Time to Healing in Displaced Pediatric Diaphyseal Forearm Fractures Treated With Bioabsorbable Compared to Titanium Intramedullary Nails: A Single-Center, Multi-Blinded, Randomized Parallel-Group, Non-Inferiority Study
Phase: NA
Conditions: Forearm Injuries, Radius Fractures, Ulna Fractures, Fractures, Bone, Child, Adolescent, Fracture Fixation, Intramedullary, Internal Fixation, Orthopedic Operations, Polymers, Fracture Healing, Radiography, Randomized Controlled Trial (RCT)
Sponsor: Children's Fractures Interest Group, Denmark

NCT Number: NCT07536581 | Protocol ID: 16-0302-99 
ClinicalTrials.gov Document Cover Page 
 
Official Title: 
Time To Radiographic Union In Displaced Pediatric Diaphyseal 
Forearm Fractures Treated With Bioabsorbable Versus 
Titanium Intramedullary Nails: A Single-Center, Randomized, 
Blinded, Parallel-Group, Non-Inferiority Trial (FOREST Trial) 
Short title: 
Time to healing in displaced pediatric diaphyseal forearm 
fractures treated with bioabsorbable compared to titanium 
intramedullary nails 
Very short title: 
Time to healing in pediatric diaphyseal forearm fractures 
Trial acronym: 
FOREST Trial - Forearm Randomized Study of ESIN Technique 
– Bioabsorbable versus Titanium Implants 
NCT Number: 
NCT07536581 
Unique Protocol ID: 
16-0302-99 
Document Date: 
31 March 2026 
Document Version: 
Version 1.1 
Sponsor/Institution: 
Copenhagen University Hospital, Herlev and Gentofte 
 
This document is submitted in accordance with ClinicalTrials.gov requirements. The above 
information identifies the study and document version for regulatory and public record 
purposes. 

FOREST Trial - Time to healing in pediatric diaphyseal forearm fractures | Trial ID: 16-0302-99 
Clinical Investigation Plan (CIP) 
 
Version 1.1 - FINAL | 31 March 2026 | Confidential – For authorized use only 
Page 1 of 66 
 
 
1 
 
2 
Forearm Randomized study of  
3 
Elastic Stable intramedullary nailing Technique  
4 
- bioabsorbable versus titanium implants 
5 
 
6 
Full title 
7 
Time To Radiographic Union In Displaced Pediatric Diaphyseal Forearm Fractures Treated With 
8 
Bioabsorbable Versus Titanium Intramedullary Nails: A Single-Center, Randomized, Blinded, Parallel-
9 
Group, Non-Inferiority Trial 
10 
Clinical Investigation Plan 
11 
Trial number: 16-0302-99 
12 
File name:  
13 
2026-04-17__PED-FOREARM-IMN-RCT__Protocol__ClinicalInvestigationPlan__v1.2__FINAL.docx/pdf 
14 
Version and date: Version 1.2 FINAL, 31.03.2026 
15 
 
16 
Principal Coordinating Investigator 
Morten Jon Andersen, MD 
Department of Orthopedic Surgery 
Copenhagen University Hospital - Herlev and Gentofte 
Copenhagen, Denmark 
Phone 
+45 38 68 14 79 
Mobile 
+45 26 14 86 24 
E-mail 
morten.jon.andersen@regionh.dk 
Sponsor 
Department of Orthopedic Surgery 
Copenhagen University Hospital - Herlev and Gentofte 
Copenhagen, Denmark 
The Danish Data Protection Agency ID: P-2022-315 
The Danish National Committee On Health Research Ethics ID: 16-0302-99 
ClinicalTrials.gov ID: NCT07536581 
 
17 
Confidentiality statement 
18 
The information provided in this document is strictly confidential and is available for review to 
19 
investigators, potential investigators and appropriate Ethics Committees (EC). No disclosure should 
20 
take place without written authorization from the sponsor, except to the extent necessary to obtain 
21 
informed consent from potential patients. 
 
22 

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Clinical Investigation Plan (CIP) 
 
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Page 2 of 66 
 
Version Date 
Author Description of Changes 
Approved by 
1.0 
2026-02-05 MJA 
Initial version 
MJA 
1.1 
2026-03-31 MJA 
Minor revisions based on EC review MJA 
1.2 
2026-04-17 MJA 
Added ClinicalTrials.gov ID 
MJA 
 
 
23 

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Clinical Investigation Plan (CIP) 
 
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Page 3 of 66 
 
Content 
24 
 
25 
Abbreviations/glossary ........................................................................................................................... 6 
26 
Definitions ............................................................................................................................................... 7 
27 
1 Synopsis ............................................................................................................................................ 8 
28 
2 Rationale and purpose of the study ................................................................................................ 13 
29 
3 General information/responsibilities ................................................................................................ 13 
30 
3.1 Responsibilities ........................................................................................................................ 14 
31 
3.2 Study site ................................................................................................................................. 14 
32 
4 Background and literature review .................................................................................................... 14 
33 
4.1 Definition and epidemiology .................................................................................................... 14 
34 
4.2 Fracture repair ......................................................................................................................... 15 
35 
4.3 Treatment options .................................................................................................................... 15 
36 
4.4 Metal implant removal in children ............................................................................................ 17 
37 
4.5 The burden of surgery ............................................................................................................. 17 
38 
4.6 Current status of research in this area .................................................................................... 17 
39 
5 Primary and secondary objectives .................................................................................................. 18 
40 
5.1 Primary objective ..................................................................................................................... 18 
41 
5.2 Secondary objective(s) ............................................................................................................ 18 
42 
5.3 Hypothesis ............................................................................................................................... 18 
43 
6 Study design .................................................................................................................................... 18 
44 
6.1 Study population and patient enrollment ................................................................................. 19 
45 
6.2 Study procedures ..................................................................................................................... 22 
46 
6.3 Study treatments ...................................................................................................................... 27 
47 
7 Definitions of outcome measures and study variables .................................................................... 33 
48 
7.1 Primary outcome ...................................................................................................................... 33 
49 
7.2 Secondary outcomes ............................................................................................................... 35 
50 
7.3 Required diagnostic procedures .............................................................................................. 39 
51 
8 Statistical planning .......................................................................................................................... 39 
52 
8.1 Non-inferiority hypotheses (primary estimand) ........................................................................ 40 
53 
8.2 Sample size considerations ..................................................................................................... 40 
54 
8.3 Statistical analysis ................................................................................................................... 42 
55 
9 Risk analysis .................................................................................................................................... 44 
56 
9.1 Treatment-related risks ............................................................................................................ 44 
57 

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9.2 Study disadvantages ............................................................................................................... 45 
58 
9.3 Study-related risks ................................................................................................................... 45 
59 
9.4 Loss of privacy ......................................................................................................................... 46 
60 
9.5 Actions to minimize increased risks ......................................................................................... 46 
61 
10 Informed consent process ............................................................................................................... 46 
62 
10.1 Where? When? By whom? ...................................................................................................... 46 
63 
10.2 How? ........................................................................................................................................ 46 
64 
10.3 Patient and Public Involvement - Involvement of children and parents from the pilot study ... 47 
65 
10.4 Voluntariness ........................................................................................................................... 47 
66 
10.5 Assessor .................................................................................................................................. 47 
67 
10.6 Consideration time ................................................................................................................... 47 
68 
10.7 Electronic Informed consent form (eICF) ................................................................................. 48 
69 
11 Adverse event reporting .................................................................................................................. 48 
70 
11.1 Definitions ................................................................................................................................ 48 
71 
11.2 Adverse event documentation ................................................................................................. 50 
72 
11.3 Serious adverse event reporting .............................................................................................. 50 
73 
11.4 Follow-up of adverse events .................................................................................................... 51 
74 
11.5 Adverse event review .............................................................................................................. 51 
75 
11.6 Device deficiency reporting ..................................................................................................... 52 
76 
11.7 Device deficiency review ......................................................................................................... 52 
77 
12 Data management ........................................................................................................................... 53 
78 
12.1 Data collection, source data, storage, and archiving ............................................................... 53 
79 
12.2 Imaging data ............................................................................................................................ 54 
80 
12.3 Confidentiality .......................................................................................................................... 54 
81 
13 Study management and quality control ........................................................................................... 54 
82 
13.1 Contract Research Organization ............................................................................................. 54 
83 
13.2 Training and organization at the study site .............................................................................. 54 
84 
14 Monitoring and safety oversight ...................................................................................................... 54 
85 
15 Regulatory affairs ............................................................................................................................ 55 
86 
16 Ethics ............................................................................................................................................... 55 
87 
17 Patient insurance ............................................................................................................................. 56 
88 
18 Study report and publication policy ................................................................................................. 56 
89 
18.1 Final Study Report ................................................................................................................... 56 
90 
18.2 Publication ............................................................................................................................... 56 
91 

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19 Termination criteria .......................................................................................................................... 56 
92 
19.1 Stopping rules .......................................................................................................................... 57 
93 
20 Disclosures and economy ............................................................................................................... 57 
94 
21 Deviations from the Clinical Investigation Plan ............................................................................... 57 
95 
22 Amendments to the Clinical Investigation Plan ............................................................................... 58 
96 
23 Time schedule ................................................................................................................................. 58 
97 
24 Authors ............................................................................................................................................ 58 
98 
25 Reference list................................................................................................................................... 59 
99 
Appendix 1 - CIP approval.................................................................................................................... 63 
100 
Appendix 2 - Study flowchart and allocation ........................................................................................ 64 
101 
Appendix 3 - Device table (Investigational device and comparator) .................................................... 65 
102 
 
103 
 
 
104 

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Abbreviations/glossary 
105 
 
106 
AE/SAE 
Adverse Event(s)/Serious Adverse Event(s) 
ADE/SADE 
Adverse Device Event(s)/Serious Adverse Device Event(s) 
BIN 
Bioabsorbable Intramedullary Nails (PLGA) 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
DICOM 
Digital Imaging and Communications in Medicine 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ESIN 
Elastic Stable Intramedullary Nails (metal) 
FDA 
Food and Drug Administration 
FSR 
Final Study Report 
FU(s) 
Follow-up(s), eg follow-up visit(s), follow-up procedure(s) 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IMP 
Investigational Medical Device 
ISF 
Investigator Site File 
ISO 
International Organization for Standardization 
ITT 
Intention to treat 
LOR 
Loss of (fracture) reduction  
PI 
Principal Investigator 
PP 
Per Protocol 
PDFF 
Pediatric Diaphyseal Forearm Fracture 
SAP 
Statistical Analysis Plan 
SC 
Study Coordinator 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure  
U(S)ADE 
Unanticipated (Serious) Adverse Device Effect 
WHO 
World Health Organization 
 
 
107 

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Definitions 
108 
Baseline 
Status post injury but pretreatment 
Discharge 
Discharge from pediatric department 
Enrolled 
Patients with written informed consent who commenced treatment within 
the study 
Follow-up visit 
FU; visit at predefined times after the treatment day 
Follow-up 
population 
Patients intended to be followed-up (i.e. enrolled population) 
Parents 
For readability, the term “parents” will be used throughout this protocol to 
refer to the participant’s parent(s) and/or legal guardian(s), unless 
otherwise specified 
Pre-injury 
Status before the injury (retrospectively assessed data) 
Treatment day 
"Day 0"; day of operation/reduction 
Written informed 
consent 
Legally binding signature on the informed consent form (ICF) (by the 
legally authorized representative), whereas the person who signs the ICF 
can understand the content of the patient information has signed and 
dated the EC approved written informed consent 
 
 
109 

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1 
Synopsis 
110 
Official title 
Time to healing in displaced pediatric diaphyseal forearm fractures treated with 
bioabsorbable compared to titanium intramedullary nails: a single-center, multi-
blinded, randomized parallel-group, non-inferiority study 
Short title 
Time to healing in displaced pediatric diaphyseal forearm fractures treated with 
bioabsorbable compared to titanium intramedullary nails 
Very short title 
Time to healing in pediatric diaphyseal forearm fractures 
Trial acronym 
FOREST Trial - Forearm Randomized Study of ESIN Technique – 
Bioabsorbable versus Titanium Implants 
Trial logo 
Sponsor 
Department of Orthopedic Surgery 
Copenhagen University Hospital – Herlev and Gentofte  
Borgmester Ib Juuls Vej 1 
2730 Herlev 
Denmark 
Registration 
The Danish Data Protection Agency ID: P-2022-315 
The Danish National Committee On Health Research Ethics ID: 16-0302-99 
Clinicaltrials.gov: NCT ID not yet assigned – pending review 
Background and 
purpose 
Pediatric forearm fractures are the most common fractures in children and are a 
leading cause of orthopedic healthcare contact. 
Displaced diaphyseal forearm fractures requiring operative stabilization are 
most treated with titanium elastic nails (TEN). Although this fixation works well, 
routine implant removal after about 6–12 months is often recommended, 
requiring an additional operation that—while usually low risk—still places a 
significant burden on the child and family and uses healthcare resources. 
Bioabsorbable intramedullary nails (BIN) have been developed for similar 
indications and may eliminate the need for elective implant removal, thereby 
reducing reoperations and associated costs. Clinical experience and early 
studies indicate that BIN are safe and feasible; however, BIN are more flexible 
than titanium implants, which may theoretically increase the risk of delayed 
union. 
The purpose of this trial is to determine whether time to radiographic healing 
after fixation with BIN is non-inferior to that achieved with TEN. 
As no prior studies have directly compared time to healing between these 
implant types using a standardized radiographic healing metric, establishing 
non-inferior healing is essential before broader implementation of BIN as 
standard treatment. 

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Clinical Investigation Plan (CIP) 
 
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Condition 
Displaced Pediatric Diaphyseal Forearm Fractures (PDFF) 
Investigational 
Medical Device 
Activa IM-Nail™ (Bioretec Ltd., Tampere, Finland) 
Comparator 
Titanium Elastic Nail System (Synthes GmbH, Oberdorf, Switzerland) 
Study type 
Interventional 
Study design 
Single-center, randomized (1:1), parallel-group, blinded, non-inferiority clinical 
investigation comparing bioabsorbable intramedullary nails (BIN) versus 
titanium elastic nails (TEN). 
Primary objective 
To demonstrate that time to radiographic healing is non-inferior after BIN 
compared with TEN. 
Secondary 
objective(s) 
To compare the two groups with respect to: 
 Pain and discomfort 
 Return to physical and recreational activities 
 Emotional and psychosocial wellbeing 
 Complications from the injury and its treatment 
 Return to baseline activities daily living 
 Participation in learning 
 Appearance and deformity 
 Recovery of manual dexterity (for upper limb fracture) 
 Cost to family 
 Ability to sleep 
 Range of motion 
 The cost of treatment 
 Child satisfaction 
Hypothesis 
Time to radiographic healing after BIN is non-inferior to that after TEN. 
Primary outcome 
measure 
Time to radiographic healing, defined as time from surgery/randomization to 
achieving mRUS ≥ 11. 
Healing is assessed on plain anteroposterior (AP) and mediolateral (ML) 
radiographs and objectively quantified using the modified Radiographic Union 
Score (mRUS). 
Secondary outcome 
measure(s) 
 Range of motion (degrees) measured by goniometer 
 Grip strength measured by dynamometer 
 Faces Pain Scale – Revised (FPS-R) 
 Questions from the Nationwide Survey of Patient Experiences 
 Complications, reoperations, and adverse events (AEs) related to the 
procedure and/or implants 
 Pediatric and Danish version of EQ-5D (EQ-5D-Y) 
 Motor function assessment: Movement Assessment Battery for Children – 
Third Edition (MABC-3), Manual Dexterity domain 

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Statistical 
considerations and 
estimated enrollment 
A statistician from the University of Copenhagen contributed to the trial design, 
including selection of statistical methods and the sample size/power 
calculations. 
 
This is a randomized, parallel-group, non-inferiority study with equal allocation 
(1:1). The primary endpoint is time to healing, defined as the time from surgery 
to achieving mRUS ≥ 11. 
 
The non-inferiority margin was selected based on clinical judgement and 
available evidence and was further contextualized by parent input from the pilot 
cohort regarding the maximum acceptable additional weeks of activity 
restriction (beyond the usual 6 weeks) in exchange for avoiding a second 
implant removal operation. We set the non-inferiority margin ∆ = 3 weeks. 
 
With a non-inferiority margin ∆ = 3 weeks, the hypotheses are: 
𝐻0: θ ≥∆ (BIN is inferior to TEN by ≥ 3.0 weeks) 
𝐻1: θ < ∆ (BIN is non-inferior to TEN) 
 
Sample size 
Significance level 
0.025 
Power (1-β) 
0.9 
Ratio of sample size 
1:1 
Standard deviation (SD) 
3 weeks 
Non-inferiority margin (∆) 
3 weeks 
Loss to follow-up/withdrawal (%) 
5 
Intercurrent events (%) 
5 
Result 
Sample size per group 
22 
Sample size per group incl. attrition 
25 
Total sample size incl. attrition 
50 
 
The required sample size is 25 per group; to ensure operational robustness we 
will enroll 30 per group (total 60). 
Start of enrollment 
May 2026 (estimated) 
Last patient/last visit 
May 2029 (estimated) / May 2031 (estimated) 

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Eligibility inclusion 
criteria 
 Children aged 3–13 years with open physes 
 Diagnosis of a traumatic diaphyseal forearm fracture of the radius, ulna, or 
both 
 Operative fixation required. Fractures must be: 
– complete (not unicortical or greenstick) 
AND 
– displaced >50% of bone width (after attempted closed reduction) 
AND/OR 
– angulated >10° in any plane (after attempted closed reduction) 
 Informed consent obtained, i.e.: 
– Willingness and ability to participate in the clinical investigation according 
to the Clinical Investigation Plan (CIP) 
– Parents able to understand the content of the patient information and 
informed consent form 
– Signed and dated EC-approved electronic informed consent form 
Eligibility exclusion 
criteria 
Preoperative exclusion criteria 
 Contraindication 
– Conditions where internal fixation is contraindicated (e.g. active or 
potential infection)  
– Grossly open fractures (Gustilo Anderson grade > 2) 
 
 Exclusion criteria 
– Fracture occurred more than 2 weeks prior 
– Fractures that are well managed conservatively (undisplaced or 
minimally displaced) 
– Previous ipsilateral forearm fracture (risk of closed medullary canal) 
– Fractures unsuited for intramedullary nailing (e.g. multifragmentary, 
metaphyseal or epiphyseal) 
– Concurrent ipsilateral wrist or elbow involvement (e.g. Monteggia or 
Galeazzi variants) 
– Unable to participate in follow-up 
– Existing bone pathology (e.g. tumor, osteogenesis imperfecta, 
degenerative disease) 
 
 Participation in any other medical device or medicinal product study within the 
previous month that could influence in opinion of the PI the results of the 
present study 
 
Intraoperative exclusion criteria 
 Fractures suitable for closed reduction and casting (see 6.3.9) 
 Indication for treatment 1 (BIN) only 
 Indication for treatment 2 (ESIN) only 
 Intraoperative decision to use implants other than the devices under 
investigation 
– E.g. plate fixation or external fixation 

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Study site 
Department of Orthopedic Surgery 
Copenhagen University Hospital – Herlev and Gentofte 
Copenhagen, Denmark 
Health authority 
The Danish National Committee On Health Research Ethics 
Imaging review 
All masked radiographs will be assessed by independent blinded radiologists 
and orthopedic surgeons during the study. 
 
111 
 
 
112 

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2 
Rationale and purpose of the study 
113 
Bioabsorbable intramedullary nails (BIN) are a feasible and seemingly safe option for the surgical 
114 
treatment of displaced pediatric diaphyseal forearm fractures (PDFF). The key potential advantage of 
115 
BIN compared with titanium elastic intramedullary nails (TEN) is the avoidance of routine secondary 
116 
surgery for implant removal. 
117 
 
118 
The operative technique for BIN and TEN is largely similar and is expected to entail a comparable 
119 
perioperative risk profile. However, BIN are more flexible than titanium implants and may, in theory, 
120 
provide less mechanical stability, which could increase the risk of delayed union. To date, no 
121 
comparative studies have evaluated time to bone union between BIN and TEN in this population. 
122 
 
123 
The primary aim of this study is to compare time to bone union in PDFF treated surgically with BIN 
124 
versus TEN. 
125 
 
126 
A single-center, randomized, parallel-group, non-inferiority design with blinding of relevant parties has 
127 
been chosen. Given the clinically meaningful benefit of BIN in avoiding a second operation, the study is 
128 
designed to determine whether BIN results in an acceptable (non-inferior) time to union compared with 
129 
TEN, allowing for a limited delay in union if balanced by the avoidance of implant removal surgery. 
130 
 
131 
All interventions are performed according to standard of care and within the approved indications for 
132 
each device. 
133 
3 
General information/responsibilities 
134 
The responsibilities of the sponsor and investigators are defined in accordance with the International 
135 
Council for Harmonisation Good Clinical Practice (ICH-GCP) and ISO 14155. Study-specific 
136 
requirements, including approvals from the responsible ethics committee (EC), are described elsewhere 
137 
in this Clinical Investigation Plan (CIP). The study site undertakes to ensure the correct and timely 
138 
conduct of the study, including accurate documentation and secure transmission of study data. 
139 
 
140 
Prior to initiation of participant enrollment, the Principal Investigator (PI) and the research team will be 
141 
instructed and trained in the conduct of the study to confirm their capability to meet the required quality 
142 
standards and to comply with applicable standard operating procedures (SOPs). 
143 
 
144 
The study site will ensure completion of study documentation for all enrolled participants. “Complete 
145 
documentation” means that all scheduled follow-up (FU) visits have been performed, that assessments 
146 
are recorded in the electronic case report forms (eCRFs) developed for this study, and that required 
147 
radiological investigations have been obtained at the FU visits. 
148 

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3.1 
Responsibilities 
149 
Principal Coordinating Investigator 
Morten Jon Andersen 
MD 
Department of Orthopedic Surgery 
Copenhagen University Hospital 
– Herlev and Gentofte 
Copenhagen, Denmark 
Phone +45 38 68 14 79 
Mobile +45 26 14 86 24 
E-mail morten.jon.andersen@regionh.dk 
Sponsor 
Department of Orthopedic Surgery 
Copenhagen University Hospital 
– Herlev and Gentofte 
Copenhagen, Denmark 
3.2 
Study site 
150 
Department of Orthopedic Surgery 
151 
Copenhagen University Hospital – Herlev and Gentofte 
152 
Copenhagen, Denmark 
153 
4 
Background and literature review 
154 
Forearm fractures are the most common fractures in children and the most frequent reason for 
155 
orthopedic assessment. For most pediatric fractures, casting remains the standard of care because 
156 
children’s bones have a substantial capacity to remodel after union, allowing acceptable healing with 
157 
greater angulation or displacement than would be tolerated in adults without long-term functional 
158 
consequences. When forearm fractures exceed remodeling potential, early closed reduction by 
159 
manipulation is generally the preferred treatment. Fractures that are not amenable to closed 
160 
management, cannot be reduced closed, or re-displace during follow-up will often require operative 
161 
stabilization [1,2]. 
162 
 
163 
Forearm fractures requiring surgical stabilization are commonly treated with elastic stable intramedullary 
164 
nailing technique (ESIN), typically using titanium elastic intramedullary nails (TEN) [3]. Removal of TEN 
165 
after 6–12 months is generally advocated [3–5]. Although implant removal is usually associated with few 
166 
complications, it represents a substantial burden for the child and family and consumes healthcare 
167 
resources [6]. Bioabsorbable intramedullary nails (BIN) have been developed for similar indications. 
168 
Because bioabsorbable implants dissolve, they spare the child a second operation and potentially 
169 
reduce overall healthcare costs [7]. 
170 
 
171 
4.1 
Definition and epidemiology 
172 
Fractures constitute 10–25% of all pediatric injuries. During childhood, at least 50% of boys and 30% of 
173 
girls will sustain a fracture. Fracture type, pattern, and mechanism vary between countries [8]. Pediatric 
174 
diaphyseal forearm fractures (PDFF) of the radius and/or ulna are among the most common reasons for 
175 
orthopedic care in children [9]. With an incidence of 6.8 per 10,000 children (8.3 for boys and 5.2 for 
176 

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girls), this injury accounts for approximately 3–6% of all pediatric fractures [8,9] and occurs primarily 
177 
between the ages of 5 and 14 years (median 8.5 years) [10]. 
178 
 
179 
Over the past three decades, the incidence of these fractures has increased markedly; however, the 
180 
precise cause remains unknown [8,11]. Proposed explanations include physical inactivity, obesity, and 
181 
vitamin D deficiency, potentially contributing to lower bone mineral density and an increasing number of 
182 
pediatric fractures [12]. 
183 
4.2 
Fracture repair 
184 
A fracture disrupts the structural continuity of the cortical bone. The biology of fracture repair and bone 
185 
healing is complex and not fully understood, but it aims to restore the injured bone to its pre-injury 
186 
structure and composition. Following a complete fracture, secondary bone healing typically occurs 
187 
through the stages summarized in Figure 1. 
188 
 
189 
 
190 
 
191 
Figure 1 - Stages of fracture healing. Hematoma formation, immediately following fracture. Granulation tissue formation, within 
192 
two weeks of fracture. Bony callus formation, within two to four weeks in children. Bone remodeling, continues for months to years 
193 
after clinical union. Case courtesy of Matt Skalski, Radiopaedia.org, rID: 57418 
194 
4.3 
Treatment options 
195 
Because of the complex functional relationship between the radius and ulna, prognosis depends on 
196 
fracture healing without excessive shortening, rotational deformity, or angulation. Minimally displaced 
197 
PDFF can be managed successfully with closed reduction and casting [13]. However, over the past two 
198 
decades there has been a significant increase in the proportion of operatively managed fractures [14]. 
199 
Non-operative management is generally considered acceptable when angulation is <10°, rotational 
200 
deformity is <30°, and translation is <100%. Re-displacement in a cast occurs in approximately 10% of 
201 
cases and may necessitate re-reduction or surgical fixation [13,15]. 
202 
 
203 
As for many fracture types, expectations for outcomes have increased over the past two decades, 
204 
particularly with respect to motion of the elbow, forearm, and wrist. In 1981, a functional range of motion 
205 
was described as elbow flexion/extension of 30–130 degrees and forearm rotation of 50 degrees of 
206 
pronation and 50 degrees of supination [16]; however, that study did not include children. More recent 
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studies suggest that contemporary activities such as using a mobile phone, tablet, or computer 
208 
keyboard may require additional range of motion [17,18]. Increasing functional demands, together with 
209 
parental expectations and socioeconomic factors, may therefore expand the indications for surgical 
210 
stabilization of PDFF. 
211 
 
212 
The most common methods for treating unstable PDFF include closed or open reduction with elastic 
213 
stable intramedullary nailing (ESIN) technique using titanium or steel nails, or open reduction and 
214 
internal fixation (ORIF) using plates and screws [15]. ORIF provides excellent reduction and stable 
215 
fixation but requires greater soft-tissue dissection and is often followed by implant removal. There is no 
216 
conclusive evidence favoring one surgical method over another; however, with the introduction of 
217 
minimally invasive ESIN, the use of this technique has increased substantially and it is now widely 
218 
regarded as the preferred operative approach [11,14,15,19]. 
219 
4.3.1 
Closed reduction and casting 
220 
Slightly angulated or minimally displaced PDFF should be treated non-operatively. Fractures that 
221 
exceed the acceptable limits of angulation, rotation, or displacement (as described above) should be 
222 
managed with attempted closed manipulation/reduction followed by a well-molded circumferential 
223 
above-elbow cast for 6-8 weeks. This approach yields good to excellent results in approximately 80% of 
224 
cases, while the remainder require re-reduction or surgical fixation [20]. 
225 
4.3.2 
Metal Elastic Stable Intramedullary Nailing (ESIN) 
226 
Elastic stable intramedullary nailing (ESIN) technique was introduced in the 1970s, initially using 
227 
Kirschner wires. In the 1990s, implants specifically designed for ESIN became widely available. Since 
228 
then, ESIN has been shown to produce excellent results with relatively few complications [4,21]. 
229 
Advantages include possible closed fracture reduction, minimal soft-tissue dissection, early mobilization, 
230 
maintenance of reduction, and straightforward implant removal. Complications are uncommon but 
231 
include soft-tissue irritation, superficial radial nerve injury, extensor pollicis longus tendon rupture, 
232 
delayed union, malunion, refracture, and infection [3,15,22,23]. 
233 
 
234 
Several metallic alloys have been used for ESIN implants. The most widely used are titanium and steel 
235 
which has favorable elastic properties [4]. 
236 
4.3.3 
Bioabsorbable implants 
237 
It is important to use a consistent and unified nomenclature within this research field. Liu et al. [24] 
238 
suggest that implants or biomaterials that are ultimately absorbed by the body should be labeled 
239 
“absorbable” or use the prefix “bio-”. The term “absorbable” emphasizes host metabolism of the 
240 
degradation products of the implanted material. In this study protocol and the final manuscript, we will 
241 
use the term “bioabsorbable” throughout. 
242 
 
243 
Bioabsorbable implants have been used since the 1970s, and numerous materials have been 
244 
investigated over time. Their use is increasing and has been shown to be a safe and feasible method for 
245 
stabilizing fractures in the growing skeleton [25–27]. By using bioabsorbable implants, the need for 
246 
routine implant removal is avoided, and the risks of late tissue reactions, stress shielding, and infection 
247 
may be reduced [28]. 
248 
 
249 
Implants manufactured from oriented poly(lactic-co-glycolic acid) (PLGA) copolymers are sufficiently 
250 
strong to support fractured bone. PLGA is composed of lactic acid and glycolic acid monomers, which 
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are part of normal human metabolism. PLGA implants undergo controlled degradation by hydrolysis into 
252 
lactic acid and glycolic acid, which are subsequently metabolized to carbon dioxide and water. The 
253 
implant retains strength and dimensions for at least eight weeks, and complete absorption typically 
254 
occurs over approximately two to six years [29,30]. 
255 
4.4 
Metal implant removal in children 
256 
In children, implant removal, including removal of metal nails, is routinely performed and represents 
257 
standard practice in Denmark, sanctioned by the Danish Health Authority. Implant removal is 
258 
undertaken due to concerns about potential interference with skeletal growth, late tissue reactions, 
259 
difficulty of delayed removal, stress shielding related to implant stiffness, interference with future 
260 
orthopedic procedures, and corrosion [31]. Removal of ESIN is associated with a low complication rate 
261 
of approximately 3% [32]. In some countries it is standard to leave metal implants, even in children. 
262 
4.5 
The burden of surgery 
263 
As noted above, surgical implant removal is generally associated with few complications; however, it 
264 
represents a substantial burden for the child and family and consumes healthcare and societal 
265 
resources. 
266 
4.5.1 Operative anxiety in children 
267 
It has been shown that 50–70% of children experience significant anxiety and stress prior to surgery 
268 
[33–35]. There is also evidence suggesting an association between preoperative anxiety and adverse 
269 
postoperative outcomes, including emergence delirium, increased analgesic requirements, and negative 
270 
behavioral changes [36]. In general, fear in children may be related to several factors, including 
271 
separation from parents, an unfamiliar and potentially threatening hospital environment, painful 
272 
procedures, the operation itself, and anesthesia. Operative anxiety in children should be prevented not 
273 
only for humanitarian reasons, but also to reduce anxiety-related psychological distress and potential 
274 
longer-term negative effects. 
275 
4.5.2 Economic burden and time away 
276 
The cost of one Activa IM-Nail™ (approximately $400) is about four times higher than that of a 
277 
traditional titanium elastic nail (TEN; approximately $100). However, the cost of implant removal is 
278 
approximately $1,900 [6,37], and the additional implant cost may therefore be offset. In a cost analysis 
279 
that included both direct medical costs and indirect costs related to lost work time, the average cost 
280 
saved per patient by using absorbable implants ranged from $410 to $903 [37]. 
281 
 
282 
Removal surgery is not only a socioeconomic concern. Parents typically need time off work for 
283 
outpatient visits related to surgical planning, on the day of surgery, and potentially for days after 
284 
treatment. This may create financial strain and, in some cases, concerns regarding job security. 
285 
Similarly, the child will require time away from school. 
286 
4.5.3 Operation room burden 
287 
Because most implants in children are routinely removed, implant removal procedures consume 
288 
substantial operating room capacity. Use of bioabsorbable implants may reduce the need for elective 
289 
removal surgery, thereby freeing capacity for other procedures. 
290 
4.6 
Current status of research in this area 
291 
To assess feasibility and safety, we conducted a prospective preliminary study including 18 children 
292 
with forearm fractures treated with bioabsorbable intramedullary nails (BIN). No serious adverse events 
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or serious adverse device effects were observed. All fractures healed, and all children regained normal 
294 
arm function within 3 months. 
295 
 
296 
An international multicenter study of 76 children treated with the Activa IM-Nail reported few 
297 
complications. In two cases, a small implant fragment was sheared off by the sharp fracture edge, 
298 
necessitating secondary surgery for fragment removal. The Activa IM-Nail Technique Guide has 
299 
subsequently been revised to emphasize additional caution when advancing the nail across the fracture 
300 
site and to recommend only light hammer blows [38]. 
301 
 
302 
In Finland, the Activa IM-Nail has been investigated since 2011 in a randomized controlled trial 
303 
comparing BIN with TEN. Both short- and long-term follow-up demonstrated similarly good outcomes 
304 
[7,30]. 
305 
 
306 
To date, no studies have evaluated differences in time to bone union when comparing BIN with TEN. 
307 
Furthermore, time to healing in PDFF has not been rigorously investigated in a prospective setting. 
308 
5 
Primary and secondary objectives 
309 
5.1 
Primary objective 
310 
 To investigate time to bone healing (weeks) in PDFF treated with bioabsorbable intramedullary nails 
311 
(BIN) versus titanium elastic intramedullary nails (TEN). 
312 
5.2 
Secondary objective(s) 
313 
 To investigate and describe 
314 
– Functional outcome 
315 
– Pain and discomfort 
316 
– Refracture rate 
317 
– Surgical complications 
318 
– Implant-related complications 
319 
– Patient-reported outcomes 
320 
– Costs related to surgery 
321 
 To investigate time to bone healing (weeks) in PDFF treated non-operatively 
322 
5.3 
Hypothesis 
323 
We hypothesize that time to bone healing with BIN is non-inferior to time to bone healing with TEN in 
324 
the treatment of PDFF. 
325 
6 
Study design 
326 
Given the potential advantages of bioabsorbable intramedullary nails (BIN), it is clinically acceptable for 
327 
BIN to have a limited delay in healing compared with TEN, provided overall outcomes remain 
328 
acceptable. Therefore, this study is designed as a non-inferiority trial. 
329 
 
330 
A single-center, randomized, parallel-group, non-inferiority design with blinding of relevant parties has 
331 
been selected, with stratification by age. The study design will follow CONSORT guidance for reporting 
332 
non-inferiority trials [39]. 
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6.1 
Study population and patient enrollment 
334 
The study will be conducted at Copenhagen University Hospital – Herlev and Gentofte, Capital Region 
335 
of Denmark. The hospital has a catchment area of approximately 600,000 inhabitants, including about 
336 
80,000 children aged 3–13 years. 
337 
 
338 
This study investigates the treatment of pediatric forearm fractures and therefore cannot be conducted 
339 
in consenting adults. Forearm fractures occur across all pediatric age groups, and it is not feasible to 
340 
restrict inclusion to older children only. The study is expected to have potential direct benefit for 
341 
participating patients and to generate knowledge that may improve care for future patients with the 
342 
same condition. 
343 
 
344 
Initial assessment in the emergency department will follow standard of care and will be independent of 
345 
subsequent treatment allocation. The assessment includes medical history, physical examination, and 
346 
radiographs in anteroposterior (AP) and mediolateral (ML) projections. 
347 
 
348 
All operations will be performed at Herlev Hospital by orthopedic trauma surgeons. 
349 
6.1.1 
Inclusion criteria 
350 
The inclusion criteria are aligned with the existing literature for the comparator (TEN). 
351 
 
352 
Inclusion criteria 
353 
 Children aged 3 to 13 years with open physes 
354 
 Acute traumatic pediatric diaphyseal forearm fracture (PDFF) of the radius, ulna, or both 
355 
 Fracture characteristics: 
356 
– Complete fracture (not unicortical or greenstick) 
357 
– Displacement >50% of bone width, and/or angulation >10° in any plane 
358 
 Written informed consent obtained, including: 
359 
– Ability of the parent(s) to understand the patient information and informed consent form (eICF) 
360 
– Signed and dated ethics committee (EC)-approved eICF 
361 
6.1.2 
Preoperative exclusion criteria 
362 
 Contraindications 
363 
– Any condition in which internal fixation is contraindicated (e.g., active or suspected infection) 
364 
– Grossly open fractures (Gustilo–Anderson grade > II) 
365 
 
366 
 Exclusion criteria 
367 
– Fracture occurred more than 2 weeks prior 
368 
– Previous ipsilateral forearm fracture (risk of an obliterated/closed medullary canal) 
369 
– Fractures not suitable for intramedullary nailing (e.g., multifragmentary, metaphyseal, or 
370 
epiphyseal fractures) 
371 
– Concurrent ipsilateral wrist or elbow involvement (e.g., Monteggia or Galeazzi variants) 
372 
– Inability to participate in follow-up (e.g., no Danish CPR number/contact information, plans to 
373 
move away within 3 months, or inability to attend visits despite offered scheduling flexibility) 
374 
– Pre-existing bone pathology (e.g., tumor, osteogenesis imperfecta, or other bone disease 
375 
affecting bone quality/healing) 
376 
– Participation in another medical device or medicinal product study within the previous month that, 
377 
in the opinion of the Principal Investigator (PI), could influence the results of the present study 
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6.1.3 
Intraoperative exclusion criteria 
379 
 Intraoperative findings indicating that only Treatment 1 (BIN) is appropriate 
380 
 Intraoperative findings indicating that only Treatment 2 (TEN) is appropriate 
381 
 Intraoperative decision to use implants other than the investigational devices (e.g., plate fixation or 
382 
external fixation) 
383 
6.1.4 
Enrollment of participants 
384 
The study site will identify all eligible patients, defined as those who meet all inclusion criteria and none 
385 
of the exclusion criteria. 
386 
 
387 
6.1.4.1 Identification/prescreening 
388 
Potential participants may present to the Emergency Department (ED), the outpatient clinic (OC), or be 
389 
referred from local clinics or other hospitals. Identification of eligible patients will occur during direct 
390 
clinical contact in the ED or OC and/or through the routine daily review of radiographs obtained in the 
391 
ED and OC or by referral. 
392 
 
393 
6.1.4.2 Minimal screening log 
394 
A minimal screening log will be maintained to document the identification and flow of potentially eligible 
395 
patients and to support transparency in recruitment (e.g., reasons for non-enrollment). The screening 
396 
log will contain only the minimum necessary information to fulfil this purpose and will be kept separately 
397 
from the study database. 
398 
 
399 
For each prescreened patient, the log will include: 
400 
 a unique screening ID (assigned at prescreening) 
401 
 date of prescreening and the clinical point of identification (e.g., ED / outpatient review) 
402 
 eligibility status (eligible / not eligible / pending) 
403 
 primary reason for non-enrollment (e.g., not meeting inclusion/exclusion criteria, declined participation, 
404 
logistical reasons) 
405 
 whether informed consent was obtained (yes/no) and, if yes, date of consent 
406 
 
407 
The screening log will not include study outcomes or detailed clinical research data. To prevent 
408 
duplicate entries and enable follow-up of pending cases, linkage to the medical record is required; this 
409 
will be limited to a single linkage element (CPR number) and stored in an access-restricted manner. 
410 
Access to the screening log will be limited to authorized study personnel (PI and delegated research 
411 
staff) and it will be stored in a secure system (REDCap) with appropriate technical and organizational 
412 
safeguards. 
413 
 
414 
No study-specific data extraction beyond the minimal screening variables will occur prior to informed 
415 
consent. Screening log data will be retained in accordance with applicable regulatory and institutional 
416 
requirements and will be deleted or anonymized when no longer required. 
417 
 
418 
6.1.4.3 Assessment of eligibility 
419 
If a patient appears to be a candidate for enrollment, and in accordance with ethics committee (EC) 
420 
approval, the study team may contact the parents in person (in the ED or OC) to assess interest and 
421 
confirm the child’s eligibility for participation. This initial contact will include a brief prescreening to verify 
422 
key eligibility criteria and a concise description of the study, and the responsibilities associated with 
423 
participation. 
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 Eligible patients/parents will be offered a scheduled study visit as soon as possible. 
425 
 Parents will be informed that they may bring an accompanying person (e.g., a support person) to the 
426 
visit. 
427 
 
428 
6.1.4.4 Study information 
429 
If the parents express interest in participation, a member of the research team will conduct the informed 
430 
consent process face-to-face. The consent discussion will stress that any participation is completely 
431 
voluntary and will cover the purpose of the study, study procedures, potential risks and benefits, 
432 
alternatives to participation, and data protection. 
433 
 
434 
 Parents will receive both oral and written information. 
435 
 All parents will sign an electronic or written Informed Consent Form (eICF/wICF), as applicable. 
436 
 The signed e/wICF will be filed in the Investigator Site File (ISF), and a copy will be provided 
437 
electronically or written to all signatory. 
438 
 
439 
6.1.4.5 Place of recruitment 
440 
Participants will be recruited at Copenhagen University Hospital – Herlev and Gentofte by delegated 
441 
members of the research team. 
442 
 
443 
6.1.4.6 Informed consent 
444 
A more detailed description of the informed consent process is provided in Section 10. 
445 
 
446 
 All participants for whom written informed consent has been obtained will be assigned a unique trial 
447 
participant number. 
448 
 The date of informed consent and recruitment details will be recorded in the study database. 
449 
 Participants who commence any study treatment are considered enrolled. 
450 
 All enrolled participants will be followed within the study unless participation is terminated prematurely 
451 
for reasons specified in Section 6.2.17. 
452 
 
453 
6.1.4.7 Recruitment period 
454 
The recruitment period is estimated to be 36 months, based on the number of eligible patients managed 
455 
at our institution over the past 5 years. If recruitment targets are not met by 24 months, the recruitment 
456 
period will be extended by an additional 12 months. 
457 
 
 
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6.2 
Study procedures 
459 
The schedule of all follow-up (FU) visits, including imaging procedures, and the data to be collected at 
460 
each visit are presented in Table 1. 
461 
 
462 
Table 1: Study schedule 
463 
 
464 
Assessment 
parameters 
 
Pre- intra- and postoperative visits 
 
 
 
Day 
0 
 
Visit 
X** 
Visit 
1 
Visit 
2 
Visit 
3 
Visit 
Y*** 
Visit 
Z*** 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Injury 
Screening 
Pre-treatment 
visit 
Intraoperative 
Post-operative / 
reduction 
1 week 
2 weeks 
4 weeks 
6 weeks 
8 weeks 
10 weeks 
12 weeks 
6 months 
1 year 
2 years 
Screening/invitation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient information 
and consent 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Radiographs 
 
X 
 
 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone age 
radiograph 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Cast removal for 
ESIN group 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Cast removal for 
BIN group 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Cast removal for 
non-operative 
group 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Clinical exam 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Reported 
Outcome 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Test of Motor 
Proficiency 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
All postoperative visits with the defined time windows are calculated from the day of surgery/randomization or reduction (Day 0). 
465 
* Fluoroscopy 
466 
** For non-operative group only 
467 
*** Visit only completed if all fractures are not healed sufficiently at previous visit. 
 
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6.2.1 
Injury 
469 
On the day of injury, the patient is treated according to standard of care. The diagnosis is established on 
470 
standard forearm radiographs (anteroposterior and lateral views). An above-elbow splint is applied to 
471 
stabilize the fracture. 
472 
6.2.2 
Screening 
473 
The screening and inclusion process is described in detail in 6.1. 
474 
6.2.3 
Preoperative visit 
475 
The enrollment and informed consent process is described in Section 6.1.4 and Section 10, as well as 
476 
in the corresponding SOP. 
477 
 
478 
 All patients prescreened against the inclusion and exclusion criteria will be recorded in the Screening 
479 
Log described in Section 6.1.4.2. 
480 
 Screening and baseline data will be entered into the eCRF. 
481 
6.2.4 
Intraoperative (day 0) 
482 
 Confirmation of the indication for treatment and assessment of any contraindications that may have 
483 
arisen since the preoperative visit 
484 
 Verification of intraoperative exclusion criteria 
485 
 Assessment for any adverse events (AEs) since the preoperative visit, including documentation and 
486 
reporting as applicable 
487 
 Treatment as described in Section 6.3 
488 
 Randomization as described in Section 6.3.6 
489 
 Documentation of surgical details 
490 
 Source data verification and entry into the eCRF 
491 
6.2.5 
Postoperative/discharge 
492 
 Postoperative ward rounds 
493 
 Discharge according to the treatment protocol described in Section 6.3.8 and related SOP 
494 
 Documentation of discharge details 
495 
 Source data verification and entry into the eCRF 
496 
6.2.6 
Visit 1 (2 weeks) 
497 
 Assessment for any adverse events (AEs) since the previous visit, including documentation and 
498 
reporting as applicable 
499 
 Radiographs 
500 
 Cast removal for the titanium elastic nail (TEN) group, if applicable 
501 
 Clinical examination and outcome assessments as described in Section 7 
502 
 Source data verification and entry into the eCRF 
503 
 Scheduling of the next visit 
504 
 Appointment for the next visit 
505 
6.2.7 
Visit 2 (4 weeks) 
506 
 Assessment for any adverse events (AEs) since the previous visit, including documentation and 
507 
reporting as applicable 
508 
 Radiographs 
509 

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 Cast removal for the bioabsorbable intramedullary nail (BIN) group, if applicable 
510 
 Clinical examination and outcome assessments as described in Section 7 
511 
 Source data verification and entry into the eCRF 
512 
 Scheduling of the next visit 
513 
 Appointment for the next visit 
514 
6.2.8 
Visit 3 (6 weeks) 
515 
 Assessment for any adverse events (AEs) since the previous visit, including documentation and 
516 
reporting as applicable 
517 
 Radiographs 
518 
 Clinical examination and outcome assessments as described in Section 7 
519 
 Source data verification and entry into the eCRF 
520 
 Scheduling of the next visit: 
521 
– If bone healing is not sufficient, defined as an mRUS < 11 in any fractured bone, a follow-up visit 
522 
will be scheduled at 8 weeks postoperatively. 
523 
– If bone healing is sufficient (mRUS ≥ 11 in all fractured bones), the next visit will be scheduled at 
524 
3 months postoperatively. 
525 
6.2.9 
Visit X (8 weeks) 
526 
This visit is only performed if bone healing was not sufficient at Visit 3 (6 weeks), defined as mRUS < 11 
527 
in any fractured bone. 
528 
 
529 
 Assessment for any adverse events (AEs) since the previous visit, including documentation and 
530 
reporting as applicable 
531 
 Radiographs 
532 
 Clinical examination and outcome assessments as described in Section 7 
533 
 Source data verification and entry into the eCRF 
534 
 Scheduling of the next visit: 
535 
– If bone healing is not sufficient, defined as mRUS < 11 in any fractured bone, a follow-up visit will 
536 
be scheduled at 10 weeks postoperatively. 
537 
– If bone healing is sufficient (mRUS ≥ 11 in all fractured bones), the next visit will be scheduled at 
538 
3 months postoperatively. 
539 
6.2.10 Visit Y (10 weeks) 
540 
This visit is only performed if bone healing was not sufficient at Visit X (8 weeks), defined as mRUS < 11 
541 
in any fractured bone. 
542 
 
543 
 Assessment for any adverse events (AEs) since the previous visit, including documentation and 
544 
reporting as applicable 
545 
 Radiographs 
546 
 Clinical examination and outcome assessments as described in Section 7 
547 
 Source data verification and entry into the eCRF 
548 
 Scheduling of the next visit 
549 
6.2.11 Visit 6 (12 weeks) 
550 
 Assessment for any adverse events (AEs) since the previous visit, including documentation and 
551 
reporting as applicable 
552 

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 Radiographs 
553 
 Clinical examination and outcome assessments as described in Section 7 
554 
 Test of Motor Proficiency administered by an occupational therapist 
555 
 Source data verification and entry into the eCRF 
556 
 Scheduling of the next visit 
557 
6.2.12 Visit 7 (24 weeks ± 2 weeks) 
558 
 Assessment for any adverse events (AEs) since the previous visit, including documentation and 
559 
reporting as applicable 
560 
 Radiographs 
561 
 Clinical examination and outcome assessments as described in Section 7 
562 
 Test of Motor Proficiency administered by an occupational therapist 
563 
 Disclosure of treatment allocation (unblinding) 
564 
 For the titanium elastic nail (TEN) group, implant removal surgery will be planned in accordance with 
565 
standard of care 
566 
 Source data verification and entry into the eCRF 
567 
 Scheduling of the next visit 
568 
6.2.13 Visit 8 (52 weeks ± 4 weeks) 
569 
 Assessment for any adverse events (AEs) since the previous visit, including documentation and 
570 
reporting as applicable 
571 
 Radiographs 
572 
 Clinical examination and outcome assessments as described in Section 7 
573 
 Source data verification and entry into the eCRF 
574 
 Scheduling of the next visit 
575 
6.2.14 TEN removal surgery 
576 
Implant removal in the titanium elastic nail (TEN) group will be performed according to standard of care, 
577 
6–12 months after implantation. 
578 
6.2.15 Visit 9 (104 weeks ± 4 weeks) 
579 
 Assessment for any adverse events (AEs) since the previous visit, including documentation and 
580 
reporting as applicable 
581 
 Radiographs 
582 
 Clinical examination and outcome assessments as described in Section 7 
583 
 Source data verification and entry into the eCRF 
584 
 End of study participation 
585 
6.2.16 Unscheduled visits 
586 
Unscheduled visits may occur at any time during the study if a medical concern arises or if deemed 
587 
necessary by the investigator for patient care. 
588 
 
589 
All unscheduled visits or unplanned patient contacts related to the injury, treatment, or study device will 
590 
be documented in the patient’s medical record as part of standard care. 
591 
 
592 
For study purposes, unscheduled visits will be captured in a dedicated Unscheduled Visit form in the 
593 
eCRF, as described in the corresponding SOP. The form will document the date, reason for contact, 
594 

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and whether the contact resulted in an adverse event, additional treatment, or a change to the follow-up 
595 
schedule. 
596 
 
597 
Treatment-related adverse events will be recorded and reported in accordance with Section 11 and the 
598 
corresponding SOP. 
599 
 
600 
Data obtained during unscheduled visits will be reviewed and, where relevant, incorporated into the 
601 
study database at the next scheduled study visit. 
602 
6.2.17 Premature study termination 
603 
A participant’s involvement in the study may end prematurely (discontinuation of study participation) 
604 
and/or the participant may discontinue the allocated treatment while remaining in study follow-up. 
605 
Reasons may include, but are not limited to: 
606 
 
607 
 Withdrawal of informed consent (for study participation and/or use of data) 
608 
 Protocol deviation/violation with potential impact on participant safety or data integrity 
609 
 Refracture and/or reoperation (e.g., infection, implant-related complication) 
610 
 Investigator’s decision (e.g., noncompliance with study procedures, safety concerns) 
611 
 Sponsor’s decision (e.g., early study termination, safety signal, or regulatory request) 
612 
 Lost to follow-up 
613 
 Death 
614 
 
615 
6.2.17.1 Procedures and documentation 
616 
For all premature terminations/discontinuations, the Investigator will document the primary reason and 
617 
relevant details in the eCRF (dropout/discontinuation form). Where appropriate, the case will be 
618 
discussed with the Sponsor. If feasible, and if the participant and parents agree, an early termination 
619 
visit will be performed to capture key outcome assessments and to collect information on adverse 
620 
events/serious adverse events up to the time of discontinuation. 
621 
 
622 
6.2.17.2 Handling of data and missing assessments (interval-censored primary endpoint) 
623 
Data collected prior to discontinuation will be retained and used in analyses in accordance with 
624 
applicable law and the scope of consent. If consent for use of data is withdrawn, previously collected 
625 
data will be handled in accordance with regulatory requirements (e.g., retention of essential safety data 
626 
where required) and the participant’s stated wishes. 
627 
 
628 
The primary endpoint (time to radiographic healing) will be analyzed as an interval-censored time-to-
629 
event outcome. For participants with radiographs demonstrating “not healed” followed by “healed,” the 
630 
event time will be considered to occur within the interval between the date of the last radiograph 
631 
showing “not healed” and the date of the first radiograph showing “healed.” 
632 
 
633 
If a participant has no radiograph demonstrating healing, the observation will be right-censored at the 
634 
date of the last evaluable radiograph/assessment. 
635 
 
636 
If a participant undergoes reoperation, experiences refracture, or otherwise has a clinical course that 
637 
precludes further valid assessment of healing, follow-up will be censored at the date of the last 
638 
evaluable radiograph prior to that event, unless the event is pre-specified as a competing event in the 
639 
Statistical Analysis Plan. 
640 

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641 
Assumptions and handling of missing radiographs (including sensitivity analyses for potentially 
642 
informative missingness) will be pre-specified in the Statistical Analysis Plan. 
643 
6.3 
Study treatments 
644 
All study treatments are provided according to standard of care and in accordance with the applicable 
645 
Technique Guide for each implant system. Treatments are considered as standardized treatment 
646 
packages consisting of either: 
647 
 
648 
 surgical treatment with bioabsorbable intramedullary nails (BIN) and casting for 4 weeks, or 
649 
 surgical treatment with titanium elastic intramedullary nails (TEN) and casting for 2 weeks. 
650 
 
651 
This is a randomized controlled study. Randomization procedures are described below. 
652 
6.3.1 
Device under investigation 
653 
The investigational medical device (IMD) in this study is the Activa IM-Nail™ (Bioretec Ltd., Tampere, 
654 
Finland), a sterile, single-use, bioabsorbable intramedullary nail intended for intramedullary fixation of 
655 
pediatric diaphyseal forearm fractures (radius and/or ulna) in the presence of appropriate 
656 
immobilization. 
657 
 
658 
6.3.1.1 Device identification (IMD) 
659 
 Device name / brand: Activa IM-Nail™  
660 
 Size range: diameters 2.0–3.2 mm; lengths 200–400 mm 
661 
 Key material characteristics (high-level): bioabsorbable polymer-based nail with a radiopaque marker 
662 
(as described in the Investigator’s Brochure/IFU).  
663 
 Degradation (high-level): biodegrades in a controlled manner within approximately two years. 
664 
 
665 
6.3.1.2 Regulatory status and conformity (high-level) 
666 
 The device is CE-marked; design examination certification for Activa IM-Nail is issued by DEKRA 
667 
Certification B.V. (Notified Body 0344), certificate 2094913DE05. 
668 
 The manufacturer’s Declaration of Conformity and applicable quality system certification references 
669 
are provided as appendices. 
670 
 Continued placing on the market and putting into service under the MDR transitional provisions is 
671 
documented by the manufacturer (including applicability to Activa IM-Nail and stated end of transition 
672 
period for bioabsorbable implants). 
673 
 
674 
6.3.1.3 Use in this clinical investigation 
675 
The Activa IM-Nail™ will be used within its intended purpose and according to the manufacturer’s 
676 
instructions (Technique Guide/IFU). No modifications to the device or deviations from its intended 
677 
purpose are planned. 
678 
 
679 
6.3.1.4 Traceability and device accountability 
680 
To ensure traceability, the following will be recorded in the eCRF (and/or device accountability log): 
681 
device name, catalogue/reference number (REF), and batch/lot number (LOT). Device labeling and 
682 
essential regulatory documentation are retained in the Investigator Site File (ISF). 
683 
 
684 
Supporting documentation (submitted as EC appendices; not repeated in the protocol text) 
685 

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Detailed device description, intended purpose, contraindications/warnings, technical characteristics, 
686 
pre-clinical and clinical evidence summaries, and conformity documentation are provided in: 
687 
 Investigator’s Brochure (Activa IM-Nail™ Product Group)  
688 
 EC Design-Examination Certificate (DEKRA) 2094913DE05  
689 
 Declaration of Conformity (Class III devices)  
690 
 Manufacturer’s Declaration regarding MDR transitional provisions (EU 2023/607)  
691 
 Essential Requirements Checklist 
692 
6.3.2 
Comparator 
693 
The comparator device in this study is the Titanium Elastic Nail (TEN™) System (DePuy Synthes). The 
694 
TEN™ system is a commercially available, CE-marked orthopedic trauma implant system used to 
695 
perform elastic stable intramedullary nailing (ESIN) for stabilization of pediatric long-bone fractures, 
696 
including pediatric diaphyseal forearm fractures. The TEN™ system is not investigational in the context 
697 
of this clinical investigation and will be used within its approved intended use/indications and according 
698 
to the manufacturer’s Instructions for Use (IFU) and Surgical Technique. 
699 
 
700 
The TEN™ system consists of flexible titanium alloy intramedullary nails supported by dedicated 
701 
instrumentation for implantation and extraction. The nails are available in multiple diameters and lengths 
702 
suitable for pediatric forearm fracture fixation (e.g., 1.5 mm × 300 mm and 2.0–4.0 mm × 440 mm). 
703 
 
704 
Device traceability will be ensured by recording the device name and relevant identifiers (e.g., article 
705 
number, and where applicable sterile/non-sterile designation and packaging identifiers) in source 
706 
documentation and the eCRF/device accountability documentation, in accordance with local 
707 
procedures. Detailed technical specifications, labeling, indications/contraindications, warnings, and 
708 
handling instructions are provided in the appended TEN™ documentation (IFU/Surgical 
709 
Technique/Investigator’s Brochure) submitted to the Ethics Committee. 
710 
6.3.3 
Constancy and assay sensitivity of the reference treatment (TEN) 
711 
Noninferiority inference in this trial relies on the assumption of constancy (assay sensitivity), i.e., that the 
712 
active control intervention (TEN) would be expected to achieve its established effectiveness under the 
713 
conditions of the present study. 
714 
 
715 
The trial is therefore designed to maintain close similarity to the evidence base supporting TEN for 
716 
pediatric diaphyseal forearm fractures with respect to (1) the enrolled population (age range, fracture 
717 
location and pattern, displacement, and operative indication), (2) the conduct of the reference 
718 
intervention (TEN performed according to manufacturer guidance and local standard practice by 
719 
appropriately experienced surgeons, with standardized key perioperative and postoperative care 
720 
pathways), and (3) outcome definitions and follow-up schedule (radiographic healing assessed using 
721 
prespecified, operational criteria and prespecified time points). 
722 
 
723 
Any clinically relevant differences from the studies underpinning TEN effectiveness (e.g., case-mix, 
724 
perioperative regimen, immobilization practice, or outcome timing/definition) will be described and 
725 
justified in the final trial report, and adherence to the planned delivery of TEN and follow-up will be 
726 
monitored to support assay sensitivity. 
727 

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6.3.4 
Treatment, surgical technique and postoperative care 
728 
All operative and non-operative management is performed according to standard of care and in 
729 
accordance with the manufacturer’s Technique Guide/IFU for the relevant implant. Operational details 
730 
are described in the corresponding site SOPs. 
731 
 
732 
Procedures are performed under general anesthesia (GA) with the patient in the supine position and the 
733 
injured arm positioned on a radiolucent arm table. GA may be supplemented with a peripheral nerve 
734 
block (PNB) in accordance with local standard practice [40]. 
735 
 
736 
6.3.4.1 Closed reduction pathway (prior to randomization) 
737 
Where applicable, an attempt at closed reduction is performed before skin incision. 
738 
 If closed reduction is achieved and the fracture no longer meets criteria for surgical stabilization, a 
739 
circumferential above-elbow cast is applied, and alignment is confirmed with intraoperative 
740 
radiographs. If alignment is satisfactory, surgery is cancelled, and the participant is managed as part 
741 
of the non-operative cohort (Section 6.3.8). 
742 
 If closed reduction is not applicable, unsuccessful, or the fracture remains irreducible and/or unstable, 
743 
the participant proceeds to randomization (Section 6.3.5). 
744 
 
745 
6.3.4.2 Operative pathway (randomized treatment packages) 
746 
Participants randomized to surgical treatment will undergo intramedullary fixation using either: 
747 
 BIN package: bioabsorbable intramedullary nail fixation with casting for 4 weeks, or 
748 
 TEN package: titanium elastic intramedullary nail fixation with casting for 2 weeks. 
749 
 
750 
The operative technique for the two interventions is largely identical, with implant-specific steps 
751 
performed according to the relevant Technique Guide. In brief, intramedullary canal access is 
752 
established and the nail is advanced under fluoroscopic guidance; fracture reduction is performed 
753 
closed where feasible, with open reduction permitted if required. Postoperative radiographs are 
754 
obtained. 
755 
 
756 
Antibiotic prophylaxis will be administered according to local standard practice (weight-based dosing). In 
757 
case of penicillin allergy, an appropriate alternative will be used per local guidelines. 
758 
 
759 
6.3.4.3 Postoperative care and discharge 
760 
Wounds are closed and dressed according to standard practice. A circumferential above-elbow cast is 
761 
applied for the duration specified by the randomized treatment package. Discharge occurs when the 
762 
child is clinically well and postoperative pain is controlled, typically on the same day or the day after 
763 
surgery, in accordance with local routines. No formalized physiotherapy is routinely prescribed; 
764 
participants and parents receive oral and written instructions regarding mobilization and home 
765 
exercises. 
766 
 
767 
Follow-up assessments are conducted according to the schedule described in Section 6.2. 
768 
6.3.5 
Allocation to study groups 
769 
Allocation will be 1:1 between the investigational (BIN) and comparator (TEN) groups, stratified by age. 
770 

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6.3.6 
Randomization process 
771 
 The participant must meet all inclusion criteria and none of the exclusion criteria, and written informed 
772 
consent from parents must be obtained. 
773 
 Randomization will be performed in the operating room (OR) with the participant under general 
774 
anesthesia (GA) if closed reduction is not applicable or is unsuccessful (i.e., the fracture remains 
775 
irreducible and/or unstable and surgical stabilization is indicated). 
776 
 A delegated member of the research team will randomize the participant to treatment with either BIN 
777 
or TEN. 
778 
 Randomization will be conducted using the REDCap Randomization module with age stratification. 
779 
 Contingency plan: If REDCap is temporarily unavailable, randomization will be performed using a 
780 
predefined, access-restricted backup procedure (e.g., sealed opaque envelopes or a pre-generated 
781 
randomization list) as described in the corresponding SOP, and the allocation will be entered into 
782 
REDCap as soon as system access is restored. 
783 
6.3.7 
Blinding 
784 
Blinding is implemented to minimize performance and assessment bias [41–43]. Due to the nature of 
785 
the interventions, the operating surgeon and operating room staff cannot be blinded to implant type. 
786 
 
787 
Allocation is concealed from participants, parents, postoperative clinical staff, outcome assessors, and 
788 
the statistician. A limited number of designated study personnel (e.g., PI and trial coordinator) are 
789 
unblinded to facilitate device logistics and, when relevant, planning of elective titanium nail removal; 
790 
these personnel will have no role in postoperative assessments, radiographic outcome evaluation, or 
791 
data analysis. 
792 
 
793 
Participant and parent unblinding will occur only after completion of the 6-month follow-up assessment, 
794 
primarily to enable planning of elective removal of titanium nails in accordance with standard practice. 
795 
All outcome assessors and the statistician will remain blinded until database lock and completion of the 
796 
primary analysis, unless unblinding is required for patient safety. 
797 
 
798 
6.3.7.1 
Blinded postoperative documentation 
799 
To maintain blinding of participants, parents, and routine postoperative caregivers, a standardized 
800 
“blinded” postoperative documentation pathway will be used in the electronic health record (EHR). The 
801 
purpose is to prevent inadvertent disclosure of treatment allocation through operative notes, discharge 
802 
documentation, or follow-up scheduling, while ensuring that complete and legally compliant source 
803 
documentation is retained and remains available to authorized clinical staff when needed.  
804 
 
805 
Immediately after surgery, documentation will be split into: 
806 
 
807 
 Blinded postoperative note (visible to routine postoperative care and to families via patient-facing 
808 
portals, where applicable): A standardized template will be used stating that the participant “underwent 
809 
intramedullary fixation with one of the two study nails according to randomization,” without naming 
810 
implant type. The note will include study information (including emergency contact information), non-
811 
allocating clinical essentials (diagnosis, reduction status, approach, complications, cast applied, 
812 
neurovascular status, activity restrictions, analgesia plan, and safety advice). 
813 
 
814 
 Additional operative record (restricted access): An additional operative record containing the implant 
815 
type, sizes, lot/batch identifiers, and any implant-specific technical details will be completed and 
816 

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retained as source documentation with access restricted to authorized staff (e.g., operating surgeon, 
817 
delegated unblinded study personnel, and clinicians requiring access for safety). Implant traceability 
818 
information (REF/LOT, sizes) will also be recorded in the device accountability log/eCRF as 
819 
prespecified. 
820 
 
821 
6.3.7.2 
Maintaining blinding despite imaging and clinical routines 
822 
For research outcome assessment, postoperative radiographs will be exported as de-identified copies 
823 
and edited to conceal implant-specific radiopaque features as described in Section 7.1. Clinical care will 
824 
continue to rely on unedited radiographs in the medical record. Study staff involved in follow-up 
825 
assessments will avoid disclosure of allocation, and participants and parents will be asked not to seek 
826 
information on implant type until after the 6-month visit. 
827 
 
828 
6.3.7.3 
Emergency unblinding 
829 
Unblinding may be performed only when knowledge of the allocated implant is deemed necessary for 
830 
urgent clinical management. Emergency unblinding will be performed by the PI, documented in the 
831 
eCRF (date, reason, person unblinded, and who was informed), and reported to the sponsor. 
832 
 
833 
6.3.7.4 
Blinded groups 
834 
The following parties will be blinded to treatment allocation: 
835 
 Participants and parents will be blinded to implant type. Families will be informed preoperatively that 
836 
postoperative immobilization duration may vary between 2–4 weeks based on radiographic 
837 
assessment, and they will not be informed that immobilization duration differs systematically between 
838 
the randomized interventions. As the implant is not externally visible after cast removal and implant-
839 
specific radiographic features are concealed for research assessments (Section 7.1), there is no direct 
840 
method for participants and parents to identify allocation during follow-up. 
841 
 
842 
 Postoperative ward/clinic caregivers and staff involved in routine care. 
843 
 
844 
 Outcome assessors and data collectors, including: 
845 
– Clinicians performing follow-up assessments 
846 
– Radiologists and orthopedic surgeons reviewing radiographs (using edited, de-identified images; 
847 
Section 7.1) 
848 
– Occupational therapists / hand therapists performing functional assessments 
849 
 
850 
 Statistician/data analyst, who will receive a dataset with groups coded (e.g., Group A/B) and will 
851 
remain blinded until database lock and completion of the prespecified primary analysis. 
852 
 
853 
6.3.7.5 
Preventing inadvertent unblinding 
854 
To reduce inadvertent disclosure, the study team will implement the following safeguards: 
855 
 Use of standardized note templates for postoperative notes and discharge summaries. 
856 
 Clear instruction to staff not to document implant type in routine follow-up notes that are accessible to 
857 
blinded parties. 
858 
 If implant type must be referenced for clinical reasons before planned unblinding, it will be 
859 
documented and handled according to the emergency unblinding procedure. 
860 
 
861 

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6.3.7.6 
Assessment of blinding success 
862 
Blinding success will be assessed immediately prior to participant/parent unblinding at the 6-month 
863 
follow-up visit. Participants/parents will be asked to guess the allocation (“bioabsorbable”, “titanium”, or 
864 
“don’t know”) and if they specify an implant, they will be asked why they chose that implant. The 
865 
proportion of correct guesses and reasons (and proportion choosing “don’t know”) will be summarized 
866 
by randomized group. 
867 
6.3.8 
Postoperative care 
868 
Following surgery, a circumferential above-elbow cast is applied. The patient will be observed and/or 
869 
admitted to the pediatric ward as clinically indicated until the effect of the peripheral nerve block (PNB) 
870 
has subsided and discharge criteria are met. The patient is encouraged to mobilize the shoulder and 
871 
fingers as soon as possible and to keep the arm elevated for the first few days. Daily activities may be 
872 
resumed as tolerated. Return to sports will be discussed individually at the 3-month follow-up visit in 
873 
accordance with standard of care. 
874 
 
875 
Before discharge, a standardized discharge and follow-up plan will be provided. 
876 
 
877 
In the investigational group (BIN), all patients will remain in a cast for 4 weeks. In the comparator group 
878 
(TEN), cast removal is planned at the 2-week follow-up visit. 
879 
 
880 
Any postoperative care not specifically described in this protocol will be provided according to standard 
881 
of care at the study site and described in a specific SOP. 
882 
6.3.9 
Non-operative treatment 
883 
If the fracture is successfully reduced by closed manipulation prior to skin incision and is considered 
884 
eligible for non-operative management, the patient will be included in an exploratory prospective non-
885 
operative cohort. Based on our pilot experience, the proportion of successful closed reductions is 
886 
anticipated to be approximately 15%. 
887 
 
888 
6.3.9.1 Eligibility for non-operative management 
889 
Fractures are considered eligible for non-operative treatment when, after reduction, the fracture is: 
890 
 not displaced by more than 50% of the bone width, and 
891 
 not angulated by more than 10° in any plane. 
892 
 
893 
The decision to manage the fracture non-operatively is at the treating surgeon’s discretion and follows 
894 
standard of care. 
895 
 
896 
6.3.9.2 Follow-up and conversion to surgery 
897 
Participants in the non-operative cohort will have a radiographic follow-up at 1 week. Thereafter, they 
898 
will follow the same follow-up schedule and outcome assessments as the randomized groups (Section 
899 
6.2). Fracture healing is typically sufficient to allow cast removal after 6–8 weeks. 
900 
 
901 
If, during subsequent follow-up no later than 14 days after injury (e.g., at the planned 1-week non-
902 
operative control), loss of reduction occurs such that the fracture again meets the study’s operative 
903 
indication criteria, the participant remains eligible for the randomized comparison. In this situation, the 
904 
participant will follow the standard pathway and be randomized in the operating room immediately prior 
905 
to surgery, using the trial’s randomization procedure (Section 6.3.5). 
906 

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907 
The period of initial non-operative management and the indication for conversion to surgery will be 
908 
documented. 
909 
 
910 
Any subsequent re-intervention or conversion to surgery occurring later than 14 days after injury will be 
911 
recorded and analyzed descriptively. 
912 
7 
Definitions of outcome measures and study variables 
913 
This study adheres to the CORE-Kids core set of outcome domains described by Marson et al. [44]. 
914 
7.1 
Primary outcome 
915 
Time to fracture healing (weeks), defined as the time from surgery/randomization (Day 0) to the first 
916 
postoperative radiographic assessment meeting the prespecified healing criterion in all fractured bones 
917 
as described in 7.1.2.3. 
918 
7.1.1 
Time to fracture healing 
919 
As described in Section 4.2, fracture repair is a complex biological process and objective assessment in 
920 
clinical trials is challenging [45]. Healing based on plain radiographs has historically been largely 
921 
subjective. Whelan et al. developed the Radiographic Union Score (RUS) to quantify healing in tibial 
922 
fractures based on callus formation and visibility of the fracture line [46]. RUS has since been shown to 
923 
be reliable and repeatable, including anatomical sites beyond the tibia [47–49], and to correlate with 
924 
biomechanical properties of healing [50]. To improve clarity and reduce ambiguity in scoring, a modified 
925 
RUS (mRUS) has been proposed, defining callus as bridging versus non-bridging [51]. 
926 
 
927 
7.1.1.1 Definition of time-to-healing (primary time origin) 
928 
Time-to-healing will be defined as the time from the date of surgery/randomization (Day 0) to the first 
929 
postoperative radiographic assessment meeting the pre-specified healing threshold in all fractured 
930 
bones. For patients with fractures of both radius and ulna, the endpoint is met when the healing 
931 
threshold is achieved for both bones; for isolated single-bone fractures, the endpoint is met when the 
932 
fractured bone reaches the threshold. Injury date will be recorded for all participants. As sensitivity 
933 
analyses, time-to-healing will also be calculated from the date of injury, and analyses may adjust for the 
934 
injury-to-surgery interval to assess robustness. 
935 
 
936 
7.1.1.2 Radiographic assessment method (mRUS) 
937 
Healing will be assessed on standard plain anteroposterior (AP) and lateral radiographs. For each 
938 
fractured bone, four cortices are scored (1–4) and summed to yield an mRUS from 4 (not healed) to 16 
939 
(fully healed). Scoring of each cortex is defined as follows: 
940 
 
941 
 visible fracture line and no callus  
 
 
is scored 1 (Figure 2.1) 
942 
 non-bridging callus with visible fracture line  
 
is scored 2 (Figure 2.2) 
943 
 bridging callus with visible fracture line  
 
is scored 3 (Figure 2.3) 
944 
 bridging callus with no visible fracture line  
 
is scored 4 (Figure 2.4) 
945 
 
946 
The sum of the four cortices constitutes the mRUS for that bone. Based on prior work, a threshold of 
947 
mRUS ≥ 11 is considered consistent with radiographic union and mRUS ≥ 13 with definite union [51]. 
948 
 
949 

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950 
 
951 
Figure 2 - Calculation of mRUS. A cortex with visible fracture line and no callus is scored one (1), with non-bridging callus and a 
952 
visible fracture line is scored two (2), with bridging callus and a fracture line is scored three (3) and with bridging callus and no 
953 
visible fracture line is scored four (4). The sum of the four scores gives the mRUS. 
954 
7.1.1.3 Radiographic healing threshold (primary endpoint) 
955 
Healing will be defined as mRUS ≥ 11 for the fractured bone with bridging callus (cortex score ≥3) 
956 
present in at least three of four cortices, and no cortex with score of 1. For combined radius and ulna 
957 
fractures, the endpoint is met when both bones meet the healing threshold on the same radiographic 
958 
assessment. 
959 
This threshold operationalizes union as bridging callus in ≥3 cortices (consistent with established 
960 
radiographic union definitions) while limiting premature classification by requiring absence of cortices 
961 
with no callus. 
962 
 
963 
Definite union (supportive threshold). As a supportive radiographic definition, definite union will be 
964 
defined as mRUS ≥ 13 for the fractured bone, which corresponds to bridging callus in all four cortices 
965 
with at least one cortex demonstrating absence of a visible fracture line (cortex score 4). This more 
966 
stringent threshold is expected to occur later in the healing trajectory and will therefore be used for pre-
967 
specified sensitivity analyses of the primary time-to-healing endpoint and for descriptive comparison of 
968 
healing profiles between groups, rather than as the primary event definition. 
969 
 
970 
7.1.1.4 Blinding of radiographs via standardized image masking 
971 
Bioabsorbable intramedullary nails are largely radiolucent, with only a radiopaque tricalcium phosphate 
972 
tip, whereas titanium nails are inherently radiopaque. To ensure blinded radiographic outcome 
973 
assessment across treatment groups, all postoperative radiographs will be de-identified and digitally 
974 
masked prior to review. Using image-editing software, visible radiopaque implant components will be 
975 
concealed, while preserving full visibility of the fracture region, cortical outlines, and callus formation 
976 
(Figure 3). All patient identifiers and acquisition metadata will be removed, and images will be assigned 
977 
a study-specific ID and a non-revealing time point label only. 
978 
 
979 
Image manipulation will be performed by a member of the research team who is not involved in 
980 
postoperative clinical assessment, outcome evaluation, or statistical analysis, and who will have no role 
981 
in adjudication of radiographic endpoints. Masking procedures will be documented to ensure 
982 
consistency. All manipulated images are stored outside PACS. All original unaltered radiographs are 
983 
stored in the hospital’s PACS. 
984 
 
985 
 
 
986 

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Original follow-up radiograph 
Edited radiograph with implant concealed 
 
Figure 3 – Example of original and edited radiograph to blind the assessor to the implant. 
 
987 
7.1.1.5 Independent review, adjudication, and reliability (quality assurance) 
988 
All masked radiographs will be assessed independently by two blinded reviewers (musculoskeletal 
989 
radiologist and orthopedic surgeon) using a pre-specified scoring manual. Reviewers will undergo a 
990 
brief calibration exercise prior to study readings. Images will be presented in random order and without 
991 
access to clinical data or treatment allocation. 
992 
 
993 
Inter-rater reliability for mRUS will be quantified using appropriate agreement statistics (e.g., ICC for 
994 
total mRUS and weighted kappa for ordinal cortex scores), and intra-rater reliability will be assessed by 
995 
repeat scoring of a randomly selected subset of examinations after a washout period (e.g., 2–4 weeks), 
996 
with re-randomization of the re-read set. Discrepant assessments of healing status relevant to the 
997 
primary endpoint will be resolved by consensus; if consensus is not achieved, a third blinded reviewer 
998 
will adjudicate. Reliability estimates will be reported with confidence intervals as part of study quality 
999 
assurance. 
1000 
7.2 
Secondary outcomes 
1001 
7.2.1 
CORE-Kids outcomes 
1002 
Marson et al. has developed the CORE-Kids core set of outcome domains for studies of childhood limb 
1003 
fractures [44]. These core outcomes are suggested to be included in all trials on childhood limb 
1004 
fractures to improve the consistency of research that can be combined for more meaningful meta-
1005 
analyses and policy development. 
1006 
 
1007 
The CORE-Kids outcome domains were agreed to include: 
1008 
 Pain and discomfort 
1009 
 Return to physical and recreational activities 
1010 
 Emotional and psychosocial wellbeing 
1011 
 Complications from the injury and its treatment 
1012 
 Return to baseline activities daily living 
1013 
 Participation in learning 
1014 
 Appearance and deformity 
1015 
 Time to union – primary outcome 
1016 
 Recovery of mobility (for lower limb fracture) 
1017 
 Recovery of manual dexterity (for upper limb fracture) 
1018 
 
1019 
Another 5 outcomes were close to the consensus threshold: 
1020 
 Cost to family 
1021 

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 Ability to sleep 
1022 
 Range of motion 
1023 
 The cost of treatment 
1024 
 Child satisfaction 
1025 
7.2.2 
EQ-5D-Y - Patient reported outcome 
1026 
To select an appropriate patient-reported outcome measure (PROM), we followed the recommendations 
1027 
of Marson et al. [52]. We selected the EQ-5D-Y questionnaire due to its ease of use, validated Danish 
1028 
translation, broad availability, use in prior research, and alignment with the intended secondary 
1029 
outcomes. 
1030 
 
1031 
The questionnaire consists of the EQ-5D-Y descriptive system (index) and the EQ visual analogue scale 
1032 
(EQ VAS). The descriptive system comprises five dimensions: 
1033 
 Mobility 
1034 
 Looking After Myself 
1035 
 Doing Usual Activities 
1036 
 Having Pain or Discomfort 
1037 
 Feeling Worried, Sad or Unhappy 
1038 
 
1039 
Each dimension has three response levels: no problems/no pain/not worried, some problems/some 
1040 
pain/a bit worried, and a lot of problems/a lot of pain/very worried. Respondents indicate their health 
1041 
state by selecting the most appropriate response level for each dimension. 
1042 
 
1043 
The EQ VAS is a 0–100 scale on which respondents rate their overall health on the day of questionnaire 
1044 
completion. It is conceptually different from the EQ-5D-Y index, which represents a value assigned to an 
1045 
EQ-5D-Y health profile using a set of weights reflecting population preferences for different health 
1046 
states. The EQ VAS reflects the respondent’s perspective, whereas most value sets reflect a societal 
1047 
perspective. 
1048 
 
1049 
For children aged 4–7 years, the proxy version will be used. A parent will complete the questionnaire 
1050 
based on their impression of the child’s health status on the day of administration. For children aged 8 
1051 
years and older, the self-reported version will be used. 
1052 
 
1053 
The EQ-5D-Y has an official Danish translation and has been evaluated. Data will be collected using the 
1054 
REDCap self-report and proxy versions (Version 2.0). Administration and scoring will follow the EQ-5D-
1055 
Y User Guide, Version 2.0 (September 2020). 
1056 
 
1057 
The original English and Danish versions are provided as appendices. 
1058 
7.2.3 
Pain and discomfort 
1059 
At each FU visit, pain and discomfort and use of medication is evaluated and documented. 
1060 
 
1061 
7.2.3.1 
Faces Pain Scale – Revised (FPS-R) 
1062 
To measure the outcome of pain in children we use the Faces Pain Scale – Revised (FPS-R) [53]. It is a 
1063 
self-report measure of pain intensity developed for children. It was adapted from the Faces Pain Scale 
1064 
[54] to make it possible to score the sensation of pain on the widely accepted 0-to-10 metric. The scale 
1065 
shows a close linear relationship with numerical rating scales (NRS). It is easy to administer and 
1066 

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requires no equipment except for the photocopied faces (Figure 4). The child is asked to point to the 
1067 
face that shows how much pain the child is in at that moment. Faces are scored 0-10, where 0 equals 
1068 
no pain and 10 equals very much pain. 
1069 
 
1070 
 
1071 
Figure 4 - Faces of the FPS-R. The child is instructed to point to the face that shows how much pain the child is in at that moment. 
1072 
Faces are scored 0, 2, 4, 6, 8 or 10 from left to right. 
1073 
7.2.3.2 
Discomfort 
1074 
Pain and discomfort are domains in the EQ-5D-Y and is reported at each FU visit. 
1075 
 
1076 
7.2.3.3 
Pain medication 
1077 
At each FU visit any use of pain medicine will be recorded. 
1078 
7.2.4 
Return to physical and recreational activities 
1079 
Return to physical and recreational activity is described in the EQ-5D-Y. Return to sports will be 
1080 
documented in the eCRF. 
1081 
7.2.5 
Emotional and psychosocial wellbeing 
1082 
Described by the domains of the EQ-5D-Y and the EQ VAS. 
1083 
7.2.6 
Complications from the injury and its treatment (adverse events) 
1084 
This section describes all anticipated AEs, SAEs, ADEs, and SADEs. Further definition and description, 
1085 
see section 11. 
1086 
 
1087 
7.2.6.1 
Re-fracture, re-displacement, or re-angulation 
1088 
At each FU the radiographs are reviewed for occurrence of re-fracture, re-displacement, or re-
1089 
angulation. If changes are below the boundaries described in the inclusion criteria in 6.1.1 no additional 
1090 
treatment is necessary. If the boundaries are exceeded the PI and the surgeon will discuss the need for 
1091 
additional treatment. 
1092 
 
1093 
7.2.6.2 
Infection 
1094 
Any surgery caries the risk of infection, however previous studies have shown very subtle infection risk 
1095 
[3,55] with the TEN procedure. We anticipate a risk of infection at 0.5%. 
1096 
 
1097 
7.2.6.3 
Nerve complications 
1098 
Studies have shown a 5% risk of nerve injury [55], however all cases had spontaneous recovery of 
1099 
nerve function. 
1100 
 
1101 
7.2.6.4 
Re-operation 
1102 
Re-operation risk is anticipated at 0.1-0.5% due for any reason following the procedure. 
1103 
 
1104 

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7.2.6.5 
Discomforts/risks from casting 
1105 
 Heat injury 
1106 
 Pressure sores and skin breakdown 
1107 
 Dermatitis 
1108 
 Joint stiffness 
1109 
 
1110 
7.2.6.6 
Adverse Device Effects and Device deficiency 
1111 
ADE and DD are defined in 11.1. Two cases of breakage of the Activa IM-Nail™ have been described. 
1112 
Steps to avoid ADE and DD have already been taken with revision of the Technique Guide. With the 
1113 
completion of our pilot study, we have gained valuable knowledge of the Activa IM-Nail™ procedure. 
1114 
7.2.7 
Return to baseline activities daily living 
1115 
Described by the domains of the EQ-5D-Y. 
1116 
7.2.8 
Participation in learning 
1117 
Partially described by the domains of the EQ-5D-Y and the EQ VAS. Return to school is entered in the 
1118 
eCRF. 
1119 
7.2.9 
Appearance and deformity 
1120 
At each FU visit clinical adverse appearance or deformity is noted in the eCRF. 
1121 
7.2.10 Recovery of manual dexterity / Range of motion 
1122 
At each visit, sensory and motor nerve function is examined, and any irregularities are recorded in the 
1123 
eCRF. 
1124 
 
1125 
Grip strength and bilateral elbow and forearm range of motion (ROM) is measured in degrees by 
1126 
goniometer and dynamometer, respectively. 
1127 
 
1128 
7.2.10.1 Motor function assessment (MABC-3) 
1129 
 
1130 
Motor function will be assessed using the Movement Assessment Battery for Children – Third Edition 
1131 
(MABC-3). MABC-3 is a standardized, age-normed performance-based test of motor coordination 
1132 
validated for children aged 3–16 years . 
1133 
 
1134 
In this study, the Manual Dexterity domain will be used as an objective measure of upper-limb motor 
1135 
performance. The domain consists of age-appropriate, timed tasks assessing fine motor control, 
1136 
coordination, and precision of hand use. Tasks are selected according to predefined age bands (3–6, 7–
1137 
10, and 11–16 years) and administered according to the standardized test manual. 
1138 
 
1139 
Assessments will be performed by trained personnel at 12 weeks post-injury. Raw scores will be 
1140 
converted to age-adjusted standard scores and percentiles using normative reference data. The primary 
1141 
MABC-3 outcome will be the Manual Dexterity standard score, analyzed as a continuous variable. 
1142 
 
1143 
MABC-3 was chosen to provide an objective, developmentally appropriate measure of functional motor 
1144 
recovery that complements radiographic healing, range of motion, grip strength, and patient-reported 
1145 
outcomes. 
1146 

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7.2.11 Cost to family 
1147 
Days off work and days off school are recorded in the eCRF. 
1148 
7.2.12 Ability to sleep 
1149 
Any problems with sleep are addressed in the eCRF. 
1150 
7.2.13 The cost of treatment 
1151 
Treatment costs are discussed in 4.5.2. We intend to produce a cost-effectiveness analysis of the 
1152 
procedures involved. 
1153 
7.2.14 Child satisfaction 
1154 
Satisfaction of the child and parents are recorded using a questionnaire from the Danish Nationwide 
1155 
Survey of Patient Experiences (Landsdækkende Undersøgelse af Patientoplevelser - LUP) during the 
1156 
FU visit after 2 years. A copy (in Danish) is amended to the EC application. 
1157 
7.3 
Required diagnostic procedures 
1158 
For diagnostic and follow-up purposes, plain radiographs of the forearm will be obtained at the following 
1159 
time points: 
1160 
 At injury / preoperatively 
1161 
 Intraoperatively (fluoroscopy) 
1162 
 Postoperatively 
1163 
 At follow-up (FU) visits until healing is established, but at a minimum at the 2-, 4-, and 6-week visits 
1164 
and possibly 8 and 10 weeks 
1165 
 At FU visits after 12 weeks, 6 months, 1 year, and 2 years 
1166 
8 
Statistical planning 
1167 
The statistical methodology for this clinical investigation—including definition of the primary estimand 
1168 
and analysis approach, justification of the non-inferiority margin, and the assumptions underlying the 
1169 
sample size and power calculations—was developed in collaboration with an independent statistician 
1170 
from the University of Copenhagen. The statistician contributed to the planning and validation of the 
1171 
statistical measures and will provide continued methodological support as needed during conduct and 
1172 
reporting of the study. 
1173 
 
1174 
 Baseline characteristics and outcomes collected at scheduled follow-up assessments will be described 
1175 
using descriptive summary statistics. 
1176 
 Categorical variables will be summarized as counts and percentages for each category. 
1177 
 Continuous variables will be summarized using the mean, standard deviation (SD), median, 
1178 
interquartile range (IQR), and minimum and maximum values. 
1179 
 When both baseline and follow-up measurements are available, continuous variables will additionally 
1180 
be summarized as within-patient change from baseline to follow-up. 
1181 
 EQ-5D-Y results will be reported in accordance with the EQ-5D-Y user guide/manual. 
1182 
 Adverse events (AEs) considered related to the study intervention will be summarized at the patient 
1183 
level. For summaries by severity, action taken, or outcome, patients experiencing more than one event 
1184 
of the same type will be classified according to the maximum severity and/or worst outcome observed. 
1185 
 Analyses will be performed using validated statistical software (e.g., R/Stata/SAS and/or SPSS for 
1186 
descriptive analyses), as specified in the SAP. 
1187 

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When designing this non-inferiority study, we have considered the risk of “technocreep,” whereby 
1188 
successive non-inferiority trials may gradually erode the reference standard through incremental 
1189 
acceptance of smaller differences. For the present study, the non-inferiority margin is not derived from 
1190 
prior non-inferiority studies of the same implant type, thereby reducing the risk that margin selection is 
1191 
influenced by accumulated non-inferiority assumptions. 
1192 
8.1 
Non-inferiority hypotheses (primary estimand) 
1193 
Let 𝑇 denote time from surgery/randomization (Day 0) to radiographic union. Let 𝜃 denote the treatment 
1194 
effect expressed as the difference in time to union (BIN − TEN), in weeks. With a non-inferiority margin 
1195 
∆ = 3 weeks, the hypotheses are: 
1196 
𝐻0: θ ≥∆ (BIN is inferior to TEN by ≥ 3.0 weeks) 
1197 
𝐻1: θ < ∆ (BIN is non-inferior to TEN) 
1198 
8.2 
Sample size considerations 
1199 
Sample size was calculated for a parallel-group, randomized (1:1), non-inferiority comparison of time to 
1200 
radiographic healing, defined as time from surgery/randomization to the first radiograph with mRUS ≥ 
1201 
11. 
1202 
 
1203 
 
1204 
Figure 5 – Power table. To better appreciate the effects on sample size four standard deviations (SD) are plotted for five different 
1205 
power levels. The chosen SD and power are circled. 
1206 
 
1207 
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0
10
20
30
40
50
60
Power 1−β
Sample Size, each group
Power table 
0.025 significance
Non-inferiority margin = 3 weeks
SD 2 weeks
SD 3 weeks
SD 4 weeks
SD 5 weeks

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1208 
Figure 6 – Table to show sample size at 3 SD for 4 different non-inferior margins. The chosen margin and sample size are circled. 
1209 
8.2.1 
Power 
1210 
To ensure a more reliable result, the power (1-β) is set to 90%. 
1211 
8.2.2 
Standard deviation 
1212 
Due to limited evidence on the exact healing times of forearm fractures in children, the values are based 
1213 
on our pilot study, available literature [14,56] and our clinical expertise. In our pilot study of 18 fractures 
1214 
median time to healing with an mRUS of at least 11, was 8 weeks. We estimate that fractures heal to an 
1215 
mRUS of ≥ 11 at an average of 8 weeks with a SD of 3 weeks. 
1216 
8.2.3 
Significance level 
1217 
Because a non-inferiority design is primarily investigating only one bound (lower or upper) of the 
1218 
confidence interval, we set a significance level (α) of 0.025 so that our one-sided test and upper 
1219 
confidence limit is comparable to results in two-sided superiority trials. 
1220 
8.2.4 
Non-inferiority margin 
1221 
The primary objective is to demonstrate that bioabsorbable intramedullary nailing (BIN) is non-inferior to 
1222 
titanium elastic stable intramedullary nailing (TEN) with respect to time to radiographic union.  
1223 
 
1224 
To support the choice of a clinically acceptable non-inferiority margin, we incorporated parent input from 
1225 
the pilot cohort. Parents were asked an acceptability question regarding the maximum additional weeks 
1226 
beyond the usual 6-week restriction for return to higher-risk activities (e.g., trampoline/contact sports) 
1227 
they would accept if their child could avoid a second operation for implant removal with bioabsorbable 
1228 
intramedullary nails. Responses were used to contextualize what families consider an acceptable trade-
1229 
off and to ensure the non-inferiority margin is aligned with patient-relevant priorities, in addition to 
1230 
clinical judgement and the existing literature. 
1231 
 
1232 
The non-inferiority margin is set at Δ = 3.0 weeks, representing the largest clinically and parent 
1233 
acceptable delay in union for BIN compared with TEN. 
1234 
0
1
2
3
4
5
6
0
20
40
60
Margin, weeks
Sample size, each group
Sample size
0.025 significance
Power 90%
SD 3

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8.2.5 
Treatment effect (primary estimand) 
1235 
The treatment effect will be expressed as the difference in time to union (in weeks): 
1236 
 
1237 
𝜃= 𝑇𝐵𝐼𝑁−𝑇𝑇𝐸𝑁 
1238 
 
1239 
where 𝑇 denotes time from surgery date to radiographic union. 
1240 
8.2.6 
Drop rate / sample size inflation 
1241 
In our pilot study, 1/18 (≈5%) participants were lost to follow-up. For the present RCT we apply a total 
1242 
inflation of 10%, comprising ~5% loss to follow-up/withdrawal and ~5% intercurrent events affecting the 
1243 
primary endpoint (e.g., healing-related reoperation). Although intercurrent events will be handled in the 
1244 
primary estimand strategy (see Section 8.3), they reduce the number of informative observations for 
1245 
time-to-union and are therefore accounted for in the sample size inflation. 
1246 
8.2.7 
Sample size estimation 
1247 
 
1248 
Sample size 
Significance level 
0.025 
Power (1-beta) 
0.9 
Ratio of sample size 
1:1 
Standard deviation 
3 weeks 
Non-inferiority margin 
3 weeks 
Loss to follow-up/withdrawal (%) 
5 
Intercurrent events (%) 
5 
Result 
Sample size per group 
22 
Sample size per group incl. attrition 
25 
Total sample size incl. attrition 
50 
Table 1. Results of sample size estimation. 
1249 
To further strengthen robustness against uncertainty in the SD estimate, potential deviations from the 
1250 
assumed distributional model, and the possibility that a greater proportion of participants than 
1251 
anticipated may have non-informative primary endpoint data (e.g., due to intercurrent events), the study 
1252 
will enroll 30 participants per group (total N = 60). This provides additional precision for estimating the 
1253 
between-group difference in time to healing and ensures that the trial maintains at least the planned 
1254 
statistical power under plausible departures from the planning assumptions. 
1255 
8.3 
Statistical analysis 
1256 
A detailed Statistical Analysis Plan (SAP) will be prepared for this study before the final analysis. An 
1257 
overview is presented in the following sections. 
1258 
8.3.1 
Non-inferiority hypotheses test 
1259 
Non-inferiority will be tested using a one-sided type I error of 2.5% (equivalently a two-sided 95% 
1260 
confidence interval [CI]): 
1261 
𝐻0: 𝜃≥𝛥  𝑣𝑠.  𝐻1: 𝜃< 𝛥 
1262 
Non-inferiority will be concluded if the upper bound of the two-sided 95% CI for  
1263 
𝜃 is strictly less than Δ (3.0 weeks). 
1264 

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8.3.2 
Analysis populations 
1265 
In non-inferiority trials, intention-to-treat (ITT) analyses may be biased toward non-inferiority due to 
1266 
treatment cross-over and non-adherence. We intend to analyze both the per-protocol (PP) and ITT 
1267 
populations. The primary non-inferiority analysis will be performed in the PP population. A supportive 
1268 
analysis will be performed in the ITT population. Non-inferiority will be considered robust if conclusions 
1269 
are consistent in both PP and ITT analyses. We suspect very few cases will cross over. We suspect to 
1270 
find similar results in both groups and a discrepancy would warrant close examination of the results. 
1271 
8.3.3 
Per-Protocol (PP) population 
1272 
Per-Protocol (PP) population will include all randomized participants who  
1273 
 (i) received the allocated surgical intervention (BIN or TEN) as randomized 
1274 
 (ii) had no major protocol deviations expected to materially affect fracture healing assessment 
1275 
 (iii) contributed sufficient radiographic follow-up to define interval-censored time to union.  
1276 
 
1277 
8.3.3.1 Major protocol deviations 
1278 
Major protocol deviations resulting in exclusion from the PP population will include:  
1279 
(1) implantation of a non-allocated device or cross-over to the alternate trial implant 
1280 
(2) failure to undergo intramedullary fixation after randomization 
1281 
(3) major deviations in post-operative immobilization that alter the treatment package (e.g., cast duration 
1282 
differing by more than ±7 days from the planned duration, unless medically indicated and documented) 
1283 
(4) healing-related reoperation prior to reaching the radiographic healing threshold (e.g., revision fixation 
1284 
for loss of reduction or refracture) 
1285 
(5) missing radiographic assessments such that the healing interval cannot be determined (e.g., 
1286 
absence of any post-operative radiograph beyond the initial post-operative imaging or missing 
1287 
consecutive assessments preventing interval definition). 
1288 
 
1289 
8.3.3.2 Minor protocol deviations 
1290 
Minor deviations (e.g., visit timing deviations within predefined windows) will not lead to PP exclusion 
1291 
and will be handled analytically through the interval-censored time-to-event framework. 
1292 
8.3.4 
Intention-to-Treat (ITT) population 
1293 
Intention-to-Treat (ITT) population will include all randomized participants analyzed according to their 
1294 
randomized treatment allocation, regardless of the treatment actually received, protocol deviations, or 
1295 
subsequent withdrawal from the assigned intervention. Participants will contribute all available follow-up 
1296 
data collected until withdrawal of consent or study end. The ITT population will be used for supportive 
1297 
analyses of the primary endpoint and for key secondary outcomes, complementing the primary Per-
1298 
Protocol analysis in this non-inferiority trial. 
1299 
8.3.5 
Testing for superiority 
1300 
If non-inferiority is established, superiority of BIN versus TEN will be assessed using the same 
1301 
confidence interval framework. Superiority will be concluded if the upper bound of the 95% CI for (BIN − 
1302 
TEN) is < 0 weeks. 
1303 
8.3.6 
Interval-censored union times 
1304 
Because union is assessed only at scheduled radiographic visits (every 2 weeks), the true time to union 
1305 
is interval-censored (occurring between the last assessment without union and the first assessment with 
1306 
union). The primary analysis will use an interval-censored time-to-event model. A parametric 
1307 

