E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult (≥ 18 years of age) overweight or obese patients (BMI ≥ 27 kg/m2 ) above 18 years of age with knee osteoarthritis (OA) defined by clinical diagnosis of knee OA according to the American College of Rheumatology (ACR) criteria confirmed by radiology but restricted to definite radiographic OA at early to moderate-stages (Kellgren-Lawrence grades 1, 2, or 3) |
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E.1.1.1 | Medical condition in easily understood language |
Volunteer overweight or obese patients above 18 years of age with knee osteoarthritis (OA) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023476 |
E.1.2 | Term | Knee osteoarthritis |
E.1.2 | System Organ Class | 100000004859 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029885 |
E.1.2 | Term | Obesity, unspecified |
E.1.2 | System Organ Class | 100000004861 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To establish the efficacy of a diet intervention combined with liraglutide 3 mg or liraglutide 3 mg placebo in inducing and maintaining weight loss over 52 weeks • To investigate the efficacy of a diet intervention combined with liraglutide 3 mg or liraglutide 3 mg placebo as a pain-reducing management strategy over 52 weeks
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E.2.2 | Secondary objectives of the trial |
• To compare the efficacy of a diet intervention combined with either liraglutide 3 mg or liraglutide 3 mg placebo for 52 weeks on knee OA-related patient reported stiffness and function scores • To compare the efficacy of a diet intervention combined with either liraglutide 3 mg or liraglutide 3 mg placebo for 52 weeks on intermittent and constant knee pain intensity, pain related distress, and the impact of OA pain on quality of life • To compare the efficacy of a diet intervention combined with either liraglutide 3 mg or liraglutide 3 mg placebo for 52 weeks on the proportion of patients loosing at least 5% or at least 10% of their body weight • To compare the efficacy of a diet intervention combined with either liraglutide 3 mg or liraglutide 3 mg placebo at week 52 on waist circumference, waist/hip ratio, and BMI
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1) Title: Observed and self-reported ADL ability in obese patients with knee OA: The benefit of weight loss and relations between observed and self-reported functional outcomes
Objectives: To assess: • If weight loss in obese patients with knee OA is associated with improvements in observed and self-reported ADL ability. • The association between change in observed and self-reported ADL ability assessed by questionnaires and interview in obese patients with knee OA obtaining a significant weight loss (> 11%) is poor.
2) Title: Biomarkers in obese patients with knee OA: The benefit of weight loss, patient reported outcomes, and biomarkers
Objectives: It is intended to identify biomarkers according to the following specific objectives: 1: To identify MicroRNA expression profiles as predictors of disease course and response to liraglutide (including adverse events) 2: To identify DNA-profile and SNPs as predictors of disease course and response to liraglutide (including adverse events) 3: To identify protein expression profiles as predictors of disease course and response to liraglutide (including adverse events) 4: To identify metabolite expression profiles as predictors of disease course and response to liraglutide (including adverse events)
3) Title: The association between weight loss and changes in physical activity in overweight/obese individuals with knee osteoarthritis: An observational cohort study
Objectives: To describe changes in physical activity associated with a significant weight loss among overweight/obese individuals with knee OA. We hypothesize that weight loss is associated with a decrease in daily time spent physically inactive.
4) Title: Multi-parametric imaging of knee osteoarthritis in obese patients with knee osteoarthritis; investigating the impact of inflammation in soft tissue and bone on clinical symptoms and cartilage.
