We will examine the clinical relevance of the change in 6MWD by comparing the proportion of patients who achieve the MID for the 6MWD for both PAH (MID = 33 m) and for SSc-PAH (MID = 24 m) by treatment assignment. Using separate multivariable logistic regression models adjusting for baseline walk distance, age, and sex, we will assess if the odds of achieving a clinically relevant improvement in 6MWD based upon the MID for PAH and for SSc-PAH differs by treatment assignment. We can then perform responder analyses to determine characteristics of SSc-MEP patients likely to achieve either MID for the primary outcome of 6MWD.

The secondary outcomes will be analyzed similarly using linear regression models adjusting for baseline values and for sex. Prior studies have demonstrated sex-specific differences in RV structure and function as assessed by CMR [ 39 ] and in PAC [ 29 ], though to our knowledge there are no studies examining differences in TAPSE between men and women. HRQoL measures may differ by sex as well.

We will also include longitudinal models of change from baseline over the time of the trial. Exploratory multivariate analyses will be performed incorporating all the available endpoint assessments (baseline, 4 months, and 12 months) in an ANCOVA model with active treatment/placebo status as the independent variable.

We will attempt to minimize missing data by encouraging full subject participation and follow-up even if the subject stops the study drug prematurely. If there are missing data, we will perform sensitivity analyses using the mean value obtained to replace this missing data. For subjects lost to follow-up, we will use all the information available until the end of follow-up. For dropouts, we will use the lowest value obtained to replace missing data in separate sensitivity analyses.

Data monitoring

The Data Safety and Monitoring Board (DSMB) will be comprised of three members: two pulmonary hypertension specialists with extensive track records of participating in and leading randomized controlled trials in PH, as well as one biostatistician experienced in clinical trial analysis. DSMB reports will be generated on a quarterly basis including expected and actual enrollment numbers. Every six months, a DSMB report will be generated that includes enrollment rates, follow-up rates, compliance levels, adverse events, mortality, and mean data on the primary and secondary analysis. If there are any complaints about the research trial, we will summarize these complaints and report them to the DSMB in these reports. Since this is a Phase II trial that would be helpful in supporting future studies of the intervention even if no difference is found between sildenafil and placebo, we have not planned for formal interim analyses for futility.

Ethics approval and consent to participate

The study is being conducted in compliance with the principles of Declaration of Helsinki and informed consent is obtained from all the participants. For each consent process, study personnel discuss the details of the study, the risks and benefits, and the subject’s rights and responsibilities if they choose to participate in the trial and their right to refuse to participate. It is made clear that their clinical care will not be affected by their decision. Subjects are permitted to provide verbal consent over the phone prior to being scheduled for a screening visit. A consent script is provided, and documentation of verbal consent is noted. When the subject arrives for the screening visit, written consent is obtained.

Johns Hopkins University and Louisiana State University Health Sciences Center are relying on a single IRB (sIRB) of record (JHU) and obtain approval and reliance agreements. IRB approval was required at both enrolling sites prior to enrollment of the first patient. Protocol changes must be approved by the sIRB prior to implementation. Unanticipated problems posing risks to subjects or others will be reported to the sIRB. Reportable events include any event that could represent an unexpected serious adverse event (SAE), any AE that could lead to a change in the informed consent, information that changes the risks and benefits of the trial, a change in FDA labeling for sildenafil, breach of confidentiality, protocol violations that might place one or more participants at increased risk or might affect the rights of the subjects.

Data management, sharing, and dissemination

Confidentiality is maintained by assigning each participant with a unique study number; no Protected Health Information (PHI) is recorded on study case report forms (CRF) or transmitted between study sites. We keep any potential identifiers separate from the participant’s CRF in a secure environment only accessible to study staff granted access to PHI. Only study staff approved by the IRB have access to study records, data, and specimens. Representatives from the funding organization, the Department of Defense, are eligible to review study records.

Clinical site personnel key in all study data into the data capture system directly. Other than the two questionnaires, study data is entered directly from the electronic medical record, rather than by use of paper CRF’s. The electronic data capture system that we are using is REDCap ( https://www.project-redcap.org/ ), which is a secure, validated web application used by both Johns Hopkins and Louisiana State University Health Sciences Center to build and manage databases. The paper forms (questionnaires) are kept in locked offices only accessible by approved study staff. To ensure data quality, all data is double-entered (enter/verify). A second method of quality control is embedded within REDCap, which provides data checks in real time as data are keyed, including data format checks (e.g., numbers or letters) and valid value checks (e.g., ranges for age). The site Principal Investigator (PI) performs continuous monitoring of data quality and completion of CRFs. Once the site personnel mark a form as complete, the data on that form is locked and all error corrections must be requested. Each time an error correction is done after the data form is locked, a rationale must be provided. Data will be exported only in de-identified custom exports and only by approval of the PI.

Results of this clinical trial will be disseminated to the research community through presentations at national/international conferences as well as through publications in peer-reviewed journals. Data collected during this clinical trial will be shared, both in aggregate through manuscripts and individual-level (de-identified) data upon request. The data will be encoded using standard methods and a coding key will be available to interested researchers. Additionally, biospecimens may be available for sharing if adequate samples remain after our analyses are complete. In this case, a Materials Transfer Agreement would be required according to institutional policy. Data will be distributed directly to interested researchers by request via an electronic file. Data may also be submitted to the NHLBI-funded Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC), as the biomarker portion of our trial aligns with their mission.

To our knowledge, once completed the SEPVADIS trial will be the first RCT to exclusively enroll patients with mildly elevated mean pulmonary artery pressure (21-24mmHg). Since the recommended definition of PH changed in 2018, there has been great uncertainty about whether PAH-specific medications are beneficial in this new subgroup of patients, especially in a high-risk group such as SSc. The SEPVADIS trial is currently enrolling patients at both clinical sites and once completed will provide important data on the impact of sildenafil on exercise capacity, right heart function, and HRQoL in SSc patients with mildly elevated pulmonary artery pressure. We anticipate that these data will lay the foundation for a larger, multi-center trial of PAH-specific medications in SSc-MEP, which has the potential to slow progression of disease and positively impact patient outcomes.

Data availability

Abbreviations.

six-minute walk distance

six-minute walk test

American College of Rheumatology

analysis of covariance

blood pressure

Cardiac index

cardiac magnetic resonance imaging

case report form

chest CT angiography

Data Safety and Monitoring Board

endothelin receptor antagonist

European League Against Rheumatism

functional class

Food and Drug Administration

high resolution computed tomography

health-related quality of life

interstitial lung disease

Johns Hopkins University

left ventricular ejection fraction

millimeters of mercury

mildly elevated pulmonary pressure

minimal important difference

mean pulmonary artery pressure

National Heart, Lung, and Blood Institute

N-terminal B-type natriuretic peptide

pulmonary artery compliance

pulmonary artery hypertension

pulmonary artery wedge pressure

phosphodiesterase-5

pulmonary hypertension

Protected Health Information

Principal Investigator

pulmonary vascular resistance

randomized controlled trial

right heart catheterization

right ventricle

serious adverse events

standard deviation

S ildenafil versus placebo for e arly p ulmonary v ascular d isease i n s cleroderma

Short Form 36 questionnaire

single institutional review board

systemic sclerosis

speckle tracking echocardiography

tricuspid annular planar systolic excursion

ventilation-perfusion scan

World Health Organization

World Symposium on Pulmonary Hypertension

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Acknowledgements

The SEPVADIS trial is funded by the Department of Defense, who has no role in the design of the study nor the collection, analysis, and interpretation of data.

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Contributions

Trial Design (MRL, MM, LAS, SH, PH, SCM, AS, LH, AK, SZ); Participant enrollment (KC, MS); Drafting manuscript (MRL); Editing of final manuscript (MRL, MM, LAS, SH, PH, SCM, AS, LH, KC, MS, AK, SZ).

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Correspondence to Matthew R. Lammi .

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Ethics approval.

The SEPVADIS trial was approved (IRB # 00265164) by the IRB at Johns Hopkins University, which serves as the sIRB for both recruiting sites.

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Competing interests.

MRL: Clinical trial participation with Gilead, Actelion/Janssen, Bayer, United Therapeutics, Altavant, Acceleron (all funds to the institution). MM: Data Safety Monitoring Board, Advarra, Inc. AS: Clinical trial grants (paid to the institution) from Kadmon Corporation, Eicos Sciences Inc, Arena Pharmaceuticals and Medpace LLC. SZ: Siemens Healthcare - partial salary support for consultation. PMH: Serves on a scientific steering committee for Merck and Co, and as an advisor for Tectonic, activities unrelated to the current work. Nothing to declare: LAS, KC, MS, AK, LH, SH, SCM.

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Lammi, M.R., Mukherjee, M., Saketkoo, L.A. et al. Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial. BMC Pulm Med 24 , 211 (2024). https://doi.org/10.1186/s12890-024-02892-3

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Received : 29 June 2023

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DOI : https://doi.org/10.1186/s12890-024-02892-3

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• Pulmonary hypertension
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