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accelerated failure time model (Weibull) will be used to estimate the treatment effect and its confidence 
1308 
interval on the pre-specified estimand scale (e.g., time ratio/acceleration factor, and/or model-based 
1309 
difference in median time to union in weeks). Sensitivity analyses will repeat the primary analysis using 
1310 
alternative parametric distributions (e.g., log-normal/log-logistic) to assess robustness. 
1311 
8.3.7 
Protocol violations 
1312 
Any protocol violations will be logged and reported to the sponsor within 10 working days. Violations 
1313 
generally increase risk or decrease benefit, affect the subject's rights, safety, or welfare, or the integrity 
1314 
of the data. 
1315 
8.3.8 
Intercurrent events 
1316 
Healing-related reoperation (e.g., for refracture, deep infection requiring implant removal, or nonunion) 
1317 
will be treated as an intercurrent event for the primary endpoint. In the primary analysis, participants will 
1318 
be censored at the last radiographic assessment prior to the intercurrent event. Sensitivity analyses will 
1319 
assess robustness using conservative assumptions, including classifying healing-related reoperation as 
1320 
not united within the follow-up window. 
1321 
8.3.9 
Patient discontinuation 
1322 
All premature discontinuations are registered in the eCRF. 
1323 
8.3.10 Missing data 
1324 
To avoid missing data all required fields in the eCRF are mandatory and the researcher is informed of 
1325 
missing or wrong input during the entry phase. All data is sought to be put into the eCRF during the 
1326 
follow-up visit or immediately after and no later than 10 days after the visit. In this way participants can 
1327 
be contacted in due time in case of missing information. The reason for any missing data will be 
1328 
investigated and reported. 
1329 
Because the primary endpoint is assessed at discrete radiographic time points, time to union will be 
1330 
analyzed using an interval-censored time-to-event framework. Therefore, no imputation of union time 
1331 
will be performed. Missed radiographs will widen the censoring interval where subsequent images are 
1332 
available; participants without radiographic confirmation of union will be treated as right-censored at 
1333 
their last evaluable radiograph. Missing data for secondary outcomes will be handled as specified in the 
1334 
SAP. 
1335 
9 
Risk analysis 
1336 
A risk–benefit analysis of the study and the devices has been performed in accordance with ISO 14971 
1337 
and ISO 14155. 
1338 
9.1 
Treatment-related risks 
1339 
The risks in this study are associated with (1) the general risks of operative treatment for pediatric 
1340 
diaphyseal forearm fractures and (2) study-related procedures. 
1341 
 
1342 
Anticipated adverse events (AEs) that may occur as a direct result of the treatment, general anesthesia, 
1343 
and the devices are identified and listed in Section 7.2.6. These risks are inherent to the standard 
1344 
management of fractures requiring surgical stabilization and would be present irrespective of study 
1345 
participation. 
1346 
 
1347 

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Standard treatment using titanium elastic intramedullary nails (TEN) typically includes forearm 
1348 
radiographs at: 
1349 
 Preoperative / injury 
1350 
 Intraoperative – using fluoroscopy 
1351 
 Postoperative 
1352 
 At FU-visits after 2 and 6 weeks and before implant removal (6-12 months). 
1353 
9.2 
Study disadvantages 
1354 
Participation in the study involves additional outpatient follow-up visits. Participants will attend 
1355 
approximately 7–9 follow-up (FU) visits, which is 3–5 more visits than typically required with standard 
1356 
care. This increased visit burden may be considered a disadvantage. However, in our pilot study, 
1357 
parents demonstrated high adherence and were willing to attend all scheduled visits. 
1358 
 
1359 
A potential disadvantage is a longer time to radiographic union and/or a longer restriction from higher-
1360 
risk activities. Parent acceptability of a potential delay was explored in the pilot cohort by asking the 
1361 
maximum additional weeks beyond the usual 6-week restriction they would accept to avoid a second 
1362 
implant removal operation, and this perspective informed how we frame and communicate the study 
1363 
trade-off. 
1364 
9.3 
Study-related risks 
1365 
Based on previous studies of the Activa IM-Nail™ [7,38], we anticipate that the risk of complications 
1366 
with bioabsorbable intramedullary nails (BIN) is comparable to, or potentially lower than, that observed 
1367 
with titanium elastic intramedullary nails (TEN). 
1368 
9.3.1 
Radiation 
1369 
During follow-up, AP and lateral radiographs of the forearm will be obtained to assess fracture 
1370 
alignment and to evaluate the study’s primary outcome. Compared with standard care, an additional 3–
1371 
5 two-view forearm radiographic examinations are expected during follow-up. 
1372 
 
1373 
Radiation exposure from extremity radiography is very low. A typical effective dose is approximately 
1374 
0.001 mSv per projection; thus, a two-view examination (AP + lateral) is approximately 0.002 mSv. The 
1375 
cumulative additional effective dose is therefore estimated to be approximately 0.006–0.010 mSv. For 
1376 
context, The Danish Health Authority (Sundhedsstyrelsen) states that the average person in Denmark 
1377 
receives about 4 mSv per year from ionising radiation from all sources, most of it from natural 
1378 
background radiation. The additional study-related dose therefore constitutes only a very small fraction 
1379 
of annual background exposure and remains well below 0.1 mSv. 
1380 
 
1381 
All imaging will be performed using pediatric low-dose protocols in accordance with the ALARA (As Low 
1382 
As Reasonably Achievable) principle, with collimation and shielding as appropriate. No CT imaging is 
1383 
required for study purposes. 
1384 
9.3.2 
Breakage of Activa IM-nail 
1385 
Two cases have been reported worldwide in which a small fragment of the implant was sheared off by 
1386 
the sharp edge of the fracture, necessitating secondary surgery for fragment removal [38]. The 
1387 
Technique Guide for the Activa IM-Nail™ has subsequently been revised to emphasize additional 
1388 
caution when advancing the nail across the fracture site and to recommend only light hammer blows. 
1389 

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9.3.3 
Fracture re-angulation 
1390 
There may be an increased risk of fracture re-angulation when using BIN due to the greater flexibility of 
1391 
the implant. This risk is mitigated by immobilization in a circumferential above-elbow cast for 4 weeks, in 
1392 
accordance with the Technique Guide for the Activa IM-Nail™. 
1393 
9.4 
Loss of privacy 
1394 
There is a risk that participants’ private and confidential medical information could be disclosed, 
1395 
resulting in a breach of confidentiality. Measures to minimize this risk are described in Section 9.5. 
1396 
9.5 
Actions to minimize increased risks 
1397 
 General treatment-related risks are present regardless of study participation and will be managed 
1398 
according to standard of care at the study site. 
1399 
 
1400 
 The potential risk of fracture re-angulation with BIN is mitigated by immobilization in a circumferential 
1401 
above-elbow cast for 4 weeks, in accordance with the Technique Guide for the Activa IM-Nail™. 
1402 
 
1403 
 The risk of loss of privacy and confidentiality will be minimized through strict adherence to data 
1404 
protection, safety, and security procedures described elsewhere in this CIP and in applicable SOPs. 
1405 
 
1406 
 The study will be conducted in accordance with applicable national and international standards and 
1407 
guidelines, including ICH-GCP and ISO 14155. The ethical framework is based on the Declaration of 
1408 
Helsinki, supporting the protection of participant rights, safety, and well-being. 
1409 
10 Informed consent process 
1410 
10.1 Where? When? By whom? 
1411 
All patients and parents will be informed at Herlev Hospital by a delegated member of the research 
1412 
team. Study information will be provided during a preoperative visit as soon as possible after the injury, 
1413 
typically within 3 days. The parents are informed about the option of bringing a support person.  
1414 
10.2 How? 
1415 
The information will be provided in an undisturbed setting, allowing sufficient time for discussion and 
1416 
questions. Study information will be provided using plain and understandable language and may be 
1417 
supported by age-appropriate materials (e.g., short videos and toys) to facilitate communication with the 
1418 
child and the parents. The nature of the study, its purpose, the procedures involved, the expected 
1419 
duration, potential risks and benefits, and any discomfort associated with participation will be explained. 
1420 
 
1421 
In this pediatric study, the parents will receive face-to-face study information and provide written 
1422 
informed consent using the study-specific participant information and electronic informed consent form 
1423 
(eICF). The child will also be informed orally in an age-appropriate manner. Assent will be obtained from 
1424 
any child considered capable of understanding the basic information provided. 
1425 
 
1426 
The parents will be informed that their child’s medical records and radiographs will be accessed by 
1427 
authorized individuals involved in the study (see Section 12). Written informed consent will be obtained 
1428 
from the parents before any study-specific procedures or assessments are performed. 
1429 
 
1430 

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The parents will be provided with the study-specific participant information and eICF, as well as the 
1431 
general information on participation in health research issued by the Danish National Committee on 
1432 
Health Research Ethics, to support an informed decision regarding study participation. 
1433 
10.3 Patient and Public Involvement - Involvement of children and parents from the pilot study 
1434 
To improve feasibility and participant understanding before study start, children and parents who 
1435 
participated in the pilot study was invited to provide structured feedback on the randomized trial design 
1436 
and participant-facing materials. This activity was intended as user-testing/advisory input to refine 
1437 
procedures and communication; no clinical outcomes data was collected. 
1438 
 
1439 
Pilot parents helped inform the clinically acceptable non-inferiority margin by responding to a short 
1440 
acceptability question on the maximum additional waiting time to resume higher-risk activities (beyond 
1441 
the typical 6 weeks for metal implants) that they would accept in exchange for avoiding a second 
1442 
implant removal operation. 
1443 
 
1444 
Feedback also focused on (1) clarity and readability of the parent information sheet and age-adapted 
1445 
child assent materials, (2) acceptability and understanding of the randomized design, including the 
1446 
rationale for random and equal allocation between treatments, and (3) understanding and acceptability 
1447 
of the proposed blinding procedures and how these are explained to families. 
1448 
 
1449 
Input was collected via an online questionnaire and optional short semi-structured interviews over 
1450 
phone. Findings was used to revise materials and, where relevant, inclusion procedures. Participation 
1451 
was voluntary and will not affect current or future care; feedback is handled confidentially and reported 
1452 
in aggregated form. 
1453 
 
1454 
Secondary outcomes are based on the CORE-Kids core outcome set for childhood limb fractures by 
1455 
Marson et al. [44], which was developed using a Delphi consensus process with active involvement of 
1456 
children and parents to ensure the selected outcome domains reflect patient- and family-priorities. 
1457 
10.4 Voluntariness 
1458 
Parents and children will be informed that participation in the study is entirely voluntary. They may 
1459 
withdraw from the study at any time without providing a reason, and withdrawal of consent will not affect 
1460 
the child’s subsequent medical care or treatment. 
1461 
10.5 Assessor 
1462 
When inviting the family to the preoperative visit, the parents will be informed that they may bring an 
1463 
accompanying person (e.g., a support person) to the visit. 
1464 
10.6 Consideration time 
1465 
Unstable or displaced diaphyseal forearm fractures typically do not require emergency surgery; 
1466 
however, timely treatment is generally preferred. Surgical planning also requires time for the treating 
1467 
team to prepare for the specific procedure. Therefore, parents will be asked to provide informed consent 
1468 
as soon as possible and no later than the day before surgery. 
1469 
 
1470 
In most cases, parents will have at least 24 hours to consider participation. In cases where surgery is 
1471 
indicated and can be performed promptly (e.g., due to clinical urgency or available operating room 
1472 
capacity), consideration time may be shorter, but not less than 2 hours whenever feasible. Treatment 
1473 

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will not be delayed for study purposes; if the family declines or is unable to decide within the available 
1474 
timeframe, the child will be treated per standard care and not enrolled. 
1475 
10.7 Electronic Informed consent form (eICF) 
1476 
Parents will indicate their willingness to allow their child to participate in the study by signing and dating 
1477 
an ethics committee (EC) approved electronic informed consent form (eICF). The eICF will be 
1478 
administered via REDCap-link sent to the parent’s personal electronic mailbox (borger.dk) which 
1479 
requires identification login with secure “MitID”. The consent form will automatically be signed and dated 
1480 
on behalf of the research team and retained as part of the study records. 
1481 
 
1482 
The signed eICF will be filed, and a copy will be provided to the parents via secure electronic mail. A 
1483 
paper version of the informed consent form will be used if parents are unable to complete the eICF 
1484 
electronically. 
1485 
11 Adverse event reporting 
1486 
Sufficient safety data will be collected on adverse events (AEs) related to the injury, surgical procedure, 
1487 
implant use, and fracture healing, including information on implant revision and any required secondary 
1488 
surgery (i.e., complications). Detailed definitions of reportable AEs are provided in Section 7.2.6 of this 
1489 
CIP. 
1490 
11.1 Definitions 
1491 
In accordance with ISO 14155, adverse events (AEs), serious adverse events (SAEs), adverse device 
1492 
effects (ADEs), serious adverse device effects (SADEs), and device deficiencies are defined in the 
1493 
following sections. A flowchart illustrating AE categorization is provided in Figure 7. 
1494 
11.1.1 Adverse event 
1495 
An AE is defined as any untoward medical occurrence, unintended disease or injury, or untoward 
1496 
clinical signs (including abnormal laboratory findings) in patients. 
1497 
11.1.2 Serious adverse event 
1498 
A SAE is defined as any AE that: 
1499 
 led to death 
1500 
 led to a serious deterioration in health of the patient that either resulted in 
1501 
 a life-threatening illness or injury, or 
1502 
 a permanent impairment of a body structure or a body function, or 
1503 
 inpatient or prolonged hospitalization, or 
1504 
 a medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment 
1505 
to a body structure or a body function 
1506 
 
1507 
Note: Planned hospitalization for a pre-existing condition or a procedure required by the CIP, without 
1508 
serious deterioration in health, is not considered as a SAE. 
1509 
The definition of an AE does not imply that there is a relationship between the AE and the device or 
1510 
procedure under investigation. 
1511 
11.1.3 Adverse device effect and serious adverse device effect 
1512 
An ADE is defined as any AE related to the use of an investigational medical device. 
1513 

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1514 
Note 1: This definition includes AEs resulting from insufficient or inadequate instructions for use, 
1515 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical 
1516 
device (see also section 11.1.5 for definition of device deficiency). 
1517 
 
1518 
Note 2: This definition includes any event resulting from use error or from intentional misuse of the 
1519 
investigational medical device. 
1520 
A SADE is defined as any ADE that results in any of the consequences characteristic of a SAE. 
1521 
11.1.4 Unanticipated (serious) adverse device effect 
1522 
An unanticipated (serious) ADE (U(S)ADE) is defined as a (S)ADE which by its nature, incidence, 
1523 
severity, or outcome has not been identified in 7.2.3. 
1524 
11.1.5 Device deficiency 
1525 
A device deficiency is defined as an inadequacy of the medical device under investigation with respect 
1526 
to its identity, quality, durability, safety, or performance. 
1527 
 
1528 
Note 1: This includes malfunctions, use errors, and inadequate labeling. 
1529 
 
1530 
Problem
Medical event in 
study patient?
Non-medical 
complaint (e.g. 
technical problem)
Serious
Related to device/
procedure
Related to device/
procedure
Adverse event (AE)
Adverse device 
effect (ADE)
Serious adverse 
event (SAE)
Serious adverse 
device effect 
(SADE)
Yes
No
No
Yes
No
Yes
Yes
No
 
1531 
 
1532 
Figure 7: Schematic representation of AE categorization 
1533 

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11.2 Adverse event documentation 
1534 
The following information is collected: 
1535 
 Name and description of the event 
1536 
 Start date of the event (if applicable)  
1537 
 Actions taken due to the occurrence of the event 
1538 
 Outcome of the event 
1539 
 Date the patient has recovered from the event 
1540 
 Relationship to device or treatment under investigation 
1541 
 Severity of the event 
1542 
 Seriousness of the event 
1543 
If detailed information regarding an AE is not available at the time of initial reporting, completion of the 
1544 
AE form must be achieved at the next possible point in time. 
1545 
 
1546 
The following steps need to be taken after a study patient has experienced an SAE: 
1547 
 
1548 
 Initial SAE report: The investigator collects as much of the following information (see SAE form) as 
1549 
possible for reporting to the sponsor, EC and/or competent authorities: 
1550 
– Subject demographics 
1551 
– Date of occurrence of the event 
1552 
– Description of the event, including severity and relationship to device or procedure 
1553 
– Possible cause of SAE other than the investigational device 
1554 
– Relevant medical history 
1555 
– Relevant test/laboratory data 
1556 
– Concomitant medications 
1557 
– Name and contact details of the person who has reported the event. 
1558 
 The investigator completes the SAE form and follows the SAE reporting instructions according to the 
1559 
local applicable regulations. 
1560 
 FU of the event: The investigator collects all additional information to the event (e.g. discharge 
1561 
summary, autopsy reports) and sends these to the sponsor, if requested. The investigator is 
1562 
responsible for updating the SAE form. 
1563 
 Documentation: The investigator ensures that the SAE is properly documented in the patient’s chart, 
1564 
eCRF, SAE form, and that the appropriate forms are retained in the ISF. 
1565 
11.3 Serious adverse event reporting 
1566 
As soon as a research team member becomes aware of an SAE, this person will ensure that the 
1567 
following people will be notified: 
1568 
 PI 
1569 
 Sponsor: For regulated studies (e.g. investigational device exemption), the sponsor will also report this 
1570 
information to the appropriate regulatory body. 
1571 
 EC 
1572 
 The investigator is obliged to submit the SAE form within 24 hours after becoming aware of the event. 
1573 
 Each SAE needs to be reported by the investigator to the EC according to their regulatory 
1574 
requirements. 
1575 
 The timelines of AE reporting are specified in the local applicable regulations. 
1576 

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11.4 Follow-up of adverse events 
1577 
Each AE will be followed up until resolved with or without persistent damage or until the end of the 
1578 
patient’s study participation. 
1579 
 
1580 
All patients experiencing an AE must be monitored until the symptoms subside and any clinically 
1581 
relevant changes in laboratory values have returned to baseline, or until there is a satisfactory 
1582 
explanation for the changes observed. The results of any additional diagnostic measure (not included in 
1583 
the CIP) that are obtained because of the occurrence of an AE or SAE should be attached to the eCRF 
1584 
highlighting the date on which these measurements were taken. 
1585 
 
1586 
For any deaths occurring during the study, a postmortem report must be supplied by the investigator to 
1587 
the sponsor, whenever possible. 
1588 
11.5 Adverse event review 
1589 
All documented AEs will be reviewed by a medical expert for completeness, medical correctness of the 
1590 
data and the classification into AE, SAE, ADE, SADE, U(S)ADE according to ISO 14155 definitions, as 
1591 
described in the SOP "Adverse Event – Documentation and Reporting" according to the “Guidelines for 
1592 
adverse event reporting under directives 90/385/eec and 93/42/eec”. 
1593 
 
1594 
Furthermore, the medical expert performs the review according to the process defined by the 
1595 
manufacturer. In case of an ADE or SADE, the manufacturer's Complaint Handling Unit needs to be 
1596 
informed using the AE and SAE review form provided by the manufacturer (see flowchart added below). 
1597 
In addition, a device report form is sent to the clinic, containing the following questions: 
1598 
 Patient's demographics 
1599 
 Name and contact details of the surgeon and clinic 
1600 
 Device related information (e.g. decontamination, article number) 
1601 
 Liability and insurance related details 
1602 
 
1603 
The manufacturer is in charge of supporting the study site in collecting this information. 
1604 

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Event
Classification by 
investigator
AOCID
Adverse event
Serious adverse 
event
Device/procedure 
related
Device/procedure 
related
No reporting 
required to 
manufacturer
Report and inform 
manufacturer
Possible or yes
Possible or yes
No
No
 
1605 
 
1606 
Figure 8: Adverse event review and reporting flowchart 
1607 
11.6 Device deficiency reporting 
1608 
The following information is collected by the investigator and reported to the sponsor: 
1609 
 Specification of the deficient device 
1610 
 Name and description of the deficiency 
1611 
 Date of the start and resolution (occurrence) of the deficiency (if applicable) 
1612 
 Actions taken due to the occurrence of the deficiency 
1613 
 Consequence of the deficiency (i.e. if the deficiency may have led or led to an AE – if an AE occurred, 
1614 
this will be documented in the AE form) 
1615 
 
1616 
The sponsor will analyze the information and must report only some deficiencies that could have led to 
1617 
a SADE. If detailed information regarding device deficiency is not available at the time of initial 
1618 
reporting, completion of the device deficiency form must be achieved at the next possible point in time. 
1619 
11.7 Device deficiency review 
1620 
In case of licensed medical device under investigation this is reported as per local law and not within the 
1621 
study. Additionally, if it is an investigational device, the sponsor will provide the procedures. 
1622 
 
1623 
Furthermore, the medical expert performs the review according to the process defined by the 
1624 
manufacturer. 
1625 
 
1626 
The manufacturer oversees supporting the study site in collecting this information as described in the 
1627 
SOP "Adverse Event – Documentation and Reporting".  
 
1628 

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12 Data management 
1629 
12.1 Data collection, source data, storage, and archiving 
1630 
Data management will be performed by the Principal Investigator (PI). Data handling and protection will 
1631 
be conducted in accordance with ISO 14155, ICH-GCP, and applicable national and institutional 
1632 
regulations. 
1633 
 
1634 
The study complies with the EU General Data Protection Regulation (GDPR) and Danish data 
1635 
protection legislation (Databeskyttelsesloven and Databeskyttelsesforordningen). 
1636 
 
1637 
The electronic case report form (eCRF) will capture all study data for each participant, as specified in 
1638 
this CIP. Any modification of the eCRF will be made only if necessary and in accordance with an 
1639 
approved amendment to the CIP. 
1640 
 
1641 
A minimal screening log will be maintained separately from the study database, as described in Section 
1642 
6.1.4.1. 
1643 
12.1.1 Electronic Hospital records (EHR) 
1644 
No study-related access to the patient’s electronic hospital record (EHR) will occur before informed 
1645 
consent for study participation has been obtained. 
1646 
 
1647 
Parents will be asked to consent to EHR access for the purposes of planning and conducting follow-up 
1648 
visits, admissions, and surgery, and for collection of relevant study data. This includes permission to: 
1649 
 
1650 
 retrieve participant-related data and review clinical documentation related to outpatient visits, 
1651 
admissions, surgical procedures, and any adverse events (AEs); 
1652 
 access and review radiographic imaging; and 
1653 
 maintain EHR access until completion of the study. 
1654 
 
1655 
By providing consent, parents authorize the Principal Investigator (PI) and relevant authorities to access 
1656 
information in the patient’s medical record for the purpose of conducting the study and for oversight 
1657 
activities, including self-inspection, quality control, and monitoring, as required. 
1658 
 
1659 
The patient’s hospital records are stored securely in the hospital EHR system (Epic Systems 
1660 
Corporation, Verona, Wisconsin, USA). 
1661 
12.1.2 Electronic CRF 
1662 
For this study, an electronic case report form (eCRF) has been designed to accommodate the specific 
1663 
features of the study design. Access to the eCRF is password protected and role-based, with functions 
1664 
assigned according to user responsibilities. The eCRF will be completed in a timely manner after each 
1665 
participant visit or other documentable event, typically within 7 days. 
1666 
 
1667 
In general, data recorded in the hospital patient record are considered source data. Data collected 
1668 
through participant- and investigator-completed electronic questionnaires are also regarded as source 
1669 
data. 
1670 
The eCRF is stored securely using Research Electronic Data Capture (REDCap; Vanderbilt University, 
1671 
USA), hosted by the Capital Region of Denmark. 
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12.2 Imaging data 
1673 
Radiographs are stored securely in the hospital’s Picture Archiving and Communication System 
1674 
(PACS). For the blinding process, radiographs provided for outcome assessment will be de-identified 
1675 
and will not contain patient-identifiable information. The images will be labeled only with the participant’s 
1676 
numeric study identifier code. 
1677 
12.3 Confidentiality 
1678 
Participant privacy and confidentiality will be maintained throughout the study. The eCRF and all other 
1679 
study documents transferred to the sponsor will be de-identified and will contain only the participant’s 
1680 
numeric study identifier code. The study site will maintain the linkage between the study identifier code 
1681 
and the participant’s identity. 
1682 
 
1683 
Fully identifiable information may be reviewed for the purpose of source data verification and 
1684 
confirmation of eCRF entries only at the study site. Such review may be performed by the sponsor or 
1685 
the sponsor’s designee, regulatory authorities, or quality assurance personnel, in accordance with 
1686 
applicable site-specific regulations and procedures. Personal medical information will be treated as 
1687 
confidential at all times. 
1688 
 
1689 
The informed consent materials will describe confidentiality safeguards and will include permission for 
1690 
authorized access to relevant medical information for study conduct and oversight purposes. 
1691 
13 Study management and quality control 
1692 
13.1 Contract Research Organization 
1693 
No Contract Research Organization (CRO) will be engaged for this clinical investigation. 
1694 
13.2 Training and organization at the study site 
1695 
Prior to enrolling the first participant, Sub-Investigators (SIs) and study coordinator(s) (SCs) will receive 
1696 
study-specific training. Training will cover the CIP procedures, inclusion and exclusion criteria, eCRF 
1697 
completion, and relevant requirements under ISO 14155 and ICH-GCP. Training will be conducted by 
1698 
the Principal Investigator (PI). In the event of changes in study site personnel, new staff will undergo the 
1699 
same training prior to performing any study-related tasks. 
1700 
 
1701 
The PI holds current GCP (or equivalent) training/certification. 
1702 
 
1703 
An Investigator Site File (ISF) will be maintained at the study site and will contain all essential study 
1704 
documents. 
1705 
 
1706 
The PI is responsible for overall supervision of the study and will provide direction, oversight, and 
1707 
training to delegated research personnel as required. 
1708 
14 Monitoring and safety oversight 
1709 
An independent monitor will be appointed before enrolment of the first participant. The monitor will be 
1710 
independent of both the research group and the Department of Orthopedic Surgery and may be based 
1711 
in another department at Copenhagen University Hospital - Herlev and Gentofte, or in another 
1712 
appropriate hospital unit. The monitor will have no role in recruitment, informed consent discussions, 
1713 

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treatment allocation, postoperative outcome assessment, radiographic endpoint evaluation, or statistical 
1714 
analysis. 
1715 
 
1716 
Monitoring will be performed according to a written monitoring plan and will focus on trial-critical 
1717 
processes and data, including informed consent documentation, eligibility, randomization, device 
1718 
traceability/accountability, source data verification for the primary endpoint, protocol deviations, and the 
1719 
completeness and timeliness of SAE/SADE reporting. Monitoring findings will be documented in written 
1720 
monitoring reports, and any corrective and preventive actions will be followed to resolution by the 
1721 
Principal Investigator and sponsor. 
1722 
 
1723 
Clinical safety oversight remains the responsibility of the Principal Investigator and sponsor as 
1724 
described in Sections 11 and 19. Any monitoring finding considered relevant to participant safety or data 
1725 
integrity will be communicated without undue delay to the sponsor and Principal Investigator. 
1726 
15 Regulatory affairs 
1727 
The Clinical Investigation Plan (CIP), associated documents, investigator financial disclosures, and the 
1728 
participant information and informed consent forms (ICFs) will be submitted to the relevant ethics 
1729 
committee (EC) for review and approval. The EC will be kept informed of study progress and relevant 
1730 
events in accordance with its regulations and procedures. 
1731 
 
1732 
If additional regulatory approvals are required, the study will commence only after all necessary 
1733 
approvals have been obtained from the appropriate authorities. 
1734 
16 Ethics 
1735 
As described in Section 9, the risks associated with surgical treatment of pediatric diaphyseal forearm 
1736 
fractures are inherent to standard clinical care. Participation in this study is not expected to materially 
1737 
increase treatment-related risk. The incremental burdens of participation are primarily additional follow-
1738 
up visits and radiographs; the additional radiation exposure is minimal, and follow-up procedures are 
1739 
designed to support both patient safety and robust outcome assessment. 
1740 
 
1741 
The study addresses a clinically relevant question: whether bioabsorbable intramedullary nails (BIN) 
1742 
provide an acceptable (non-inferior) time to radiographic healing compared with titanium elastic 
1743 
intramedullary nails (TEN). 
1744 
 
1745 
The ethical balance of this trial includes a patient-relevant trade-off: potential avoidance of a second 
1746 
implant removal operation versus the possibility of delayed healing and/or delayed return to higher-risk 
1747 
activities. To ensure this trade-off is communicated transparently and reflects family priorities, parents 
1748 
from the pilot cohort reviewed the information materials and contributed acceptability input on the 
1749 
maximum additional weeks of activity restriction they would consider acceptable. 
1750 
 
1751 
The study will be conducted in accordance with the principles of the Declaration of Helsinki and 
1752 
applicable requirements under ICH-GCP and ISO 14155. Participation is voluntary. Parents and 
1753 
children will be informed that they may withdraw consent at any time without consequences for the 
1754 
child’s current or future medical care. Children will be informed in an age-appropriate manner, and 
1755 

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assent will be obtained when appropriate. Participant confidentiality and data protection will be ensured 
1756 
as described in Section 12. 
1757 
 
1758 
We acknowledge that longer-term registry-based follow-up could provide valuable supplementary 
1759 
information on later healthcare utilization and complications related to the two treatment strategies, 
1760 
including implant removal procedures, reoperations, refracture, and other late healthcare contacts. An 
1761 
approximately 5-year registry-based follow-up is therefore considered scientifically relevant. However, 
1762 
such follow-up is not part of the present active study period and will only be undertaken following a 
1763 
separate protocol amendment and any required ethics, data protection, and registry approvals. 
1764 
17 Patient insurance 
1765 
As with all treatment provided within the Danish healthcare system, all participants are covered by the 
1766 
Danish Patient Compensation Association (Patienterstatningen). 
1767 
18 Study report and publication policy 
1768 
18.1 Final Study Report 
1769 
The results of the statistical analyses will be summarized in a statistical report, which will form the basis 
1770 
for the comprehensive Final Study Report (FSR). The comprehensive FSR will serve as the primary 
1771 
source document for subsequent publications. 
1772 
18.2 Publication 
1773 
The publication strategy will be agreed between the sponsor and the Principal Investigator (PI), and any 
1774 
other relevant parties. 
1775 
 
1776 
This Clinical Investigation Plan (CIP) may be submitted for publication in a peer-reviewed international 
1777 
journal. 
1778 
 
1779 
The study will be reported to the European database on medical devices (EUDAMED) in accordance 
1780 
with the Medical Device Regulation (EU) 2017/745, as applicable. 
1781 
 
1782 
The final study results—including positive, negative, and inconclusive findings—will be submitted for 
1783 
publication in a peer-reviewed international orthopedic journal and may also be presented at national 
1784 
and international scientific meetings. 
1785 
If publication in a peer-reviewed journal is not achieved within a reasonable period after completion of 
1786 
the Final Study Report, the results will instead be made publicly available through an alternative publicly 
1787 
accessible channel, such as a preprint server and/or an institutional or sponsor repository 
1788 
19 Termination criteria 
1789 
Study progress, including recruitment and safety aspects, will be closely monitored in collaboration with 
1790 
the sponsor. The sponsor may decide to terminate the study for reasons defined in Section 19.1. In the 
1791 
event of early study termination, all participants already enrolled will, where feasible, continue follow-up 
1792 
until the final follow-up visit as defined in this CIP. 
1793 

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Page 57 of 66 
 
19.1 Stopping rules 
1794 
To identify potential safety signals or unexpected complications, an interim safety review will be 
1795 
performed after approximately 50% of the planned randomized participants have reached the 12-week 
1796 
follow-up visit (or have achieved radiographic healing, whichever occurs first). 
1797 
 
1798 
The interim safety review will be conducted by the PI in collaboration with the sponsor and will include 
1799 
review of adverse events (AEs), adverse device effects (ADEs), serious adverse events (SAEs), serious 
1800 
adverse device effects (SADEs), and key clinical outcomes (refracture, deep infection, reoperation, loss 
1801 
of reduction, delayed union). If predefined stopping criteria are met, recruitment will be temporarily 
1802 
paused while the events are reviewed and appropriate actions are taken (including notification of the 
1803 
ethics committee, as applicable). 
1804 
 
1805 
This interim review is for safety monitoring only (AEs/ADEs/SAEs/SADEs and prespecified healing-
1806 
related safety signals including refracture and delayed healing) and is not a formal interim analysis of 
1807 
the primary noninferiority hypothesis; no early stopping for noninferiority/superiority efficacy is planned, 
1808 
and no alpha-spending adjustment will be applied based on this safety review. 
1809 
 
1810 
Recruitment will be put on hold for safety reasons if at least one of the following incidents occurs and is 
1811 
assessed as possibly related to the investigational device (BIN): 
1812 
 
1813 
 Refracture: An absolute refracture rate >25% (within the study follow-up period) will not be tolerated 
1814 
and will constitute a criterion for pausing recruitment. 
1815 
 Delayed healing: An observed mean time to radiographic healing >12 weeks in the investigational 
1816 
(BIN) group will constitute a criterion for pausing recruitment. 
1817 
 
1818 
After review, the sponsor and PI will decide whether recruitment can resume unchanged, resume with 
1819 
protocol modifications/risk-mitigation measures, or whether the study should be terminated. 
1820 
20 Disclosures and economy 
1821 
The initiative for this study has been taken solely by the authors. 
1822 
 
1823 
The authors and affiliated colleagues have not received financial payments or other benefits from any 
1824 
commercial entity related to the subject of this study. The authors declare that they have no conflicts of 
1825 
interest. 
1826 
 
1827 
Participants will not receive any financial compensation, gifts, or other economic benefits for 
1828 
participation in this study. 
1829 
21 Deviations from the Clinical Investigation Plan 
1830 
Deviations from the procedures described in this CIP, or changes to the CIP without following the 
1831 
defined process, are not permitted. 
1832 
 
1833 
A CIP deviation is any non-adherence to the protocol that does not involve eligibility (inclusion/exclusion 
1834 
criteria), the primary endpoint, or compliance with GCP/ISO 14155 requirements. Deviations are 
1835 

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Clinical Investigation Plan (CIP) 
 
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Page 58 of 66 
 
considered minor and are not expected to have a major impact on participant safety or data integrity. 
1836 
Deviations will be documented and reported to the sponsor within 10 working days. 
1837 
 
1838 
A CIP violation is any significant divergence from the protocol by the participant, investigator, sponsor, 
1839 
or other responsible party that may affect, for example, eligibility (inclusion/exclusion criteria), the 
1840 
primary endpoint, or compliance with GCP/ISO 14155 requirements. The sponsor must be notified 
1841 
within 5 working days of becoming aware of the violation. Violations will be documented at the study site 
1842 
and recorded in the eCRF. 
1843 
22 Amendments to the Clinical Investigation Plan 
1844 
No changes to the approved CIP are permitted except where necessary to eliminate an immediate 
1845 
hazard to participant safety or where changes are purely administrative or logistical and do not affect 
1846 
participant safety or the scientific validity of the study. Any urgent change implemented to protect the 
1847 
life, health, or well-being of enrolled participants will be reported to the relevant bodies in accordance 
1848 
with applicable requirements, and no later than 5 days after implementation. 
1849 
 
1850 
If changes to this CIP become necessary during study conduct, a formal amendment will be prepared, 
1851 
issued, and submitted for approval and/or notification to the relevant ethics committee and other 
1852 
required authorities, as applicable, prior to implementation. 
1853 
23 Time schedule 
1854 
Ethics Committee approvals 
2.2026 
to 
05.2026 
First patient/first visit 
 
 
05.2026 
Last patient/first visit 
 
 
05.2029 
Last patient/last visit 
 
 
05.2031 
Data analysis 
06.2031 
to 
12.2031 
Final Study Report 
01.2032 
to 
03.2032 
24 Authors 
1855 
CIP developed by 
1856 
 
1857 
PI 
Morten Jon Andersen, MD 
 
Department of Orthopedic Surgery Copenhagen University 
Hospital - Herlev 
and Gentofte, Copenhagen, Denmark 
Additional author(s) 
Jeppe Vejlgaard Rasmussen, MD, ph.d., professor 
Rasmus Wejnold Jørgensen, MD, ph.d. 
 