Objectives: 1: To identify non-contrast and contrast enhanced MRI imaging markers of inflammation as predictors of disease course and clinical response to Liraglutide 2: To identify imaging markers of inflammation as predictors of changes in cartilage health and response to Liraglutide 3: To identify dual energy CT markers of crystal deposition disease in the soft tissue as predictors of disease course and clinical response to Liraglutide 4: To identify ultrasound markers of inflammation as predictors of disease course and clinical response to Liraglutide
The primary hypotheses are: 1: Weight loss and Liraglutide will have a larger anti-inflammation effect, measured with MRI and ultrasound and thus a better clinical response, compared to weight loss and placebo 2: Weight loss and Liraglutide will have and better cartilage protective effect measured by MRI, compared to weight loss and placebo |
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E.3 | Principal inclusion criteria |
• Informed consent obtained • Clinical diagnosis of knee OA (American College of Rheumatology (ACR) criteria) confirmed by radiology but restricted to definite radiographic OA at early to moderate-stages (Kellgren-Lawrence grades 1, 2, or 3) • Age ≥ 18 years and < 75 years • Body mass index (BMI) ≥ 27 kg/m2 • Stable body weight during the previous 3 months (< 5 kg self-reported weight change) • Motivated for weight loss
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E.4 | Principal exclusion criteria |
• On-going participation, or participation within the last 3 months, in an organised weight loss programme (or within the last 3 months) • Current or history of treatment with medications that may cause significant weight gain for at least 3 months before this trial • Current use or use within three months before this trial of GLP-1 receptor agonist, pramlintide, sibutramine, orlistat, zonisamide, topiramate, or phentermine • Use of opioids or similar strong analgesics • Type 1 diabetes • Type 2 diabetes treated with glucose-lowering drugs other than metformin • Alloplasty in target knee joint (see section 6.3) • End stage disease in target knee joint (Kellgren-Lawrence grade 4) • Pregnancy or insufficient anti-conception therapy for female fertile patients • Breast-feeding • Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x above upper normal range (UNR) • Surgery scheduled for the trial duration period, except for minor surgical procedures • Surgical procedures such as arthroscopy or injections into a knee within 3 months prior to enrolment • Previous surgical treatment for obesity (excluding liposuction >1 year before trial entry) • Thyroid stimulating hormone (TSH) outside of the range of 0.4-6.0 mIU/L • Obesity secondary to endocrinologic or eating disorders or to treatment with medicinal products that may cause weight gain • Family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 • Inflammatory bowel disease • Congestive heart failure, New York Heart Association (NYHA) class III-IV • Diabetic gastroparesis • History of or current diagnosis of pancreatitis (acute and/or chronic) or pancreatic cancer • History of cancer with the exception of in-situ malignancies of the skin or cervix uteri • History of major depressive disorder, a PHQ-9 (Patient Health Questionnaire-9) score of more than 15, or a history of other severe psychiatric disorders or diagnosis of an eating disorder • Subjects with a lifetime history of a suicide attempt or history of any suicidal behaviour within the past month before entry into the trial • Inability to speak Danish fluently • A mental state impeding compliance with the program |
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E.5 End points |
E.5.1 | Primary end point(s) |
In order to demonstrate that liraglutide 3 mg not only safely and efficaciously lowers body weight, but also reduce pain, these endpoints have been selected as co-primary. • Change in body weight Time frame; week 0 to 52 • Change in the KOOS pain subscale Time frame; week 0 to 52
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Confirmatory secondary endpoints
• Change in the KOOS symptom subscale Time frame; week 0 to 52 • Change in the KOOS ADL subscale Time frame; week 0 to 52 • Change in the KOOS sport and recreation subscale Time frame; week 0 to 52 • Change in the KOOS health related QoL subscale Time frame; week 0 to 52 • Change in the WOMAC pain subscale Time frame; week 0 to 52 • Change in the WOMAC stiffness subscale Time frame; week 0 to 52 • Change in the WOMAC function subscale Time frame; week 0 to 52 • Change in total score and subscales in the ICOAP questionnaire Time frame; week 0 to 52 • Proportion of participants with ≥5% weight loss Time frame; week 0 to 52 • Proportion of participants with ≥10% weight loss Time frame; week 0 to 52 • Change in BMI Time frame; week 0 to 52 • Change in waist circumference and in waist/hip ratio Time frame; week 0 to 52
Supportive secondary endpoints
• Change in C-reactive protein (CRP), glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), ALT, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and total cholesterol (TC) Time frame; week 0 to 52 • Change in resting heart rate and blood pressure Time frame; week 0 to 52 • Change in the TRIM-weight questionnaire Time frame; week 0 to 52 • Change in SF-36 total as well as mental and physical composite scores Time frame; week 0 to 52 • Change in IWQoL-lite questionnaire Time frame; week 0 to 52 • Proportion of participants responding according to the O-OA Time frame; week 0 to 52 • Proportion of participants meeting metabolic syndrome criteria Time frame; week 0 to 52 • Proportion of participants meeting pre-diabetes criteria Time frame; week 0 to 52
Safety endpoints
• Changes outside the reference limits (+/- 2 SD) in haemoglobin, thrombocytes, leucocytes, differential cell count, creatinine, and electrolytes Timing; at visits T0 as well as T15 or Tx • Changes outside the reference limits (+ 150 %) in ALT and CRP Timing; at visits T0 as well as T15 or Tx • Incidence of AEs Timing; at visits –T7 to T15 or Tx, and Tz • Incidence of suicidal behaviour and/or ideation, assessed by the C-SSRS Timing; at visits -Tx, T0 to T14, T15 or Tx, and Tz • Incidence of depression, assessed by the PHQ-9 Timing; at visits -Tx, T0, T15 or Tx, and Tz • Incidence of patients with and without a binge eating disorder, assessed by the BES Timing; at visits T0, T15 or Tx, and Tz
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints: week 0 and 52
Safety endpoints: week -8, -7, 0, 52, and 64 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last patient last visit at week 64. |
Sidste patients sidste besøg ved uge 64. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |