Generalizability of Overweight Patients With Knee Osteoarthritis Awaiting Knee Surgery Accepting to Join a Weight Loss Randomized Trial: Protocol for a Cross-sectional Study Comparing Baseline Characteristics and Propensity of Patients Accepting/Declining Enrolment
Conditions: Knee Osteoarthritis
Sponsor: Marius Henriksen

The INKA Generalizability Protocol: 1 
 
 
PROTOCOL: The INKA trial  
DATE: 09-01-2021 VERSION:  1 
 
Generalizability of overweight patients with knee osteoarthritis 
awaiting knee surgery accepting to join a weight loss randomized 
trial: Protocol for a cross-sectional study comparing baseline 
characteristics and propensity of patients accepting/declining 
enrolment 
 
Authors/Collaborators: 
Saber Muthanna Saber, MD, PhD Fellow; Robin Christensen, MSc, PhD, Professor; Marius 
Henriksen, PT, MSc, PhD, Professor; Henning Bliddal, MD, DMSc, Professor; Anders Troelsen, 
MD, PhD, Professor; Malene Regitze Bertelsen, MD, PhD Fellow, Camilla Toft Nielsen, MD, PhD 
Fellow; Kristine Ifigenia Bunyoz, MD, PhD fellow; Søren Overgaard, MD, PhD, Professor. 
 
Affiliations: 
SMS: 1 Copenhagen University Hospital, Bispebjerg, Department of Orthopaedic Surgery and Traumatology & 2The 
Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark. 
RC: 1The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen & 2Research Unit of Rheumatology, 
Department of Clinical Research, University of Southern Denmark, Odense University Hospital, Denmark. 
MH: The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark 
HB: The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark  
MRB: The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark 
AT: Copenhagen University Hospital, Hvidovre, Department of Orthopaedic Surgery 
CTN: Department of Radiology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark  
KIB: 1 Copenhagen University Hospital, Hvidovre, Department of Orthopaedic Surgery & 2The Parker Institute, 
Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark. 
SO: 1Copenhagen University Hospital, Bispebjerg, Department of Orthopaedic Surgery and Traumatology & 
2University of Copenhagen, Department of Clinical Medicine, Faculty of Health and Medical Sciences 
 
 
 

The INKA Generalizability Protocol: 2 
 
Corresponding author 
Professor Søren Overgaard, MD, PhD 
Department of Orthopaedic Surgery, Bispebjerg, Copenhagen University Teaching Hospitals, Denmark.  
Nielsine Nielsens Vej 5,  
DK- 2400 Copenhagen 2400 
Denmark  
e-mail: soeren.overgaard@regionh.dk  
ORCID iD: 0000-0001-6829-4787 
web: https://www.bispebjerghospital.dk/afdelinger-og-klinikker/ortopaedkirurgisk-afdeling/forskning-og-
udvikling/Sider/default.aspx  
 
Disclaimers 
The views expressed in the submitted protocol are the authors’ own and not an official position of the institution or 
funder. 
 
Source of support 
The Parker Institute, Bispebjerg and Frederiksberg Hospital is supported by a core grant from the Oak Foundation 
(OCAY-13-309). 
 
Conflict of interest declaration 
None declared. 
 
 
 

The INKA Generalizability Protocol: 3 
 
SUMMARY 
Background: Overweight is a main and modifiable risk factor for developing knee osteoarthritis (OA). 
Studies indicates a beneficial effect of weight loss on the symptoms of knee OA. The INtensive diet vs Knee 
Arthroplasty (INKA) trial is a RCT, which aims to assess weight loss as a non-inferior intervention and/or an 
alternative to surgical knee arthroplasty in overweight and obese patients suffering from knee OA. As RCTs 
carry a risk for selection bias and thereby risk for low external validity, comparison of the recruited trial 
participants and the invited participants, who decline trial participation will enable assessment of the 
external clinical validity and generalizability of the INKA trial 
Objective: The objective of this study is to compare baseline characteristics of overweight knee OA 
patients accepting vs. declining enrolment in the INKA trial to explore if enrolled patients differ 
systematically from the declining participants with respect to both measured as well as unmeasured 
baseline characteristics. 
Design: Cross-sectional study collecting baseline characteristics of patients with Knee OA eligible for 
enrolment in the INKA trial, whether accepting or declining enrolment. 
Setting: Potential trial participants will be identified during their routine visits in the orthopaedic outpatient 
clinics at Copenhagen University Hospital Bispebjerg-Frederiksberg and Copenhagen University Hospital 
Amager-Hvidovre. 
Participants: Adults ≥ 18 years old, obese (BMI≥30 kg/m2), with an indication for primary knee arthroplasty 
(unicondylar or total arthroplasty) due to knee OA are included either with consent or refusal to 
participation in the INKA trial. We will recruit 400 patients in total, 200 in each group.  
Measurements: Baseline characteristics for the 2 groups are obtained extracting data from the participants 
medical records including questionnaires answered by all patients, of which the main is The Oxford Knee 
Score (the primary outcome for INKA participants). 
Data synthesis: We will use standardized difference of the mean (or medians) of continuous variables or 
the prevalence of dichotomous baseline covariates between INKA and nINKA participants a standardized 
difference of ≥0.2 to indicate that there might be a meaningful imbalance in the baseline covariate, whereas 
a standardized difference ≥0.8 will be considered as definitive incomparability. We will also apply the PROC 
NPAR1WAY procedure (using SAS software) to compute empirical distribution function (EDF) statistics. 
Finally, we will do a logistic regression to calculate propensity scores to represent the probability that a 
consent participation based on observed covariates.  

The INKA Generalizability Protocol: 4 
 
Registration: This protocol will be registered with ClinicalTrials.gov before recruiting the participants. Data 
management (storage, analysis, backup and deletion) will be consistent with standard procedures of Region 
Hovedstaden. 
 
 

The INKA Generalizability Protocol: 5 
 
 
INTRODUCTION 
Osteoarthritis (OA) is the most common joint disorder in the world, with a prevalence of around 
16% for individuals aged ≥ 15 years, and around 23% for individuals older than 39 years old 
worldwide. It is found as a leading cause for disability and loss of function with huge costs to the 
society through lost workdays, early retirement and direct treatment costs (1,2). Knee OA stands 
for 83% of all OA localizations, with 250 million cases worldwide (3) Many risk factors, like 
increasing age, acute joint injury, joint deformity and overweight have been identified, where 
overweight is considered to be a main risk factor for developing knee OA (1,4). The treatment of 
knee OA is a multi-step process, that starts with physiotherapy, weight loss, non-pharmacological 
treatment and simple medical treatment as step one,  advanced pharmacological treatment as step 
2, a last pharmacological attempt on the third step, and ends with joint replacement for the end 
stage disease if not contra-indicated (5). Given the fact that the obesity is a modifiable risk factor, 
weight loss is an important part of the treatment strategy of knee OA (5,6). A weight reduction of 
over 5.1% bodyweight within 20-weeks period is found to significantly improve disability in a 
systematic review and meta-analysis from 2007 (7). A more recent randomized, 2-phase, parallel-
group trial found that a mean 10%  weight reduction with a 1-year weight maintenance program 
improves symptoms in patients with knee OA and a subsequent long term follow-up showed that 
the use of daily meal replacements or intermittent low-energy diet maintained weight reduction 
for 3 years (8,9). In the pursuit of reducing the incidence of joint replacement surgery, a cohort 
study from Australia suggests that the risk of total knee replacement (TKR) can be reduced with 
weight loss of >7.5% of body weight in adults with overweight or obesity, but no such correlation 
could be found for total hip replacement (THR) (10). Furthermore, a weight reduction of 10% before 
TKR surgery is found to improve the general health-related outcomes one year after TKR (11).  
The INtensive diet vs Knee Arthroplasty (INKA) trial is a RCT, which aims to assess 
weight loss as a non-inferior intervention and/or an alternative to surgical knee arthroplasty in 
overweight and obese patients suffering from knee OA. The INKA study carries by the nature 
design of a RCT a high internal validity. The external validity of the trial is important to know to 
convince professionals to change the treatment strategy, as it reflects the generalizability of the 
trial results.  

The INKA Generalizability Protocol: 6 
 
 
RATIONALE 
Many systematic reviews of published articles have found a tendency of poor representativeness 
of external validity (12–15). To interpret the generalizability of a RCT, evaluation of excluded and 
declining patients is of importance. In the INKA trial, we may speculate that those declining 
inclusion have a more severe knee problem whereas those who are included may be more 
concerned about having knee surgery. A comparison of the recruited trial participants and the 
invited participants, who decline trial participation on a range of clinical, para-clinical, and 
phenotypical variables will enable assessment of the external clinical validity and generalizability 
of the INKA trial, which will strengthen the usefulness and relevance of the INKA trial results. 
 
 
OBJECTIVE(S) 
The objective of this study is to compare baseline characteristics of overweight knee OA patients 
accepting vs. declining enrolment in the INKA trial, in order to explore if the enrolled patients differ 
systematically from the declining participants in both measured as well as unmeasured baseline 
characteristics. 
 
 
METHODS 
 Study design 
The INKA trial is designed as a pragmatic, randomized, parallel-group trial. The trial is designed to 
compare the effectiveness of a supervised weight loss program to surgical knee arthroplasty in 
obese individuals with knee OA. 
We will use a cross-sectional study design collecting baseline characteristics of 
patients with knee OA eligible for enrolment in the INKA trial, accepting or declining enrolment in 
the clinical trial, while recruiting patients for the trial. Data collection starts on the 01.01.2022 and 
ends with the inclusion of the last patient in INKA study (i.e. anticipated: 01-06-2023) Figure 1. 

The INKA Generalizability Protocol: 7 
 
 
Figure 1- study flow chart 
 Setting 
Potential trial participants will be identified by an investigator or his/her delegate in the 
orthopaedic outpatient clinics at Copenhagen University Hospital Bispebjerg-Frederiksberg and 
Copenhagen University Hospital Amager-Hvidovre. The identification of potential participants 
may occur during regular clinical visits. 
 
 Participants 
All patients found eligible in INKA study (inclusion criteria for INKA) and accepting and declining 
enrolment in the INKA study are invited to participate in our study. We report the number of 
patients assessed for eligibility and reasons of exclusion. Study participants will be adults (i.e. at 

The INKA Generalizability Protocol: 8 
 
least 18 years old), have a diagnosis of knee osteoarthritis with an indication for primary knee 
arthroplasty (unicondylar or total arthroplasty), and be obese (BMI≥30 kg/m2). An individual will be 
eligible for study participation if he/she meets the following criteria: 
1. Age 18 or more 
2. A clinical and radiological diagnosis of knee OA 
3. BMI ≥ 30 kg/m2 
4. Motivated for weight loss as by the provided program 
5. Signed informed consent. 
A possible participant will, however, be excluded from the study if he/she meets any of the 
following criteria: 
1. The scheduled surgery is for revision of an existing prosthesis 
2. Planned surgery for more than one knee within the observation period 
3. KA indication due to sequelae of fracture(s) 
4. Injection of medication or substances in the target knee within 3 months prior to 
participation 
5. Immuno-inflammatory arthritis as cause of the knee OA 
6. Current systemic treatment with glucocorticoids equivalent to > 7.5 mg of 
prednisolone/day 
7. Previous or planned obesity surgery 
8. Inability to understand or read Danish incl. instructions and questionnaires 
9. Any other condition or impairment that, in the opinion of the investigator (or 
his/her delegate), makes a potential participant unsuitable for participation or which 
obstruct participation. 
 
 Variables 
The following variables will be assessed at baseline independent of their acceptance to participate 
in the INKA Trial 
1. Age 
2. Sex 
3. Disease duration 

The INKA Generalizability Protocol: 9 
 
4. Height (meters) 
5. Body weight (kg) 
6. Type of scheduled arthroplasty (Total vs Unicondylar prosthesis) 
7. The Oxford Knee Score (OKS) 
8. Health outcome and quality of life survey (EuroQoL questionnaire) 
9. Use of analgesics 
10. The Knee injury and Osteoarthritis Outcome Score (KOOS) – 12 item short form 
11. Patient’s global assessment of impact of the knee in daily life (PGA) 
12. Illness perception questionnaire 
Table 1: Collected baseline characteristics 
Characteristics 
Patients accepting 
INKA group 
Patients declining 
nINKA group 
Standardised Difference 
Total, no. (%) 
 
 
 
Age, year 
 
 
 
Gender: 
 
 
 
Females, no. (%) 
 
 
 
Males, no. (%) 
 
 
 
Disease duration, years 
 
 
 
Height, meters 
 
 
 
Weight, kg 
 
 
 
Type of scheduled arthroplasty: 
 
 
 
Total knee arthroplasty, no. (%) 
 
 
 
Unicondylar knee arthroplasty, no. 
(%) 
 
 
 
The Oxford Knee Score (OKS) 
 
 
 
EuroQoL Index 
 
 
 
EuroQoL VAS 
 
 
 
Regular use of analgesics no. (%) 
 
 
 
Paracetamol/acetaminophen 
 
 
 
NSAIDs 
 
 
 
Acetylic acids 
 
 
 
Opiods  
 
 
 
The Knee injury and Osteoarthritis 
Outcome Score (KOOS) – 12 item short 
form: 
 
 
 

The INKA Generalizability Protocol: 10 
 
Pain score 
 
 
 
Function score 
 
 
 
QoL score 
 
 
 
Patient’s global assessment of impact 
of the knee in daily life (PGA) 
 
 
 
Illness perception questionnaire: 
 
 
 
Item 1, score 
 
 
 
Item 2, score 
 
 
 
Item 3, score 
 
 
 
Item 4, score 
 
 
 
Item 5, score 
 
 
 
Item 6, score 
 
 
 
Item 7, score 
 
 
 
Item 8, score 
 
 
 
 
 Data sources/measurements 
 
The Oxford Knee Score (Primary Outcome) 
The Oxford Knee Score (OKS) is a 12-item Patient Reported Outcome questionnaire developed 
specifically to assess the patient's perspective on the outcomes of knee arthroplasty (KA) with 
respect to combined pain and physical function. Standardized answer options are given (5 Likert 
boxes) and each question is assigned a score from 0 to 4. Thus, a total score is calculated that ranges 
from 0 and 48, with 48 indicating the best outcome. The OKS is short, practical, reliable, valid, and 
sensitive to clinically important changes over time (16). 
 
 
Health outcome and quality of life survey (EQ-5D-5L)  
EQ-5D-5L is a standardized patient-reported instrument for use as a measure of health outcome 
and quality of life. EQ-5D-5L is designed for self-completion by respondents and is ideally suited 
for use in surveys. 
The EQ-5D-5L consists of a descriptive system and the EQ Visual Analogue scale (EQ VAS). The 
descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression). Standardized answer options are given (5 Likert boxes) and each question 

The INKA Generalizability Protocol: 11 
 
is assigned a score from 1 to 3. It is simple, taking only a few minutes to complete. Instructions to 
respondents are included in the questionnaire. 
The EQ-5D VAS records the respondent’s self-rated health on a 20 cm vertical, visual 
analogue scale with endpoints labelled ‘the best health you can imagine’ and ‘the worst health you 
can imagine’. This information can be used as a quantitative measure of health as judged by the 
individual respondents. 
 
 
Analgesic use 
At clinical outcome assessment visit, the participants will be interviewed by an investigator about 
their use of analgesics since last visit. The interview will be focused on intake of 
1. Paracetamol/acetaminophen 
2. NSAIDS 
3. Acetylic acids 
4. Opioids  
The use of these analgesics will be recorded as a 0-3 points Likert scale (0, never; 1, rarely; 2, 2-3 
times per week; 3, daily o almost daily). 
 
 The Knee Injury and Osteoarthritis Outcome Score – 12 item short form (KOOS-
12)  
KOOS-12 is a 12-item measure derived from the original 42-item Knee injury and Osteoarthritis 
Outcome Score (KOOS) (17,18). KOOS-12 contains 4 KOOS Pain items, 4 KOOS Function 
(Activities of Daily Living and Sport/Recreation) items, and 4 KOOS Quality of Life (QOL) items  
(19). KOOS-12 provides scale scores for knee-specific Pain, Function and QOL, along with a 
summary measure of overall knee impact. KOOS-12 is intended to elicit people’s opinions about 
the difficulties they experience due to problems with their knee and covers aspects of pain, 
functional limitations and knee-related quality of life. 

The INKA Generalizability Protocol: 12 
 
Reliability, validity and responsiveness of the KOOS-12 scales have been shown to be acceptable 
(19) and there is evidence that supports the use of KOOS-12 for evaluating joint replacement 
outcomes (20). 
Each item is scored from 0 to 4, left to right, with 0 representing no knee problems 
and 4 representing extreme knee problems. The separate KOOS-12 Pain, Function and QOL scale 
scores are calculated using the method of summated ratings, in which item responses in a scale are 
simply summed. KOOS-12 scale scores are transformed so 0 is the worst possible and 100 is the 
best possible score. 
The KOOS-12 Summary knee impact score is calculated as the average of the KOOS-
12 Pain, KOOS-12 Function and KOOS-12 QOL scale scores. A Summary impact score is not 
calculated if any of the three scale scores are missing. The KOOS-12 Summary impact score also 
ranges from 0 to 100, where 0 is the worst possible and 100 is the best possible score. 
 
 
Patient’s global assessment of impact of the knee in daily life (PGA)  
The participant's assessment of the impact of their knee on everyday life is measured as the 
response to the question “Taking into account all the activities you have during your daily life, your 
level of pain, and your functional impairment, how much does your [left/right] knee impact your daily 
life?”. A 100 mm visual analogue scale (VAS) will be used as assessment instrument with anchors: 
0 = “No impact” and 100 = “Worst imaginable impact”. The actual question asked will be in Danish. 
 
 
Body weight 
The participants body weight is transferred from the medical records of their visit in the 
orthopaedic outpatient clinic.  
 
 
Brief Illness perception questionnaire (B-IPQ) 
B-IPQ is a generic 9-item questionnaire developed to rapidly assess the cognitive and emotional 
representations in a variety of illnesses. B-IPQ is a short version of the 84-item revised illness 
perception questionnaire (IPQ-R) (21). B-IPQ assesses perceptions on the following five 

The INKA Generalizability Protocol: 13 
 
dimensions: Identity, Cause, Timeline, Consequences and Cure-Control. Five of the items assess 
cognitive illness representations; two of the items assess emotional representations; and one item 
assesses illness comprehensibility. The ninth item is a free text field in which the respondent can 
formulate their beliefs about their condition (cause). We will not use this field in our study. 
The first 8 items are scored on a 0-3 Likert scale with descriptors (none or extreme) at 
either end. The B-IPQ scores have shown good test-retest reliability and adequate concurrent, 
discriminative, and predictive validity amongst patient samples with musculoskeletal disorders and 
other chronic disorders (22,23). 
 
 Sample size and power considerations 
As illustrated below, since the INKA trial will include 200 patients in total (approximately 100 
individuals in each group), we anticipate that the present study (comparing INKA vs non-INKA 
participants) will enrol around 400 patients in total; i.e. the enrolment of the “non-INKA 
participants” (nINKA) will be recruiting individuals during the exact same time period as the INKA 
trial is enrolling eligible patients, which is estimated to be: 
First Patient First Visit (FPFV): 01-02-2022 
Last Patient First Visit (LPFV): 01-07-2023 
The present study will be focusing on whether the treated (INKA) and untreated (nINKA) subjects 
have similar distributions of observed baseline covariates. We will assess whether the propensity 
score model has been correctly specified: comparing mean’s and prevalence’s of baseline 
characteristics using standardized differences. 

The INKA Generalizability Protocol: 14 
 
 
Figure 2 sample size and power considerations 
As illustrated in figure 2, we will tentatively assume that a standardized difference between groups 
could be indicative of a “significant” difference between the groups. 
NOTE: In the INKA trial the primary outcome is the OKS at week 38. For the intensive diet intervention 
strategy to be worthwhile it needs to demonstrate non-inferiority in the OKS score after 38 weeks 
compared to KA: The minimally important difference estimate applicable for group comparisons in 
RCTs has been suggested to be 4.84 OKS points. Therefore, we will consider a difference in group mean 
OKS scores smaller than or equal to 4 OKS points as showing non-inferiority. Based on a recent 
observational study on 960 KA patients in our region, a standard deviation of 8 OKS points after 38 
weeks is expected. Thus, if the true difference between groups is 0 OKS points in a balanced design 
(1:1 randomization), a one-sided t-test with a significance level of 0.025 will have a power of 90.3% to 
reject the null hypothesis that the intensive diet intervention is inferior to KA, with a sample size of 86 
patients per group (172 in total). To account for attrition (incl. possible “cross-over”) in the ITT 
population it is decided to aim for, and randomize, 200 patients in total, which correspond to - based 
on the above assumptions - a statistical power of 94% to reject the null-hypothesis that intensive diet 
is inferior to KA. Power and sample size analyses were conducted using ‘proc power’ in SAS (SAS 
Institute Inc., Cary, 968 North Carolina). 

The INKA Generalizability Protocol: 15 
 
 Bias and confounding variables 
Confounding is an important concept in epidemiology, because, if presents, it can cause an over- 
or underestimate of the observed association between exposure and health outcome. The 
distortion introduced by a confounding factor can be large, and it can even change the apparent 
direction of an effect. However, unlike selection and information bias, it can be adjusted for in the 
analysis. 
The challenge with observational data (like the proposed comparison) is that the 
groups (INKA vs nINKA) are not applied randomly, leading to selection bias and thus potentially 
confounding variables. For example, when we study the impact entering a “promising weight loss 
trial” before having direct access to a KA, and we compare the outcome among th0se (who accept 
the invitation to join the INKA trial) versus all of those who declined, we would potentially have 
some selection bias, as those who decline are different per definition. The difference can range 
from baseline characteristics that would influence the outcome; i.e., an advanced disease stage 
that make any potential delay of the surgery intolerable, or failure/ineffectiveness of previous 
weight loss trials. Or it can be a characteristic with neglectable effect on the outcome, ie., not 
having the time or the desire to be included in a clinical trial. Improved confounding variable 
balance (i.e. de-confounding) between INKA and nINKA groups can be achieved by matching 
observations from each group based on the propensity score, which in this case would be the 
probability that a patient accept participation in INKA given the observed covariates. 
 
 Statistical methods 
We will use the term balance diagnostics to describe the methods we use to assess whether the 
distribution of baseline covariates is similar between the two groups (INKA and nINKA, 
respectively). We designed the study to compare the mean (or medians) of continuous variables or 
the prevalence of dichotomous baseline covariates between INKA and nINKA participants. We will 
report the means and/or medians of continuous variables and the distribution of categorical 
variables for each of the two groups. These crude comparisons (between INKA=treatment and 
nINKA=control, respectively) will enable an assessment of the comparability of the two groups 
which will be indicative of the generalizability of the INKA trial (24). 

The INKA Generalizability Protocol: 16 
 
Standardized differences for comparing means and prevalences between groups: For continuous 
variables, the standardized difference is defined as 
 
where x’s denote the sample means of the covariate in treated (INKA) and control (nINKA) 
participants, respectively, while the s2’s denote the sample variance of the covariate in the groups. 
For dichotomous variables, the standardized difference will be defined as 
 
where p’s denote the prevalence or mean of the dichotomous variable in treated (INKA) and control 
(nINKA) participants, respectively. 
By using the standardised differences, it allows for the comparison of the relative 
balance of variables measured in different units (e.g. age in years with a ‘Timed Up and Go’). Unlike 
t-tests and other statistical tests of hypothesis, the standardized difference is not influenced by 
sample size. Thus, the use of the standard difference will be used to compare balance in measured 
variables between treated and untreated subjects. Standardized differences are increasingly being 
used to compare balance in baseline covariates between groups in the propensity-score matched 
samples. A limitation to their use is lack of consensus as to what value of a standardized difference 
denotes important residual imbalance between treated and untreated subjects in the matched 
sample. While there is no clear consensus on this issue (24), as illustrated in the figure above, we 
will apply a standardized difference of ≥0.2 to indicate that there might be a meaningful imbalance 
in the baseline covariate (i.e. possibly poor generalizability); whereas a standardized difference 
≥0.8 will be considered as definitive incomparability. 

The INKA Generalizability Protocol: 17 
 
We will also apply the PROC NPAR1WAY procedure (using SAS software) to compute 
empirical distribution function (EDF) statistics, to statistically test the distribution of the baseline 
variables. PROC NPAR1WAY provides a summary of the Wilcoxon scores for the analysis baseline 
variable by class level (INKA and nINKA, respectively). It also displays the one-way ANOVA 
statistic, which for Wilcoxon scores corresponds to the Kruskal-Wallis test: If the statistical test 
indicates that there might be difference between groups <0.05 this (P<0.05) leads to rejection of 
the null hypothesis that the groups are similar. 
The propensity score is the conditional probability that a participant accepts the 
invitation to participate in the INKA (weight loss vs direct surgery) trial given the participant’s 
observed covariates (i.e. baseline measures). The goal of the propensity scoring will be to evaluate 
whether the data is comparable between the datasets by enabling a balancing observed covariate 
between individuals in INKA and nINKA, respectively. We will organise our data into a single 
dataset with all the baseline (potential confounding) variables that we collect in this study, along 
with the column that indicates whether the patient accepted participation in INKA (i.e. 1=’yes’ and 
0=’N0’, respectively). From this data matrix, logistic regression will be used to develop propensity 
scores, represent the probability that a patient accept participation in INKA based on the 
participant’s observed covariates. Thus, we will create a logistic regression model in which the 
baseline variables are used to balance between our groups are used as our predictors of group, our 
dependent variable (y=1, INKA participation; while y=0, nINKA) in the logistic regression model. 
 
 
HEALTH RESEARCH ETHICS 
 General considerations 
This study only involves questionnaire and medical records and is hence exempt from approval 
from The Health Research Ethics Committee and can be implemented without permission from the 
Ethics Committee according to Danish legislation (heath Research Ethics Committee Act § 1, 
paragraph 1). 
Nevertheless, we will conduct this study obeying high health research ethical 
standards. Prior to screening, all potential trial participants are informed, both orally and in writing, 
about the purpose of this study, its process, and costs and benefits of participation. All participants 
are informed of their rights to withdraw from the study at any time without this impacting on any 

The INKA Generalizability Protocol: 18 
 
future investigations and/or treatments at any site or by any of the members of the study group. 
After the information is delivered, read and understood, voluntary informed consent is given by the 
participant by signing a consent form before trial participation can take place. 
 
 Written information and informed consent  
A written consent to participation in the study is given after verbal explanation and consent. 
A written information material and informed consent form (ICF) have been prepared (both 
attached as appendices, files in Danish). By signing the ICF the participant accepts to be contacted 
by an investigator (or his/her delegate) and authorise him/her to collect relevant information from 
the participant’s hospital record according to Danish legislation (Act on Processing of Personal 
Data). 
The ICF must be signed and dated by the participants prior to participation in the study. 
A copy of the form is provided to the participants. A note will be made in the patients’ hospital 
records about participation in the study and signed authorisation to collect relevant data from the 
records. 
 
 
REGULATORY STANDARDS 
 Notification to the Danish Data Protection Agency 
Because the study is carried out at hospital departments, it is regarded as "public" in accordance 
with the Data Protection Agency guidance. The study will be notified to the Data Protection 
Agency. 
 
 Participant confidentiality  
Participant medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. 
With the participant’s permission, medical information may be collected for scientific 
use and shared with his or her personal physician or with other medical personnel responsible for 
the participant’s welfare. 

The INKA Generalizability Protocol: 19 
 
When the data from this study are published, the presentation format will not include 
names, recognizable photos, personal information or other data which compromises the 
anonymity of participating participants. 
 
 Quality assurance 
All data will be entered into a study database for analysis and reporting. Any data captured 
electronically will be stored electronically in a separate database according to standard procedures 
of Region Hovedstaden. Upon completion of data entry, the databases will be checked to ensure 
acceptable accuracy and completeness. System backups and record retention for the study data 
will be consistent with Region Hovedstadens standard procedures. 
Individuals involved in study evaluations will be trained to perform the efficacy 
evaluations and activity measurements described in the protocol. 
 
 Financing and insurance information 
The study has not received any specific funding. If funding is obtained, the amount and donor will 
be disclosed on the written information material. 
The participants are insured by the Danish Patient Insurance Association. Financing 
and insurance issues are addressed in the written information material. 
 
 
LIST OF APPENDICES  
• Questionnaires  
• Written information material (In Danish) 
• Informed consent form (In Danish) 
• Screening log (In Danish) 
 
 
 

The INKA Generalizability Protocol: 20 
 
 
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