1858 
CIP approval signatures 
1859 

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Page 59 of 66 
 
 
1860 
Name 
Function 
Date 
Signature 
Morten Jon 
Andersen 
Principal Coordinating 
Investigator 
 
 
 
1861 
25 Reference list 
1862 
1. British Orthopaedic Association Standard for Trauma (BOAST): Early Management of Paediatric 
1863 
Forearm Fracture. Injury. 2021;52:2052. https://doi.org/10.1016/j.injury.2021.07.043 
1864 
2. Waters PM, Skaggs DL, Flynn JM (Jack), Court-Brown C. Rockwood and Wilkins’ fractures in 
1865 
children. 9th ed. Wolters Kluwer; 2019.  
1866 
3. Poutoglidou F, Metaxiotis D, Kazas C, Alvanos D, Mpeletsiotis A. Flexible intramedullary nailing in the 
1867 
treatment of forearm fractures in children and adolescents, a systematic review. J Orthop. Elsevier; 
1868 
2020;20:125–30. https://doi.org/10.1016/j.jor.2020.01.002 
1869 
4. Lascombes P, Haumont T, Journeau P. Use and abuse of flexible intramedullary nailing in children 
1870 
and adolescents. J Pediatr Orthop. 2006;26:827–34. 
1871 
https://doi.org/10.1097/01.bpo.0000235397.64783.d6 
1872 
5. Fernandez FF, Langendörfer M, Wirth T, Eberhardt O. Failures and complications in intramedullary 
1873 
nailing of children’s forearm fractures. J Child Orthop. 2010; https://doi.org/10.1007/s11832-010-0245-y 
1874 
6. Simanovsky N, Tair MA, Simanovsky N, Porat S. Removal of flexible titanium nails in children. J 
1875 
Pediatr Orthop. 2006;26:188–92. https://doi.org/10.1097/01.bpo.0000218534.51609.aa 
1876 
7. Korhonen L, Perhomaa M, Kyrö A, Pokka T, Serlo W, Merikanto J, et al. Intramedullary nailing of 
1877 
forearm shaft fractures by biodegradable compared with titanium nails: Results of a prospective 
1878 
randomized trial in children with at least two years of follow-up. Biomaterials. Elsevier; 2018;185:383–
1879 
92.  
1880 
8. Mäyränpää MK, Mäkitie O, Kallio PE. Decreasing incidence and changing pattern of childhood 
1881 
fractures: A population-based study. J Bone Miner Res. 2010;25:2752–9. 
1882 
https://doi.org/10.1002/jbmr.155 
1883 
9. Rennie L, Court-Brown CM, Mok JYQ, Beattie TF. The epidemiology of fractures in children. Injury. 
1884 
2007;38:913–22. https://doi.org/10.1016/j.injury.2007.01.036 
1885 
10. Naranje SM, Erali RA, Warner WC, Sawyer JR, Kelly DM. Epidemiology of Pediatric Fractures 
1886 
Presenting to Emergency Departments in the United States. J Pediatr Orthop. 2016;36:e45–8. 
1887 
https://doi.org/10.1097/BPO.0000000000000595 
1888 
11. Sinikumpu JJ, Lautamo A, Pokka T, Serlo W. The increasing incidence of paediatric diaphyseal 
1889 
both-bone forearm fractures and their internal fixation during the last decade. Injury. 2012;43:362–6. 
1890 
https://doi.org/10.1016/j.injury.2011.11.006 
1891 
12. Jones G. Growth , Children , and Fractures. 2004;  
1892 

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Clinical Investigation Plan (CIP) 
 
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13. Rodríguez-Merchán EC. Pediatric fractures of the forearm. Clin Orthop. 2005. 
1893 
https://doi.org/10.1097/01.blo.0000156480.76450.04 
1894 
14. Flynn JM, Jones KJ, Garner MR, Goebel J. Eleven years experience in the operative management 
1895 
of pediatric forearm fractures. J Pediatr Orthop. 2010; https://doi.org/10.1097/BPO.0b013e3181d98f2c 
1896 
15. Sinikumpu JJ, Serlo W. The shaft fractures of the radius and ulna in children: Current concepts. J. 
1897 
Pediatr. Orthop. B. 2015. https://doi.org/10.1097/BPB.0000000000000162 
1898 
16. Morrey BF. The elbow and its disorders. Saunders; 2008.  
1899 
17. Sardelli M, Tashjian RZ, MacWilliams BA. Functional elbow range of motion for contemporary tasks. 
1900 
J Bone Jt Surg - Ser A. 2011;93:471–7. https://doi.org/10.2106/JBJS.I.01633 
1901 
18. Valone LC, Waites C, Tartarilla AB, Whited A, Sugimoto D, Bae DS, et al. Functional Elbow Range 
1902 
of Motion in Children and Adolescents. J Pediatr Orthop. 2020;40:304–9. 
1903 
https://doi.org/10.1097/BPO.0000000000001467 
1904 
19. Cruz AI, Kleiner JE, DeFroda SF, Gil JA, Daniels AH, Eberson CP. Increasing rates of surgical 
1905 
treatment for paediatric diaphyseal forearm fractures: A national database study from 2000 to 2012. J 
1906 
Child Orthop. 2017; https://doi.org/10.1302/1863-2548.11.170017 
1907 
20. Sinikumpu J-J, Victorzon S, Antila E, Pokka T, Serlo W. Nonoperatively treated forearm shaft 
1908 
fractures in children show good long-term recovery. Acta Orthop. 2014;85:620–5. 
1909 
https://doi.org/10.3109/17453674.2014.961867 
1910 
21. Kruppa C, Bunge P, Schildhauer TA, Dudda M. Low complication rate of elastic stable 
1911 
intramedullary nailing (ESIN) of pediatric forearm fractures: A retrospective study of 202 cases. 
1912 
Medicine (Baltimore). 2017;96:e6669. https://doi.org/10.1097/MD.0000000000006669 
1913 
22. Antabak A, Luetic T, Ivo S, Karlo R, Cavar S, Bogovic M, et al. Treatment outcomes of both-bone 
1914 
diaphyseal paediatric forearm fractures. Injury. 2013;44:S11–5. https://doi.org/10.1016/S0020-
1915 
1383(13)70190-6 
1916 
23. Han B, Wang Z, Li Y, Xu Y, Cai H. Risk factors for refracture of the forearm in children treated with 
1917 
elastic stable intramedullary nailing. Int Orthop. International Orthopaedics; 2019;43:2093–7. 
1918 
https://doi.org/10.1007/s00264-018-4184-4 
1919 
24. Liu Y, Zheng Y, Hayes B. Degradable, absorbable or resorbable—what is the best grammatical 
1920 
modifier for an implant that is eventually absorbed by the body? Sci. China Mater. 2017. 
1921 
https://doi.org/10.1007/s40843-017-9023-9 
1922 
25. Rokkanen PU, Böstman O, Hirvensalo E, Mäkelä EA, Partio EK, Pätiälä H, et al. Bioabsorbable 
1923 
fixation in orthopaedic surgery and traumatology. Biomaterials. 2000;21:2607–13. 
1924 
https://doi.org/10.1016/S0142-9612(00)00128-9 
1925 
26. Krucinska I, Zywicka B, Komisarczyk A, Szymonowicz M, Kowalska S, Zaczynska E, et al. Biological 
1926 
properties of low-toxicity PLGA and PLGA/PHB fibrous nanocomposite implants for osseous tissue 
1927 
regeneration. Part I: Evaluation of potential biotoxicity. Molecules. 2017;22:1–25. 
1928 
https://doi.org/10.3390/molecules22122092 
1929 
27. Xue AS, Koshy JC, Weathers WM, Wolfswinkel EM, Kaufman Y, Sharabi SE, et al. Local Foreign-
1930 
Body Reaction to Commercial Biodegradable Implants: An in Vivo Animal Study. Craniomaxillofacial 
1931 
Trauma Reconstr. 2014; https://doi.org/10.1055/s-0033-1364199 
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28. Waris E, Konttinen YT, Ashammakhi N, Suuronen R, Santavirta S. Bioabsorbable fixation devices in 
1933 
trauma and bone surgery: Current clinical standing. Expert Rev. Med. Devices. Taylor & Francis; 2004. 
1934 
p. 229–40. https://doi.org/10.1586/17434440.1.2.229 
1935 
29. Tiainen J, Soini Y, Törmälä P, Waris T, Ashammakhi N. Self-reinforced polylactide/polyglycolide 
1936 
80/20 screws take more than 1 1/2 years to resorb in rabbit cranial bone. J Biomed Mater Res - Part B 
1937 
Appl Biomater. 2004;70:49–55. https://doi.org/10.1002/jbm.b.30013 
1938 
30. Perhomaa M, Pokka T, Korhonen L, Kyrö A, Niinimäki J, Serlo W, et al. Randomized Controlled 
1939 
Trial of the Clinical Recovery and Biodegradation of Polylactide-co-glycolide Implants Used in the 
1940 
Intramedullary Nailing of Children’s Forearm Shaft Fractures with at Least Four Years of Follow-Up. J 
1941 
Clin Med. 2021;10:995. https://doi.org/10.3390/jcm10050995 
1942 
31. Schmittenbecher PP. Implant removal in children. Eur J Trauma Emerg Surg. 2013;39:345–52. 
1943 
https://doi.org/10.1007/s00068-013-0286-2 
1944 
32. Lieber J, Dietzel M, Scherer S, Schäfer JF, Kirschner H-J, Fuchs J. Implant removal associated 
1945 
complications after ESIN osteosynthesis in pediatric fractures. Eur J Trauma Emerg Surg Off Publ Eur 
1946 
Trauma Soc. 2022;48:3471–8. https://doi.org/10.1007/s00068-021-01763-4 
1947 
33. Zn K, Lc M, Tz O, Dv C. Preoperative anxiety in children. Predictors and outcomes. Arch Pediatr 
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Adolesc Med [Internet]. Arch Pediatr Adolesc Med; 1996 [cited 2024 Jan 8];150. 
1949 
https://doi.org/10.1001/archpedi.1996.02170370016002 
1950 
34. Fincher W, Shaw J, Ramelet A-S. The effectiveness of a standardised preoperative preparation in 
1951 
reducing child and parent anxiety: a single-blind randomised controlled trial. J Clin Nurs. 2012;21:946–
1952 
55. https://doi.org/10.1111/j.1365-2702.2011.03973.x 
1953 
35. Kain ZN, Wang S-M, Mayes LC, Krivutza DM, Teague BA. Sensory Stimuli and Anxiety in Children 
1954 
Undergoing Surgery: A Randomized, Controlled Trial. Anesth Analg. 2001;92:897–903. 
1955 
https://doi.org/10.1097/00000539-200104000-00018 
1956 
36. Vutskits L, Davidson A. Perioperative Anxiety in Children. Mill Anesth [Internet]. Ninth edition. 
1957 
Philadelphia, PA: Elsevier; 2020 [cited 2024 Jan 8]. https://www-clinicalkey-
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com.ep.fjernadgang.kb.dk/#!/content/book/3-s2.0-B9780323596046000778?scrollTo=%23hl0001284. 
1959 
Accessed 8 Jan 2024 
1960 
37. Böstman OM. Metallic or absorbable fracture fixation devices. A cost minimization analysis. Clin 
1961 
Orthop. 1996;233–9.  
1962 
38. Roeder C, Alves C, Balslev-Clausen A, Canavese F, Gercek E, Kassai T, et al. Pilot Study and 
1963 
Preliminary Results of Biodegradable Intramedullary Nailing of Forearm Fractures in Children. Children. 
1964 
2022;9:754. https://doi.org/10.3390/children9050754 
1965 
39. Piaggio G, Elbourne DR, Pocock SJ, Evans SJW, Altman DG, CONSORT Group. Reporting of 
1966 
noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA. 
1967 
2012;308:2594–604. https://doi.org/10.1001/jama.2012.87802 
1968 
40. Simić D, Stević M, Stanković Z, Simić I, Dučić S, Petrov I, et al. The safety and efficacy of the 
1969 
continuous peripheral nerve block in postoperative analgesia of pediatric patients. Front. Med. 2018. 
1970 
https://doi.org/10.3389/fmed.2018.00057 
1971 
41. Karanicolas PJ, Farrokhyar F, Bhandari M. Blinding: Who, what, when, why, how? Can J Surg. 
1972 
2010;53:345–8.  
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42. Wartolowska K, Beard D, Carr A. Blinding in trials of interventional procedures is possible and 
1974 
worthwhile. F1000Research. 2018;6:1663. https://doi.org/10.12688/f1000research.12528.2 
1975 
43. Karanicolas PJ, Bhandari M, Taromi B, Akl EA, Bassler D, Alonso-Coello P, et al. Blinding of 
1976 
outcomes in trials of orthopaedic trauma: an opportunity to enhance the validity of clinical trials. J Bone 
1977 
Joint Surg Am. 2008;90:1026–33. https://doi.org/10.2106/JBJS.G.00963 
1978 
44. Marson BA, Manning JC, James M, Craxford S, Deshmukh SR, Perry DC, et al. Development of the 
1979 
CORE-Kids core set of outcome domains for studies of childhood limb fractures. Bone Jt J. 2021;103-
1980 
B:1821–30. https://doi.org/10.1302/0301-620X.103B.BJJ-2020-2321.R2 
1981 
45. Morshed S, Corrales L, Genant H, Miclau T. Outcome assessment in clinical trials of fracture-
1982 
healing. J Bone Joint Surg Am. 2008;90 Suppl 1:62–7. https://doi.org/10.2106/JBJS.G.01556 
1983 
46. Whelan DB, Bhandari M, Stephen D, Kreder H, Mckee MD, Zdero R, et al. Development of the 
1984 
radiographic union score for tibial fractures for the assessment of tibial fracture healing after 
1985 
intramedullary fixation. J Trauma - Inj Infect Crit Care. 2010; 
1986 
https://doi.org/10.1097/TA.0b013e3181a7c16d 
1987 
47. Leow JM, Clement ND, Tawonsawatruk T, Simpson CJ, Simpson AHRW. The radiographic union 
1988 
scale in tibial (RUST) fractures: Reliability of the outcome measure at an independent centre. Bone Jt 
1989 
Res. 2016;5:116–21. https://doi.org/10.1302/2046-3758.54.2000628 
1990 
48. Kooistra BW, Dijkman BG, Busse JW, Sprague S, Schemitsch EH, Bhandari M. The radiographic 
1991 
union scale in tibial fractures: Reliability and validity. J Orthop Trauma. 2010;24:81–6. 
1992 
https://doi.org/10.1097/BOT.0b013e3181ca3fd1 
1993 
49. Patel SP, Anthony SG, Zurakowski D, Didolkar MM, Kim PS, Wu JS, et al. Radiographic scoring 
1994 
system to evaluate union of distal radius fractures. J Hand Surg. Elsevier Inc; 2014;39:1471–9. 
1995 
https://doi.org/10.1016/j.jhsa.2014.05.022 
1996 
50. Cooke ME, Hussein AI, Lybrand KE, Wulff A, Simmons E, Choi JH, et al. Correlation between RUST 
1997 
assessments of fracture healing to structural and biomechanical properties. J Orthop Res. 2018; 
1998 
https://doi.org/10.1002/jor.23710 
1999 
51. Litrenta J, Tornetta P, Mehta S, Jones C, O’Toole RV, Bhandari M, et al. Determination of 
2000 
Radiographic Healing: An Assessment of Consistency Using RUST and Modified RUST in 
2001 
Metadiaphyseal Fractures. J Orthop Trauma. 2015;29:516–20. 
2002 
https://doi.org/10.1097/BOT.0000000000000390 
2003 
52. Marson BA, Craxford S, Deshmukh SR, Grindlay DJC, Manning JC, Ollivere BJ. Quality of patient-
2004 
reported outcomes used for quality of life, physical function, and functional capacity in trials of childhood 
2005 
fractures. Bone Jt J. 2020;102-B:1599–607. https://doi.org/10.1302/0301-620X.102B12.BJJ-2020-
2006 
0732.R2 
2007 
53. Hicks CL, Von Baeyer CL, Spafford PA, Van Korlaar I, Goodenough B. The Faces Pain Scale - 
2008 
Revised: Toward a common metric in pediatric pain measurement. Pain. 2001;31:1177. 
2009 
https://doi.org/10.1016/S0304-3959(01)00314-1 
2010 
54. Bieri D, Reeve RA, Champion GD, Addicoat L, Ziegler JB. The faces pain scale for the self-
2011 
assessment of the severity of pain experienced by children: Development, initial validation, and 
2012 
preliminary investigation for ratio scale properties. Pain. 1990;41:139–50. https://doi.org/10.1016/0304-
2013 
3959(90)90018-9 
2014 

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Page 63 of 66 
 
55. Sinikumpu JJ, Lautamo A, Pokka T, Serlo W. Complications and radiographic outcome of children’s 
2015 
both-bone diaphyseal forearm fractures after invasive and non-invasive treatment. Injury. 2013;44:431–
2016 
6. https://doi.org/10.1016/j.injury.2012.08.032 
2017 
56. Lu D, Lin Z, Zhang J-D, Chen H, Sun L-J. Treatment of pediatric forearm midshaft fractures: Is there 
2018 
a difference between types of orthopedic surgeon? Orthop Traumatol Surg Res OTSR. 2017;103:119–
2019 
22. https://doi.org/10.1016/j.otsr.2016.11.008 
2020 
 
2021 
Appendix 1 - CIP approval 
2022 
 
2023 
Study site 
Department of Orthopedic Surgery 
Copenhagen University Hospital – Herlev and Gentofte 
Borgmester Ib Juuls Vej 1 | 2730 Herlev | Denmark 
 
2024 
 
2025 
CIP approval signature of Principal Investigator 
2026 
 
2027 
Name 
Position 
Date 
Signature 
Morten Jon 
Andersen 
MD, PI 
 
 
 
2028 
 
2029 
With signing this statement, I agree and confirm: 
2030 
 To have read and understood this CIP and to have informed and to have supervised the appropriate 
2031 
training of all research team members of this study site involved with the conduct of the study. 
2032 
 To assume responsibility to conduct the study in compliance with this protocol and future amendments 
2033 
at this study site. 
2034 
 To obtain written approval from the independent EC before initiating the clinical investigation at this 
2035 
study site. 
2036 
 To not implement any changes to the protocol or the corresponding procedures without written 
2037 
agreement from the sponsor and the EC, except where necessary to eliminate immediate risk to the 
2038 
study patients. 
2039 
 That I and all team members involved in the conduct of this clinical investigation are aware and trained 
2040 
in all aspects of ICH-GCP and all applicable regulatory requirements. 
2041 
 
 
2042 

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Appendix 2 - Study flowchart and allocation 
2043 
 
2044 
+
 
2045 

FOREST Trial - Time to healing in pediatric diaphyseal forearm fractures | Trial ID: 16-0302-99 
Clinical Investigation Plan (CIP) 
 
Version 1.1 - FINAL | 31 March 2026 | Confidential – For authorized use only 
Page 65 of 66 
 
Appendix 3 - Device table (Investigational device and comparator) 
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Investigational device (BIN) 
Comparator device (TEN) 
Device role in study 
Investigational device 
Comparator device 
Product type / generic 
name 
PLGA bioabsorbable 
intramedullary nail 
Titanium Elastic Intramedullary 
Nail 
Trade name 
Activa IM-Nail™ 
Titanium Elastic Nail (TEN™) 
System 
Manufacturer 
Bioretec Ltd., Tampere, Finland Synthes GmbH, Oberdorf,  
Switzerland 
Specific model(s) used 
in trial 
B-ANIM-27400 Activa IM-Nail™ 
2.7 x 400 mm 
B-ANIM-32400 Activa IM-Nail™ 
3.2 x 400 mm 
475.9xxS (xx=mm diameter) 
(sterile “S” variants) 
Sizes / range relevant 
to study 
2.0–3.2 mm x 200–400 mm 
1.5 mm × 300 mm 
2.0–3.0 mm × 440 mm 
CE-marked 
Yes 
Yes 
Device class (MDR) 
Class III 
Class III 
Notified Body 
DEKRA Certification B.V.  
(NB 0344) 
TÜV SÜD (NB 0123) 
Sterile 
Yes 
Yes 
Measuring function 
No 
No 
Reusable surgical 
device 
No 
No 
Invasive / implantable 
Yes / Yes 
Yes / Yes 
Incorporates medicinal 
substance / blood 
derivative 
No 
No 
Incorporates non-
viable tissues/cells 
(human/animal) 
No 
No 
Intended use 
(high-level) 
Intramedullary fixation of 
pediatric forearm diaphyseal 
fractures  
Bone fixation nails are intended 
for temporary fixation, correction 
and stabilization of bones 

FOREST Trial - Time to healing in pediatric diaphyseal forearm fractures | Trial ID: 16-0302-99 
Clinical Investigation Plan (CIP) 
 
Version 1.1 - FINAL | 31 March 2026 | Confidential – For authorized use only 
Page 66 of 66 
 
Target population (IFU) Pediatric 
Recommended for skeletally 
immature patients 
Key contraindications 
(headline) 
 Multifragmentary fractures 
 Metaphyseal or epiphyseal fractures 
 
General contraindications to internal fixation / use: 
 Active or suspected infection 
Key potential adverse 
events / residual risks 
Infection, malunion/non-union, neurovascular damage, implant 
migration/loosening/breakage, compartment syndrome, etc. 
Accessories / related 
components used 
BIN system instruments  
(awl, dilator, inserter, cutter, 
impactor, etc.) 
TEN system instruments  
(awl, inserter, cutter, impactor, 
extraction pliers, etc.) 
Sterilization / 
reprocessing notes 
Device is delivered in a sterile 
state and re-sterilization by any 
method is restricted in the 
labelling. 
Sterile devices: irradiated; single-
use devices not to be reused 
MRI information 
MRI safe 
MRI Conditional: non-clinical 3T 
testing described in IFU 
Implant removal 
No 
Routine removal after bone 
healing 
 
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